Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial

Abstract

Background: In view of evidence that statin therapy increases risk of diabetes, the balance of benefit and risk of these drugs in primary prevention has become controversial. We undertook an analysis of participants from the JUPITER trial to address the balance of vascular benefits and diabetes hazard of statin use.

Methods: In the randomised, double-blind JUPITER trial, 17,603 men and women without previous cardiovascular disease or diabetes were randomly assigned to rosuvastatin 20 mg or placebo and followed up for up to 5 years for the primary endpoint (myocardial infarction, stroke, admission to hospital for unstable angina, arterial revascularisation, or cardiovascular death) and the protocol-prespecified secondary endpoints of venous thromboembolism, all-cause mortality, and incident physician-reported diabetes. In this analysis, participants were stratified on the basis of having none or at least one of four major risk factors for developing diabetes: metabolic syndrome, impaired fasting glucose, body-mass index 30 kg/m(2) or higher, or glycated haemoglobin A(1c) greater than 6%. The trial is registered at ClinicalTrials.gov, NCT00239681.

Findings: Trial participants with one or more major diabetes risk factor (n=11,508) were at higher risk of developing diabetes than were those without a major risk factor (n=6095). In individuals with one or more risk factors, statin allocation was associated with a 39% reduction in the primary endpoint (hazard ratio [HR] 0·61, 95% CI 0·47-0·79, p=0·0001), a 36% reduction in venous thromboembolism (0·64, 0·39-1·06, p=0·08), a 17% reduction in total mortality (0·83, 0·64-1·07, p=0·15), and a 28% increase in diabetes (1·28, 1·07-1·54, p=0·01). Thus, for those with diabetes risk factors, a total of 134 vascular events or deaths were avoided for every 54 new cases of diabetes diagnosed. For trial participants with no major diabetes risk factors, statin allocation was associated with a 52% reduction in the primary endpoint (HR 0·48, 95% CI 0·33-0·68, p=0·0001), a 53% reduction in venous thromboembolism (0·47, 0·21-1·03, p=0·05), a 22% reduction in total mortality (0·78, 0·59-1·03, p=0·08), and no increase in diabetes (0·99, 0·45-2·21, p=0·99). For such individuals, a total of 86 vascular events or deaths were avoided with no new cases of diabetes diagnosed. In analysis limited to the 486 participants who developed diabetes during follow-up (270 on rosuvastatin vs 216 on placebo; HR 1·25, 95% CI 1·05-1·49, p=0·01), the point estimate of cardiovascular risk reduction associated with statin therapy (HR 0·63, 95% CI 0·25-1·60) was consistent with that for the trial as a whole (0·56, 0·46-0·69). By comparison with placebo, statins accelerated the average time to diagnosis of diabetes by 5·4 weeks (84·3 [SD 47·8] weeks on rosuvastatin vs 89·7 [50·4] weeks on placebo).

Interpretation: In the JUPITER primary prevention trial, the cardiovascular and mortality benefits of statin therapy exceed the diabetes hazard, including in participants at high risk of developing diabetes.

Funding: AstraZeneca.

Conflict of interest statement

Conflicts of Interest: The JUPITER trial was an investigator-initiated project funded by AstraZeneca. Dr. Ridker is the Principle Investigator of the trial and received grant support from AstraZeneca for its conduct. Dr. Ridker has served as a consultant to Merck, ISIS, Vascular Biogenics, Boerhinger, Abbott, and Genzyme; receives additional research grant support from Novartis; and is listed as a co-inventor on patents held by the Brigham and Women’s Hospital related to inflammatory biomarkers in cardiovascular disease and diabetes that have been licensed to Seimens and AstraZeneca. Dr. Glynn is the independent academic trial statistician for JUPITER and has received grant support from AstraZeneca for its conduct. Dr. Libby is an unpaid consultant or involved in clinical trials for AstraZeneca, GlaxoSmithKline, Merck, Novartis, Pfizer, ProNova, and Sigma-Tau, and is a member of the scientific advisory boards for Athera Biotechnolgies, Carolus Therapeutics, Interleukin Genetics, and BIND Biosciences. Dr. Pradhan, and Ms. MacFadyen report no conflicts of interest with regard to this manuscript.

Copyright © 2012 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Incidence rates (per 100 person years) of physician diagnosed diabetes in the JUPITER trial according to baseline fasting glucose levels. Data are shown separately for those allocated to placebo (white bars) and those allocated to rosuvastatin (black bars). Numbers in parentheses indicate the absolute number of individuals who developed diabetes in each group.

Figure 2

Cumulative incidence of cardiovascular events and total mortality among those with and without major risk factors for diabetes.

Figure 3

Cumulative incidence of diabetes among those with and without major risk factors for diabetes.

Figure 4

Hazard ratios and 95% confidence intervals for specific vascular events, total mortality, and diabetes in subgroup analyses among those with or without metabolic syndrome; among those with fasting glucose ≥ or 2; and among those with HbA1c > or ≤ 6 percent.