T2DM & CKD with Ryzodeg Hamba 2024-1.pptx

Ryzodeg CKD

1. The Problem in T2DM Patients & Chronic Kidney Disease Dr. Taufiqurrokhman SpPD RSUD H. Abdoel Madjid Batoe 29-08-2024

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

3. CKD has a global prevalence of 9.1%; prevalence is higher in women than in men 7.3% of men 9.5% of women CKD has a major effect on global health, both as a direct cause of global morbidity and mortality It is the 12 th leading cause of death worldwide resulting in 1.2 million deaths and 35.8 million DALYs in 2017 Chronic kidney disease – Global statistics 3 The National Kidney Foundation KDIGO define CKD as: 1 Duration of >3 months of either: Kidney damage, as defined by structural or functional abnormalities of the kidney, with or without decreased GFR manifest by either: Pathological abnormalities; or Markers of kidney damage, including albuminuria ≥30 mg/g (≥3 mg/mmol) or other abnormalities in the composition of urine, or abnormalities in histology or imaging tests, or history of kidney transplantation GFR <60 mL/min/1.73 m 2 with or without kidney damage ESRD* is the final stage of kidney disease, when the kidneys no longer function well enough to meet the needs of everyday life 2 Definition ESRD What is Chronic Kidney Disease ? KDIGO definition criteria **End-stage renal disease - defined by maintenance dialysis that is sustained for at least 30 days, renal transplantation, or eGFR <15 mL/min per 1.73 m 2 sustained for at least 30 days 1,4,5 CKD, chronic kidney disease; DALY, disability-adjusted life year; ESRD, end-stage renal disease; GFR, glomerular filtration rate; KDIGO, Kidney Disease Improving Global Outcome 1. KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int 2020; 98(4S):S1–S115 2. Rodger RSC et al. Clin Med 2012; 12(5):472–475; 3. Carney EF. Nat Rev Nephrol 2020; 16(5):251; 4 . Perkovic V et al. Lancet Diabetes Endocrinol 2018; 6(9):691–704; 5. Mann JFE et al. N Engl J Med 2017 ; 377(9):839–848

4. CKD Risk Factors Non-Modiafiable Family history of kidney disease, diabetes, or hypertension Age 60 or older (GFR declines normaly with age) Race Modifiable Diabetes Hypertension History of AKI Frequent NSAID use

5. Promotes a pro-inflammatory state 2 Smoking Damage from hyperglycaemia includes injury to filtration mechanisms 1,2 Causes damage to blood vessels in the kidney 1,2 3.7 Diabetes Hypertension Results in hypertension, poor renal function and proteinuria 3 Atherosclerotic disease Familial predisposition and genetic risk factors for CKD 2 Toxic agent that damages or destroys the cells and/or tissues of the kidneys 5 Renal function decreases with age in both men and women 2 Increases blood pressure and physical compression of the kidneys 4 Age Nephrotoxins Family history Obesity Most common causes of CKD 1 CKD risk factors and causes CKD, chronic kidney disease 1. NIDDK. Available from: Causes of Chronic Kidney Disease | NIDDK (nih.gov) accessed May 2021; 2. Kazancioğlu R. Kidney Int Suppl (2011) 2013; 3(4):368–371; 3. Woolfson R. Postgrad Med J 2001; 77(904):68–74; 4. Hall ME et al. Int J Nephrol Renovasc Dis 2014; 7:75 – 88; 5. Orr SE et al. Int J Mol Sci 2017; 18:pii: E1039

6. Natural History of Diabetic Kidney Disease *Kidney complications: anemia, bone and mineral metabolism, retinopathy, and neuropathy. Alicic . CJASN. 2017;12:2032. Slide credit: clinicaloptions.com Diagnosis Yr 2 5 10 20 30 Hyperglycemia Cellular injury Mesangial expansion glomerulosclerosis, tubulointerstitial fibrosis, and inflammation Microalbuminuria Macroalbuminuria GFR High Normal Low ESRD Hypertension Kidney complications* Cardiovascular disease, infections, death

7. Mechanistic Links Between Prediabetes, Diabetes, DKD, and End-Stage Kidney Disease Prediabetes, Diabetes Chronic hyperglycemia, metabolic syndrome, dyslipidemia, increased fatty acid metabolism Hemodynamic Inflammation cytokines, chemokines Oxidative stress ROS Apoptosis/autophagy Mitochondrial dysfunction mitophagy Diabetic nephropathy Extracellular matrix accumulation Glomerular nodular sclerosis Glomerular basement membrane thickening Glomerular hyalinosis podocytopathy End-stage kidney disease Nicholas. NephSAP. 2020;19:110. Slide credit: clinicaloptions.com

8. Structural Changes in Diabetic Kidney Disease Alicic. CJASN. 2017;12:2032. Reproduced with permission. Slide credit: clinicaloptions.com

9. Type 2 diabetes and Chronic Kidney Disease

10. Why Treat Advanced CKD: Is it Too Late? Prevent/delay progression to dialysis/treatment Prevent progression of other complications (blindness, amputation) Prevent CV events, including CHF Improve quality of life Reduce cost of care of ESRD Slide credit: clinicaloptions.com

11. Diabetic Kidney Disease Is a Serious Matter Kidney disease is a frequent diabetic complication Type 1 diabetes ~ 30% Type 2 diabetes ~ 40% Diabetes is the most common cause of CKD and ESRD in the developed and developing worlds Diabetes prevalence in US ESRD patients: 66%-86% depending on race Diabetic kidney disease amplifies CVD risk Much of diabetes-associated excess CVD risk occurs in diabetic kidney disease National Kidney Foundation. https://www.kidney.org/atoz/content/diabetes Slide credit: clinicaloptions.com

12. CKD is a common complication of T2D, with significant disease burden Growing global incidence of diabetes in adults aged 20–79 years 1 CKD is common in diabetes 2 2021 536.6 MILLION 2045 783.2 MILLION T 1D T 2D CKD No CKD 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

13. Progression of CKD in diabetes 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 An initial hyperfiltration is followed by progressive decline in GFR accompanied by microalbuminuria progressing to macroalbuminuria

14. Cardiovascular, kidney and metabolic conditions are intimately interconnected 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. KD, 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

15. Type 2 diabetes and Chronic Kidney Disease Management

16. Repeat and confirm: If possible, evaluate temporary and for different causes Consider the use of cystatin C and creatinine analyses to estimate GFR more accurately Only presence of persistent abnormalities confirm CKD diagnosis Initiate evidence-based treatment Who to screen and when ? T1D Yearly starting 5 years post-diagnosis T2D Yearly starting at diagnosis How to screen ? Spot UACR eGFR + 1 2 What to do following a positive result ? 3 What defines CKD diagnosis ?* 4 Persistent † UACR ≥30   mg/g Persistent † eGFR <60 mL/min/1.73 m 2 Other evidence of kidney damage and/or and/or Screening & Diagnosed CKD ADA, American Diabetes Association; CGM, continuous glucose monitoring; CKD, cardiovascular disease; KDIGO, Kidney Disease: Improving Global Outcomes; SMBG, self-monitored blood glucose. American Diabetes Association. Diabetes Care 2022;45( Suppl 1):S1–264.

17. CHRONIC KIDNEY DISEASE AND RISK MANAGEMENT Risk of chronic kidney disease (CKD) progression, frequency of visits, and referral to nephrology according to glomerular fi ltration rate (GFR) and albuminuria. Chronic Kidney Disease and Risk management : Standards of Care in Diabetes - 2024 . Diabetes Care 2024;47(Suppl. 1):S219-230 CHRONIC KIDNEY DISEASE AND RISK MANAGEMENT

18. Multifactorial Approach to Risk Reduction Reduction in Diabetes Complications Glycemic Management Blood Pressure Management Lipid Management Agents With Cardiovascular and Kidney Benefit Lifestyle Modification and Diabetes Education Cardiovascular Disease and Risk Management: Standards of Care in Diabetes - 2024 . Diabetes Care 2024;47(Suppl. 1):S179-S218

19. Glycaemic control - Recomendations ADA, American Diabetes Association; CGM, continuous glucose monitoring; CKD, cardiovascular disease; KDIGO, Kidney Disease: Improving Global Outcomes; SMBG, self-monitored blood glucose. American Diabetes Association. Diabetes Care 202 4 ;4 7 (Suppl 1):S1–264. Glycaemic assessment using HbA 1c Twice-yearly for people with stably controlled T2D who are meeting treatment goals Quarterly assessment in people with T2D who are managed intensively had changes in therapy are not meeting treatment goals ADA and KDIGO recommendations acknowledge the limitations regarding the precision and accuracy of HbA 1c measurements in people with advanced CKD and kidney failure treated by dialysis, and that HbA 1c is not able to adequately capture glycaemic variability and hypoglycaemic events ADA and KDIGO emphasise concurrent use of 1 HbA 1c as a metric for defining therapeutic targets CGM to assess effectiveness and safety glycaemic management in people with T2D at risk for hypoglycaemia overall glycaemia when HbA 1c is inaccurate SMBG to direct medication adjustment, especially under insulin treatment 1 2 3

20.   Factors guiding decisions on individual HbA1c targets CKD , chronic kidney disease; G1 , estimated glomerular filtration rate (eGFR) ≥90 ml/min per 1.73 m 2 ; G5 , eGFR <15 ml/min per 1.73 m 2 ; HbA1c , glycated hemoglobin. Kidney Int 2022;102(4S):S1–127

21. Individualised HbA1c targets Initial HbA 1c target of < 7.0% in most non-pregnant adult people with T1D and T2D without hypoglycaemia risk Reduction of microvascular complications Higher HbA 1c targets (< 8.0%) are recommended for people with limited life expectancy and when potential risks might impact quality of life HbA 1c range: < 6.5% to < 8.0% for people with T2D and CKD not treat with dialysis These targets are linked with beneficial effects on survival, CV outcomes, microvascular endpoints, and CKD progression 1 2 CKD, chronic kidney disease; CV, cardiovascular. 1. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. Kidney Int 2022;102(4S):S1–123; 2. American Diabetes Association. Diabetes Care 2024;47( Suppl 1):S1–264.

22. Use of IDegAsp on patients with CKD

23. Ryzodeg ® : First in Class Co-Formulation Insulin 1,5 1. Indonesia Ryzodeg ® Prescribing Information 2022 . 2. Heise T, et al . Diabetes Care . 2011; 34(3): 669-74. 3. Jonassen I, et al . Pharm Res . 2012; 29(8): 2104-14. 4. Heller S, et al . Diabetes Metab Res Rev . 2012; 28: 50-61. 5. Kalra et al. Adv Ther (2018) 35:928-936 2,3 4

24. Insulin Degludec represent a useful insulin treatment options in subject with co-morbid diabetes & impaired renal functions Hepatic function PK properties of insulin degludec are not significantly influenced by renal & hepatic function & thus specific dose adjustment may not be required for subject with renal & hepatic impairment PK, pharmacokinetic. Kupčová et al. Clin Drug Investig 2014;34:127–33 ; Kiss et al. Clin Pharmacokinet 2014;53:175–83 ; Korsatko et al. Drugs Aging 2014;31:47–53

25. Use of IDegAsp in renal insufficiency Label recommendations In d i a l ab el EU l ab el US l ab el Indonesia Label recommendations: IDegAsp can be used in renal impaired patients. Glucose monitoring is to be intensified and the insulin dose adjusted on an individual basis Ryzodeg TM CDSCO approved package insert version (8-9564-26-010-7), dated (11 JAN 2019); Ryzodeg® August 2018. https:// www.novo-pi.com/ryzodeg7030.pdf EU SmPC, October 2018. Ryzodeg PI Indonesia, 2022

26. Kaneko study report Case report Hemodialysis case: 61 years old male patients with T2DM Insulin Degludec switched to IDegAsp This result based on two hemodialysis patients case study reported by Kaneko et.al 2017. Please refer to local product information for information related to the use of IDegAsp in patient with renal impairment. Kaneko, Shizuka et al. “IDegAsp provides simple intensification without the addition of another insulin injection and simple delivery system.”  Diabetes management  7 (2017): 177.

27. Kaneko study report Case report Hemodialysis case: 74 years old male patients with T2DM & liver cirrhosis child A Regular insulin switched to IDegAsp This result based on two hemodialysis patients case study reported by Kaneko et.al 2017. Please refer to local product information for information related to the use of IDegAsp in patient with renal impairment. Kaneko, Shizuka et al. “IDegAsp provides simple intensification without the addition of another insulin injection and simple delivery system.”  Diabetes management  7 (2017): 177.

28. Insulin use in T2DM patients with renal impairment IDeg is conjugated with fatty acid & binds to albumin Fluctuations of IDeg concentration remain stable and minimal Interstitial fluids volume did not affect dissolution of IDeg/IDegAsp No need IDegAsp dosage adjustment in the day of dialysis. If needed, only minimal. The pH of the body fluid will change before (PH 7.0) and after hemodialysis (PH 7.4) IDegAsp did not affected by pH changes , this will not make a difference in the solubility and absorption Insulin Degludec is a useful options for patients with renal impairment, including patients undergoing dialysis. 1 2 3 This result based on two hemodialysis patients case study reported by Kaneko et.al 2017. Please refer to local product information for information related to the use of IDegAsp in patient with renal impairment. Kaneko, Shizuka et al. “IDegAsp provides simple intensification without the addition of another insulin injection and simple delivery system.”  Diabetes management  7 (2017): 177.

29. Summary

30. Summary Most common cause of CKD is affected by diabetes, hypertension, age, family history, smoking, obesity, nephrotoxin . CKD is a common complication of T2D, with significant disease burden HbA1c range: < 6.5% to < 8.0% for people with T2D and CKD (KDIGO) Ryzodeg is the first co-formulation insulin PK & PD did not affected by increasing degree of renal impairment From the case report: IDegAsp is a useful options for patients with renal impairment, including patients undergoing dialysis.

31. 56 FPG , fasting plasma glucose; HbA 1c , glycosylated haemoglobin; PPG , postprandial plasma glucose. 1 . Ryzodeg ® indonesia Prescribing Information 2022. 2 . Onishi, et al. Diabetes Obes Metab 2013;15:826–32 . Benefits of initiation with Ryzodeg ® than Insulin glargine Superior Glycemic Control IDegAsp targeting FPG & PPG 2 Numerical lower risk of Nocturnal Hypoglycemia 2 Simple to use OD with largest meals 1  HbA 1c OD Flexibility in the timing of insulin adminstrations 1 START with CONFIDENCE

32. 202 3 © Novo Nordisk A/S For Healthcare Professional Only Experience the Freedom with Ryzodeg ® 2-in-1 Co - Formulation Insulin