Emulation of the STEP-HFpEF DM Heart Failure Trial in Healthcare Claims Data

Eligible cohort entry dates:

Optum: Study period between January 1, 2018 to November 30, 2024. Marketscan: Study period between January 1, 2018 to December 31, 2023. Medicare: Study period between January 1, 2018 to December 31, 2020.

FOLLOWING ELIGIBILITY OF THE STEP-HFpEF DM TRIAL

Inclusion Criteria:

• Male or female, age above or equal to 18 years at the time of signing informedconsent.

• BMI ≥ 30.0 kg/m2

• NYHA Class II-IV

• LVEF ≥ 45%

• No hospitalizations due to heart failure between screening (V1) and randomization (V2)

• At least one of the following:

• If BMI <35.0: NT-proBNP ≥ 220 pg/mL (for patients with sinus rhythm) or NTproBNP ≥660 pg/mL (for patients with persistent/permanent atrial fibrillation); if BMI ≥ 35.0: NT-proBNP ≥ 125 pg/mL (for patients with sinus rhythm) or NTproBNP ≥ 375 pg/mL (for patients with persistent/permanent atrial fibrillation) at screening (NT-proBNPanalyzed by the central laboratory) in combination with at least one of thefollowing (documented by echocardiography within 12 months prior to or atscreening): i. Septal é < 7cm/sec or lateral é < 10 cm/sec or average E/é ≥ 15 ii.PA systolic pressure >35mmHg iii. Left atrial (LA) enlargement (LA width ≥3.8 cm orLA length ≥ 5.0cm or LA area ≥ 20.0cm2 or LA volume ≥ 55mL or LA volume index ≥29mL/m2) iv. LV hypertrophy with septal thickness or posterior wall thickness ≥1.2cm

• Hospitalization with a primary diagnosis of decompensated heart failure whichrequired intravenous loop diuretic treatment, within the previous 12 months incombination with at least two of the following (documented by echocardiographywithin 12 months prior to or at screening): i. Septal é < 7cm/sec or lateral é < 10cm/sec or average E/é ≥15 ii. PA systolic pressure >35mmHg iii. LA enlargement (LAwidth ≥3.8cm or LA length ≥ 5.0cm or LA area ≥20.0cm2 or LA volume ≥ 55mL or LAvolume index ≥ 29mL/m2) iv. LV hypertrophy with septal thickness or posterior wallthickness ≥1.2cm

• Diagnosed with T2D ≥ 90 days prior to the day of screening.

• Subject treated with diet, exercise, and/or antidiabetic treatment* according tolocal label in stable dosing for at least 30 days prior to screening: o *OAD(s):unchanged drug(s), dose and dosing frequency o *Insulin(s): unchanged regimen (basal, basal + bolus, premix combination) with stable total daily insulin dose asjudged by the investigator

Exclusion Criteria:

• Myocardial infarction, stroke, hospitalization for heart failure, unstable anginapectoris or transient ischemic attack within 30 days prior to the day of screening.

• Systolic blood pressure > 160 mmHg at screening.

• Any other condition judged by the investigator to be the primary cause of dyspnea (such as heart failure due to restrictive cardiomyopathy or infiltrative conditions (e.g. amyloidosis), hypertrophic obstructive cardiomyopathy, primary pulmonaryarterial hypertension, chronic obstructive pulmonary disease, right heart failuredue to pulmonary disease, complex congenital heart disease, anemia, or more thanmoderate heart valve disease).

• Bariatric surgery prior to screening or planned bariatric surgery within the trialtime course.

• History of type 1 diabetes (history of gestational diabetes is allowed).

• Treatment with any GLP-1 receptor agonist within 90 days prior to the day ofscreening.

• Uncontrolled and potentially unstable diabetic retinopathy or maculopathy.

• Recurrent severe hypoglycemic episodes within the last year as judged by theinvestigator.

• Treatment with continuous subcutaneous insulin infusion

• Personal or first-degree relative(s) history of multiple endocrine neoplasia type 2or medullary thyroid carcinoma.

• Presence of acute pancreatitis within the last 180 days prior to screening.

• History or presence of chronic pancreatitis.

• End-stage renal disease or chronic or intermittent hemodialysis or peritonealdialysis.

• Presence or history of malignant neoplasm within 5 years prior to the day ofscreening. Basal and squamous cell cancer and any carcinoma in-situ are allowed.

• Female who is pregnant, breast-feeding or intends to become pregnant or is ofchild-bearing potential and not using a highly effective contraceptive method.

• Any disorder, including severe psychiatric disorder, suicidal behavior within 90days before screening, and suspected drug abuse, which in the investigator´s opinionmight jeopardize subject´s safety or compliance with the protocol.

RELAXING ELIGIBILITY OF THE STEP-HFpEF DM TRIAL

Inclusion Criteria:

• Men or women ≥ 18 years old

• History of type 2 diabetes mellitus

• BMI ≥ 27.0 kg/m2

• Heart failure

• Preserved ejection fraction

Exclusion Criteria:

• Prior treatment with any GLP-1-RA

• History of type 1 diabetes mellitus

• End-stage renal disease or chronic or intermittent hemodialysis or peritonealdialysis

• History of bariatric surgery

• History of nursing home admission

• Pregnant female or breast-feeding

• Uncontrolled and potentially unstable diabetic retinopathy or maculopathy

• Treatment with continuous subcutaneous insulin infusion

• Multiple endocrine neoplasia type 2 or medullary thyroid carcinoma

• Have a history of an active or untreated malignancy or are in remission from aclinically significant malignancy (other than basal- or squamous-cell skin cancer,in situ carcinoma of the cervix, or in situ prostate cancer) for less than 5 years