Semaglutide Beneficial in HFpEF Patients With Diabetes

ATLANTA — Weekly injections of the glucagon-like peptide (GLP-1) receptor agonist semaglutide (Wegovy, Ozempic), relieves symptoms in patients with heart failure with preserved ejection fraction (HFpEF), obesity, and diabetes much like it does in similar patients without diabetes, according to results of a pivotal trial likely to expand the drug’s approved indications.

Like a related trial published last year, the new study conducted in HFpEF patients with obesity added type 2 diabetes (T2DM) as an enrollment criterion and showed similar benefits, reported principal investigator Mikhail N. Kosiborod, MD, vice president of research for the St. Luke’s Health System, Kansas City, Missouri.

In this population, like those without T2DM, there was an advantage relative to placebo in the co-primary endpoints of significant weight loss and improvement in quality of life (QOL). The new trial, called STEP-HFpEF DM, like the previous STEP-HFpEF, also associated semaglutide with a lower risk for serious adverse events.

In both studies, semaglutide 2.4 mg weekly compared with placebo “produced larger reductions in HF-related symptoms and physical limitations, greater weight loss, and greater improvements in physical function,” Kosiborod reported.

BMI > 30 Was a Study Entry Criterion

In STEP-HFpEF DM, 616 adult patients with a BMI > 30 and HFpEF, defined as left ventricular ejection fraction of ≥ 45%, were randomly assigned to semaglutide or placebo administered over a 16-week dose-escalation phase. It was followed by 36 weeks on the assigned therapy, which in the experimental arm was semaglutide in a target dose of 2.4 mg weekly. 

For entry, patients were required to have had at least one HF hospitalization in the previous 12 months and to have abnormal levels of natriuretic peptides at baseline. The majority of patients in both arms of the study were on guideline-directed medical therapy (GDMT) for HFpEF, said Kosiborod, who presented these results in a Featured Clinical Research session at the annual meeting of the American College of Cardiology.

At the end of the study with follow-up for approximately 95% of patients in both arms, there was a highly significant advantage for QOL, as measured with the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), in favor of semaglutide. Even though KCCQ-CSS had climbed from baseline in both arms, the 7.3 point greater rise (13.7 vs. 6.4 points) with treatment was highly statistically significant (P < .001) and clinically meaningful, Kosiborod reported.

Weight Reduced More on Semaglutide

A reduction in body weight, the other co-primary endpoint, was also seen in both groups but was significantly greater in those randomly assigned to semaglutide (–9.8% vs. –3.4%; P < .001), said Kosiborod, again characterizing the greater change as clinically meaningful.

The results of STEP-HFpEF DM were published online in the New England Journal of Medicine simultaneously with Kosiborod’s presentation. A pooled analysis of both STEP-HFpEF and STEP-HFpEF DM studies was published in The Lancet. 

Several secondary endpoints were consistent with a clinical advantage for semaglutide. This included a greater increase in the 6-minute walk distance (+12.7 vs –1.6 meters; P = .008), mean CRP ratio reduction from baseline (0.58 vs. 0.87; P < .001), and a reduction in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) (–23.2 vs –4.6; 95% CI, 0.7 - 0.9).

Differences in event rates were not calculated for statistical significance, but Kosiborod reported that they moved in a direction consistent with a potential benefit from semaglutide. 

Overall, there were only seven heart failure events (hospitalization or urgent visit for HF) over the course of follow-up in the semaglutide group vs 18 in the placebo group, providing a 40% reduction in the calculation of a hazard ratio (HR, 0.40; 95% CI, 0.15 – 0.92). The win ratio for events overall, including different stratifications for improvement in KCCQ-CCS score, was 58.7 for semaglutide vs 36.8 for placebo.

Even though only about 35% of patients enrolled in this study were taking an SLGT2 inhibitor at baseline, the co-primary outcomes were reassessed in those with or without exposure. 

For patients receiving both, an attenuation of relative benefit from semaglutide was observed for KCCQ-CSS (5.3 vs 8.3-point increase for those taking or not taking an SGLT2 inhibitor, respectively) and weight loss (4.7 percentage point reduction vs 7.2 percentage point reduction, respectively). Yet, the direction of benefit was the same and remained significant for weight loss regardless of SGLT2 exposure, Kosiborod reported. 

CV Events Are Significantly Lower on Semaglutide

The incidence of hypoglycemia events was low in both arms and not significantly different, but there was a significantly lower rate of cardiac disorders (6.1% vs. 13.1%; P = .004) and a numerically lower rate of all-cause mortality (1.9% vs. 3.3%) for those randomized to semaglutide.

These results are highly consistent with the previously published STEP-HFpEF study. In that trial with 616 HFpEF patients with obesity but without T2DM, semaglutide relative to placebo was again associated with a significant climb in mean KCCQ-CCS score (13.7 vs. 6.4 points; P < .001) and a significant mean difference in percentage weight loss (-9.8% vs. -3.4%; P < .001) over the 52-week trial.

Other endpoints, such as physical function represented by the 6-minute walk distance (P = .008) and reduction in CRP levels (P < .001), favored semaglutide. As in STEP-HFpEF DM, the rate of serious adverse events was lower in the group randomized to semaglutide than placebo (17.7% vs 28.8%).

“Collectively, these two studies indicate that treatment with semaglutide is a valuable therapeutic approach in the management of patients with obesity-related HFpEF,” said Kosiborod, specifying that STEP-HFpEF DM extends the evidence to patients with comorbid T2DM. 

Even though the STEP-HFpEF study already established a benefit for semaglutide in HFpEF patients who are obese, it was important to conduct this second trial in patients who also have T2DM, said Beth L. Abramson, MD, associate professor of cardiology at the University of Toronto and professor of preventive cardiology and women’s health at St. Michael’s Hospital.

“There is evidence to suggest that the mechanics of heart failure is different in patients with diabetes relative to those with obesity,” she said. Now with data from STEP-HFpEF DM, there is evidence that the same type of benefit is achieved “when the two metabolic diseases occur together.”

On the basis of a cross-study comparison with STEP-HFpEF, she did point out that the median percent weight loss was less in those with T2DM (–6.4% vs –10.7%), but she was impressed with several aspects of the study, including the improvements in physical function, the consistency of benefit across important biomarkers of cardiovascular risk, such as NTproBNP, and that benefit was observed on top of high rates of GDMT. 

Moreover, the improvements in QOL and weight loss were achieved in the subgroup of patients on top of an SGLT2 inhibitor.

“In the subgroup on SGLT2, the additional effect when semaglutide was added suggests independent activity on weight loss,” she said.

Based on these data, Abramson said, weekly semaglutide is “something that should be considered in most patients” that fit entry criteria of this study.

Asked if change in QOL, which is traditionally considered a soft endpoint, is clinically relevant, Abramson emphasized that its importance “cannot be underestimated.”

The study was funded by Novo Nordisk. Kosiborod reports financial relationships with approximately 25 pharmaceutical companies, including Novo Nordisk, which produces semaglutide. Abramson reports financial relationships with Amgen, Bayer, Boehringer Ingelheim, Janssen, Novartis, and Novo Nordisk but was not involved in the STEP-HF trials. 

Ted Bosworth is a medical journalist based in New York City.