clinical topic updates
Glucose-Lowering Agents and Cardiovascular Risk Reduction in Type 2 Diabetes
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.
Editor in Chief, Johns Hopkins Diabetes Guides
“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.”
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.
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