HFpEF is defined by a left ventricular ejection fraction (LVEF) of ≥ 50% and accounts for approximately half of cases of HF [1]. Obesity is considered one of the strongest risk factors for the development of HFpEF [2]. In fact, 60 to 70% of patients with HFpEF are obese [1]. Semaglutide, at a dose of 2.4 mg subcutaneously once a week, is a glucagon-like peptide-1 receptor (GLP-1R) agonist approved for the treatment of obesity [3]. In addition, a large randomized trial has shown that semaglutide (1.0 mg/week) decreased cardiovascular (CV) events in patients with type 2 diabetes [4]. However, in the latter study, hospitalization for heart failure, a secondary outcome, was not reduced by semaglutide; hazard ratio 1.11 (95% CI, 0.77 to 1.61, P = 0.57) [4]. No anti-obesity agents were specifically evaluated to see the impact of weight loss on symptoms of HFpEF [2]. Studies using non-pharmacological therapy for weight reduction in HFpEF have shown some cardiac benefits. Kitzman et al. [5] randomized 100 obese patients with HFpEF [mean body mass index (BMI) 39.3 kg/m²] to 4 groups: diet, exercise, exercise + diet, and a control group. After 20 weeks of intervention, mean weight loss was 7% in the diet group, 3% in the exercise group, 10% in the diet + exercise group, and 1% in the control group. In parallel to these weight reductions, peak oxygen consumption (VO2) improved significantly with exercise (1.2 ml/kg/min) and diet (1.3 ml/kg/min), and the effect was additive with diet + exercise (2.5 ml/kg/min) [5]. These results suggest that weight loss per se may improve exercise tolerance in obese patients with HFpEF. Thus, semaglutide, in its anti-obesity doses of 2.4 mg weekly, was recently evaluated in a trial called STEP-HFpEF for the treatment of obese patients with HFpEF [6]. The main purpose of this article is to provide an appraisal of semaglutide as a novel therapeutic agent for obese subjects with HFpEF based on the results of the STEP-HFpEF.

The STEP-HFpEF Trial

The STEP-HFpEF trial was a randomized, double-blind, placebo-controlled, multinational study [6,7]. The two co-primary endpoints of STEP-HFpEF were the change in KCCQ-CSS and weight from baseline to the end of treatment at 52 weeks. The KCCQ-CSS is a questionnaire that measures symptoms and physical and social limitations in patients with heart failure [8]. It is scored from 0 to 100, with a higher score indicating fewer symptoms [8]. Intervention in STEP-HFpEF consisted of semaglutide 2.4 mg given subcutaneously once a week [6]. No specific caloric restriction or exercise program was provided [6]. Patients included (n = 263 in the semaglutide group and 266 in the placebo group) were 56% women and 96% whites, with a median age of 69 years (interquartile range 62–75) [6]. Inclusion criteria were BMI ≥30 kg/m², New York Heart Association (NYHA) class II-IV, and LVEF ≥45% [6]. In addition, participants had to have one of the following: elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels plus echocardiographic abnormalities (72% of patients), elevated cardiac filling pressure documented during catheterization (15% of patients), or hospitalization due to heart failure in the previous 12 months (13% of patients) [6]. At baseline, the median KCCQ-CSS score was 58.9 points. 66% of patients had NYHA class II, and 34% had either class III or IV [6]. Patients with type 2 diabetes are excluded because a separate trial called STEP-HFpEF DM dedicated to obese patients with type 2 diabetes, and HFpEF is underway [7].

After 52 weeks, the mean change in KCCQ-CSS was significantly higher with semaglutide compared with placebo, 16.6 points and 8.7 points, respectively; estimated difference 7.8 points (95% CI, 4.8 to 10.9; P<0.001) [6]. Of note, a change of 5 points in the KCCQ score is considered clinically significant [8]. The mean percentage weight loss at 52 weeks was -13.3% and -2.6% with semaglutide and placebo, respectively; estimated difference: -10.7 percentage points (95% CI, -11.9 to -9.4; P<0.001). [6]. Inspection of the trajectory of weight loss did not reveal evidence of a plateau effect with time up to 52 weeks of follow-up [6]. In addition, the mean increase in 6MWD, a confirmatory secondary end point, was significantly greater with semaglutide vs. placebo, 21.5 m vs. 1.2 m (estimated difference, 20.3 m, 95% CI, 8.6 to 32.1, P<0.001) [6]. Another confirmatory secondary endpoint was the effect of semaglutide on CRP levels. Participants randomized to semaglutide had a 43% reduction in CRP levels (mean ratio of week 52 value to baseline value was 0.56) compared with 7.3% reduction in those randomized to placebo (mean ratio of week 52 value to baseline value was 0.93), estimated treatment ratio 0.61 (95% CI, 0.51 to 0.72), P<0.001 [6]. There was a trend toward a decreased number of hospitalizations or urgent visits for heart failure in the semaglutide group (1 of 263 subjects) compared with the placebo group (12 of 266 subjects), hazard ratio (HR) 0.08 (95% CI, 0.00 to 0.42) [6]. During follow-up, new-onset atrial fibrillation (AF) occurred in 2.7% and 11.3% of patients randomized to semaglutide and placebo, respectively (P<0.001) [6]. No difference was demonstrated in the number of deaths, which were 3 and 4 in the semaglutide and placebo groups, respectively [6].

Mechanisms of Cardiac Benefits of Semaglutide

Weight loss appears to be a major mechanism whereby semaglutide improves outcomes in obese patients with HFpEF. Thus, amelioration in KCCQ-CSS, 6 MWD, and CRP increased in parallel to the magnitude of weight reduction. For instance, for each 10% weight loss, the increase in KCCQ-CSS was 6.4 points (95% CI, 4.1 to 8.8) and in the 6MWD was 14.4 m (95% CI, 5.5 to 23.3), and the reduction in CRP levels was 28% (95% CI, 16 to 37) [9]. The direct effects of semaglutide on cardiac structures are an unlikely mechanism because the localization of GLP-1 receptors in human cardiomyocytes and cardiac blood vessels remains elusive [10].

Safety of Semaglutide in Heart Failure

The safety profile of semaglutide in obese patients with HFpEF was generally similar to that of other patient populations. Thus, GI symptoms were the most commonly reported adverse effects and were the most frequent cause of premature discontinuation of semaglutide. In fact, proportions of patients who discontinued semaglutide due to adverse effects were more than double those who discontinued placebo, 13.3% and 5.3%, respectively [6]. Meanwhile, the frequency of cardiac disorder events (defined as AF and flutter, cardiac failure, and congestive heart failure) was significantly lower in the semaglutide group versus the placebo group, 2.7% versus 11.3% (P<0.001) [6].

Semaglutide versus Sodium-glucose Cotransporter 2 Inhibitors for treatment of Heart Failure with Preserved Ejection Fraction

In two landmark trials, the EMPEROR and DELIVER, the two sodium-glucose cotransporter 2 (SGLT2) inhibitors, empagliflozin and dapagliflozin, have been shown to decrease rates of hospitalization for heart failure by approximately 23 to 29% in patients with HFpEF, irrespective of obesity and diabetes status [11,12]. In the EMPEROR and DELIVER studies, patients were much less obese than in the STEP-HFpEF trial, with a mean baseline BMI of approximately 29.8 kg/m² compared with a median of 37.0 kg/m² in the STEP-HFpEF trial [6,11,12]. Moreover, empagliflozin therapy was associated with a significant increase in the KCCQ-CSS score, although the magnitude of the increase was minimal; the difference from placebo was 1.32 (95% CI, 0.45 to 2.19) [13]. Hence, SGLT2 inhibitors are currently considered the first treatment of choice for patients with HFpEF [2]. The mechanisms of the cardiac benefits of SGLT2 inhibitors are not totally unclear, but their diuretic actions represent a major factor. Weight loss induced by SGLT2 inhibitors is unlikely to play a major role. Indeed, the placebo-adjusted weight loss with empagliflozin in the EMPEROR trial was modest: -1.28 kg (95% CI, -1.54 to -1.03) [11]. Table 1 illustrates the main differences between semaglutide and SGLT2 inhibitors for the treatment of HFpEF.

Table 1: Semaglutide versus SGLT2 inhibitors for treatment of HFpEF.

Abbreviations in the table: SGLT2: sodium-glucose co-transporter-2, HFpEF: heart failure with preserved ejection fraction, BMI: body mass index, KCCQ-CSS: Kansas City Cardiomyopathy Questionnaire clinical summary score.

Advantages

Apart from SGLT-2 inhibitors, the efficacy of pharmacologic therapy for HFpEF is limited [2]. No doubt, semaglutide represents a useful addition for the treatment of the obese phenotype of HFpEF. The main advantages of semaglutide are the amelioration of symptoms, exercise tolerance, and a clear trend towards a decrease in hospitalizations or urgent care visits because of heart failure [6]. Furthermore, semaglutide therapy led to substantial weight loss coupled with a decrease in the inflammatory marker CRP [6]. In a post-hoc analysis of 3 randomized trials of semaglutide, Verma et al. [14] have shown that semaglutide decreased CRP levels by 39–48% after 68 weeks compared with placebo. The reduction of CRP by semaglutide is most likely secondary to its weight-loss effects because, after adjustment for body weight, the reduction in CRP levels by semaglutide was no longer statistically significant [14]. In the STEP-HFpEF trial, 52% of patients had AF at baseline [6]. AF occurs in 40 to 60% of patients with HFpEF and contributes to worsening symptoms and an increased risk of hospitalization and mortality [2,15]. Thus, the lower rates of incident AF in the semaglutide group (2.7%) versus the placebo group (11.3%) represent an added advantage of semaglutide [6].

Limitations

As far as the treatment of obese patients with HFpEF is concerned, semaglutide suffers from several important limitations. First, due to the relatively small size of the STEP-HFpEF trial and its short duration, the impact of semaglutide on hard CV events and mortality could not be assessed. Second, the limited number of participants in the STEP-HFpEF trial did not allow us to explore semaglutide efficacy in various subgroups classified by gender, age, degree of obesity, and baseline comorbidities. Third, more than double of patients discontinued semaglutide prematurely compared with placebo due to adverse effects. Fourth, GLP-1R agonists accelerate heart rate as a class effect [11,12]. It should be emphasized that an increase in heart rate confers an unfavorable prognosis in patients with HFpEF [16]. Unfortunately, the investigators of STEP-HFpEF did not mention the effect of semaglutide on heart rate [6]. Fifth, regarding the representativeness of patients, while 60–65% of patients with HFpEF consist of the female gender, women in the STEP-HFpEF were underrepresented, forming 56% of the study population [6]. In addition, 96% of patients in the trial were white. Therefore, the efficacy of semaglutide in minority groups with HFpEF has yet to be studied.

By showing significant improvement in exercise tolerance, semaglutide 2.4 mg once weekly represents a breakthrough in the management of obese patients with HFpEF. International guidelines should recommend semaglutide as a new treatment option for HFpEF with obesity. This recommendation is likely to be adopted soon given the Federal Drug Administration's (FDA) endorsement of potential approval of a drug based on improving health status alone [17]. It will be interesting to design a large randomized trial that compares the efficacy of the combination of semaglutide and a SGLT2 inhibitor (empagliflozin or dapagliflozin) versus each treatment alone. Since the underlying mechanisms are quite distinct (see table 1), it is possible that the combination of semaglutide and either empagliflozin or dapagliflozin might exert additive benefits in HFpEF. Other GLP-1 based therapy is also being evaluated for treatment of HFpEF. For instance, the SUMMIT trial (NCT04847557), a phase 3 clinical trial designed to evaluate efficacy and safety of the dual GLP-1 R agonist and gastric inhibitory polypeptide-receptor (GIP-R) agonist tirzepatide in obese patients with HFpEF, is underway [18]. SUMMIT will include approximately 700 patients with a BMI > 30 kg/m², with or without type 2 diabetes (those with glycated HbA1c > 9.5% are excluded). Inclusion of patients with and without diabetes in the same study will allow us to examine any differential effects of tirzepatide based on glycemic status. Importantly, long-term randomized trials are needed to examine the effects of semaglutide and tirzepatide on CV events and mortality in obese patients with HFpEF.

Conflict of interest

The author has no conflict of interest to declare.

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