Statins and diabetes risk: Fact, fiction, and clinical implications
ABSTRACTStatin drugs now carry a US Food and Drug Administration warning that they may increase the risk of diabetes mellitus and may worsen glycemic control in patients who already have diabetes. Though the association is clear, until some contradictory observations can be resolved and plausible mechanisms of action elucidated, causality cannot be established. From a clinical standpoint, there is currently no evidence that elevations in blood glucose while taking lipid-lowering drugs are associated with an increased risk of cardiovascular events or that they attenuate the beneficial effects of the therapy. Until further study is done, statins should continue to be used based on a careful assessment of risk and benefit.
KEY POINTS
- The evidence from individual clinical trials is mixed, but meta-analyses indicate that statin therapy is associated with approximately a 9% higher risk of diabetes (an absolute difference of about 0.4%).
- We need to interpret this information cautiously. Many potentially confounding factors are involved, and rigorous prospective trials are needed to examine this issue.
- The benefit of preventing serious cardiovascular events seems to outweigh the higher risks of diabetes and poorer glycemic control, and we should continue to give statins to patients at moderate to high risk, including those with diabetes, with vigilance for these side effects.
Statin dose as a risk factor
Intensive-dose statin therapy has been shown to reduce cardiovascular risk more than low-dose or moderate-dose therapy, thus supporting more aggressive treatment of LDL-C in higher-risk patients. However, some controlled studies comparing more-potent with less-potent statin regimens suggest that there may also be a higher risk of incident diabetes at higher doses.21–24
In a post hoc analysis of the Pravastatin or Atorvastatin Evaluation and Infection Therapy– Thrombolysis in Myocardial Infarction 22 (PROVE-IT TIMI 22) trial,21 patients who had experienced an acute coronary syndrome had a greater increase in hemoglobin A1c if treated with atorvastatin 80 mg/day than with pravastatin 40 mg/day.
Waters et al23 reported a higher risk of new diabetes with atorvastatin 80 mg than with placebo and a trend toward a higher risk with atorvastatin 80 mg than with atorvastatin 10 mg or simvastatin 20 mg.
In contrast, a review by Yousef et al24 of the data from the Enhanced Feedback for Effective Cardiac Treatment (EFFECT) study did not find a higher diabetes risk with more intensive statin therapy based on the magnitude of LDL-C reduction. A propensity-matched examination of deaths, recurrent acute ischemic events, or new diabetes in patients previously hospitalized with myocardial infarction found no differences in these end points each year out to 5 years. The risk of diabetes was in fact lower (but the difference was not statistically significant) in the high-dose groups out to 5 years. The risk of myocardial infarction or death was numerically different in the high-dose groups, but the difference was not statistically significant.
Preiss et al25 in 2011 performed a meta-analysis of the impact of intensity of statin therapy on diabetes risk. They examined data from 32,752 participants without diabetes at baseline in five randomized controlled trials with more than 1,000 participants and more than 1 year of follow-up, comparing high-dose therapy against moderate-dose statin therapy.21,22,26–28 New diabetes was considered present if there was an adverse event report of diabetes, if glucose-lowering drugs were started, or if two fasting plasma glucose measurements were higher than 7 mmol/L (126 mg/dL).
Diabetes developed in 1,449 (8.8%) of the intensive-therapy group and 1,300 (8.0%) of the moderate-therapy group (OR 1.12, 95% CI 1.04–1.22). In contrast, incident cardiovascular disease occurred in 3,134 (19.1%) of the intensive-therapy group and 3,550 (21.7%) of the moderate-therapy group (OR 0.84, 95% CI 0.75–0.94). Therefore, there was an 0.8% absolute increase in diabetes cases on high-dose statins and a 2.6% absolute reduction in adverse cardiovascular events.
CAUTION IN INTERPRETING THESE DATA
There are many reasons for caution in interpreting these studies.
The trials were not designed to look for diabetes
The data supporting the relationship between statin therapy and higher risk of diabetes are primarily from observational studies. These studies were not prospectively designed to address this question, and we therefore need to view this as association and not as causation.
The definition of diabetes varied between trials, and new-onset diabetes was often not rigorously screened for. In many trials the outcome of diabetes was at least partially based on nonstandardized, nonadjudicated physician reporting.
Consequently, if statins reduce the risk of diabetes, the results from WOSCOPS may overstate the reduction, since this study used a non-standard definition of incident diabetes (fasting plasma glucose > 126 mg/dL plus a > 36 mg/dL increase from baseline). When Sattar et al11 reanalyzed WOSCOPS data using a more standard definition, they found a smaller effect.
On the other hand, nonstandardized physician reporting may overstate an adverse effect. Sattar et al11 also found that when fasting plasma glucose levels alone were used as the definition for diabetes, the overall risk was attenuated and was no longer statistically significant (OR 1.07, 95% CI 0.97–1.17).
Perhaps statin therapy uncovers diabetes only in people at risk of diabetes
Perhaps statin therapy uncovers diabetes only in people at higher baseline risk of developing diabetes. Therefore, this adverse effect may be restricted to certain groups and not applicable to the general population.
In JUPITER, one of the two trials in which, on independent analysis, statin use was associated with new diabetes, 77% of patients in the rosuvastatin group who developed diabetes had impaired fasting glucose at entry and therefore were at higher risk of developing diabetes.6
Possibly, the relationship is driven by preexisting metabolic syndrome or other risk factors for diabetes. In the two studies that reported a statistically significantly higher incidence of new diabetes, more than 40% of patients in JUPITER met the criteria for metabolic syndrome, and metabolic syndrome, which increases in prevalence with age, was likely more prominent in the elderly population in PROSPER.
Waters et al23 grouped patients according to whether they had risk factors for diabetes (impaired fasting glucose, obesity, elevated triglycerides, and hypertension) and found that those who had none or one of these risk factors had no difference in the rate of new-onset diabetes with either moderate or intensive statin therapy, but the risk was pronounced in those who had three or four risk factors.
Ridker et al29 reanalyzed the JUPITER data from patients who did not have cardiovascular disease at baseline. Overall, for every 54 new cases of diabetes in follow-up, 134 cardiovascular events or deaths were prevented. In subgroup analysis, those who had one or more risk factors for diabetes at baseline (metabolic syndrome, impaired fasting glucose, obesity, or hemoglobin A1c > 6%) had a 39% reduction in the primary end point and a 28% increase in new diabetes. Those who had none of these risk factors had a 52% lower rate of cardiovascular events but no increase in diabetes.
Other confounding factors
Bias and confounding factors are difficult to control for in studies without prospectively defined, recognized, and analyzed outcomes.
Although it may be a bit of a stretch, residual confounding factors such as myalgia side effects while on statins may reduce exercise in the statin-treatment groups. Perhaps a change to a healthier lifestyle after cardiovascular events may be more common in placebo groups. Improved survival with statins may allow more people at risk of diabetes to live longer and present with the diagnosis.30
