Newer glucose-lowering drugs also treat obesity and heart failure

 - Kenny Lin, MD, MPH

Last June, the U.S. Food and Drug Administration (FDA) approved a weekly semaglutide (Wegovy) subcutaneous injection for chronic weight management in adults with obesity or overweight with at least one weight-related condition, based on randomized controlled trial (RCT) evidence that it produces substantial weight loss in persons with a body mass index of 27 or greater without diabetes. A lower dose of semaglutide (Ozempic), a glucagon-like peptide-1 (GLP-1) receptor agonist, had previously been approved by the FDA as a second-line therapy for patients with type 2 diabetes that reduced risk of major adverse cardiac events (MACE) in patients with established cardiovascular disease (CVD).

A 2021 BMJ clinical practice guideline examined the benefits and harms of GLP-1 receptor agonists and sodium-glucose cotransporter 2 (SGLT-2) inhibitors and made recommendations for use of these two drug classes in persons with type 2 diabetes and different levels of CVD risk with and without chronic kidney disease, summarized in Patient-Oriented Evidence That Matters in the January issue of American Family Physician. A related editorial by Dr. Sandy Robertson discussed how evidence can inform when to recommend starting a diabetes drug from one of these two CVD risk-lowering classes:

Current data strongly support a reduction in MACE and all-cause mortality with SGLT-2 inhibitors and GLP-1 agonists in patients who have diabetes with established CVD or kidney disease. These patients should be offered one of these medications in the absence of contraindications, regardless of glucose control. Because there is no significant reduction in cardiovascular outcomes in patients who have diabetes without established CVD, patient-centered shared decision-making about adding an SGLT-2 inhibitor or a GLP-1 agonist for cardiovascular benefit is important and ... based on other established benefits such as weight control (moderate net weight loss for GLP-1 agonists and small weight loss for SGLT-2 inhibitors) against risks of genital infections (SGLT-2 inhibitors) or gastrointestinal disturbances (GLP-1 agonists).

Although GLP-1 agonists are associated with greater weight loss than SGLT-2 inhibitors, a population-based cohort study using Medicare and two U.S. commercial claims data sets found that starting a SGLT-2 inhibitor, compared to starting a GLP-1 agonist, reduced the relative risk of hospitalization for heart failure by about 30 percent in patients with and without CVD. A recent international RCT (622 centers in 23 countries) found that adding the SGLT-2 inhibitor empagliflozin (Jardiance) to usual therapy for patients with heart failure with preserved ejection fraction improved a composite outcome of CVD mortality and hospitalization, regardless of the presence of diabetes (RRR=19%, NNT=31). Similarly, a systematic review and meta-analysis of 8 earlier RCTs found that in heart failure patients without diabetes, SGLT-2 inhibitor treatment reduced the risk of this composite outcome by 20 percent.

Based on this new data, should primary care physicians consider adding a SGLT-2 inhibitor to the standard combination of drug therapies for their patients with heart failure? A qualitative study of Australian general practitioners suggested that knowledge gaps, drug adverse effects, and a preference for subspecialists to initiate SGLT-2 inhibitor therapy may be obstacles to increased prescribing of these drugs, which remain very expensive in the U.S.