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Review
. 2011 Jul;26(4):342-7.
doi: 10.1097/HCO.0b013e3283470359.

Are Statins Diabetogenic?

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Free PMC article
Review

Are Statins Diabetogenic?

Uchechukwu K Sampson et al. Curr Opin Cardiol. .
Free PMC article

Abstract

Purpose of review: Statins are widely utilized for low-density lipoprotein lowering and for prevention of atherosclerotic cardiovascular disease. Although these drugs have a good safety record, increased risk of developing diabetes during extended use has recently garnered attention. Here we review clinical trial evidence related to statin use and incident diabetes, and the potential mechanisms for this association.

Recent findings: The increased incidence of diabetes with rosuvastatin treatment in Justification for the Use of Statins in Primary Prevention: an intervention Trial Evaluating Rosuvastatin (JUPITER) reignited attention on the link between statin therapy and diabetes. The JUPITER findings are supported by two recent meta-analyses of large-scale placebo-controlled and standard care-controlled trials, which, respectively, observed a 9% [odds ratio 1.09; 95% confidence interval (CI) 1.02-1.17] and 13% (risk ratio 1.13; 95% CI 1.03-1.23) increased risk for incident diabetes associated with statin therapy. However, the underlying mechanisms for this association remain unclear. Experimental evidence supports a paradigm implicating inhibition of β-cell glucose transporters, delayed ATP production, pro-inflammatory and oxidative β-cell effects of plasma-derived cholesterol, inhibition of calcium channel-dependent insulin secretion, and β-cell apoptosis.

Summary: The aggregate of large clinical trials supports the notion that statins modestly increase the risk of incident diabetes. Because diabetes is a risk equivalent condition for coronary and peripheral arterial diseases, these findings create a paradox whereby needed statin therapy may be withheld to avoid excess risk of diabetes while representing the strongest cardiovascular risk reduction tool in diabetics. We simply recommend regular glucose monitoring in patients taking statins.

Figures

Figure 1
Figure 1. Hypothetical paradigm for statin-induced impairment of glucose metabolism
(1) Intracellular arrival of glucose via glucose transporter (Glut2 in β-cells) leads to phosphorylation by glucokinase, and routing to the metabolic pathway. The resulting cascade of closure of ATP-dependent potassium channel, depolarization, and calcium influx leads to insulin secretion; this process may be inhibited by statins [23,24]. (2) Glucokinase is inhibited by abundance of plasma cholesterol [28], and thus is conceivably affected by statin-induced inhibition of de-novo cholesterol synthesis with increased uptake of plasma LDL. (3) Statin inhibition of HMG-CoA reductase suppresses synthesis of ubiquinone (CoQ10), an essential factor in the mitochondrial electron-transfer system, resulting in inhibition of insulin secretion due to reduced production of ATP [25]. (4) Statin inhibition of HMG-CoA reductase suppresses the synthesis of isoprenoids, thus causing downregulation of Glut4 expression on adipocyte cells, leading to impaired glucose uptake. (5) The inhibition of HMG-CoA reductase causes upregulation of LDL receptors, leading to enhanced uptake of LDL-cholesterol in an effort to replenish intracellular stores. However, the intracellular fate of plasma-derived LDL-cholesterol may be distinct from that of de-novo synthesized cholesterol. (6) The oxidation of LDL-cholesterol may incite an inflammatory cascade that compromises the functional – for example insulin secretion apparatus – and ultimately structural integrity of the islet β-cells. (7) Furthermore, cytokine-induced over-production of nitric oxide (NO) has been shown to induce β-cell apoptosis via the activation of calpain – a calcium-dependent protease [29]. ATP, adenosine triphosphate; CHOL, cholesterol (de-novo synthesized); Glut2, glucose transporter 2; Glut4, glucose transporter 4; HMG-CoA, 3-hydroxy-methylglutaryl coenzyme A; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol (plasma-derived); LDL-R, LDL receptor; OxLDL, oxidized LDL; NO, nitric oxide.

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