The use of statins in people at risk of developing diabetes mellitus: Evidence and guidance for clinical practice
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.Statin Patient characteristics Study design (N) Mean follow up Main observations Rosuvastatin 10 mg [92] Mixed
References (111)
- et al.
30-year trends in serum lipids among United States adults: results from the National Health and Nutrition Examination Surveys II, III, and 1999–2006
Am J Cardiol
(2010) - et al.
Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study
Lancet
(2004) - et al.
Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines
J Am Coll Cardiol
(2004) - et al.
Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study
Lancet
(2010) - et al.
Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol <50 mg/dl with rosuvastatin. The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin)
J Am Coll Cardiol
(2011) - et al.
Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial)
Am J Cardiol
(2003) - et al.
Effects of lovastatin on cognitive function and psychological well-being
Am J Med
(2000) - et al.
Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial
Lancet
(2012) - et al.
Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials
Lancet
(2010) - et al.
Statins are diabetogenic–myth or reality?
Atheroscler Suppl
(2012)
Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials
J Am Coll Cardiol
Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial
Lancet
2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult
Can J Cardiol
Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study
Lancet
Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials
Lancet
Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy: effect of baseline risk factors for diabetes
J Am Coll Cardiol
Balancing the cardiometabolic benefits and risks of statins
Lancet
Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial
Lancet
Atorvastatin causes insulin resistance and increases ambient glycemia in hypercholesterolemic patients
J Am Coll Cardiol
Pitavastatin 4 mg significantly reduces LDL-P and increases HDL size compared with pravastatin 40 mg (PREVAIL US)
J Clin Lipidol
Deterioration of glucose homeostasis in type 2 diabetic patients one year after beginning of statins therapy
Atherosclerosis
Differing effect of statins on insulin sensitivity in non-diabetics: a systematic review and meta-analysis
Diabetes Res Clin Pract
Meta-analysis of impact of different types and doses of statins on new-onset diabetes mellitus
Am J Cardiol
Pitavastatin 4 mg provides significantly greater reduction in LDL-C compared to pravastatin 40 mg with neutral effects on glucose metabolism: prespecified safety analysis from the short-term phase 4 PREVAIL US trial in patients with primary hyperlipidemia or mixed dyslipidemia
J Am Coll Cardiol
Short-term and long-term effects of pitavastatin and simvastatin on fasting plasma glucose in patients with primary hyperlipidemia or mixed dyslipidemia and >=2 risk factors for CHD
J Am Coll Cardiol
Mitochondrial dysfunction in pancreatic beta cells
Trends Endocrinol Metab
Differential metabolic effects of distinct statins
Atherosclerosis
Muscle mitochondria and insulin resistance: a human perspective
Trends Endocrinol Metab
European Cardiovascular Disease Statistics
European guidelines on cardiovascular disease prevention in clinical practice (Version 2012): the Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice
Int J Behav Med
ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS)
Eur Heart J
Standards of medical care in diabetes–2014
Diabetes Care
Total cardiovascular risk: a new treatment concept
J Hypertens Suppl
ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD)
Eur Heart J
Statins in the primary prevention of cardiovascular disease
Nat Rev Cardiol
2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines
Circulation
EUROASPIRE III. Management of cardiovascular risk factors in asymptomatic high-risk patients in general practice: cross-sectional survey in 12 European countries
Eur J Cardiovasc Prev Rehabil
Trends in age-specific coronary heart disease mortality in the European Union over three decades: 1980-2009
Eur Heart J
The effect of elevated body mass index on ischemic heart disease risk: causal estimates from a Mendelian randomisation approach
PLoS Med
Global guidelines for Type 2 diabetes
Projections of global mortality and burden of disease from 2002 to 2030
PLoS Med
Take action to prevent diabetes–the IMAGE toolkit for the prevention of type 2 diabetes in Europe
Horm Metab Res
Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins
Lancet
Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials
Lancet
Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis
Lancet
The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials
Lancet
Statins for the primary prevention of cardiovascular disease
Cochrane Database Syst Rev
Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial
J Am Med Assoc
Effect of two intensive statin regimens on progression of coronary disease
N Engl J Med
Adverse events associated with individual statin treatments for cardiovascular disease: an indirect comparison meta-analysis
QJM
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