Abstract & Commentary
Synopsis: The analysis of 2 secondary prevention trials with pravastatin demonstrate that pravastatin lowered cardiac mortality and morbidity in diabetics who had LDL cholesterol levels below 125 mg%.
Source: Sacks FA, et al. Circulation. 2002;105:1424-1428.
In 2 large secondary prevention studies of pra-vastatin, risk reduction was not significant in participants who had low baseline LDL-C concentration (ie, < 125 mg/dL).1 Sacks and colleagues conducted an exploratory analysis of participant characteristics, lipid risk factors, and risk reduction in subgroups of these studies.
There were 13,173 participants with coronary heart disease (CHD); 2607 had baseline LDL-C < 125 mg/dL. Those with LDL-C < 125 mg/dL were more likely to be diabetic (15% vs 9%), hypertensive, male, have higher triglycerides, lower HDL-C and similar body mass index (BMI). During a 5.8 year (mean) follow-up, HDL-C and triglycerides were both significantly stronger predictors of recurrent CHD events in participants with LDL-C < than 125 mg/dL than in participants with LDL-C > 125 mg/dL.
The changes in LDL-C and HDL-C were more favorably effected in the nondiabetic group than in the diabetic patients. Despite these findings, in diabetic subjects with low LDL-C, pravastatin decreased CHD events from 34% to 22% (relative risk, 0.56; P = 0.004), significantly different from the nondiabetic participants who did not benefit from pravastatin treatment.
Among patients with CHD who have low LDL-C, diabetics have a much higher rate of subsequent CHD event rates than do nondiabetics. Pravastatin reduced the event rate in diabetics to that of nondiabetic participants. The results also suggest enhanced therapeutic potential for improving HDL-C and triglycerides in patients with CHD who have low LDL-C concentrations.
Comment by Ralph R. Hall, MD, FACP
The clinical benefits of statins have been primarily attributed to their lipid lowering effect. But as Young and Tsao note in a recent editorial, "subgroup analysis of large clinical trials indicates that statin treated individuals have significantly less cardiovascular disease than patients with comparable serum cholesterol levels" who are not receiving statins.2
Statins are known to have many functions other than their lipid lowering effects. They have beneficial effects on inflammation, cellular migration, proliferation, and survival. In the Scandinavian Simvastatin Survival Study, simvastatin reduced the risk of bone fracture. So as Young and Tsao point out, "it is clear that statins have significant noncholesterol lowering effects, both in the vascular and nonvascular systems." Statins improve endothelial function in nondiabetics but recent studies indicate that this may not be the case in diabetes.3
It is important to note the short comings of this study. Sacks et al cautioned that the risk reduction in patients with diabetes was not a prespecified hypothesis, but rather one that emerged from exploratory analysis of patient subgroups. Consequently, despite strong probability values in risk reduction, the observation supporting the use of pravastatin in diabetic patients with LDL-C levels < 125 mg% may have been due to chance.
The number of patients that physicians have to treat in order to prevent an event is very important in the diabetic patient. The cost of drugs to treat glucose levels, lipids, hypertension, and congestive heart failure is overwhelming for these patients. It is not clear, at this time, that all diabetics with low LDL-C should be treated with statins. Until further studies confirm these benefits, the guidelines established by the National Cholesterol Education Program still apply.4
Dr. Hall, Emeritus Professor of Medicine, University of Missouri-Kansas City School of Medicine, is Associate Editor of Internal Medicine Alert.
1. Sacks FM. Circulation. 2000;102:1893-1900.
2. Young AC, Tsao P. Circulation. 2002;105:2937-2938.
3. van Venrooij FV, et al. Diabetes Care. 2002;25:1211-1216.
4. JAMA. 2001;285:2486-2497.