LEADER Analysis Reassures on Liraglutide in Diabetic Patients With Heart Failure

New post hoc data from the LEADER trial should reassure prescribing physicians that liraglutide (Victoza; Novo Nordisk) is safe in patients with type 2 diabetes with or without a history of NYHA class I and II heart failure, and that the reduction in cardiovascular death, nonfatal MI, and nonfatal stroke seen in the overall trial was consistent regardless of whether or not patients had mild-to-moderate heart failure at baseline.

Moreover, no increased risk of heart failure hospitalization was seen, regardless of heart failure history.

That’s somewhat at odds with recent DAPA-HF findings for a different diabetes drug, dapagliflozin (Farxiga; AstraZeneca), which reduced the risk of heart failure death and worsening heart failure in patients both with and without diabetes as compared to standard care, said lead author Steven Marso, MD (Midwest Heart and Vascular Institute, Overland Park, KS).

What’s emerging, he told TCTMD, is the possibility that the two newest classes of diabetes medications—the glucagon-like peptide-1 (GLP-1) agonists like liraglutide and the sodium-glucose cotransporter-2 (SGLT2) inhibitors like dapagliflozin—may offer different types of cardiovascular benefits in diabetic patients and to a potentially much wider group of patients.

“There are really two different ways to apply these medications,” Marso explained. “One is to reduce CVD death and heart failure and the other is, if you will, ‘athero-prevention.’ Quite simply, in my practice—and this is how I’ve translated this data and have since these trials were published—if you have a diabetic patient whose history is one of myocardial infarction or stroke and you're worried about recurrent ischemic events, I would lean more towards liraglutide. On the other hand, if they have heart failure or are at increased risk for heart failure readmission, I think a SGLT2 inhibitor is the way to go. That strategy hasn't been studied in clinical studies, but it's a rational way to think about how one might use these agents in practice.”

The main LEADER results were first published in the New England Journal of Medicine in 2016, showing that liraglutide on top of standard care in patients with type 2 diabetes significantly reduced the risk of major adverse cardiovascular events compared with a placebo plus standard care—a benefit that appeared to be driven primarily by a reduction in the risk of cardiovascular mortality. The new analysis zeroing in on heart failure patients was published early online this week in the Journal of the American College of Cardiology.

Reassuring Results

That liraglutide did not appear to have different effects in LEADER according to heart failure status is reassuring, the authors note. While a spate of trials of GLP-1 agonists in diabetes have supported cardiovascular safety, with some, like LEADER, suggesting that this class of agents may even reduce the risk of MACE, at least two trials—FIGHT and LIVE—have hinted that this may not be the case in patients with heart failure and reduced ejection fraction (HFrEF).

Marso et al’s analysis focused on the 18% of patients in LEADER with NYHA functional class I to III heart failure randomized to liraglutide (n = 835) or placebo (n = 832). There was no difference in the risk of MACE in patients with and without a history of heart failure (HR 0.81 vs 0.88; P for interaction = 0.53). Fewer deaths, numerically, occurred with liraglutide in patients both with and without HF (P for interaction = 0.63), while rates of HF hospitalization as well as a composite of heart failure hospitalization or cardiovascular death were “consistent” for liraglutide in patients both with and without a history of HF.

“Based on these findings, liraglutide should be considered suitable for patients with [type 2 diabetes] with or without a history of NYHA functional class I to III HF,” the authors conclude. They add that only 13% of the patients in LEADER had NYHA III HF, such that “our findings are mostly based on people with NYHA functional class I and II HF, and may not be generalizable to more advanced cases of HF.”

More Robust Evidence Needed

In an editorial accompanying the LEADER analysis, G. William Dec, MD (Massachusetts General Hospital, Boston, MA), digs a bit deeper into trial differences between LEADER, FIGHT, and LIVE. He concludes that it may indeed be the fact that FIGHT and LIVE enrolled patients with more-severe HF and more patients with reduced EF than LEADER. As for whether GLP-1 agonists have an edge in diabetes patients with established atherosclerotic disease, Dec points out that the SGLT2 inhibitors have also been shown to reduce atherosclerotic MACE “to a similar degree” as the GLP-1 agonists while also decreasing heart failure hospitalizations.

As such, Dec concludes, “the findings from the LEADER trial suggest that liraglutide is at least safe and potentially beneficial in lowering the rate of adverse cardiac events among HF patients. However, findings from ongoing, statistically more robust randomized clinical trials will determine whether liraglutide, another GLP-1 agonist, or the rapidly expanding class of SGLT2 inhibitors will ‘lead’ adjunctive diabetic management among established HF patients.”

It will be the next generation of doctors who will be prescribing these agents, I'm convinced of this. Steven Marso

To TCTMD, Marso predicted that the specific role of these different agents in different disease combinations will become clearer in future trials, noting that the SGLT2 inhibitors are already being studied in heart failure patients without diabetes and the GLP-1 agonists are being studied in obese patients with no history of diabetes.

Both liraglutide as well as semaglutide (Ozempic; Novo Nordisk) have received US Food and Drug Administration approval to reduce cardiovascular events in patients with diabetes. Dapagliflozin is FDA-approved to reduce heart failure hospitalization in diabetes, empagliflozin (Jardiance; Boehringer Ingelheim/Eli Lilly) for decreasing the risk of cardiovascular death in adults with type 2 diabetes and established cardiovascular disease, and canagliflozin (Invokana; Janssen), another SGLT2 inhibitor, for reducing major adverse cardiovascular event risk in a similar patient population.

In time, said Marso, he’s optimistic that cardiologists will feel more comfortable prescribing these agents.

“We’re not prescribing them now, but we should,” he said. Cardiologists may be concerned about side effects such as hypoglycemia, he added, but in fact when these agents are not prescribed on top of sulfonylureas or insulin, the risk of hypoglycemia is “virtually nonexistent.” Cardiologists are also not as comfortable, historically, with prescribing injectables but this, Marso noted, is changing as PCSK9 inhibitors are more widely used.

“The last barrier to implementing them is cost,” Marso admitted. “These things are still expensive and so unfortunately they are cost prohibitive for a lot of our patients. But boy, we should be prescribing them. And I think we will over time. . . . It will be the next generation of doctors who will be prescribing these agents, I'm convinced of this.”