CLINICAL DIABETES These pages are best viewed with Netscape version 3.0 or higher or Internet Explorer version 3.0 or higher. When viewed with other browsers, some characters or attributes may not be rendered correctly. LANDMARK STUDIES Atherosclerosis in Normolipidemic Patients With Diabetes or Impaired Fasting Glucose Levels: It's Time for an Aggressive Approach to Lipids Reviewed by Kevin D. O'Brien, MD STUDY Goldberg RB, Mellies MJ, Sacks FM, Moye LA, Howard BV, Howard WJ, Davis BR, Cole TG, Pfeffer MA, Braunwald E, for the CARE investigators: Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the Cholesterol and Recurrent Events (CARE) Trial. Circulation 98:2513-19, 1998. SUMMARY Objective. This study, a post-hoc analysis of the Cholesterol and Recurrent Events (CARE) Trial, examined whether lipid-lowering therapy with the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor pravastatin is of benefit in normocholesterolemic coronary heart disease (CHD) patients with diabetes or impaired fasting glucose levels. Design and Methods. The CARE Trial was a 5-year study in which 4,159 post-myocardial infarction (MI) patients with total cholesterol levels <240 mg/dl were randomized either to placebo or to 40 mg/day of pravastatin. This analysis compares risk of coronary events and the effect of pravastatin treatment in the 586 patients (14.1%) in the CARE Trial who reported a clinical diagnosis of diabetes at trial entry as compared to those in whom a clinical diagnosis of diabetes was absent. It also evaluates risk of events and effect of therapy in 342 patients with impaired fasting glucose levels (110–125 mg/dl). Analyses were performed on an intention-to-treat basis. Results. Comparison of baseline demographics and clinical characteristics showed that, as compared to nondiabetic subjects, diabetic subjects were slightly older, were more likely to have histories of congestive heart failure, stroke, claudication, hypertension, and coronary artery bypass graft (CABG) surgery, and were less likely to have had a percutaneous transluminal coronary angioplasty (PTCA) procedure. As compared to nondiabetic subjects, diabetic subjects had slightly but significantly lower low-density lipoprotein (LDL, 139 vs. 136 mg/dl) and high-density lipoprotein (HDL, 39.0 vs. 37.6 mg/dl) cholesterol levels and slightly higher levels of triglycerides (154 vs. 164 mg/dl). On pravastatin, LDL cholesterol levels were 96 + 21 mg/dl in diabetic subjects and 99 + 19 mg/dl in nondiabetic subjects. Reductions in total cholesterol and triglycerides were also similar in both groups. In the placebo group, the 5-year incidence of the primary endpoint (CHD death or nonfatal MI) was 67% higher in diabetic subjects than nondiabetic subjects (20 vs. 12%), and diabetes conferred a 167% increase in risk of stroke (8 vs. 3%). Diabetic subjects were also significantly more likely to suffer fatal MI, develop unstable angina, or undergo CABG surgery. Pravastatin treatment resulted in similar relative reductions in coronary event risk in diabetic and nondiabetic subjects (–25% and –23%, respectively), but because the absolute risk of coronary events was substantially higher in diabetic subjects, their absolute risk reduction was greater (–8.1% and –5.2%, respectively). Importantly, impaired fasting glucose levels were associated with a 30% higher absolute risk of coronary events as compared to normal fasting glucose levels. However, the impaired- and normal-fasting-glucose-level groups had similar relative risk reductions for coronary events with pravastatin treatment. Conclusion. In patients with normal cholesterol levels, both diabetes and impaired fasting glucose levels confer a substantial increase in risk of recurrent coronary events. Pravastatin treatment substantially reduces this risk in both groups. COMMENTARY It has been well established that diabetes confers an increased risk of coronary mortality in patients without known coronary disease,1 as well as increased risk for both short-term2 and long-term1,3 mortality following MI. A recent population-based study from Finland1 emphasized the dramatic effect of diabetes on coronary risk by demonstrating that diabetic patients without prior MI had a coronary mortality risk equal to that of nondiabetic patients with prior MI. While the benefit of lipid-lowering therapy in reducing coronary mortality in nondiabetic patients has been well established, the question as to whether lipid-lowering therapy is of specific benefit in diabetic patients has been addressed only recently, by two studies. The first of these, a subgroup analysis of the Scandinavian Simvastatin Survival Study (4S), demonstrated that treatment with the HMG-CoA reductase inhibitor simvastatin reduced coronary events in hyperlipidemic diabetic subjects by 55%.3 The second is this landmark study by Goldberg and associates, which extends the findings of the 4S subgroup analysis in several important ways. First, it demonstrates that the benefit of HMG-CoA reductase inhibition in coronary risk reduction extends to diabetic patients with "normal" levels of cholesterol. Because the risk of coronary events in these patients is so substantial, pravastatin therapy prevented 81 coronary events/1,000 diabetic patients treated. Thus, the strategies of aggressive glycemic control, for which microvascular disease benefit is clear, and aggressive lipid-lowering, for which macrovascular disease benefit is now proved, are complementary. Secondly, Goldberg and associates have demonstrated that lipid-lowering therapy not only benefits normocholesterolemic diabetic patients but also normocholesterolemic individuals with impaired fasting glucose levels. It has been estimated that 10–20% of patients have clinically evident coronary and/or peripheral vascular disease at the time of diagnosis of type 2 diabetes.4 By demonstrating a 30% increase in coronary event risk in patients with impaired fasting glucose levels, this study confirms that the increased risk of macrovascular events extends to the period before the development of overt diabetes. How should these results be translated into clinical practice? First, they strongly support the recent recommendation of the American Diabetes Association (ADA) that patients with diabetes should be treated aggressively with lipid-lowering therapy to a goal of LDL cholesterol <100 mg/dl.5 Aggressive gycemic control, while important, simply is not sufficient to minimize the risk of coronary and noncoronary vascular events in diabetic patients. The HMG- CoA reductase inhibitors simvastatin and pravastatin are highly effective in lowering LDL cholesterol levels, and both have now been proved to be safe and effective in diabetic patients with known coronary disease.3,6 Second, this study suggests that patients with impaired fasting glucose levels should also be strongly considered for lipid-lowering therapy. My preference is to include an impaired fasting glucose level as a risk factor when using the National Cholesterol Education Program Adult Treatment Panel II guidelines to make decisions about lipid-lowering therapy.7 In summary, data has accumulated over the past 2 years that confirms the benefits of aggressive lipid lowering in both hypercholesterolemic and normocholesterolemic diabetic patients with CHD. Further, the substantial risk of cardiovascular events in diabetic patients without known CHD suggests that the aggressive approach to lipid lowering advocated by the ADA is warranted in these patients as well. Finally, patients with impaired fasting glucose levels clearly are at increased risk for cardiovascular events, and lipid-lowering therapy may be beneficial in these patients, as well. References 1Haffner S, Lehto S, Ronnemaa T, Pyorala K, Laakso M: Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 339:229-34, 1998. 2Woodfield S, Lundergan C, Reiner J, Greenhouse S, Thompson M, Rohrbeck S, Deychak Y, Simoons M, Califf R, Topol E, Ross A: Angiographic findings and outcome in diabetic patients treated with thrombolytic therapy for acute myocardial infarction: the GUSTO-I experience. J Am Coll Cardiol 28:1661-69, 1996. 3Pyorala K, Pedersen T, Kjekshus J, Faergeman O, Olsson A, Thorgeirsson G, the Scandinavian Simvastatin Survival Study (4S) Group: Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. Diabetes Care 20:614-20, 1997. 4Colwell J: Pharmacological strategies to prevent macrovascular disease in NIDDM. Diabetes 46:S131-34, 1997. 5American Diabetes Association: Position statement: management of dyslipidemia in adults with diabetes. Diabetes Care 21:179-82, 1998. 6Goldberg R, Mellies M, Sacks F, Moye L, Howard B, Howard W, Davis B, Cole T, Pfeffer M, Braunwald E: Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels. Circulation 98:2513-19, 1998. 7National Cholesterol Education Program (NCEP): Summary of the second report of the NCEP expert panel on detection, evaluation, and treatment of high blood cholesterol (Adult Treatment Panel II). JAMA 209:3015-23, 1993. Kevin D. O'Brien, MD, is an assistant professor of medicine in the Division of Cardiology at the University of Washington in Seattle. Note of disclosure: Dr. O'Brien has received honoraria for speaking engagements from and is a paid consultant for Merck Corporation, which manufactures cholesterol-lowering drugs. He has also received honoraria from Bristol-Myers Squibb, manufacturer of the cholesterol-lowering drug pravastatin, which was used in the CARE trial. Copyright © 1999 American Diabetes
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