An estimated 10 million persons in the U.S. meet the Diabetes Prevention Program, DPP, eligibility criteria for fasting glucose, age, and BMI [1]. Impaired glucose tolerance, 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, CVD [2].

When adjusted for covariates such as BMI, blood pressure, and cholesterol, IGT increased the hazard rate for CVD mortality by 34% [3]. 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 [4]. In NHANES III, however, a cross-sectional association between IGT and nonfatal myocardial infarction and stroke was entirely attributable to traditional CVD risk factors [5].

CVD risk factors are typically present in individuals with IGT [6–8]. 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 [9]. A recent report from NHANES suggests an overall metabolic syndrome prevalence in the U.S. of ~ 22% or ~ 47 million people [10].

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.

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 [10-14] 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.

 

References

  1. Trends in the prevalence and incidence of self-reported diabetes mellitus—United States, 1980–1994. MMWR Morb Mortal Wkly Rep. 1997;46:1014–1018.
  2. Unwin N, Shaw J, Zimmet P, Alberti KGMM. Impaired glucose tolerance and impaired fasting glycaemia: the current status on definition and intervention. Diabet Med. 2002;19:708–723.
  3. DECODE Study Group. Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hr diagnostic criteria. Arch Intern Med. 2001;161:397–405.
  4. Saydah SH, Loria CM, Eberhardt MS, Brancati FL. Subclinical states of glucose intolerance and risk of death in the U.S. Diabetes Care. 2001;24:447–453.
  5. Qureshi AI, Giles WH, Croft JB. Impaired glucose tolerance and the likelihood of nonfatal stroke and myocardial infarction: the Third National Health and Nutrition Examination Survey. Stroke. 1998;29:1329–1332.
  6. Laakso M, Lehto S. Epidemiology of risk factors for cardiovascular disease in diabetes and impaired glucose tolerance. Atherosclerosis. 1998;137:S65–S73.
  7. Rodriguez BL, Curb JD, Burchfiel CM, Huang B, Sharp DS, Lu GY, Fujimoto W, Yano K. Impaired glucose tolerance, diabetes, and cardiovascular disease risk factor profiles in the elderly: the Honolulu Heart Program. Diabetes Care. 1996;19:587–590.
  8. Liao D, Shofer JB, Boyko EJ, McNeely MJ, Leonetti DL, Kahn SE, Fujimoto WY. Abnormal glucose tolerance and increased risk for cardiovascular disease in Japanese Americans with normal fasting glucose. Diabetes Care. 2001;24:39–44.
  9. National Institutes of Health: Third reportof the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). Bethesda, MD, National Institute of Health, 2001 (NIH publ. no. 01-3670)
  10. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the Third National Health and Nutrition Examination Survey. JAMA. 2002;287:356–359.
  11. Goldberg RB, Mellies MJ, Sacks FM, Moye LA, Howard BV, Howard WJ, Davis BR, Cole TG, Pfeffer MA, Braunwald E. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analysis in the Cholesterol and Recurrent Events Trial. Circulation. 1998;98:2513–2519.
  12. Haffner SM, Alexander CM, Cook TJ, Boccuzzi SJ, Musliner TA, Pedersen TR, Kjekshus J, Pyorala K. Reduced coronary events in simvastatin treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study. Arch Intern Med. 1999;159:2661–2667.
  13. Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000;355:253–259.
  14. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999;341:410–418.

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