Statin Use Raises Diabetes Risk 'Even in High-Risk Patients'

Liam Davenport

October 23, 2017

Long-term statin use is associated with an increased risk of type 2 diabetes of approximately 30% in individuals at high risk of the disease, even after taking into account known risk factors and potential confounders, say US researchers.

They looked at the development of diabetes among statin users in the Diabetes Prevention Program (DPP), which included more than 3200 participants.

Over 10 years, statin use was linked to a 36% increased risk of being diagnosed with type 2 diabetes, falling to 27% after taking into account baseline risk factors and clinical criteria used to determine the need for statins.

The findings are consistent with previous studies suggesting that statin use substantially increases the risk of type 2 diabetes.

The new study was published online October 23 in BMJ Open Diabetes Research & Care by lead author Jill P Crandall, MD, department of medicine and diabetes research center, Albert Einstein College of Medicine, New York, New York, and colleagues.

As previously reported by Medscape Medical News, a study of more than 8700 Finnish men aged 45 to 73 years showed that over 6 years of statins therapy were linked to a 46% increased risk of type 2 diabetes — more than double prior estimates.

This was followed by recent data from the Australian Longitudinal Study on Women's Health, which indicated that, among almost 8400 women aged 76 to 82 years, the risk of new-onset diabetes ranged from 17% with the lowest statin doses to 51% with the highest doses.

Despite accumulating evidence, the current researchers still maintain that the overall healthcare advice remains unchanged — the benefits of statins outweigh the risks.

"For individual patients, a potential modest increase in diabetes risk clearly needs to be balanced against the consistent and highly significant reductions in myocardial infarction, stroke, and cardiovascular death associated with statin treatment," they state.

They add: "Nonetheless, glucose status should be monitored and healthy lifestyle behaviors reinforced in high-risk patients who are prescribed statins for cardiovascular disease prophylaxis."

First Look at Diabetes Risk From Statins in High-Risk Patients

The researchers point out that the diabetogenic effect of statins has previously been studied in individuals typically at relatively low risk of diabetes and that the incidence of disease was based on self-report, rather than being the primary outcome.

They therefore set out to examine the issue in DPP participants, which included 3234 US adults randomized to intensive lifestyle intervention, metformin, or placebo.

After a mean follow-up of 3.2 years, participants were invited to take part in the DPP outcomes study, which included quarterly lifestyle sessions alongside open-label metformin for those originally randomized to the drug and two additional lifestyle programs per year for those originally randomized to the lifestyle intervention.

Approximately 50% of DPP participants were from ethnic groups and 20% were aged ≥ 60 years. To be included, they had to be aged ≥ 25 years and have a body mass index ≥ 24 kg/m2. They also had to have a fasting plasma glucose (FPG) of 95–125 mg/dL and impaired glucose tolerance, placing them at high risk of type 2 diabetes.

The primary end point was diabetes diagnosis using an annual 75-g oral glucose tolerance test or semiannual FPG level with repeat confirmation testing. Lipids and blood pressure were assessed annually and statin use was based on self-report.

From a baseline of approximately 4%, statin use progressively increased at the 10-year follow-up to reach 35% in the placebo group, 37% in the metformin group, and 33% in the lifestyle intervention group (P = .36 between groups).

Simvastatin was the most commonly used statin, taken by 40% of participants, followed by atorvastatin by 37% and, much less frequently, lovastatin and pravastatin, by 9% and 8%, respectively.

Statins users were typically older and more likely to be men than nonusers but did not differ by ethnicity. Compared with nonusers, they also had modestly higher baseline FPG and HbA1c, higher baseline low-density lipoprotein (LDL) cholesterol and triglycerides, and were more likely to have a history of cardiovascular disease and hypertension.

Taking into account age, sex, and ethnicity, researchers found that statin use was associated with a significantly increased risk of developing diabetes, at a hazard ratio (HR) of 1.36 for all three groups combined.

Further adjustment for baseline diabetes risk factors, including family history of diabetes and FPG, reduced the HR to 1.35, and additional adjustment for statin treatment confounders, such as blood pressure, cholesterol levels, baseline cardiovascular risk factors, and socioeconomic status, lowered the HR to 1.27.

Diabetes risk did not differ depending on statin potency or magnitude of LDL-cholesterol reduction, although longer statin use was significantly associated with greater diabetes risk (HR per visit with statin use, 1.06; P=.007).

Mechanisms Underlying Effect "Poorly Understood"

Discussing the findings, the researchers say that "it has been suggested that statins may 'uncover' diabetes in individuals at high risk, which on a population basis, could result in modest increase in diabetes risk."

They point out, however, that "variation in baseline diabetes risk factors failed to explain the further risk associated with statin therapy in our cohort, and the HR estimate was greatest among our lifestyle participants, who experienced the largest study-related reductions in diabetes risk."

The mechanisms underlying any diabetogenic effect of statins are "poorly understood," they add.

Although several studies have looked at changes in insulin sensitivity during statin use, "we saw no evidence of an effect of statins to modify insulin resistance, assessed as fasting insulin concentrations," they write.

And although statins have been reported to reduce pancreatic beta-cell insulin secretion in vitro, "the relevance to insulin secretion in vivo is not known," they state.

Taken together, evidence from studies published so far points to "an acceleration of typical glycemic deterioration, rather than a unique or statin-specific mechanism," they conclude.

The research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, General Clinical Research Center Program, National Center for Research Resources, Department of Veterans Affairs, National Institute of Child Health and Human Development, National Institute on Aging, National Eye Institute, National Heart, Lung, and Blood Institute, Office of Research on Women's Health, National Institute on Minority Health and Health Disparities, Centers for Disease Control and Prevention, and American Diabetes Association. The research was also supported by Bristol-Myers Squibb, Parke-Davis, LifeScan, Health O Meter, Hoechst Marion Roussel, Lipha (Merck-Sante), Merck-Medco Managed Care, Merck, Nike Sports Marketing, Slimfast Foods, Quaker Oats, McKesson BioServices, Matthews Media Group, and Henry M Jackson Foundation. The authors report no relevant financial relationships.

BMJ Open Diab Res Care. Published online October 23, 2017. Full text

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