Therapy of Type 2 Diabetes

UPDATES TO CONTENT COMPARED TO THE PREVIOUS YEAR'S VERSION

Part 1 of the clinical practice guideline

Change 1: An additional section on the prevalence and incidence of type 2 diabetes in Germany has been added.
Reason: These current figures highlight the medical, psychosocial and health policy significance of this complex disease.

Change 2: On the basis of current data, the various risk factors and their structured assessment (including the increasing importance of fatty liver) for the development of cardiovascular and renal complications are again highlighted.
Reason: For an individual therapy decision, the in-depth risk assessment is very helpful Supporting reference: [6] [7]

Change 3: The short diagnostics section has been brought forward
Reason: More logical order of sections

Change 4: The section on plasma glucose self-measurement was supplemented to include the possibilities and possible necessity of using CGM in people with type 2 diabetes
Reason: The treatment of people with type 2 diabetes is becoming more individual and therefore more complex. Temporary information about TiR and TuR can at minimum be helpful in the treatment decision.

Change 5: In the section on nutritional therapy, current literature citations were introduced and new evidence on the benefits of moderate coffee consumption in many chronic diseases, including type 2 diabetes, was mentioned. Hypocaloric nutrition, intermittent fasting, etc. play an important role
Reason: Evidence from the cited literature

Change 6: A section on fatty liver disease and its treatment options has been added.
Reason: Fatty liver disease as an important risk disease for chronic liver disease and as a risk factor for cardiovascular and renal complications in people with type 2 diabetes still plays a subordinate role in screening. The regular determination of the FIB-4 index is simple and prognostically significant.
Supporting references: Updated S2K Guideline Non-Alcoholic Fatty Liver Disease; Diabetes and Fatty Liver section in this supplement Part 2 of the clinical practice guideline

Change 7: In contrast to the ESC guideline (avoidance of metformin), the DDG, the National Treatment Guideline on type 2 diabetes as well as the ADA/EASD consensus recommendations, the section on metformin emphasizes that SGLT-2 inhibitors and/or GLP-1RAs (usually with metformin) should be used in high-risk patients and in people with already manifest cardiovascular (including heart failure) and renal diseases.
Reason: RCTs and their meta-analyses

Change 8: In new analyses of RCTs, sulfonylureas (SHs) were associated with a significantly higher rate of severe hypoglycaemia and cardiovascular events, including all-cause mortality. On the other hand, a large Scottish cohort study showed that no higher rates of cardiovascular events, including mortality, were observed for sulfonylureas as the 2nd antidiabetic agent after metformin compared to DPP4 inhibitors or pioglitazone. From this, the authors concluded that SHs continue to be recommended as second-line medications, especially in health systems that cannot afford more expensive antidiabetic drugs.
Supporting reference: [67]

Change 9: A recent meta-analysis of 82 studies showed that DPP4 inhibitors were significantly associated with a higher risk (22%) of gallbladder and biliary tract disease.
Supporting reference: [104]

Change 10: In the SGLT inhibitors section, the new [Tab. 4] on the approval and (contra)indications of dapagliflozin, empagliflozin and ertugliflozin for type 2 diabetes, nephropathy and heart failure (HF pEF, HFmEF, HFrEF).
Reason: New approvals and indications
Supporting references: Current instructions for use

Change 11: A large number of new clinical studies and their meta-analyses on the use of SGLT-2 inhibitors approved in Germany and their effects on cardiovascular and renal endpoints are discussed.
Reason: An update was necessary

Change 12: Section on the effect of SGLT-2 inhibitors on the liver
Reason: An update was necessary

Change 13: Updates in the GLP-1 receptor agonists section as a whole and in the discussion of the individual substances. In most cases, the newer data were added at the end of the discussion of the respective active ingredient.
Reason: An update was necessary.

Change 14: [Tab. 6] in Part 2 (Additional informations) on cardiovascular and renal benefits (absolute risk reduction and hazard ratios) of SGLT-2 inhibitors and GLP-1 RAs based on a recent meta-analysis
Supporting reference : [318

Change 15: The Basal insulins section describes a head-tohead comparison of injectable incretin-based drugs IBGLMs (short- and long-acting GLP-1 RAs and tirzepatide) vs. basal insulin therapy (NPH, glargine, detemir, degludec). In all studies (n = 20) with a total of 11843 patients, there was a reduction in HbA1c of 0.48% (0.45–0.52) more with IBGLMs than with basal insulins. This effect was particularly evident with the long-acting GLP-1 RAs and tirzepatide (pooled doses: ΔHbA1c –0.90% [−1.06; −0.75]). Short-acting GLP-1 RAs were comparably effective compared to basal insulin (p = 0.90). All IBGLM subgroups resulted significantly in lower body weight (−4.6 [−4.7; −4.4] kg), in particular tirzepatide (−12.0 [−13.8–10] kg). Based on the analyses, the authors again underline that in the event of therapy escalation to injectable drugs, IBGLMs should be considered first instead of basal insulins.
Supporting reference: [353]
Change 16: icodec insulin is described
Reason: Current data

The Clinical Practice Guidelines of the German Diabetes Society/Deutsche Diabetes Gesellschaft (DDG) are based on the contents of the National Healthcare Guideline (Nationale VersorgungsLeitlinie (NVL)) “Type 2 Diabetes” [1]. The modifications in therapy and their justifications made in the present Clinical Practice Guidelines were largely updated on the basis of new randomized controlled trials (RCTs) and meta-analyses.

In order to improve the work with the extensive clinical practice guideline in daily practice, the authors have decided to move the individual glucose-lowering pharmaceuticals and some algorithms in the current clinical practice guideline to a detailed appendix. The corresponding list of references can also be found in the appendix.

Definition of type 2 diabetes

Type 2 diabetes is a chronic, very heterogeneous, multi-factorial, progressive disease characterized by inherited and acquired insulin resistance and qualitative and quantitative insulin secretion disturbances.

Prevalence and incidence of diabetes

Estimates of the prevalence of diabetes in Germany from the surveys of the Robert Koch Institute (RKI) are 7.2% (18 to 79-years-old), from RKI telephone surveys 8.9% (18-year-olds and older) and 9.9% (all age groups) based on data from people with statutory health insurance [2]. From the analysis of Schmidt et al. [3], the Data Transparency Regulation (Datentransparenzverordnung, DaTraV) data (data processing point in the German Institute for Medical Documentation and Information [Deutsches Institut für Medizinische Dokumentation und Information, DIMDI] of all approx. 70 million people with statutory health insurance) for the reporting years 2011, 2012 and 2013 show that the prevalence of diabetes in 2011 was 9.7% (women: 9.4%, men: 10.1%). The authors found significant differences in prevalence between the federal states, with a maximum difference of 7.1 percentage points (age-standardised: 4.0 percentage points). In 2012, 565,040 insured persons were newly diagnosed with diabetes, representing 1.0% of the insured persons (women: 1.0%, men: 1.1%). The prevalence of diabetes was significantly age-dependent. In this context, it is also important to note that many people with manifest type 2 diabetes remain undiagnosed for a long time, especially at an older age (approx. 2 million in Germany) [4].

Also based on nationwide health insurance data from approximately 63 million people with statutory health insurance, age- and gender-specific trends in the type 2 diabetes incidence rate were estimated using regression models [5]. In the period studied from 2014 to 2019, about 450,000 new cases of type 2 diabetes were diagnosed annually. Across all age groups, the incidence rate for women and men decreased from 6.9 (95% confidence interval: [6.7, 7.0]) and 8.4 [8.2, 8.6] per 1000 people in 2014 to 6.1 [5.9, 6.3] and 7.7 [7.5, 8.0] per 1000 people in 2019, corresponding to an annual decrease of 2.4% [1.5, 3.2] and 1.7% [0.8, 2.5], respectively. Only in the 20–39 age group did the incidence rate in men increase by 0.4% [–0.4; 1,2] and in women by 0.6% [–0.2; 1,4]. Age- and gender-adjusted incidence rates decreased in almost all districts [6]. While this downward trend is encouraging, it does not necessarily mean that the prevalence has also decreased. On the contrary, it can be assumed that due to intensified diabetes screening and more reliable diagnostics in recent years, the prevalence will probably continue to increase for the time being, namely by one diabetes case every 156 seconds: https://ddz.de/diabetes-uhr/.

Risk factors for type 2 diabetes

Influenceable and uninfluenceable risk factors for type 2 diabetes are listed in the “Risk factors for type 2 diabetes” info box.

RISK FACTORS FOR CARDIOVASCULAR DISEASES AND TYPE 2 DIABETES

Uninfluenceable

• Higher age

• Sex (male > female)

• Ethnicity

• Diabetes in the family

• Gestational diabetes (in the history)

• Intrauterine development (foetal programming)

Influenceable

• Visceral obesity

• Fatty liver/Fibrosis (FIB)-4 Index

• Depression

• Obstructive sleep apnoea (OSA)

• Physical inactivity

• High-energy, low-fibre food

• High sugar consumption (soft drinks etc.)

• Excessive alcohol consumption (fatty liver)

• Smoking

• Diabetogenic drugs

• Diabetogenic environment (e. g., deprivation = disadvantage due to lack of resources, exposure to excessive chronic noise and air pollution)

The risk factors listed here are based on an expert consensus. The order of the enumeration does not represent the weighting. For several factors, limits for an increased risk (weight, blood pressure, lipids) have been set elsewhere by individual professional societies. Since individual low-grade exceedances do not result in a major increase in risk, a comprehensive integrative assessment of the influencing risk factors is important. It should be borne in mind that with increasing age and increasing severity of comorbidities, the likelihood of benefiting from an additional intervention decreases [1]. The recently published review of risk factors for cardiovascular outcome in people with diabetes once again impressively underlines the importance of treatable classical risk factors such as weight, HbA1c, low-density lipoprotein (LDL) cholesterol, blood pressure, albuminuria and smoking [7].

A recent analysis shows that the currently available 22 cardiovascular risk scores for people with type 2 diabetes are insufficient. New predictive models are needed to ensure that risk factors and corresponding outcome data are better matched [8].

METABOLIC SYNDROME

At least 3 out of 5 criteria must be fulfilled [9]:

• Abdominal obesity (waist circumference): male *> 94 cm; female ** > 80 cm,

• Triglycerides *** : ≥ 150 mg/dl or ≥ 1.7 mmol/l,

• HDL cholesterol***: male < 40 mg/dl or < 1.03 mmol/l; female: < 50 mg/dl or < 1.29 mmol/l,

• Elevated blood pressure*** : ≥ 130/ ≥ 85 mmHg,

• Fasting plasma glucose*** : ≥ 100 mg/dl or ≥ 5 mmol/l or pre-existing diabetes.

*/**People from Southeast Asia or China: 90/80 cm; people from Japan: 90/85 cm

***Pharmacological intervention is an alternative criterion

Diagnostics

Medical history and clinical examinations as well as monitoring of people with type 2 diabetes are compiled in the annex to this clinical practice guideline.

Diagnostics are ensured by standardized and quality-assured laboratory tests for both plasma glucose and HbA1c. Devices for self-measurement (Point-of-care testing [POCT] systems) must successfully pass internal and external quality assurance otherwise they are unsuitable for diagnostics. Since a large number of preanalytical, analytical and interpretational problems are present in the diagnosis of diabetes, the updated and detailed clinical practice guidelines for diabetes diagnosis should be referred to in addition to other sources of information [10] [11] [12] [13].

In the differential diagnosis of the heterogeneous disease type 2 diabetes, subtypes of diabetes are increasingly defined and partly clinically considered in practice [14] [15] [16].

Therapy goals

In the present guidelines, target corridors are specified which, with varying degrees of evidence, inform the doctor and the patient which target corridor/target value (e. g., HbA1c, blood pressure, LDL cholesterol values) should normally be aimed for according to the current state of medical knowledge and on the basis of evidence and consensus. This does not affect the superordinate goal of setting personal therapy goals (both superordinate and secondary) primarily together with the patient and possibly together with relatives, and agreeing on them in writing on a quarterly basis (e. g., in the Diabetes Health Pass). According to the current partial publication of the National Healthcare Guideline [1] and Elwyn and Vermunt [17], the 3 categories of goals: superordinate goals (e. g., maintaining quality of life or independence), function-related goals (e. g., maintaining eyesight and job) and disease-related goals (e. g., eliminating pain, improving metabolism) should be discussed and prioritised in terms of shared decision-making.

General and specific therapy goals

The therapy goals of people with type 2 diabetes depend on patient preference, comorbidity, age and life expectancy, quality of life, cultural conditions, psychosocial circumstances and possibilities as well as abilities of the persons concerned to implement therapy goals. The diagnosis of type 2 diabetes, which is often experienced by those affected as a severe life restriction, requires a strategy of acceptance and gradual intensification of therapy (exception: severe metabolic decompensation).

In the Type 2 Diabetes Healthcare Guideline [1], a section was created on shared decision-making (SDM) and participation in all relevant areas of life. The following recommendations with a high degree of recommendation [1] should be implemented in the care of people with diabetes:

1. People with type 2 diabetes and their doctors should jointly agree on and prioritise individual therapy goals at the beginning and frequently during the course of the disease.

2. Therapy goals agreed upon individually with the patient should be evaluated regularly and as needed during the course of treatment and followed up, or adjusted, according to the results.

3. The doctor should document and make available the individual therapy goals, and if necessary, the reasons for not having achieved the goals, in a way that is comprehensible for the patient and the professional care groups. This also applies to the evaluation of achieving therapy goals.

4. When providing information on the diagnosis and treatment options for type 2 diabetes, the different options with their advantages and disadvantages should be presented comprehensively and in an understandable form.

5. When health-related decisions regarding type 2 diabetes are to be made, the discussion should be conducted in accordance with the concept of shared decision-making.

6. Personal and environmental contextual factors should be taken into account when agreeing and prioritising individual treatment goals and evaluating the treatment strategy.

7. The effects on participation in all relevant areas of life should be taken into account.

8. If individual therapy goals agreed according to the concept of shared decision-making are not achieved, a structured approach should be taken [1] [4]. A detailed discussion of shared decision-making is presented in the section “Fundamentals of Diabetes Management” in this Supplement.

GENERAL TREATMENT AND CARE GOALS

• Preservation or restoration of quality of life

• Empowerment of those affected in dealing with the disease and its complications

• Reduction of stigma associated with the disease

• Treatment satisfaction

• Promotion of therapy adherence

• Reduction of risk for cardiac, renal, cerebrovascular and other macrovascular complications

• Avoidance and treatment of microvascular and neurological complications (e. g. peripheral sensorimotor and autonomic polyneuropathy)

• Avoidance and treatment of diabetic foot syndrome

• Treatment and improvement of comorbidities

• Minimisation of side effects of therapy (e. g., severe hypoglycaemia, weight gain)

• Reduction of the burden of complex therapies (polypharmacy, drug interactions)

• Reduction of morbidity

• Normalisation of shortened life expectancy with good quality of life

In people with type 2 diabetes, individualized therapy goals should be agreed for the following vascular risk parameters (info box “General treatment and care goals”; [Table 1]):

• Lifestyle

• Blood pressure

• Glucose metabolism

• Lipid status

• Body weight

Table 1 Orientation criteria for therapy goals.

Indicator	Orientation parameters for therapy goals
	mg/dl	mmol/l
Fasting/preprandial plasma glucose (venous)	100–125	5.6–6.9
Postprandial plasma glucose (venous) 1–2 h postprandial	140–199	7.8–11.0
Indicator	Individualisation of the therapy goals
HbA1c	HbA1c target range of 6.5–7.5% (48-58 mmol/mol Hb) to prevent complications and severe hypoglycaemia. In elderly people with multimorbidity and people with severely reduced life expectancy HbA1c<8.0% (< 64 mmol/mol Hb), sometimes<8.5% (< 69 mmol/mol Hb). If only antidiabetic medications without intrinsic hypoglycaemia risk are used, lower HbA1c targets<6.5% (< 48 mmol/mol Hb) may also be defined.
Uric acid	Serum levels ≤ 6.0 mg/dl (357 μmol/l) [18]
Lipids	LDL cholesterol reduction: Very high risk in primary and secondary prevention: ≥ 50% LDL-C reduction from baseline before lipid-lowering therapy and an LDL-C target<1.4 mmol/l (< 55 mg/dl) High risk: ≥ 50% LDL-C reduction from baseline and an LDL-C<1.8 mmol/l (< 70 mg/dl). Moderate risk:<2.6 mmol/l (< 100 mg/dl) [19] [20].
Weight loss at excess weight	For BMI from 27–35 kg/m2:>5% weight reduction; for BMI>35 kg/m2:>10% weight reduction
Blood pressure	Systolic blood pressure: 120-140 mmHg (≥ 65 years 130–140 mmHg;≤ 65 years 120–129 mmHg); diastolic blood pressure:<80 mmHg (not<70 mmHg); if the therapy has no relevant side effects [21] [22] [23] [24]

LDL: low-density lipoprotein; BMI: body mass index.

Prioritisation of the therapy goal on the basis of the personal risk profile

The guiding factors for selecting the appropriate therapy strategy are the jointly prioritised, time-coordinated therapy goals and the probability of benefiting from a certain therapy due to individual disease factors. On the basis of the evidence currently available, these basic, possible approaches should be followed:

• Excess weight/obesity: maintain weight or, better yet, lose weight.

• Reduction of diabetes complications by controlling glucose parameters (metabolic stability,% time-in-range, no severe hypoglycaemia) and/or the HbA_1c value as a surrogate for metabolic control if the mentioned parameters are not available.

• Reduction of the probability of a specific cardiovascular and renal event by administering drugs that reduce these endpoints.

It should be emphasized at this point that the above-mentioned paths ideally complement each other.

Therapy

Basic therapy

Adapting to a healthy lifestyle is crucial not only to prevent type 2 diabetes, but also to reduce the complex pharmacotherapy and the development and progression of diabetic complications of type 2 diabetes. In this context, it makes sense to address not only one, but as many risk factors as possible through lifestyle modification [25] [26] [27] [28].

Education and training

As an indispensable part of diabetes treatment, all persons affected by diabetes mellitus and, if applicable, their family members should be offered structured, evaluated and target group- and topic-specific training and treatment programmes as well as, if necessary, problem-oriented follow-up training [29] [30].

Plasma glucose self-monitoring

The situations in [Table 2] should be considered for people with type 2 diabetes and an indication for plasma glucose self-measurement. However, the measurements must result in behavioural and therapeutic consequences. Glucose monitoring (plasma or interstitial) plays an increasingly important role in therapy. In order to interpret the interpretation of glucose values (intermittent or continuous glucose measurement [CGM]) in a meaningful way, behavioural factors related to this biochemical parameter such as eating, physical exercise, sleep, medication intake, but also parameters such as stress, anxiety, depression should be taken into account (monitoring). A recent review discusses the major importance of this precision monitoring for the individualisation of therapeutic interventions. Analysing big data makes this possible, but this is currently hardly used [30].

Table 2 Situations in which plasma glucose self-monitoring is necessary or may be temporarily necessary in people with type 2 diabetes.

	Clinically defined situations
Diabetes stage	Newly diagnosed, adjustment phase
Diabetes along its course	Unstable with frequent hypoglycaemia (at this point, measure before all meals until the therapy goal is achieved, then return to targeted situational measurements) Therapy intensification Temporarily after switching from insulin to oral antidiabetic therapy
Additional illnesses/interventions	Serious infections Planned operations Mental illnesses with unreliable intake of medication During sport/exercise and blood glucose-lowering substances, which may be associated with hypoglycaemia, and corresponding symptoms occur Acute changes in diet due to illness (e. g., diarrhoea/vomiting)
Diabetes therapy	Oral antidiabetics (OAD) with hypoglycaemia potential (sulfonylureas, glinides, then occasional measurements) Insulin therapy and necessity of insulin dose self-adjustment Intensified conventional insulin therapy (before all meals, occasionally at night) Insulin pump therapy (before all meals, occasionally at night) Situations with special hazards (e. g. shift work, driving lorries, buses, cranes, etc.)

Although CGM systems and AID applications (AID: “automated insulin delivery”) are becoming increasingly important in the treatment of type 1 diabetes, initial studies have also shown comparable advantages in people with type 2 diabetes, especially with insulin therapy: greater metabolic stability, more patients in the agreed TiR range, fewer hypoglycaemias and greater treatment satisfaction. However, short-term applications of CGM systems can also provide important insights for further therapeutic strategies for people with type 2 diabetes in the future [31] [32] [33] [34].

Urinalysis for glucose or ketone bodies

Urine glucose analyses are unsuitable for the diagnosis, therapy decision-making and monitoring, because urine glucose is only positive in the case of high blood glucose values (renal glucose transport capacity is very different between individuals, it is age-dependent, it is not systematically examined at reduced kidney function, it lowers with certain diseases and is not useful in pregnancy or with the use of drugs such as SGLT-2 inhibitors [SGLT-2: sodium-glucose linked transporter-2]).

However, in the assessment of hyperglycaemic metabolic derailment and in the case of suspected ketoacidosis under therapy with SGLT-2 inhibitors, the measurement of ketonuria is crucial for therapy.

Nutritional therapy and consultation

A detailed discussion of the dietary strategies for people with type 2 diabetes is provided in the clinical practice guideline of this supplement. According to the National Healthcare Guideline, the following key points should be taken into account in nutrition:

• Motivation to maintain a healthy, well-balanced diet considering the patient’s previous nutrition routine and to restrict calories. At the same time, the joy of eating should be maintained.

• As far as possible, the use of industrially-processed food should be avoided, and the intake of sucrose should be limited (World Health Organization [WHO] recommendation<25 g/day). The German Nutrition Society (DGE) recommends limiting mono- and disaccharide consumption to<10% of daily energy intake.

• No generalized ban on sugar, but avoidance of large amounts of regular sugar, fructose, sugar alcohols (e. g., sorbitol, xylitol) or drinks containing these substances.

• The estimation of type and amount of carbohydrates of each meal should be used as an essential metabolic control strategy for people with type 2 diabetes who inject insulin.

• People with type 2 diabetes without insulin therapy should be able to recognize foods which raise blood glucose.

• For people with type 2 diabetes and renal insufficiency, a daily protein intake of 0.8 g/kg is recommended. At the dialysis therapy stage, the protein intake should be increased to 1.2–1.3 g/kg.

• People with type 2 diabetes should be advised how to deal with alcohol in a differentiated manner as part of the individual consultation.

• Practical recommendations for a healthy and balanced diet, ideally the Mediterranean diet [35] [36] [37] [38] [39].

• Avoiding large portions and frequent consumption of fatty foods, e. g., fatty meat, fatty sausages, fatty cheese, fatty baked goods, fatty ready-made products, fatty fast food, cream, chocolate, crisps, etc.

• Choosing vegetable fats, e. g., oils, nuts, seeds.

Plan meals enriched with dietary fibres, e. g., vegetables, fresh fruit, whole grain cereals [40].

Coffee consumption leads to a significant dose-dependent risk reduction for a number of chronic diseases including type 2 diabetes [41] [42] [43]. However, this should not be understood as a general recommendation to significantly increase coffee consumption, as depending on the comorbidity, negative effects of increased coffee consumption are also to be expected.

The effectiveness of weight loss and improvement of the vascular risk profile always depends on how the diet is designed: low-carb, vegan, Mediterranean or the various types of intermittent fasting - how well the acceptance and adherence as well as the long-term management of the dietary change succeed [44] [45] [46]. The current review of interval fasting (time restricted eating) found no evidence of safety problems in people with type 2 diabetes when metabolic control was adjusted [47].

In a recent Cochrane analysis [45], there were little or no differences in weight loss and changes in cardiovascular risk factors in overweight or obese people with and without type 2 diabetes when low-carb or carbohydrate-balanced diets were compared. In the most comprehensive review to date of 11 meta-analyses from 130 randomized controlled trials (RCTs), intermittent fasting, especially alternate day fasting, found significant and favourable associations with BMI, body weight, body fat mass, LDL cholesterol, triglycerides, fasting glucose, insulin resistance, and blood pressure. This was especially true for people who were overweight and obese. The observation periods were on average 3 months, so that no reliable statements could be made about long-term effects [47]. Long-term follow-up periods of up to 36 years showed in a cohort study including the Nurses̓ Health Study (NHS; 1984-2020) and the Health Professionals Follow-up Study (HPFS; 1986-2020) that greater adherence to various healthier dietary patterns was associated with a lower risk of all-cause and disease-specific mortality [48]. Meta-analyses of hypocaloric diets do not support a particular macronutrient profile over others in the treatment of obese people with type 2 diabetes [49]. This is also reflected in the current evidence-based recommendations of the European Diabetes Association [50].

Weight reduction

Weight reduction in overweight and obese people with type 2 diabetes results in the reduction of vascular risks, increases self-esteem, quality of life and can lead to remission in the early stages of type 2 diabetes [51] [52] [53] [54] [55] [56]. In the current clinical practice guidelines in this supplement, there is an extensive section on obesity and diabetes [57].

Physical activity and exercise (see Appendix; [Fig. 1])

Increased physical activity and sport are essential therapeutic interventions for all forms of diabetes. Physical activity is particularly beneficial for people with type 2 diabetes for a number of reasons [58] [59] [60] [61]. The structured approach is outlined in the step-by-step programme [see Appendix] of the National Healthcare Guideline. Extensive practical recommendations can be found in this supplement [62].

In brief

• People with type 2 diabetes should be motivated to increase their physical activity.

• It should be decided on an individual basis which types of exercise or sports are suitable for people with type 2 diabetes.

• Aerobic endurance training and strength training to build and maintain muscles should be offered as structured movement programmes.

• At least 150 min of moderate intensity exercise are recommended per week [61].

• Low-intensity training is associated with lower drop-out rates compared to high-intensity training and appears to be more successful in the long run [63]. In particular, it is recommended for people with type 2 diabetes in the second half of their life to train dexterity, reactions, coordination, flexibility and mobility.

• Sociodemographic characteristics and other components such as motivations, social support, reasonable goal setting and the establishment of an everyday “routine” were most important for the implementation of long-term physical exercise [64] [65] [66].

Cessation of smoking

Active and passive smoking, in addition to being a preventable cause of significantly increased morbidity and mortality, are also significant risk factors for type 2 diabetes [67]. In a recently published metaanalysis, smoking was shown to be an independent risk factor for the progression of albuminuria [68]. Albuminuria is one of the strongest predictors for the development and progression of cardiovascular complications. When appropriate to the situation, smokers should therefore always be educated and specifically counselled about the particular risks of smoking for type 2 diabetes, microvascular and macrovascular complications, and pulmonary disease. They should be strongly advised to stop smoking tobacco.

Further information on tobacco cessation and support for quitting smoking can be found in the S3 guideline “Smoking and Tobacco Dependence: Screening, Diagnosis and Treatment”, Update 2021 [69] and in the Tobacco Atlas Germany [70].

Smokers who are willing to change should receive regular counselling regarding possible tobacco cessation procedures (see Appendix; [Fig. 2]).

Pharmacotherapy

The basic therapy (at every therapy) comprises lifestyle-modifying, non-drug therapy measures, but these are often not sufficient on their own. In patients for whom lifestyle-modifying measures are not expected to be sufficiently successful (due to severity of metabolic derailment, adherence problems, multimorbidity), these measures should be combined with metformin and, if contraindicated or incompatibility, with another antidiabetic drug. Most people with type 2 diabetes have multimorbidity and thus, depending on the individual therapy goal, there is a need for polypharmacy with prioritisation according to the severity of vascular risks ([Fig.1]).

The step-by-step procedure provided in the therapy algorithm ([Fig. 1]–[3]) refers to the time of clinical diagnosis of type 2 diabetes in the stage of relative metabolic compensation. Newly diagnosed patients with metabolic decompensation should simultaneously receive basic pharmacotherapy and pharmacotherapy adapted to the metabolic situation (e. g. insulin), the strategy of which should be evaluated and adapted within a short period of time [1].

Fig. 1 Therapy algorithm for type 2 diabetes. 1 Lifestyle-modifying, non-drug therapy measures are the basic therapy at every therapy level. AHA: American Heart Association; ACC: American College of Cardiology; ESC: European Society of Cardiology; EAS: European Atherosclerosis Society; EASD: European Association for the Study of Diabetes; KDIGO: Kidney Disease: Improving Global Outcomes; NVL: National Healthcare Guideline.

Fig. 2 Algorithm for drug therapy in type 2 diabetes. HR: Heart rate; SGLT-2: Sodium-glucose transporter 2; GLP-1 RA: glucagon-like-peptide 1 receptor agonist; DPP4: dipeptidyl peptidase 4.

Fig. 3 Algorithm for insulin therapy. Source: National Healthcare Guideline. NVL-2 Diabetes – Partial Publication, 2nd Edition: www.leitlinien.de/ themen/diabetes. [rerif].This figure is a supplement to [Fig.2]. The algorithm does not refer to people with severe metabolic decompensation or emergency situations. Current specialist information must be taken into account. Superscript blue star: Review the therapy strategy and the therapy goal in 3-6 months at the latest.

The therapy recommendations apply to the individual substances keeping in mind the respective current specialist information, in particular with regard to kidney function (eGFR limits!).

Risk assessment

Before starting drug treatment, a detailed risk assessment is absolutely necessary, because this determines the choice and possible combination of antidiabetic and organ-protective drugs. In [Table 3], important risk factors are listed in accordance with the National Healthcare Guideline.

Table 3 Risk factors for which, in cumulative cases, early use of organ-protective drugs is indicated. Data according to [1]

Duration of diabetes ( > 10 years) (Biological) age Gender (male > female) Lifestyle: unbalanced diet/physical inactivity/excessive alcohol consumption Family history of early cardiovascular disease (Men < 55 years; women < 60 years) Hypertension or antihypertensive therapy Dyslipidaemia or lipid-lowering therapy Obesity ( > 30 kg/m2) Renal insufficiency (eGFR < 60 ml/min.) Albuminuria ( > 30 mg/g creatinine in urine) Smokers and ex-smokers Subclinical arteriosclerosis or cardiovascular disease and/or cerebrovascular disease Left ventricular hypertrophy Obstructive sleep apnoea syndrome

eGFR: estimated glomerular filtration rate.

Due to the complexity and the large number of risk factors ([Table 3]), which have not been evaluated in their entity, the risk assessment cannot be depicted in the form of scores [2]. The analysis of important RCTs impressively shows how heterogeneous the inclusion criteria for the study participants were ([Table 4]). In addition, most RCTs (strict inclusion and exclusion criteria) only represent a maximum of 4-50% of real-world patients. In order to assess the effectiveness of interventions in randomised controlled trials (RCTs) in real-world settings, pragmatic and register studies with the same patient characteristics as in corresponding RCTs are therefore necessary [71]. Thus, only an individual careful assessment of the risk for cardiovascular and renal diseases before implementation of the corresponding therapy algorithm is helpful at present ([Fig. 1]–[3]).

Table 4 Criteria used to diagnose high cardiovascular risk (in patients without manifest atherosclerotic heart disease) in 12 published cardiovascular “Outcome” studies on the effect of GLP-1 receptor agonists or SGLT-2 inhibitors: EMPA-REG, CANVAS Program, DECLARE TIMI-58, VERTIS CV, ELIXA, LEADER, SUSTAIN-6, EXSCEL, REWIND, HARMONY Trials, PIONEER-6, AMPLITUDE-O.

Criteria	Frequency (n)	Frequency (%)	Comment
Age ≥ 50, 55, or 60 years	6	100	Basic criterion, requires additional risk factors
Plus reduced renal function (eGFR 25-59.9 ml/min.)	1	17	Also occurs as CHD-equivalent
Plus ≥ 1 (n=4) or ≥ 2 (n=2) further risk factors (see below)	6	100	Further risk factors (see below)
Diabetes duration ≥ 10 years	1	17	Main criterion according to ESC
Arterial hypertension (> 140 and>90 mmHg or antihypertensive medication)	3	50	Surprisingly low rated
Smoking/tobacco use	3	50	Surprisingly low rated
Micro- or macroalbuminuria	5	83	Central and meaningful criterion
HDL cholesterol low (e. g.,<1 mmol/l or 42.5 mg/dl)	2	33	Surprisingly low rated
LDL cholesterol elevated (e. g.,>3.36 mmol/l/or 130 mg/dl)	2	33	Surprisingly low rated
Lipid-modifying therapy	1	17	Surprisingly low rated
Left ventricular hypertrophy (in arterial hypertension)	3	50	Hypertension with end organ damage
Left ventricular systolic or diastolic dysfunction	3	50	Heart failure
Ankle-brachial index<0.9 (≥ 1 leg affected)	3	50	Is also used for already manifested PAOD
Obesity	1	17	Surprisingly low rated
First-degree relative(s) with coronary heart disease with manifestation ≤ 55 years (men) or ≤ 65 years (women)	1	17	Seldom mentioned

6 of 12 cardiovascular “outcome” studies recruited patients without manifest disease due to risk factors. The percentages refer to this total number (6 studies). Criteria that were used consistently often (≥ 50%) are highlighted in bold . All other criteria were suggested in a maximum of 33% of the studies. CHD: coronary heart disease; eGFR: estimated glomerular filtration rate; ESC: European Society of Cardiology; HDL: high-density lipoprotein; LDL: low-density lipoprotein; PAOD: peripheral arterial occlusive disease.

Overview with regard to metabolic effects and clinical endpoints

[Table 5] provides a quick, orientating overview with regard to metabolic effects and clinical endpoints of the pharmaceuticals discussed in this clinical practice guideline – apart from oral semaglutide, which was not inferior to subcutaneous semaglutide in terms of clinical endpoints. The table is a careful interpretation of the available evidence from randomised controlled trials and metaanalyses, which was compiled and consulted by the Medical Centre for Quality in Medicine and the National Healthcare Guidelines working group (www.leitlinien.de/nvl/diabetes; AWMF Register No. 001; [1] and supplemented by the author group of this clinical practice guideline because of new study results.

Table 5 Informative, comparative consideration of the substance classes (supplement to the algorithm ( [Fig. 2] )). This table is a summary interpretation of the evidence. For a detailed presentation of the evidence, see the text. Quelle: Medical Center for Quality in Medicine (Ärztlichen Zentrums für Qualität in der Medizin (ÄZQ)) German Medical Association (Bundesärztekammer), National Association of Statutory Health Insurance Physicians (Kassenärztliche Bundesvereinigung), Association of Scientific Medical Societies (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften) et al. National Healthcare Guideline on Type 2 Diabetes Long version. 3rd edition, 2023. AWMF register no.: nvl-001e.

Medicine	Total mortality	Cardiovascular endpoints	Microvascular endpoints 1	Renal endpoints	Hypoglycaemias	HbA1c, weight	Comments/selected safety information
Metformin	0	0	0	0	↔ ↑	HbA 1c ↓ ↓ Weight: ↔ ↓	Risk of lactic acidosis, taking a break in form of sick days when unwell
SGLT-2 inhibitors							Risk of genital infections, atypical ketoacidosis, Fournier gangrene Taking a break in form of sick days when unwell Weight reduction (undesired in cases of frailty)
Dapagliflozin	0*sinks with patients with HF	MACE: 0 CV death: 0 heart failure-related hospitalisation: ↓ sinks	n/a Retinopathy, neuropathy, amputations: 0	↓ sinks	↔	HbA 1c ↓ ↓ Weight: ↓
Empagliflozin	↓ sinks*	MACE: ↓ sinks CV death: ↓ sinks heart failure-related hospitalisation: ↓ sinks	n/a	↓ sinks	↔	HbA 1c ↓ ↓ Weight: ↓
Ertugliflozin		MACE: 0 CV death: 0 heart failure-related hospitalisation: ↓ sinks		0 (eGFR decrease is reduced)
GLP-1 RA							Gastrointestinal side effects, gallstones Low risk of pancreatitis Injections necessary Weight reduction (undesired in cases of frailty)
Dulaglutide	0	MACE: ↓ sinks CV death: 0 heart failure-related hospitalisation: 0	Retinopathy: 0 n/a: amputations, neuropathy	↓ sinks	↔	HbA 1c ↓ ↓ Weight: ↓
Exenatide	↓ sinks*	MACE: 0 CV death: 0 heart failure-related hospitalisation: 0	Amputations: 0	n/a	↔	HbA 1c ↓ ↓ Weight: ↓
Liraglutide	↓ sinks*	MACE: ↓ sinks CV death: ↓ sinks heart failure-related hospitalisation: 0	Retinopathy: 0 n/a: neuropathy, amputations:	↓ sinks	↔	HbA 1c ↓ ↓ Weight: ↓
Lixisenatide	0*	MACE: 0 CV death: 0 heart failure-related hospitalisation: 0	n/a on: Retinopathy, amputations, neuropathy:	n/a	↔	HbA 1c ↓ ↓ Weight: ↓
Semaglutide	0*	MACE: ↓ sinks CV death: 0 heart failure-related hospitalisation: 0 for semaglutide ORAL MACE: 0 CV death: ↓ heart failure-related hospitalisation: 0	Retinopathies: ↑ n/a: neuropathy, amputations:	↓ sinks	↔	HbA 1c ↓ ↓ Weight: ↓
Sulfonylureas	0	MACE: (0)* CV death: (0) heart failure-related hospitalisation:	(0 to ↓)	(0 to ↓)	↑ ↑	HbA 1c ↓ ↓ Weight: ↑	Risk of severe, prolonged hypoglycaemias CVOT study: no difference in the primary CV endpoint in direct comparison to CV-neutral linagliptin
DPP4 inhibitors	(0)	MACE: (0) certain CV death: (0) heart failure-related hospitalisation: (0)	(0)	(0)	↔	HbA1c ↓ Weight: ↔	Very rare: pancreatitis, inflammation bowel diseases CVOT present for sitagliptin, saxagliptin, linagliptin Vildagliptin has NO CVOT Saxagliptin is not recommender with pre-existing heart failure
Possibly as of stage 3 of the algorithm
Insulin	(0)	(0)	(↓)	(0)	↑ ↑	HbA 1c ↓ ↓ (dose-dependent) Weight: ↑ ↑	Risk of hypoglycaemias, especially at the start of therapy Lipohypertrophy

Effects on endpoints: ↓: positive effect (endpoint was reached less frequently in the studies), ↑: negative effect (endpoint was reached more frequently in the studies); 0: endpoint was not affected in the studies considered, assumptions in parentheses () are from studies with low methodological quality, or there was insufficient evidence to assess. All-cause mortality endpoint*: The study was not laid out for the endpoint all-cause mortality. MACE: cardiovascular death, stroke, myocardial infarction (for exact definition, see cardiovascular endpoint studies); CV death: cardiovascular death, HHI: heart failure-related hospitalisation; GLP-1 RA: glucagon-like peptide-1 receptor agonist; DPP4: dipeptidyl peptidase-4; CVOT: cardiovascular outcome studies. n/a: not specified (the effect sizes were not given in the main publication or without a confidence interval). Hypoglycaemia: ↑ increased risk, ↔ low risk; HbA1c: ↓: decrease; weight: ↑: weight gain, ↓: weight loss. Compared with linagliptin in CVOT dapagliflozin and ertugliflozin are approved for the treatment of chronic heart failure. This applies to patients with impaired left ventricular function (HFrEF). Then dapagliflozin can be given up to an eGFR of 30 ml/min. and empagliflozin up to an eGFR of 20 ml/min. Safety aspects and effects listed represent the state of discussion of the available evidence in the expert group and should not be considered a comprehensive presentation. 1 microvascular endpoints: retinopathy, neuropathy, amputations.

Reasons for the therapy level non-drug basic therapy

Basic therapy includes all lifestyle-modifying, non-drug measures. These include education and training of the patient, nutritional therapy, increasing physical activity and smoking cessation, as well as stress management strategies. An important goal is to strengthen the will to lead a healthy lifestyle (refraining from smoking, maintaining a diabetes-appropriate diet, increased physical activity, limiting alcohol consumption) ([Fig. 2], [3] ). Digital tools and telemedical support are becoming increasingly important for the implementation of a personalised basic therapy [72].

Since many people with type 2 diabetes have a variety of other vascular risk factors in addition to chronic hyperglycaemia or already have cardiovascular, renal and other diseases, the treatment of these people is complex and should take into account all vascular risk factors and individually prioritise manifested clinical diseases. To emphasise this more clearly, the previous treatment algorithm has been expanded to address major cardiovascular risks in more detail.

Reasons for pharmacotherapy therapy level

The basic therapy plays an important role in every further level of therapy modification. Pharmacotherapy is indicated to achieve the individual therapy goals if these lifestyle-modifying measures cannot be implemented or cannot be implemented adequately by the person with diabetes and are therefore not successful or do not make sense in the foreseeable future (2-3 months). Whenever possible, the advantages of metformin (see appendix) should be used and doses should start gradually and increase slowly (e. g., starting with 500 mg with the main meal and increasing by another 500 mg each week up to a total dose of 2 × 1000 mg per day).

In case of contraindications (eGFR<30 ml/min.) or poor tolerability of metformin (mainly dose-dependent gastrointestinal complaints), other options for monotherapy are available and should be used according to the patient risk profile (cardiorenal risks and morbidity) and the other patient-relevant benefits (influence on body weight, risk of hypoglycaemia, metabolic effects, side effect profile and clinical endpoints). It is essential that patient preferences are taken into account, as this is the only way to ensure good treatment adherence.

In patients with cardiovascular or renal diseases or a very high cardiovascular risk ([Table 3]), substances that reduce evidence-based cardiovascular and renal diseases as well as mortality (SGLT-2 inhibitors, GLP-1 receptor agonists) should be used primarily in combination with metformin (eGFR>30 ml/min.!). For people with type 2 diabetes with HbA1c levels significantly outside the individual glucose target range (e. g.,>1.5% above the target range) at diagnosis, initial pharmacotherapy, including the use of multiple combinations including insulin, if necessary, is warranted. After reaching the HbA1c target value, the therapy should be adjusted at individually agreed intervals.

Reason for combination therapies

A dual combination is necessary for many patients for metabolic reasons and is more favourable with regard to side effects of the individual substances, since in some cases lower doses can be used in the combination.

An early combination therapy should be aimed for in order to avoid derailing the metabolic parameters far from the agreed target range [73] [74]. The target values should usually be checked at 3-month intervals. There is now a large number of publications with good evidence for the selection of combinations. Patient preferences, individual therapy goals, simplicity of treatment, existing cardiovascular, cerebrovascular and renal diseases and possible contraindications also play an important role. If the number of oral medications becomes too complex due to the complexity of the therapy, vascular risk factors or comorbidities (including chronic obstructive pulmonary disease [COPD], depression, chronic pain conditions, etc.), fixed combinations should be used wherever possible. Parenteral blood glucose-lowering principles (GLP-1 RAs, insulins) can also be useful and helpful for these patients and significantly increase therapy adherence. The higher the HbA1c level, the more likely the use of insulin, but this does not mean that initial insulin therapy must be continued after metabolic recompensation. Deescalation strategies should be considered for each patient.

The administration of more than 2 oral antidiabetic agents may be individually appropriate if therapy with a GLP-1 RA or insulin is not yet indicated ([Fig. 3]), the patient is not yet comfortable with injection therapy, or this therapy should be delayed for other reasons.

Oral triple therapy in the combination with metformin, a DPP4 inhibitor and an SGLT-2 inhibitor is a safe, effective and simple therapy. Potentiation of side effects has not been observed with oral triple combination; they are essentially the same as those observed with monotherapy for the respective substance. A new option is the combination of a “classic” oral antidiabetic drug with semaglutide orally [75] [76] [77] [78].

In case of non-response to therapy, the patient’s compliance with therapy should always be discussed before increasing the dose or changing the treatment [1].

Reasons for injection therapy

Due to the lower rates of hypoglycaemia and a favourable body weight course (compared to intensified insulin therapy), GLP-1 RA-assisted oral diabetes therapy or basal insulin treatment in combination with oral antidiabetic drugs is recommended for people with type 2 diabetes if individual therapy goals are not achieved ([Fig. 3]).

Insulin dose reduction should absolutely be considered in case of acute and chronic worsening renal function in order to avoid severe hypoglycaemia.

A combination of GLP-1 RA with oral antidiabetic drugs (except DPP4 inhibitors) is an effective treatment if the individual therapy goal was not achieved with the previous oral antidiabetic drugs in mono- or multiple combinations or if side effects make a new therapy strategy absolutely necessary. In principle, the use of GLP-1 RA should be considered before starting a therapy with insulin, especially because of the very low hypoglycaemia risk of the substance class, the favourable weight progression and the favourable cardiovascular and renal outcome data of these substances.

Combinations of a GLP-1 RA with a basal insulin lead to a significant delay in the intensification of antidiabetic therapy (e. g., escalation of the basal insulin dose or additional administration of prandial insulin), to significantly better metabolic control without a significant increase in the risk of hypoglycaemia and to favourable weight effects. This is also underlined by data comparing fixed-mix therapy of GLP-1 RA and insulin with a free combination of GLP-1 RA plus basal insulin [79] [80] [81] [82] [83] [84] [85] [86] [87] [88]

Only when these combination therapies are no longer sufficiently effective or indicated will a further intensification of insulin therapy with prandial insulin be required in a next step.

Flexibility of treatment decisions due to the heterogeneity of type 2 diabetes and the dynamically adaptable individual therapy goals is necessary at every stage of treatment. In most cases, it is necessary to persuade patients to accept injection treatment and extensive education/training. In individual cases, CSII is indicated if the therapy goals are not achieved sufficiently with ICT. In individual cases, AID therapy should also be considered for medical and psychosocial reasons [89] [90] [91].

Treatment of a lipid metabolism disorder

A lipid metabolism disorder is common in people with type 2 diabetes and is an important vascular risk factor. Detailed information on the treatment of lipid metabolism disorder can be found in the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guideline [19] [92] and in the clinical practice guideline of this supplement [20].

Treatment of arterial hypertension

Arterial hypertension is an important cardiovascular and renal risk factor that should be treated early and consistently. Structured training on hypertension, including practical training of patients to self-monitor their blood pressure, is helpful. Detailed information on the treatment of hypertension has been discussed, among others, in guidelines [21] [22] [23] [24] [93] [94] [95] [96] [97] [98].

Therapy of nephropathy

Nephropathy is a serious complication in people with type 2 diabetes not only for the kidney itself, but also for the cardiovascular system and other organ systems. Therefore, regular screening for kidney disease and early multifactorial therapy is necessary [1] [99] [100] [101] [102] [103] [104] [105]. Recent meta-analyses and systematic reviews have described the benefits of Finerone, especially in combination with SGLT-2 inhibitors [106] [107] [108].

Treatment of non-alcoholic fatty liver disease (NAFLD)

Because of the multiple metabolic dysfunctions and diet-related association, this disease has been redefined: “metabolic dysfunction associated fatty liver disease” (MAFLD). In particular, people with type 2 diabetes often (about 70%) have MAFLD. Screening for this disease to estimate overall risk, including significant association with cardiovascular comorbidities, should be done periodically in people with type 2 diabetes. For this purpose, the determination of the fibrosis (FIB)-4 index as a laboratory value-based score for the severity of NAFLD is suitable: FIB-4=[age (years) × aspartate aminotransferase (AST) (U/L)]/[platelets (109/L) × (alanine aminotransferase (ALT) (U/L)1/2]. The calculation and assessment is very easy online: low-risk (FIB-4:<1.30), intermediate risk (FIB-4: 1.30-2.67), high risk (FIB-4:>2.67) of advanced liver fibrosis.

The knowledge of the presence of MAFLD is important for the risk assessment and the now possible treatment strategy of people with type 2 diabetes [109] [110].

German Diabetes Association: Clinical Practice Guidelines This is a translation of the DDG clinical practice guidelinepublished in Diabetol Stoffwechs 2023; 18 (Suppl 2): S162–S217DOI 10.1055/a-2076-0024

Additional information

Appendix

Medical history and clinical examinations

Table 1 Medical history and clinical examinations in people with type 2 diabetes.

History and examination
History It should be noted that type 2 diabetes is frequently poor in symptoms or asymptomatic and that the symptoms are often overlooked.	Excess weight/obesity High blood pressure Lipid metabolism disorders Fatty liver Thirst Frequent urination Involuntary weight loss Tendency to infection – especially infections of the skin or mucous membranes Exhaustion, fatigue, weakness Physical inactivity Drug intake (e. g., glucocorticoids, psychotherapeutics) Excessive alcohol consumption Smoking Depression Exertional dyspnoea NYHA Class? Angina symptoms Intermittent claudication (walking distance) Cognitive impairment (e. g. memory and concentration disorders) Visual disturbances, retinopathy Periodontitis Erectile dysfunction Birth of children>4000 g
Family history	Diabetes Excess weight High blood pressure Lipid metabolism disorders Retinopathy Heart disease (angina pectoris, myocardial infarction, heart failure) Stroke Kidney disease Amputation
Physical examination	Height Weight (BMI) Waist circumference (in the middle between lower rib-bone and upper iliac crest right after exhaling normally) Cardiovascular system Abdominal organs Genitourinary system Hypertension Edema (e. g., heart failure, kidney disease) Peripheral arteries, pulse status [1] Peripheral nervous system [2] Skin Oral hygiene (periodontitis) Eye examinations [3] Foot examinations [4]
Laboratory values optional GAD: antibodies test for the sometimes-difficult differentiation to type 1 diabetes or LADA and insulin or better C-peptide (with HOMA2-B and HOMA2-IR) in cases of unclear differential diagnosis or for subtyping if this results in a therapeutic consequence (see also the clinical practice guideline “Definition, Classification and Diagnosis of Diabetes Mellitus” in this supplement)	Plasma glucose Blood count HbA1c Creatinine/eGFR Potassium Lipid profile (total, HDL, non-HDL cholesterol, triglycerides) Gamma GT AST ALT [5] Determination of the (FIB-4 Index) [5] Uric acid [6] Urinalysis incl. albuminuria (UACR: albumin in urine mg/g creatinine), ketones in urine or blood (only for high glucose values; for SGLT-2 inhibitor therapy, also at plasma glucose values<250 mg/dl [13.9 mmol/l])
Technical examinations	Resting and exercise ECG [7] [8] Echocardiography with or without pharmacological stress as an alternative to a stress ECG; ask about heart failure (HFpEF/HFrEF) Abdominal sonography (fatty liver and others) Eye examination Ankle-brachial index for weak or not palpable pulses in the feet (caveat: media sclerosis)

BMI: body mass index; GAD: glutamate decarboxylase; LADA: Late onset autoimmune diabetes in the adult; HOMA2-B: homeostatic model assessment 2-beta-cell function; HOMA2-IR: homeostatic model assessment 2 insulin resistance; eGFR: estimated glomerular filtration rate; HDL: high-density lipoprotein; gamma GT: gamma glutamyl transferase; AST: aspartate aminotransferase; ALT: alanine aminotransferase; FIB-4: fibrosis-4; SGLT-2: sodium glucose linked transporter 2; ECG: Electrocardiogram; HFpEF: Heart Failure with preserved Ejection Fraction; HFrEF: heart failure with reduced ejection fraction.

Monitoring of people with type 2 diabetes

Table 2 Monitoring of people with type 2 diabetes.

History/examination/screening
History	Diabetes duration Weight/BMI, waist-height ratio if applicable (weight progression, excess weight) Blood pressure Foot status Previous therapy (complete medication plan if possible) Physical activity Eating habits Smoking Diabetes education and training programme carried out, blood glucose self-monitoring Hypoglycaemia (frequency and severity) Anxiety Depression Erectile dysfunction
Physical examination	Weight Blood pressure Cardiovascular system Lungs Oral hygiene (periodontitis) Examination of injection sites Examination of the FGM/CGM puncture or implant sites
Laboratory values	HbA1c Creatinine clearance rate (eGFR) Lipid profile including LDL, HDL-cholestrol Uric acid BNP or NT-proBNP Determination of the FIB-4 Index (fatty liver?) Urinalysis incl. albuminuria (UACR: albumin in urine mg/g creatinine), ketones in urine or blood (only for high glucose values; for SGLT-2 inhibitor therapy)
Screening for diabetic neuropathy [2] , [10]	People with type 2 diabetes neuropathy should be screened once per year from the moment of diagnosis for sensorimotor and autonomic neuropathy.
Screening for foot lesions [4] [10]	People with type 2 diabetes also with no clinical findings of sensorimotor neuropathy should be examined for foot lesions at least once a year. If clinical findings of sensorimotor neuropathy are already present, regular examinations for foot lesions should be carried out every 3−6 months.
Screening for nephropathy [9] , [10]	People with type 2 diabetes should be examined for albuminuria at least once a year, as this allows a significant additional risk assessment for cardiovascular and renal complications. In addition, the eGFR should be determined, whereby the frequency of the measurement varies depending on the stage of the renal disease and possible renal complications (nephrotoxic substances, contrast agents, hypovolemia).
Screening for retinal complications [3] , [10]	An ophthalmic screening should be performed: For type 2 diabetes upon diagnosis (initial examination). If no diabetic retinal change is detected, the screening interval should be 2 years in case of known low risk (=no ophthalmological risk and no general risk), 1 year for all other risk constellations. If the ophthalmologist does not know the general risk factors, the patient should be treated as with an unfavourable general risk profile. Patients with diabetic retinopathy changes (=ophthalmic risk) should be examined annually or more frequently, depending on the findings. In the case of newly-occurring symptoms such as deterioration of vision, distorted vision, blurred vision and/or floaters, an examination should be carried out promptly at the ophthalmologist.
Assessment of macro- and microvascular overall risk	People with type 2 diabetes should be examined for vascular risks (hypertension) at least once a year and they should be asked whether they smoke. In addition, HbA1c, lipids, uric acid and circulatory parameters (blood pressure measurement and pulse measurement at different sites) should be controlled and a micro-/macroalbuminuria should be measured quantitatively. Looking for symptoms of heart failure and laboratory values should be performed at least twice a year.

BMI: body mass index; FGM: flash glucose monitoring; CGM: continuous glucose monitoring; eGFR: estimated glomerular filtration rate; LDL: low-density lipoprotein; HDL: high-density lipoprotein; BNP: brain natriuretic peptide; NT-proBNP: n-terminal pro brain natriuretic peptide; FIB-4: fibrosis-4; SGLT-2: sodium glucose linked transporter 2.

Physical exercise

Regular exercise is particularly important for people with type 2 diabetes. Data according to [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] (Fig.1).

Table 3 Benefits of regular physical activity.

Lowers blood pressure Reduces heart rate at rest and under stress Improves dyslipidaemia Reduces cardiovascular risk Reduces insulin resistance Supports weight loss Improves the flow of blood Reduces the risk of thrombosis Relieves chronic pain Prevents certain types of cancer Strengthens the immune system Strengthens confidence in one’s own ability and thus self-esteem Lifts the mood and reduces stress Promotes mobility and coordination, especially in older people Promotes general well-being

Critical presentation of the individual antidiabetic pharmaceuticals

Metformin

Metformin continues to be the first-line antidiabetic drug for the treatment of type 2 diabetes due to its good efficacy in lowering HBA1C, known safety profile, regulatory conditions with other substances with neutral effects in cardiovascular outcome studies, evidence of its potential positive effects on common cancers, long experience and low cost. The low risk of hypoglycaemia (caveat: simultaneous alcohol consumption) and the beneficial effect of slightly reducing weight are also advantageous. The indication as monotherapy and in combination therapy with metformin was expanded in February 2017 [23] :

• Patients with a renal insufficiency up to degree 3b (eGFR > 30 ml/min) can be treated with metformin if there are no other contraindications.

• Maximum daily dose is 1000 mg (500-0-500 mg) for an eGFR of 30–44 ml/min. At this eGFR, a metformin therapy should not be started.

• Maximum daily dose is 2000 mg for an eGFR of 45–59 ml/min.

• To be on the safe side, a dose reduction to 500 mg per day can be carried out at an eGFR of 30–44 ml/min, because the eGFR can worsen acutely at this level, particularly in elderly people with exsiccosis or due to kidney toxic drugs.

The pros and cons of metformin therapy at an eGFR of 30–44 ml/min must be explained to the patient.

In the population-based large study involving 75 413 patients of the Geisinger Health System, an analysis of all patients with regard to hospitalisation due to acidosis was carried out. 2335 hospitalisations due to acidosis were found in the period from 2004 to 2017 (mean follow-up 1–84 time of 5.7 years). In this clinical real-world setting and compared to other antidiabetic drugs (excluding insulin), metformin was only associated with lactate acidosis if the eGFR was lower than<30 ml/min. [24] [Table 1] [2] .

As far as clinical endpoints are concerned, despite the frequent use of metformin, the data are inconclusive. Positive data from the UK Prospective Diabetes Study (UKPDS) can be found in a relatively small number of overweight patients and from several small studies. In a recent meta-analysis, neither significant positive nor negative effects of metformin on cardiovascular endpoints were found [25] ; however, the authors admit that the numbers are too small for a meta-analysis and a large controlled study (which is certainly not to be expected) would be necessary to clarify the question. Correspondingly, there is no evidence of an advantage of metformin for a given combination therapy with respect to cardiovascular endpoints and all-cause mortality [25] [26] [27] [28] . In contrast to the National Healthcare Guideline (NVL) Type 2 diabetes and the current consensus statements of the American Diabetes Association (ADA) and European Association for the Study of Diabetes ( EASD), the European Society of Cardiology Guidelines has replaced primary metformin therapy with SGLT-2 inhibitors and GLP-1 RA in patients with newly diagnosed type 2 diabetes and already suffering from atherosclerotic cardiovascular disease, as there is no cardiovascular endpoint study for metformin in this collective. The ESC argues that evidence-based treatment strategies should be used in patients with Atherosclerotic Cardiovascular Disease (ASCVD) etc. (independently/in addition to/concomitant glucose-lowering drugs). Therefore, newly diagnosed or drug-naïve patients should start treatment with GLP-1 RA or SGLT-2 inhibitors (possibly at the same time as metformin). Sub-analyses of endpoint studies with SGLT-2 inhibitors and/or GLP-1 RAs show that metformin intake has no modulating effect on the cardioprotective effect of these substances [29] . In accordance with the recommendations of the NVL Type 2 Diabetes [1] and the ADA/EASD Consensus, the DDG continues to recommend that metformin should be started as the primary therapy if tolerated and the contraindications for metformin should be observed, and that metformin should be used as a primary therapy if there is a clinical indication (manifest cardiovscular and renal diseases or patients at high cardiac or cardiorenal risk (Part 1; [Table 3] [4] ) early/simultaneously start combination therapy with SGLT-2 inhibitors and/or GLP-1 RA. A recent meta-analysis shows that metformin alone has no significant advantage over other glucose-lowering drugs or placebo in terms of microvascular complications [30] . With a median follow-up of 21 years, metformin did not show any positive effects of metformin on all-cause, cardiovascular and cancer mortality in the Diabetes Prevention Program and Diabetes Prevention Program outcome studies [30] . In Germany, a sustained-release metformin preparation (XR=extended release) is available, which is best taken only once in the evening and is therefore apparently associated with better tolerability and adherence to therapy [31] .

Metformin is currently gaining great interest due to interesting pleiotropic effects that influence changes at the epigenetic level and gene expression and are thus potentially protective against carcinomas [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] .

A recent national prospective registry study from Denmark (period 1997–2016) found that preconception metformin therapy in fathers was associated with a significant accumulation, in particular, of male genital birth defects. Confirmation from other countries and, in particular, data on the causality of these defects with metformin are pending [44] .

Metformin and COVID-19

A number of analyses have shown that hospitalized COVID-19 infection is associated with significantly lower mortality in people with diabetes on prehospital metformin therapy [45] [46] [47] [48] . This was confirmed in a recent meta-analysis, which found a significant reduction in the odds ratio for mortality in COVID-19 patients with diabetes treated with metformin compared to those not treated with metformin: OR 0.62; 95%-CI: 0.43–0.89 [49] . In some of the studies, the confounding variables were not or only insufficiently taken into account. As long as no controlled studies are available, metformin should be maintained or used with great caution in seriously-ill inpatients infected with COVID-19 because of the risk of lactic acidosis [50] .

Fig. 1 Step-by-step programme for physical activity Data according to [369]

Fig. 2 Algorithm for dealing with smoking. Quelle: German Medical Association (BÄK), National Association of Statutory Health Insurance Physicians (KBV), Association of the Scientific Medical Societies (AWMF). National Healthcare Guideline Therapy of Type 2 Diabetes – Long version, 1st edition. Version 4. 2013, last modified: November 2014. DOI: 10.6101/AZQ/000213 [rerif].

Table 4 Approvals and indications for SGLT-2 inhibitors in Germany. eGFR: estimated glomerular filtration rate; CKD: chronic nephropathy. HFrEF: Heart failure with reduced left ventricular ejection fraction: EF <40%; HFmEF: Heart failure with moderately impaired left ventricular ejection fraction: EF 40−49%; HFpEF: Heart failure with preservation of left ventricular ejection fraction: EF< 50%.

Indication	Dapagliflozin	Empagliflozin	Ertugliflozin
Type 2 diabetes	eGFR ≥25 ml/min/1.73m 2 10 mg daily	eGFR ≥60 ml/min/1.73m 2 10 mg daily 30−36 ml/min/1.73m 2 10 mg daily	eGFR ≥45 ml/min/1.73m 2 5−15 mg daily
CKD	eGFR ≥25 ml/min/1.73m 2 10 mg daily	eGFR ≥30 ml/min/1.73m 2 10 mg daily	0
HFrEF	eGFR ≥25 ml/min/1.73m 2 10 mg daily	eGFR ≥20 ml/min/1.73m 2 10 mg daily	0
HFmEF/HFpEF	eGFR ≥25 ml/min/1.73m 2 10 mg daily	eGFR ≥20 ml/min/1.73m 2 10 mg daily	0

Summary of the therapy with metformin:

• Kidney function must be checked regularly (every 3–6 months). Caveat: metformin must be discontinued immediately if eGFR drops to<30 ml/min.

• Beware of diseases which increase the risk of lactic acidosis (e. g., acute deterioration of kidney function due to gastroenteritis, respiratory insufficiency, acute diseases and infections or non-steroidal anti-inflammatory drugs).

• Caution when initiating therapy with ACE inhibitors or AT-1 receptor blockers, diuretics, at the beginning of therapy with non-steroidal anti-inflammatory drugs.

• When administering x-ray contrast media, prior to interventional or major surgical procedures, the patient should discontinue the use of metformin and only restart taking it after 48 h, and only if the eGFR is>30 ml/min postoperatively and the patient can eat again.

• In cardiovascular and renal high-risk individuals or people with manifest cardiorenal disease, extreme caution is advised.

Sulfonylureas

Sulfonylureas have been used for decades because they effectively lower blood glucose, are well tolerated and are inexpensive. Sulfonylureas usually lead to moderate weight gain.

Due to their ability to increase insulin secretion by inhibiting the potassium channels of the β-cells independently of glucose, they have the highest hypoglycaemic potential of all oral antidiabetics, with the risk of sometimes severe and prolonged hypoglycaemia, especially in older people with impaired renal function and polypharmacy. Sulfonylureas are largely contraindicated with decreasing renal function (eGFR<30 ml/min) with the exception of gliclazide and gliquidone. Due to the high risk of severe hypoglycaemia in patients with cardiovascular and renal complications, sulfonylureas should not be used in these people.

Favourable effects on microvascular endpoints were found in the UKPDS more than 6 years after treatment initiation for chlorpropramide and glibenclamide (mainly reduced rate of photocoagulation in retinopathy). In the ADVANCE trial, gliclazide was found to have positive effects on microvascular complications, mainly by reducing nephropathy [51] [52] .

In the prospective, randomised, controlled CAROLINA study (mean observation time 6.3 years, approx. 3000 patients in each study arm; in both study arms 42% of the participants already suffered from clinically manifest cardiovascular complications at baseline), a comparison was made between linagliptin (5 mg/day) and glimepiride (1–4 mg/day) with regard to cardiovascular endpoints, hypoglycaemia and weight progression. There was no difference when comparing the two study arms for 3P-MACE, 4P-MACE, all-cause and cardiovascular death, and mortality with overall comparable HbA1c levels [53] . Weight progression was more favourable with linagliptin compared with glimepiride (−1.54 kg), and rates of all, moderate and severe hypoglycaemic events requiring hospitalisation were significantly lower with linagliptin compared with glimepiride at all doses between 1 and 4 mg (1 mg: HR 0.23; 95% CI 0.21–0.26; p<0.0001, 2 mg: HR 0.18; 95% CI 0.15–0.21; p<0.0001, 3 mg: HR 0.15; 95% CI 0.08–0.29; p<0.0001, 4 mg: HR 0.07; 95% CI 0.02–0.31; p=0.0004). The authors concluded from the CAROLINA trial data that there are no reasons, other than the lower cost of glimepiride, to use glimepiride more preferentially than linagliptin in antidiabetic therapy [53] .

In several retrospective observational studies, in a large randomised pragmatic trial, analyses from registry data and their meta-analyses, and Cochrane reviews, sulfonylureas were shown to have no benefits in terms of macrovascular endpoints, either in monotherapy or in combination therapy. Rather, increased cardiovascular morbidity and mortality were described [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] . In a hospital-based observational study (American Heart Association Registry; outcome data at 12 months) found an association of SH therapy with higher mortality and hospitalisation rate for heart failure in elderly people with diabetes (age: 68–82 years) who were hospitalized for heart failure and received either metformin or a sulfonylurea (SH). This was especially true for people with EF≤40% [64] . In the systematic review and meta-analysis by Volke et al. [65] , in 31 studies involving 26204 patients, 11711 patients on sulfonylureas were compared with 14493 on comparator medications such as gliptins, metformin, SGLT 2 inhibitors and liraglutide). Sulfonylureas were associated with a higher odds ratio for all-cause mortality (OR 1.32, 95% CI 1.00–1.75), MACE (OR 1.32, 95% CI 1.07–1.61), myocardial infarction (lethal and non-lethal) (OR 1.67, 95% CI 1.17–2.38), and hypoglycaemia (OR 5.24, 95% CI 4.20–6.55). There were differences between the individual SHs, with glimepiride having the best risk profile. On the other hand, a large Scottish cohort study [66] found that SHs, as a second antidiabetic drug, did not have higher rates of MACE, heart failure, ischemic stroke, cardiovascular death, and all-cause mortality in people with type 2 diabetes who were poorly controlled on metformin compared to DPP4 inhibitors or pioglitazone. These data support the consensus of the ADA/EASD, which recommends SHs as second-line drugs for blood glucose lowering after metformin, especially in health care systems that cannot afford more expensive antidiabetic drugs [67] .

Repaglinide

Due to a decision of the Federal Joint Committee (G-BA), a comprehensive prescription restriction for glinides was implemented as of July 01, 2016. The prescription restriction reads: Except treatment of patients with renal insufficiency and a eGFR < 25 ml/min repaglinide is allowed if no other oral antidiabetic agents are suitable and insulin therapy is not indicated. Despite a detailed evidence-based statement (see also https://www.deutsche-diabetes-gesellschaft.de/politik/stellungnahmen) to the G-BA and BMG, the G-BA decision unfortunately still stands without corresponding evidence.

DPP4 inhibitors

DPP4 inhibitors are increasingly replacing therapy with sulfonylureas for reasons of a favourable safety profile, even in progressive renal insufficiency and a good tolerability, which is particularly important for elderly people. Therapy adherence and persistence with DDP-4 inhibitors (in 594138 patients) were suboptimal despite good tolerability: after 1 year of therapy, adherence was 56.9% (95% CI 49.3–64.4) and after 2 years, 44.2% (95% CI 36.4–52.1) [63] .

With the exception of linagliptin, the dosage of all DPP4 inhibitors on the market must be adjusted to the kidney function. In addition, DPP4 inhibitors show largely weight-neutral effects with similar anti-hyperglycaemic effects and low hypoglycaemic rates. DPP4 inhibitors seem to exert better metabolic control for longer than sulfonylureas (observation period 104 weeks) [68] .

The results of the CAROLINA study [53] (see section on sulfonylureas) were examined in a real-world study with inclusion criteria as in the CAROLINA study in a propensity score matching (PSM) [69] . There were 24 131 study pairs for linagliptin and glimepiride analysed. As in the CAROLINA study, no differences were found with regard to cardiovascular safety.

The results of the RCTs SAVOR TIMI 53 (saxagliptin [70] ), EXAMINE (alogliptin [71] ), TECOS (sitagliptin [72] ), CARMELINA (linagliptin) [73] [74] on the effect of DPP4 inhibitors on cardiovascular and renal endpoints each show one cardiovascular safety across all eGFR ranges (<30 ml/min. to > 60 ml/min.) of the investigated DPP4 inhibitor in their primary endpoint, which was also confirmed in extensive reviews and meta-analyses [75] [76] [77] [78] [79] [80] [81] [82] . In a large US database, a 3-year follow-up showed that DDP-4 inhibitors reduced the risk of the composite clinical endpoint (eGFR decline>50%, end-stage renal failure or all-cause mortality) more significantly compared with sulfonylureas but were less effective than GLP-1 RA and SGLT-2 inhibitors [83] .

In a recent Cochrane analysis, DDP-4 inhibitors found no evidence of a significant reduction in cardiovascular mortality (OR 1.00, 95% CI 0.91–1.09), myocardial infarction (OR 0.97, 95% CI 0.88–1.08), stroke (OR 1.00, 95% CI 0.87–1.14) and all-cause mortality (OR 1.03, 95% CI 0.96–1.11). There was also no reduction in hospitalisation for heart failure (OR 0.99, 95% CI 0.80–1.23). DPP4 inhibitors were not associated with deterioration of renal function (OR 1.08, 95% CI 0.88–1.33) and did not lead to an increased risk of fractures (OR 1.00, 95% CI 0.83–1.19) or hypoglycaemia (OR 1.11, 95% CI 0.95–1.29) [84] .

Nevertheless, DPP4 inhibitors are effective antidiabetics with few side effects and can be used very well as monotherapy and combination therapy if contraindications to the use of metformin are present and there is a corresponding patient preference. Another advantage is that DPP4 inhibitors act largely weight-neutrally, hardly induce hypoglycaemia and the use of linagliptin is not contraindicated even in (pre)terminal renal insufficiency.

Hospitalisation for heart failure was not increased with the use of DPP4 inhibitors, except for saxagliptin (SAVOR TIMI 53). In a large meta-analysis on the risk of DPP4 inhibitors with regard to heart failure or hospitalisation for heart failure including RCTs and observational studies, the authors concluded that the effect of DPP4 inhibitors on heart failure remains uncertain (due to relatively short observation periods and overall weak data) [77] . A recent meta-analysis of alogliptin, linagliptin, saxagliptin and sitagliptin showed a neutral effect on myocardial infarction, stroke, heart failure (OR 1.06; 95% CI 0.96–1.18) and cardiovascular death [78] .

In the GRADE study, which included 5047 people with type 2 diabetes on metformin and were followed up for an average of 5 years on a 2nd antidiabetic drug (sitagliptin, glimepiride, insulin glargine, liraglutide), all 4 drugs were shown to lead to a significant improvement in HbA1c, with the reduction being better with insulin glargine and liraglutide than with the other two antidiabetic drugs [85] . The effects on microvascular events (moderately elevated or strongly elevated albuminuria, change in eGFR, peripheral neuropathy) and macrovascular effects (MACE, other cardiovascular diseases, hospitalisation for heart failure, cardiovascular death) were comparable between the 4 study arms [86] .

Based on NAFLD and NASH studies with imaging and liver histology, DPP4 inhibitors showed no significant benefit in people with type 2 diabetes and NAFLD, in contrast to GLP-1 RAs or SGLT-2 inhibitors [87] . In a meta-analysis, Kumar et al. [88] reported on improvements in transaminases and hepatic histology in patients with diabetes and NAFDL, especially with pioglitazone, but also with DDP-4 inhibitors and other newer antidiabetic drugs. In the current S2k guideline for non-alcoholic fatty liver disease, there is no contraindication for the treatment of diabetes by modern antidiabetic drugs and they may even have a favourable effect on the course of liver disease [89] .

DPP4 inhibitors in hospitalised patients

The use of DPP4 inhibitors in people with type 2 diabetes and moderate, relatively stable hyperglycaemia has been shown in a number of RCTs to have a good safety profile, effective blood glucose-lowering and insulin savings with insulin co-medication [90] . DPP4 inhibitors may be able to slow down the over-activated immune system in people with Sars-CoV-2 infection and thus contribute to a more favourable cardiovascular outcome [91] . However, in the absence of randomised trials, the observational studies available to date do not provide robust evidence to use DPP4 inhibitors in COVID-19 infection [92] . In a meta-analysis, a significantly reduced mortality risk was found among DPP4 inhibitors in COVID-19 infected persons (odds ratio=0.58; CI 0.34–0.99) [93] . This is contradicted by a national observational study of 2,851,465 people with type 2 diabetes. In an observation period from February 16 to August 31, 2020 from the UK, the deaths under antidiabetic therapy were analyzed: HR (95% CI) for metformin was 0.77 (95% CI 0.73–0.81), for insulin 1.42 (1.35–1.49); for meglintinide 0.75 (0.48–1.17); SGLT-2 inhibitors 0.82 (0.74–0.91); thiazolidinedione 0.94 (0.82–1.07); sulfonylureas 0.94 (0.89–0.99); GLP-1 RAs 0.94 (0.83–1.07); DPP4 inhibitors 1.07 (1.01–1.13) and for alpha-glucosidase inhibitor 1.26 (0.76–2.09).

The authors' conclusion was that, based on these analyses, there is no clear indication to change the glucose-lowering drugs under COVID-19 infections [94] . However, a recent metanalysis showed that metformin, GLP-1 RAs, and SGLT-2 inhibitors were associated with a lower risk of mortality, while DPP4 inhibitors were associated with a higher risk of mortality from COVID-19. SHs, glitazones, and alpha-glucosidase inhibitors showed neutral behaviour [95] .

Safety aspects

In the meta-analysis of the 3 RCTs on DPP4 inhibitors (SAVOR TIMI 53, EXAMINE and TECOS), an increased incidence of acute pancreatitis was found compared with corresponding controls (odds ratio 1.79; 95% CI 1.13–2.82; p=0.013), although the absolute risk of acute pancreatitis was low overall and only 0.13% higher in absolute terms under DPP4 inhibitors [96] . A newer meta-analysis found an association between DPP4 inhibitors and the risk of acute pancreatitis (OR 1.72; 95% CI 1.18–2.53). However, the authors stated that the number of cases was too small to make a definite statement [97] . The new Cochrane analysis also reports a significantly increased risk of pancreatitis (OR 1.63, 95% CI 1.12–2.37) [84] . Therefore, great caution should be exercised when using DPP4 inhibitors in people with type 2 diabetes and a history or risk of pancreatitis.

A clear association between DPP4 inhibitor therapy and bullous pemphigoid has been seen in a number of cases [98] .

It has also been shown that DPP4 inhibitors are not associated with a higher rate of carcinomas [99] [100] .

DPP4 inhibitors were associated with a significantly higher incidence of inflammatory bowel disease in type 2 diabetes in a large population-based study (HR 1.75; 95%- CI 1.22–2.49) [101–103] . This association was highest 3–4 years after DPP4 inhibitor therapy but became significantly lower thereafter. The association started 2–4 years after the start of therapy. However, two meta-analyses found no associations between DPP4 inhibitors and inflammatory bowel disease [102] [103] .

In a meta-analysis of 82 clinical trials involving 104833 people with type 2 diabetes, the effects of placebo were compared with non-incretin substances. DPP4 inhibitors were significantly associated with a higher risk of the composite endpoint of gallbladder and biliary tract disease (OR 1.22 (95% CI 1.04–1.43)). DPP4 inhibitors were found to have a larger association with the risk of cholecystitis (OR 1.43 (1.14–1.79)), but not for cholelithiasis [104] .

In combination with metformin, sitagliptin was certified by the G-BA as having a low added benefit (BAnz AT 29.04.2019). However, neither in monotherapy nor in combination therapy was saxagliptin granted an added benefit (BAnz AT 18.01.2017, BAnz AT 13.03.2018 B2). The combination of linagliptin and empagliflozin was also not considered to be of additional benefit (BAnz AT 24.12.2019 B3).

SGLT-2 inhibitors

SGLT-2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin) are effective anti-hyperglycaemic substances in the treatment of type 2 diabetes in both mono- and combination therapy with all other glucose-lowering drugs.

Their efficacy profile is favourable, also because the risk of hypoglycaemia is low, patients lose weight and there is a clinically-relevant reduction in systolic blood pressure [105] [106] [107] [108] [109] [110] [111] [112] [113] [114] [115] [116] [117] [118] [119] [120] [121] .

Which SGLT-2 inhibitors are approved in Germany with which indication and which eGFR is shown in [Table 4] .

Not approved or withdrawn in Germany: Canagliflozin. Sotagliflozin was withdrawn by the European Commission for the EU in March 2022: https://www.ema.europa.eu/en/documents/public-statement/public-statement-zynquistawithdrawal-marketing-authorisation-european-union_en.pdf. On 26.05.2023, sotagliflozin was approved by the FDA for heart failure (HFrEF and HFpEF).

Safety aspects

However, there is a significantly increased risk of genital infections with SGLT-2 inhibitors in RCTs [122] [123] . The relative risk of SGLT-2 inhibitors for genital infections was more than 3 times higher than placebo (RR 3.37; 95% CI 2.89–3.93) and almost 4 times higher than an active comparator (RR 3.89; 95% CI 3.14–4.82). By contrast, the risk of urinary tract infections was not significantly increased by SGLT-2 inhibitors compared to placebo (RR 1.03; 95% CI 0.96–1.11) or an active comparator therapy (RR 1.08; 95% CI 0.93–1.25). In a large retrospective cohort study of a US database, an approximately 3-fold higher risk of genital infection was found with SGLT-2 inhibitors compared to DPP4 inhibitors, starting in the first 4 weeks of therapy and as long as therapy was continued [124] . Comparable results were also seen in the real-world analysis of people with diabetes at a relatively advanced age (71.8±5 years) [125] . The 3- to 4-fold increased risk of genital infections is a class effect of SGLT-2 inhibitors. Women and people with a history of genital infection had the highest risk of this complication [126] . The safety of SGLT-2 inhibitor therapy was researched in a recently published meta-analysis. In 10 studies with more than 76000 patients, the number needed to harm (NNH) was calculated in outcome data over a period of 2.35 years. The following NNH were determined: ketoacidosis 1014, fractures 522, amputations 418, urinary tract infections 319, volume depletion 139 and genital infections 41 [127] .

A necrotizing fasciitis of the perineum and genitals (Fournier gangrene) is a very rare, severe infection with the need for immediate antibiotic and usually surgical intervention. Diabetes is one of the risk factors. With the introduction of SGLT-2 inhibitor therapy, a few cases of Fournier gangrene under SGLT-2 inhibitor therapy were described. A Red Hand letter was published in consultation with the European Medicines Agency (EMA) and the Federal Institute for Drugs and Medical Products/Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) to clarify the “Risk of a Fournier gangrene (necrotizing fasciitis of the perineum) when using SGLT-2 inhibitors (sodium glucose cotransporter-2 inhibitors)”.

A recently published real-world study investigated the incidence of Fournier gangrene in patients after starting therapy with SGLT-2 inhibitors (n=93 197) or with DPP4 inhibitors. No increased risk of this gangrene was found with SGLT-2 inhibitor therapy compared with persons with DPP4 inhibitor treatment [128] .

In a recent meta-analysis of all randomised controlled trials of SGLT-2 inhibitors (n=84) in patients with type 2 diabetes, no differences were found in the risk of Fournier gangrene, abscess, cellulitis or erysipelas with SGLT-2 inhibitors vs. comparators or placebo. The rate of Fournier gangrene was very low at 3.53 per 100 000 patient years [129] .

The canagliflozin CANVAS programme [130] trials showed a higher risk of amputations (predominantly toe and metatarsal areas) with canagliflozin compared with placebo (event rate 6.3 vs. 3.4 persons per 1000 patient years; HR 1.97; 95% CI 1.41–2.75; p<0.001). The meta-analysis by Huang et al. [131] also found no evidence that SGLT-2 inhibitors were associated with an increased risk of amputation. In a recent meta-analysis including the CANVAS program, as well as the CREDENCE, EMPA-REG OUTCOME, DECLARE-TIMI 58, DAPAHF and EMPA-REG RENAL studies, no higher risk of fractures was found even with different degrees of renal insufficiency [132] . The Centricity Electronic Medical Records from the USA identified 169739 people with SGLT-2 inhibitor therapy. The analysis of this cohort also found no higher risk of amputation compared to other antidiabetic drugs [133] .

The FDA has issued a warning about an increased fracture risk due to reduced bone density under canagliflozin (http://www.fda.gov/Drugs/DrugSafety/ucm461449.htm). However, numerous RCTs and their meta-analyses did not show any evidence of higher fracture risks [134] [135] [136] [137] [138] . In the meta-analysis cited above, a NNH of 522 was found [127] .

When SGLT-2 inhibitors were used, ketoacidosis was occasionally observed in people with type 2 diabetes [127] [139] [140] . The SGLT-2 inhibitor manufacturers in Germany already informed physicians and pharmacists about the situation in 2015.

A comprehensive analysis of all reports of ketoacidosis cases with a possible connection to SGLT-2 inhibitors that were listed in the US Food and Drug Administration Adverse Event Reporting System (FAERS) between January 2014 and October 2016 has been published [141] . They found a Proportional Reporting Ratio (PPR) of 7.9 (95% CI 7.5–8.4). The PPR is the ratio of spontaneous reports for a specific drug (in this case SGLT-2 inhibitors) associated with a specific adverse event (=ketoacidosis) divided by the corresponding ratio for all or some other drugs with this adverse event. However, the PPR does not describe a relative risk, i. e., the real risk for ketoacidosis. Detailed analysis of 2397 reports of ketoacidosis in FAERS showed a predominance in people with type 1 diabetes, in women, across a wide age and body weight range, and high variability in the duration of SGLT-2 inhibitor therapy. 37 people (1.54%) died from ketoacidosis. In the large randomised controlled trials of SGLT-2 inhibitors, the risk of ketoacidosis was significantly increased with SGLT-2 inhibitors in type 2 diabetes but was less than 1%. The meta-analysis published in 2020 (39 RCTs with 60 580 patients) again confirmed a statistically significant increased rate of ketoacidosis with SGLT-2 inhibitors (0.18%) compared to controls (0.09%) with an OR of 2.13 (95% CI 1.38–3.27). Older age and longer use of SGLT-2 inhibitors played a role [142] . In the current meta-analysis, the risk of ketoacidosis was also comparably high: RR 2.23, (95% CI 1.36–3.63) [143] .

Normoglycaemia or mild hyperglycaemia does not exclude a ketoacidosis with SGLT-2 inhibitors. Risk factors for the development of a (euglycaemic) ketoacidosis with SGLT-2 inhibitors included a rapid and significant reduction of the insulin dose, severe dehydration, and alcohol consumption; almost all patients with ketoacidosis were in a catabolic state (operations, myocardial infarction, severe infections, long fasting, excessive physical strain, cocaine consumption).

Therefore, the German Diabetes Association (DDG) recommends that the following be considered when dealing with SGLT-2 inhibitors:

• Discontinuation of SGLT-2 inhibitors at least 3 days (=about 5 half-life times equivalent to 11-13 hours) before major elective surgery [144] [145] , immediate pausing of SGLT-2 inhibitor therapy in emergencies and acute illness,

• Caution during ongoing insulin therapy (avoid significant reduction or discontinuation of insulin therapy),

• Avoidance of prolonged periods of fasting, ketogenic/extremely low-carbohydrate diets and excessive alcohol consumption.

• The combination of SGLT-2 inhibitors with metformin increases the risk of ketoacidosis [146] and

• If symptoms are present, consider the possibility of euglycaemic ketoacidosis and initiate the appropriate diagnostic procedures (plasma glucose and ketones in blood, possibly also necessary venous blood gas analysis).

Effects on cardiovascular and renal endpoints

In an extensive meta-analysis of 816 studies with 471038 patients, the effects of 13 different classes of substances compared to standard treatments were tested [147] . SGLT-2 inhibitors, as well as GLP-1 RAs, reduced all-cause mortality by 12%. The analysis also confirmed the benefits of SGLT-2 inhibitors and GLP-1 RAs in the significant reduction of cardiovascular death, non-lethal myocardial infarction, hospitalisation for heart failure, and end-stage renal disease. Only GLP-1 RA reduced the number of non-fatal strokes, while SGLT-2 inhibitors were superior to all other classes of substances in reducing cases of end-stage renal disease. Treatment with GLP-1 RAs and probably also SGLT-2 inhibitors and the GIP/GLP-1 receptor agonist tirzepatide improved quality of life. In view of the complexity of the treatment options for type 2 diabetes, regular critical analyses of the various substance classes with regard to advantages and disadvantages and clear indications/contraindications are helpful and necessary also for health economic reasons.

In another recent meta-analysis, SGLT-2 inhibitors showed significant reductions of: MACE in patients with prior myocardial infarction (OR 0.83, 95% CI 0.73-0.94, p=0.004, without myocardial infarction OR 0.82, 95% CI 0.74-0.90, p<0.0001), hospitalisation for heart failure with previous myocardial infarction (OR 0.69, 95% CI 0.55-0.87, p=0.001) and without myocardial infarction (OR 0.63, 95% CI 0.55-0.72, p<0.00001), cardiovascular and all-cause mortality were reduced and renal events decreased (OR 0.73, 95% CI 0.58-0.91, p=0.004) [148] .

A number of other meta-analyses evaluated the heart failure clinical endpoint. In the analysis by Aziri et al. [149] 12 RCTs with a total of 83878 patients met the strict inclusion criteria. Study data from the following SGLT-2 inhibitors canagliflozin, empagliflozin, dapagliflozin, ertugliflozin and sotagliflozin (dual SGLT-2 inhibitor) were included. The pooled meta-analytical data were: atrial fibrillation odds ratio (OR)=0.83, 95% (CI): 0.68-1.01; hospitalisation for heart failure OR=0.69, 95% CI: 0.60-0.78, cardiovascular death OR=0.82, 95% CI: 0.58-1.15 and MACE OR=0.90, 95% CI: 0.77-1.06. SGLT-2 inhibitors significantly improved the quality of life of people with heart failure. The systematic review and meta-analysis by Ahmad et al. [150] included 4 studies (dapagliflozin n=1; sotagliflozin n=1; empagliflozin n=2). The follow-up was 20 months, the number of study participants was 15684. The following reductions were observed: all-cause mortality hazard ratio (HR) 0.91, 95% (CI) 0.82-1.01, p=0.071; cardiovascular mortality HR 0.88, 95% CI 0.79-0.97, p=0.012); hospitalisation for heart failure HR 0.70, 95% CI 0.64-0.77, p<<0.001). The meta-analysis of the DELIVER and EMPEROR-Preserved, DAPA-HF and EMPEROR-Reduced, and SOLOIST-WHF studies evaluated the primary endpoint (composite endpoint of cardiac death or hospitalisation for heart failure) with SGLT-2 inhibitor therapy [151] . SGLT-2 inhibitors reduced the risk of cardiovascular death or hospitalisation for heart failure (HF) by 23% (HR 0.77 [0.72-0.82]), cardiovascular death by 13% (0.87 [HR 0.79-0.95]), 1st hospitalisation for heart failure by 28% (HR 0.72 [0.67-0.78]), and all-cause mortality by 8% (0.92 [0.86-0.99]) [151] . Comparable cardiovascular outcome data were reported by the authors of the meta-analysis by Marilly et al. [152] , where risk was calculated as an incidence rate ratio (IRR): Risk of all-cause mortality (IRR 0.86 [95% CI 0.78, 0.95]), MACE (IRR 0.91 [95% CI 0.86, 0.96]), HF (IRR 0.69 [95% CI 0.62, 0.76]) and end-stage renal disease (IRR 0.67 [95% CI 0.53, 0.84]).

Patients with advanced renal insufficiency benefited from therapy with SGLT-2 inhibitors: The primary clinical endpoint (deterioration of renal function, end-stage renal disease or renal-related death) was reduced by 23% (RR 0.77, 95% CI 0.61-0.98, p=0.04) [153] . In the meta-analysis by Mannucci et al. [154] the authors also reported comparable risk reductions for cardiovascular endpoints with SGLT-2 inhibitors. At the same time, they found positive effects in terms of nephropathy: Worsening of albuminuria OR 0.67 (0.55-0.80) and doubling of serum creatinine OR 0.58 (0.44-0.79).

Dapagliflozin

The DECLARE-TIMI 58 study with dapagliflozin [155] included 6974 patients (40.6%) with known cardiovascular diseases and 10 186 (59.4%) with multiple risk factors for arteriosclerotic cardiovascular diseases. The mean follow-up of the patients was 4.2 years. A total of 3962 patients stopped the study prematurely (=5.7% per year): 1811 of the 8574 patients (21.1%) on dapagliflozin and 2151 of 8569 (25.1%) in the control group. Dapagliflozin resulted in a significantly lower hospitalisation rate for heart failure compared to placebo (HR 0.73; 95% CI 0.61-0.88). There was no difference between the dapagliflozin group and the placebo group in the rate of 3P-MACE (8.8 vs. 9.4%; HR 0.93; 95% CI 0.84-1.03; p=0.17), cardiovascular morality (HR 0.98, 95% CI 0.82-1.17) and all-cause mortality (HR 0.93, 95% CI 0.82-1.04). In the renal composite secondary endpoint (≥40% reduction in eGFR, newly-developed terminal renal failure or death of renal or cardiac genesis), dapagliflozin led to a significant reduction in renal endpoints (HR 0.76; 95% CI 0.67-0.87).

Extensive sub-analyses of the DECLARE-TIMI 58 population confirmed the beneficial effects of dapagliflozin on the development and progression of renal [156] [157] [158] and cardiovascular endpoints [159] [160] .

In the detailed post-hoc analysis of the DECLARE-TIMI 58 study, in people with type 2 diabetes and a high cardiovascular risk and relatively low renal risk, dapagliflozin was shown to significantly improve renal outcome parameters: eGFR, chronic and acute time course of decline in eGFR. Dapagliflozin thus showed a beneficial effect on renal function in patients with high cardiac but relatively low renal risk [158] .

In a further post-hoc analysis of the DECLARE-TIMO 58 trial, dapagliflozin was shown to reduce the risk of initial and overall non-elective hospitalisations, regardless of pre-existing cardiovascular, renal, and metabolic causes. These findings are of great importance, among other things, for the quality of life of the study participants as well as for the costs in the health care system [161] .

In the DAPA-HF study, at a median follow-up of 18.2 months of 2373 study participants, the primary composite endpoint of worsening heart failure (hospitalisation or intravenous therapy for heart failure) or cardiovascular death was met in 386 (16.3%) in the dapagliflozin group and 502 (21.2%) in the placebo group: HR 0.74, 95% CI 0.65-0.85; p<0.001. The primary endpoints were comparable between people with (42% of the study population) and without diabetes (HR 0.75, 95% CI 0.63-0.90 vs HR 0.73, 95% CI 0.60-0.88). Dapagliflozin reduced numerous secondary endpoints such as total number of hospitalisations for heart failure (first and recurrent), reduction in all-cause mortality and improvement in quality of life [162] . In the RCT on the influence of dapagliflozin therapy in people with heart failure and preserved ejection fraction (HEpEF), there was a significant improvement in patient-complained symptoms and physical performance according to internationally recognized scores during the 12-week observation period [163] .

In the multicenter DAPA-CKD trial [164] , patients (n=4304; 68% of patients had type 2 diabetes) with an albumin:creatinine ratio of 200-5000 mg/g and an eGFR of 25-75 mL/min were randomised 1:1 to dapagliflozin (10 mg/d) or placebo. The median follow-up was 2.4 years. The primary endpoint was composed of a decrease in eGFR of more than 50%, ESRD, renal or cardiovascular death. Secondary endpoints were the primary endpoint other than cardiovascular death, a composite endpoint of cardiovascular death or hospitalisation for heart failure and all-cause mortality. The relative risk reduction of the primary endpoint was consistent with dapagliflozin between patients with diabetes (HR 0.64, 95% CI 0.52-0.79) and patients without diabetes (HR 0.50, 0.35-0.72). Comparable results were seen for the renal secondary endpoint (0.57 [0.45-0.73] vs 0.51 [0.34-0.75]), cardiovascular death or hospitalisation for heart failure (0.70 [0.53-0.92] vs 0.79 [0.40-1.55]) and all-cause mortality (0.74 [0.56-0.98] vs 0.52 [0.29-0.93]). A post-hoc analysis of the DAPA-CKD study evaluated the efficacy and safety of dapagliflozin at the different stages of renal insufficiency. Of the 4304 participants in the study, 14.4% had a moderately high risk, 31.3% had a high risk, and 54.3% had a very high risk, according to the KDIGO stages [165] . Dapagliflozin reduced the relative risk of worsening renal insufficiency, heart failure, cardiovasular and all-cause mortality across all three levels of kidney disease. This could be observed equally for people with and without diabetes [166] .

In the DELIVER study of 6263 patients with a left ventricular ejection fraction (EF)>40%, taking dapagliflozin 10 mg was followed for a median of 2.3 years. The primary endpoint of the study (worsening of heart failure (HF) or cardiovascular death) was met in 19.5% of the placebo group and 16.4% in the DAPA group: HR 0.82; 95% CI, 0.73-0.92; p<0.001. A worsening of HF was also significantly lower with DAPA (11.8% vs. 14.5%: HR 0.79; 95%). Fewer cardiovascular deaths were also recorded (7.4% vs. 8.3%; NS). These results were comparable to those of EF<<60% between patients with an EF of>60% [167] .

Further results from the DELIVER study showed that DAPA significantly reduced the combined risk (worsening of HF or cardiovascular death) in patients with heart failure and little or no impairment of EF, regardless of age [168] and whether patients had previously been hospitalized for HF [169] . Patients who had an improvement in EF≤40% after>40% (HFimpEF) also benefited from 10 mg DAPA as measured by clinical endpoints such as HF and cardiovascular death [170] .

The DELIVER study also showed that baseline renal function did not reduce the benefit of DAPA in terms of cardiovascular outcomes and that DAPA slowed the decline in eGFR over the 36-month period [171] .

In the meta-analysis of the two major RCTS, DAPA-HF and DELIVER, the authors Jhund PS et al. [172] of the total study participants included (n=11007) with a mean EF of 44%, the risk of cardiovascular death (HR 0.86, 95% (CI) 0.76-0.97; p=0.01), death from other causes (HR 0.90, 95% CI 0.82-0.99; p=0.03), hospitalisation due to HF (RR 0.71, 95% CI 0.65-0.78; p<0.001) and MACE (HR 0.90, 95% CI 0.81-1.00; p=0.045) under DAPA

The meta-analysis by Kawei et al. [173] , compared to GLP-1 RAs, SGLT-2 inhibitors were associated with a significantly lower renal risk in people with and without albuminuria: RR [95% CI]: 0.75 [0.63-0.89] and 0.59 [0.44-0.79].

The 3 SGLT-2 inhibitors empagliflozin (EMPA-REG OUTCOME), canagliflozin (CANVAS programme and CREDENCE trial) and dapagliflozin (DECLARE-TIMI 58) with a total of 38 723 study participants resulted in the meta-analysis by Neuen et al. [174] in a significant risk reduction for dialysis, kidney transplantation or mortality due to renal failure (RR 0.67, 95% CI 0.52-0.86, p=0.0019). SGLT-2 inhibitors also reduced the risk of end-stage renal failure (RR 0.65, 95% CI 0.53-0.81, p<0.0001) and acute renal failure (RR 0.75, 95% CI 0.66-0.85, p<0.0001) across all studies. There was a clear advantage of all 3 SGLT-2 inhibitors across all eGFR subgroups and also independent of the degree of albuminuria at baseline. A recent meta-analysis of 11 trials involving 93 502 patients showed similar beneficial effects of SGLT-2 inhibitors in older people with type 2 diabetes (>65 years) on MACE (HR 0.90; 95% CI 0.83-0.98), hospitalisation for heart failure (HR 0.62; 95% CI 0.51-0.76) and composite renal endpoint (HR 0.57; 95% CI 0.43-0.77) [175] . In the meta-analysis by Bae et al. [176] of 17 trials involving 87 263 patients, SGLT-2 inhibitors significantly reduced renal risks such as microalbuminuria (OR 0.64; 95% CI 0.41-0.93), macroalbuminuria (OR 0.48; 95% CI 0.24-0.72), worsening renal function (OR 0.65; 95% CI 0.44-0.91) and end-stage renal failure (OR 0.65; 95% CI 0.46-0.98) compared with placebo. In the most comprehensive meta-analysis of 736 trials with a total of 421 346 patients, SGLT inhibitors led to robust significant reductions in all-cause and cardiovascular mortality, non-fatal myocardial infarctions, and renal failure, but also, as expected, increased genital infections. SGLT-2 inhibitors had less robust evidence on weight reduction. Weak or no evidence was found for positive effects of SGLT-1 inhibitors on amputations, retinopathy or loss of sight, neuropathic pain, and health-related quality of life. The absolute benefit of SGLT-2 inhibitors was found across a broad spectrum in patients with low and high cardiovascular and renal outcomes [177] .

The 2021 Cochrane review showed that SGLT-2 inhibitors reduced the risk of cardiovascular mortality (OR 0.82, 95% CI 0.70-0.95), all-cause mortality (OR 0.84, 95% CI 0.74-0.96), hospitalisation for heart failure (OR 0.65, 95% CI 0.59-0.71) and incidence of worsening renal insufficiency (OR 0.59, 95% CI 0.43-0.82). However, the risk of myocardial infarction (OR 0.97, 95% CI 0.84-1.12) and stroke (OR 1.12, 95% CI 0.92-1.36) was not reduced [84] . Kaze et al. [166] evaluated (meta-analysis) the safety of SGLT-2 inhibitors in people with renal insufficiency. The risk profile of SGLT-2 inhibitors was evaluated in [Table 5] .

Table 5 Meta-analysis on the safety of SGLT-2 inhibitors in people with renal insufficiency. Data according to [166]

Outcome	Studies (n)	Study population	Events (n)	RR (95% CI)
Genital infections men	2	4091	98	3.89 (1.42−10.62)
Genital infections women	2	2100	53	2.50 (1.32−4.72)
Diabetic ketoacidosis	2	14974	56	3.54 (0.82−15.39)
Volume depletion	4	18832	1016	1.29 (1.13−1.48)
Amputations	4	18832	248	1.21 (0.85−1.72)
Bone fractures	4	18832	475	1.00 (0.84−1.20)
Urinary tract infections	4	18832	1739	1.04 (0.95−1.14)
Acute renal failure	3	8255	197	0.85 (0.66−1.11)
Hyperkalaemia	3	8255	359	0.82 (0.67−1.01)

RR: relative risk; CI: confidence interval.

Empagliflozin

The effects of SGLT-2 inhibitor therapy on clinical endpoints were investigated for empagliflozin in a large RCT published in 2015 (EMPA-REG OUTCOME study [178] ). Patients with type 2 diabetes and already manifested cardiovascular diseases showed fewer cardiovascular events (10.5 vs. 12.1%; HR 0.86; 95% CI 0.74−0.99; p<0.04 for superiority) during an observation period of 3.1 years on average with empagliflozin compared to placebo. There was no difference in the rate of myocardial infarction and stroke, but a significantly lower event rate for cardiovascular mortality (3.7 vs. 4.1%; HR 0.62; 95% CI 0.49-0.77; HR 0.49- p<0.001); for all-cause mortality (5.7 vs. 8.3%; HR 0.68; 95% CI 0.57-0.82; p<0.001) and hospitalisation for heart failure (2.7 vs. 4.1%; HR 0.65; 95% CI 0.50-0.85; p=0.002). The risk of cardiovascular events was greater when cardiovascular risk factors were less well controlled at baseline. The cardioprotective effect of empagliflozin was consistent regardless of the degree of risk factor control [179] . Analysis of recurrent events (including outcome of coronary events, hospitalisation for heart failure, hospitalisation for other reasons) and cardiovascular mortality showed significant reductions with empagliflozin compared to placebo [180] .

Further analyses of the EMPA-REG OUTCOME study [181] showed that empagliflozin slows the development and progression of nephropathy in patients with an eGFR initial of≥30 ml/min: beginning or progression of nephropathy with empagliflozin compared to standard therapy (12.7 vs. 18.8%; HR 0.61; 95% CI 0.53-0.70; p<0.001).

The post-hoc renal endpoint (doubling of S-creatinine, renal replacement therapy, or death from kidney disease) was significantly lower for empagliflozin compared to placebo (HR 0.54; 95% CI 0.40-0.75; p<0.001). In an analysis of the short-term and long-term effects (164 weeks) of empagliflozin on albumin excretion, a significant reduction of 22% on average in the microalbuminuria group and 29% in the macroalbuminuria cohort was observed, irrespective of the level of initial albuminuria [182] . Based on 1738 participants in the EMPA-REG-OUTCOME trial with a history of coronary artery bypass at baseline, empagliflozin reduced the risk of all-cause mortality by 43%, cardiovascular mortality by 48%, hospitalisation rate for heart failure by 50% and nephropathy (onset or worsening) by 35% [183] .

The EMPEROR-REDUCED study [184] included 3730 patients (50% with diabetes) with functional class II, III or IV heart failure and an ejection fraction≤40% were treated with either empagliflozin (10 mg/d) or placebo (1:1) in addition to guideline-guided heart failure therapy. The median duration of the study was 16 months. With empagliflozin, the primary composite endpoint (cardiovascular death or hospitalisation for worsening of heart failure) occurred in 19.4% of patients versus 24.7% with placebo. The hazard ratio was 0.75; 95% CI 0.65-0.86; p<0.001. The effect of empagliflozin on the primary endpoint was independent of whether patients had diabetes or not. The total number of hospitalisations was lower in the empagliflozin compared with the placebo group (HR 0.70; 95% CI 0.58-0.85; p<0.001). The annual decline in eGFR was lower in the empagliflozin vs. placebo group (−0.55 vs. −2.28 ml/min./year; p<0.001). The rate of serious renal complications was also lower with empagliflozin: HR 0.50 (0.32–0.77). In the prospectively collected pre-specified information on patients in the EMPEROR-Reduced Trial, emagliflozin reduced the combined risk of mortality, hospitalisation for heart failure (HF) or acute worsening of HF by 24% compared to placebo (HR 0.76; 95% CI, 0.67–0.87; p<0.0001). After further analyses, the authors concluded that empagliflozin significantly reduced the risk and total number of inpatient and non-stationary HF events after just a few days and lasting over the entire 16-month observation period [185] [186] .

In the post-hoc analysis of the EMPEROR-REDUCED study [187] , the positive effects of empagliflozin on the course of markedly impaired heart failure (HFrEF) were reconfirmed, regardless of pre-existing medication. Therefore, the authors conclude that empagliflozin should be used as a foundational therapy.

The EMPEROR-PRESERVED study evaluated 5988 study patients with heart failure (HF) of stage II-IV and an ejection fraction (EF) of>40%. They were randomised to 1:1 placebo or 10 mg/d EMPA in addition to the usual treatment. The mean follow-up was 26.2 months. The primary endpoint (cardiovascular death or hospitalisation for heart failure) was documented in 13.8% in the empagliflozin group and 17.1% in the placebo group (HR 0.79; 95% CI 0.69-0.90; p<0.001). The effects were comparable for patients with and without diabetes. Total hospitalisations for HF were 27% lower with empagliflozin than with placebo (HR 0.73; 95% CI, 0.61-0.88; p<0,0001) [188] . Empagliflozin showed similarly beneficial effects on HF with HFpEF in women and men [189] .

However, in contrast to the EMPEROR-REDUCED study, no positive renal outcome data were found in the EMPEROR-PRESERVED study with empagliflozin [190] . In a further analysis of the EMPEROR-PRESERVED study, comparable outcome data for heart failure with empagliflozin ranged between 25% and<65%, regardless of the ejection fraction [191] . A recent evaluation in the EMPEROR-Preserved study found that empagliflozin can be used safely and effectively without blood pressure having a significant impact on empagliflozin-induced effects on HF [192] . In the same study, empagliflozin had comparable effects on cardiovascular endpoints, regardless of degree of renal impairment, up to an eGFR of 20 ml/min/1.73m ² [193] .

Patients (n=530; randomisation 1:1 empagliflozin vs placebo) with acute heart failure were treated with an initiation of empagliflozin or placebo immediately after hospitalisation (EMPULSE study). Empagliflozin therapy resulted in a significant benefit for patients regardless of the baseline of HF in terms of clinical symptoms, physical resilience and quality of life. The effect was detected after about 15 days and over the study period of 90 days [194] [195] .

In the EMPA-KIDNEY study, 6609 patients with an eGFR of≥20 to 45 ml/min/1.73m ² or patients with an eGFR of≥45 to<90 ml/min/1.73m ² and a urine albumin: Creatinine ratio of at least 200 randomized and treated with either placebo or 10 mg empagliflozin daily and observed on average for 2 years. The primary endpoint was a composite endpoint (end-stage renal disease, a steady decrease in eGFR after<10 mL/min/1.73 m ² , a steady decrease in eGFR to≥40 10ml/min/1.73m ² from baseline, or death from renal events) or cardiovascular death. This endpoint was met in 13.1% in the empagliflozin group and 16.9% in the placebo group (HR 0.72; 95% CI, 0.64-0.82; p<0.001). The results were consistent in people with or without diabetes. The hospitalisation rate was significantly lower by 14% with empagliflozin. However, there were no significant differences in outcome in terms of hospitalisation for HF, cardiovascular death, or all-cause mortality [196] .

In a recently published comparison, Alnsasra et al. [197] the effects of dapagliflozin versus empagliflozin on cardiovascular death in patients with heart failure throughout the stages of ejection fraction restriction. The NNT to achieve a cardiovascular endpoint event was 100 (95% CI 58-∞) for DAPA in the pooled analysis of the DAPA-HF and DELIVER versus 204 studies (95% CI 71-∞) for empagliflozin in the analysis of the EMPEROR-REDUCED and EMPEROR-PRESERVED studies.

Ertugliflozin

The cardiovascular safety of ertugliflozin was investigated in the VERTIS-CV study. 2750 patients were included in each of the 3 study arms (standard therapy/placebo; 5 mg ertugliflozin, 15 mg ertugliflozin daily) and were followed for approximately 3.5 years. MACE was slightly lower in ertugliflozin groups compared with the placebo group (HR 0.97; 95.6% CI 0.85–1.11; p<0.001 for non-inferiority). Data on cardiovascular death or hospitalisation for heart failure (ertugliflozin vs. placebo: 8.1% vs. 9.1% (HR 0.88; 95.8% CI 0.75–1.03; p=0.11 for superiority), cardiovascular death (0.92 (95.8% CI 0.77–1.11), renal death, renal replacement therapy, or doubling of serum creatinine 0.81 (95.8% CI 0.63-1.04) were also not significant. Amputations were reported in 2% with ertugliflozin (5 mg) therapy and in 1.6% with 15 mg dose. The amputation rate with placebo was also 1.6% [198] . In a post-hoc analysis of the VERTIS MET [199] and VERTIS SU [200] trials, ertugliflozin reduced eGFR in the first 6 weeks but returned to baseline after 104 weeks and therefore resulted in preservation of renal function. The eGFR was slightly higher at both ertugliflozin doses (5 and 15 mg) than in patients who did not receive ertugliflozin. Ertugliflozin significantly reduced albumin excretion rates by 30 and 38% in people who had albuminuria at baseline (21%) [201] . Another analysis of the VERTIS-CV trial showed that at a mean follow-up of 3.5 years, the exploratory composite endpoint (time to doubling of serum creatinine, dialysis (kidney transplantation or renal death) was significantly reduced with ertugliflozin compared with placebo (HR 0.66; 95% CI 0.50-0.88). Renal function and albumin excretion rates were stabilised [202] .

In the VERTIS programme, a number of studies with ertugliflozin were published that analysed combination therapies with metformin, metformin plus sitagliptin, insulin or sulfonylureas, which were recently summarised in a review [203] .

In a sub-analysis of the VERTIS-CV study analysing patients with renal insufficiency (CKD 3a + 3b), renal function remained stable at baseline after 18 weeks of therapy with ertugliflozin [204] . In a recent secondary analysis of the VERTIS-CV study, there were no differences in clinical outcomes when the overall outcome data were broken down with those of the different age groups. Thus, ertugliflozin did not increase the risk of MACE, cardiovascular death or hospitalisation due to heart failure, cardiovascular death alone, or the composite renal endpoint (doubling of serum creatinine, dialysis or transplantation, or renal-related death). Compared to placebo, ertugliflozin reduced the risk of hospitalisation for heart failure and the renal composite endpoint (40% steady decline in eGFR, dialysis, or transplantation, or renal-related death) in the different age groups (50% of study participants were≥65 years, 11%≥75 years). These data are particularly important in view of the growing population of elderly people with type 2 diabetes and cardiorenal diseases [205] . The meta-analysis by Cheng et al. [206] found non-significant positive cardiovascular outcome data of ertugliflozin for myocardial infarction (RR 1.00, 95% CI: 0.83-1.20, p=0.333) and angina pectoris (RR 0.85, 95% CI: 0.69-1.05, p=0.497). Ertugliflozin therapy for more than 52 weeks showed a decrease in eGFR of 0.60 ml/min/1.73 m ² (95% CI: -1.02-0.17, p=0.006). In a metanalysis of the efficacy of SGLT-2 inhibitors in patients with chronic renal insufficiency, sotagliflozin alone was found to significantly reduce the risk of stroke in this cohort (HR 0.73, 95% CI 0.54-0.98) [207] .

Canagliflozin

Outcome RCT data on canagliflozin [130] (CANVAS programme) show a significant reduction in composite endpoint (cardiovascular death, non-fatal myocardial infarction and stroke) with canagliflozin compared with placebo of 14% (HR 0.86; 95% CI 0.75-0.97), decrease in hospitalisation rate due to heart failure of 33% (HR 0.67; 95% CI 0.52-0.87) and renal outcome data with a reduction in the progression of albuminuria by 27% (HR 0.73; 95% CI 0.67-0.79) and composite endpoint (40% reduction in eGFR, renal replacement therapy, renal death) by 40% (HR 0.60; 95% CI 0.47-0.77) [100] . Another large RCT (CREDENCE trial) was conducted with canagliflozin in relation to a primary combined renal endpoint [208] . Patients already had renal insufficiency at randomisation, significant proteinuria and had to be already treated with an ACE inhibitor or AT blocker. Canagliflozin (100 mg per day) was shown to significantly reduce the relative risk of the composite endpoint (dialysis, transplantation or sustained eGFR<15 ml/min), doubling of serum creatinine, death from renal or cardiovascular causes (HR 0.70, 95% CI 0.59-0.82; P = 0.00001). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (HR 0.80, 95% CI, 0.67-0.95) and also a reduced risk of hospitalisation for heart failure (HR 0.61; 95% CI, 0.47-0.80). In the recently published post hoc analysis of the CANVAS programme and the CREDENCE trial, canagliflozin was not associated with a reduction in myocardial infarction in the study populations [209] .

Canagliflozin is currently not available on the German market despite positive patient-relevant endpoints. Therefore, no update of the canagliflozin study data has been made.

Sotagliflozin

Sotagliflozin is a dual SGLT-1 and SGLT-2 inhibitor. In a meta-analysis on the safety and side effects of sotagliflozin in people with type 2 diabetes, SGLT-2 inhibitors showed a well-known increased risk of genital infections in a dose-dependent manner (200 and 400 mg/day) (RR: 2.83, 95% Cl: 2.04-3.93, p<0.001). Sotagliflozin may increase the risk of ketoacidosis (RR: 1.30, 95% Cl: 0.34-4.99, p=0.70). There were other risks of side effects such as diarrhoea and a lack of volume (RR: 1.44, 95% Cl: 1.26-1.64, p<0.001; RR: 1.25, 95% Cl: 1.07-1.45, p<0.01; resp.) [210] .

Two large studies have been published so far for the treatment of type 2 diabetes. In the SOLOIST-WHF trial, people with type 2 diabetes and decompensated heart failure were studied with sotagliflozin (n=608) or placebo (n=614) for a median of 9 months. Mean ejection fraction (EF) was 35% and baseline heart failure therapy was the same in both groups. There was a significant reduction in the composite primary endpoint (cardiovascular death and hospitalisation or acute hospitalisation for heart failure) with sotagliflozin compared with placebo: hazard ratio (HR) 0.67, 95% CI 0.52-0.85, p<0.001). The hazard ratios for cardiovascular death were 0.84 (95% CI, 0.58-1.22) and for all-cause mortality 0.82 (95% CI, 0.59-1.14), slightly lower with sotagliflozin compared to placebo. As the study had to be discontinued due to COVID-19 and a lack of financial support, the calculated event rates were not achieved, so that the data of this study are not sufficiently robust overall [211] .

In the randomised controlled SCORED trial [212] , 10584 patients with type 2 diabetes and renal insufficiency (eGFR 25-60 ml/min.) and cardiovascular risk factors were randomised 1:1 (sotagliflozin:placebo). The median follow-up was 16 months. The primary endpoint was changed during the study to a composite endpoint (all-cause cardiovascular mortality, hospitalisation for or acute care for heart failure). The primary endpoint (cardiovascular death, hospitalisation for heart failure, emergency care for heart failure) was significantly lower with sotagliflozin compared to placebo: HR ratio 0.74; 95%, CI 0.63-0.88; p<0.001). This study also had to be stopped early for financial reasons. In a recent meta-analysis with 11 RCTs and 16441 patients, there was a reduction in myocardial infarction (OR 0.72, 95% CI 0.54-0.97) and heart failure (OR 0.68, 95% CI 0.58-0.79) compared to placebo. However, sotagliflozin showed neutral effects on all-cause mortality, cardiovascular death, and stroke [213] .

Effects of SGLT-2 inhibitors on the liver

In three recently published systematic reviews with meta-analyses, various parameters of liver morphology and function were investigated. Zhou et al. [214] analysed studies on liver fibrosis and stiffness using the FibroScan. Both measurement parameters improved significantly with SGLT-2 inhibitors compared to other antidiabetic drugs, with longer-term RCTs missing. In the extensive analysis of Gu et al. [215] in patients with type 2 diabetes and NAFLD positive effects on liver function (alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase) and on morphological parameters of hepatic steatosis (LSM, CAP) were found under therapy with dapagliflozin and GLP-1 RAs. The authors also came to comparable results with regard to SGLT-2 inhibitors in another systematic review, although the data do not yet allow definitive conclusions due to the shortness of the investigations and the study sizes [216] .

Summary of the effects of SGLT-2 inhibitors on cardiovascular and renal endpoints

Clinically relevant effects of SGLT-2 inhibitors on all-cause mortality as well as on cardiovascular and renal endpoints in corresponding risk populations have been demonstrated and confirmed in numerous meta-analyses [217] [218] [219] [220] [221] [222] [223] [224] [225] [226] [227] [228] [229] [230] . The latest meta-analyses on the effect of SGLT-2 inhibitors on cardiorenal endpoints also confirm the previous extensive evaluations [231] [232] [233] [234] [235] .

A systematic review with meta-analysis of real-world studies (34 studies from 15 countries; study participants total n=1494373) showed that SGLT-2 inhibitors were associated with a 46% lower risk of renal insufficiency (HR 0.54, 95% CI 0.47-0.63). SGLT-2 inhibitors were associated with a lower risk of renal insufficiency when compared with DPP4 inhibitors and other glucose-lowering antidiabetic drugs (HR 0.50, 95% CI 0.38-0.67 and HR 0.51, 95% CI 0.44-0.59, respectively). When the positive effects of SGLT-2 inhibitors were compared with the effects of GLP-1 RAs, no significant differences were found (HR 0.93, 95% CI 0.80-1.09) [236] .

An equally systematic review with metanalysis including 76 studies with a total of 116,375 participants showed neither a risk reduction nor an accumulation of carcinomas (RR 1.03; 95% CI, 0.96-1.10) and cancer mortality (RR 0.99; 95% CI, 0.85-1.16) [237] .

The underlying mechanisms of cardiac and renal protection of SGLT-2 inhibitors are the subject of extensive studies [238] [239] [240] [241] [242] .

GLP-1 receptor agonists (RAs)

GLP-1 RAs are antidiabetic drugs for the subcutaneous or oral therapy of type 2 diabetes. They can on average lower plasma glucose more than classic oral antidiabetics and also have blood pressure-lowering (slight), weight-reducing [243] and specific cardiorenal protective (see below) effects. If the individual therapeutic objective is not achieved, GLP-1 RAs are useful combination partners to metformin, other OADs (except DPP4 inhibitors) and/or basal insulin. GLP-1 RAs themselves have a low hypoglycaemic risk. It has proven useful to distinguish between short- and long-acting GLP-1 RAs. Short-acting GLP-1 RAs have a relatively short elimination half-life and are injected at least once daily. Nevertheless, there are periods in the course of a 24-hour day that are characterized by ineffective, very low circulating concentration of the active ingredient. The concentrations thus fluctuate rapidly between "negligibly low" and "highly effective". Long-acting GLP-1 RAs, on the other hand, are characterized by relatively small fluctuations over the course of the day (or week). After a few hours, this leads to a weakening of the effect on gastric emptying (tachyphylaxis) [244] , which is only marginally affected after a few weeks, while this effect is always maintained in short-acting GLP-1 RAs [244] [245] . The significance of the differentiation between short- and long-acting GLP-1 RA lies in the different influence on postprandial glucose increases, which are reduced either by a permanent delay in gastric emptying (short-acting GLP-1 RAs) or, to a lesser extent, by stimulation of insulin secretion and suppression of glucagon secretion (long-acting GLP-1 RAs).

Short-acting GLP-1 RAs

Approved in Germany: exenatide, lixisenatide (only in fixed combination with insulin glargine).

Long-acting GLP-1 RAs

Approved in Germany: Dulaglutide, exenatide LAR, liraglutide, semaglutide. Not available in Germany: albiglutide, efpeglenatide.

Short-acting GLP-1 RAs

Exenatide

In the EXSCEL study 14 752 patients (73.1% with cardiovascular disease) were treated at a mean of 3,2 years with 2.0 mg exenatide once a week. Patients with or without cardiovascular disease showed no significant difference in the incidence of MACE between those who received exenatide or a placebo. Critical for the evaluation of the effects in the EXSCEL study is the very high dropout rate of over 40%. Compared to the control group, there were no differences in cardiovascular mortality, non-fatal or fatal myocardial infarction or stroke, hospitalisation for heart failure and incidence of acute pancreatitis, pancreatic carcinoma, medullary thyroid carcinoma or other serious side effects [246] .

In the EXSCEL study, the benefits of exenatide, namely risk reduction in all-cause mortality (-14%) and first hospitalisation for heart failure (-11%), could only be seen in study participants who did not have heart failure at baseline [247] [248] . The risk reduction for all-cause mortality was confirmed in a recent meta-analysis [249] .

The combination of exenatide (1 × weekly) plus dapagliflozin resulted in a significant reduction in HbA1c (-1.7 vs. -1.29%) compared to exenatide plus placebo; dapagliflozin plus placebo decreased HbA1c by -1.06% over the same 104-week period. There were also clinically-relevant positive changes for fasting glucose, 2-h postprandial glucose, body weight and systolic blood pressure. Severe hypoglycaemia was not observed in any of the treatment arms [250] .

In the meta-analysis by Bethel et al. [251] , the 4 large RCTs ELIXA (lixisenatide), LEADER (liraglutide), EXSCEL (exenatide 1 × weekly) and SUSTAIN 6 (semaglutide) were evaluated. Compared with placebo, GLP-1 RAs showed a significant risk reduction (HR 0.90; 95% CI 0.82-0.99; p=0.033) in the primary endpoint (cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke), a relative risk reduction (RRR) of 13% for cardiovascular mortality (HR 0.87; 95% CI 0.79-0.96; p=0.007) and for all-cause mortality of 12% (HR 0.88; 95% CI 0.81-0.95; p=0.002). However, the statistical heterogeneity between the studies was large. No significant reductions were found by GLP-1 RAs for non-fatal or fatal myocardial infarction, stroke, hospitalisation for unstable angina or heart failure.

Exenatide 1 × weekly resulted in a significant reduction in albumin excretion of 26 rel.% (95% CI -39.5 to -10) compared with a control group. Compared with oral antidiabetics, the reduction in albuminuria was -29.6% (95% CI -47.6 to -5.3); with insulin therapy, the value was -23.8 rel.% (95% CI -41.8 to -0.2) [252] .

A study in children and adolescents (age 10 –<18 years; n=83, observation period: 24 weeks) with type 2 diabetes were randomized (5:2) to receive exenatide 2 mg 1 ×/week or placebo after previous therapy was inadequate. HbA1c decreased by –0.36% in the exenatide group and increased by +0.49% in the placebo group. The group difference was – 0.85%; 95% CI –1.51, –0.19; p=0.012. Body weight decreased by –1.22 kg (–3.59, 1.15; p=0.307). Side effects were less with exenatide than with placebo: 36 (61.0%) and 17 (73.9%) [253] .

In a recent detailed review, the data for the DURATION 1-8 and EXSCEL studies were very well summarised because although therapy with exenatide 1× weekly (2 mg) is safe, there is a very limited indication in patients with high cardiorenal risk, especially since other GLP-1 RAs showed clearly positive effects on the mentioned risks [254] .

Lixisenatide

After this GLP-1 RA showed only non-inferior effects on cardiovascular endpoints in the ELIXA study [255] and was thus inferior to other GLP-1 RAs, the combination of insulin glargine with lixisenatide (iGlarLixi) was then investigated [256] . In a meta-analysis, 8 studies (study duration: 24-30 weeks) with 3538 participants were evaluated. In this analysis, iGlarLixi was superior to therapy with combination insulin: -0.50%- units (95% CI -0.93 to -0.06), basal bolus therapy -0.35% (-0.89 to + 0.13) and basal plus therapy -0.68% (-1.18 to -0.17). When compared with combi-insulin therapy, there were fewer symptomatic hypoglycaemias and less weight gain. Analyses of cardiovascular or renal endpoints were not reported.

In one RCT, the combination of iGlarLixi was discontinued compared to GLP-1 RA therapy (liraglutide, dulaglutide, albiglutide or exenatide) over 26 weeks after randomisation. HbA1c decreased more markedly in the iGlarLixi group compared to the GLP-1 RA group, although the body weight increased under iGlarLixi ((+1.7±3.9 kg). Fasting and postprandial insulin decreased significantly with a 35% improvement in ß-cell sensitivity to glucose [257]

The SoliMix study evaluated the safety and efficacy of iGlarLixi versus BIAsp 30 in people with type 2 diabetes. In the open-label study over 26 weeks, 887 study participants were randomised 1:1. The HbA1c of the included patients was≥7.5% to≤10.0% (≥58 to≤86 mmol/mol). Patients treated with basal insulin plus OADs were compared for 26 weeks with those receiving therapy with iGlarLixi (1×/day) or BiAsp 30 2×/day. PROs (patient-related outcomes) were identified using specific questionnaires: Treatment-Related Impact Measure Diabetes (TRIM-D) and Global Treatment Effectiveness Evaluation (GTEE) questionnaires. The study showed that, in addition to better metabolic control, body weight was more favourable and fewer hypoglycaemias occurred with iGlarLixi. Also, the PROs were better with iGlarLixi compared to therapy with BIAsp 30 [258] .

Long-acting GLP-1 RAs

Liraglutide

In a randomised trial in obese patients, liraglutide resulted in greater weight loss than placebo in all intensively-treated patients compared to placebo: liraglutide (3 mg/d) compared to physical activity alone: 8 weeks after a low-calorie diet resulted in a weight loss of 13.1 kg. At the end of the study (after one year), weight loss with increased physical activity was -4.1 kg (95% CI -7.8 to -0.4; p=0.03); in the liraglutide group -6.8 kg (95% CI -10.4 to -3.1; p<0.001); in the combination physical activity plus liraglutide -9.5 kg (95% CI -13.1 to -5.9; p<0.001). The combination therapy also resulted in a 3.9% reduction in body fat mass, which was approximately 2-fold higher than in the physical activity group (-1.7%; 95% CI -3.2 to -0.2; p=0.02) and in the liraglutide group alone (-1.9%; 95% CI -3.3 to -0.5; p=0.009) [259] . For the GLP-1 receptor agonist (RA) liraglutide, the RCT (LEADER trial) showed positive effects on clinically relevant endpoints [260] . The median follow-up of the 9340 patients was 3.8 years. The composite primary endpoint (first event for cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) was significantly lower with liraglutide compared with placebo (13 vs. 14.9%; HR 0.87; 95% CI 0.78-0.97; p<0.001 for noninferiority and p=0.01 for superiority). Fewer patients died from cardiovascular causes (4.7 vs. 6.0%; HR 0.78; 95% CI 0.66-0.93; p=0.007). All-cause mortality was also lower with liraglutide (8.2 vs. 9.6%; HR 0.85; 95% CI 0.74-0.97; p=0.02). Thus, for the first time, a positive effect on patient-relevant outcomes could also be demonstrated for a GLP-1 RA in an RCT.

A sub-analysis of the LEADER study population showed that 72% of patients had vascular disease at baseline. 23% of this subpopulation had polyvascular disease and 77% had monovascular disease. Liraglutide led to a reduction in MACE at 54-month follow-up: in polyvascular disease (HR 0.82; 95% CI 0.66-1.02) and in monovascular disease (HR 0.82; 95% CI 0.71-0.95) compared with placebo. No positive effects of liraglutide were found in patients without vascular complications [261] . The analysis by Marso et al. [262] , which demonstrated a reduction in myocardial infarctions with liraglutide in patients at high vascular risk, points in the same direction. In the meta-analysis published by Duan et al. in 2019 [263] , patients in the liraglutide group compared with controls were found to have lower risks of: MACE (RR 0.89, 95% CI 0.82-0.96, p=0.002), acute myocardial infarction (RR=0.85, 95% CI 0.74-0.99, p=0.036), all-cause mortality (RR 0.84, 95% CI 0.74-0.96, p=0.009) and cardiovascular death (RR 0.77, 95% CI 0.65-0.91, p=0.002). However, the incidence of stroke was not reduced in the liraglutide group (RR 0.86, 95% CI 0.70-1.04, p=0.124).

In the analysis of secondary renal endpoints in the LEADER study, liraglutide was associated with a lower rate of development and progression of the renal composite endpoint (HR 0.78; 95% CI 0.67-0.92; p=0.003) and persistence of macroalbuminuria (HR 0.74; 95% CI 0.60-0.91; p=0.004) compared with placebo [264] .

A pooled analysis of the data from the SUSTAIN 6 (semaglutide s. c.; duration 2.1 years) and the LEADER study (liraglutide; 3.8 years) showed a significant reduction in albuminuria of 24% (95% CI, 20%-27%) compared to placebo over the 2-year period. With semaglutide (1 mg) and liraglutide, the loss of eGFR was significantly slowed, with the effect greater when eGFR was<60 ml/min vs.>60 ml/min. The protective effect of both GLP-1 RAs was greater in people with pre-existing chronic kidney disease [265] .

A post-hoc analysis of the LEADER study investigated whether a higher annual rate of hypoglycaemia (defined as self-measured plasma glucose of<3.1 mmol/l; 56 mg/dl; level 1 hypoglycaemia) led to frequent severe hypoglycaemia (condition requiring outside assistance; level 2 hypoglycaemia). At the same time, the association of hypoglycaemia with cardiovascular outcome was examined. There was a clear association between the incidence of level 1 hypoglycemia (2-11 per year vs. 12 per year) and level 2 hypoglycaemia: adjusted HR 5.01 [95% CI, 2.84-8.84]. In patients with level 1 hypoglycaemia (>12 episodes per year), there was a clear association with MACE (HR 1.50 [95% CI, 1.01-2.23]), cardiovascular death (HR 2.08 [95% CI, 1.17-3.70]) and all-cause mortality (HR 1.80 [95% CI, 1.11-2.92]). It must therefore be the goal not only to register severe hypoglycaemia, but also to document and prevent it [266] .

In the LIRA-PRIME study, patients who had inadequate metabolic control with metformin (mean HbA1c 8.2%) were randomised under real-world conditions. One group was randomized to liraglutide and the control group to OAD. Depending on the preference of the attending physician, the following OADs were prescribed: SGLT-2 inhibitor (48%), DPP4 inhibitor (40%), sulfonylurea (11%), thiazolidinediones (1.1%) or alpha-glucosidase inhibitor (0.5%). The observation period was longer for liraglutide than for OADs (109 vs 65 weeks). Changes in HbA1c and body weight were significantly better with liraglutide than with OAD. Hypoglycaemia rates were comparable in both groups [267] .

The meta-analysis by Kristensen et al. [268] showed a significant reduction in MACE of 12% (HR 0.88; 95% CI 0.82-0.94; p<0.0001) with GLP-1 RA. The hazard ratios were 0.88 (95% CI 0.81-0.96; p=0.003) for death from cardiovascular events, 0.84 (95% CI 0.76-0.93; p<0.0001) for fatal and non-fatal stroke, and 0.91 (95% CI 0.84-1.00; p=0.043) for non-fatal and fatal myocardial infarction. GLP-1 RA resulted in a 12% reduction in all-cause mortality (HR 0.88; 95% CI 0.83-0.95; p=0.001) and a 9% reduction in hospitalisation for heart failure (HR 0.91; 95% CI 0.83-0.99; p=0.028). The composite renal endpoint (development of new macroalbuminuria, reduction in eGFR, progression to ESRD) decreased by 17% (HR 0.83; 95% CI 0.78-0.89; p<0.0001), mainly due to the reduction in albuminuria. No increased risk of hypoglycaemia, pancreatitis or pancreatic carcinoma was reported with GLP-1 RA.

The very detailed and critical meta-analysis by Liu et al. also came to a comparable conclusion [269] . All-cause mortality was slightly lower under GLP-1 RAs compared to control therapies: OR 0.89 (95%-KI 0.80-0.98).

The association of GLP-2 RAs with renal events under real-world conditions was analysed in a large Scandinavian study [270] . 38 731 users of GLP-1 RAs (liraglutide 92.5%, exenatide 6.2%, lixisenatide 0.7%, dulaglutide 0.6%) were studied 1:1 in a propensity-matched control group taking DPP4 inhibitors. The primary composite endpoint (renal replacement therapy, renal-related death and hospitalisation for renal complications) was significantly lower with GLP-1 RA than with DPP4 inhibitor therapy: HR 0.76 (95% CI 0.68-0.85). In particular, renal replacement therapy (HR 0.73, 95% CI 0.62-0.87) and hospitalisation rates (HR 0.73, 95% CI 0.65-0.83) were significantly lower with GLP-1 RA.

In a large study, the GRADE Study Group compared 4 antidiabetic drugs (insulin glargine U-100, glimepiride, liraglutide, or sitagliptin) in people with type 2 diabetes under "inadequate" metformin treatment (=basal HbA1c mean 7.5% [6.8-8.5%]) (n=5047; duration of diabetes<10 years; observation period 5 years). The primary endpoint was an HbA1c of≥7.0%. The cumulative incidence rate differed within the study arms: for insulin glargine 26.5 per 100 patient-years; for liraglutide 26.1; glimepiride 30.4 and for sitagliptin 38.1. For patients with higher baseline HbA1c levels, the benefit was substantially greater for all 4 study arms. Severe hypoglycaemia was rare but markedly higher with glimepiride and insulin glargine (2.2% vs 1.3%) and markedly lower with liraglutide (1.0%) and sitagliptin (0.7%). Overall, the metabolic benefits for liraglutide were highest [271] . In the same study, microvascular and cardiovascular endpoints were analysed. There were no significant differences in the incidence of arterial hypertension and dyslipidaemia and microvascular parameters (albuminuria, eGFR and peripheral neuropathy). The treatment groups also did not differ in rates for MACE, hospitalisation for heart failure, and cardiovascular death. However, there were discrete differences in the area of cardiovascular disease with a rate of 1.9, 1.9, 1.4, and 2.0 in the study arms for insulin glargine, glimepiride, liraglutide, and sitagliptin, respectively. [272] . However, SGLT-2 inhibitors and newer GLP-1 RAs were not tested in this extensive RCT.

Effects of liraglutide on the liver

A recent systematic review with meta-analysis of 16 RCTs with 845 patients showed that liraglutide leads to a significant and safe reduction of visceral and ectopic liver fat [273] .

Dulaglutide

In the AWARD trial programme, dulaglutide was shown to be effective in lowering blood glucose and weight, and for a low incidence of hypoglycaemia when used as monotherapy and in combination with prandial and basal insulin. Patients with various degrees of chronic renal insufficiency were also included [274] . The multi-centre (371 study centres in 24 countries), randomised, double-blind placebo-controlled study on the cardiorenal effects of dulaglutide therapy (REWIND study; 1.5 mg s.c. weekly) was recently published [275] , [276] . Included were 9901 patients with type 2 diabetes (mean age 66 years, mean HbA1c 7.2%). This study differs from the previously published studies on the cardiovascular and renal outcome under GLP-1 RA in the following important points: longer observational period (mean 5.4 years), 69% of the study participants had cardiovascular risk factors, but no clinically manifested cardiovascular pre-illnesses and the ratio between women and men was fairly balanced (46% women). Compared to placebo, dulaglutide was able to reduce the mean HbA1c baseline value of 7.2% over the entire study (HbA1c: –0.46% for dulaglutide, + 0.16% for placebo; body weight: –2.95 kg dulaglutide, –1.49 kg placebo). In addition, dulaglutide showed a reduction of the secondary combined microvascular endpoint (HR 0.87; 95% CI 0.79-0.95), with this reduction predominantly affecting the renal outcome (HR 0.85; 95% CI 0.77-0.93; p=0.0004). The primary endpoint 3P-MACE was significantly lower with dulaglutide (HR 0.88; 95% CI 0.79-0.99; p=0.026), as was the risk of nonfatal stroke (HR 0.76; 95% CI 0.61-0.95; p=0.017). No risk reductions were found for the following endpoints: non-fatal and fatal myocardial infarction, fatal stroke, cardiovascular death, all-cause mortality, and hospitalisation for heart failure. Compared to placebo, dulaglutide did not show any differences with regard to relevant side effects: Cancer (pancreatic, medullary thyroid carcinoma, other thyroid carcinomas), acute pancreatitis or pancreatic enzyme elevations, liver diseases, cardiac arrhythmias and hypoglycaemia rate.

In an explorative analysis of the REWIND data [276] renal outcome data concerning dulaglutide, a significant risk reduction for the summarized renal endpoint (new macroalbuminuria, eGFR reduction of≥30% or chronic renal replacement therapy; HR 0.85; 95% CI 0.77-0.93; p=0.0004) was determined with the clearest effect with respect to the macroalbuminuria component (HR 0.77; 95% CI 0.68-0.87; p<0.0001).

In a post-hoc analysis of the REWIND trial, the incidence of MACE (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) or non-cardiovascular death was 35.8 per 1000 person years in the dulaglutide group and 40.3 per 1000 person years in the placebo group (HR 0.90, 95% CI 0.82-0.98, p=0.020). The incidence data on more complex MACE (MACE plus heart failure, unstable angina or revascularisation) were more impressive: dulaglutide vs. placebo 67.1 vs. 74.7 per 1000 person years: HR 0.93 (95% CI 0.87-0.99) p=0.023 [223] .

The outcome of the REWIND study in terms of cardiovascular endpoints was comparable regardless of whether patients had metformin therapy at baseline: The composite endpoint of non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, or death from unknown causes showed no statistically significant differences: with metformin vs. without metformin: HR 0.92 (95% CI, 0.81-1.05) vs. with metformin 0.78 (0.61-0.99; Interaction: p=0.18) [277] .

In a post-hoc analysis of the REWIND study with a median follow-up of 5.4 years, there was no reduction in heart failure (HF) events with dulaglutide compared to placebo (4.3% vs. 4.6%; HR 0.93, 95% CI, 0.77-1.12; p=0.456). In the study participants with heart failure at baseline (8.6%), there were no changes in MACE and HF events with dulaglutide in patients with and without HF. Dulaglutide did not lead to a reduction in HF events regardless of the status of HF at baseline [278] .

The AWARD-PEDS double-blind study examined young people (age: 10 –<18 years; BMI],>85th percentile; n=154) with type 2 diabetes randomized 1:1:1 (lifestyle modification alone or with metformin: with or without basal insulin: 1×/week dulaglutide 0.75 or 1.5 mg s.c.). The safety profile of dulaglutide was comparable to that in adults. Dulaglutide resulted in better metabolic control at both doses: Over the 26 weeks, more participants in the DULA group had HbA1c<7.0% (51% vs. 14%, p < 0,001) and fasting glucose decreased by 18.9 mg/dl and increased by 17.1 mg/dl in the control groups; ( p<0.001). BMI progression showed no differences between the study groups [279] .

Semaglutide

Semaglutide s. c

Semaglutide 1 × weekly s. c. showed a greater HbA1c reduction (-0.4%) and weight loss (-2.5 kg) compared to other GLP-1 RAs [280] .

In the STEP-1 study with semaglutide (1 × weekly s. c.), a mean weight loss of -14.9% was observed in the observation period of 68 weeks compared to placebo of only -2.4%. The difference in weight loss of -12.4% was highly significant. More patients in the semaglutide group than in the placebo group achieved weight losses of≥5% (86.4 vs. 31.5%),≥10% (69.1 vs. 12.0%) and≥15% (50.5 vs. 4.9%), all of which were highly significant with a p=0.001 [281] . The STEP 3 and STEP 4 trials showed similar favourable effects of semaglutide on weight progression [282] [283] .

In the SUSTAIN-6 trial, cardiovascular benefit was demonstrated by significant reduction in the primary endpoint 3P-MACE compared to the control group. In patients with a high cardiovascular risk, there was a significant risk reduction (HR 0.74; 95% CI 0.58-0.95) for the primary endpoint (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) in the semaglutide group compared to placebo [284] . In the recently published post-hoc analysis of the SUSTAIN-6 study, semaglutide 1 × weekly s.c. vs. placebo was found to reduce the risk of MACE in all study participants regardless of sex, age or cardiovascular risk profile at baseline [285] .

The subcutaneous administration of semaglutide showed significantly better weight loss in the analysis of a systematic review compared to liraglutide, exenatide and dulaglutide: 1 mg semaglutide resulted in a greater weight difference than 2 mg exenatide (-3.78 kg [95 CI -4.58, -2.98], p<0.0001), 1.2 mg liraglutide (-3.83 kg [95 CI −4.57 to -3.09], p<0.0001) and 1.5 mg dulaglutide (-3.55 kg [95 CI -4.32 to -2.78], p<0.0001). In contrast, tirzepatide (dual GIP/GLP-1 receptor c,o-agonist) was associated with more significant weight differences compared to 1 mg semaglutide at all doses: 5 mg −1.9 kg [95 CI -2.8 to -1.0], p<0001), 10 mg -3.6 kg [95 CI -4.5 to -2.7], p<0001), 15 mg -5.5 kg [95 CI -6.4 to -4, 6], p<0 0,001 [286] .

Oral semaglutide

In the PIONEER-6 trial of oral semaglutide 1 × daily (n=3183 patients, 84.7%>50 years with cardiovascular or chronic renal complications; mean observation time 15.9 months) the following results were found: MACE was found in 3.8% in the oral semaglutide and 4.8% in the placebo group (HR 0.79; 95% CI 0.57-1.11; p<0.001 for non-inferiority); cardiovascular death (HR 0.49; 95% CI 0.27-0.92); non-fatal myocardial infarction (HR 1.18; 95% CI 0.73-1.90); non-fatal stroke (HR 0.74; 95% CI 0.35-1.57); all-cause mortality (HR 0.51; 95% CI 0.31-0.84) [287] . In the meta-analysis published in 2020, oral semaglutide was shown to reduce the risk of all-cause mortality (OR 0.58; 95% CI 0.37-0.92) and cardiovascular mortality (OR 0.55; 95% CI 0.31-0.98) compared with placebo. However, it showed a neutral effect with regard to myocardial infarction, stroke and severe hypoglycaemia [288] .

In the SUSTAIN program (semaglutide 1.0 mg 1 × weekly s.c.), HbA1c decreased by 1.0%-1.8% more markedly than with sitagliptin, liraglutide, exenatide (extended release), dulaglutide, cangliflozin and insulin glargine. In the PIONEER program, semaglutide 14 mg decreased 1× weekly orally by 1.0–1.4% more than sitagliptin, empagliflozin and comparable to liraglutide over the 26-week observation period. While semglutide s.c. reduced body weight more markedly than all comparator substances, oral semaglutide showed an advantage over sitagliptin and liraglutide, but not over empagliflozin [289]

In a new analysis, it was reported that in the PIONEER program (PIONEER 1-5, 7 and 8) the changes in HbA1c and body weight from baseline were significantly greater with oral semaglutide and the odds ratio for the target HbA1c<7.0% for semaglutide (14 mg flex) comparable to semaglutide 7 mg and more favourable to the comparator therapies (empagliflozin, liraglutide, sitagliptin). In Asian patients, the reduction in HbA1c was greater than in other ethnic groups (−1.5% to −1.8% vs. −0.6% to −1.6%). Gastrointestinal adverse reactions were significantly more common with oral semaglutide compared to all other comparator substances [290] . In a combined post-hoc analysis of the two cardiovascular outcome trials SUSTAIN 6 and PIONEER 6, the effect of semaglutide was analysed in patients with a continuum of initial cardiovascular risk. Thereby, semaglutide showed a significant absolute and relative risk reduction of MACE (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) across the spectrum of cardiovascular risk compared to comparator therapies. This was also found for the individual components of MACE [291] .

However, in the recent re-analysis of the SUSTAIN 6 and PIONEER 6 studies [292] , the authors placed the analyses in a broader context to the results of the other studies SUSTAIN 1-5 and PIONEER 1–5, 7–8. The hazard ratio for MACE was 0.85 with a wide confidence interval (95% CI: 0.55–1.33) because of the low event rates in most studies.

Treatment with GLP-1 RAs or SGLT-2 inhibitors was associated with significantly lower all-cause mortality compared with DPP4 inhibitors or other antidiabetic drugs or no therapy in the meta-analysis by Zheng SL et al. (HR 0.88; 95% CI 0.81–0.94 and/or HR 0.80; 95% CI 0.71–0.89, respectively). Similar data were also found for cardiovascular mortality as well as myocardial infarction and heart failure compared to the control groups [293] .

In the meta-analysis of the GLP-1 RAs exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide and semaglutide published in 2017, there was a significant reduction in the incidence of nephropathy compared with other antidiabetic drugs (OR 0.74; 95% CI 0.60-0.92; p=0.005) [294] . The post-hoc analysis of the SUSTAIN 1-7 trials of Mann et al. [295] showed that semaglutide initially led to a reduction in eGFR in normal and mildly impaired renal function (in the SUSTAIN 6 trial with 1.0 mg semaglutide). From week 30 onwards, there was no difference in eGFR between the semaglutide vs. placebo groups in the SUSTAIN 1–5 and SUSTAIN 7 trials and at week 104 for SUSTAIN 6. In the SUSTAIN 1–6 trials, albuminuria decreased in patients with microalbuminuria and macroalbuminuria. In patients with normoalbuminuria, there was no difference in albuminuria from the beginning to the end of the study.

Oral empagliflozin and semaglutide show comparable cardiovascular mortality risks. The annual NNT (Number Needed to Treat) for empagliflozin in the EMPA-REG-OUTCOME study was 141 (95% CI, 104–230) and for oral semaglutide in the PIONEER 6 study was also 141 (95% CI, 95–879). However, the cost of the two treatment options is significantly cheaper for empagliflozin, so this fact should certainly play a role in the therapy decision [296] .

Compared to placebo, oral semaglutide (7 and 14 mg) resulted in a reduction in HbA1c of 1.06% (95% CI, 0.81–1.30) and 1.10% (95% CI, 0.88–1.31) in a recent meta-analysis of 11 RCTs with 9821 patients, respectively. Compared to other antidiabetic drugs, semaglutide resulted in a reduction in HbA1c of 0.26% (95% CI, 0.15–0.38) and 0.38% (95% CI, 0.31–0.45) respectively. The higher dosage of semaglutide (14 mg) did not increase the incidence of discontinuation of medication due to gastrointestinal adverse reactions [297] .

The effects of semaglutide after s.c. and oral administration on ischemic central nervous system complications were evaluated in the SUSTAIN 6 and PIONEER 6 studies. Of a total number of study participants (n=6480), 106 had a stroke (1 event/100 patient years of the observation period (PYO). Semaglutide reduced stroke incidence compared to placebo (0.8 vs. 1.1 event/100 PYO; HR 0.68 [95% CI, 0.46–1.00]; p=0.048) mainly due to the reduction of the risk of small vessel occlusion: 0.3 vs. 0.7 events/100 PYO; HR 0.51 [95% CI, 0.29–0.89]; p=0017). The hazard ratio for risk for each form of ischaemia was 0.60 (95% CI, 0.37–0.99) with semaglutide therapy compared with placebo [298] . In a metanalysis of 28 RCTs with 74 148 patients, the authors found that there was a significant reduction in the risk of ischaemic stroke for dulaglutide and semaglutide (s.c. and oral) in particular compared to placebo (RR 0.83; 95% CI, 0.76–0.91; I2=0%). This was particularly seen in people with shorter diabetes duration and higher eGFR [299] .

Semaglutide and G-BA

In a detailed statement by the German Diabetes Society (DDG), the German Society of Cardiology (DGK), the German Society for Atherosclerosis Research (DGAF), the German Ophthalmological Society (DOG), the Retinological Society (RG), the Professional Association of Ophthalmologists (BVA), the Research Group Diabetes e.V. at Helmholtz Zentrum München, and the Federal Association of Registered Diabetologists (BVND) on the dose assessment (A20-93, version 1. 0, status 28.1.2021) of the Institute for Quality and Efficiency in Health Care (IQWiG) on the benefit assessment of semaglutide in the form of a subcutaneous application as well as in an oral dosage form for the treatment of patients with type 2 diabetes mellitus, the experts of the professional societies came to the conclusion that the negative assessment of semaglutide (oral and s. c.) by IQWiG is unjustified [www.deutsche-diabetes-gesellschaft.de/politik/stellungnahmen/]. Nevertheless, with the decision of the Federal Joint Committee of 15.04.2021, no additional benefit was granted to semaglutide (BAnz AT 02.06.2021 B5).

Albiglutide

Safety and cardiorenal outcome data have been published for albiglutide [300] [301] . Cardiovascular outcome data on albiglutide (HARMONY outcomes trial [302] ) were analysed and published in 2018. At that time, albiglutide had already been withdrawn from the market worldwide (July 2017). The HARMONY trial enrolled and randomised 9463 patients (albiglutide 30-50 mg, n=4731; placebo n=4732). The median observation period was only 1.6 years. There was no evidence of a difference in major adverse events between the two study arms. In the 3P-MACE, a significant risk reduction with albiglutide (HR 0.78; 95% CI 0.68-0.90; non-inferiority p=0.0001, superiority p=0.0006) was already evident after this short study duration.

In a recent publication, the authors reported that albiglutide was able to completely replace prandial insulin in 54% of study participants in patients with type 2 diabetes on baseline bolus insulin therapy, with concomitant improvement in metabolic control, reduction of hypoglycaemia and body weight [303] .

Since albiglutide is not commercially available in Germany, no update of the studies has been carried out.

Efpeglenatide

Efpeglenatide is an exendin-based GLP-1 RA that has recently been studied in large RCTs (multi-centre and international) in 4076 patients with type 2 diabetes and a history of cardiovascular disease or renal insufficiency (eGFR 25.0 to 59.9 ml/min) plus another cardiovascular risk factor. Patients were randomised 1:1:1 (efpeglenatide 4 mg: efpeglenatide 6 mg: placebo) and analysed after a median observation period of 1.8 years. The primary endpoint was MACE. This was found in 7.0% with efpeglenatide and 9.2% with placebo: HR 0.73; 95% CI 0.58-0.92; p<0.001 for non-inferiority; p=0.007 for superiority. The composite renal endpoint (reduction in eGFR or macroalbuminuria) was found in 13% in the efpeglenatide group and 18.4% in the placebo group: HR 0.68; 95% CI 0.57-0.79; p<0.001) [304] .

Analysis of the effect of efpleglenatide in combination with an SGLT-2 inhibitor (initially no vs. one SGLT-2 inhibitor) compared to placebo revealed a markedly reduced MACE of HR 0.74 [95% CI, 0.58-0.94] vs. 0.70 [0.37-1.30], renal composite endpoint HR 0.70 [0.59-0.83] vs. 0.52 [0.33-0.83]) and MACE or death HR 0.74 [0.59-0.93] vs. 0.65 [0.36-1.19]). The conclusion of the AMPLITUDE-O study is that the efficacy and safety of efpeglenatide appears to be independent of concomitant medication and thus the combination of both modes of action makes sense [305] .

In the AMPLITUDE-O study, Gerstein et al. found that at a mean follow-up of 1.8 years, efpeglenatide significantly reduced MACE compared to placebo in a dose-dependent manner: at 6 mg efpeglenatide 35% (HR, 0.65 [95% CI, 0.5-0.86]; p=0.0027), and at 4 mg 18% (HR, 0.82 [95% CI, 0.63-1.06]; p=0.14). The higher dose of efpeglenatide also improved the secondary endpoint MACE, coronary revascularisation, hospitalisation for unstable angina with an HR of 0.73 (p=0.011). Renal composite endpoint (newly developed macroalbuminuria,≥40% reduction in eGFR or end-stage renal disease) also improved: HR, 0.63 for 6 mg, p<0.0001; HR, 0.73 for 4 mg, p=0.0009).

Combination peptides in the near future (dual or tri-agonists that can activate multiple receptors)

Tirzepatide (dual GIP/GLP-1 receptor co-agonist)

Tirzepatide is a dual receptor agonist (RA) that can bind to and activate both GIP receptors (preferred) and GLP-1 receptors [307] . Tirzepatide is a linear peptide with 39 amino acids borrowed from either the sequence of glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1) or exendin-4 (carboxyl-terminus) [308] . A few positions are occupied by alpha-aminobutyric acid or freely chosen amino acids. Tirzepatide has a side chain consisting of a di-fatty acid with 20 carbon atoms, which mediates binding to albumin in a similar way as liraglutide and semaglutide. Tirzepatide combines the effects of both origin peptides in a new molecule [309] [310] . In the recently published results of the RCT SURPASS 1 study, tirzepatide was superior at all doses (5 mg, n=121; 10 mg, n=121; 15 mg, n=121) compared to placebo (n=115) at the end of the study (40 weeks): mean HbA1c decreased by 1.87% (20 mmol/mol), 1.89% (21 mmol/mol), and 2.07% (23 mmol/mol Hb) respectively from baseline. There was no increased risk of hypoglycaemia. With placebo, the value increased by 0.04% (+ 0.4 mmol/mol Hb). Tirzepatide resulted in a dose-dependent weight loss of 7.0 to 9.5 kg [311] . When comparing metabolic effects, tirzepatide was not inferior to semaglutide, but superior in terms of reduction of HbA1c and body weight [312] . As the first peptide of a new substance class, another therapy option will soon be available for the treatment of type 2 diabetes, obesity and fatty liver [313] , [314] .

In a pre-determined cardiovascular meta-analysis including all 7 RCTs (SURPASS program) with intervention data of>26 weeks, the time to the 1st event of MACE-4 (cardiovascular death, myocardial infarction, stroke, hospitalisation due to unstable angina) was calculated between tirzepatide and the comparator substances (insulin degludec, insulin glargine, semaglutide (1 mg) or dulaglutide (1.5 or 0.75 mg). The HRs were for tirzepatide versus comparator substances: MACE-4 0.80 (95% CI, 0.57-1.11), cardiovascular death 0.90 (95% CI, 0.50-0.61), and all-cause mortality 0.80 (95% CI, 0.51-1.25) [315] . In the 7 RCTs used for further meta-analysis, tirzepatide showed a reduction in mean plasma glucose, albeit relatively small, compared to the comparator therapies, significantly better weight loss compared to GLP-1 RAs of between 1.7 kg (tirzepatide 5 mg) and 7.2 kg (tirzepatide 15 mg). Hypoglycaemia rates were comparable to placebo but significantly lower than with basal insulin. Specifically, with a tirzepatide dose of 15 mg, there was increased nausea OR 5.60 [95% CI, 3.12-10.06], vomiting OR 5.50 [95% CI, 2.40-12.59]) and diarrhoea OR 3.31 [95% CI, 0.40-7.85]. Premature cessation of tirzepatide therapy was therefore more common [316] .

In the first Cochrane analysis of tirzepatide, 6 RCTs (n=3484 patients) were included [317] . In this analysis, tirzepatide had significantly more favourable effects on plasma glucose (prandial and postprandial), HbA1c, lipid profile and, in particular, on weight development compared to dulaglutide, semaglutide, insulin degludec and insulin glargine over a period of one year. However, due to data heterogeneity and publication bias, the authors graded the previous data moderate to low.

Benefits of GLP-1 RAs and SGLT-2 inhibitors on cardiovascular and renal endpoints

A recent systematic review using meta-nalysis and meta-regression evaluated the cardiovascular and renal benefits of GLP-1 RAs with the exception of tirzepatide [318] . For this purpose, 34 reports from 22 RCTs were analysed (9 GLP-RAs, 13 SGLT-2 inhibitor studies). These included 154 649 study participants (mean age 62-72 years). All RCTs had a low risk of bias. The results can be found in the [Table 6] , which show the absolute benefit of GLP-1 RAs and SGLT-2 inhibitors depending on initial cardiovascular risk. According to the authors' calculations, the number needed to high vascular risks is 9 and the highest 5-year absolute risk reduction for heart failure was seen in patients with the highest cardiovascular risk on SGLT-2 inhibitors and was 11.6% [318] .

Table 6 Cardiovascular and renal benefits under therapy with GLP-1 receptor agonists and SGLT-2 inhibitors compared to placebo in a recent extensive meta-analysis [318] .

Endpoints		Hazard ratio (95% CI)	Absolute risk reduction,% (5 years)
Cardiovascular mortality	GLP-1 Ras	0.87 (0.80−0.96)	1.16
	SGLT-2 inhibitor	0.86 (0.81−0.92)	1.33
MACE	GLP-1 Ras	0.87 (0.79−0.97)	2.18
	SGLT-2 inhibitor	0.88 (0.82−0.95)	2.12
Hospitalisation for heart failure	GLP-1 Ras	0.89 (0.81−0.99)	0.8
	SGLT-2 inhibitor	0.70 (0.67−0.74)	4.25
Connected renal endpoint	GLP-1 Ras	0.84 (0.73−0.97)	0.98
	SGLT-2 inhibitor	0.65 (0.58−0.74)	2.57

CI: confidence interval; GLP-1 RAs: glucagon-like peptide-1 receptor agonists; SGLT-2: sodium-dependent glucose co-transporter 2.

Safety aspects of GLP-1 RAs

Retinopathy remained unchanged among GLP-1 RAs except for semaglutide, which had a negative effect on changes in the ocular fundus (OR 1.75; 95% CI 1.10-2.78; p=0.018) [319] . Whether this is related to the rapid optimisation of the metabolism is being discussed [320] . In addition, only patients with pre-existing retinopathy were affected. A corresponding study was initiated to clarify the retinopathy risk when using semaglutide (Clinical-Trials.gov number, NCT03 811 561). However, the meta-analysis by Avgerinos et al. on oral semaglutide showed no evidence of a higher rate of retinopathy [288] . The meta-analyses by Sattar [320] , by Bethel et al. [321] and Wang et al. [322] also found no higher risk of retinopathy among GLP-1 RAs. Also in the AngioSafe T2D study, the authors affirm that GLP-1 RA showed no effect on angiogenesis and no association of GLP-1 RA exposure on severe retinopathy [323] .

A recently published meta-analysis of 13 RCTs found that GLP-1 RAs (including liraglutide, semaglutide and dulaglutide) were associated with an increased risk of rapid worsening of diabetic retinopathy: OR 1.23, 95% CI 1.05-1.44. The association was significant in subgroups of RCTs with a longer study duration (52 weeks) (OR 1.2, 1.00-1.43). The association was not significant in study participants in RCTs from different countries (OR 1.2, 0.99-1.46) or patients with diabetes duration≥10 years (OR 1.19, 0.99-1.42) [324] .

Pancreatitis and cholecystolithiasis as well as neoplasms:

Of 113 studies included in the analysis by Monami et al. [325] , 13 found no data on pancreatitis. No pancreatitis or pancreatic carcinoma events were reported in 72 studies. In the remaining studies (n=28), the incidence of pancreatitis and pancreatic carcinomas with GLP-1 RAs was comparable with the comparative drugs (pancreatitis OR 0.93; 95% CI 0.65-1.34; p=0.71; pancreatic carcinomas OR 0.94; 95% CI 0.52-1.70; p=0.84). However, the risk for gallstones was increased (OR 1.30; 95% CI 1.01-1.68; p=0.041). In the comprehensive analysis of RCTs published in 2020 with incretin-based therapies (SAVOR-TIMI 53 (saxagliptin), EXAMINE (alogliptin), TECOS (sitagiptin), ELIXA (lixisenatide), and with liraglutide in LEADER and semaglutide in SUSTAIN-6) no significant risk increase for pancreatitis and pancreatic carcinoma for GLP-1 RA could be found in contrast to therapies with DPP4 inhibitors [326] . In the meta-analysis by Cao et al. there was also no evidence for an increased cancer risk under therapy with GLP-1 RAs [327] . In the meta-analysis published in 2018 by Bethel et al. [321] , there were no differences in pancreatitis, pancreatic carcinoma and medullary thyroid carcinoma in patients treated with GLP-1 RA therapy compared to participants treated with placebo. In addition, the large multinational population-based cohort study with 1 532 513 patients included in the period from January 1, 2007 to June 30, 2013, and followed up until June 30, 2014, showed no association of a higher risk for pancreatitis among incretin-based therapies compared to other OADs [328] . These data are consistent with the results of a meta-analysis of real-world data, which also found no evidence of a higher risk for pancreatitis among incretin-based therapies [329] .

The rate of cholangiocarcinoma was not increased with incretin-based therapy in a large cohort study [330] . A recent meta-analysis also found no evidence for a higher risk of breast neoplasia with GLP-1 RA therapy [331] .

In the meta-analysis of 14 observational studies, Hidayat et al. [332] showed no association between GLP-1 RA therapies and an increased risk of carcinoma. Thus, when all data were combined, no increased risk of pancreatic carcinoma was demonstrated (RR 1.04, 95% CI 0.87, 1.24). The particular problems of the included studies are short observation periods (≤5 years) and a high risk of bias due to confounding factors.

Incretin-based therapies and fatty liver

Non-alcoholic fatty liver (NASH) is a risk factor for the manifestation of type 2 diabetes, is commonly present in people with type 2 diabetes and is associated with higher morbidity and mortality. In a recent study with an observation period of 72 weeks, 380 patients with NASH and fibrosis F2 and F3 were randomised to receive semaglutide s. c. (0.1 mg; n=80 or 0.2 mg; n=78 or 0.4 mg; n=82) or placebo (n=80). In contrast to placebo, regression of fatty liver without progression of fibrosis was found with semaglutide: 40% in the 0.1 mg group, 36% in the 0.2 mg group and 59% in the 0.4 mg group. In the placebo group, the improvement was only 17% ( p<0.001 for semaglutide 0.4 mg vs. placebo). However, neoplasia (benign, malignant or unspecified) was found in 15% of patients in the semaglutide group and 8% in the placebo group, with no specific organ manifestations observed [333] .

In a sub-study of the SURPASS-3 study, 296 patients were randomized to therapy with tirzepatide 5 mg, n=71; tirzepatide 10 mg, n=79; tirzepatide 15 mg, n=72; and insulin degludec, n=74). The baseline data (demographic and clinical) were similar. The initial liver fat content (LFC) was 15.7%. At 52 weeks, the data of patients on tirzepatide 10 and 15 mg were pooled (LFC: -8.1%) and compared with the insulin degludec group (LFC: 3.4%). The difference of -4.7% was significant (95% CI -6.72 – -2.70; p<0.0001). Tirzepatide also reduced visceral fat, abdominal subcutaneous fat, and body weight. However, these changes were not significant [334] .

In the recently updated S2k Guideline Non-Alcoholic Fatty Liver Disease of the German Society for Gastroenterology, Digestive and Metabolic Diseases, the following was recommended with a strong consensus [335] :

• Due to the favourable effects on NASH, glucagon-like peptide 1 (GLP-1) analogues, e. g., liraglutide or semaglutide, should be used in non-cirrhotic NAFLD patients with type 2 diabetes (metformin plus).

• The use of sodium-dependent glucose transporter 2 (SGLT-2) inhibitors, e. g., empagliflozin and dapagliflozin or the thiazolidinedione pioglitazone, can be considered in these patients.

• Patients with NASH-associated liver cirrhosis and type 2 diabetes can receive metformin in patients with Child-Pugh score A compensated liver cirrhosis and normal renal function.

More up-to-date information on the individual GLP-1 RAs in the context of NAFLD can be found in the discussion of the individual GLP-1 RAs.

Combination of GLP-1 receptor agonists and SGLT-2 inhibitors

Compared with GLP-1 RA monotherapy, 7 studies of combination therapy of GLP-1 RA/SGLT-2 inhibitors (n=1913 patients) showed a 0.61% lower HbA1c value (95% CI -1.09% to -0.14%, 4 studies), reduced body weight (-2.59 kg, -3.68 to -1.51 kg, 3 studies) and a reduction in systolic blood pressure (-4.13 mmHg, -7.28 to -0.99 mmHg, 4 studies). Compared with SGLT-2 inhibitor monotherapy, the combination of GLP-1 RA/SGLT-2 inhibitors showed a reduction in HbA1c of 0.85%, -1.19% to -0.52%, 6 studies) and systolic blood pressure (-2.66 mmHg, -5.26 to -0.06 mmHg, 6 studies). Body weight was unchanged in 5 analysable studies (-1.46 kg, -2.94 to 0.03 kg). Combination therapy did not lead to increased severe hypoglycaemias. Data on clinical endpoints were insufficient [336] . Three case-control studies investigated the association of therapy with SGLT-2 inhibitors, GLP-1 RAs and their combination with the risk of MACE (major cardiovascular, heart failure and cerebral events). The data are from England and Wales (primary care data from the Clinical Practice Research Datalink and Secure Anonymised Information Linkage Databank with linkage to hospital and mortality records). Each patient with a MACE was matched with up to 20 control subjects. Of the 336 334 people with type 2 diabetes without cardiovascular disease, 5.5% developed MACE. In a type 2 diabetes cohort of 411 206 people without heart failure (HF), 4.4% had HF. Compared to other regimens, adjusted pooled OR (95% CI) was found for MACE with SGLT-2 inhibitor 0.82 (0.73, 0.92), with GLP-1 RAs 0.93 (0.81, 1.06), and with the combination of SGLT-2 inhibitors plus GLP-1 RAs 0.70 (0.50, 0.98). Comparable data were obtained for the HF: SGLT-2 inhibitors 0.49 (0.42, 0.58), GLP-1 RA 0.82 (0.71, 0.95), and SGLT-2i/GLP-1 RA 0.43 (0.28, 0.64) [337] .

Insulins

With the manifold possibilities of oral antidiabetic therapy with or without combination with GLP-1 RAs, insulin therapy can in many cases be postponed to later stages of the disease. However, a necessary insulin administration should not be delayed by years, as can sometimes be observed [338] . Insulin therapy can be easily combined with other antidiabetics, and the large number of insulins and injection aids facilitates individualisation of the therapy.

An extensive discussion on new insulins, however, would go far beyond the scope of this clinical practice guideline but comprehensive reviews was recently published as a contribution to 100 years of insulin [339] [340] [341] .

Therefore, the authors have concentrated on a few aspects of new insulin preparations in the clinical practice guidelines.

Basal insulin analogues

Insulin degludec (n=3818) is not inferior to insulin glargin 100 (n=3819) in the therapy of people with type 2 diabetes and a high risk of cardiovascular events in terms of MACE. The HbA1c values were identical in both groups over the observational period of 2 years (7.5±1.2%), but the fasting plasma glucose values were significantly lower under insulin degludec. The hazard ratio was 0.91 (95% CI 0.78-1.06) for the primary endpoint (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke). By contrast, the rate of severe hypoglycaemia (secondary endpoint) was significantly lower for insulin degludec (4.9%) than for insulin glargin 100 (6.6%) (hazard ratio 0.60; 95% CI 0.48-0.76; p<0.001). The rate of severe side effects such as benign and malignant neoplasia was comparable (DEVOTE study [342] ). In the DEVOTE study, it was shown once again that confirmed severe hypoglycaemia was associated with an increased rate of all-cause mortality in a period of 15-365 days before the clinical endpoint [343] .

Pharmacokinetic and pharmacodynamic studies have shown that insulin glargin 300 has a flatter efficacy profile, lasts slightly longer and has a lower day-to-day variability than insulin glargin 100. Metabolic control was comparable for both insulin types, while the rate of nocturnal hypoglycaemia was significantly lower for insulin glargin 300 than for insulin glargin 100 [344] [345] [346] .

In the DELIVER PROGRAMME, the electronic health data (real-world data) of people with type 2 diabetes who received insulin glargine 300 were compared with those treated with insulin glargine 100, insulin detemir or insulin degludec [347] . Like insulin degludec, Gla-300 showed better blood glucose-lowering efficacy compared to Gla-100 or insulin detemir and significantly lower rates of hypoglycaemia. Thus, the same positive metabolic effects were found under real-world conditions as with RCTs.

Biosimilar insulin glargin 100:

Pharmacokinetics and -dynamics are comparable for insulin glargin 100 and biosimilar insulin glargin 100 in people without and with type 2 diabetes [348] [349] . In the meta-analysis by Yamada et al. [350] , there were no differences between biosimilar insulins and the original insulins in terms of HbA1c value, fasting plasma glucose, hypoglycaemia, injection site reactions, insulin antibodies, allergic reactions, and mortality.

When comparing different insulin analogues (insulin glargin and insulin degludec) with human insulin, a large cohort study from Denmark, Finland, Norway, Sweden and Great Britain found no evidence of an increased carcinoma risk, neither for insulin glargin nor for insulin degludec compared to human insulin for the 10 examined carcinomas in a mean observational period of 4.6 years [351] .

Nauck et al. [352] recently performed an analysis on the head-to-head comparison of IBGLMs (short- and long-acting GLP-1 RAs and tirzepatide) and basal insulins (NPH, glargine, detemir, degludec). The primary endpoint was the difference in HbA1 reduction between the two substance groups. The secondary endpoints were fasting plasma glucose, body weight, HbA1c, hypoglycaemia, blood pressure, and lipids. In all studies (n=20) with a total of 11843 patients, there was a reduction in HbA1c of 0.48% (0.45-0.52) more with IBGLMs than with basal insulins. This effect was particularly evident with the long-acting GLP-1 RAs and tirzepatide (pooled doses: ΔHbA _1c -0.90 [-1.06; -0.75]. Short-acting GLP-1 RAs were comparably effective to basal insulin (p=0.90). All IBGLM subgroups resulted significantly in lower body weight (-4.6 [-4.7; -4.4] kg), in particular tirzepatide (-12.0 [-13.8-10] kg). They reduced hypoglycaemia, blood pressure, and improved dyslipidaemia. The risk of bias was low in all studies. IBGLM led to increased side effects with a higher incidence of nausea, vomiting and a higher discontinuation rate of the corresponding drug. Based on the analyses, the authors again underline that in the event of therapy escalation to injectable drugs, IBGLMs should be considered first instead of basal insulins.

Insulin icodec:

This insulin analogue is designed for 1×-weekly injections. The prolonged effect and clearance of this insulin was achieved by binding albumin to a C20 fatty acid side chain of insulin and substitution of 3 amino acids of the insulin molecule (A14E, B16H and B25H). This resulted in pharmacokinetic/pharmacodynamic properties with a mean half-life of 196 hours and a uniform glucose-lowering profile over one week [353] . In one of the first RCTs for 26 weeks with 1×/week insulin icodec, this insulin resulted in a safety profile and blood glucose reduction comparable to that of insulin glargine U 100 [354] . Similar effects were also reported by Bajaj et al. [355] . In the ONWARDS program (1-5), several RCTs on the effects of insulin icodec in people with type 2 diabetes have been set up and some have already been published. For example, in the randomised (1:1), open-label international study over 26 weeks (ONWARDS 4 Trial), comparable improvements in plasma glucose control parameters were found under insulin icodec when comparing the effects of insulin icodec 1× weekly versus insulin glargine U 100 1× daily in combination with 2-4 daily insulin aspart injections. This was associated with fewer basal insulin injections, lower doses of bolus insulin without increased rates of hypoglycaemia with insulin icodec [356] . The meta-analysis by Ribeiro et al. [357] with 3 studies comparing insulin icodec with insulin glargine, it also shows that insulin icodec was associated with a reduction, albeit small, in HbA1c and a higher time-in-range (TiR) at a comparable rate of hypoglycaemia compared with insulin glargine U 100. In the randomised, open-label ONWARDS 2 study, the effects of insulin icodec were compared with those of insulin degludec [358] . People with type 2 diabetes on basal insulin treatment with OAD were switched to insulin degludec or insulin icodec. During the 26-week follow-up period, there was a significant improvement in HbA1c in both treatment arms, with slight superiority in the reduction of HbA1c for insulin icodec associated with a small weight gain, as well as a statistically non-significant increase in level 2 and 3 hypoglycaemias.

Combination of long-acting insulin plus GLP-1 RA

The fixed combination of long-acting insulin plus GLP-1 RA or free simultaneous or consecutive combinations have advantages over intensified insulin therapy with prandial and basal insulin in terms of therapy adherence, rate of hypoglycaemia, weight progression and insulin usage. Compared to intensified insulin therapy, however, gastrointestinal side effects were more frequent with GLP-1 RA [359] [360] [361] . In a recent meta-analysis, the authors concluded that combinations of basal insulin with long-acting GLP-1 RA were superior to combinations of basal insulin with short-acting GLP-1 RA in terms of weight reduction, HbA1c value reduction, lower fasting glucose values and benefits in terms of gastrointestinal side effects [362] .

In a comparative study of insulin glargine 100 with the GLP-1 RA lixisenatide (iGlar-Lixi) with the combination of biphasic insulin aspart 30 (30% insulin aspart and 70% insulin aspart protamine) over 26 weeks, iGlar-Lixi was superior to the insulin fixed combination: HbA1c -0.2% [97.5%, CI -0.4-0.1], body weight -1.9 kg [95% CI, -2.3-1.4]). The incidence and rate of hypoglycaemia (levels 1 and 2) was significantly lower with iGlar-Lixi [363] .

The first fixed combination approved in Germany is insulin glargine (100 I.U./ml) and lixisenatide (see above).

Fast-acting insulin analogues

Insulin lispro 200 shows potential advantages for a higher concentrated insulin especially in cases of severe insulin resistance (e. g., obesity), since less volume has to be injected with the same amount of insulin. Compared to insulin lispro 100, insulin lispro 200 showed also significant improvements in variability of fasting glucose, HbA1c, hypoglycaemia rate and satisfaction with therapy. At the same time, a reduction of 20% insulin was possible [364] .

Ultra-fast insulin aspart is absorbed by the blood twice as fast and thus has an approximately 50% higher insulin effect with significantly lower postprandial blood glucose values, especially in the first 30 min after injection. The faster onset of action means that glucose is even better controllable, especially in people with type 1 diabetes and those on insulin pump therapy [365] . Ultra-fast insulin aspart showed a similar reduction of HbA1c (observation time 26 weeks) compared to insulin aspart in people with type 2 diabetes (ONSET 2 trial); the 1-hour postprandial glucose values were significantly lower after injection of fast insulin aspart, but not 2-4 h after a test meal. The total rates of severe hypoglycaemia were not different between the two insulins. However, the relative risk of hypoglycaemia 0-2 h postprandially was significantly higher with fast insulin aspart (RR 1.60; 95% CI 1.13-2.27) [366] .

The insulin effect of ultrafast-acting insulin lispro (URLI=Ultra Rapid Lispro insulin) led to significantly better postprandial glucose control, regardless of whether this insulin was injected s.c. before, during or after the meal (–15 to + 15 minutes) [367] . Postprandial glucose excursions over 5 hours were reduced by 29% to 105% with URLI. Recent data on the more favourable pharmacokinetics and dynamics of URLI compared to insulin lispro have been published for subcutaneous injection and continuous administration in patients with type 1 and type 2 diabetes [368] .

Conflict of Interest

R. Landgraf, as first author, declares the following potential conflicts of interest: Advisory boards: Lilly Deutschland, Novo Nordisk Pharma; lecture fees: Lilly Deutschland, Novo Nordisk. Other activities: Trustee of the German Diabetes Foundation, member of the steering group for the development and updating of the National Healthcare Guidelines on Diabetes.J. Aberle declares that he has received fees as a member of advisory committees and as a speaker from: Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co, Merck Sharp & Dohme, Novo Nordisk, Sanofi. Institutional research funding: Boehringer Ingelheim.As co-author, B. Gallwitz declares the following potential conflicts of interest in the last 3 years: Advisory boards/consultant activities: AstraZeneca, Bayer Vital, Boehringer Ingelheim, Eli Lilly & Co., Merck Sharp & Dohme, Novo Nordisk; lecture fees: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly & Co., Merck Sharp & Dohme, Novo Nordisk.Company shares: none.As co-author, M. Kellerer declares the following potential conflicts of interest: Research Support (RCT): AstraZeneca, Lilly, Novo Nordisk. Membership in advisory bodies: Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Lilly, Merck Sharp & Dohme, Novo Nordisk, Sanofi. Lecture fees: Bayer, Boehringer Ingelheim, BMS, Novartis, Merck Sharp & Dohme, Novo Nordisk.As co-author, H. H. Klein declares the following potential conflicts of interest: Advisory body: Janssen Cilag, Boehringer Ingelheim, Novartis; Lecture fee: Berlin-Chemie.As co-author, D. Müller-Wieland declares the following potential conflicts of interest: Member of the advisory board and lecture fees over the last 3 years of the following companies: Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, Roche Diabetes Care, Sanofi.M. A. Nauck, as co-author, declares the following potential conflicts of interest: Membership of advisory committees or consultant fees: Berlin Chemie, Eli Lilly & Co., Merck Sharp & Dohme, Novo Nordisk, Regor, ShouTi (Gasherbrum); lecture fees: Berlin Chemie, Boehringer Ingelheim, Eli Lilly & Co., Medscape, Merck Sharp & Dohme, Novo Nordisk, research support: Eli Lilly & Co., Merck Sharp & Dohme, Novo Nordisk.T. Wiesner is a member of the respective advisory boards and has received lecture fees from the following companies: Amgen, AstraZeneca, Boehringer Ingelheim, Lilly, Merck Sharp & Dohme, Sanofi, Berlin Chemie; Novo Nordisk. E. Siegel, as a co-author, declares that he has had no economic or personal connections with the manuscript during the last 3 years.

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Publication History

Article published online:
10 April 2024