The use of statins in people at risk of developing diabetes mellitus: Evidence and guidance for clinical practice

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Abstract

Reducing low-density lipoprotein cholesterol (LDL-C) levels using statins is associated with significant reductions in cardiovascular (CV) events in a wide range of patient populations. Although statins are generally considered to be safe, recent studies suggest they are associated with an increased risk of developing Type 2 diabetes (T2D). This led the US Food and Drug Administration (FDA) to change their labelling requirements for statins to include a warning about the possibility of increased blood sugar and HbA1c levels and the European Medicines Agency (EMA) to issue guidance on a small increased risk of T2D with the statin class. This review examines the evidence leading to these claims and provides practical guidance for primary care physicians on the use of statins in people with or at risk of developing T2D. Overall, evidence suggests that the benefits of statins for the reduction of CV risk far outweigh the risk of developing T2D, especially in individuals with higher CV risk. To reduce the risk of developing T2D, physicians should assess all patients for T2D risk prior to starting statin therapy, educate patients about their risks, and encourage risk-reduction through lifestyle changes. Whether some statins are more diabetogenic than others requires further study. Statin-treated patients at high risk of developing T2D should regularly be monitored for changes in blood glucose or HbA1c levels, and the risk of conversion from pre-diabetes to T2D should be reduced by intensifying lifestyle changes. Should a patient develop T2D during statin treatment, physicians should continue with statin therapy and manage T2D in accordance with relevant national guidelines.

Introduction

Cardiovascular disease (CVD) accounts for approximately 50% of all deaths in Europe and, as the primary cause of disease burden, is estimated to cost the European economy Euros 196 billion, annually [1]. Major modifiable risk factors for CVDs include tobacco use, dyslipidaemia, hypertension, Type 2 diabetes mellitus (T2D), poor diet, physical inactivity and obesity [2], [3], [4]. Because these risk factors tend to co-exist with a multiplicative, rather than additive, effect on CV risk [5], [6], [7], it is important to assess and treat the individual patient's overall CV risk [2], [3]. Moreover, since T2D and CVD have some overlapping risk factors and often co-exist, the 2013 European Society of Cardiology (ESC)/European Association for the Study of Diabetes (EASD) Guidelines on Diabetes, Pre-diabetes, and Cardiovascular Diseases suggest that all patients with CVD or CV risk factors should routinely be screened for T2D [8] using either glycated haemoglobin (HbA1c) or fasting plasma glucose (FPG) as markers. Diabetes risk scores should be used in advance of deciding which patients would benefit from glycaemia testing.

Current best practice for reducing CV risk includes lifestyle changes such as improved diet, weight loss, regular physical activity, and (when applicable) smoking cessation, together with pharmacotherapy to improve lipid profile and blood pressure [2], [8], [9], [10], [11], [18]. Although the management of CV risk factors has improved over recent years [12], the clinical impact of these gains will potentially be attenuated by the increasing pandemics of obesity and T2D as atherosclerotic disease is accelerated in T2D [12], [13], [14]. Currently, the worldwide incidence of T2D is predicted to increase from 342 million in 2011 to 534 million by 2030 [15] and the number of CV deaths is predicted to increase from 17.1 million in 2004 to 23.6 million in 2030 [16]. The fact that both CVD and T2D are strongly related to a western lifestyle (i.e. smoking, insufficient exercise, and a high-fat, high-refined sugar diet comprising a large proportion of processed food) suggests that greater efforts are needed at every level (including Governmental policies targeted at the food industry) to encourage lifestyle changes. A tool kit providing practical advice for healthcare professionals has recently been developed to aid this process [8], [17].

Section snippets

Statins are safe and effective for the reduction of CV risk in a wide range of patients

Dyslipidaemia – characterised by increased concentrations of the pro-atherogenic apolipoprotein-B containing lipoproteins (low-density lipoproteins [LDLs], very-low density lipoproteins [VLDLs], chylomicrons [CMs] and VLDL-/CM-remnants) and reduced levels of potentially antiatherogenic apolipoprotein-A-I containing high-density lipoproteins [HDLs] – accounts for a significant proportion of the population-attributable risk for cardiovascular disease [7]. Numerous clinical trials have

Guidelines for the management of dyslipidaemia and CVD

International guidelines for the management of dyslipidaemia and CVD recommend reducing LDL-C to specific targets or by specific statin regimes depending on a patient's overall level of CV risk [2], [3], [4], [8], [11], [53], [54], [55]. Patients with established T2D are either classified as high risk or, for those with T2D and at least one other CV risk factor or target organ damage, very high risk. For patients without T2D, CV risk stratification is carried out using the European Systematic

T2D diagnosis

The development of T2D is a gradual process that is typically associated with a cluster of modifiable risk factors, including atherogenic dyslipidaemia, raised blood pressure, obesity, smoking and/or a sedentary lifestyle, all of which increase the risk of CVD. Thus among those with impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) (pre-diabetes), the risk of incident CVD may be elevated due to the presence of the associated risk factors. Some, but not all, patients with

Evidence for the diabetogenicity of statins

The first study to report on T2D risk with statin use was the all-male West Of Scotland Coronary Prevention Study (WOSCOPS; N = 5974) [37]. This study suggested that, compared to placebo, pravastatin was associated with a 30% relative risk reduction (P = 0.042) in the hazard of developing T2D after 5 years. Therefore, the finding in Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study (N = 17,802) that treatment with

Mechanistic rationale for the diabetogenic effects of statins

T2D is a complex disorder characterised by both pancreatic beta cell dysfunction and insulin resistance of skeletal muscle, adipose tissue and liver. The precise reasons for the increased incidence of T2D with statins have not yet been identified. Possible explanations include residual confounding factors, such as improved survival with statin treatment and a greater chance of identifying incident T2D in statin-treated patients. However, analysis of electronic medical records from 500 UK

Further research

In order to fully understand the best treatment strategy for people with or at risk of developing statin-mediated T2D, a number of outstanding questions need to be answered. In addition to understanding whether there are differences between statins in diabetogenic potential, studies are required to determine whether statin-mediated changes in glucose levels represent true T2D (i.e., is statin-related hyperglycaemia reversible after cessation of statin-therapy?), and, to what extent long-term

Recommendations for the use of statins in patients with, or at risk of developing, T2D

Recommendations for the use of statins in patients at risk of developing T2D: The decision to prescribe a statin should always take into account risk vs. benefit. It is clear that the benefits of statin-use far outweigh the small absolute risk of developing T2D in patients with elevated CV risk and that, even if a patient develops T2D, the risks associated with CVD are much greater than the risks associated with T2D. Indeed, individuals with a higher risk of developing T2D have an increased

Conclusions

Statins are the recommended first-line lipid-lowering drugs for the majority of patients with any level of CV risk. Although they are generally considered to be safe and well-tolerated, recent studies have demonstrated a dose-dependent increase in T2D with statins (Fig. 2, Fig. 3). A number of plausible mechanisms have been suggested to support this effect (Section 5), but definitive proof for responsible mechanisms is lacking. Although our understanding of the diabetogenic effects of statins

Conflict of interest

Naveed Sattar has consulted for Astrazeneca, BMS, BI, Amgen, Sanofi, and Kowa; Henry Ginsberg reports have received consulting fees from: Kowa, Merck, Pfizer, AstraZeneca, BMS, Sanofi, Regeneron, Amgen, Novartis. Research funding from Merck, Sanofi, Regeneron, Genzyme, Amgen, Novartis.

Kausik Ray reports to having received honoraria for advisory boards or lectures from Agerion, Abbott, Pfizer, AZ, Sanofi, Regeneron, Amgen, MSD, Roche, Kowa, Novartis, Novo Nordisk, Daiichi, Bayer and Lily. John

Funding declaration

Publication of this supplement has been funded by Kowa Pharmaceutical Europe. Pitavastatin is a product marketed by the sponsor of the supplement. Authors received support with the preparation of their articles from GK Pharmacomm, an agency funded by the sponsor. The sponsor had no input in terms of the content of this supplement.

. Studies comparing the diabetogenic effects of statins.

StatinPatient characteristicsStudy design (N)Mean follow upMain observations
Rosuvastatin 10 mg [92]Mixed

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