Ramadan and Insulin use for diabetic patients

Ramadan and Insulin

1. Simplify Care: Live the Ramadan Spirituality with Premix HPL_EL_PC2025_09

2. Patient case study 1. International Diabetes Federation. IDF Diabetes Atlas. 8th ed. Brussels, Belgium: International Diabetes Federation; 2021. Mr. X Male 58 Years of age Bangladeshi Medical History T2DM, diagnosed 6 years ago Hypertension Dyslipidemia Medication Metformin 2g BID Glimepiride 4 mg Sitagliptin 100 mg QD Ramipril 10mg QD Rosuvastatin 10mg QD Which Medication would be preferable and comfortable choice for this patient? Physical Examination Weight 85 Kg Height 5 feet 7 inch BMI 29.3 kg/m 2 BP 140/90 mmHg Waist circumference 39 inch Laboratory Report HbA1C 8.7 % RBS 14.4 mmol /L Total Cholesterol 196 mg/dl LDL 109 mg/dl HDL 36 mg/dl Triglyceride 145 mg/dl eGFR/Creatinine Normal

3. Glycemic control: Need to address both FPG & PPG Delay in insulin initiation due to inertia may leads to β cell failure Clinical evidence suggests that reducing PPG is as important as reducing FPG Combination injectables CLINICAL INERTIA X Oral / injectable combination + + CLINICAL INERTIA X Oral dual / triple therapy + CLINICAL INERTIA X Oral monotherapy CLINICAL INERTIA X Lifestyle modification Patient lose 70% of β cell function Data from Heine RJ et al. BMJ . 2006; 333: 1200 ‒ 1204

4. Poor control may leads to complication related mortality: Death by cause for all ages Mr X Male 58 Years of age Bangladeshi This patients has all the CV risks and multiple co- morbidities which will reduce life expectancy Challenges: Reach at Glycemic goal CV risk reduction Manage other co-morbidities Majority are dying due to CV complications Data obtain from WHO

5. Back to our patient case study Mr X Male 58 Years of age Bangladeshi Which Medication would be preferable and comfortable choice for this patient? Physical Examination Weight 85 Height 5 feet 7 inch BMI 29.3 kg/m 2 BP 140/90 mmHg Waist circumference 39 inch Laboratory Report HbA1C 8.7 % RBS 14.4 mmol /L Total Cholesterol 196 mg/dl LDL 109 mg/dl HDL 36 mg/dl Triglyceride 145 mg/dl eGFR/Creatinine Normal Fasting Plasma Glucose Post-Breakfast Blood Sugar Post-Lunch Blood Sugar Post-Dinner 7 11.7 13.6 12.7 Reason for visit: Uncontrolled blood sugar despite multiple oral anti diabetic agents

6. ADA-EASD Guidelines Outline Medications for Glycaemic Control and Weight Management as Adjuncts to Lifestyle Interventions 1,2 Goal | Achievement and Maintenance of Glycaemic Goals Glycaemic Management: Choose approaches that provide the efficacy to achieve goals Efficacy for Glucose Lowering 1 Dulaglutide Semaglutide Tirzepatide Insulin Combination oral Combination injectable (GLP-1RA/insulin) Very High Medications for the management of T2D can have varying effects on clinical outcomes, including body weight, that vary between, and sometimes within, drug classes 2 DPP-4=Dipeptidyl Peptidase-4; GLP-1RA=Glucagon-Like Peptide-1 Receptor Agonist; SGLT-2=Sodium-Glucose Cotransporter-2; SU=Sulfonylurea; TZD=Thiazolidinedione. 1. Davies MJ, et al. Diabetes Care. 2022;45(11):2753-2786. 2. Apovian CM, et al. Adv Ther . 2019;36:44-58. GLP-1RA (not listed above) Metformin SGLT-2 inhibitor SU (Damages ß cell) TZD High DPP-4 inhibitor Intermediate

7. Addressing total glycemic control with Insulin Survey shows multiple concerns for using complex regimen 1. Peyrot et al. Diabet Med 2012;29:682-9; 2. Marrett et al. Diabetes 2008;57 (Suppl. 1):A174| Mean HFS ii worry score There is need for simple & flexible insulin regimen to overcome the challenges of complex inflexible regimens & fear of hypoglycemia *Total patient sample, n=1530; t Total patient sample, n=1984. HFS, Hypoglycemia Fear Survey.

8. Target of Glycemic Status should be individualized FBG ≥ 14mmol/l &/or HbA1c ≥10% &/or RBG ≥ 18mmol/l FBG 10.0-<14 mmol/l &/or HbA1c 8.5-<10.0%% &/or RBG12-18mmol/l Bangladesh National Guideline What will be preferred medication for our case? LS+ Insulin ( HumalogMix ) ± Metformin Diabetes Management Algorithm in Uncomplicated, Non Pregnant adults with T2DM (Based on Glycemic Status) FBG<10.0 mmol/l &/or HbA1c <8.5% &/or RBG<12mmol/l Life style (LS) + Metformin Asymptomatic Symptomatic LS+Metformin+Sulphonyluria or Other agent LS+ Insulin (Premix/Basal/Split-mix) ± Metformin s tatus should

9. ADA/EASD and AACE guidelines which prefer basal insulin for initiation. 9 Premix insulin – What guidelines say Viswanathan Mohan, et al., Consensus on Initiation and Intensification of Premix Insulin in Type 2 Diabetes Management. JAPI. 2017;65; Kalra, Sanjay & Gupta, Yashdeep . (2015). Journal of diabetes and metabolic disorders. 14. 17. 10.1186/s40200-015-0146-1. IDF 2012 Initiation of premix insulin OD or BID when 1st or 2 nd line therapies fail to achieve glycemic target of HbA1c < 7%. NICE guideline OD premix insulin should be considered when HbA1c level is ≥ 9%. INCG 2013 Premix insulin OD as an add-on therapy to metformin when HbA1c level is > 7.5% to ≤ 8.5% If HbA1c > 7% and FPG > 110 mg/dL, then premix insulin is titrated to achieve FPG < 110 mg/dL. Initiation with premix insulin therapy at a starting dose of 10 U CDA 2016 Initiation of premix insulin at 5-10 U OD or BID JAPI 2014 Recommends premix insulin /co-formulation OD in patients with HbA1c > 9% and high FPG and PPG Many International and Indian guidelines recommend insulin initiation either with a basal or premixed/co-formulation insulins

10. HbA1c reduction expected with class of drugs Average HbA1c reduction expected with available class of drug Viswanathan Mohan, et al., Initiation and intensification of insulin therapy in type 2 diabetes mellitus: Physician barriers and solutions – An Indian perspective. Endocrine and Metabolic Science 4 (2021) 100103 Sodium-glucose transport protein 2 inhibitors Dipeptidyl peptidase-4 inhibitors Alpha-glucosidase inhibitors Alpha-glucosidase inhibitors Sulfonylureas Glinides Metformin Basal Insulin Premix insulin Basal Bolus 1.12 0.74 0.74 0.72 0.77 0.64 1.21 1.28 1.91 1.22 Drug class Average reduction in %

11. Patient profile for premix insulin initiation HbA1C > 8.5% or RBS >12 mmol/l or FPG> 10 mmol/l 11 1. Bangladesh National Guideline; 2. Kumar A,, et al. Indian reality of managing type 2 diabetes: an expert review of global and national guidelines for optimum insulin use. J Diabetol 2020;11:148‑57. Adults at early or progressed stage of disease Elderly patients in need of simple therapy Limited sources & literacy, simple and easy to explain insulin therapy is needed Patient on high carbohydrate diet Simple and convenient option needed for intensification Limited literacy and a simple and easy‑to‑understand regimen Simple and convenient options needed for future intensification GLYCEMIC FACTORS PHASE OF LIFE Bangladesh REALITIES PSYCHOSOCIAL FACTORS

12. Why choose premix insulin? Coverage of both FPG and PPG Effective HbA1c control Improved PPG control (compared to basal insulin alone) A single delivery device Fewer injections (compared to basal bolus) Less dosing errors Convenient Option to intensify with same insulin 12 H. E. Turner, et al., The use of fixed-mixture insulins in clinical practice. European journal of clinical pharmacology. 2000 Apr;56(1):19-25.

13. Finding appropriate Premix insulin Paradigm Study: HumalogMix 25 Vs basal bolus thrapy Study Objective Demonstrate non-inferiority of HumalogMix25 to BBT Humalog Mix 25 Basal Bolus Therapy 1 Injection 2 Injection 3 Injection 1 Injection 2-3 Injection 4 Injection If target not achieved Increase to BID injection If target not achieved Increase to TID injection Once daily. Pre-dinner. 10U Inj. Add 1 dose at pre-BF, Total daily dose Divided into 2 for Pre-BF & dinner Additional 3 units at Pre-lunch Once daily. Pre-bed. 10U Inj. Add bolus at Pre-meal if not covered Add bolus at Pre-meal up To 3 times daily

14. PARADIGM: LS Mean Change in HbA1c From Baseline to Endpoint Bowering K et al. Diabet Med 2012;29:e263-72 LS Mean Change in HbA1c (%) % of Patients Reaching HbA1c Target Glargine + Lispro (n=184) HumalogMix 25 (n=177) Target HbA1c <7.0%, n (%) 70 (39.1) 68 (40.0) Target HbA1c ≤6.5%, n (%) 34 (19.0) 36 (21.2) Between-treatment difference (95% CI): -0.04% (-0.25, 0.17)

15. PARADIGM: Mean HbA1c at week 48 Mean HbA1c at week 48 Number of injections % (SD) HumalogMix 25 1 injection 7.3 (1.04) 2 injections 7.2 (0.82) 3 injections 7.3 (1.26) G + L 1 glargine dose 7.2 (0.74) G + 1 lispro injection 7.6 (1.31) G + 2 lispro injections 7.6 (1.28) G + 3 lispro injections 7.2 (0.89) LM25: insulin lispro mix 25, 25% lispro, 75% insulin lispro protamine suspension, G: insulin glargine, L: insulin lispro injection, HbA1c: haemoglobin A 1c , SD: standard deviation Reference: Bowering et al. Diabetes Med. 2012;29(9):e263-272.

16. Intensification by HumalogMix 25 ensures similar safety in a simple & convenient way * Glargine only. † LM25 not used 4 times per day. G: insulin glargine , L: insulin lispro injection Reference: Bowering et al. Diabetes Med. 2012;29(9):e263-272. 1 injection per day* 2 injections per day 3 injections per day 4 injections per day † Overall Hypoglycemia

17. 7-Point SMBG Profiles and PPG levels Glargine + Lispro (n=184) Insulin Lispro Mix 25 (n=177) LS mean (SE) change in PPG levels from baseline to endpoint, mmol/l 4.89 (1.2) 5.24 (1.2) Blood Glucose ( mmol /L) 1. Bowering K et al. Diabet Med 2012;29:e263-72; 2. Riddle et al. Diabetes Obes Metab 2014;16:396–402 For initiation & intensification HumalogMix 25, the only premix insulin to achieve non-inferiority vs BBT 1,2

18. Key findings from RCTs Comparison between premix and basal plus regimen Jin et al. 2016 Tinahones et al . 2014 Bowering K et al. 2012;29:e263-72 (PARADIGM) Aschner et al. 2015 (GALAPAGOS) Riddle et al. 2014 BIAsp 30 BID vs. glargine OD + IGlu OD/BID BIAsp 30 BID vs. glargine OD ± IGlu OD vs. glargine OD + IGlu ≤TID BIAsp 30/LM 25 OD/BID vs. glargine OD ± IGlu OD LM 25 BID vs. glargine OD + Humalog OD LM 25 BID/TID vs. glargine OD + ILispro TID Studies in insulin-naïve patients Overall hypoglycemia HbA 1c Studies in patients previously receiving basal insulin Insulin dose Weight Favours premix No difference Favours basal plus BIAsp, biphasic insulin aspart; BID, twice daily; glargine, insulin glargine; IGlu , insulin glulisine; LM, lispro mix; OD, once daily; RCT, randomised controlled trial; TID, three times daily Aschner et al. J Diabetes Complications 2015;29:838 – 45; Jin et al. J Diabetes 2016;8:405 – 13 ; Riddle et al. Diabetes Obes Metab 2014;16:396–402; Tinahones et al. Diabetes Obes Metab 2014; 16:963–70; Vora et al. Diabetes Obes Metab 2015;17:1133 –41 Non Inferiority of Premix X X X X HumalogMix 25 Only Premix Analogue insulin ensure Non-inferiority Vs BBT Non Inferior

19. Patient Follow Up Mr. X Male 58 Years of age Bangladeshi Follow-up after 12 weeks He is now taking Humalog Mix25 BD 18+0+12 units His A1c has fallen to 7.2% Treatment Change Glimepiride has stopped Humalog Mix 25 twice daily before breakfast and dinner initiated 12 units before breakfast 08 units before dinner He reports occasional feelings of hypoglycemia but no documented or severe hypoglycemia. Patient has now grown concern about Ramadan Fasting Notes Loves the month of Ramadan, and is very keen on fasting Frequently eats out at iftar Previous Year Ramadan Review Last year had no serious hypoglycaemic events during Ramadan and managed with Human Premix 30/70 BD Recalls that his HbA1c was high after Ramadan

20. 94.8% of Muslims with T2DM fast for at least half of Ramadan, and nearly two-thirds fast every day The Majority of Muslims With T2DM Fast Every Day During Ramadan (DAR Global Survey) 1 T2DM = type 2 diabetes mellitus. 1. IDF DAR Practical Guidelines 2020 2. Hassanein , M., et al., The DAR 2020 Global survey: Ramadan fasting during COVID 19 pandemic and the impact of older age on fasting among adults with Type 2 diabetes.Diabetes research and clinical practice, 2021 © 2021 Eli Lilly and Company. In UAE, 83.2% of patients fasted during Ramadan In India, 76.8% of patients fasted during Ramadan There is significant variation between countries in the proportion of individuals fasting every day. Out of those who fast at least 15 days, 61.9% fast every day 63.6% Percentage of patients with T2DM fasting for specific periods during Ramadan 1,2 5.8% (<15 days) 94.2% (≥15 days) In Bangladesh, ~ 98.1% of patients fasted during Ramadan In KSA, 97.1% of patients fasted during Ramadan

21. Sleep Patterns Change During Ramadan 1 REM = rapid eye movement. 1. IDF DAR Practical Guidelines 2020 . 2. BaHammam A, et al. Appetite . 2010;54(2):426-429. 3. Roky R, et al. J Sleep Res . 2001;10(4):319-327. © 2021 Eli Lilly and Company. Typical Sleep and Meal Patterns During Ramadan and Non-Ramadan Periods 1 Decreased total sleep time 2,3 Delayed sleep 3 Decreased REM sleep duration 3 Decreased proportion of REM sleep 3 Increased proportion of non-REM sleep 3 The impact of Ramadan sleeping pattern may include: 00:00 Non-Ramadan 6:00 12:00 18:00 Ramadan Asleep Awake Physiological changes are most marked in countries with more daylight hours 1

22. Blood Glucose Levels Rise Rapidly After Iftar in Patients With Diabetes CGM = continuous glucose monitoring. Lessan N, et al. Diabetes Metab . 2015;41(1):28-36. © 2021 Eli Lilly and Company. 6.0 8.0 12.0 10.0 4.0 2.0 Time (hours) Mean Interstitial Glucose (mmol/L) Fasting Non-fasting 04:00 02:00 00:00 22:00 20:00 18:00 16:00 14:00 12:00 10:00 08:00 06:00 Iftar Mean CGM Profiles From Patients With Diabetes Before and During Ramadan

23. HCPs and Religious Leaders Must Deliver the Same Message Regarding Which Patients Should Not Fast HCP = healthcare professional. 1. Gaborit B, et al. Diabetes Metab . 2011;37(5):395-402. 2. Hui E, et al. Int J Clin Pract . 2012;66(9):910-911. © 2021 Eli Lilly and Company. Unification Religious Leaders Some patients prefer to discuss fasting with their local imam rather than their HCP 1,2 HCPs Not all patients will consult their HCP before fasting Key Risks Associated With Ramadan Fasting in Patients With Diabetes 1 Risks Hyperglycaemia Dehydration Hypoglycaemia Diabetic ketoacidosis 1. Al- Arouj M, et al. Diabetes Care . 2005;28(9):2305-2311. 2. Al- Arouj M. J Pak Med Assoc . 2015;65(5 suppl 1): S18-S21. © 2021 Eli Lilly and Company Fasting periods can last 13-20 hours per day and are often undertaken in hot and humid conditions 2

24. IDF-DAR Practical Guidelines for Risk Calculation for People with Diabetes that seek to fast during Ramadan DAR = Diabetes and Ramadan International Alliance; IDF = International Diabetes Federation. I . IDF DAR Practical Guidelines 2021 © 2021 Eli Lilly and Company. SCORE 0 TO 3 LOW RISK SCORE 3.5 TO 6 MODERATE RISK SCORE > 6 HIGH RISK

25. More Frequent Blood Glucose Monitoring During the Day Is Recommended 1,2 *Consider individualisation of care. 1. IDF DAR Practical Guidelines 2020 2. Hassanein M, et al. Indian J Endocrinol Metab . 2014;18(6):794-799. 3. Lessan N, et al. Diabetes Metab . 2015;41(1):28-36. © 2021 Eli Lilly and Company. . Pre-dawn meal (suhoor) Sunset meal (iftar) All patients should break their fast if: Blood glucose is <70 mg/dL (3.9 mmoI/L) Re-check within 1 hour if blood glucose is 70-90 mg/dL (3.9-5.0 mmoI/L) Blood glucose is >300 mg/dL* (16.7 mmoI/L) Symptoms of hypoglycaemia, dehydration or acute illness occur Night Day Morning Midday (12:00) Pre-dawn Evening Afternoon Midnight (00:00) Morning Midday Mid-afternoon 2 hours after iftar Dawn Sunset Or at any time when there are symptoms of hypoglycaemia or hyperglycaemia or if feeling unwell 12.0 10.0 8.0 Time (hours) Glucose (mmol/L) 6.0 Fasting Non-fasting 04:00 02:00 00:00 22:00 20:00 18:00 16:00 14:00 12:00 10:00 08:00 06:00 Iftar

26. Medical management of T2DM during Ramadan fasting There are different risks and recommendations associated with the different therapies that individuals with T2DM might be treated The primary concerns for the use of any antidiabetic therapy are glycaemic control and risk of hypoglycaemia IDF-DAR Practical Guidelines 2021 https://idf.org/component/attachments/attachments.html?id=2411&task=download

27. Sulfonylureas (SUs) IDF-DAR Practical Guidelines 2021; https://idf.org/component/attachments/attachments.html?id=2411&task=download Medical management of T2DM during Ramadan fasting SGLT2-i RECOMMENDATION For stabilisation , SGLT2Is should be initiated at least two weeks to one month prior to Ramadan. SGLT2Is are recommended to be administered at the time of evening meal (Iftar). Increasing fluid intake during the non-fasting hours of Ramadan is recommended. SGLT2I do not require treatment modifications during Ramadan. RECOMMENDATION GLP-1 RA can be continued during Ramadan The risk of hypoglycaemia is low but may be higher when used alongside sulfonylureas. DOSE-TITRATION prior to Ramadan (at least 2–4 weeks) NO FURTHER TREATMENT MODIFICATIONS are required if patient is well tolerated GLP-1 RAs Newer SUs such as gliclazide MR, gliclazide and glimepride are preferred over older class SUs such as glibenclamide NO DOSE ADJUSTMENTs are required during Ramadan

28. Medical management: long or short-acting insulins recommendations Where long/intermediate or short acting insulins are used the following guide should be considered  IDF-DAR Practical Guidelines 2021 https://idf.org/component/attachments/attachments.html?id=2411&task=download

29. 29 Medical management: Premix insulins recommendations

30. Mr. X’s risk stratification DAR = Diabetes and Ramadan International Alliance; IDF = International Diabetes Federation. I . IDF DAR Practical Guidelines 2020 © 2021 Eli Lilly and Company. Mr. X Male 58 Years of age Bangladeshi Risk Score = 3 Low Risk Would you recommend that Mr. X fast during Ramadan? Category 1 High Risk Category 2 Moderate Risk Category 3 Low Risk A. B. C.

31. IDF-DAR Guidelines Recommend Changes to Premixed Insulin Dosing During Ramadan International Diabetes Federation and the DAR International Alliance. 2016. https://www.idf.org/e-library/guidelines/87-diabetes-and-ramadan-practical-25. Accessed 8 March 2018. Company Confidential © 2019. Eli Lilly and Company. Hypothetical patient profile Once-Daily Dosing Thrice-Daily Dosing Twice-Daily Dosing Omit afternoon dosage Carry out dosage titration every 3 days Take normal dosage at iftar Take normal dosage at iftar Reduce suhoor dosage by 25%-50% Adjust iftar and suhoor dosages Notes Frequently eats out at iftar HbA1c increased at the end of Ramadan No serious hypoglycaemic events last Ramadan History of hypertension HbA1c 7.2% Weight 85 kg BMI 29.3 kg/m 2 BP 140/90 Current Treatment Human Premix 30/70 BID 28 IU am 22 IU pm

32. Question How can we modify Mr. X’s insulin treatment to better match his glucose profile in Ramadan? Company Confidential © 2019. Eli Lilly and Company. Notes Frequently eats out at iftar HbA1c increased at the end of Ramadan No serious hypoglycaemic events last Ramadan History of hypertension HbA1c 7.2% Weight 85 kg BMI 29.3 kg/m 2 BP 140/90 Current Treatment Human Premix 30/70 BID 28 IU am 22 IU pm Hypothetical patient profile A. Modify the dosage of current insulin B. Alter the timing of his insulin dosages C. Use a different insulin for one or more of Mr. X’s daily dosages D. Other

33. Typical Bangladeshi Iftar And our response Iftar offers

34. HbA1c (%) Pre-Ramadan HbA1c Hui E, et al. Int J Clin Pract. 2010;64(8):1095-1099. P= .0001 6 8 10 4 2 9.05 8.56 Humalog Mix50 Human insulin Mix 30 Post-Ramadan HbA1c P= .007 8.98 9.27 Humalog Mix50 Is Another Treatment Option and Has Been Studied in Patients Fasting During Ramadan Comparison of Humalog Mix 50 With Human Insulin Mix 30 in Type 2 Diabetes Patients During Ramadan The International Journal of Clinical Practice E. Hui, V. Bravis, S. Salih, M. Hassanein, D. Devendra

35. Patients Receiving Humalog Mix50 Had a Reduction in the Mean Number of Hypoglycaemic Events Between-group difference in change in hypoglycaemic events from baseline was not statistically significant ( P =.36). Hypoglycaemic Events Hypoglycaemic Events per Person Humalog Mix50 0.5 0.6 0.7 0.4 0.2 Pre-Ramadan Post-Ramadan Human insulin Mix 30 0.3 0.1 P= .43 P= .81 Hui E, et al. Int J Clin Pract . 2010;64(8):1095-1099.

36. Company Confidential © 2019. Eli Lilly and Company. Hypothetical patient profile Case Summary Enact lifestyle changes with a focus on meal planning Use Humalog Mix 25/75 at Suhr & Reduce dosage by 25%-50% Consider switching iftar insulin dosage to Humalog Mix50

37. The Post-Ramadan assessment There is a need for HCPs to have an assessment with individuals with diabetes after Ramadan fasting has been completed This assessment provides the chance to: Gather valuable individual information on successes and challenges faced during Ramadan fasting Provide information on the risks of overindulgence during Eid ul- Fitr Ensure there have been no adverse effects or complications that have occurred during Ramadan fasting IDF-DAR Practical Guidelines 2021 https://idf.org/component/attachments/attachments.html?id=2411&task=download

38. Summary Inertia to start right medication Despite the availability of a range of pharmacological agents in many patients with T2DM poor glycaemic control for prolonged periods of time still occur Delay in insulin initiation & Intensification Treatment Initiation & intensification is often delayed, commonly due to a multitude of factors Humalog® Mix 25 Only Premix Analogue ensures non-inferiority & comparable safety VS Basal Bolus therapy Humalog® Mix 25 During Ramadan simple and convenient option with effective HbA1c control targeting both PPG and FPG with single device Humalog® Mix 50 could be the proven savior to control high PPG excursion & FPG control during Ramadan

39. Thank You