Abstract and Introduction
Multiple sodium glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have been shown to impart significant cardiovascular and kidney benefits, but are underused in clinical practice. Both SGLT-2i and GLP-1RA were first studied as glucose-lowering drugs, which may have impeded uptake by cardiologists in the wake of proven cardiovascular efficacy. Their significant effect on cardiovascular and kidney outcomes, which are largely independent of glucose-lowering effects, must drive a broader use of these drugs. Cardiologists are 3 times more likely than endocrinologists to see patients with both type 2 diabetes and cardiovascular disease, thus they are ideally positioned to share responsibility for SGLT-2i and GLP-1RA treatment with primary care providers. In order to increase adoption, SGLT-2i and GLP-1RA must be reframed as primarily cardiovascular and kidney disease risk-reducing agents with a side effect of glucose-lowering. Coordinated and multifaceted interventions engaging clinicians, patients, payers, professional societies, and health systems must be implemented to incentivize the adoption of these medications as part of routine cardiovascular and kidney care. Greater use of SGLT-2i and GLP-1RA will improve outcomes for patients with type 2 diabetes at high risk for cardiovascular and kidney disease.
Cardiovascular disease is a common cause of premature death and disability for patients with type 2 diabetes (T2D). Although a plethora of therapeutic agents targeting traditional risk factors are proven to reduce cardiovascular risk in patients with T2D,[2–5] decades of clinical research evaluating medications and strategies designed to treat its pathognomonic hallmark, hyperglycemia, have not translated into improvements in cardiovascular outcomes associated with glycemic control per se. Whether hyperglycemia is not causally contributing to cardiovascular risk, interventions were tested too late into the disease process or for too short periods of time, or any benefits of glucose control may have been countered by harm associated with glucose-lowering therapies remains unclear. These observations had resulted in a waning of enthusiasm for glucose-lowering therapies as agents for cardiovascular event prevention until the surprise results from positive trials evaluating sodium glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) that have been reported since 2015. Rather than reviewing the cardiovascular efficacy and putative mechanisms, which have been covered elsewhere in detail,[6–9] this article provides a consensus view on the key reasons for underuse of SGLT-2i and GLP-1RA by cardiologists.
The first outcomes trials evaluating the cardiovascular effects of novel glucose-lowering therapies in patients with T2D to show significant reductions in cardiovascular events were EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose), which evaluated the SGLT-2i empagliflozin, followed by the LEADER trial (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results), which evaluated the GLP1-RA liraglutide. EMPA-REG OUTCOME randomized 7020 participants with established cardiovascular disease to 1 of 2 doses of empagliflozin or placebo for a median follow-up of 3.1 years. The LEADER trial randomized 9340 participants, of whom 84% had established cardiovascular disease, to liraglutide or placebo for a median follow-up of 3.8 years. Not only did each agent reduce the risk for the primary composite outcome of cardiovascular death/myocardial infarction/stroke, but each also demonstrated significant reduction for cardiovascular and for all-cause death. The caveats to interpreting composite cardiovascular end points are well-documented, but the impact of these medicines (empagliflozin and liraglutide, in particular) on both cardiovascular and all-cause death is compelling. Whereas subsequent trials have revealed some heterogeneity in the estimated magnitude of effect on atherosclerotic cardiovascular events across the SGLT-2i class, the outcome trials of empagliflozin, canagliflozin,[13,14] dapagliflozin, and ertugliflozin support a consistent effect of SGLT-2i on reducing hospitalization for heart failure and propensity for kidney disease progression.[8,17,18] In contrast, the GLP-1RA trials that followed the LEADER trial showed marked heterogeneity in cardiovascular efficacy, potentially explained by variation in each agent's structural homology, pharmacology, adherence to protocol, and the studied population.[19,20] Outcomes trials evaluating the GLP1-RAs albiglutide, dulaglutide, and semaglutide demonstrated significant reductions in atherosclerotic events, with meta-analyses revealing favorable but relatively modest effects on heart failure hospitalizations and kidney disease progression. Trials of extended-release exenatide and lixisenatide, however, showed cardiovascular safety without significant cardiovascular benefit.
Through the demonstration of cardiovascular risk reduction in their respective cardiovascular outcome trials, multiple compounds from each class have received cardiovascular-specific indications in their regulatory product labeling. Society consensus statements and guidelines[27–29] have subsequently integrated SGLT-2i and GLP-1RA under the umbrella term of "glucose-lowering drugs with cardiovascular benefit" and recommended their use in patients with T2D at high cardiovascular risk. However, despite robust clinical trial observations, product labeling, multidisciplinary society endorsement, and an ever-growing body of routinely collected clinical data further supporting the safety and efficacy of these agents in patients with T2D at varying degrees of cardiovascular risk,[30–37] <10% of eligible patients receive either class of drug in the United States.[38,39] Whereas varying insurance coverage and out-of-pocket costs are important contributors to underuse, there remains a number of system-, patient- and clinician-level barriers to optimal adoption by the cardiovascular and renal communities.
Circulation. 2021;144(1):74-84. © 2021 American Heart Association, Inc.