Statins may affect diabetes risk primarily in patients with prediabetes

There was a dose-response relationship between statin use and new diabetes diagnoses, with most cases seen in patients whose glycemic markers were close to the diagnostic threshold for diabetes at baseline, an individual-patient meta-analysis found.

Statins may increase risk for new diabetes diagnoses primarily in patients with prediabetes, a new study found.

Researchers from the Cholesterol Treatment Trialists' Collaboration performed a meta-analysis of individual-patient data from double-blind randomized controlled trials involving at least two years of statin therapy and 1,000 participants. The goal of the study was to evaluate the effects of assignment to statins on new-onset diabetes (based on diabetes-related adverse events, use of new glucose-lowering medications, glucose concentrations, or HbA1c values) and worsening glycemia in people who had diabetes (defined as complications of glucose control, increased use of glucose-lowering medication, or an HbA1c increase of ≥0.5%). The results were published March 27 by The Lancet Diabetes and Endocrinology.

Nineteen trials involving 123,940 participants, 25,701 (21%) with diabetes, compared statins and placebo over a median follow-up of 4.3 years. In addition, four trials compared more- versus less-intensive statin therapy in 30,724 participants, 5,340 (17%) with diabetes, over a median follow-up of 4.9 years. Allocation to low- or moderate-intensity statin therapy versus placebo resulted in a 10% proportional increase in new-onset diabetes (2,420 of 39,179 vs. 2,214 of 39,266 [1.3% vs. 1.2% per year]; rate ratio [RR], 1.10 [95% CI, 1.04 to 1.16]), while allocation to high-intensity statin therapy resulted in a 36% proportional increase (1,221 of 9,935 vs. 905 of 9,859 [4.8% vs. 3.5% per year]; RR, 1.36 [95% CI, 1.25 to 1.48]).

The researchers noted that the rate of new-onset diabetes in the placebo group for each trial depended mostly on the proportion of participants who had at least one follow-up measurement of HbA1c and that this was much higher in high-intensity trials than in low- or moderate-intensity ones. "Consequently, the main determinant of the magnitude of the absolute excesses in the two types of trial was the extent of HbA1c measurement rather than the proportional increase in risk associated with statin therapy," they wrote.

In participants without diabetes at baseline, mean glucose level increased by 0.04 mmol/L (0.7 mg/dL) with both low- to moderate-intensity statins and high-intensity statins, and mean HbA1c level increased by 0.06% with low- to moderate-intensity statins and 0.08% with high-intensity statins. Most cases of new-onset diabetes occurred in participants who already had high-normal glycemia at baseline. Among participants who had diabetes at baseline, the RRs for worsening glycemia were 1.10 (95% CI, 1.06 to 1.14) for low- or moderate-intensity statins and 1.24 (95% CI, 1.06 to 1.44) for high-intensity statins versus placebo.

The authors noted that the trials included in their analysis weren't designed to test the effect of statins on diabetes diagnoses and that they could not determine which type of diabetes patients had, among other limitations. "Among people without diabetes, statin therapy produces a dose-dependent increase in the rate of diagnosis of diabetes by inducing a very small increase in glycaemia. People are most at risk of exceeding the diagnostic threshold for diabetes due to statin therapy if their glycaemic control is close to the threshold before treatment," they concluded. "The diabetes-related risks arising from the small changes in glycaemia resulting from statin therapy are greatly outweighed by the benefits of statins on major vascular events when the direct clinical consequences of these outcomes are taken into consideration."

An accompanying editorial agreed with the authors that the cardiovascular benefits of statins in high-risk patients are unlikely to be outweighed by the potential increased incidence of diabetes and said that the study findings demonstrate the importance of holistic care. "As people at risk for cardiovascular outcomes are also at risk for type 2 diabetes, any prescription of a statin should be accompanied by promoting proven strategies to prevent or delay diabetes, such as modest weight reduction and increased physical activity," the editorialists wrote. "Finally, these findings emphasise the importance of always being alert for harmful adverse effects, even with the most beneficial and successful preventive therapies."