Position Paper on Lipid Therapy in Patients with Diabetes Mellitus

Introduction

Patients with diabetes mellitus generally have a significantly increased cardiovascular risk. For this reason, lipid therapy and a reduction in LDL cholesterol based on risk stratification are an integral part of diabetes therapy; the following position paper should therefore also be viewed as a topic-related supplement to the annually updated recommendation for the treatment of type 2 diabetes and should also be updated annually in future together with the DDGʼs practical recommendations.

The recently published guidelines and recommendations of the European Society of Cardiology (ESC), the European Atherosclerosis Society (EAS), the American Association of Clinical Endocrinologists (AACE), the American Diabetes Association (ADA) and the American National Lipid Society (NLA) [1] [2] [3] [4] [5] form the basis for the information contained below.

This position paper is therefore to be understood as a short, current, clinically-oriented recommendation for action in patients with diabetes; for in-depth explanations on lipid metabolism and the use of lipid disorders, please refer to the literature provided.

Stratification of Cardiovascular Risk

Patients with diabetes mellitus usually have a significantly increased cardiovascular risk [6]. It is nonetheless recommended to break this risk down further. The same risk factors apply as for patients without diabetes ([Table 1]). It should be noted that the presence of several risk factors has a cumulative effect on the overall risk [7]. The estimated overall risk is an essential determinant of whether and, if so, how intensively a lipid-lowering therapy should be carried out.

Table 1 Further risk factors to be considered.

Risk factor	Comment
Positive family history for premature atherosclerosis events	Atherosclerotic events before the age of 55 or 65 in men and women respectively; this age limit is currently not evidence-based and should possibly be shifted upwards in the future in view of increasing life expectancy.
Nicotine abuse	Number of “pack years” is relevant.
Impaired renal function	The impairment of kidney function leads to an increase in the risk of atherosclerosis depending on the dosage.
HDL cholesterol reduction	Inverse risk factor in population studies; low HDL-C especially increases CV risk; frequent with high triglycerides
Hypertriglyceridemia	Independent risk factor; probably also as an indicator for elevated non-HDL cholesterol with atherogenic remnant particles	Elevated blood pressure values	> 130/85 mmHg or with antihypertensives

Lipid Diagnostics

The basis is made up of the determination of total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides as well as the calculation of the of the non-HDL cholesterol level.

The lipoprotein(a) value should be determined once only. If there is no hypertriglyceridemia and the LDL cholesterol is determined directly, the determination can be carried out in a non-fasting state [8]. If the LDL cholesterol is calculated using the Friedewald formula, the patient should be fasting as the triglyceride level is included in the calculation. Genetic diagnosis is clinically justified in cases of high suspicion of familial hypercholesterolemia, if this has consequences for the indication and therapy strategy.

Lipid Phenotype

A distinction is made between hypercholesterolemia, hypertriglyceridemia and combined hyperlipidaemia. Clinically, secondary causes must be excluded or treated and important primary disorders, e. g. familial hypercholesterolemia, must be considered ([Table 2]).

Table 2 Classification of lipid metabolic disorders.

Lipid disorder	Cholesterol	Triglyceride	LDL chol	HDL chol	non-HDL chol
LDL hypercholesterolemia	↑	n	↑	n	↑
Hypertriglyceridemia	↑	↑	n	↓	↑
Combined hyperlipoproteinemia↑	↑	↑	↑	↓	↑
Isolated HDL cholesterol reduction↑	n	n	n	↓	↑
Lipoprotein(a) increase	Can occur in isolation or in combination with any lipid metabolism disorder.

n=not changed.

Treatment of Lipid Metabolism Disorders in Patients with Diabetes Mellitus

The primary goal of the treatment is to reduce the increased cardiovascular risk of patients with diabetes mellitus. The most important measure is the reduction of LDL cholesterol. Furthermore, the risk of acute pancreatitis can be reduced by lowering excessively elevated triglyceride levels. Normalization of elevated triglyceride levels can also improve blood glucose control ([Table 3]).

Table 3 Treatment targets for lipid metabolism disorders.

Treatment	Clinical effect	Evidence
LDL cholesterol reduction	Reduction of atherosclerosis events	Proven
Non-HDL cholesterol reduction	Reduction of atherosclerosis events	Proven
Lowering of lipoprotein(a)	Reduction of atherosclerosis events	Presumed
Decrease triglycerides	Reduction of atherosclerosis events	Presumed
Reduction of highly elevated triglycerides	Reduction of the incidence of acute pancreatitis	Proven

Therapy Strategies Aimed at Lowering LDL Cholesterol Levels

In accordance with the recommendations of the European specialist societies, the reduction of LDL cholesterol levels is “target value-oriented”, taking into account the cardiovascular risk [1]. A distinction is made between 3 categories that apply equally to patients with type 1 and type 2 diabetes mellitus ([Table 4]).

Table 4 Lipid target values in patients with diabetes mellitus.

		Primary goal	Secondary targets
Risk group	Definition	LDL chol	Non-HDL chol	ApoB
Very high risk	Proven atherosclerosis and/or additional serious risk factors1 and/or end organ damage2 or early manifested type 1 diabetes with long diabetes duration (>20 years)	≥ 50 % reduction and target<55 mg/dl (1.4 mmol/l) * ”ideal” target; clinically “good.” at<70 mg/dl (1.8mmol/l)	<85 mg/dl (2.2 mmol/l)	<65 mg/dl
High risk	Without proven atherosclerosis, without terminal organ damage2 with diabetes duration>10 years or other risk factors	<70 mg/dl (1.8 mmol/l) and ≥ 50 % reduction of initial value	<100 mg/dl	<80 mg/dl
Moderately increased risk	Young patients with type 1 diabetes (<35 years) and type 2 diabetes (<50 years) with diabetes duration<10 years and no other risk factors	<100 mg/dl (2.6 mmol/l)	<130 mg/dl (3.4 mmol/l)	undefined

For patients at the age of ≤ 30 years and without indications for vascular damage or microalbuminuria, it seems reasonable to wait until the age of 30 years before beginning a statin therapy.¹ Hypertension, nicotine abuse, severe dyslipoproteinemia ² E.g. microalbuminuria, retinopathy or neuropathy * This addition to a clinical evaluation by the author group of this practical recommendation is based on the fact that the evidence for a further effective absolute risk reduction when comparing LDL-C values in treatment between<70 mg/dl and<55 mg/dl is still low and depends very much on the individual patient risk.

Secondary target values are the concentrations of non-HDL cholesterol and apolipoprotein B. This reflects the fact that probably all lipoproteins containing apolipoprotein B are atherogenic [9].

The non-HDL cholesterol value (=total cholesterol minus HDL cholesterol) also approximately reflects this and includes VLDL cholesterol and remnant cholesterol in addition to LDL cholesterol. The non-HDL cholesterol target value is therefore relevant in patients with hypertriglyceridemia or mixed hyperlipidaemia (typically in patients with diabetes mellitus).

In normotriglyceridemia the VLDL/remnant cholesterol concentration is<30 mg/dl (which corresponds to a triglyceride value of approximately 150 mg/dl), which is why non-HDL cholesterol target values are each 30 mg/dl above the LDL cholesterol target value ([Table 4]). For patients who meet the LDL cholesterol target but not the non-HDL cholesterol target, the non-HDL cholesterol level can be achieved by either lowering the triglyceride level (reduction of VLDL/remnant cholesterol) or further reducing the LDL cholesterol.

In addition, it should be mentioned that the American Diabetes Association (ADA) solely considers the age criteria (under/over 40 years) and presence of atherosclerosis (yes/no) [5]. All patients with atherosclerosis receive a high dose of statin (atorvastatin 40–80 mg/d or rosuvastatin 20–40 mg/d) and can also be treated with ezetimibe and PCSK9 inhibitors if the LDL cholesterol level remains above 70 mg/dl. For patients without atherosclerosis, those under 40 years of age do not generally receive a statin and those over 40 years of age receive a moderate statin dose (e. g. atorvastatin 20 mg/d or rosuvastatin 10 mg/d).

Even if, at first glance, there are clear differences between the ADA and ESC recommendations, in both cases the fact is that the vast majority of patients with diabetes mellitus should be treated with statins.

In order to achieve the ESC target values mentioned above, a gradual therapy of statins, ezetimibe and PCSK9 antibodies can be used ([Fig. 1]) [10]. After excluding or treating secondary causes of hyperlipidaemia, statins are used as the therapy of choice. If, despite a sufficient dose, this is not sufficient to achieve the individual target value, the next step is to combine it with ezetimibe and, as a third step, to combine it with PCSK9 inhibitors, especially in cases of clinical progression of cardiovascular disease.

Fig. 1 Therapy algorithm to achieve the LDL cholesterol target values. LSM: Lifestyle measures; * according to the G-BA; ** as per individual benefit-risk assessment.

According to the decision of the Federal Joint Committee/ Gemeinsamen Bundesausschuss (G-BA), PCSK9 inhibitors must be prescribed by a doctor of internal medicine with a specialization in cardiology, nephrology, endocrinology, angiology or by a special lipid outpatient clinic and can then be prescribed by the family doctor. As a last option, regular lipoprotein apheresis therapy is also possible, however, this should only be used when all other drug approaches have been exhausted. If the clinical indication is LDL apheresis, the G-BA decision is that the administration of a PCSK9 inhibitor is considered an alternative and economical option. In patients who are already on lipoprotein apheresis therapy primarily to lower LDL cholesterol, the administration of a PCSK9 antibody should reduce the apheresis frequency and even aim to terminate this therapeutic concept [11].

Therapy Strategies for Elevated Triglycerides

Lifestyle measures and blood glucose control are the primary strategies for hypertriglyceridemia and for the reduction of triglycerides in combined hyperlipidaemia [1]. The use of fibrates and high-dose fatty acids to further reduce significantly elevated triglyceride levels must be decided individually, as endpoint studies in combination with statins have shown no clear cardiovascular benefit ([Table 5]).

Table 5 Therapy strategies for elevated triglycerides.

Measure	Comment
Reaching LDL cholesterol target value	Always; normally necessary to administer statins
Reaching non-HDL target value	If possible, either further LDL cholesterol reduction or reduction of VLDL/remnant cholesterol (and thus triglyceride reduction).
Lifestyle measures	Always, as this can usually significantly improve hypertriglyceridemia. Always, as this can usually significantly improve hypertriglyceridemia.
Blood glucose control	Individual assessment, possibly after achieving LDL cholesterol target values in cases of very high risk and persistent hypertriglyceridemia; 1 cautious use, as no convincing endpoint studies in combination with statins have been conducted so far; note: increased risk of myopathy in combination with statins.
Fibrates	Individual assessment, possibly after achieving LDL cholesterol target values in cases of very high risk and persistent hypertriglyceridemia; cautious use, as no convincing endpoint studies in combination with statins have been conducted so far.
	As a dietary fat substitute for very high triglyceride values.

¹ Repeated fasting triglyceride levels > 500 mg/dl (5.7 mmol/l) should be treated with fibrates and/or high-dose omega-3 fatty acids to reduce the risk of acute pancreatitis.

Therapy Strategies for Special Situations

Increased lipoprotein(a) levels

Elevated Lp(a) values (or also low HDL cholesterol levels) cannot currently be specifically influenced by medication, therefore in these cases the remaining risk profile must be optimized and thus, e. g., an optimal adjustment of the LDL cholesterol should be sought. It is important to note that approx. 20% of the Lp(a) concentration is included in the LDL cholesterol determination, i. e. the LDL cholesterol value must be “corrected” for this. If lipoprotein(a) values are significantly elevated (>60 mg/dl) and there is evidence of progressive atherosclerosis over one year despite optimal control of all other risk factors, regular lipoprotein apheresis therapy can be started to lower elevated lipoprotein(a) values.

Statin intolerance

Patients with diabetes mellitus and statin intolerance should be treated similarly to patients without diabetes and statin intolerance. At least 3 different statins should be used before a statin intolerance is diagnosed (exception: rhabdomyolysis induced by a statin - then a second statin should only be used very cautiously). In many patients, it is possible to use a low statin dose in combination with ezetimibe to significantly reduce LDL cholesterol levels. PCSK9 inhibitors are well-tolerated by a high number of patients with statin intolerance and can be used in patients with very high risk and significant distance to the target value. Data from Germany show that PCSK9 inhibitors are used in 70–80 % of patients with statin intolerance.

Quelle einfügen: Drugs Real World Outcomes. 2019 Sep; 6 (3):115–123. doi: 10.1007/s40801-019-0158-0. PEARL: A Non-interventional Study of Real-World Alirocumab Use in German Clinical Practice. Parhofer KG, von Stritzky B, Pietschmann N, Dorn C, Paar WD.

Severe hypertriglyceridemia

Triglyceride values above 1000 mg/dl significantly increase the risk of acute pancreatitis [12]. By consistently implementing lifestyle measures (alcohol abstinence, largely abstaining from refined carbohydrates) and a strict blood glucose control it is usually possible to lower the values significantly. In order to minimize the risk of pancreatitis in severe hypertriglyceridemia, fibrates and/or high doses of omega-3 fatty acids can be used to significantly reduce triglyceride levels. If acute pancreatitis occurs at triglyceride concentrations above 1000 mg/dl, plasmapheresis is a treatment option to rapidly reduce the triglyceride concentration. Further treatment options include the administration of heparin and/or insulin (activation of lipoprotein lipase) and fasting. It is particularly worth trying a replacement of dietary fats with MCT fatty acids in cases of very high triglyceride values.

Conclusion

Cardiovascular events are a major cause of premature mortality and multimorbidity in people with diabetes. Risk stratified patient-related LDL cholesterol reduction is an evidence-based integral part of diabetes therapy and can improve the clinical prognosis of our patients. In the case of severe hypertriglyceridemia with values above 1000 mg/dl, the following measures reduce triglyceride concentrations and therefore significantly reduce the risk of pancreatitis: lifestyle measures (alcohol abstinence, largely abstaining from refined carbohydrates), good blood glucose control, possible administration of fibrates and/or omega-3 fatty acids.

Company Representatives

K.G. Parhofer and D. Müller-Wieland represent the DDG.

A.L. Birkenfeld represents the AG Diabetes und Herz.

W. Krone and M. Merkel represent the DGE.

M. Lehrke, N. Marx, K.S. Schütt and A. Zirlik represent the AG Herz und Diabetes of the DGK.

Marx, W. Krone, D. Müller-Wieland represent the AG Herz- Hormone-Diabetes of the DGK-DGE-DDG.

Conflict of interest

K.G.P. received lecture fees, fees for Advisory Board activities, fees for DMC activity and/or research support from the following companies: Aegerion, Akcea, Amarin, Amgen, Berlin- Chemie, Boehringer-Ingelheim, Ionis, Lilly, MSD, Regeneron, Sanofi. A.L.B. received lecture fees from Amgen, MSD and Sanofi. W.K. received lecture fees from Amgen, Bayer Vital, Boehringer Ingelheim, OmniaMed, Roche and Sanofi. N.M. has received support from Boehringer Ingelheim to lead clinical trials, acts as a consultant to Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, MSD, NovoNordisk and Sanofi- Aventis and receives research funding from MSD and Boehringer Ingelheim. In addition, he has lectured for Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Lilly, MSD, NovoNordisk and Sanofi-Aventis. has received research funding for experimental and clinical studies from Boehringer Ingelheim and MSD; he has served as a consultant for Boehringer Ingelheim, Sanofi-Aventis, MSD, AstraZeneca, Lilly, Novo- Nordisk, Amgen and Bayer and as a speaker for Boehringer Ingelheim, Sanofi-Aventis, MSD, AstraZeneca, Lilly, NovoNordisk and Bayer. has received fees and/or research funding from Amgen, Berlin- Chemie, MSD and Sanofi.

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