An estimated 10 million persons in the U.S. meet the DPP eligibility criteria for fasting glucose, age, and BMI (26
). IGT, although not usually considered a clinical disease in its own right, is recognized as a risk factor for the future development of both diabetes and cardiovascular disease (27
). Stern (28
) hypothesized that both stem from a “common soil” of risk factors with variable expression of pathophysiologic changes over time. Metaregression analysis demonstrates a continuous and positive relationship between 2-h postglucose levels and the subsequent development of CVD (29
). When adjusted for covariates such as BMI, blood pressure, and cholesterol, IGT increased the hazard rate for CVD mortality by 34% (30
). The National Health and Nutrition Examination Survey (NHANES) II data showed a 42% increased relative risk of all causes of mortality and a 19% increased risk for CVD death among the subset with IGT (31
). In NHANES III, however, a cross-sectional association between IGT and nonfatal myocardial infarction and stroke was entirely attributable to traditional CVD risk factors (32
). These data highlight the need for a randomized controlled clinical trial such as DPP to better assess causality.
CVD risk factors are typically present in individuals with IGT (33
). Increased abdominal obesity together with hyperinsulinemia, hypertension, elevated triglyceride levels, and lower HDL cholesterol levels are observed in patients with IGT and constitute the core characteristics of metabolic syndrome as defined by ATP III (36
). A recent report from NHANES suggests an overall metabolic syndrome prevalence in the U.S. of ~ 22% or ~ 47 million people (37
The DPP cohort entered the study with prevalence of hypertension of 30%, hypertriglyceridemia of 29%, and hypercholesterolemia of 44%. Annual assessment of these outcomes demonstrated progressive increases in prevalence of hypertension and dyslipidemia in the placebo and metformin groups with attenuation by intensive lifestyle intervention. Aggressive blood pressure management was mandated by protocol, and all treatment groups demonstrated absolute reductions in systolic and diastolic blood pressures; however, intensive lifestyle intervention achieved this with only 5% additionally requiring antihypertensive therapy, compared with 14–15% in the placebo and metformin participants.
Annual assessment of lipids was performed and placed into risk categories according to the ATP II standards applicable at the time. Although mean levels of total cholesterol and LDL cholesterol changed very little during the course of the trial and did not differ among treatment groups, the need for LDL-lowering pharmacologic therapy was significantly less in the intensive lifestyle group compared with that in either placebo or metformin groups (both P < 0.001). Triglyceride levels fell during intensive lifestyle intervention compared with the other treatments, and again participants in this group required less pharmacologic intervention (12% of participants) compared with placebo and metformin (16 and 20.1% with P < 0.03, respectively). The deterioration in lipid levels and blood pressure demonstrated by those in the placebo group reflect the high-risk status of our population with IGT and the lack of efficacy of metformin in modulating that risk.
Reductions in serum triglyceride levels were accompanied by concomitant increases in HDL cholesterol levels and LDL cholesterol size in the intensive lifestyle group, sustained over the course of the study. LDL density, assessed by Rf, was comparable among treatment groups at study entry with mean values at the threshold for the small dense LDL phenotype. Intensive lifestyle intervention caused a prompt increase in LDL size with mean values well into the large buoyant range and a significant (P < 0.001) reduction in the percentage of patients with the proatherogenic phenotype B.
The few CVD events in the DPP did not provide adequate statistical power to test for a significant impact of lifestyle interventions. The ongoing additional 5 years of follow-up in the DPP Outcomes Study will permit additional study of the impact of DPP interventions on CVD events.
In summary, intensive lifestyle intervention reduced known risk factors for CVD including hypertension, high triglyceride levels, low HDL levels, and small dense LDL. Such risk factor modification in other trials (38
) resulted in substantial reductions in both fatal and nonfatal CVD events, suggesting that prolonged observation of our cohort may ultimately demonstrate a beneficial CVD effect of lifestyle change.