Evidence from randomized controlled trials (RCTs), observational studies, and meta-analyses have found a modest but significant increase in new-onset diabetes with statin therapy. The percentage risk ranged from 9% to 12% based on meta-analyses. In contrast, population-based studies reported a greater range, starting at 18% with one study suggesting up to a 99% increased risk of diabetes. The discrepancy may be due to the difference in clinical trial population versus general population (clinical trials typically include patients with high total low-density lipoprotein [LDL] cholesterol and previous cardiovascular event history). Risk factors for diabetes onset while on statin therapy may include a more intense statin regimen along with elderly (age > 70 years), female sex, and Asian ethnicity. The degree of LDL lowering being correlated with greater risk of diabetes onset is debated, as results are conflicting. There is a lack of studies that compare different statins with similar intensity and risk for diabetes. [1], [2], [3], [4], [5], [6], [7]
The JUPITER trial was one of the earliest studies that presented findings for new-onset diabetes associated with statin therapy. In a total of 17,802 patients included for randomization, rosuvastatin 20 mg at a median follow-up of 1.9 years showed a small but significant increase in physician-reported diabetes (3.0% in the rosuvastatin group vs. 2.4% in the placebo group; p= 0.01). Glycated hemoglobin and fasting glucose at 24 months were not different between groups, however, the findings were not adjudicated by the end-point committee. [8]
There are multiple theories as to how statin therapy may increase the risk of diabetes, but a consensus has not been met. In vitro studies have found that diabetogenic statins can reduce insulin sensitivity and insulin secretion through inhibition of HMGCoAR (the main target of statin therapy) or impairing beta-cell function. Laasko et al. has noted that the majority of studies implicate simvastatin, atorvastatin, and rosuvastatin as the most diabetogenic statins in population-based studies, clinical studies, and in vitro experiments. In contrast, pravastatin was cited to have the lowest risk of diabetes. Yet these studies and experiments are performed in wildly different scenarios which makes it difficult to draw reliable conclusions from the results. [5], [6], [7]
A 2011 meta-analysis (N= 32,752; 5 RCTs) examined the association between the intensive- or moderate-dose statin therapy and the risk of new-onset diabetes. Patients were considered to have developed diabetes if (1) there was an adverse event report of newly diagnosed diabetes during the trial, (2) the patient was initiated on glucose-lowering medication during the trial, or (3) the patient had 2 fasting plasma glucose (FPG) values ≥ 126 mg/dL during the trial. Data were also collected for a composite cardiovascular end point consisting of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary artery bypass surgery, percutaneous coronary intervention and for specific cardiovascular events and all-cause mortality. Results revealed that 2,749 patients (8.4%) developed diabetes over a mean follow-up period of 4.9 ± 1.9 years; 1,449 of these patients (52.7%) had received intensive-dose therapy, whereas 1,300 (47.3%) received moderate-dose therapy (odds ratio [OR] 1.12; 95% confidence interval [CI], 1.04 to 1.22). The authors reported 2.0 additional cases of diabetes per 1,000 patient-years among intensive-dose recipients (mean 18.9 ± 5.2 cases per 1,000 patient-years with high-dose vs. 16.9 ± 5.5 cases per 1,000 patient-years with moderate-dose). The number needed to harm was 498 per year. No significant heterogeneity was reported between trials for new-onset diabetes (X2 for heterogeneity= 2.59; p= 0.60; I2= 0%; 95% CI, 0% to 79%), and included trials were reported to be of high quality. [8]
A subgroup analysis revealed the odds of developing diabetes with intensive- vs. moderate-statin therapy was similar in patients with different ages, body mass index (BMI), high-density lipoprotein (HDL) cholesterol levels, and FPG levels at baseline but was higher in patients with triglyceride concentrations below the median compared to patients with above the median triglyceride levels (OR 1.27; 95% CI, 1.11 to 1.45 below mean vs. OR 1.06; 95% CI, 0.96 to 1.17 above mean; p= 0.04). Intensive statin therapy was, however, associated with fewer cardiovascular events (OR 0.84; 95% CI, 0.75 to 0.94). These benefits were reported to be consistent across all subgroups and for each component of the primary cardiovascular efficacy endpoint. The authors reported that the relative LDL-cholesterol reduction was greater in patients who used atorvastatin 80 mg vs. those used simvastatin 80 mg, but the odds of developing diabetes was similar in both groups; however, there was a significantly lower odds of developing cardiovascular events with high-dose atorvastatin as opposed to high-dose simvastatin. The authors concluded that intensive-dose therapy was associated with an increased risk of new-onset diabetes compared with moderate-dose statin therapy. [9]
A 2016 network meta-analysis was performed on 29 RCTs to investigate the direct and indirect evidence of statin use and risk of diabetes development. The likelihood of developing diabetes from statin use was found to be 12% (pooled OR 1.12; 95% CI 1.05 to 1.21; p= 0.002; 18 RCTs). Based upon the network meta-analysis, the authors ranked the risk of developing diabetes from highest to lowest: atorvastatin 80 mg, rosuvastatin, simvastatin 80 mg, simvastatin, atorvastatin, pravastatin, lovastatin, and pitavastatin. From the results, the authors concluded that intensive statin treatment and lipophilic statins are more likely to increase the risk for developing diabetes. While network meta-analyses allow for such comparisons and inferences, the findings need to be verified in subsequent studies. [10]
A 2014 meta-analysis investigated the relationship between LDL cholesterol target levels with statin use and new-onset type-2 diabetes. Fourteen randomized clinical trials with a duration > 2 years and > 1000 participants were included (N= 95,102), which found a greater incidence of new-onset diabetes in patients with LDL cholesterol target level ≤ 1.8 mmol/L (OR 1.33; 95% CI 1.15 to 1.54) and between 1.8 mmol/L to 2.59 mmol/L (OR 1.16; 95% CI 1.06 to 1.28). In contrast, the risk did not increase when LDL target levels were ≥ 2.59 mmol/L (OR 1.01; 95% CI 0.92 to 1.10). A meta-regression analysis found that baseline LDL levels, target LDL levels, and relative LDL reduction were risk factors for new-onset diabetes after statin therapy. While the results seem to implicate lower LDL target levels, only two studies observed LDL goals <1.8 mmol/L. These two studies consisted of rosuvastatin 20 mg and atorvastatin 80 mg; the studies were different in design. How diabetes was diagnosed also varied between the studies and there were noticeably missing data from certain studies which could lower statistical power. [11]