Statin-induced diabetes

HMG-CoA reductase inhibitors - statins - have transformed risk management for cardiovascular disease. Their benefit is proportional to baseline risk, and is therefore more marked in high risk groups than in the general population. Since the risk of heart attack or stroke is doubled in diabetes, statins are a well-validated component of their management. They do however enhance progression to diabetes in the non-diabetic population. The magnitude of this excess risk has been estimated at 9-13%, or in absolute terms, at one additional case of diabetes for every 255 people treated for 4 years. The mechanism is uncertain, but the risk of new diabetes is greatest in those with higher baseline glucose levels, age and BMI. Increased risk of diabetes appears to be a class effect and proportional to cholesterol-lowering efficacy. Overall, the cardiovascular benefits of statins greatly outweigh the risks of a modest increase in glucose levels, but it should be noted that the risk of diabetes appears greater in older women, who may derive less benefit from statins.

Introduction

"Few drugs have had such a dramatic effect upon health outcomes"[1]. Over 4 years of statin use, a 1 mmol/l (39mg/dl) reduction in LDL cholesterol reduces mortality by 9% in those with diabetes and 13% in those without, and even greater benefits accrue over longer-term use. (see our page on the use of Statins).

All useful drugs have unwanted effects, however, and a 25% excess risk of progression to diabetes emerged from the JUPITER (Justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin) study[2]. Since millions of people take statins, this translates into a large number of new cases of diabetes, and has prompted careful evaluation.

Meta-analysis findings.

Sattar and colleagues performed a meta-analysis of 13 trials involving 91,140 participants, 4278 of who developed diabetes, and found that the risk of incident diabetes increased by 9% [OR 1.09; 95%CI 1.02-1.17][3]. This equates to one extra case of diabetes for every 255 people treated. The investigators put this into perspective by pointing out that statin treatment would also prevent 5.4 coronaries and similar numbers of strokes or revascularization procedures in the same sample of users.

A further pooled analysis examined 5 trials involving 32,752 people which compared intensive versus moderate dose statin therapy, and showed that intensive therapy increased the risk of diabetes by 12% [OR 1.12; 95%CI 1.04-1.22] as compared with standard dosing[4].

A Cochrane review estimated the increase in risk at 18% [RR 1.18 95%CI 1.01-1.39][5].

Observational Studies

An observational study of 153,840 post-menopausal women aged 50-79 treated with one or other of 5 statins found a 48% increase in the incidence of diabetes [OR 1.48;95%CI 1.38-1.59]. Unexpectedly, women with a BMI below 25 had a greater risk than those above 30[6].

A population-based study from Canada examined the relative risk of developing diabetes in users of different statin preparations. Using pravastatin as the reference, the investigators found a 22% increased risk for users of rosuvastatin, an 18% increase in risk for atorvastatin, and a 10% increase in risk for simvastatin. There was no increased risk (relative for pravastatin) for fluvastatin or lovastatin. The excess risk of diabetes was directly related to the relative potency of these agents[7].

Mechanisms

There has been much debate concerning possible mechanisms by which statin therapy might induce diabetes. There are conflicting findings concerning insulin resistance, although some studies have shown increased insulin levels and HOMA-IR. There may be differences between individual statins in this respect; pravastatin may actually increase insulin sensitivity. Effects on beta cell function, mitochondrial function in skeletal muscle and adiponectin levels have also been described, and no simple explanation has yet emerged[8].

Discussion

Evidence described in this article shows that statins do modestly increase the risk of diabetes. This is a class effect, and the relative risk of different doses and agents appears to relate mainly to LDL-cholesterol-lowering potency.

Many commonly used therapies are also known to increase the risk of diabetes, including thiazide diuretics, beta-blockers and nicotinic acid (niacin). In general, such effects are most likely to manifest in those already predisposed to diabetes because of age, overweight or borderline glucose intolerance. This applies also to the statins, with the additional caution that older people, women and those of Asian extraction may be more susceptible to statin-induced diabetes[9]

Screen-detected diabetes appears to have a better prognosis than sporadic diabetes, because the latter usually implies greater glycaemic exposure prior to diagnosis. Statin-induced diabetes probably falls into the same category and, as pointed out above, the likely benefits will generally far outweigh the risk of diabetes.

Since the risk of diabetes increases with age, and the benefits of statin therapy diminish, these should be prescribed with caution in older people at increased risk of diabetes.

References

  1. ^ Goldfine AB. Statins: is it really time to reassess benefits and risks? New Engl J Med 2012;366:1752-5

  2. ^ Ridker PM et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. New Engl J Med 2008;359:2195-207

  3. ^ Sattar N et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials.

  4. ^ Preiss D et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. J Am Med Assoc 2011;305:305:2556-64

  5. ^ Taylor F et al. Statins for the primary prevention or cardiovascular disease (Review). Cochrane Library 2013, Issue 5.

  6. ^ Culver AL et al. Statin use and risk of diabetes mellitus in postmenopausal women in the women's health initiative. Arch Intern Med 2012;172:144-52

  7. ^ Carter AA et al. Risk of incident diabetes among patients treated with statins: population-based study.BMJ 2013;346:f2619 doi: 10.1136/bmj.f2610(23rd May)

  8. ^ Sattar N, Taskinen M-R. Statins are diabetogenic - myth or reality? Atherosclerosis supplements 2102;13:1-10

  9. ^ Goldstein MR, Mascitelli L. Do statins cause diabetes? Curr Diab Rep (Published online 2 March 2013)

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