POSSIBLE EXPLANATIONS, BUT NO UNIFYING MECHANISM
If mechanisms could be identified to explain the association between statins and diabetes, this would strengthen the argument that it is a cause-and-effect relationship. Many explanations have been proposed as to how statins may influence glucose metabolism and insulin sensitivity.31–34 These are possible explanations based on other observations.
In theory, statins may improve insulin sensitivity via their anti-inflammatory effect, since inflammatory markers and proinflammatory cytokines have been linked with insulin resistance. However, other effects of statins may adversely affect glycemic control.
In vivo analysis has shown that some but not all statins increase insulin levels and decrease insulin sensitivity in a dose-dependent fashion. Some statins decrease adiponectin and may worsen glycemic control through loss of adiponectin’s proposed protective anti-proliferative and antiangiogenic properties. In vitro studies and animal studies have demonstrated a decrease in expression of insulin-responsive glucose transporter 4 (GLUT4) with atorvastatin, and an increase in GLUT1. It has been hypothesized that reduction in isoprenoid biosynthesis or decreased insulin signaling may explain these effects and that changes in glucose transport in adipocytes may cause insulin resistance. Other studies suggest that dysregulation of cellular cholesterol may attenuate beta-cell function. Impaired biosynthesis of ubiquinones may result in delayed production of adenosine triphosphate and consequently diminish insulin release.
But different effects have been reported for atorvastatin, simvastatin, and pravastatin, arguing against a unifying explanation or, alternatively, suggesting that differences in lipophilicity and potency among statins are important. Hydrophilic statins may be less likely to be taken up by extrahepatic cells such as pancreatic cells and adipocytes, possibly lessening these effects. However, the strong association between rosuvastatin (which is hydrophilic) and new diabetes would not support this hypothesis.
Despite these speculations, lack of conformity in response to different statins and discrepancies in the clinical outcomes noted in trials fail to clearly identify a common causative mechanism.
OTHER COMMON THERAPIES MAY INFLUENCE GLYCEMIC CONTROL
Statins are not the first drugs for reducing cardiovascular risk that have been shown to affect glucose levels during treatment.
Niacin
Niacin has been known to increase glucose levels but has long been used as a treatment for dyslipidemia despite this caution. Reduced glycemic control during niacin treatment in diabetic patients does not seem to alter the beneficial effects of treatment.35–37
In a post hoc analysis of the Coronary Drug Project (CDP), in patient subgroups defined by baseline fasting plasma glucose and compared with placebo, niacin reduced the 6-year risk of recurrent myocardial infarction and the combined end point of coronary heart disease death or nonfatal myocardial infarction similarly (interactive P value nonsignificant) across all levels of baseline fasting plasma glucose, including levels of 126 mg/dL or higher at study entry.36
In another post hoc analysis of CDP patient subgroups defined by the change in glycemic status from baseline to 1 year, niacin reduced the 6-year risk of the same end points similarly (interactive P value nonsignificant) across all levels of change in fasting plasma glucose from baseline to year 1, whether baseline fasting plasma glucose levels decreased, stayed the same, or increased to 10 mg/dL or higher on niacin therapy.36
Therefore, the beneficial effect of niacin of reducing the rate of recurrent nonfatal myocardial infarction and coronary heart disease events was not significantly diminished when impaired fasting glucose or diabetes was present when therapy was started or by on-therapy increases from baseline fasting plasma glucose.
In addition, on-therapy changes in glycemic control may be dose-related and minimized by surveillance and therapy adjustments. The Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan Trial (ADVENT)38 found that changes in glycemic control were minimal as measured by fasting glucose and hemoglobin A1c; were associated with a higher niacin dose (1.5 g/day vs 1 g/day); and, when present, were successfully managed by adjusting the diabetes treatment regimen.
Antihypertensive drugs
Diuretics as well as beta-blockers have been reported to increase the incidence of diabetes in patients with hypertension.15,38–40
A retrospective longitudinal cohort study40 in 2009 examined the development of new-onset diabetes (defined as a new ICD-9 code for diabetes or initiation of diabetes treatment) in 24,688 treated hypertensive patients without diabetes at baseline; 4,385 (17.8%) of the patients developed diabetes. After adjusting for sex and age, the risk of new diabetes was significant in users of diuretics (OR 1.10), beta-blockers (OR 1.12), and calcium channel blockers (OR 1.10) compared with users of angiotensin-converting enzyme inhibitors, (OR 0.92), angiotensin receptor blockers (OR 0.90), or alpha-blockers (OR 0.88).
However, the increase in blood glucose does not seem to attenuate the beneficial effects of reducing cardiovascular events. In the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT),15 a long-term follow-up of those developing new-onset diabetes while taking chlorthalidone (Hygroton) found no difference in the risk of death from cardiovascular disease or from any cause (hazard ratio = 1.04).15
CLINICAL IMPLICATIONS
Balancing the benefits and risks of statins
It is important to examine how the 0.4% increase in absolute risk of new-onset diabetes as calculated in meta-analyses compares with the benefits of statin treatment in terms of cardiovascular risk reduction.
Using data from the Cholesterol Treatment Trialists (CTT) meta-analysis of statin trials in 71,370 participants, Sattar et al11 estimated that statin treatment is associated with 5.4 fewer deaths from coronary heart disease and cases of nonfatal myocardial infarction per 255 patients treated over 4 years for each 1-mmol/L (39 mg/dL) reduction in LDL-C compared with controls. The benefit would be even greater if stroke, revascularization, and hospitalization are included as end points. This benefit is contrasted with the risk of developing 1 additional case of diabetes for every 255 patients treated with statins over the same period.
Preiss et al25 calculated that there were 2 more cases of diabetes per 1,000 patient-years in patients receiving intensive doses than in those receiving moderate doses (18.9 vs 16.9), corresponding to 1 additional case of diabetes for every 498 patients treated per year. However, there were 6.5 fewer first major cardiovascular events per 1,000 patient-years (44.5 vs 51.0), corresponding to a number needed to treat per year to prevent 1 cardiovascular event of 155. Most of the benefit was due to fewer revascularizations, followed by nonfatal myocardial infarctions. The 12% increase in new diabetes with high-dose therapy contrasted with a 16% reduction in new cardiovascular disease combined events (OR 0.84, 95% CI 0.75–0.94).
As previously noted, in the JUPITER trial, the benefits of preventing cardiovascular events with statin therapy outweighed the risk of new diabetes in people both with and without baseline risk factors for diabetes.29 Similar to the observations with niacin and some antihypertensive drugs, the increase in blood glucose with statins does not appear to reduce the benefits of cardiovascular risk reduction in these patients at moderate to high risk, even when used at high doses.