Risk Prevention
Diabetes Drugs and Cardiovascular Event Reduction: A Paradigm Shift Erik M Kelly, MD 1 and Donald E Cutlip, MD 1,2 1. Division of Cardiology and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA; 2. Baim Institute for Clinical Research, Boston, MA
Abstract This review article summarizes the recent cardiovascular outcome data for sodium–glucose cotransporter-2 inhibitors and glucagon-like peptide-1 analogues, which have been found to reduce cardiovascular events. We also detail the implications these new medications will have on clinical practice through a review of recent diabetes guidelines and cost-effectiveness data.
Keywords Cardiovascular outcomes, cost-effectiveness, glucagon-like peptide-1 analogues, guidelines, sodium–glucose cotransporter-2 inhibitors, diabetes Disclosure: The authors have no conflicts of interest to declare. Received: 26 November 2017 Accepted: 15 January 2018 Citation: US Cardiology Review 2018;12(1):46–50. DOI: 10.15420/usc.2017:35:1 Correspondence: Erik M Kelly, Division of Cardiology and Department of Medicine, Beth Israel Deaconess Medical Center, West Campus, Baker 4, 185 Pilgrim Road, Boston, MA 02215. E: emkelly@bidmc.harvard.edu
Diabetes mellitus is one of the most common chronic diseases, affecting >30 million people in the US and 422 million worldwide.1,2 Alarmingly, both the incidence and prevalence of type 2 diabetes have doubled in the US since 1990.3 This is driven by an aging population, obesity, physical inactivity, and prolonged survival in those with diabetes, among other factors. It is estimated that diabetes will affect >54 million people in the US by 2030.4 Cardiologists routinely care for patients with diabetes, as those with the condition have a two- to four-fold increased risk of developing coronary heart disease.5 Indeed, coronary heart disease is the leading cause of morbidity and mortality in those with diabetes, with over one-third having a myocardial infarction in their lifetimes.6 Furthermore, diabetes patients with an acute coronary syndrome have worse clinical outcomes compared with people without diabetes.7 Patients with diabetes also have a two- to five-fold increased risk of developing heart failure.8
cardiovascular safety of these drugs arose following the University Group Diabetes Program study in 1975, which demonstrated excess cardiac deaths in patients treated with tolbutamide compared with placebo or insulin.13 Subsequent studies with other agents in this drug class demonstrated similar results.14–16 For example, a recent review and meta-analysis of 82 randomized controlled trials and 26 observational studies showed an increased risk of all-cause mortality, cardiovascularrelated mortality, myocardial infarction, and stroke with sulfonylureas compared with other glucose-lowering drugs.17 As a result of the totality of evidence, all drugs in the sulfonylurea class carry a ‘black box’ warning for increased risk of cardiovascular mortality.
The UK Prospective Diabetes Study, among others, found that intensive glycemic control significantly reduces microvascular complications but fails to modify macrovascular risk in patients with diabetes.9 While contemporary meta-analyses suggest that intensive glycemic control does reduce the risk of cardiovascular events, these benefits appear modest compared with the cardiovascular risk reductions associated with the modification of other traditional risk factors.10,11 Importantly, several classes of diabetes medications have been associated with adverse cardiovascular events. Specifically, sulfonylureas are associated with increased cardiovascular mortality while thiazolidinediones and dipeptidyl peptidase-4 (DPP-4) inhibitors are associated with higher rates of heart failure.
Thiazolidinediones are synthetic ligands for peroxisome proliferativeactivated receptor gamma, which improves insulin sensitivity in peripheral tissues.18 First approved by the US Food and Drug Administration (FDA) in 1999, the safety of these agents was called into question following a 2007 meta-analysis showing that rosiglitazone was associated with an increased risk of myocardial infarction and death from cardiovascular causes.19 These drugs have also been associated with an increased risk of heart failure.20,21 More recent studies dispute the increased risk of myocardial infarction with rosiglitazone and there are data supporting the cardioprotective effects of pioglitazone.22,23 However, the increased risk of heart failure, weight gain and bone fractures, along with a potential association with bladder cancer, has led to significant reductions in the use of these drugs.24 The concerns about peripheral edema and heart failure have also resulted in product labels cautioning against the use of thiazolidinediones in patients with heart failure, with a contraindication for initiation in patients with New York Heart Association Class III or IV.25
Sulfonylureas have been used for the treatment of type 2 diabetes for >50 years. Their main effect is through raising serum insulin concentrations via stimulation of the pancreatic beta cells.12 Concerns over the
DPP-4 inhibitors are a class of oral hypoglycemic agents that block the action of endogenous DPP-4 – a protease that degrades incretin hormones such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory
46
Access at: www.USCjournal.com
USC_Cutlip_FINAL.indd 46
© RADCLIFFE CARDIOLOGY 2018
02/03/2018 16:00