Dr. Ron’s Research Review – February 29, 2012

This week’s research review focuses on controversies with the metabolic syndrome.

"The metabolic syndrome... is dead!"

Part of the scientific community has elected to totally "dismiss" the concept of the metabolic syndrome. Meanwhile, the best available evidence from three consecutive large meta-analyses has systematically shown that people with metabolic syndrome are at increased risk of cardiovascular events. The most recent and largest of them included near one million patients (total n = 951,083). The investigators concluded that the metabolic syndrome is associated with a 2-fold increase in cardiovascular outcomes and a 1.5-fold increase in all-cause mortality rates. (Tenenbaum and Fisman 2011)

In contrast to Framingham score, the criteria for the metabolic syndrome does not includes age, cholesterol, LDL-C, as well as a variety of strong predictors used in other risk-stratification scores: previous myocardial infarction, heart failure, smoking, family history, etc. (Tenenbaum and Fisman 2011)

Metabolic syndrome is a complex disorder defined by a cluster of interconnected factors that increase the risk of cardiovascular atherosclerotic diseases and diabetes mellitus type 2. Currently, several different definitions of metabolic syndrome exist, causing substantial confusion as to whether they identify the same individuals or represent a surrogate of risk factors. Recently, a number of other factors besides those traditionally used to define metabolic syndrome that are also linked to the syndrome have been identified. (Kassi, Pervanidou et al. 2011)

Although the insulin resistance syndrome was first described in 1988, Harold Himsworth addressed the “Mechanisms of Diabetes.” in his 1939 Goulstonian Lectures to the Royal College of Physicians in London. Himsworth believed that the majority of patients with type 2 diabetes mellitus were “insulin insensitive.” Despite the fact that Himsworth was among the most distinguished clinical investigators of his time, the idea that resistance to insulin action could have adverse consequences had little resonance over the next several decades. (Reaven 1988) (Reaven 2005)

Dr. Ron


Articles

Metabolic syndrome: definitions and controversies

            (Kassi, Pervanidou et al. 2011) Download

Metabolic syndrome (MetS) is a complex disorder defined by a cluster of interconnected factors that increase the risk of cardiovascular atherosclerotic diseases and diabetes mellitus type 2. Currently, several different definitions of MetS exist, causing substantial confusion as to whether they identify the same individuals or represent a surrogate of risk factors. Recently, a number of other factors besides those traditionally used to define MetS that are also linked to the syndrome have been identified. In this review, we critically consider existing definitions and evolving information, and conclude that there is still a need to develop uniform criteria to define MetS, so as to enable comparisons between different studies and to better identify patients at risk. As the application of the MetS model has not been fully validated in children and adolescents as yet, and because of its alarmingly increasing prevalence in this population, we suggest that diagnosis, prevention and treatment in this age group should better focus on established risk factors rather than the diagnosis of MetS.

Metabolic syndrome and risk of acute myocardial infarction a case-control study of 26,903 subjects from 52 countries

            (Mente, Yusuf et al. 2010) Download

OBJECTIVES: This study examines the risk of acute myocardial infarction (MI) conferred by the metabolic syndrome (MS) and its individual factors in multiple ethnic populations. BACKGROUND: The risk of the MS on MI has not been well characterized, especially in multiple ethnic groups. METHODS: Participants in the INTERHEART study (n = 26,903) involving 52 countries were classified using the World Health Organization (WHO) and International Diabetes Federation (IDF) criteria for MS, and their odds ratios (ORs) for MI were compared with the individual MS component factors. RESULTS: The MS is associated with an increased risk of MI, both using the WHO (OR: 2.69; 95% confidence interval [CI]: 2.45 to 2.95) and IDF (OR: 2.20; 95% CI: 2.03 to 2.38) definitions, with corresponding population attributable risks of 14.5% (95% CI: 12.7% to 16.3%) and 16.8% (95% CI: 14.8% to 18.8%), respectively. The associations are directionally similar across all regions and ethnic groups. Using the WHO definition, the association with MI by the MS is similar to that of diabetes mellitus (OR: 2.72; 95% CI: 2.53 to 2.92) and hypertension (OR: 2.60; 95% CI: 2.46 to 2.76), and significantly stronger than that of the other component risk factors. The clustering of > or =3 risk factors with subthreshold values is associated with an increased risk of MI (OR: 1.50; 95% CI: 1.24 to 1.81) compared with having component factors with "normal" values. The IDF definition showed similar results. CONCLUSIONS: In this large-scale, multi-ethnic, international investigation, the risk of MS on MI is generally comparable to that conferred by some, but not all, of its component risk factors. The characterization of risk factors, especially continuous variables, as dichotomous will underestimate risk and decrease the magnitude of association between MS and MI.

Insulin resistance, type 2 diabetes mellitus, and cardiovascular disease: the end of the beginning

            (Reaven 2005) Download

Banting lecture 1988. Role of insulin resistance in human disease

            (Reaven 1988) Download

Resistance to insulin-stimulated glucose uptake is present in the majority of patients with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) and in approximately 25% of nonobese individuals with normal oral glucose tolerance. In these conditions, deterioration of glucose tolerance can only be prevented if the beta-cell is able to increase its insulin secretory response and maintain a state of chronic hyperinsulinemia. When this goal cannot be achieved, gross decompensation of glucose homeostasis occurs. The relationship between insulin resistance, plasma insulin level, and glucose intolerance is mediated to a significant degree by changes in ambient plasma free-fatty acid (FFA) concentration. Patients with NIDDM are also resistant to insulin suppression of plasma FFA concentration, but plasma FFA concentrations can be reduced by relatively small increments in insulin concentration. Consequently, elevations of circulating plasma FFA concentration can be prevented if large amounts of insulin can be secreted. If hyperinsulinemia cannot be maintained, plasma FFA concentration will not be suppressed normally, and the resulting increase in plasma FFA concentration will lead to increased hepatic glucose production. Because these events take place in individuals who are quite resistant to insulin-stimulated glucose uptake, it is apparent that even small increases in hepatic glucose production are likely to lead to significant fasting hyperglycemia under these conditions. Although hyperinsulinemia may prevent frank decompensation of glucose homeostasis in insulin-resistant individuals, this compensatory response of the endocrine pancreas is not without its price. Patients with hypertension, treated or untreated, are insulin resistant, hyperglycemic, and hyperinsulinemic. In addition, a direct relationship between plasma insulin concentration and blood pressure has been noted. Hypertension can also be produced in normal rats when they are fed a fructose-enriched diet, an intervention that also leads to the development of insulin resistance and hyperinsulinemia. The development of hypertension in normal rats by an experimental manipulation known to induce insulin resistance and hyperinsulinemia provides further support for the view that the relationship between the three variables may be a causal one.(ABSTRACT TRUNCATED AT 400 WORDS)

"The metabolic syndrome... is dead": these reports are an exaggeration

            (Tenenbaum and Fisman 2011) Download

The debates continue over the validity of the metabolic syndrome concept. The continuous increment of the obesity pandemic is almost worldwide paralleled by rising rates of metabolic syndrome prevalence. Then, it seems obvious that these debates drove the need for further investigations as well as a deeper cooperation between relevant national and international organizations regarding the issue. Instead, part of the scientific community elected to totally "dismiss" the concept of the metabolic syndrome. Meanwhile, the best available evidence from three consecutive large meta-analyses has systematically shown that people with metabolic syndrome are at increased risk of cardiovascular events. The most recent and largest of them included near one million patients (total n = 951,083). The investigators concluded that the metabolic syndrome is associated with a 2-fold increase in cardiovascular outcomes and a 1.5-fold increase in all-cause mortality rates. One of the ways to hit the metabolic syndrome is an utterly simplistic view on this concept as a predictive tool only. Of course, the presence of the metabolic syndrome possesses a definite predictive value, but first of all it is a widely accepted concept regarding a biological condition based on the complex and interrelated pathophysiological mechanisms starting from excess central adiposity and insulin resistance. Therefore, it is completely unfair to compare it with statistically constructed predictive tools, including stronger prognostic variables even unrelated to each other from the biological point of view. For example, in the criteria for metabolic syndrome (in contrast to Framingham score) age and cholesterol--presumably low density lipoprotein-cholesterol (LDL-C)--levels are not included, as well as a variety of strong predictors used in other risk-stratification scores: previous myocardial infarction, heart failure, smoking, family history, etc. However, the metabolic syndrome identifies additional important residual vascular risk mainly associated with insulin resistance and atherogenic dyslipidemia (low high density lipoprotein-cholesterol (HDL-C), high triglycerides, small, dense LDL-C). Therefore, the metabolic syndrome could be a useful additional contributor in estimation of global cardiovascular risk beyond age, high LDL-C or other standard risk factors. The components of the metabolic syndrome have partially overlapping mechanisms of pathogenic actions mediated through common metabolic pathways. Therefore their total combined effect could be less than the summed of the individual effects. The concept that the metabolic syndrome is a consequence of obesity and insulin resistance, provides a useful "life-style changes" approach for prevention and treatment: caloric restriction, weight-loss and increased physical activity. The next step could theoretically be pharmacological interventions such as metformin, acarbose, fibrates, weight-loss drugs (currently only orlistat is practically available) and perhaps glucagon-like peptide-1 agonists. A third step should probably be kept for bariatric surgery.

References

Kassi, E., P. Pervanidou, et al. (2011). "Metabolic syndrome: definitions and controversies." BMC Med 9: 48.

Mente, A., S. Yusuf, et al. (2010). "Metabolic syndrome and risk of acute myocardial infarction a case-control study of 26,903 subjects from 52 countries." J Am Coll Cardiol 55(21): 2390-8.

Reaven, G. (2005). "Insulin resistance, type 2 diabetes mellitus, and cardiovascular disease: the end of the beginning." Circulation 112(20): 3030-2.

Reaven, G. M. (1988). "Banting lecture 1988. Role of insulin resistance in human disease." Diabetes 37(12): 1595-607.

Tenenbaum, A. and E. Z. Fisman (2011). ""The metabolic syndrome... is dead": these reports are an exaggeration." Cardiovasc Diabetol 10(1): 11.