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1 January 2011
High-dose statins and risk of new-onset diabetes

A meta-analysis shows that although high-dose statins may cause new-onset diabetes, the benefits of treatment still outweigh the risks.

Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD, DeMicco DA, Barter P, Cannon CP, Sabatine MS, Braunwald E, Kastelein JJ, de Lemos JA, Blazing MA, Pedersen TR, Tikkanen MJ, Sattar N, Ray KK
Summary
Comments & References
STUDY SUMMARY
Objectives To investigate whether intensive-dose statin therapy is associated with increased risk of new-onset diabetes compared with moderate-dose statin therapy
Methods
  • Type of study: Meta-analysis of randomized controlled end-point trials that compared intensive-dose with moderate-dose statin therapy and included more than 1,000 participants followed up for more than 1 year
  • Data sources
    • Literature search of MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (January 1, 1996, through March 31, 2011)
    • Unpublished data obtained from investigators
  • Statistical analysis
    • Calculation of trial-specific odds ratios (ORs) for new-onset diabetes and major cardiovascular events
    • Random-effects model meta-analysis
Main results
  • Five relevant statin trials with 32,752 participants without diabetes at baseline identified
  • Mean follow-up: 4.9 ± 1.9 years
  • 12% increase in relative risk of incident diabetes in patients receiving the intensive-dose therapy compared with those receiving the moderate-dose therapy ([OR] 1.12; 95%CI, 1.04-1.22)
  • 16% decrease in relative risk of major cardiovascular events in patients receiving the intensive-dose therapy compared with those receiving the moderate-dose therapy ([OR] 0.84; 95% CI, 0.75-0.94)
Authors’ conclusion In a pooled analysis of data from 5 statin trials, intensive-dose statin therapy was associated with an increased risk of new-onset diabetes compared with moderate-dose statin therapy

COMMENT

The meta-analysis of 90,056 people from 14 randomized trials of statin therapy (the Cholesterol Treatment Trialists’ [CTT] Collaboration)1 showed that lowering LDL-C by 1 mmol/L (39 mg/dL) reduced the risk of major vascular events (defined as the composite outcome of myocardial infarction or coronary death, stroke, or coronary revascularization) by about one-fifth. Incidentally, these results demonstrated that despite its efficacy, statin therapy left unaddressed a huge residual vascular risk.

In the CTT analysis, however, the proportional reduction in major vascular events differed significantly (P<0·0001) according to the absolute reduction in LDL-C achieved, with an approximately linear relationship (Figure 1): roughly, 1.8 mg/dL reduction in LDL-C led to a 1% reduction in cardiovascular events. This provided the rationale for intensive statin therapy with the aim of lowering LDL-C levels to 70 mg/dL or even less in very high-risk patients. Other analyses published on this website show that this strategy increasingly adopted for the management of intermediate and high-risk patients further decreases vascular events but still leaves a sizeable residual vascular risk.

Clinical trials and clinical experience raised concerns about a possible increase in muscle toxicity in patients receiving intensive-dose statin therapy. Another newer safety issue was raised by recent publications showing an increased risk of de novo diabetes in patients treated with statins. 

In 2010, a meta-analysis of 13 statin trials with 91,140 participants (mean follow-up, 4 years) demonstrated that statin therapy was associated with a 9% increased risk for incident diabetes (odds ratio [OR] 1.09; 95% CI 1.02-1.17).2 Treatment of 255 patients with statins for 4 years resulted in one extra case of diabetes. The authors concluded that the risk was low both in absolute terms> and when compared with the reduction in coronary events.

Although this publication reported no link between the change in LDL-cholesterol concentrations and the variation of diabetes risk, a new meta-analysis compared the risk of incident diabetes in patients treated with intensive-dose and moderate-dose statin therapy.

In the meta-analysis of Preiss et al.,3 an intensive statin regimen of 80-mg simvastatin or atorvastatin was compared with moderate 10-to-20-mg doses of the same drugs, or 40 mg pravastatin.
Diabetes developed in 1,449 and 1,300 patients assigned intensive and moderate-dose therapy, respectively (2.0 additional cases in the intensive-dose group per 1,000 patient-years), while major cardiovascular events occurred in 3,134 and 3,550 patients, respectively (6.5 fewer cases in the intensive-dose group per 1,000 patient-years).

Calculation of the number-needed-to-harm and the number-needed-to-treat for intensive-dose statin therapy showed that treatment of 498 patients for one year resulted in one extra case of diabetes, while treatment of 155 patients for one year resulted in the prevention of one cardiovascular event.

For the investigators, the cardiovascular benefits of intensive-dose statin therapy clearly outweigh the risk of incident diabetes. However, clinicians should be vigilant for diabetes developing in patients on such therapy and investigating the long-term risk of diabetes related to intensive statin therapy is warranted, they stated.

The mechanism by which statin therapy may cause diabetes is unclear.  Preiss et al. wrote that "data from an animal model suggest that statin-induced myopathy is associated with the development of muscle insulin resistance, providing a potential mechanism."

Figure 1. Proportional reduction in events rates as a function of reduction of LDL cholesterol level.1

References
  1. Baigent C, Keech A, Kearney PM, et al., Cholesterol Treatment Trialists’ Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267–78.
  2. Sattar N, Preiss D, Murray HM, et al. Statins  and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010 Feb 27;375(9716):735-42.
  3. Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 2011;305:2556-64.