Evidence of heterogeneity in statin-associated type 2 diabetes mellitus risk: A meta-analysis of randomized controlled trials and observational studies

https://doi.org/10.1016/j.diabres.2019.04.005Get rights and content

Highlights

  • Statin users had higher risk of incident type 2 diabetes compared to non-users.

  • Statin-associated risk of diabetes higher among observational studies.

  • Heterogeneity observed by study design and among observational studies.

  • Younger ages and lower cholesterol levels associated with higher incident diabetes.

Abstract

Aims

To conduct a meta-analysis of statin-associated type 2 diabetes mellitus (T2D) risk among randomized controlled trials (RCTs) and observational studies (OBSs), excluding studies conducted among secondary prevention populations.

Methods

Studies were identified by searching PubMed (1994-present) and EMBASE (1994-present). Articles had to meet the following criteria: (1) follow-up >one year; (2) >50% of participants free of clinically diagnosed ASCVD; (3) adult participants ≥30 years old; (4) reported statin-associated T2D effect estimates; and (5) quantified precision using 95% confidence interval. Data were pooled using random-effects model.

Results

We identified 23 studies (35% RCTs) of n = 4,012,555 participants. OBS participants were on average younger (mean difference = 6.2 years) and had lower mean low-density lipoprotein cholesterol (LDL-C, mean difference = 20.6 mg/dL) and mean fasting plasma glucose (mean difference = 5.2 mg/dL) compared to RCT participants. There was little evidence for publication bias (P > 0.1). However, evidence of heterogeneity was observed overall and among OBSs and RCTs (PCochran = <0.05). OBS designs, younger baseline mean ages, lower LDL-C concentrations, and high proportions of never or former smokers were significantly associated with increased statin-associated T2D risk.

Conclusions

Potentially elevated statin-associated T2D risk in younger populations with lower LDL-C merits further investigation in light of evolving statin guidelines targeting primary prevention populations.

Introduction

Hmg CoA reductase inhibitors, commonly known as statins, are the most widely prescribed class of medication used to reduce cardiovascular disease (CVD) risk and to treat elevated low density lipoprotein cholesterol (LDL-C) [1], [2], [3]. Changes in cholesterol treatment recommendations from the Third Adult Treatment Panel (ATP III) of the National Cholesterol Education Program guidelines to the American College of Cardiology/American Heart Association (ACC/AHA) 2013 guidelines increased the number of adults newly eligible for statin therapy for primary prevention by an estimated 10.4 million, with 80% of the increase attributable to individuals between the ages of 60–75 [4].

While the cardioprotective effect of statins are undeniable [5], [6], experimental and observational research has also suggested that statins may lead to harm in lower risk individuals by increasing the risk of type 2 diabetes mellitus (T2D) [7], [8], [9], [10], [11]. Yet, most meta-analyses have combined primary and secondary prevention populations to examine statin associated T2D risk. Secondary prevention populations, however, include survivors of ASCVD whose mortality risk has been estimated to be five to six times higher than that of people of the same age who did not experience an ASCVD [12]. Further, the risk of T2D may differ when used for primary vs. secondary prevention [13], complicating efforts to quantify statin-associated T2D risk in primary prevention populations. As primary prevention populations are most impacted by the statin-eligibility recommendations, additional research quantifying statin-associated T2D risk is needed.

In addition to combining primary and secondary populations, published meta-analyses of statin-associated T2D risk have also been restricted to either randomized controlled trials (RCTs) or observational studies (OBSs). Yet, meta-analyses that incorporate summary data from both study designs may take advantage of the internal validity of RCTs and the external validity of OBSs. This approach better reflects the existing evidence base, and may increase statistical power to investigate heterogeneity and expand upon past meta-analyses’ limited heterogeneity assessments [14], [15]. Therefore, to estimate the effect of statins on T2D among populations most affected by changes to statin use guidelines and examine potential sources of heterogeneity, we performed a systematic review and meta-analysis of statin-associated T2D risk by synthesizing published data from RCTs and OBSs, excluding secondary prevention populations.

Section snippets

Materials and methods

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines throughout the design, implementation, analysis, and reporting of this meta-analysis [16].

Results

The systematic review identified a total of 459 candidate studies for screening (Fig. 1). Of these studies, 23 (5%; eight RCTs and 15 OBSs) met the eligibility criteria for inclusion in the meta-analyses (see Supplement for article references). Eligible studies were conducted between 1998 and 2016, with OBSs on average being published more recently (mean publication date = 2012 vs 2005) and using more recent data (mean baseline study year = 2000 vs 1998) compared to RCTs (Table 1, Table 2). In

Discussion

Results of this meta-analysis, which are consistent with earlier studies synthesizing estimates of statin-associated T2D risk in primary and secondary prevention populations [8], [11], suggest that statins have a moderate effect on T2D risk, increasing risk 11–55%. Yet, strong evidence of heterogeneity was observed, particularly with regard to participant age and baseline LDL-C level. Potential evidence of heterogeneity was not fully examined in earlier meta-analyses and merits further

Acknowledgements

Funding: This work was supported by National Heart, Lung, and Blood Institute training grant T32 predoctoral fellowship T32HL007055.

Conflict of interest

The authors declare no conflict of interest.

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