Does intensive cholesterol lowering increase the risk of diabetes?

Abstract

To the Editor: Dr Kostapanos and colleagues reported that in hyperlipidaemic patients with impaired fasting glucose, rosuvastatin treatment was associated with a dose-dependent increase in insulin resistance (1). In the accompanying editorial, Dr Wierzbicki highlighted the puzzling effects of cholesterol-lowering drugs on diabetes risk (2). We suggest that the effect of statin therapy on the subsequent risk of diabetes might be influenced by the amount of drug-induced cholesterol reduction. Increasing evidence indicates that statins, beyond their cholesterol-lowering action, may exert a variety of inhibitory effects on inflammatory processes; this anti-inflammatory potential seems to be mediated to a considerable part independent of cholesterol lowering (3). On the other hand, it is well known that the development of type 2 diabetes may be preceded by subclinical systemic inflammation, which is believed to be pathogenic in diabetogenesis by way of an increase in insulin resistance or even a decrease in insulin secretion (4). However, mounting evidence suggests also a critical role for endogenous cholesterol in the normal function of pancreatic beta-cells. It has recently been demonstrated that the inhibition of cholesterol biosynthesis impairs insulin secretion (5). Moreover, an observational study performed in a very large number of Veteran patients found that statin therapy was associated with a rise of fasting plasma glucose levels over a mean duration of 2 years in patients with and without diabetes (6). Retrospective analysis of the West of Scotland Coronary Prevention Study (WOSCOPS) revealed that 5 years of treatment with pravastatin reduced diabetes incidence by 30% (7). It was suggested that although lowering of triglyceride levels could have influenced diabetes incidence, other mechanisms such as anti-inflammatory action might have been involved. In the multivariate Cox model, baseline total cholesterol did not predict the development of diabetes (7). Of note, the median low density lipoprotein (LDL) cholesterol level in individuals assigned to pravastatin at the end of follow-up was roughly 140 mg/dl (8). Furthermore, pravastatin did not decrease diabetes incidence in the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) trial, which included glucose-intolerant patients (median LDL cholesterol level in the pravastatin group at the end of the trial was roughly 110 mg/dl) (9). On the other hand, in the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, which studied apparently healthy persons without hyperlipidaemia but with elevated high-sensitivity C-reactive protein levels (10), the risk of diabetes was significantly increased by a factor of 1.25 among individuals receiving rosuvastatin 20 mg daily compared with placebo. Strikingly, among persons assigned to rosuvastatin, the median LDL cholesterol level at 12 months was 55 mg/dl. Estimates of global diabetes prevalence (11) indicate that the number of people with diabetes, a pathology closely related to unhealthy lifestyles, is projected to increase from 246 million to up to 380 million by 2025. On the basis of these projections, it is therefore imperative that a serious battle against this pandaemia should mainly rely on lifestyle modifications. In this setting, it should be noted that salutary lifestyle measures, which might exert their beneficial actions through an anti-inflammatory mechanism without a strong cholesterol-lowering effect, beyond reducing cardiovascular events and total mortality, might also reduce the risk of diabetes and other chronic degenerative diseases. Therefore, it is plausible that, at high statin doses, the drug-induced cholesterol depletion is limiting, overwhelming any anti-inflammatory beneficial effect on diabetogenesis. Lowering cholesterol at the expense of increasing diabetes might be counterproductive over the long-term. Most importantly, this needs our attention, given the widespread use of statins at high doses even in the primary prevention of cardiovascular disease. None.