Endocrinology

Type 2 Diabetes

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Glucose-Lowering Agents and Cardiovascular Risk Reduction in Type 2 Diabetes

clinical topic updates by Rita Rastogi Kalyani, MD, MHS, FACP

Overview

Our featured expert highlights the movement toward a more global approach for reducing cardiovascular risk in patients with type 2 diabetes. This consists of traditional risk factor reduction and a consideration of the profiles of the newer glucose-lowering agents.

Expert Commentary

Rita Rastogi Kalyani, MD, MHS, FACP

Editor in Chief, Johns Hopkins Diabetes Guides
Director, Diabetes Management Service
Johns Hopkins Total Pancreatectomy Islet Auto Transplant Program
Associate Professor of Medicine
Johns Hopkins University School of Medicine
Baltimore, MD

When we talk about cardiovascular risk in type 2 diabetes today, it is not just the traditional cardiovascular risk factors that we consider. We are also thinking about the glucose-lowering agents that we are prescribing and their respective risk reduction profiles.”

Rita Rastogi Kalyani, MD, MHS, FACP

Evaluating cardiovascular risk in patients with type 2 diabetes has traditionally focused on patient-related factors such as dyslipidemia, hypertension, smoking, age, race, ethnicity, obesity, diet, and physical inactivity (ie, general cardiovascular risk factors that are not specific to type 2 diabetes). Additional type 2 diabetes–related risk factors include the duration and stage of disease. With regard to hyperglycemia, the evidence of its impact on cardiovascular risk is not definitive in that studies have not consistently shown increased risk with higher hemoglobin A1C levels vs lower ranges. In general, glycemic targets are thought to improve the prevention of microvascular disease. However, for macrovascular disease, with the exception of the UKPDS 34 long-term follow-up study with metformin, which suggested cardiovascular benefits, the benefits of cardiovascular risk reduction with glucose-lowering strategies in clinical trials have been less definitive. Therefore, the role of intensive glycemic management to reduce cardiovascular risk is still debated. 

The stricter regulatory evaluation of newly US Food and Drug Administration (FDA)–approved type 2 diabetes agents requires post-marketing cardiovascular outcome trials. The results of these outcome trials, which have been carried out since 2008, conclude that the majority of newer agents have cardiovascular safety. Importantly, some of these newer drugs further show cardiovascular superiority with significant reductions in cardiovascular events during follow-up. These include agents in the glucagon-like peptide 1 receptor agonist class (eg, dulaglutide, liraglutide, and the injectable version of semaglutide) and those in the sodium-glucose cotransporter-2 inhibitor class (eg, canagliflozin, empagliflozin, and dapagliflozin). Two of these agents (ie, dulaglutide and dapagliflozin) are approved by the FDA for type 2 diabetes and have an additional indication for cardiovascular event or heart failure risk reduction (ie, primary prevention), respectively, in those with type 2 diabetes and established cardiovascular disease or multiple cardiovascular risk factors. These medications simultaneously manage type 2 diabetes and cardiovascular risk. 

Although the older type 2 diabetes agents did not have large cardiovascular outcome trials since these were not FDA mandated at the time, there is evidence that some of these older agents, such as pioglitazone and metformin, may potentially offer similar cardiovascular benefits. 

In conclusion, we are moving toward a more global approach to risk reduction. When we talk about cardiovascular risk in type 2 diabetes today, it is not just the traditional cardiovascular risk factors that we consider. We are also thinking about the glucose-lowering agents that we are prescribing and their respective risk reduction profiles.

References

Arnott C, Neal B. Do GLP-1 receptor agonists care if you have heart failure? Circulation. 2019;140(20):1623-1625. doi:10.1161/CIRCULATIONAHA.119.043303

Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group [published correction appears in Lancet. 1998;352(9139):1558]. Lancet. 1998;352(9131):854-865.

Herrera Comoglio R, Vidal Guitart X. Cardiovascular events and mortality among type 2 diabetes mellitus patients newly prescribed first-line blood glucose-lowering drugs monotherapies: a population-based cohort study in the Catalan electronic medical record database, SIDIAP, 2010-2015. Prim Care Diabetes. 2021;15(2):323-331. doi:10.1016/j.pcd.2020.11.002

Kalyani RR. Glucose-lowering drugs to reduce cardiovascular risk in type 2 diabetes. N Engl J Med. 2021;384(13):1248-1260. doi:10.1056/NEJMcp2000280

Wright AK, Suarez-Ortegon MF, Read SH, et al. Risk factor control and cardiovascular event risk in people with type 2 diabetes in primary and secondary prevention settings. Circulation. 2020;142(20):1925-1936. doi:10.1161/CIRCULATIONAHA.120.046783

Rita Rastogi Kalyani, MD, MHS, FACP

Editor in Chief, Johns Hopkins Diabetes Guides
Director, Diabetes Management Service
Johns Hopkins Total Pancreatectomy Islet Auto Transplant Program
Associate Professor of Medicine
Johns Hopkins University School of Medicine
Baltimore, MD

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