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. have 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. A 2019 review concluded diabetic risk appears to be a classwide effect, with pravastatin and pitavastatin potentially having less impact on risk. Mechanistically, pitavastatin does not appear to impair adipocyte maturation at clinical doses, which may lead to improved leptin and adiponectin secretion. However, these studies and experiments are performed in vastly different scenarios, which makes it difficult to draw universal conclusions from the results. [1], [2], [3]
A 2015 cross-sectional study examined the relationship between statin use and glycemic control in 1,093 patients with type 1 diabetes (T1DM) who were under care at the Steno Diabetes Center in Denmark. These patients, with no known heart disease, underwent a comprehensive evaluation that included physical examination, questionnaires, and echocardiography while maintaining blinding to laboratory measurements. Results found that 43.5% of the participants were receiving statin therapy, with these individuals tending to be older, possessing longer diabetes duration, and exhibiting more severe kidney disease. In multivariable analysis, statin use was significantly associated with higher HbA1c levels by 0.2% (95% CI, 0.1 to 0.4), suggesting impaired glycemic control in this cohort. Despite the observed association, the investigation could not establish a causal relationship. Nevertheless, the findings underscore the need to carefully consider insulin adjustments for patients with T1DM commencing statin therapy, while maintaining the cardiovascular protective benefits of statins. [4]
A 2016 network meta-analysis was performed on 29 randomized controlled trials (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 odds ratio [OR] 1.12; 95% confidence interval [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 (OR 1.17; 95% CI: 1.02 to 1.35), simvastatin 80 mg, simvastatin, atorvastatin, pravastatin, lovastatin, and pitavastatin (OR 0.74 95% CI: 0.31 to 1.77). From the results, the authors concluded that intensive statin treatment and lipophilic statins are more likely to increase the risk of developing diabetes. While network meta-analyses allow for such comparisons and inferences, the findings need to be verified in subsequent studies. [5]
Another meta-analysis evaluating the effects of pitavastatin on glycemia and new-onset diabetes mellitus (NODM) in non-diabetic individuals included 15 placebo or statin-controlled RCTs (~ 1,600 person-years; average age of 60 years; body mass index [BMI] 26.7 kg/m2; fasting blood glucose [FBG] <100 mg/dL) with a follow-up of ≥ 12 weeks. No significant differences associated with pitavastatin (vs. control) were observed for FBG (mean difference [MD] –0.01 mg/dL; 95% CI –0.77 to 0.74; I2= 0%), HbA1c (MD –0.03% based on 7 trials; 95% CI –0.11 to 0.05; I2= 43%) or NODM (relative risk [RR] 0.70; 95% CI 0.30 to 1.61; I2= 0%). Analysis based on the patients that completed the follow-up, excluding 7.7% and 9.8% drop-out in pitavastatin and control arms, did not show significant changes in FBG, HbA1c or NODM. Results of this meta-analysis might be limited by the short follow-up duration of included trials and patients at a higher risk of developing NODM while on statin therapy were not adequately included in this study as reflected by the baseline characteristics. In the present meta-analysis, pitavastatin did not adversely affect glucose metabolism or diabetes development compared with placebo or other statins, even though rosuvastatin was not one of the statins being evaluated. [6]
A 2011 meta-analysis (N= 32,752; 5 RCTs) examined the association between 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 endpoint 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 (OR 1.12; 95% 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. [7]
A subgroup analysis revealed the odds of developing diabetes with intensive- vs. moderate-statin therapy was similar in patients with different ages, 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 low-density lipoprotein (LDL) 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. [8]
A 2016 retrospective cohort study evaluated the association between statins and NODM in Korean patients with ischemic heart disease (IHD). The study was conducted using data from the Korean Health Insurance Review and Assessment (HIRA) database. Adult patients with IHD who initiated statin therapy at any point during the study period were included; patients with previous use of statins within the last year or existing diabetes diagnosis were excluded. Of the total study population that used statins (N= 94,370), 11,851 patients were initiated on rosuvastatin and 4,075 on pitavastatin. Among rosuvastatin users, the risk of developing NODM was 8.1% (incidence rate 3.77/100 patient years, adjusted hazard ratio [HR] 2.00, 95% CI 1.85 to 2.15) compared to pitavastatin users, with a risk of 6.8% (incidence rate 3.17/100 patient years, adjusted HR 1.70, 95% CI 1.50–1.92). Patients exposed to more than one type of statin, (the ‘complex group’), were at the highest risk of NODM (adjusted HR 2.18, 95% CI 1.89 to 2.51). Subgroup analyses revealed that the adjusted NODM HR for statin users versus non-statin users was more significant among male patients (adjusted HR 1.88, 95% CI 1.79 to 2.13) and the risk of NODM was most significant among statin users under the age of 40 years (adjusted HR 5.71, 95% CI 4.00 to 8.18). The authors concluded that all statins are associated with the risk of NODM in patients with IHD and recommended periodic screening and monitoring for diabetes during prolonged statin therapy. [9]