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

Karen J. Rees-Milton; Patrick Norman; Corinne Babiolakis; Maggie Hulbert; Mandy E Turner; Claudie Berger; Tassos P. Anastassiades; Wilma M Hopman; Michael A. Adams; Wendy L. Powley; Rachel M. Holden

Disclosures

J Endo Soc. 2020;4(8) 

In This Article

Abstract and Introduction

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.

Introduction

Hypercholesterolemia is a major cardiovascular risk factor and an important therapeutic target. Statins, or 3-hydroxy-3-methyl-glutaryl coenzyme-A (HMG-CoA) reductase inhibitors, are a first-line therapy to lower cholesterol levels and, thus, are widely prescribed drugs. Analysis of the drug dispensing patterns of a seniors pharmacare program in Canada showed a dramatic increase in statin prescription, from 5% to 20%, between the years 2000 and 2013.[1]

Statins have been shown to consistently reduce cardiovascular events in the general population and are thus amongst the first-line therapies for patients at high risk for cardiovascular disease. Statins reduce atherosclerosis by decreasing low-density lipoprotein (LDL) cholesterol and by improving endothelial function.[2,3] However, statins may also have less desirable pleiotropic actions, including a reduction in insulin secretion and worsening of insulin resistance.[4–6] Some, but not all, large trials of primary prevention have reported an increased incidence of diabetes with statins.[7,8] From a pooled analysis of randomized trials, factors associated with the development of diabetes in statin users included elevated triglycerides, elevated body mass index (BMI), and a history of hypertension.[9] However, these studies continued to demonstrate a reduction in cardiovascular endpoints despite the increased incidence of diabetes; thus, no change in clinical practice has occurred.

Several factors are proposed to contribute to the pleiotropic effects of statins. First, the pleiotropic actions of statins may differ based on the lipophilicity versus the hydrophilicity of the particular statin drug,[10,11] suggesting that certain statins may decrease cardiovascular risk without increasing the risk of diabetes. Pravastatin and rosuvastatin are hydrophilic statins, whereas atorvastatin, fluvastatin, lovastatin, and simvastatin are lipophilic. Hydrophilic statins require carrier-mediated uptake, while lipophilic statins may diffuse passively through the hepatocellular membrane; thus, lipophilic statins tend to have been implicated in the development of insulin resistance. The second factor contributing to pleiotropic effects of statins is potency. Rosuvastatin is transported with greater affinity than lipophilic statins (despite being a hydrophilic drug) and is the most potent statin drug to reduce LDL-cholesterol levels. Potency is a second consideration when comparing pleiotropic effects of different statins. In one meta-analysis, rosuvastatin carried the highest risk for the development of type 2 diabetes.[12]

Statin drugs have not consistently shown a similar level of cardiovascular benefit in patients with low kidney function, and an increased risk of stroke was observed to be associated with statins in 1 large, well-conducted, randomized, controlled trial.[13] Evidence from 1 study of patients with reduced kidney function demonstrated that statin drug use was associated with greater severity of coronary artery calcification (CAC) at baseline and greater progression of calcification over 1.5 years.[14] A critical tissue-based inhibitor of vascular calcification is matrix Gla protein, 1 of several vitamin K–dependent proteins in the body.[15,16] There is emerging data to suggest that by inhibiting the production of intermediates of cholesterol biosynthesis, statins also inhibit the mevalonate pathway and impede the production of vitamin K2 in peripheral tissues.[17,18] There is growing evidence to suggest that vitamin K2 plays a key role in glucose homeostasis[19–22] as well as vascular calcification.[23–27] On this background, we hypothesized that statin use would be associated with both insulin resistance and vascular calcification in community-dwelling participants of a large longitudinal study of osteoporosis.

Our primary objective was, firstly, to evaluate the association between statin use and insulin resistance assessed by the homeostasis model assessment (HOMA-IR) in nondiabetic participants at year 10 from the Kingston center of the population-based observational Canadian Multicenter Osteoporosis Study (CaMos)[28] and, secondly, to evaluate the association between statin use and abdominal aortic calcification (AAC) assessed by the Framingham method in participants at year 10 of the CaMos study. Our secondary objective was to explore the impact of the hydrophilicity versus lipophilicity of the specific statin drug on the outcomes.

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