Evidence of heterogeneity in statin-associated type 2 diabetes mellitus risk: A meta-analysis of randomized controlled trials and observational studies
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.
References (50)
- et al.
Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials
The Lancet
(2010) - et al.
Statin use and risk of new-onset diabetes: a meta-analysis of observational studies
Nutr, Metab Cardiovasc Dis
(2017) - et al.
Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement
Int J Surg
(2010) - et al.
Evidence of the depletion of susceptibles effect in non-experimental pharmacoepidemiologic research
J Clin Epidemiol
(1994) - Gu Q, Paulose-Ram R, Burt V, Kit B. Prescription cholesterol-lowering medication use in adults aged 40 and over: United...
- et al.
Trends in prescription drug use among adults in the United States from 1999–2012
JAMA: J Am Med Assoc
(2015) - et al.
ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines
J Am Coll Cardiol
(2013) - et al.
ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines
Circulation
(2013) The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials
The Lancet
(2012)Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174 000 participants in 27 randomised trials
The Lancet
(2015)
Statin therapy and risk of developing type 2 diabetes: a meta-analysis
Diabetes Care
Statins for the primary prevention of cardiovascular disease
Cochrane Library
Statins for prevention of cardiovascular disease in adults evidence report and systematic review for the US preventive services task force
JAMA: J Am Med Assoc
WHO study on Prevention of REcurrences of Myocardial Infarction and StrokE (WHO-PREMISE)
Bull World Health Organ
Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age
Circulation
Should meta-analyses of interventions include observational studies in addition to randomized controlled trials? A critical examination of underlying principles
Am J Epidemiol
Randomized controlled trials vs. observational studies: why not just live together?
BMC Anesthesiol
EndNote X7
Users' guides to the medical literature
Effect of smoking cessation on mortality after myocardial infarction: meta-analysis of cohort studies
Arch Intern Med
The relative ability of different propensity score methods to balance measured covariates between treated and untreated subjects in observational studies
Med Decis Making
Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials
BMJ
Bias in meta-analysis detected by a simple, graphical test
BMJ
Operating characteristics of a rank correlation test for publication bias
Biometrics
Trim and fill: a simple funnel-plot–based method of testing and adjusting for publication bias in meta-analysis
Biometrics
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