2. dr. Nanang - New Data from FLOW Trial_What Can We Learn About Semaglutide OW for People with CKD and T2D.pptx

Semaglutide once weekly improve renal impairment in DKD

1. 1 New Data from FL O W Trial: What Can We Learn About Semaglutide OW for People with CKD and T2D? dr. Nanang Miftah Fajari , SpPD -KEMD, FINASIM PKB PAPDI Kalsel XXII 2024 10 August 2024

2. Disclosure I have received honorarium as speaker/consultant, support for research/attendance at educational meetings from: Novo Nordisk Other companies 2

3. Outline 3 CKD. Chronic Kidney Disease; T2D, Type 2 Diabetes CKD and Type 2 Diabetes GLP-1 Receptor Agonist Semaglutide in CKD and T2D The FL O W Trial: Is Semaglutide The New Kid( ney ) On The Block?

4. Outline 4 CKD. Chronic Kidney Disease; T2D, Type 2 Diabetes CKD and Type 2 Diabetes GLP-1 Receptor Agonist Semaglutide in CKD and T2D The FL O W Trial: Is Semaglutide The New Kid( ney ) On The Block?

5. CKD is a common complication of T2D With significant disease burden 5 Growing global incidence of diabetes in adults aged 20–79 years 1 CKD is common in diabetes 2 T 1D T 2D CKD No CKD 2021 536.6 MILLION 2045 783.2 MILLION 46% increase CKD, chronic kidney disease; T1D, type 1 diabetes; T2D, type 2 diabetes. 1. Sun H et al. International Diabetes Federation. IDF Diabetes Atlas. Diabetes Research and Clinical Practice. 2022; 183:109119 Available at IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045 – ScienceDirect ; 2. Alicic RZ et al. Clin J Am SoNc ephrol 2017;12:2032-2045

6. Cardiovascular, kidney and metabolic conditions are interconnected 6 Conditions of the cardio-kidney-metabolic systems affect more than 1 billion people worldwide 3,4 ~37% of adults with diabetes have been diagnosed with CKD* 1 Diabetes and/or hypertension is the primary cause of ~75% of ESKD prevalent cases in the US 2 ~One-third of patients with T2D have CV disease 3,4 CV disease is the leading cause of mortality in patients with T2D 5,6 CV mortality accounts for 40-50% of deaths in patients with advanced CKD or ESKD (compared to 26% in controls with normal kidney function) 7 Organ damage and dysfunction *As per NHANES 2011–2012 data. CKD, chronic kidney disease; CV, cardiovascular; ESKD, end-stage kidney disease; HF, heart failure; NHANES, National Health and Nutrition Examination Survey; T2D, type 2 diabetes 1. Murphy D et al. Ann Intern Med 2016; 165(7):473-481; 2. Saran R et al. Am J Kidney Dis 2019; S0272-6386(19)31008-X; 3. Einarson TR et al. Cardiovasc Diabetol 2018; 17(1):83; 4. International Diabetes Federation. IDF Diabetes Atlas. 9th edn. 2019. https://www.diabetesatlas.org/ (accessed August 2020); 5. Morrish NJ et al. Diabetologia 2001; 44(Suppl. 2):S14; 6. American Diabetes Association. Diabetes Care 2020; 43(S1):S1-S212; 7. Jankowski J et al. Circulation. 2021; 143:1157-1172

7. Cardiovascular disease and chronic kidney disease Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of morbidity and mortality 1 ASCVD manifests primarily as heart attacks and strokes 1 Inflammation is a critical in the development of ASCVD 2 Chronic kidney disease (CKD) is associated with systemic inflammation and CKD patients have an increased risk of ASCVD and death 3,4 An estimated 5 million patients with ASCVD have CKD and inflammation 5 ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CVD, cardiovascular disease 1. World Health Organization. Cardiovascular diseases (CVDs). Available at: https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds) (accessed October 2020);.2. Lawler PR, Eur Heart J. 2021 Jan 1;42(1):113-131 3. Foley RN et al. Am J Kidney Dis 1998;32:S112–S119; 4. Alani H et al. World J Nephrol 2014;3:156–168; 5. Novo Nordisk Market Research. Data on file;

8. Diabetic Kidney Disease – Leading to CKD Screening Diabetes Care. 2022;45(12):3075-3090. doi:10.2337/dci22-0027

9. Date of Download: 11/8/2023 Copyright © 2023 American Diabetes Association. All rights reserved. Diabetic Kidney Disease Classification Diabetes Care. 2022;45(12):3075-3090. doi:10.2337/dci22-0027

10. Progression of CKD in diabetes An initial hyperfiltration is followed by progressive decline in GFR accompanied by microalbuminuria progressing to macroalbuminuria 10 Functional Changes in diabetic kidney disease Hyperfiltration Microalbuminuria, hypertension Macroalbuminuria, reduced GFR Years with diabetes Urinary albumin (mg/day) Glomerular filtration rate (mL/min) 150 100 50 5 10 15 20 25 20 200 1000 5000 Microalbuminuria with normal renal function Hyperfiltration and renal hypertrophy Micro or macroalbuminuria with reduced renal function End-stage renal disease GFR Albuminuria CKD, chronic kidney disease; GFR, glomerular filtration rate; UA, urinary albumin. Modified, based on: Leoncini G et al.  J Nephrol 2020; 33(5):949-963 and Bailey CJ et al. Br J Diabetes Vasc Dis 2012; 12(4):167–171

11. CKD is associated with an increased risk of CVD mortality in people with T2D 11 CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; UACR, urinary albumin:creatinine ratio; T2D, type 2 diabetes 1. Foley RN et al. Am J Kidney Dis 1998; 32:S112–S119; 2. Alani H et al. World J Nephrol 2014; 3:156–168; 3. Drury PL et al. Diabetologia 2011; 54:32–43; 4. Tuttle KR et al. Diabetes Care 2014; 37:2864–2883 CKD is associated with an increased risk of CV morbidity and mortality compared to the general population - the risk is even higher in peoples with CKD and diabetes 1,2 UACR and eGFR are independently associated with both CV and all-cause mortality 3,4 eGFR 30-59 eGFR 60-89 eGFR ≥90 Cardiovascular risk of eGFR groups, according to presence or not of baseline albuminuria (A1) (A2) (A3)

12. People with T2D and CKD have a higher mortality rates than those without kidney disease 12 Incidence of mortality percentages indicate excess mortality above the reference group (individuals with no diabetes or kidney disease). CKD, chronic kidney disease; GFR, glomerular filtration rate; T2D, type 2 diabetes Afkarian M et al. J Am Soc Nephrol 2013; 24(2):302-308 10-year mortality in T2D by kidney disease manifestation Standardised 10-year cumulative incidence of mortality (%) 15,046 participants in the Third National Health and Nutrition Examination Survey (NHANES III) by linking baseline data from NHANES III with the National Death Index 4.1% 17.8% 23.9% 47.0% Excess mortality

13. Outline 13 CKD. Chronic Kidney Disease; T2D, Type 2 Diabetes CKD and Type 2 Diabetes GLP-1 Receptor Agonist Semaglutide in CKD and T2D The FL O W Trial: Is Semaglutide The New Kid( ney ) On The Block?

14. What is a GLP-1? 14 GLP-1 secretion and receptor expression 2–10 Human endogenous GLP-1 GLP-1 is a member of incretin family, a group of metabolic hormones known for lowering blood glucose levels by stimulating insulin secretion in response to energy intake GLP-1 is a peptide comprised of 30 or 31 amino acids His Ala Thr Ala Ala Ala Arg Asp Glu Glu Glu Gly Gly Gly Gly Thr Phe Phe Ser Ser Ser Val Val Gln Leu Tyr Leu Ile Trp Lys Lys Enzymatic degradation by DPP-4 t ½ =1.5–2 min GLP-1 is synthesised and secreted by: L-cells of the gut Neurons in hindbrain GLP-1 R is not expressed in the liver GLP-1 R is expressed in: Pancreas GI tract Kidney Brain Heart (AV node) Muscle Lungs AV, atrioventricular; DPP-4, dipeptidyl peptidase-4; GI, gastrointestinal; GLP-1 R, glucagon-like peptide-1 receptor; t½, half-life. 1. https://pubchem.ncbi.nlm.nih.gov/compound/16135499. Accessed January 2023; 2. Drucker DJ & Nauck MA. Lancet 2006;368:1696–705; 3. Baggio LL & Drucker DJ. Gastroenterology 2007;132:2131–57; 4. Ban K et al. Circulation 2008;117:2340–50; 5. Vrang N et al. Prog Neurobiol 2010;92:442–62; 6. Pyke C et al. Endocrinology 2014;155:1280–90; 7. Wang X-C et al. World J Gastroenterol 2014;20:14821–30; 8. Lee J et al. Diabetes Metab J 2012;36:262–7; 9. Sharma S et al. PLoS One 2011;6:e25269; 10. Drucker DD. Cell Metab 2016;24:15–30 . 

15. GLP-1 RA=glucagon-like peptide-1 receptor agonist; t1/2= half-life; DPP-4=dipeptidyl peptidase-4. References: 1. Ozempic ® Prescribing Information, Indonesia 2023 ; 2. Dhruv UA et al. JCD. 2016;2:18-25. 3. Kapitza C et al. J Clin Pharmacol . 2015;55 (5) :497-504; 4. Lau J et al. J Med Chem 2015;58:7370–80. GLP-1 RA Semaglutide Half-life of one week allowing a convenient once-weekly dosing 15 Lys Ala His Thr Ala Ala Ala Arg Asp Glu Glu Glu Gly Gly Gly Gly Thr Phe Phe Ser Ser Ser Val Val Lys Gln Leu Tyr Leu Ile Trp 94% homology to human GLP-1 1 t 1/2 ~ 1 week 1 Smallest once-weekly GLP-1 RA ( 4.11 kDa ) 2 Amino acid substitution prevents C-18 fatty diacid binding at the wrong site 3 Arg 34 Amino acid substitution at position 8 protects against DPP-4 degradation 3 Aib 8 spacer COOH 26 Spacer and C-18 fatty diacid chain provide strong binding to albumin 3 Lys

16. Role of GLP-1 and GLP-1 RA in controlling blood glucose level 16 DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1 Baggio LL, et al. Gastroenterology . 2007;132(6):2131-2157. Food Gut Food intake activates GLP-1 response DPP-4 enzyme breaks down GLP-1 GLP-1 RA works like natural GLP-1, but are DPP-4 resistant DPP-4 GLP-1 receptor Insulin secretion (glucose-dependent) Beta-cell pancreas Alpha-cell pancreas GLP-1 GLP-1 receptor Glucagon suppression (glucose-dependent)

17. GLP-1RA have multifactorial effects PHARMACOLOGICAL EFFECTS OF GLP-1 RAs 17 GI, gastrointestinal; GLP-1 RA, glucagon-like peptide-1 receptor agonist; RAAS, renin angiotensin aldosterone system. 1. Campbell JE, DJ Drucker. Cell Metab 2013;17:819–37; 2. Armstrong MJ et al. J Hepatol 2016;64:399–408; 3. Armstrong MJ et al. Lancet 2016;387:679–90; 4. Tong J, D'Alessio D. Diabetes 2014;63:407–9; 5. Baggio LL, Drucker DJ. J Clin Invest 2014;124:4223–6; 6. Flint A et al. J Clin Invest 1998;101:515–20; 7. Blundell J et al. Diabetes Obes Metab 2017;19:1242–51; 8. Greco EV, et al. Medicina (Kaunas) 2019; 55:233; 9. DeFronzo RA. Diabetes Obes Metab 2017; 19:1353–1362; 10. MacDonald PE et al. Diabetes 2002;51(Suppl 3):S434–42. Hyperglycaemia T2D Liver  Hepatic glucose production 2  Hepatic insulin sensitivity 2  De novo lipogenesis 2  Steatosis 3 GI tract  Gastric emptying 4 Kidneys  N atriuresis 8,9  Diuresis 8  Inflammation 8,9  Oxidative stress; RAAS 8 Brain  Body weight 5  Food intake 1  Satiety 6,7 Muscles  Insulin sensitivity 10  L ipotoxicity 2 Pancreas ( beta cell)  B eta -cell function 1  Insulin biosynthesis 1 β Pancreas ( alpha cell)  Glucagon secretion 1 α

18. Semaglutide modifies risk factors for CV complications Semaglutide has pleiotropic effects on CV risk factors & reduces MACE risk in T2D 1–7 18 Shown to have anti-atherosclerotic effects in mouse models 7 Once-weekly semaglutide lead to reduced risk of MACE in patients with T2D at high CV risk 3–5 Reduces inflammation 1,6 Improves glucose metabolism 1 Improves lipid profile and reduces blood pressure 1,2 Reduces body weight 1–3 SEMAGLUTIDE CV, cardiovascular; MACE, major adverse cardiovascular events; T2D, type 2 diabetes.  1. Wilding JPH et al. N Engl J Med 2021;384:989; 2. Aroda VR et al. Diabetes Metab 2019;45:409–18; 3. Marso SP et al. N Engl J Med 2016;375:1834–44; 4. Husain M et al. N Engl J Med 2019;381:841–51; 5. Husain M et al. Diabetes Obes Metab 2020;22(3):442–51; 6. Knudsen LB & Lau J. Front Endocrinol (Lausanne) 2019;10:155; 7. Rakipovski G et al. JACC Basic Transl Sci 2018;3:844–57.

19. Outline 19 CKD. Chronic Kidney Disease; T2D, Type 2 Diabetes CKD and Type 2 Diabetes GLP-1 Receptor Agonist Semaglutide in CKD and T2D The FL O W Trial: Is Semaglutide The New Kid( ney ) On The Block?

20. CHALLENGING MANAGEMENT OF DKD Prevent or Delay progression to Dialysis Prevent CV events, including CHF Improve QoL Reduce Cost CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 76 • NUMBER 11 NOVEMBER 2009

21. Albuminuria Categories Description and Range (mg albumin/g creatinine) A1 Optimal and high-normal A3 Very high and nephrotic A2 High G1 High and optimal >90 G2 Mild 60 to 89 G3a Mild-moderate 45 to 59 G3b Moderate-severe 30 to 44 G4 Severe 15 to 29 G5 Kidney failure <15 Canagliflozin: CREDENCE 1 (CKD & T2D) Trial population: eGFR 30 to <90 mL/min/1.73 m 2 UACR 300 to ≤5000 mg/g Finerenone: FIDELIO 2 & FIGARO (CKD & T2D) Trial population : eGFR 25 to <60 mL/min/1.73 m 2 UACR 30 to <600 mg/g POSITIVE RESULT ANNOUNCED! Dapagliflozin: DAPA-CKD 3 (CKD) Trial population : eGFR 25 to ≤75 mL/min/1.73 m 2 UACR 200 to ≤5000 mg/g Empagliflozin: EMPA-KIDNEY 4 (CKD) Trial population : eGFR 20 to <45 mL/min/1.73 m 2 OR eGFR 45 to <90 mL/min/1.73 m 2 with UACR ≥200 mg/g (or protein creatinine ratio ≥300 mg/g) 2019 2020 2021 2023/4 eGFR stages, description and range (mL/min/1.73 2 ) Semaglutide: FLOW trial 5 Trial population eGFR 50 to ≤75 and UACR >300 mg/g OR eGFR 25 to <50 and UACR >100 mg/g 2023/4 Summary of Ongoing Renal Outcome Trials to Be Completed by 2023-2024 1. Perkovic. NEJM. 2019;380:2295 . 2. Bakris. NEJM. 2020;383:2219. 3. Heerspink. NEJM. 2020;383:1436. 4. NCT03594110. 5. NCT03819153.

22. The four pillars of cardiorenal protection in people with CKD and T2D # The definitive place in the treatment of people with T2D and CKD remains to be established. Semaglutide is the only GLP-1RA demonstrating effects in a dedicated kidney outcomes trial. CKD, chronic kidney disease; CVOTs, cardiovascular outcomes trials; GLP-1 RAs, glucagon-like peptide-1 receptor agonists; ns-MRA, non-steroidal mineralocorticoid receptor antagonists; RAS, Renin–angiotensin system; SGLT-2i, sodium-glucose cotransporter-2 inhibitor; T2D, type 2 diabetes. Figure design adapted from: 2023 ADA, Standards of Medical Care in Diabetes - 2023: Diabetes Care, December 2022, Vol.46, Supplement 1; Agarwal R et al, Nephrology Dialysis Transplantation (2023) 38: 253–257 REDUCTION IN CKD COMPLICATIONS IN PEOPLE WITH T2D LIFESTYLE MODIFICATION AND DIABETES EDUCATION RAS blockade SGLT-2i ns-MRA GLP-1 RAs # RENAAL IDNT CREDENCE DAPA-CKD EMPA-KIDNEY FIDELIO-DKD F LOW

23. FL O W trial overview The first dedicated kidney outcomes trial with a GLP-1RA in participants with CKD and T2D 23 Rossing P et al. Nephrol Dial Transplant. 2023; https://doi.org/10.1093/ndt/gfad009 ; Perkovic V, et al. N Engl J Med. 2024: DOI: 10.1056/NEJMoa2403347 countries and areas 28 Europe: 963 Canada: 159 USA: 706 Brazil: 124 Argentina: 128 Australia: 59 South Africa: 101 India: 231 China: 30 Japan: 256 387 sites 4 years and 6 months trial duration 3,533 participants

24. FL O W trial design 24 Trial information Randomised, double-blind, parallel-group, multinational phase 3b trial Eligibility criteria designed to select broad population with CKD and T2D and at risk for progression of CKD Number of participants with eGFR ≥60 mL/min/1.73 m 2 at randomisation was capped at 20% to ensure predominance of participants with moderate-to-severe CKD Adults with CKD and T2D Age ≥18 years † HbA 1c ≤10% (≤86 mmol/mol) ​ eGFR ≥50 to ≤75 mL/min/1.73 m 2 and UACR >300 to <5,000 mg/g​ OR​ eGFR ≥25 to <50 mL/min/1.73 m 2 and UACR >100 to <5,000 mg/g​ On background RAAS blockade​ † ≥20 years in Japan; *Stratified by sodium-glucose cotransporter-2 inhibitor use (yes/no). CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; EOT, end of treatment; N, number of participants; OW, once-weekly; RAAS, renin-angiotensin-aldosterone system; s.c., subcutaneous; UACR, urine albumin-to-creatinine ratio; W, week. Rossing P et al. Nephrol Dial Transplant. 2023 Aug 31;38(9):2041-2051; Perkovic V, et al. N Engl J Med. 2024: DOI: 10.1056/NEJMoa2403347

25. FL O W objectives 25 Perkovic V, et al. N Engl J Med. 2024: DOI: 10.1056/NEJMoa2403347 To demonstrate that semaglutide delays the progression of renal impairment and lowers the risk of renal and cardiovascular mortality compared to placebo, both added to standard-of-care, in subjects with type 2 diabetes and chronic kidney disease Primary objective Secondary objectives To compare the effect of treatment with semaglutide versus placebo with regards to cardiovascular morbidity, peripheral artery disease, glycaemic control, body weight, blood pressure, and safety

26. 93% of the participants were at high or very high risk for CKD progression 26 Adapted from KDIGO Diabetes Work Group. KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease; Kidney International (2022) 102 (Suppl 5S), S1–S127. CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; KDIGO, Kidney Disease: Improving Global Outcomes; UACR, urine albumin-creatinine ratio. Rossing P et al. Nephrol Dial Transplant 2023;38:2041–2051; Perkovic V, et al. N Engl J Med. 2024: DOI: 10.1056/NEJMoa2403347 According to KDIGO guideline categorisation, 68.2% were at very high risk for CKD progression     UACR categories ( mg/g)     <30 ≥30–<300 ≥300 eGFR categories (mL/min/1.73 m²) ≥90 1 (<0.1) 7 (0.2) 23 (0.6) ≥ 60–<90 24 (0.7) 173 (4.9) 491 (13.9) ≥ 45–<60 37 (1.0) 324 (9.2) 694 (19.6) ≥ 30–<45 40 (1.1) 414 (11.7) 905 (25.6) ≥ 15–<30 7 (0.2) 87 (2.5) 306 (8.6) <15 NA NA NA KDIGO risk categories among FL O W participants, n (%) Very high risk n=2,413 (68.2%) Low risk n=25 (0.7%) Moderate risk n=217 (6.1%) High risk n=878 (24.8%) FL O W population

27. Semaglutide  1 mg: 24% risk reduction of a composite outcome , incl. kidney disease progression, CV and kidney death in people with CKD and T2D 27 Time to first occurrence of a composite endpoint consisting of: Onset of persistent ≥50% reduction in eGFR compared with baseline Onset of persistent eGFR <15 mL/min/1.73 m 2 Initiation of chronic renal replacement therapy (dialysis or kidney transplantation) Renal death CV death 6 12 18 24 30 36 42 48 Proportion of participants (%) 5 10 15 20 25 35 40 30 Placebo 23.2% HR 0.76 (95% CI 0.66, 0.88) p=0.0003* Semaglutide 18.7% 1,767 1,738 1,693 1,640 1,489 1,131 742 392 1,572 Semaglutide 1,766 1,736 1,682 1,605 1,516 1,408 1,048 660 354 Placebo Time since randomisation (months) First composite kidney event: Primary outcome Full analysis set. Data from the in-trial period. * Superiority if p value <0.0322 Numbers shown in the lower panels represent the number of participants at risk. CI, confidence interval; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HR, hazard ratio; RRR, relative risk reduction. Perkovic V, et al. N Engl J Med. 2024: DOI: 10.1056/NEJMoa2403347 24% RRR

28. Full analysis set. Data from the in-trial period. *Data on file. End-stage kidney disease was a 3-component composite endpoint consisting of initiation of chronic replacement therapy (dialysis or kidney transplantation), onset of persistent eGFR, <15 mL/min/1.73 m 2 , and kidney death.CI, confidence interval; eGFR, estimated glomerular filtration rate; HR, hazard ratio. Perkovic V, et al. N Engl J Med. 2024: DOI: 10.1056/NEJMoa2403347 Consistent risk reduction across the components of the primary composite endpoint 28 HR (95% Cl) Semaglutide (n/N) Placebo (n/N) Primary endpoint: Composite kidney outcome 0.76 (0.66, 0.88) 331/1,767 410/1,766 Onset of persistent ≥50% reduction in eGFR 0.73 (0.59, 0.89) 165/1,767 213/1,766 Onset of persistent eGFR <15 mL/min/1.73 m 2 0.80 (0.61, 1.06) 92/1,767 110/1,766 Initiation of chronic kidney replacement therapy 0.84 (0.63, 1.12) 87/1,767 100/1,766 Kidney death 0.97 (0.27, 3.49) 5/1,767 5/1,766 CV death 0.71 (0.56, 0.89) 123/1,767 169/1,766 0.1 0.4 7.3 1.0 2.7 Favours placebo Favours semaglutide Both kidney and cardiovascular components of the primary composite endpoint contributed to the risk reduction. Consistent risk reductions for kidney disease components of the primary composite endpoint.

29. Absolute risk difference for primary kidney composite event 29 Full analysis set. Data from the in-trial period. Numbers shown in the lower panels represent the number of participants at risk. CI, confidence interval; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HR, hazard ratio. Perkovic V, et al. N Engl J Med. 2024: DOI: 10.1056/NEJMoa2403347 Time to first occurrence of a composite endpoint consisting of: Onset of persistent ≥50% reduction in eGFR compared with baseline Onset of persistent eGFR <15 mL/min/1.73 m 2 Initiation of chronic renal replacement therapy (dialysis or kidney transplantation) Renal death CV death Over 3 years, 20 people would need to be treated to prevent one primary outcome Time since randomisation (months) Proportion of participants (%) 5 10 15 20 25 35 40 30 6 12 18 30 36 42 48 24 Absolute risk difference at week 104: –2.7% (95% CI –4.4, –0.9 ) Events: Semaglutide, 109; Placebo, 156 Number needed to treat: 37 Absolute risk difference at week 156: –4.9% (95% CI –7.3, –2.5) Events: Semaglutide, 220; Placebo, 303 Number needed to treat: 20 Placebo 23.2% Semaglutide 18.7% 742 392 1,767 1,738 1,693 1,640 1,489 1,131 1,572 Semaglutide 660 354 1,766 1,736 1,682 1,605 1,516 1,408 1,048 Placebo

30. Semaglutide 1 mg slower loss of kidney function by a mean eGFR of 1.16 mL/min/1.73m 2 /year 30 Full analysis set. Data from the in-trial period. Numbers shown in the lower panels represent the number of participants at risk. Error bars indicating +/- the standard error. * Superiority if p value <0.0322. The initial eGFR reduction, sometimes referred to as an ‘eGFR dip’, is thought to be a hemodynamic effect that occurs as a result of the reduction in intraglomerular pressure. An acute eGFR dip has also been observed with other classes of kidney protective therapies, including RAAS inhibitors and SGLT2i. CI, confidence interval; eGFR, estimated glomerular filtration rate; ETD, estimated treatment difference. Perkovic V, et al. N Engl J Med. 2024: DOI: 10.1056/NEJMoa2403347 ETD (95% Cl) at week 104 = 1.16 mL/min/1.73m 2 /year (0.86, 1.47) p<0.001* 12 52 104 156 208 Time since randomisation (weeks) eGFR (mL/min/1.73m 2 ) 38 40 42 46 48 44 36 Observed mean Semaglutide 1,766 1,663 1,609 1,441 876 199 Placebo Semaglutide -2.19 Placebo -3.36 Annual rate of change in eGFR (calculated with serum creatinine): Confirmatory secondary endpoint 1,766 1,665 1,606 1,468 952 218 1,590 651 1,345 1,521 1,573 1,284 1,490 609

31. Semaglutide 1 mg demonstrated 18% risk reduction of MACE 31 Numbers shown in the lower panel represent the number of participants at risk. # Superiority if p value <<0.0322 CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction. Perkovic V, et al. N Engl J Med. 2024: DOI: 10.1056/NEJMoa2403347 6 12 18 24 30 36 42 48 Proportion of participants (%) 5 10 15 20 25 35 40 30 1767 1725 1672 1622 1515 1176 793 430 1575 Semaglutide 1766 1721 1663 1583 1535 1478 1133 731 418 Placebo Time since randomisation (weeks) Placebo 14.4% Semaglutide 12.0% HR 0.82 (95% CI 0.68, 0.98) p=0.029 # CV death, non-fatal MI or non-fatal stroke: MACE confirmatory secondary end point

32. Time since randomisation (months) 6 12 18 24 30 36 42 48 Proportion of participants (%) 5 10 15 20 25 35 40 30 1767 1739 1703 1665 1583 1234 838 460 1627 Semaglutide 1766 1737 1697 1641 1601 1544 1185 772 437 Placebo All-cause death: secondary confirmatory end point Placebo 15.8% Semaglutide 12.8% HR 0.80 (95% CI 0.67, 0.95) p=0.01 # Semaglutide 1 mg demonstrated 20% risk reduction of all cause death 32 Numbers shown in the lower panel represent the number of participants at risk. # Superiority if p value <<0.0322 CI, confidence interval; HR, hazard ratio.​ Perkovic V, et al. N Engl J Med. 2024: DOI: 10.1056/NEJMoa2403347

33. FL O W trial outcomes: Summary 33 First composite kidney event HR: 0.76 [ 0. 66 ; 0. 88 ] 95% CI Annual rate of change in eGFR (total slope) ETD: 1.16 [ 0. 86 ; 1 . 47 ] 95% CI MACE HR: 0. 82 [ 0. 68 ; 0. 98 ] 95% CI All-cause-death HR: 0. 80 [ 0. 67 ; 0. 95 ] 95% CI 24% RRR ETD 1.16 ml/min/1.73m 2 /year 18% RRR 20% RRR The p-value limit was determined by the Lan-DeMets alpha spending function, approximating the O'Brien-Fleming’s stopping boundaries accounting for the group sequential design (interim analysis). eGFR was calculated using the CKD-EPI formula . CI, confidence interval; MACE, major adverse cardiovascular event; eGFR, estimated glomerular filtration rate; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration. Perkovic V, et al. N Engl J Med. 2024: DOI: 10.1056/NEJMoa2403347

34. Summary 34 CKD is a common complication of T2D 22% of CKD cases in Indonesia are contributed by diabetes nephropathy CKD is associated with an increased risk of CVD mortality in people with T2D GLP-1 RA have multifactorial effects, including in kidney In kidney, GLP-1 RA has roles in increasing natriuresis & diuresis, reducing inflammation, oxidative stress, RAAS In FL O W trial, GLP-1 RA Semaglutide  1 mg demonstrates 24% risk reduction of a composite outcome , incl. kidney disease progression, CV and kidney death in people with CKD and T2D Following positive FL O W trial outcomes, GLP-1 RA has been recommended as one of the 4 pillars of cardio-renal protection in people with CKD and T2D

35. Semaglutide is considered as one of the agents with very high glucose lowering and weight efficacy. Semaglutide is recommended for achieving and maintaining glycaemic and weight management goals Addition of “ delayed gastric emptying ” in Uncommon (≥1/1 , 000 to <1/100) undesirable effects. Ozempic Prescribing Information Indonesia 2023 Safety Update as per 22 Dec 2023