Fig. 1Association 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. 2Impacts of statins on insulin sensitivity. Adapted from Baker et al. Diabetes Res Clin Pract 2010;87:98-107, with permission from Elsevier [25].
Fig. 3Hypothetical 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].
Table 1Absolute number of events, incidence rates, and hazard ratios for cardiovascular endpoints, death, and diabetes in the JUPITER trial in participants with or without major diabetes risk factors, according to random allocation to rosuvastatin or placebo
Table 2Risk of new-onset type 2 diabetes mellitus according to number of risk factors at baseline