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The diabetogenic action of statins — mechanisms and clinical implications

Nature Reviews Endocrinology volume 12, pages 99–110 (2016)Cite this article

Subjects

Key Points

  • Meta-analyses of clinical trial data reveal a 10–12% increased risk of new-onset diabetes mellitus (NODM) associated with statin therapy; the risk is further increased with intensive treatment regimens

  • Mendelian randomization studies suggest that the effect of statins on glucose homeostasis reflect reduced activity of the target of statin therapy (HMG-CoA reductase)

  • In vitro and in vivo data suggest that statins reduce synthesis of mevalonate pathway products and increase cholesterol loading, which leads to impaired β-cell function and decreased insulin sensitivity

  • The benefits of statins in reducing cardiovascular disease (CVD) events far outweigh the harm of NODM; therefore, the use of statin therapy should be governed by individual patient risk

  • Statin use before a diagnosis of NODM does not increase the prevalence of microvascular disease; furthermore, effects on glycaemic control are small among individuals with diabetes mellitus

  • Statin-treated patients (particularly those with risk factors for NODM) should be monitored for the development of dysglycaemia and given appropriate diet and lifestyle advice to prevent development of NODM

Abstract

Treatment with statins has transformed primary and secondary prevention of cardiovascular disease (CVD), including thrombotic stroke. Evidence-based data demonstrate the benefits and safety of statin therapy and help to guide clinicians in the management of populations at high risk of CVD. Nevertheless, clinical trials, meta-analyses and observational studies highlight a 10–12% increase in new-onset diabetes mellitus (NODM) among patients receiving statins. The risk further increases with intensive therapy and among individuals with known risk factors for NODM. Mechanisms underpinning this effect are not yet fully understood; however, Mendelian randomization studies suggest that they are related to lowered activity of HMG-CoA reductase, the target of statin therapy. In vitro research indicates that statins potentially impair β-cell function and decrease insulin sensitivity but how these findings relate to patients is unknown. In the clinic, statins should be prescribed on the basis of CVD risk and individual patient characteristics. In addition, diet and lifestyle interventions should be emphasized to help mitigate the risk of NODM. Individuals who develop NODM while taking statins do not exhibit increased microvascular disease, which is reassuring. In diabetes mellitus of long duration, the effect of statins on glycaemic control is small and unlikely to be clinically important.

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Figure 1: Potential sites of action of statins on cellular insulin action identified from in vitro studies.
Figure 2: Potential sites of action of statins on β-cell function identified from in vitro studies.

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  1. Department of Diabetes & Endocrinology, University College Hospitals Trust, 3rd Floor Central, 250 Euston Road, London, NW1 2PQ, UK

    D. John Betteridge

  2. Department of Medicine, University of Valencia, Avenida Blasco Ibañez, 17, Valencia, 46010, Spain

    Rafael Carmena

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D.J.B. and R.C. contributed equally to researching the data for the article, discussion of the content, writing the article and to reviewing and/or editing of the manuscript before submission.

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Betteridge, D., Carmena, R. The diabetogenic action of statins — mechanisms and clinical implications. Nat Rev Endocrinol 12, 99–110 (2016). https://doi.org/10.1038/nrendo.2015.194

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