Statin therapy and the risk for diabetes among adult women: do the benefits outweigh the risk?

Abstract

Purpose of review:

The purpose of this review was to examine statin therapy and the risk for diabetes among adult women using a selective review.

Recent findings:

The literature contains reports of new-onset diabetes associated with statin use. While many studies do not report sex-specific results, there is evidence indicating the risk to benefit ratio may vary by gender. However, the absolute effects are not clear because women have historically been under-represented in clinical trials.

Summary:

A review of the literature indicates that the cardiovascular benefits of statins appear to outweigh the risk for statin-related diabetes. However, the effect may depend upon baseline diabetes risk, dose, and statin potency. Rigorous, long-term studies focused on the risks and benefits of statins in women are unavailable to sort for gender-specific differences. Until this changes, individualized attention to risk assessment, and strong prevention with lifestyle changes must prevail.

Introduction

Cardiovascular disease (CVD) is the leading cause of death among American women [CDC, 2007]. The 2011 American Heart Association (AHA) update on effectiveness-based guidelines for the prevention of CVD in women [Mosca et al. 2011] endorses low-density lipoprotein (LDL)-lowering drug therapy for a10-year Framingham [D’Agostino et al. 2008] or Reynolds [Ridker et al. 2007] CVD risk score of at least 10%[Mosca et al. 2011]. A recent meta-analysis conducted by the Cholesterol Treatment Trialists’ Collaborators concluded that the cardiovascular benefit of lowering LDL cholesterol with statins exceeds known risk even in individuals with less than 5% risk of CVD over 5 years [Cholesterol Treatment Trialists’ Collaborators et al. 2012]. New guidelines for the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel IV) expected to be released in late 2012 may thus encourage statin treatment in individuals under this low risk threshold. With more statins becoming available as generic brands, the use of statins by US women may increase further.

Diabetes and women’s health

Over 25 million Americans have diabetes, and more than half of them are women [CDC, 2011], placing them at high risk for CVD. Risk patterns in women differ from those of men. Women are more likely than men to have a stroke [Roger et al. 2011]. Moreover, following a myocardial infarction, the risk of mortality is higher in women with diabetes than in men [Marrugat et al. 1998]. Hence, diabetes prevention may be uniquely important in women. Since statins have been associated with increased diabetes incidence preferentially among women [Mora et al. 2010], this presents a challenge to clarify both the risk and the benefits of statin therapy in women.

Benefits of statins

In primary and secondary prevention, statins for men and women combined have been associated with a strong decrease in CVD events overall, and also when applied to subpopulations with certain risk indicators, including elevated high-sensitivity C-reactive protein, abnormal lipid profile plus hypertension, age, family history of CVD, and smoking [Gotto et al. 2000; Mora et al. 2010; Ridker et al. 2009]. Separately, though, statin benefit in women is less robust, especially in primary prevention. The Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) found significant benefit from rosuvastatin in women only for reduction of revascularization/unstable angina outcomes [hazard ratio (HR) 0.24, 95% confidence interval (CI) 0.11–0.51, p < 0.0001, p for heterogeneity = 0.01] [Mora et al. 2010; Ridker et al. 2008]. In contrast, men derived benefit for all other CVD component endpoints save all-cause mortality, in which men and women did not significantly benefit until results were pooled. However, the composite CVD risk reductions between men and women were similar (HR 0.54, 95% CI 0.37–0.80, p = 0.002 for women; HR 0.58, 95% CI 0.45–0.73, p < 0.0001 for men with nonsignificant p values for interaction by sex = 0.80). The investigators calculated that 36 women versus 22 men would need to be treated over 5 years to prevent one primary endpoint. Of interest, women represented 61% of the JUPITER participants [Mora et al. 2010].

A meta-analysis of 18 trials in primary and secondary prevention separated data by gender, and reported that statins conveyed significant benefit on cardiovascular event outcomes for both men and women, though trending at slightly different rates: odds ratio (OR) 0.81, 95% CI 0.75–0.89, p < 0.0001 for women; OR 0.77, 95% CI 0.71–0.83, p < 0.0001 for men [Kostis et al. 2012]. All-cause mortality was lower for women than for men, especially in primary prevention trials, though this was not significant by interaction with men (OR 0.87, 95% CI 0.87–0.97, p = 0.01, p for interaction with men = 0.51). However, only 28.5% of participants in the trials were women, with most from a single open-label trial, the Primary Prevention of Cardiovascular Disease with Pravastatin in Japan (MEGA) [Kostis et al. 2012]. Since the absolute effect was not measured, the results are only cautiously encouraging, and underscore the need for rigorous study of women in greater numbers.

A second sex-based meta-analysis looked at differences in benefit between men and women in 11 strictly selected secondary prevention trials. This analysis also found similar overall CVD benefit for men and women as measured in terms of relative risk compared with placebo: RR 0.81, 95% CI 0.74–0.89 for women; RR 0.82, 95% CI 0.78–0.85 for men [Gutierrez et al. 2012]. The authors note that only 20.6% of participants in the trials were women, and that women carried worse cardiovascular risk status than men, with older age, and a higher prevalence of hypertension. Although statins did not significantly benefit women for outcomes of stroke and all-cause mortality in stratified analysis, the effect size of outcomes in women match that in men [Taylor and Ebrahim, 2012].

Despite the limitations of inter-trial and intra-trial variability in diagnostic and statistical methods, the under-representation, and the unbalanced status of women compared with men, the CVD benefit of statins in women seems credible.

Association between statin use and risk of diabetes

The incidence of diabetes with statin use among women is less clear than that for men. Meta-analyses place the risk of diabetes at 9–13%, with higher incidence at higher statin doses/potency and with higher baseline risk for diabetes [Sattar et al. 2010; Preiss et al. 2011; Rajpathak et al. 2009]. Whether women are at greater risk for statin-related diabetes than men is unclear.

A subanalysis of the JUPITER trial reported that rosuvastatin was associated with an increased risk of physician-reported new-onset diabetes among women (HR 1.49, 95% CI 1.11–2.01, p = 0.008) compared to men (HR 1.14, 95% CI 0.91–1.43, p = 0.24) [Mora et al. 2010]. Notably, more women than men were at highest baseline risk for diabetes in JUPITER. A later JUPITER subanalysis combined men and women in an effort to define risk of incident diabetes versus benefit derived from rosuvastatin, finding a 28% increased incidence of diabetes with rosuvastatin in those with pre-existing risk factors for diabetes [e.g. metabolic syndrome, body mass index greater than or equal to 30 kg/m² or a hemoglobin A1c (HbA1c) of more than 6%] [Ridker et al. 2012]. For those without diabetes risk factors, a HR of 0.99 with 95% CI 0.45–2.21, and p = 0.99 suggests a null effect on diabetes onset associated with rosuvastatin. The authors calculate that rosuvastatin 20 mg/day prevented 134 CVD events while accelerating 54 cases of new-onset diabetes by 5–6 weeks in high-risk individuals. For those without baseline diabetes risk, 86 CVD events were prevented alongside no cases of diabetes. Given the wide confidence interval and large p value in the null effect finding, it would be useful to explore sex-specific results in this analysis.

Statin use was related to an increased risk of self-reported new-onset diabetes in postmenopausal women using data from the Women’s Health Initiative (HR 1.48, 95% CI 1.38–1.59). As only 7.04% reported statin use at baseline, this translates to an absolute risk rate of one case of incident diabetes for every 1000 women taking statins per year [Culver et al. 2012]. Observational analysis is limited, but this gives weight to the need to study diabetes risk and benefits of statins in large populations of adult women of diverse ethnicities and ages [Katsiki and Banach, 2012a, 2012b; Mitka, 2012].

A retrospective cohort study using Taiwanese national health insurance data over an average of 7.2 years found an increased incidence of diabetes with statin use with HR 1.15 (95% CI 1.08–1.22, p < 0.001) [Wang et al. 2012]. As in previous studies, the cardiovascular benefit outweighed the risk for diabetes in secondary and high-risk populations. The authors caution that the results are population specific, reflecting clinical practice with lower doses than in many trials. While this study did not separate women from men, the analysis found a trend favoring statin use for CVD outcomes before diabetes diagnosis compared with those taking statins after diagnosis of diabetes with HR 0.75 (95% CI 0.59–0.97, p = 0.027).

Statins’ effect on glucose homeostasis

How statins affect glucose homeostasis is not established, nor has this mechanism been explored by gender. A meta-analysis of 16 trials found that statins did not have a significant impact on insulin sensitivity compared with placebo/control [Baker et al. 2010]. Results varied by type of statin. Pravastatin was found to significantly improve insulin sensitivity, whereas simvastatin significantly worsened insulin sensitivity. However, these were small-scale trials (n < 100). Several short-term studies examined the effect of various statins on HbA1c and fasting glucose, and show conflicting results among different populations [Kostapanos et al. 2010]. A trend for either neutral or beneficial effect appears only with pravastatin [Kostapanos et al. 2010]. Other statins trend toward a negative effect [Koh et al. 2010].

Summary

The cardiovascular benefits appear to outweigh the risk for incident diabetes reported in association with statin use in adult women beyond childbearing years. However, both the benefits and the risk for diabetes in women are less clear than for men, especially in primary prevention and in young women. The AHA guidelines to prevent CVD in women recognize that women carry and manage risks differently than men, and call upon an emerging research focus on gender differences over long-term, randomized trials, and real-world settings to determine better treatment and prevention guidance [Mosca et al. 2011]. How to implement and strengthen lifestyle changes to CVD in women (and in men) seems paramount.