Report from the Congress of the American Diabetes Association (ADA): Orlando 2005

“The metabolic syndrome is the largest epidemic in the United States after the Spanish influenza and is the disease with the highest impact on the world wide economy” the president of the American Diabetes Association said while opening the American Diabetes Association 65th Annual Scientific Sessions in San Diego, 10 - 14 June 2005. Since this syndrome was a major topic at the ADA congress, with several sessions covering various aspects, this congress report will focus on this metabolic condition.

One of the first sessions with this topic was entitled: “The physiologic basis for the metabolic syndrome”.

Dr. Ferrannini, University of Pisa, Italy, Department of Metabolism, started to review the epidemic expansion of diabetes mellitus and the metabolic syndrome world wide. Obesity constitutes one of the most serious public health problems, with a rapidly increasing prevalence in all Western societies. Consequently, metabolic syndrome, a condition strongly associated with obesity, has become an epidemic problem. The insulin resistance of fat, muscle and liver is a central pathophysiological event in the development of this disease. Genetic and environmental factors play a major role in this process, although the precise pathogenesis of insulin resistance and type 2 diabetes is still largely unknown. Recent studies have contributed to a deeper understanding of the molecular mechanisms underlying the metabolic syndrome. To date, 5 different definitions are known, giving not only different weights on the pathogenic components, but also making a unique testing procedure difficult due to the inconsistent way of measuring these parameters. Dr. Ferraninni said that agreement exists in the fact that the intraabdominal/visceral fat plays a major role, with an inverse relation to risk of developing the metabolic syndrome. An increase from 0.5 kg to 1.5 kg visceral fat mass increases insulin resistance approximately 15-fold. The identification of the molecular pathophysiological mechanisms of insulin resistance and type 2 diabetes is essential for the development of novel and more effective therapies to better treat our patients with insulin resistance and type 2 diabetes. Dr. Ferraninni presented associations of insulin resistance and visceral obesity, and their influence on the metabolic syndrome, showing a direct correlation of visceral fat with the waist circumference, different for men and women. Blood pressure, triglycerides and intima-media thickness correlate with waist circumference, fasting and post-prandial glucose and low HDL correlates with both insulin resistance and waist circumference. Physical activity has an effect on the insulin resistance, but not on the waist circumference. Furthermore, he said, the free fatty acid levels are associated only with insulin resistance.

All these factors were summarized by Dr. Ferrannini in a bifactorial concept for the pathogenesis of the metabolic syndrome, with insulin resistance and the waist circumference as the two main drivers (Fig. [1]).

Fig. 1 Bifactorial concept for the metabolic syndrome.

He proposed a new concept of how to understand the metabolic syndrome. In the past, insulin resistance has been mostly regarded as the basis for the metabolic syndrome. Dr. Ferraninni showed that insulin resistance is important, but not responsible alone for the metabolic dysnormality of this syndrome. Factors characterized by the waist circumference seem to be independent promotors of the metabolic syndrome. This could have implications in the understanding and much more for the prevention of the metabolic syndrome.

The pathogenesis of the metabolic syndrome was also a topic in other sessions such as “Resistance - fatty acids or circulating factors?” where Mitchell Lazar, University of Pennsylvania School of Medicine, Philadelphia, PA, USA and Gerald I. Shulman, Howard Hughes Medical Institute Yale University School of Medicine, New Haven, USA, gave lectures.

Two different concepts were presented on how insulin resistance developes based on existing obesity. Dr. Lazar started with the clinical problem that several patients are obviously insulin resistant, but do not have a metabolic syndrome and, on the other hand, persons with a metabolic syndrome are not insulin resistant. He said, “This tells us that beside the resistance against insulin, other factors play an important role - independently or as second hit if the insulin resistance exists.” Dr. Lazar presented the concept of fatty tissue acting as an endocrine organ. Recent studies demonstrate that a chronic alteration of the endocrine system is implicated in the pathophysiology of the metabolic syndrome. This involves adipose tissue, as well as muscle tissue secreting hormones, which influence insulin resistance. There is now increasing evidence that the adipose tissue not only produces free fatty acids which contribute to insulin resistance, but also acts as a relevant endocrine organ producing mediators (adipokines), and the muscle tissue (myokines) can also modulate insulin signalling. Adipokines having a beneficial effect on insulin resistance are leptin and adiponectin: adiponectin knock-out mice develop insulin resistance.

Dr. Lazar presented recent results regarding resistin, showing a hyperresistinaemia leading to insulin resistance, but in the resistin knock-out mice a protection against insulin resistance was seen. Between man and mice, however, major differences exists in the localisation of resistin expression: in man, resistin is expressed in macrophages, while in mice it is expressed in adipose tissue. A further negative effect on insulin resistance and the metabolic syndrome are elevated free fatty acids (FFA), reduced cellular glucose uptake, and increased levels of PAI-1, resistin and TNF α.

Dr. Shulman introduced the concept of development of insulin resistance due to circulating free fatty acids and intra-organ fat content in insulin sensitive organs. Dr. Shulman showed that slim offsprings from type 2 diabetic patients have a higher risk for insulin resistance due to an increased triglyceride content in muscle with no relationship to levels of adipokines like TNF-alpha, IL-6, resistin or adiponectin. It is known that FFA can induce insulin resistance in muscle tissue due to inhibition of glucose uptake. Accordingly, the levels of circulating FFA are inversely correlated with insulin sensitivity in humans. Dr. Shulman reported a model where FFA due to activation of the PKC-theta in muscle result in an impairment of signalling through PI3-K/PKB and a translocation of GLUT-4 into the plasma membrane, leading to impaired cellular glucose uptake supported by the PKC-theta knock-out mice - they are resistant against FFA-induced insulin resistance. A similar mechanism exists in liver. Dr. Shulman presented that elimination of FFA from muscle markedly improve insulin sensitivity. This hypothesis is also supported by the results from several mice models: a reduced uptake of FFA in knock-out mice for the fatty acid- transporter (FATP-1) and the activated metabolisation of intracellular FFA (overexpression of the uncoupling protein-3 (UCP-3) in mice) leads to improvement in insulin sensitivity.

The dimension of the metabolic syndrome for the society was covered in the session: “Epidemiology of metabolic syndrome”.

Dr. James Sowers, University of Missouri-Columbia, Columbia, USA, started with his lecture describing the increasing prevalence of the metabolic syndrome. Based on trends in the incidence of obesity and other contributing risk factors for the metabolic syndrome, e.g., insulin resistance, Dr. Sowers noted that this number is expected to increase dramatically in the future. The prevalence of diabetes has also reached epidemic proportions; heart disease is currently the most common cause of mortality in patients with diabetes, he said. As defined by the National Cholesterol Education Program (NCEP) ATP III Guidelines, metabolic syndrome is diagnosed when patients have three or more of the following characteristics as shown in Table [1].

Table 1 Men Women Abdominal obesity (waist circumference) > 102 cm > 88 cm High levels of triglycerides ≥ 150 mg/dL Low levels of high-density lipoprotein cholesterol (HDL-C) < 40 mg/dL < 50 mg/dL High blood pressure ≥ 130/≥ 85 mm Hg Elevated fasting blood glucose ≥ 110 mg/dL

In another session entitled: Exercise, metabolic syndrome, and type 2 diabetes in youth, the prevalence of the metabolic syndrome in children was discussed by Dr. Sonia Caprio, Professor of Pediatrics/Pediatric Endocrinology & Metabolism, Yale-New Haven Hospital, USA.

Dr. Sonia Caprio said that childhood obesity has contributed to an increased incidence of type 2 diabetes mellitus and metabolic syndrome among children. Children exposed to maternal obesity were at increased risk of developing metabolic syndrome, which suggests that obese mothers, who do not fulfill the criteria for gestational diabetes mellitus, may still have metabolic factors that affect fetal growth and postnatal outcome. This strongly implies that we should also consider treating such mothers. Given the increased obesity prevalence, these findings have implications for the perpetuation of the cycle of obesity, insulin resistance, and their consequences in subsequent generations.

Dr. Steven Haffner, University of Texas Health Sciences Center, San Antonio, TX, USA spoke in the session “Metabolic syndrome and increased cardiovascular risk” and discussed the mechanisms that drive the strong link between metabolic syndrome, risk for cardiovascular disease (CVD), and increased CVD mortality. First, plasma free fatty acids (FFAs) might mediate insulin resistance and impaired glucose tolerance associated with abdominal obesity and type 2 diabetes. Dr. Haffner said that adiponectin also plays an important role in the modulation of glucose and lipid metabolism in insulin-sensitive tissues, and may be an important marker of the metabolic syndrome. Moreover, the metabolic syndrome is an inflammatory and prothrombic condition. Indeed, markers of inflammation and thrombosis can help in the diagnosis. Lastly, the metabolic syndrome is associated with chronic kidney disease and microalbuminuria, both known predictors of CVD risk in patients with diabetes.

Dr. Haffner presented data about the Multiple Risk Factor Intervention Trial (MRFIT), which included 347,978 men, age 35 to 57 years, who were followed for CVD mortality for 12 years. In this trial increased total cholesterol (> 200 mg/dL), systolic blood pressure (> 120 mm Hg), and cigarette smoking were found to be significant predictors of CVD mortality for men, with and without diabetes. Notably, as the number of risk factors increased, the absolute risk of CVD death rose much more steeply for diabetic men than for non-diabetic men leading to a three times higher CVD risk for diabetic than non-diabetic men. After an average 12-year follow-up, 11.6 % of 5163 men, who reported taking medication for diabetes died due to CVD. Among the 342 815 men not taking medication for diabetes, 2.6 % died due to CVD. These findings emphasize the importance to prevent diabetes, and also the need for rigorous sustained intervention to control blood pressure in patients with diabetes, to lower serum cholesterol, and to abolish cigarette smoking. These interventions should ultimately reduce the risk of CVD mortality in patients with metabolic syndrome or diabetes.

This question was also discussed in the next session: Strategies for reducing CV risk in metabolic syndrome by Dr. Richard Nesto, Harvard Medical School, Boston, MA, USA. Current recommendations for treating the metabolic syndrome focus on the correction of its components (i.e., hypertension, dyslipidemia, visceral adiposity, and abnormal glucose tolerance), he said. Diet, exercise, and weight loss each independently improve insulin resistance and reduce progression to type 2 diabetes. Even though the success of lifestyle modification is limited, the importance of such therapy cannot be overemphasized. Dr. Nestro postulated that the success of metformin use in the Diabetes Prevention Program (DPP) suggests that one medication or drug class could be used to treat the entire syndrome. Thiazolidinediones have been shown to directly improve insulin resistance. He added that new research data presented at the ADA meeting provide strong evidence in support of strategies to prevent the development of metabolic syndrome. For instance, in a sub-analysis of the Study in Insulin Resistance (SIR) trial, the effect of treating the metabolic syndrome with tesaglitazar (0.1, 0.25, 0.5 or 1.0 mg, once daily) was tested in non-diabetic patients with manifestations of insulin resistance. After 12 weeks, treatment with 0.5 mg tesaglitazar reduced the proportion of persons with metabolic syndrome by 45 %, compared with a 6 % reduction in the placebo group. Treatment with tesaglitazar also reduced the prevalence of impaired fasting glucose by 59 %, compared with a 22 % increase in prevalence among patients in the placebo group. Patients with diabetes and dyslipidemia should be treated aggressively, with both non-pharmacologic and pharmacologic measures, in an effort to reduce the risk of CVD, Dr. Nesto said. This means a strong public health message is critical to increase awareness of the consequences of obesity and sedentary lifestyle.

The effect of lifestyle intervention on the metabolic syndrome was discussed in the session: “Evidence for benefit from lifestyle interventions on metabolic syndrome”.

Dr. Pirjo Ilanne-Parikka, Department of Internal Medicine, University Hospital, Tampere, Finland, analyzed the benefit on the prevention of the metabolic syndrome in the type 2 diabetes prevention trial (DPT). She pointed out that in the prevention studies (DPP and DPT), lifestyle intervention was efficient to reduce the prevalence of the metabolic syndrome. 53 % of the probands in the American Diabetes Prevention Program (DPP) had a metabolic syndrome. After the end of the study, 43 % of the probands still had a metabolic syndrome, versus 62 % in the control group. In the metformin group, there was no change in prevalence (55 %). In both studies, the group of persons with no change in body weight had the highest increase in metabolic syndrome. Dr. Ilanne-Parikka concluded that physical activity and the change in eating behaviors (reducing fat and eating more food rich in fibers) has the best effect on the prevention of the metabolic syndrome. However, the major problem in this case, she said, is not the disease itself, it is the aimlessness of how to act to prevent our society to bankrupt itself due to the disease burden. Due to the lack in cure of diabetes and the metabolic syndrome, the only way to reduce the personal and socio-economic burden of this syndrome and its severe vascular complications is prevention. The prevention will require an integrated, international approach. She concluded: “We have to accept that the risk of getting a metabolic syndrome is not a disease; it is a symptom of a much larger problem - the adaptation of our metabolism to sedentary globalization.”

Metabolic syndrome is likely to remain a huge threat to public health in the years to come. Therefore, affordable strategies and concepts are needed for primary prevention. Integration of lifestyle intervention into current health care systems will require a simple network of health care professionals to provide effective programs of lifestyle intervention. A large proportion of metabolic syndrome is preventable.

The effects of prevention trials on diabetic complications were discussed in the session entitled: “Retinopathy in recent onset diabetes and persons at high risk of diabetes in the diabetes prevention program”.

Dr. Hamman, University of Colorado Health Sciences Center, USA presented data showing that lesions of diabetic retinopathy were detected in 7.6 % of pre-diabetic patients in the Diabetes Prevention Program, suggesting that retinopathy is an early, rather than late, complication of type 2 diabetes. “Additionally, almost 13 % of patients with early type 2 diabetes have diabetic retinopathy,” said Dr. Hamman, Vice Chair of the Diabetes Prevention Program. Since retinopathy is sometimes present before patients progress to type 2 diabetes, early retinopathy may be a marker for more widespread vascular disease. Interestingly, patients with early retinopathy showed an average blood pressure of 129/80 mm Hg versus 124/78 mm Hg for those with no evidence of retinopathy. Likewise, those with retinopathy had slightly elevated HbA1c. It amounted to 6.5 % and 6.3 % for those diagnosed with and without retinopathy, respectively. The 126 mg/dL glucose level currently used to define diabetes was selected because it is the level that was considered the threshold for the development of typical complications of diabetes - retinal, kidney and nerve damage. Dr. Hamman said that it is too early to recalculate “normal” thresholds. “But I do think this means that a full eye examination is necessary at the time of diagnosis of diabetes, because it is clear that retinopathy is present at blood glucose levels much lower than we previously thought.” It would also be prudent, he said, to recommend eye exams for patients who have newly diagnosed diabetes or impaired glucose tolerance.

This session presented more evidence for the importance of blood pressure control in the management of patients with the metabolic syndrome and diabetes, as well as the control of related risk factors like lipids and cardiovascular health.

New therapies for diabetes and the metabolic syndrome were discussed in the session: “Exenatide: Glycemic control, weight loss, and hypoglycemia”.

Dr. Robert J. Heine, VU University Medical Center, Amsterdam, The Netherlands, presented findings of a phase III multicenter trial of exenatide, a novel incretin mimetic hormone which releases, like glucagon-like peptide-I (GLP-I), endogenous insulin. Exenatide improved glycemic control, with a low incidence of hypoglycemia and without weight gain, in patients with type 2 diabetes who were inadequately controlled by treatment with metformin and/or a sulfonylurea. Treatment with exenatide was associated with a mean weight loss of - 2.3 ± 0.2 kg, versus a weight gain with insulin glargine of + 1.8 ± 0.2 kg (p < 0.001) which was used as comparator. Exenatide reduced postprandial excursions following breakfast and dinner, while glargine predominantly reduced fasting glucose (- 1.2 mmol/L and - 2.9 mmol/L, respectively; p < 0.001). Nausea was the most common adverse effect in the exenatide arm, occurring in 57 % of patients. Symptomatic hypoglycaemia rates were similar in the exenatide and insulin glargine groups, but nocturnal hypoglycaemia was lower for exenatide. Overall, said Dr. Heine, this trial demonstrated that exenatide was associated with tighter postprandial control, less nocturnal hypoglycaemia, and progressive reductions in body weight. By comparison, insulin glargine was associated with greater reductions in fasting plasma glucose (FPG), less daytime hypoglycaemia, and progressive weight gain.

Summarizing the results about exenatide, Dr. David M. Kendall, University of Minnesota, Minneapolis, MN, USA, noted that clinical trials have shown that exenatide:

enhances glucose-dependent insulin secretion suppresses elevated glucagon secretion reduces food intake and body weight slows gastric emptying increases beta cell mass.

He presented findings from a cohort of 265 patients who had been treated with exenatide 10 µg twice daily, in addition to metformin, or a sulfonylurea, or both, for 82 weeks. At baseline, the patients had a mean body mass index (BMI) of 34 kg/m² and a mean HbA1c level of 8.3 %. Following exenatide treatment, patients had sustained reductions in HbA1c (- 1.2 ± 0.1 %) and body weight (- 4.6 ± 0.3 kg). There were also improvements in several lipid parameters with a triglyceride (TG) reduction from 239 to 202 mg/dL and an increase of high density lipoproteins (HDL) from 37.9 to 42.4 mg/dL. The diastolic blood pressure was reduced from 78.6 to 75.3 mm Hg. Nausea was the most frequent adverse effect, occurring in 46 % of patients. Again, this was generally mild-to-moderate in intensity, and was responsible for 3.6 % patient withdrawals.

In the session “Late-breaking clinical trials”, Dr. André Scheen, University of Liege, Belgium, reported findings of the Rimonabant In Obesity (RIO)-Diabetes trial, and Professor David M. Kendall, University of Minnesota, Minneapolis, MN, USA, reported on recent muraglitazar trials.

Results of a one year study in type-2-diabetes presented by Dr. Scheen, revealed reduced body weight, slimmer waistline and less risk of heart disease. Rimonabant, a substance active at the cannaboid receptor in the brain lead to a loss, 1.4 kg in the placebo group and 4.3 kg for rimonabant 20 mg. Mean reduction in waist circumference was 1.9 cm and 5.2 cm, respectively. Those probands taking rimonabant had a sustained HDL increase of 6.6 mg/dL, triglycerides drops of 31.6 mg/dL, and systolic blood pressure falls of an average of 2 mm Hg. Compared with the placebo group, all results were significant at p < 0.001. Importantly, more than 50 % of the improvements in HDL levels were calculated to be beyond those attributed to weight loss alone (p < 0.001). Moreover, the prevalence of metabolic syndrome was reduced by 18.9 % in the rimonabant 20 mg group compared to a 7.6 % reduction in the placebo group (p = 0.007). A covariant analysis of the findings suggests that 0.3 % of the reduction in HbA1c (including an 0.1 % rise among placebo patients) is attributable to weight loss alone, but 0.4 % of the reduction is not explained by weight loss and is, therefore, an effect of the drug. “Rimonabant offers a new approach to the management of type 2 diabetes addressing multiple cardiometabolic risk factors commonly observed in type 2 diabetes,” Dr. Scheen concluded.

Dr. Kendall presented the clinical trials with muraglitazar. As a dual α/γ peroxisome proliferator-activated receptor (PPAR) agonist, muraglitazar has a wide-ranging clinical potential. PPAR-γ activation reduces insulin resistance and improves glycaemic control and free fatty acid (FFA) metabolism, specifically by reducing plasma triglycerides and increasing HDL-C. He described a study in which two years of treatment with muraglitazar reduced HbA1c levels and improved lipid profiles in patients with type 2 diabetes, but the drug was also associated with a weight gain of almost 6 kg. Patients treated with 5 mg of muraglitazar achieved an average HbA1c of 6.4 %, which was an absolute reduction of 1.52 % from the mean baseline HbA1c of 7.92 %, as well as reduced triglyceride levels by 22 % from a baseline mean of 156 mg/dL, and increased HDL by 29 % from a baseline mean of 40 mg/dL. Five percent of the patients treated had significant side effects like congestive heart failure and peripheral edema events. Muraglitazar was also compared with pioglitazone in a phase III trial of patients who were taking metformin. In this trial, 589 patients were randomized to muraglitazar 5 mg, and 550 patients were treated with pioglitazone 30 mg, for 24 weeks. HbA1c was reduced by 1.12 % following muraglitazar, compared with a reduction of 0.74 % following treatment with pioglitazone (p < 0.0001). In addition, muraglitazar reduced TG levels by 22 % from a baseline mean of 156 mg/dL, and increased HDL-C by 29 % from a baseline mean of 40 mg/dL after 104 weeks. Patients treated with muraglitazar had a mean weight gain of 2.5 kg, compared with 1.6 kg under pioglitazone.

1 ADA-meeting Merck observer group: A. Bierhaus, S. Böhnke, H. Fink, A. Hennige, M. Lankisch, M. Laudes, M. Möhlig, W. Schechinger, S. Schinner, P. Schwarz, N. Soydan, A. Starke, A. Stirban, B. Stratmann, C. Thamer, A. Vogt, T. Wiesner, H. J. Wörle.