Effects of Semaglutide on Heart Failure with Preserved Ejection Fraction

The STEP-HFpEF trial investigated the impact of semaglutide on heart failure with preserved ejection fraction (HFpEF) across different left ventricular ejection fraction (LVEF) ranges. Results showed significant improvements in symptoms, physical limitations, exercise function, inflammation, and weight reduction with semaglutide 2.4 mg across LVEF subgroups of 45-49%, 50-59%, and 60%. This study sheds light on potential treatment benefits for HFpEF patients with varying LVEF values.

• Semaglutide
• Heart failure
• Preserved ejection fraction
• STEP-HFpEF
• LVEF

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1. Effects of Semaglutide Across the Range of Left Ventricular Ejection Fraction in Obesity Phenotype of Heart Failure with Preserved Ejection Fraction: The STEP-HFpEF Trial Javed Butler1,2, Sanjiv J. Shah, Steen Z. Abildstr m, Rebecca Lynn Altschul, Barry A. Borlaug, Melanie J. Davies, G Kees Hovingh, Dalane W. Kitzman, Dani l VegaM ller, Mark C. Petrie, S ren Rasmussen, Subodh Verma, Mikhail N. Kosiborod 1Baylor Scott & White Research Institute, Dallas, TX, USA; 2University of Mississippi, Jackson, MS, USA The STEP-HFpEF trial was sponsored by Novo Nordisk and is registered with ClinicalTrials.gov (NCT04788511). Administrative support and development of figures and tables was provided by Sophie Walton, MSc, CMPP, of Apollo, OPEN Health Communications, funded by Novo Nordisk A/S in accordance with Good Publication Practice guidelines (https://www.ismpp.org/gpp-2022). Butler J, et al. Presented at the Heart Failure Society of America Annual Scientific Meeting, October 6 9, 2023.

2. Presenter disclosure Javed Butler reports the following: Consultant: Abbott, American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Edwards, Element Science, Eli Lilly, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, LivaNova, Janssen Pharmaceuticals, Medtronics, Merck, Occlutech, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, PharmaIN Corporation, Roche, Sequana, SQ Innovation, and Vifor Pharma Speaker: AstraZeneca, Bayer, Boehringer Ingelheim, Impulse Dynamics, Merck, and Vifor Pharma The STEP-HFpEF trial was sponsored by Novo Nordisk HFpEF, heart failure with preserved ejection fraction; STEP, Semaglutide Treatment Effect in People with obesity. Butler J, et al. Presented at the Heart Failure Society of America Annual Scientific Meeting, October 6 9, 2023.

3. Background Patients with HF are classified, based on EF, into HFrEF, HFmrEF, or HFpEF1 HFpEF has traditionally been defined as LVEF >40%, >45%, or 50%2,3 Although SGLT2is improve HF outcomes across the range of LVEF, benefits of other therapies (ARNis, MRAs, ARBs) are restricted to patients with HFrEF/HFmrEF, but not true HFpEF4 7 This has fueled a debate on the differential effects of HF treatment across LVEF subgroups8 In the STEP-HFpEF trial, semaglutide 2.4 mg produced statistically significant and clinically meaningful improvements in symptoms, physical limitations, exercise function and inflammation, and reduced body weight9 We performed a prespecified analysis of semaglutide effects on these key trial endpoints in patients with LVEF 45 49%, 50 59%, and 60% ARB, angiotensin receptor blocker; ARNi, angiotensin receptor-neprilysin inhibitor; EF, ejection fraction; HF, heart failure; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium-glucose co-transporter-2 inhibitor; STEP, Semaglutide Treatment Effect in People with obesity. 1. Wagner S, Cohn K. Arch Intern Med 1977;137:675 8; 2. McDonagh TA, et al. Eur Heart J 2021;42:3599 726; 3. Heidenreich PA, et al. J Am Coll Cardiol 2022;79:1757 80; 4. Solomon SD, et al. Eur Heart J 2016;37:455 62; 5. Lund LH, et al. Eur J Heart Fail 2018;20:1230 9; 6. Solomon SD, et al. Circulation 2020;141:352 61; 7. Butler J, et al. Eur Heart J 2022;43:416 26; 8. Paulus WJ. Circulation 2022;145:1374 6; 9. Kosiborod MN, et al. N Engl J Med 2023;389:1069 84. Butler J, et al. Presented at the Heart Failure Society of America Annual Scientific Meeting, October 6 9, 2023.

4. Potential mechanisms of benefit for semaglutide in the HFpEF obesityphenotype1 Plasma volume and stressed blood volume Vascular protection Improved microvascular function Visceral, pericardial, and intramuscular fat Potential benefits of semaglutide in the HFpEF obesity phenotype Improved myocardial structure, function, and energetics Demand for high cardiac output/tissue perfusion Improved insulin sensitivity and metabolic efficiency Intracardiac and pulmonary pressures Weight loss-related mechanisms Additional mechanisms Inflammation Reduced physical limitations Increased exercise capacity Weight loss Improved symptoms HFpEF, heart failure with preserved ejection fraction. 1. Kosiborod MN, et al. JACC Heart Fail 2023;11:1000 10. Butler J, et al. Presented at the Heart Failure Society of America Annual Scientific Meeting, October 6 9, 2023.

5. STEP-HFpEF trial design1,2 SoC treatment plus: 1.7 mg Follow-up Once-weekly subcutaneous semaglutide 2.4 mg 1.0 mg 0.5 mg 0.25 mg Randomized patients Adults aged 18 years, BMI 30 kg/m2 N=529 Follow-up Once-weekly subcutaneous placebo 1.7 mg 1.0 mg 0.5 mg 0.25 mg Week 0 Randomization Week 52 End of treatment Week 16 Week 57 End of dose escalation Key inclusion criteria Key exclusion criteria Baseline LVEF Assessed at screening visit in all patients using echocardiography (performed and interpreted locally) LVEF 45%, NYHA functional class II IV, KCCQ-CSS <90 points, 6MWD 100 m, and 1 of the following: Prior/planned bariatric surgery Recent self-reported weight change >5 kg (11 lbs) Elevated left ventricular filling pressures (invasively measured) Recent adverse CV event or HF hospitalization Elevated natriuretic peptide levels and structural echo abnormalities SBP >160 mmHg at screening HbA1c 6.5% or known medical history of diabetes HF hospitalization (previous 12 months) and ongoing requirement for diuretics and/or structural echo abnormalities 6MWD, 6-minute walk distance; BMI, body mass index; CV, cardiovascular; echo, echocardiographic; HbA1c , glycated hemoglobin; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; KCCQ-CSS, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; SBP, systolic blood pressure; SoC, standard of care; STEP, Semaglutide Treatment Effect in People with obesity. 1. Kosiborod MN, et al. JACC Heart Fail 2023;11:1000 10; 2. Kosiborod MN, et al. N Engl J Med 2023;389:1069 84. Butler J, et al. Presented at the Heart Failure Society of America Annual Scientific Meeting, October 6 9, 2023.

6. Dual primary and confirmatory secondary endpoints1,2 Dual primary endpoints Change in KCCQ-CSS from baseline to week 52 Change in body weight from baseline to week 52 Confirmatory secondary endpoints Change in 6MWD from baseline to week 52 Hierarchical composite endpoint comprising: Time to all-cause death Number of HF events requiring hospitalization or urgent HF visit Time to first HF event requiring hospitalization or urgent HF visit Differences of at least 15, 10, and 5 points in KCCQ-CSS change between baseline and week 52 Difference of at least 30 meters in 6MWD change between baseline and week 52 Change in CRP from baseline to week 52 6MWD, 6-minute walk distance; CRP, C-reactive protein; HF, heart failure; KCCQ-CSS, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score. 1. Kosiborod MN, et al. JACC Heart Fail 2023;11:1000 10; 2. Kosiborod MN, et al. N Engl J Med 2023;389:1069 84. Butler J, et al. Presented at the Heart Failure Society of America Annual Scientific Meeting, October 6 9, 2023.

7. Analyses according to baseline LVEF Patients stratified according to baseline LVEF (45 49%, 50 59%, and 60%) Dual primary and confirmatory secondary efficacy endpoints for semaglutide vs placebo were assessed at week 52 across the LVEF subgroups for all randomized patients using the intent-to-treat principle (treatment policy estimand) Statistical analyses Continuous endpoints in the LVEF subgroups were assessed by ANCOVA at week 52, adjusted for the baseline value of the relevant outcome variable and BMI group Multiple imputations (n=1000) were performed to account for missing observations at week 52 Interaction p-values were derived from an F-test of equality between the treatment differences across the LVEF subgroups ANCOVA, analysis of covariance; BMI, body mass index; LVEF, left ventricular ejection fraction. Butler J, et al. Presented at the Heart Failure Society of America Annual Scientific Meeting, October 6 9, 2023.

8. Participant disposition1 Randomized (FAS) N=529 Exposed (SAS) N=529 (100%) Placebo n=266 (100%) Semaglutide 2.4 mg n=263 (100%) On 2.4 mg at treatment completion n=185 (83.7%) On 2.4 mg at treatment completion n=219 (97.8%) Completed treatment n=221 (84.0%) Completed treatment n=224 (84.2%) Completed trial n=256 (97.3%) Completed trial n=254 (95.5%) FAS, full analysis set; SAS, safety analysis set. 1. Kosiborod MN, et al. N Engl J Med 2023;389:1069 84. Butler J, et al. Presented at the Heart Failure Society of America Annual Scientific Meeting, October 6 9, 2023.

9. Baseline characteristics by baseline LVEF (1 of 2) Total (N=529) 297 (56.1) LVEF 45 49%* (n=85) 30 (35.3) LVEF 50 59% (n=215) 119 (55.3) LVEF 60% (n=229) 148 (64.6) Characteristic p-value Female, n (%) <0.001 Age, years 69 (62, 75) 69 (59, 74) 69 (63, 76) 70 (62, 75) 0.35 Ethnicity, n (%) 0.44 Hispanic or Latino 36 (6.8) 2 (2.4) 19 (8.8) 15 (6.6) Not Hispanic or Latino 493 (93.2) 83 (97.6) 196 (91.2) 214 (93.4) Race, n (%) 0.07 Black/African American 21 (4.0) 1 (1.2) 5 (2.3) 15 (6.6) White 507 (95.8) 84 (98.8) 209 (97.2) 214 (93.4) Other 1 (0.2) 0 1 (0.5) 0 Bodyweight, kg 105.1 (92.4, 120.8) 106.8 (96.7, 120.0) 103.7 (92.0, 121.7) 104.4 (90.5, 119.0) 0.25 Body mass index, kg/m2 37.0 (33.7, 41.4) 36.0 (33.9, 39.8) 36.9 (33.3, 41.5) 37.9 (34.0, 41.6) 0.11 Waist circumference, cm 119.4 (110.5, 128.0) 122.0 (112.0, 128.5) 120.0 (110.5, 128.0) 117.0 (110.0, 127.2) 0.12 SBP, mmHg 133.0 (121.0, 144.0) 133.0 (120.0, 143.0) 133.0 (121.0, 145.0) 132.0 (122.0, 143.0) 0.76 NT-proBNP, pg/mL 450.8 (218.2, 1015.0) 586.9 (314.6, 1160.3) 467.7 (206.4, 1053.7) 378.9 (204.7, 937.0) 0.01 hsCRP, mg/L 3.8 (1.9, 7.7) 3.4 (1.7, 6.7) 3.8 (1.8, 8.6) 4.1 (2.1, 7.5) 0.22 LVEF, % 57.0 (50.0, 60.0) 46.0 (45.0, 48.0) 55.0 (51.0, 56.0) 60.0 (60.0, 65.0) N/A KCCQ-CSS, score 58.9 (41.7, 72.9) 62.5 (47.4, 75.0) 58.3 (40.6, 70.8) 57.8 (40.6, 74.0) 0.26 6MWD, meters 320.0 (240.0, 389.0) 365.0 (255.5, 415.6) 300.0 (238.4, 384.8) 318.7 (244.0, 382.0) 0.25 Percentages may not equal 100% due to rounding. Data are median (IQR) unless otherwise stated and are from the full analysis set. *Includes one participant with LVEF of 33%. Race and ethnicity were reported by the investigator. 6MWD, 6-minute walking distance; hsCRP, high-sensitivity C-reactive protein; IQR, interquartile range; KCCQ-CSS, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score; LVEF, left ventricular ejection fraction; N/A, not applicable; NT-proBNP, N-terminal pro-brain type natriuretic peptide; SBP, systolic blood pressure. Butler J, et al. Presented at the Heart Failure Society of America Annual Scientific Meeting, October 6 9, 2023.

10. Baseline characteristics by baseline LVEF (2 of 2) Total (N=529) 81 (15.3) LVEF 45 49%* (n=85) 15 (17.6) LVEF 50 59% (n=215) 41 (19.1) LVEF 60% (n=229) 25 (10.9) Characteristic p-value HF hospitalization within 1 year, n (%) 0.04 Comorbidities at screening, n (%) Atrial fibrillation 275 (52.0) 49 (57.6) 116 (54.0) 110 (48.0) 0.09 Hypertension 433 (81.9) 69 (81.2) 173 (80.5) 191 (83.4) 0.52 Coronary artery disease 98 (18.5) 35 (41.2) 78 (36.3) 67 (29.3) 0.03 Obstructive sleep apnea 66 (12.5) 9 (10.6) 20 (9.3) 37 (16.2) 0.07 NYHA functional class, n (%) 0.23 Class II 350 (66.2) 55 (64.7) 146 (67.9) 149 (65.1) Class III IV 179 (33.8) 30 (35.3) 69 (32.1) 80 (34.9) Concomitant medications, n (%) Diuretics 427 (80.7) 77 (90.6) 180 (83.7) 170 (74.2) <0.001 Loop diuretics 329 (62.2) 58 (68.2) 144 (67.0) 127 (55.5) 0.01 Thiazides 90 (17.0) 12 (14.1) 31 (14.4) 47 (20.5) 0.09 MRA 184 (34.8) 35 (41.2) 82 (38.1) 67 (29.3) 0.02 ACEi/ARB 397 (75.0) 74 (87.1) 158 (73.5) 165 (72.1) 0.02 ARNi 27 (5.1) 10 (11.8) 8 (3.7) 9 (3.9) 0.02 Beta-blocker 418 (79.0) 71 (83.5) 169 (78.6) 178 (77.7) 0.31 SGLT2i 19 (3.6) 7 (8.2) 7 (3.3) 5 (2.2) 0.02 Percentages may not equal 100% due to rounding. Data are from the full analysis set. *Includes one participant with LVEF of 33%. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor-neprilysin inhibitor; HF, heart failure; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; SGLT2i, sodium- glucose co-transporter-2 inhibitor. Butler J, et al. Presented at the Heart Failure Society of America Annual Scientific Meeting, October 6 9, 2023.

11. Change in KCCQ-CSS from baseline to week 52 Dual primary endpoint Overall mean change By baseline LVEF Mean (SE) change in KCCQ-CSS 16.6 points 18 16 ETD (95% CI): 7.8 points (4.8, 10.9); p<0.001 14 Mean treatment difference (95% CI), points Population p-value 12 10 (points) 8 Overall 7.8 (4.8, 10.9) <0.001 8.7 points 6 4 LVEF 45 49% 5.0 ( 2.7, 12.8) 2 Interaction: 0.56 0 LVEF 50 59% 9.8 (5.0, 14.6) -2 -4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 Time since randomization (weeks) 52* LVEF 60% 7.4 (2.8, 12.0) -5 0 5 10 15 Patients Difference (95% CI) Sema 2.4 mg Placebo 263 266 249 242 225 217 243 237 263 266 Favors placebo Favors semaglutide Semaglutide 2.4 mg Placebo Overall mean baseline KCCQ-CSS (points) 56.7 Data are for the treatment policy estimand. *Data are estimated mean changes from baseline to week 52 for the treatment policy estimand, using ANCOVA and an imputation approach for missing data. P-values are for the test for interaction between treatment and LVEF subgroups except , which is for the treatment difference for semaglutide vs placebo. ANCOVA, analysis of covariance; CI, confidence interval; ETD, estimated treatment difference; KCCQ-CSS, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score; LVEF, left ventricular ejection fraction; SE, standard error; sema, semaglutide. Butler J, et al. Presented at the Heart Failure Society of America Annual Scientific Meeting, October 6 9, 2023.

12. Change in body weight from baseline to week 52 Dual primary endpoint Overall mean change By baseline LVEF Mean (SE) change in body 0 2.6% Mean treatment difference (95% CI), %-points Population p-value ETD (95% CI): 10.7%-points ( 11.9, 9.4); p<0.001 -5 weight (%) -10 Overall 10.7 ( 11.9, 9.4) <0.001 13.3% LVEF 45 49% 7.6 ( 10.7, 4.4) -15 Interaction: 0.08 LVEF 50 59% 10.6 ( 12.6, 8.6) -20 -4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 Time since randomization (weeks) 52* LVEF 60% 11.9 ( 13.8, 9.9) -15 -10 -5 0 5 Patients Difference (95% CI) Sema 2.4 mg Placebo 263 266 255 259 254 249 250 250 246 243 252 246 239 243 243 239 240 233 246 242 263 266 Favors semaglutide Favors placebo Semaglutide 2.4 mg Placebo Overall mean baseline body weight (kg) 108.4 Data are for the treatment policy estimand. *Data are estimated mean changes from baseline to week 52 for the treatment policy estimand, using ANCOVA and an imputation approach for missing data. P-values are for the test for interaction between treatment and LVEF subgroups except , which is for the treatment difference for semaglutide vs placebo. ANCOVA, analysis of covariance; CI, confidence interval; ETD, estimated treatment difference; LVEF, left ventricular ejection fraction; SE, standard error; sema, semaglutide. Butler J, et al. Presented at the Heart Failure Society of America Annual Scientific Meeting, October 6 9, 2023.

13. Change in 6MWD from baseline to week 52 Confirmatory secondary endpoint Overall mean change By baseline LVEF Mean (SE) change in 6MWD (m) 28 21.5 m 24 Mean treatment difference (95% CI), m ETD (95% CI): 20.3 m (8.6, 32.1); p<0.001 Population p-value 20 16 12 Overall 20.3 (8.6, 32.1) <0.001 8 1.2 m LVEF 45 49% 3.5 ( 33.0, 26.0) 4 Interaction: 0.19 0 LVEF 50 59% 23.9 (5.6, 42.3) -4 -4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 52* LVEF 60% 27.3 (9.9, 44.8) Time since randomization (weeks) -50 -25 0 25 50 Patients Difference (95% CI) Sema 2.4 mg Placebo 263 266 245 232 240 225 263 266 Favors placebo Favors semaglutide Semaglutide 2.4 mg Placebo Overall mean baseline 6MWD (m) 317.1 Data are for the treatment policy estimand. *Data are estimated mean changes from baseline to week 52 for the treatment policy estimand, using ANCOVA and an imputation approach for missing data. P-values are for the test for interaction between treatment and LVEF subgroups except , which is for the treatment difference for semaglutide vs placebo. 6MWD, 6-minute walk distance; ANCOVA, analysis of covariance; CI, confidence interval; ETD, estimated treatment difference; LVEF, left ventricular ejection fraction; SE, standard error; sema, semaglutide. Butler J, et al. Presented at the Heart Failure Society of America Annual Scientific Meeting, October 6 9, 2023.

14. Hierarchical composite endpoint Confirmatory secondary endpoint By baseline LVEF 60.1 Win ratio of clinical benefit 34.9 5.1 Stratified win ratio (95% CI): 1.72 (1.37, 2.15); p<0.001 1.5 Time to death 1.1 Population Win ratio (95% CI) p-value 3.3 Number of HF events 0.0 0.0 Overall 1.72 (1.37, 2.15) <0.001* 0.0 Time to first HF event 33.7 Change in KCCQ-CSS 15 points LVEF 45 49% 1.72 (0.95, 3.09) 17.5 Interaction: 0.43 LVEF 50 59% 2.10 (1.46, 3.04) 7.2 Change in KCCQ-CSS 10 points 5.5 Semaglutide 2.4 mg winner LVEF 60% 1.47 (1.04, 2.07) 8.1 Change in KCCQ-CSS 7.0 5 points Placebo winner 0 1 1 2 4 0.25 0.5 6.3 Change in 6MWD 3.7 Ties Ratio (95% CI) 30 m Favors placebo Favors Ties semaglutide 5.1 0 10 20 30 40 50 60 70 Percentage Assessments of the win ratio compared all patients randomized to semaglutide 2.4 mg with all patients randomized to placebo, stratified by BMI group. Data are for the treatment policy estimand, using an imputation approach for KCCQ-CSS and 6MWD. P-values are for the test for interaction between treatment and LVEF subgroups using Cochran s Q-test except *, which is for the treatment difference for semaglutide vs placebo. 6MWD, 6-minute walk distance; BMI, body mass index; CI, confidence interval; HF, heart failure; KCCQ-CSS, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score; LVEF, left ventricular ejection fraction. Butler J, et al. Presented at the Heart Failure Society of America Annual Scientific Meeting, October 6 9, 2023.

15. Change in CRP from baseline (screening) to week 52 Confirmatory secondary endpoint Overall mean change By baseline LVEF Mean (SE) CRP ratio to baseline 1.2 0.93 1.0 ETR (95% CI): 0.61 (0.51, 0.72); p<0.001 Mean treatment ratio (95% CI) Population p-value 0.8 0.6 Overall 0.61 (0.51, 0.72) <0.001 0.56 0.4 LVEF 45 49% 0.49 (0.33, 0.74) Interaction: 0.26 0.2 LVEF 50 59% 0.71 (0.54, 0.92) 0.0 -4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 Time since randomization (weeks) 52* LVEF 60% 0.56 (0.44, 0.73) 0 1 1 2 0.25 0.5 Patients Ratio (95% CI) Sema 2.4 mg Placebo 263 266 250 246 241 243 263 266 Favors semaglutide Favors placebo Semaglutide 2.4 mg Placebo Overall median baseline CRP (mg/L) 3.8 Data are for the treatment policy estimand. *Data are estimated mean changes from screening at week 2 to week 52 for the treatment policy estimand, using ANCOVA and an imputation approach for missing data. P-values are for the test for interaction between treatment and LVEF subgroups except , which is for the treatment difference for semaglutide vs placebo. ANCOVA, analysis of covariance; CI, confidence interval; CRP, C-reactive protein; ETR, estimated treatment ratio; LVEF, left ventricular ejection fraction; SE, standard error; sema, semaglutide. Butler J, et al. Presented at the Heart Failure Society of America Annual Scientific Meeting, October 6 9, 2023.

16. Change in NT-proBNP from baseline to week 52 Exploratory endpoint Overall mean change By baseline LVEF 0 Mean change in NT-proBNP (%) 5.3 Mean treatment ratio (95% CI) -5 Population p-value -10 Overall 0.84 (0.71, 0.98) LVEF 45 49% 0.82 (0.56, 1.19) Interaction: 0.96 -15 LVEF 50 59% 0.86 (0.67, 1.10) 20.9 -20 LVEF 60% 0.82 (0.65, 1.04) 1 1 2 0.25 ETR (95% CI): 0.84 (0.71, 0.98) -25 Ratio (95% CI) Favors semaglutide Favors placebo Semaglutide 2.4 mg Placebo Overall median baseline NT-proBNP (pg/mL) 450.8 P-values are for the test for interaction between treatment and LVEF subgroups. CI, confidence interval; ETR, estimated treatment ratio; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-brain natriuretic peptide. Butler J, et al. Presented at the Heart Failure Society of America Annual Scientific Meeting, October 6 9, 2023.

17. Adverse events by baseline LVEF Serious adverse events Cardiac serious adverse events* 50 50 40.2 Proportion of patients (%) Proportion of patients (%) 40 40 30 30 20.7 20 20 16.7 15.0 13.3 12.5 8.6 8.1 10 10 6.3 4.4 1.8 0.0 0 0 60% 60% LVEF 45 49% 50 59% 45 49% 50 59% Patients 3 6 17 41 15 24 0 3 5 17 2 10 Semaglutide 2.4 mg Placebo Data are from the on-treatment period. *Defined as serious events in the MedDRA cardiac disorder system organ class. LVEF, left ventricular ejection fraction; MedDRA, Medical Dictionary for Regulatory Activities. Butler J, et al. Presented at the Heart Failure Society of America Annual Scientific Meeting, October 6 9, 2023.

18. Conclusions In patients with HFpEF and obesity, semaglutide 2.4 mg improved symptoms, physical limitations, and exercise function, and reduced inflammation and body weight to a similar extent across the LVEF subgroups There were no safety concerns in any of the LVEF subgroups These data support treatment with semaglutide for improving heart failure related symptoms, physical limitations, exercise function and weight loss in patients with the obesity phenotype of HFpEF regardless of LVEF at baseline Scan the QR code or visit the website below for these slides: https://sciencehub.novonordisk.com/hfsa2023 /Butler.html?cid=qr-xowcpo75j0 HFpEF, heart failure with preserved ejection fraction; LVEF, left ventricular ejection fraction. Butler J, et al. Presented at the Heart Failure Society of America Annual Scientific Meeting, October 6 9, 2023.

19. Associated manuscript published in the Journal of the American College of Cardiology Butler J, Abildstr m SZ, Borlaug BA, et al. J Am Coll Cardiol 2023; doi:10.1016/j.jacc.2023.09.811 Accessible from: Butler J, et al. Presented at the Heart Failure Society of America Annual Scientific Meeting, October 6 9, 2023.