Statins and Diabetes: Causal Link Reinforced in New Analysis

Treating patients at high risk for diabetes with a statin increases their risk of developing diabetes by approximately 30% over a 10-year period, according to the results of a new observational analysis.

The risk of diabetes is higher than that observed in previous clinical trials, although investigators say that for individual patients the “potential modest increase” in diabetes risk must still be weighed against the “consistent and highly significant reductions” in cardiovascular events with statin therapy.

“Nonetheless, glucose status should be monitored and healthy lifestyle behaviors reinforced in high-risk patients who are prescribed statins for cardiovascular disease prophylaxis,” writes lead investigator Jill Crandall, MD (Albert Einstein College of Medicine, New York, NY), and colleagues online October 23, 2017, in BMJ Open Diabetes Research and Care.  

The risk of diabetes with statin therapy is nothing new, although this latest analysis extends the signal to patients at high risk for diabetes, such as those with elevated fasting plasma glucose levels and impaired glucose tolerance.

The US Food and Drug Administration (FDA) added a warning to the drug’s label as far back as 2012, cautioning prescribers that statin use may cause a small increase in blood glucose levels and raise the risk of diabetes. The FDA decision was based on data from randomized clinical trials and a series of meta-analyses showing a heightened risk of diabetes among statin users.

In 2010, Naveed Sattar, MD (University of Glasgow, Scotland), published a meta-analysis of 13 statin trials with more than 90,000 participants. In that study, treating patients with statin therapy increased the risk of diabetes 9% compared with individuals who did not receive the LDL-lowering drugs. In 2011, another meta-analysis, one that evaluated the effect of dose on diabetes risk, showed that high-dose statin therapy increased the risk of diabetes by 12% compared with a moderate dose.  

To TCTMD, Sattar said that while the study results are not novel, he thinks the risk estimate is inflated. In the observational analysis, there are potential issues of confounding and treatment biases—statin therapy was not randomized—that may result in an overestimation of the diabetes risk, he said.

“Even so, any modest diabetes risk is not a concern for the vast majority of patients at elevated cardiovascular risk, where the heart benefits they gain from statins will substantially outweigh any risk of developing diabetes in the future,” said Sattar.

For Michael Blaha, MD (Johns Hopkins Medical Institute, Baltimore, MD), however, the observational analysis was well-performed and “statistically appropriate,” with the researchers accounting for baseline diabetes risk factors and confounding variables affecting statin therapy.

The analysis suggested a mild to moderate increased of diabetes with statin therapy, which isn’t completely out of line with other studies, particularly given the study’s observational nature and high-risk patient population, said Blaha.

Observational Analysis of Statin Therapy in DPP Trial

The study, which is an analysis of the Diabetes Prevention Program (DPP) Outcomes Study, included 3,234 individuals randomized to one of three treatments for diabetes prevention (placebo, metformin, or lifestyle intervention). Statins at the start of trial were used in approximately 4% of patients, and use was left to the discretion of the treating physicians. At 10 years, approximately one-third of patients had started statin therapy prior to the diagnosis of diabetes.

In the pooled cohort, the risk of diabetes was 27% higher among statin-treated patients. In an analysis stratified by diabetes treatment, there was only a trend toward increased risk among statin users who received the placebo, while diabetes risk was 33% and 43% higher among statin users treated with metformin and managed with lifestyle changes, respectively.   

Although the researchers did not have information on dose, they analysed diabetes risk by statin potency, with atorvastatin, rosuvastatin, simvastatin, and cerivastatin classified as high potency agents. Diabetes risk, however, did not differ between the high- and low-potency statins.

David Preiss, PhD (University of Oxford, England), who led the meta-analysis evaluating diabetes risk by statin dose, pointed out that the risk observed in the present study, which was as high as 36% in the model adjusted only for patient demographics, is substantially greater than any increase observed in statin trials. Such a finding, he said, may have detrimental effects, such as potentially raising concerns in the minds of patients and doctors.

“It mirrors an analysis of the Women’s Health Initiative a few years ago which gained substantial media attention despite its implausible results suggesting that new-onset diabetes on a statin was increased more than 40%, far greater than what we know is truly the case,” Preiss told TCTMD.

New-onset diabetes is generally accepted as a risk of statin therapy, but the risk is in the range of 10% to 20%, he added. Even at the high end of the spectrum, the 20% increased risk of diabetes is likely only among patients receiving maximum doses of the most potent statins, which patients in the DPP Outcomes study were unlikely to receive. 

Preiss agrees with Sattar, as well as with investigators, that given the substantial reduction in cardiovascular events, the risk-benefit ratio heavily favors using statins in patients with cardiovascular disease and in those at medium to high risk.

Making Positive Lifestyle Changes

Equally important, however, is that these new data reinforce the importance of positive lifestyle changes when physicians initiate statin therapy, say the experts.

“Any lifestyle changes also benefit the patients’ hearts so it’s a win-win,” said Sattar. “There is also another positive in that doctors are more regularly checking for risk of diabetes in those about to start statins and, in this way, we are picking up more people at elevated diabetes risk who can gain considerably from more targeted lifestyle interventions to mitigate such risks.”

To TCTMD, Blaha said that whenever he prescribes a statin, he reminds patients the drug isn’t a “free pass” to ignore the need for important lifestyle changes, such as dietary changes and increased physical activity. It also serves a reminder to patients that given the potential increased risk of diabetes with therapy, it’s all the more reason to adhere to diet and exercise.

“It’s just a prudent prevention message that needs to be doubled down on at the time of statin prescription,” said Blaha. Several studies published to date, including one by his group, have shown that an individual’s physical fitness level is protective against developing diabetes from statins. “I also use that as a reason to tell my patients exercise and physical activity is all the more important now that you’re going on a statin,” he stressed.