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Steven M. Haffner, Abdominal obesity, insulin resistance, and cardiovascular risk in pre-diabetes and type 2 diabetes, European Heart Journal Supplements, Volume 8, Issue suppl_B, May 2006, Pages B20–B25, https://doi.org/10.1093/eurheartj/sul004
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Abstract
Cardiovascular (CV) disease remains the leading source of premature mortality in western populations. There is an increasing prevalence of obesity, particularly abdominal obesity. Nine states in the USA now report a prevalence of obesity [body mass index (BMI) >30 kg/m2] of 25% or more, and the prevalence of abdominal obesity (waist circumference >102 cm for men and 88 cm for women) has increased by 20% in men and 14% in women in a single decade. The intra-abdominal adiposity associated with abdominal obesity increases cardiometabolic risk directly, via altered secretion of adipokines, and indirectly, via promotion insulin resistance, diabetes and the cluster of cardiometabolic risk factors associated with the metabolic syndrome. Patients with type 2 diabetes, or subjects with pre-diabetic dysglycaemia are at greater risk of CV events, compared with normoglycaemic subjects. A large and growing body of evidence indicates that abdominal obesity is a more powerful predictor of adverse CV outcomes than BMI. Measurement of waist circumference as an index of intra-abdominal adiposity should be included in routine evaluations of overall cardiometabolic risk.
Introduction
In the USA, cardiovascular (CV) disease remains a larger source of excess mortality than other major killers, including malignant neoplasms and respiratory disease.1 More than 70 million inhabitants of the USA had CV disease in 2002, with about one in five having clinical evidence of coronary heart disease [history of myocardial infarction (MI) or angina pectoris], and almost one million Americans died from a CV cause in 2002 alone.2 The total cost to the US taxpayer relating to the management of CV disease in 2005 was $393.5 billion.1 The situation is equally daunting in Europe. In the same year, age-standardized mortality rates from circulatory disease in the elderly population (≥65 years) were 1991/100 000 for circulatory disease (mostly ischaemic heart disease and cerebrovascular disease), compared with 1045/100 000 for malignant neoplasms and 352/100 000 for diseases of the respiratory system.3
Thus, CV disease remains the leading cause of premature mortality in western populations, and achieving a more complete understanding of the pathogenesis of CV disease is important if we are to design more effective interventions to reduce this burden. The continuing burden of CV disease is driven in part by a high and increasing prevalence of obesity. The development of obesity, particularly abdominal obesity, promotes insulin resistance and a cluster of risk factors for CV disease, including hypertension, atherogenic dyslipidaemia, inflammation, and altered haemostasis.4–6 Abdominal obesity and type 2 diabetes often coexist,7,8 and patients with type 2 diabetes are well known to be at elevated risk of first or repeat CV events, compared with their non-diabetic counterparts.9 However, the elevated CV risk associated with insulin-resistant states begins long before patients present for a clinical diagnosis of type 2 diabetes.10 The purpose of this review is to explore the relationships between abdominal obesity, insulin resistance, and CV outcomes in diabetic and pre-diabetic subjects.
Obesity and cardiometabolic risk
Epidemic of obesity
The prevalence of obesity has risen dramatically in the USA in recent years.11Figure 1 shows the prevalence of obesity [body mass index (BMI) >30 kg/m2] from routine surveys carried out within the USA.12,13 In 1991, the prevalence of obesity in individual states of the Union was 10–14% in most cases, with only four states reporting a higher prevalence. Only 5 years later, in 1996, 30/50 states reported a prevalence of obesity of 15–19%. In 2001, 20–24% of the populations of the majority of states (29/50) were obese, and the latest data available (2004) show the first reports from states where more than one-quarter of the population is obese.
Determinants of elevated CV risk in dysglycaemia
Type 2 diabetes and adverse CV outcomes
Patients with type 2 diabetes are at a two- to four-fold higher risk of mortality from coronary heart disease, compared with non-diabetic subjects.14–17 The East-West Study compared the incidence of MI during seven years of follow-up in a population of 1059 patients with diabetes and in 1373 non-diabetic subjects (Table 1).9 Non-diabetic patients without prior MI were at the lowest risk of MI during follow-up, and patients with type 2 diabetes and a prior history of MI were at the highest risk of MI during follow-up, as would be expected. The incidence of MI was almost identical in the remaining two groups (non-diabetic patients with prior MI, and patients with diabetes but no history of MI). Consistent with these observations, the risk of death from coronary heart disease (adjusted for age, sex, smoking, hypertension, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, and triglycerides in a Cox proportional hazards model) did not differ significantly between non-diabetic patients with a prior MI and diabetic patients without a prior MI [hazard ratio 1.4 (95% CI 0.7 to 2.6), P=0.5]. These and similar observations led to the concept of type 2 diabetes as a CV risk equivalent in guidelines for the management of CV and metabolic diseases.18
The presence of the metabolic syndrome amplifies the adverse prognosis associated with type 2 diabetes, as shown by a study involving 2815 subjects enrolled in the San Antonio Heart Study.19 The risk of mortality from CV disease during 12.5 years of follow-up was increased by about two- to three-fold in subjects with either diabetes or the NCEP/ATPIII metabolic syndrome at baseline (Figure 2). The increase in risk was much larger, however, in subjects with both diabetes and the metabolic syndrome at baseline, with hazard ratios for CV mortality of 9.40 (95% CI 4.36–20.3) in women and 2.50 (95% CI 1.40–4.52) in men.
Other well-designed observational studies confirm the amplification by the metabolic syndrome of the adverse prognosis associated with type 2 diabetes. The Kuopio Ischaemic Heart Disease Risk Factor Study was a population-based prospective study of a cohort of 1209 Finnish middle-aged men (42–60 years), initially free of CV disease, who were followed for an average of 12 years.20 The NCEP/ATPIII metabolic syndrome was associated with an increase in the risk of 4.3-fold (95% CI 1.6–11.2) after extensive multivariate adjustment (for age, LDL-cholesterol, tobacco and alcohol use, family coronary heart disease (CHD) history, fibrinogen, white blood cell levels, socioeconomic status, and examination year). The Botnia Study is another large observational study conducted in Scandinavia. The prevalence of prior coronary heart disease among 1430 type 2 diabetic patients within the Botnia cohort was 27% in patients with the metabolic syndrome (World Health Organization definition),21 compared with 14% in patients without the metabolic syndrome (P<0.001).22 The relative risk (RR) of CHD after the adjustment for age and gender was 2.2 (95% CI 1.5–3.3). Similarly, in this type 2 diabetic population, more patients with the metabolic syndrome had a history of MI [RR 2.3 (95% CI 1.3–4.1), (P=0.007)] compared with patients without the metabolic syndrome.
Pre-diabetic dysglycaemia and adverse CV outcomes
The elevation in cardiometabolic risk associated with dysglycaemia is not restricted to patients with clinical diabetes. The Nurses Health Study recruited a population of 117,629 women, free of CV disease at baseline, in 1976.23 Within this population, 1508 women had type 2 diabetes at baseline and 5894 women developed diabetes during 20 years of subsequent follow-up. The risk of adverse CV outcomes in the sub-population that developed diabetes was analysed separately for the periods prior to and subsequent to the diagnosis of diabetes. Figure 3 shows the risks of non-fatal MI and non-fatal stroke in this analysis. Women who developed diabetes either before or during the study had elevated CV risk, with the higher risk in the group with diabetes at baseline, consistent with their longer duration of diabetes. However, for those who developed diabetes during the study, the risk of these adverse outcomes was also clearly elevated before the diagnosis of type 2 diabetes.
Previous analyses of the NHANES24 and the Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe25 cohorts have demonstrated a significantly higher incidence of adverse CV outcomes in subjects with elevated post-load plasma glucose concentrations indicative of impaired glucose tolerance (IGT). Impaired fasting glucose (IFG), characterized by elevated, but non-diabetic levels of fasting plasma glucose (FPG) with normal post-load plasma glucose, has also been associated with increased cardiometabolic risk, with IFG and IGT together producing higher risk still.26,27 However, a large Scandinavian observational study (6766 patients followed for 7–10 years) suggested that IGT may be a more powerful CV risk factor than IFG.28 Also, the Risk Factors in IGT for Atherosclerosis and Diabetes study showed that post-load hyperglycaemia was more strongly related to increased carotid intima-media thickness (a surrogate for coronary atherosclerosis) than elevated FPG.29,30 Overall, it is clear that the pathogenesis of diabetes-associated elevation of cardiometabolic risk therefore begins long before the patient presents for diagnosis of diabetes.
Pre-diabetic dysglycaemia is primarily a risk factor for the development of type 2 diabetes.10 Randomized intervention trials in populations or sub-populations with IGT have demonstrated marked and significant reductions in the risk of new-onset diabetes with intensive lifestyle interventions31,32 or pharmacological treatment with metformin,31 acarbose,33 or orlistat.34 Cardiometabolic risk factors other than dysglycaemia are also risk factors for developing type 2 diabetes. For example, the Insulin Resistance in Atherosclerosis Study (IRAS) followed 580 normoglycaemic subjects and 292 subjects with IGT for 5 years.35 IGT was strongly predictive of the development of type 2 diabetes during this period, although other cardiometabolic risk factors also significantly predicted new-onset diabetes (Figure 4). In addition, the San Antonio Heart Study demonstrated that IGT and the metabolic syndrome increased synergistically the risk of developing type 2 diabetes (Figure 5).36 Patients who go on to develop type 2 diabetes tend to have more cardiometabolic risk factors compared with those who do not, including abdominal obesity, high triglycerides, low HDL-cholesterol, fasting hyperglycaemia and hyperinsulinaemia, and high blood pressure.37 Thus, common cardiometabolic risk factors drive an elevated risk of CV disease and progression from pre-diabetic dysglycaemia to clinical diabetes, and elevations in the risk of CV disease begin long before diabetes is diagnosed.
Conversely, interventions designed to prevent or delay diabetes onset result in improvements in CV risk profiles. The intensive lifestyle interventions in the Diabetes Prevention Program (DPP)31 in the USA induced significant improvements, relative to patients receiving placebo and standard lifestyle advice, in body weight, blood pressure, and indices of atherogenic dyslipidaemia, namely, increased levels of HDL-cholesterol, and reduced levels of triglycerides and small, dense (Pattern B) LDL-cholesterol.38 Treatment with metformin also resulted in improvements in cardiometabolic risk factors, though to a lesser extent. The Finnish Diabetes Prevention Study, compared an intensive lifestyle intervention with standard lifestyle advice in a manner similar to that in the DPP.32 This intervention reduced blood pressure and triglycerides in the first year of treatment32 and increased insulin sensitivity over four years of treatment, with the magnitude of improvement strongly correlated with changes in body weight.39 A significant reduction in the incidence of a composite CV event [HR 0.51 (95% CI 0.28–0.95), P=0.03], of MI [HR, 0.09 (95% CI 0.01 to 0.72), P=0.02], and of new cases of hypertension [HR 0.66 (95% CI 0.49–0.89), P=0.006] was observed following randomization to acarbose, compared with placebo, in the STOP-NIDDM study.40 However, the CV outcomes data were based on a relatively small number of endpoints, and should be interpreted with some caution.
Abdominal obesity
The prevalence of abdominal obesity, according to NCEP/ATPIII criteria (waist circumference >102 cm for men and >88 cm for women18) is also high and growing. In an NHANES cohort recruited between 1998 and 1994, 30.1% of men had abdominal obesity; by 1999–2000, the prevalence of this cardiometabolic risk factor had increased to 36.0% (an increase in prevalence of 20%).41 A comparable increase in the prevalence of abdominal obesity was observed in women during this period, from 45.7 to 51.9% (increase in prevalence of 14%). These overall figures conceal potentially important differences between ethnic groups.42 The prevalence of abdominal obesity was markedly lower in African-American men (23.3%) compared with White men (30.5%) or Mexican-American men (30.6%), but higher in African-American and Mexican-American women (62.1 and 62.7%, respectively), compared with White women (43.5%). Most cases of the metabolic syndrome that physicians will encounter in their daily practice are likely to be associated with abdominal obesity.
A growing database of clinical evidence suggests that abdominal obesity is a stronger predictor of adverse CV outcomes than BMI. A prospective study in a consecutive series of 756 men or women undergoing coronary angiography evaluated the prognostic significance of abdominal obesity (waist circumference or waist-hip ratio) and BMI, with regard to clinical outcomes.43 BMI did not correlate significantly with the incidence of vascular or all-cause mortality, or the incidence of major coronary events during an average of 2.2 years of prospective follow-up. In contrast, waist circumference correlated significantly with vascular mortality in men (OR adjusted for age smoking and cholesterol [2.3 (95% CI 1.2–4.6), P=0.017] and women [8.7 (95% CI 1.8–42.7), P=0.008], with similar results for waist-hip ratio. Indeed, both waist circumference and waist-hip ratio were significantly associated with adverse vascular outcomes even after multivariate adjustment for BMI and other cardiometabolic risk factors (Figure 6).
A further analysis based on 10.6 years of follow-up of a cohort of 1346 men in the Finnish Monitoring of Trends and Determinants in Cardiovascular Disease study evaluated the influence of increasing measures of adiposity on the risk of CV events.44 The RR of an acute coronary event in men with the highest quartile of waist circumference (>95.5 cm) was 2.02 (95% CI 1.17–3.48), compared with the lowest quartile (P=0.012). Measuring abdominal obesity by quartiles of waist-hip ratio (highest quartile ≥0.98) gave a similar increased RR [2.91 (95% CI 1.49–5.67), P=0.002]. In contrast, men in the highest quartile for BMI (>28.7 kg/m2) were not at increased risk of acute coronary events, with a RR of 1.52 (05% CI 0.88–2.63), compared with the lowest quartile (P=0.137). Finally, data from the San Antonio Heart Study and the Nurses Health Study45 showed that increasing waist circumference or waist-hip ratio increased the risk of developing coronary heart disease or the metabolic syndrome, respectively, at each level of BMI. These observations are consistent with the finding that abdominal obesity accounted for about one-fifth of the total population-attributable risk of a first MI in the InterHeart study, a large case–control study involving 29,972 participants in 52 countries.46
Excess intra-abdominal adiposity increases overall cardiometabolic risk in part through alterations in the secretion of a series of biologically active molecules (adipokines). These include increased secretion of free fatty acids, which can induce insulin resistance in muscle and β-cell toxicity in the pancreas, inflammatory mediators, such as TNFα, IL-6, resistin and PAI-1, and decreased secretion of the cardioprotective adipokine, adiponectin.47–49 Increased secretion of IL-6 from intra-abdominal adipocytes stimulates hepatic secretion of C-reactive protein, a marker of chronic low-grade systemic inflammation. Elevated levels of these inflammatory markers are significantly associated with the development of arterial stiffness, an early sign of atherosclerosis.50 The circulating concentration of C-reactive protein has been shown to increase linearly according to the number of cardiometabolic risk factors present.51
Conclusions
An increasing prevalence of obesity, especially abdominal obesity, is driving the global pandemic of diabetes with its associated burden of insulin resistance and CV complications. Abdominal obesity is particularly important, as excess intra-abdominal adiposity increases cardiometabolic risk directly, via altered secretion of adipokines and indirectly via promotion of insulin resistance and the metabolic syndrome. Risk stratification should include measurement of waist circumference as an index of intra-abdominal adiposity, and therapeutic interventions should focus on the management of intra-abdominal adiposity, insulin resistance, and inflammation.
. | Diabetes . | |
---|---|---|
. | Yes . | No . |
. | ||
Prior MI | ||
Yes | 45.0 | 18.8 |
No | 20.2 | 3.5 |
. | Diabetes . | |
---|---|---|
. | Yes . | No . |
. | ||
Prior MI | ||
Yes | 45.0 | 18.8 |
No | 20.2 | 3.5 |
. | Diabetes . | |
---|---|---|
. | Yes . | No . |
. | ||
Prior MI | ||
Yes | 45.0 | 18.8 |
No | 20.2 | 3.5 |
. | Diabetes . | |
---|---|---|
. | Yes . | No . |
. | ||
Prior MI | ||
Yes | 45.0 | 18.8 |
No | 20.2 | 3.5 |
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