Effect of semaglutide 2.4 mg once weekly on function and symptoms in subjects with obesity-related heart failure with preserved ejection fraction.

Heart Failure with Preserved Ejection Fraction:
Heart failure (HF) is a haemodynamic disorder where the heart fails to keep up
with the circulatory demands of the body (HFrEF), or does so at the expense of
raised left ventricular filling pressures (HFpEF). HFpEF is a clinical syndrome
of heart failure symptoms combined with normal or nearto- normal LVEF and
increased left ventricular filling pressures. The increased pressure can be
measured by cardiac catheterization or estimated by echocardiography. Other
echocardiographic findings include both structural and functional changes as
part of diagnosing HFpEF, and left ventricular diastolic dysfunction (abnormal
relaxation) is a key defining feature of HFpEF. The increased pressure
generally leads to elevation of NT-proBNP and BNP due to increased ventricular
wall tension, but levels of NT-proBNP are inversely related to body weight in
both the general population and in the HFpEF patient population. The prevalence
of HFpEF has increased during the last decades and is now more frequent than
heart failure with reduced ejection fraction (HFrEF). HF, including HFpEF,
remains to be a leading
cause of morbidity and mortality. To date, no pharmacological interventions to
address HFpEF have been approved, and the current HF therapies do not directly
target the fundamental metabolic derangements, thus making it one of the
greatest unmet needs in cardiology today.
Obesity-related HFpEF:
Obesity, a chronic disease resulting in decreased health-related quality of
life and 5-10 years reduced life expectancy, has been identified as a major
risk factor for the development of HFpEF. The impact of obesity on HFpEF is
probably due to a combination of mechanical mechanisms, volume overload,
endocrine-, metabolic- and cellular signalling together with an altered
inflammatory status. The aggregate of these factors ultimately lead to
cardiomyocyte dysfunction and impaired diastolic function of the heart, while
contractility is preserved. More than 83% of patients with HFpEF are found to
have either overweight or obesity. Obesity is associated with systemic
inflammation and with increased risk of a variety of comorbidities including
T2D, hypertension, dyslipidaemia, cardiovascular diseases, and risk of early
death. A study of elderly subjects with HFpEF and obesity has indicated that a
weight loss of 3-7 kg increases exercise tolerance and improvement in
HF-specific health-related quality of life
as assessed by the KCCQ. Lifestyle intervention in the form of diet and
exercise is first line treatment for obesity, but most people with obesity
struggle to achieve and maintain their weight loss without pharmacotherapy.
Consequently, semaglutide may serve as a valuable adjunct to lifestyle
intervention for individuals with obesity-related HFpEF in order to achieve and
sustain a clinically relevant weight loss, to improve complications and
health-related quality of life.

Primary objective
To investigate the effects of semaglutide s.c. 2.4 mg once-weekly on physical
function, symptoms and body weight compared with placebo, both added to
standard of care, in subjects with obesityrelated HFpEF.
Secondary objectives
To investigate the effects of semaglutide s.c. 2.4 mg once-weekly on walking
distance, biomarker of inflammation, body composition, disease specific
aspects, social limitation, and health-related quality of life compared with
placebo, both added to standard of care, in subjects with obesityrelated HFpEF.

This is a 52-week, randomised, placebo-controlled, double blind, multi-centre
clinical trial
comparing semaglutide s.c. 2.4 mg with placebo in subjects with obesity-related
heart failure with preserved ejection fraction. Eligible subjects will be
randomised in a 1:1 manner to receive either semaglutide s.c. 2.4 mg or placebo
once weekly as add-on to standard of care. The trial includes a screening visit
to assess the subject*s eligibility followed by a randomisation visit. A period
of 16 weeks of dose escalation is planned to minimise gastrointestinal adverse
events with a dose increase every 4th weeks. Hereafter a visit will take place
every 8th week until end of treatment (week 52). Follow-up period is 5 weeks
after end of treatment.
A subset of 240 randomised subjects will undergo echocardiography assessment at
randomisation to ensure at least 180 subjects undergoing echocardiography at
the end of treatment.
Randomisation will be stratified by BMI into two subgroups (BMI <35.0 and BMI
>=35.0).

Once weekly semaglutide/placebo subcuteneous injection, dose 2.4 mg.

Necessary precautions have been implemented in the design and planned conduct
of the trial in order to minimize the risks and inconveniences of participation
in the trial. The safety profile for semaglutide generated from the clinical
and non-clinical development programme has not revealed any safety issues that
would prohibit administration of semaglutide 2.4 mg. The results of the phase
3a weight management programme (NN9536, STEP) indicate that semaglutide
provides a clinically meaningful weight loss that will provide benefit and is
expected to relieve symptoms and improve physical function. The anticipated
benefits from healthy lifestyle counselling will include all
subjects participating in this trial.
Considering the measures taken to minimise risk to subjects participating in
this trial, the potential risks identified in association with semaglutide are
justified by the anticipated benefits that may be afforded to subjects with
obesity-related HFpEF.