Effect of Semaglutide 2.4 mg once-weekly on function and symptoms in subjects with obesity-related
heart failure with preserved ejection fraction, and type 2 diabetes

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 near-to- 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
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 leads 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 obesity-related HFpEF and T2D.

Secondary objectives
To investigate the effects of semaglutide s.c. 2.4 mg once-weekly on walking
distance, biomarker of inflammation, disease specific aspects, social
limitation, change in body composition and health-related quality of life, and
glycaemic control and hypoglycaemia compared with placebo, both added to
standard of care, in subjects with obesity-related HFpEF and T2D.

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
HFpEF and T2D.
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 potential gastrointestinal adverse events with a dose
increase every 4th week. 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 at
randomisation to ensure at least 180 subjects undergoing echocardiography at
the end of treatment. Measures of diastolic dysfunction will be evaluated as
exploratory endpoints in order to gain mechanistic insights associated with
weight loss on semaglutide treatment.
Randomisation will be stratified by BMI into two subgroups (BMI <35.0 and BMI
>=35.0).To ensure sufficient statistical power for subgroup analyses according
to BMI, a maximum of 50% of subjects will be included in the lower BMI
subgroup.

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 and T2D.