Semaglutide in patients with obesity and heart failure

It has long been known that the active ingredient class of glucagon-like peptide-1 agonists (GLP-1) reduces cardiovascular consequences in diabetics and leads to significant weight loss in patients with obesity. Results from STEP-HFpEF, a randomized controlled trial (RCT) testing semaglutide versus placebo in patients with obesity and heart failure with preserved ejection fraction (HFpEF), were presented at the ESC Congress in Amsterdam [2].

Heart failure with preserved ejection fraction (HFpEF) accounts for more than half of all cases of heart failure (HF) [3], is a major cause of morbidity and mortality, and is associated with a high burden of symptoms and physical disability [4]. The prevalence of HFpEF is increasing due to an ageing population and the rising prevalence of obesity and type 2 diabetes (T2D) [5]; however, despite this rapidly increasing economic and health burden, few treatments have been shown to improve outcomes [6,7].

HFpEF is often also a consequence of obesity and associated metabolic and hemodynamic disorders [5,8–14]. Patients with the obesity phenotype represent the majority of patients with HFpEF and have a unique phenotype [14–17]. Compared to the non-obese phenotype, individuals with the obese phenotype of HFpEF have increased plasma volume and stressed blood volume, more concentric left ventricular remodeling and a high prevalence of hypertension (which in itself is an important factor in the development and progression of HFpEF), more severe right ventricular dysfunction, increased epicardial fat thickness, and higher total epicardial cardiac output [14,18]which leads to a greater symptom burden, poorer functional capacity and a more impaired quality of life (QOL) [19,20].

One of the likely reasons for the lack of effective therapies for HFpEF is that none of the HF therapies currently in use directly target the most fundamental disorder leading to HFpEF (i.e. obesity). In patients with the obesity phenotype of HFpEF, caloric restriction resulted in a 7% weight loss and an improvement in exercise capacity and health status as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) [8]. Observational studies have shown that clinically meaningful weight loss can lead to a significant reduction in filling pressure and an improvement in cardiac function, which can be expected to improve symptoms, physical limitations and quality of life, as well as reduce clinical events [21,22].

None of the clinical trials to date have investigated pharmacotherapy for weight loss as a potential intervention for the obesity phenotype of HFpEF. The emergence of potent long-acting glucagon-like peptide-1 receptor agonists (GLP-1RAs) represents a unique opportunity to develop a novel treatment option for the obesity phenotype of HFpEF [23,24]. In previous studies, once-weekly administration of semaglutide in overweight and obese patients with and without T2D resulted in significant weight loss, which was associated with improvement in several cardiometabolic risk factors (including systolic blood pressure (SBP) and diastolic blood pressure) [23,25,26]. In addition, semaglutide significantly reduced the risk of major adverse cardiovascular events (MACE) in patients with T2D [27].

ESC Hot Line for the STEP-HFpEF study

The STEP-HFpEF program comprises two randomized, international, multicenter, double-blind, placebo-controlled studies in people with the obesity phenotype of HFpEF: STEP-HFpEF (Semaglutide Treatment Effect in People with obesity and HFpEF) (in people with obesity and HFpEF and without diabetes) and STEP-HFpEF DM (Semaglutide Treatment Effect in People with obesity and HFpEF and type 2 diabetes) (in people with obesity, HFpEF and T2D). In both studies, eligible participants were randomized in a 1:1 ratio to receive either 2.4 mg semaglutide administered subcutaneously or a matching placebo once weekly as an adjunct to standard treatment (Fig. 1) [2]. Randomization was stratified according to baseline body mass index (BMI) (<35.0 ^kg/m2 or ≥35.0 ^kg/m2). Both studies included a screening visit to determine eligibility, followed by a randomization visit for those who were found to be eligible and agreed to participate. Randomization was followed by a 16-week dose escalation to minimize gastrointestinal side effects, with the dose being increased every fourth week until the maximum tolerated dose was reached. Thereafter, a study visit took place every eighth week until the end of treatment (week 52), with a follow-up period of five weeks after the end of treatment.

Participants in both studies were eligible if they had a left ventricular ejection fraction (LVEF) ≥45%, NYHA functional class II to IV, KCCQ-Clinical Summary Score (CSS) <90 Punkte und ≥1 der folgenden Punkte aufwiesen: 1) erhöhter Füllungsdruck (basierend auf einer Rechtsherzkatheteruntersuchung oder einer Fernmessung des Pulmonalarteriendrucks); 2) erhöhte natriuretische Peptidwerte (NP) (mit Schwellenwerten, die nach dem Ausgangs-BMI gestaffelt sind) plus echokardiografische Anomalien; oder 3) HF-Krankenhausaufenthalt in den vorangegangenen 12 Monaten plus Bedarf an laufenden Diuretika und/oder echokardiografische Anomalien. Zu den wichtigsten Ausschlusskriterien gehörten eine vorangegangene oder geplante bariatrische Operation, eine selbst angegebene Veränderung des Körpergewichts von mehr als 5 kg innerhalb von 90 Tagen vor der Randomisierung, ein kürzlich (innerhalb der letzten 30 Tage) aufgetretenes unerwünschtes kardiovaskuläres Ereignis oder eine HF-Hospitalisierung oder ein Blutdruck von mehr als 160 mm Hg beim Screening. Patienten mit einem glykosylierten Hämoglobinwert von ≥6,5% wurden von STEP-HFpEF ausgeschlossen, Patienten mit einem glykosylierten Hämoglobinwert von>10% of STEP-HFpEF DM.

Primary goal and endpoints

The primary objective of the study is to investigate the effects of once-weekly semaglutide 2.4 mg on physical function, symptoms and body weight compared to placebo, both in addition to standard treatment, in participants with the obesity phenotype of HFpEF. The corresponding dual primary endpoints are: 1) the change in KCCQ-CSS from baseline to 52 weeks; and 2) the percentage change in body weight from baseline to 52 weeks.

The KCCQ is a standardized, self-administered instrument with 23 items that quantifies HF-related symptoms (frequency, severity and recent changes), physical function, quality of life and social function [28]. For each domain, validity, reproducibility, responsiveness and interpretability were independently demonstrated for both HF with restrained ejection fraction and HFpEF populations [29]. The scores are transformed into a range from 0 to 100, with higher scores reflecting a better state of health [30]. The KCCQ-CSS comprises the symptom and physical functional areas of the KCCQ.

Secondary and exploratory objectives and endpoints

The confirmatory secondary objectives of the program are to investigate the effects of once-weekly semaglutide 2.4 mg on overall clinical benefit, 6MWD and inflammation as reflected by C-reactive protein (CRP). The corresponding confirmatory secondary endpoints include the hierarchical composite endpoint of overall clinical benefit (consisting of all-cause death, HF events, multiple thresholds for change in KCCQ-CSS from baseline to 52 weeks, and change in 6MWD of 30 m or more from baseline to 52 weeks), change in 6MWD from baseline to 52 weeks, and change in CRP from baseline to 52 weeks.

Supporting secondary and exploratory objectives include the effects of semaglutide on various thresholds of weight loss and the KCCQ-CSS, the 6MWD, effects on other domains of the KCCQ and additional patient-reported outcomes, change in blood pressure and waist circumference, change in diuretic and blood pressure medication, HF biomarkers, and effects on HF events.

Patients with significant functional limitations were recruited into the study

In both studies, around half of the participants were women. 75% of the participants had HFpEF (ejection fraction ≥50%) and 25% had HF with a slightly reduced ejection fraction (ejection fraction 45-49%). The median BMI was ~37 ^kg/m2, comorbidities such as hypertension, coronary disease and atrial fibrillation were common. The levels of N-terminal natriuretic peptide type B (NT-proBNP) were elevated at baseline in both studies. The majority of participants in both studies were treated with beta-blockers, renin-angiotensin blockers and diuretics, and about a third received mineralocorticoid receptor antagonists. Although the use of a sodium-glucose cotransporter 2 (SGLT2) inhibitor was rare in the STEP-HFpEF study, almost one-third of the participants in the STEP-HFpEF-DM study were taking an SGLT2 inhibitor at baseline. It is worth noting that patients in STEP-HFpEF and STEP-HFpEF DM had significant impairments in symptoms, physical limitations and physical performance, with a baseline KCCQ-CSS score of ~59 in both studies and a 6MWD of 320 m and 280 m, respectively.

Co-primary endpoints: Quality of life increases, body weight decreases

Patients in the semaglutide group had a mean improvement in the KCCQ-CSS of 16.6 points, while patients in the placebo group had a mean improvement of 8.7 points (estimated treatment difference 7.8 points, 95% confidence interval 4.8 to 10.9; p<0.001). The semaglutide group also showed a mean body weight loss of 13% compared to just under 3% in the placebo group (estimated treatment difference 10.7%, 95% CI -11.9 to -9.4; p<0.001).

Stronger symptomatic improvement and weight reduction

All other secondary endpoints were also achieved in the study. These included a greater improvement in the 6-minute walk test (almost 22 m longer walking distance) and a so-called “win-ratio” for hierarchically structured clinical endpoints, which included mortality, heart failure events and improvement in quality of life (KCCQ-CSS). Semaglutide was also found to be superior here.

Finally, semaglutide also showed a significant reduction in the inflammation marker C-reactive protein. In exploratory analyses, the heart failure marker NT-proBNP was also examined, which, according to the literature, shows lower serum levels with increasing obesity. Interestingly, parallel to the significant weight reduction in the study, there was also a significant reduction in NT-proBNP after one year in the semaglutide group compared to the placebo group.

Improvement in heart failure symptoms and performance

In the STEP-HFpEF study presented here, the administration of semaglutide resulted in a greater improvement in quality of life and walking distance after one year compared to placebo, as well as a significant reduction in body weight. This was also associated with a greater reduction in NT-proBNP and C-reactive protein. Semaglutide has thus been shown for the first time to bring about a functional improvement in patients with HFpEF and overweight/obesity. The extent to which this influences event-free survival is the subject of current, further studies. Dr. Mikhael Kosiborod, Vice President of Research at St. Luke’s Mid America Heart Institute in Kansas City, concludes that semaglutide is now the first compound to show that it can specifically address obesity in patients with HFpEF, and in particular that the extent of symptomatic improvement in patients has not been seen before with any other compound. The extent to which drug therapy for obesity positively alters the increased filling pressures and reduced ventricular compliance that are the pathophysiological basis of HFpEF, and also reduces clinical endpoints such as heart failure-related hospitalizations, has not yet been investigated and is currently the subject of ongoing studies [1].

Congress: ESC 2023

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