Statins unlikely to increase diabetes risk in some patients

Patients who do not have risk factors for diabetes are unlikely to develop the disease due to statin use, and although statins may increase the rate of new onset diabetes (NOD) in patients at high risk of the disease, the benefits of reducing cardiovascular events outweigh the complications of diabetes. These are the conclusions of a meta-analysis published Jan. 15 in the Journal of the American College of Cardiology.

David D. Waters, MD, of San Francisco General Hospital in California, and colleagues reviewed data from the TNT (Treating From New Targets) and IDEAL (Incremental Decrease in Endpoints Through Aggressive Lipid Lowering) trials, attempting to stratify the risk of NOD among patients receiving high or low doses of statins according to the presence of diabetes risk factors. The TNT study comprised 10,001 patients ranging in age from 35 to 75 years, who had documented stable coronary disease and an off-therapy low-density lipoprotein-cholesterol between 3.4 and 6.5 mmol/l. They were randomized to atorvastatin at either 10mg or 80 mg per day.

The 8,888 IDEAL patients were under 80 years of age, had experienced an MI, and were randomized to simvastatin (Zocor, Merck) at 20 mg to 40 mg per day, or atorvastatin 80 mg per day. Researchers followed TNT patients for a mean of 4.9 years, while IDEAL patients were followed for a mean of 4.8 years. In both trials, fasting blood glucose (FBG) was measured at every six month visit.

For the purpose of their meta-analysis, Waters et al defined NOD as at least two post-baseline FBG levels of at least 7mmol/l (126mg/dl) and at least one post-baseline glucose measurement greater than 2mmol/l (36 mg/dl) above baseline. They also included those patients for whom NOD was reported as an adverse event. They excluded patients who had diabetes at baseline, had a baseline FBG of 7 mmol/l or higher, or for whom insufficient data was available. The final cohort for meta-analysis was 15,056 patients.

The cardiovascular (CV) endpoints were coronary heart disease death, nonfatal MI, resuscitated cardiac arrest, fatal and nonfatal stroke. The defined risk factors for diabetes were FBG greater than 100mg/dl, history of hypertension, body mass index greater than 30 and fasting triglycerides greater than 150 mg/dl.  A total of 8,825 patients had either zero or one risk factor for diabetes at baseline (low risk) and 6,231 patients had two to four risk factors (high risk).

In the low risk group, 142 of the 4,407 (3.22 percent) patients randomized to receive 80 mg/day atorvastatin (high-dose group) developed NOD, as did 148 of 4,418 (3.35 percent) patients randomized to either 10mg/day atorvastatin or simvastatin (low-dose group). CV endpoints were experienced by 8.51 percent of the high-dose group and by 9.8 percent of the low-dose group.

In the high-risk group, 14.32 percent of those receiving high doses developed NOD, as did 11.86 percent of those patients receiving low doses. These high-risk patients experienced CV endpoints at a rate of 10.07 percent for those receiving high doses of statins and 12.02 percent for those receiving low doses.

Among all patients, 9.16 percent who received high doses of statins and 10.72 percent who received low doses experienced at least one CV endpoint during the follow-up period. In the high-dose group, 690 patients experienced 874 endpoint events, and 806 patients taking low doses experienced 1,038 events. The researchers reported that high doses of statins were associated with a nonstatistically significant reduction in the rate of multiple events. The most common CV event was nonfatal MI (1,030), followed by 458 nonfatal strokes, 355 coronary heart disease deaths, 48 fatal strokes and 48 resuscitated cardiac arrests.

The results indicated that high doses of statins are associated with increased risk of NOD in patients with two to four risk factors for diabetes, but not for patients at low risk of diabetes. “These results should reassure physicians treating patients at low risk of diabetes,” the authors wrote. “Such patients do not appear to incur an increased risk of diabetes with high-dose atorvastatin and derive benefit in terms of CV event reduction.”

Among the high-risk group of 6,231 patients, “treatment with atorvastatin 80 mg compared with a lower statin dose was associated with 80 more cases of NOD and the prevention of 94 major CV events in 58 patients,” Waters et al reported.

The researchers pointed out that although diabetes is a serious disease which limits quality of life, “the impact of NOD is relatively minor compared with the CV events included in this analysis. ...Many patients with established vascular disease, such as those in this study, will die from an atherosclerotic event before they develop complications from diabetes.”

Acknowledged limitations of the study included the fact that diabetes was not a defined endpoint in the TNT or IDEAL trials, and the definition of NOD adopted for this analysis may underestimate the incidence of NOD. Also, almost all the participants in the TNT and IDEAL trials were white, and the results may not be applicable to other populations.