Elsevier

The Lancet

Volume 380, Issue 9841, 11–17 August 2012, Pages 565-571
The Lancet

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

https://doi.org/10.1016/S0140-6736(12)61190-8Get rights and content

Summary

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/m2 or higher, or glycated haemoglobin A1c 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.

Introduction

Statin therapy effectively reduces cardiovascular events. Yet, trial data1 and meta-analyses2, 3, 4 suggest that statins also confer increased risk of development of diabetes. In particular, recent overviews show that all statin agents are associated with a small increase in risk of incident type 2 diabetes (hazard ratio [HR] 1·09, 95% CI 1·02–1·17),3 and that intensive doses might be associated with higher risk than are lower doses (HR 1·12, 95% CI 1·04–1·22).4 For these reasons, on March 1, 2012, the US Food and Drug Administration added a warning about diabetes risk to the labels of all statin agents,5 and similar concern has been raised by European drug authorities. These regulatory changes have engendered controversy in the lay and medical press as to whether the cardiovascular benefit of treatment with statins exceeds the diabetes risk, particularly in primary prevention, a setting in which these agents have seen increasing use. The JUPITER (Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin)1 trial provided a contemporary opportunity to address this issue directly.

Section snippets

Participants and procedures

JUPITER was a randomised, double-blind, placebo-controlled trial designed to investigate whether rosuvastatin 20 mg daily compared with placebo would decrease the rate of first-ever cardiovascular events in 17 802 apparently healthy men and women with LDL cholesterol lower than 3·37 mmol/L (130 mg/dL) and high-sensitivity C-reactive protein (hsCRP) 2 mg/L or higher.1, 6 An important prespecified secondary aim of the trial was to address the effects of rosuvastatin on incident type 2 diabetes;

Results

Of 17 802 JUPITER trial participants, 121 (1%) were missing data for at least one risk factor for diabetes and 78 (<1%) were found at randomisation to have fasting glucose 6·99 mmol/L or greater or clinical diabetes. The remaining 17 603 trial participants (99%) had complete data and were included in this analysis. By comparison with trial participants with no major diabetes risk factors (n=6095), those with one or more major diabetes risk factor (n=11 508) were more likely to be female, have

Discussion

Although JUPITER was the first placebo-controlled statin trial to formally report an increased risk of developing diabetes,1 post-hoc evaluations of previously completed trials showed that this small increase in risk is present for all statins and might relate to drug potency (panel).2, 3, 4 In secondary prevention in high-risk patients with established coronary artery disease, the diabetes risk associated with statin therapy is low in absolute terms when compared with the reduction in

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