Statin Use is Associated With Insulin Resistance in Participants of the Canadian Multicentre Osteoporosis Study

Abstract

Context Statins have been linked to the development of diabetes and atherosclerotic plaque calcification in patients with cardiac disease. Objective To determine the association between statin use and statin characteristics and insulin resistance and abdominal aortic calcification (AAC) in participants of the Canadian Multicentre Osteoporosis Study (CaMos). Design Observational study. Setting General community. Participants Nondiabetic participants of the Kingston CaMos site Intervention Insulin resistance and AAC in statin users and nonstatin users were compared with and without the inclusion of a propensity score (PS) to be on a statin. The covariates of hypertension, sex, body mass index, smoking, kidney stones, and age that were included in the PS were selected based on clinical judgment confirmed by the statistical analysis of a difference between statin users and nonstatin users. Main Outcome Measures Insulin resistance measured by the homeostasis model assessment (HOMA-IR) and AAC assessed on lateral spine radiographs using the Framingham methodology. Results Using a general linear model, statin use was associated with higher levels of HOMA-IR after stratified PS adjustment (β = 1.52, [1.18–1.95], P < 0.01). Hydrophilic statin users (n = 9) and lipophilic statins users (n = 30) had higher HOMA-IR compared to nonstatin users (n = 125) ([β = 2.29, (1.43–3.68), P < 0.001] and [β = 1.36, (1.04–1.78), P < 0.05]), respectively, in general linear models after stratified PS adjustment. Statin use was associated with AAC without stratifying by PS in the Wilcoxon test, but was no longer significant when stratified by PS. Conclusions Statins, widely prescribed drugs to lower cholesterol, may have unintended consequences related to glucose homeostasis that could be relevant in healthy aging.

Historical Review of the Use of Relative Risk Statistics in the Portrayal of the Purported Hazards of High LDL Cholesterol and the Benefits of Lipid-Lowering Therapy

“…In a paper addressing the controversy over JUPITER, the trial director considered the increase in diabetes as only a “play of chance” [ 47 ]. However, the significant increase in the incidence of diabetes with statin treatment has been reported in numerous subsequent publications [ 60 - 64 , 85 ], including an RCT that characterized the mechanistic basis as to how statins increase the susceptibility of users to develop diabetes [ 65 ]. This finding is relevant to why RCTs have demonstrated an increase in fasting blood glucose in patients with and without diabetes [ 66 ], as well as a meta-analysis that suggested females are more susceptible than males to develop type 2 diabetes with statin treatment [ 60 ].…”

Statin therapy is not warranted for a person with high LDL-cholesterol on a low-carbohydrate diet

“…The absence of a relation between LDL-C and coronary event reduction with statin treatment suggests that it is their pleiotropic, for example, antiinflammatory and anticoagulant, effects [229][230][231][232][233][234][235][236][237][238], rather than LDL-C reduction, per se, that results in a relatively small reduction in coronary events and mortality. Therefore, a person on an LCD with a nonatherogenic lipid profile (low TGs/high HDL-C) is more likely to experience the adverse effects of statins [239][240][241][242][243][244][245][246][247][248][249][250][251][252], including an increased risk of new onset type 2 diabetes [246,[253][254][255][256][257][258], an increase in fasting blood glucose in patients with and without diabetes [259], mitochondrial dysfunction [260][261][262], tendinopathy [263], myopathy [264,265], acute kidney injury/renal failure [266][267][268] and cognitive deficits [247,[269]…”

Molecular Mechanisms Involved in Insulin Resistance: Recent Updates and Future Challenges

“…The mechanism that regulates CoQ levels in IR is unknown. Intriguingly, statins, which are commonly used as cholesterol-lowering drugs, have been linked to IR in humans [196], with the possibility that this relationship is related to the statin-induced reductions in CoQ biosynthesis [44]. Unfortunately, given the low bioavailability of CoQ , oral supplements, which are frequently recommended as an antioxidant strategy, are unlikely to be successful in replenishing the mitochondrial CoQ pool in patients with IR or even in individuals who take statins.…”