JAMA: Is statin use linked to diabetes, regardless of dose?
While statin therapy is meant to reduce a patient’s risk of cardiovascular events, a meta-analysis has found that the drug class was associated with an excess risk on new-onset diabetes. The meta-analysis was published in the June 21 issue of the Journal of the American Medical Association.

“Given the cardiovascular benefits of statins and the likely increasing use of intensive statin regimens, it is important to quantify any potential long-term risks to enable physicians and patients to make informed choices,” wrote David Preiss, MRCP, of the University of Glasgow in Scotland, and colleagues.

To understand whether specific patient populations are at a higher risk of diabetes when receiving statin therapy, the researchers evaluated the associations between intensive-dose statin therapy and moderate-dose therapy on diabetes and CV events.

The meta-analysis included data from five statin trials—TNT, IDEAL, PROVE IT-TIMI 22, A to Z and SEARCH. The studies enrolled 32,752 nondiabetic patients and mean follow-up was 4.9 years. 

The authors reported that 2,749 patients developed diabetes (1,449 who were administered intensive-dose therapy and 1,300 who received moderate-dose therapy). Of the 32,752 patients, 6,684 patients experienced a cardiovascular event (3,134 in the intensive-dose group and 3,550 in the moderate-dose group).

Of the patients who had experienced an onset of diabetes during the trial, there were 149 more cases of diabetes in the patients’ prescribed intensive statin treatment than those receiving moderate treatment. This equated to two additional cases of diabetes per 1,000 patient years in those receiving intensive-dose therapies.

In addition, the researchers reported 416 fewer patients with cardiovascular events in the patient cohort who received intensive-dose therapy. This equated to 6.5 fewer first major cardiovascular events per 1,000 patient-years among those who received intensive statin therapy. The more intensive dose did not lower all-cause mortality compared with moderate-dose statin therapy (1,318 cases/16,408 patients vs. 1,360 cases/16,342 patients).

The researchers also found that intensive statin therapy was not associated with lower rates of noncardiovascular death compared with moderate-dose statin (559 cases vs. 571 cases). In addition, cardiovascular benefit was similar across all subgroups including those defined by age, HDL cholesterol levels, triglyceride concentration, BMI and FDG level above and below the trial medians at baseline.

“The odds of developing diabetes among participants receiving intensive compared with moderate statin therapy was also similar for patients differing by age, HDL cholesterol level, BMI (2,626 events), and FPG level (1,302 events) at baseline but was higher in those with triglyceride concentrations below the median compared with those with higher triglyceride levels,” the authors wrote.

Of the five studies, two trials studied 80 mg simvastatin (Zocor, Merck Pharmaceuticals) and three studied 80 mg atorvastatin (Lipitor, Pfizer). The researchers found the odds of developing diabetes to be similar for both drugs. However, while there was no increased CV benefit over moderate-dose therapy with simvastatin, patients administered atorvastatin saw significant CV benefit.

Results of a recent meta-analysis published in the Journal of the American College of Cardiology found that higher doses of a statin were associated with an increased risk to develop diabetes. The meta-analysis of three large randomized controlled trials--TNT, IDEAL and SPARCL--found that atorvastatin compared with placebo was associated with an increased risk of new-onset type 2 diabetes. While Waters et al concluded that the benefits of atorvastatin outweighed the risk in patients with coronary or cerebrovascular disease, the researchers noted that the potential risk of new-onset diabetes required careful monitoring.

“In this combined trial population, although the risk of new-onset diabetes and the benefit of cardiovascular event reduction for patients receiving intensive therapy were similar in relative terms, when expressed in absolute terms there was one additional case of diabetes for every 498 patients treated for one year compared with one fewer patient experiencing a cardiovascular event for every 155 patients treated for one year,” Preiss et al wrote.

The researchers said that the potential mechanism to explain the findings of a higher incidence of diabetes with statin therapy remains unknown. However, the researchers said that this could include a direct and off-target effect. “For example, statins may influence muscle or liver insulin action directly, resulting in higher diabetes risk.”

Preiss et al said that it also remains unknown whether statin therapy is associated with a generalized tendency for an increase in diabetes risk in many patients who take statins and whether there is a specific group of patients at a particular risk. Lastly, the researchers said, “Although statin therapy is associated with a higher incidence of diabetes, to what extent this may carry with it the important associated long-term risks of developing microvascular disease is unknown."

Preiss and colleagues concluded that future trials should investigate the impact on glycemic control and treatment requirements in patients who established diabetes. “Our findings suggest that clinicians should be vigilant for the development of diabetes in patients receiving intensive statin therapy,” the authors concluded.