Diabetes Metab J.  2013 Dec;37(6):415-422. 10.4093/dmj.2013.37.6.415.

Diabetogenic Effect of Statins: A Double-Edged Sword?

• Yoon JS
• Lee HW

• KMID: 2174222
• DOI: http://doi.org/10.4093/dmj.2013.37.6.415

Abstract

Statins are widely prescribed cholesterol-lowering agents, which have been demonstrated to significantly reduce cardiovascular morbidity and mortality. However, recent trials have reported that statins cause worsening of hyperglycemia and increase the risk of new-onset diabetes. The association between the diabetogenic effect of statins with intensive dose and accompanying major risk factors for diabetes has been demonstrated. However, statins do not appear to have a class effect on insulin sensitivity in non-diabetic patients. Numerous mechanisms have been suggested to explain how statins cause beta-cell insulin secretory dysfunction and peripheral insulin resistance leading to incident diabetes. According to findings from an aggregate of large clinical trials, the benefits of statin treatment appear to outweigh the risk of new-onset diabetes. Therefore, it would be inappropriate to discontinue the use of statins for prevention of cardiovascular events because of its potential risk for development of incident diabetes. This review addresses the currently available evidence related to statin use and new-onset diabetes from a clinical perspective.

Keyword

Cardiovascular diseases; Diabetes; Statins

MeSH Terms

Cardiovascular Diseases
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors*
Hyperglycemia
Insulin
Insulin Resistance
Mortality
Risk Factors
Insulin

Figure

• 

  Fig. 1 Association between statin therapy and incident diabetes in 13 major cardiovascular trials (weights are from random-effects analysis). OR, odds ratio; CI, confidence interval; ASCOT-LLA, Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm; HPS, Heart Protection Study; JUPITER, Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin; WOSCOP, West of Scotland Coronary Prevention Study; LIPID, Long-Term Intervention with Pravastatin in Ischemic Disease; CORONA, Controlled Rosuvastatin Multinational Study in Heart Failure; PROSPER, Pravastatin in Elderly Individuals at Risk of Vascular Disease; MEGA, Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese; AFCAPS/TEXCAPS, Air Force/Texas Coronary Atherosclerosis Prevention Study; 4S, Scandinavian Simvastatin Survival Study; ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; GISSI-HF, Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Heart Failure Trial; GISSI-PREV, GISSI-Prevenzione Trial. Adapted from Sattar et al. Lancet 2010;375:735-42, with permission from Elsevier [7].

• 

  Fig. 2 Impacts of statins on insulin sensitivity. Adapted from Baker et al. Diabetes Res Clin Pract 2010;87:98-107, with permission from Elsevier [25].

• 

  Fig. 3 Hypothetical paradigm for statin-induced impairment of glucose metabolism. 1) Statins inhibit cascade of closure of adenosine triphosphate (ATP)-dependent potassium channel, depolarization, and calcium influx leads to insulin secretion. 2) Glucokinase is inhibited by highly increased uptake of plasma low density lipoprotein cholesterol (LDL-C; plasma-derived) by statins. 3) Statins suppress synthesis of CoQ10, resulting in inhibition of insulin secretion due to reduced production of ATP. 4) Statin suppresses the synthesis of isoprenoids, thus causing downregulation of glucose transporter 4 (GLUT4) expression on adipocyte cells. 5) Statins cause unregulation of LDL receptors (LDL-Rs), leading to enhanced uptake of LDL-C. 6) Oxidation of LDL-C may incite an inflammatory cascade. 7) Over-production of nitric oxide (NO) has been shown to induce β-cell apoptosis via activation of calpain. CHOL, cholesterol (de novo synthesized); HMG-CoA, 3-hydroxy-methylglutaryl coenzyme A; OxLDL, oxidized low density lipoprotein. Adapted from Sampson et al. Curr Opin Cardiol 2011;26:342-7, with permission from Wolters Kluwer Health [30] and Sattar et al. Atheroscler Suppl 2012;13:1-10, with permission from Elsevier [31].

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