case studies presentation about xultophy

Review about novel insulin combination with GLP1agnonist

1. Clinical case Discussion Dr. Kiran Sony, Endocrinologist Chiangrai Prachanukhroh Hospital INSULIN DAY: NORTH STARS 28 th JUNE 2024

2. Mr. A Miss. C Mrs . B Our patients

3. Mr. A ผู้ป่วย ชายไทย อายุ 53 ปี ภูมิลำเนา จังหวัด เชียงราย อาชีพ รับราชการครู Consult for uncontrolled T2D Long standing T2D for 7 yrs. ตรวจพบขณะตรวจสุขภาพ ไม่มีอาการผิดปกติ ใดๆ Well controlled HT, DLP รักษาที่ OPD med มาตลอด ปรับยามาเรื่อย ๆ เริ่มฉีด insulin มา 2 ปีเพราะน้ำตาลคุมไม่ได้

4. พย 2566 : FPG 145 mg/dl HbA1C 8.7 % Cr 1.02 mg/dl eGFR 69 Urine microalbumin 94.6 mg/ L (UACR 47.7 mg/g) , No DR Family history : no family history of DM Social history : ไม่สูบบุหรี่ occasional alcohol drinking Personal history :Sedentary life style, สอนพิเศษ ทุกวัน

5. Current medications Jardiance-duo (12.5/1000) 1 tab once daily BIAsp 30 (premix) 22 units BID Losartan 50 mg/day Simvastatin 20 mg/day

6. FPG (md/dl) HbA1C (%) Body Weight Aug 2022 164 9.0 61 Feb 2023 134 8.0 64 May 2023 156 7.8 65.7 Aug 2023 104 7.7 66.1 Nov 2023 145 8.7 66.8 Jan 2024 155 9.1 68.7 Points of concern : BW increment 8 kg/2 yrs + uncontrolled HbA1C/Night time hypoglycemia มีปัญหา น้ำตาลต่ำช่วงกลางคืน น้ำหนักเพิ่มเรื่อย ๆ จึงส่งมาปรึกษา OPD DM

7. 112 230 120 5 /10 15/12 8 /12 224 ตี 3 68 183 22 /11 14 /12 ตี 1 76 ตี 1 71 23 /11 220 9 /12 230

8. Insulin-experienced T2D BID BOOST INTENSIFY PREMIX I

9. Both trials open-label. *One patient randomized to BIAsp 30 was excluded from the trial before receiving insulin treatment, as the patient did not fulfill the inclusion criteria. BIAsp 30, biphasic insulin aspart 30; BID, twice daily; BMI, body mass index; DPP-4, dipeptidyl peptidase-4 inhibitors; IDegAsp, insulin degludec/insulin aspart; OAD, oral antidiabetic drug; OD, once daily; T2D, type 2 diabetes 1. Fulcher et al. Diabetes Care 2014;37:2084–90. BOOST: INTENSIFY PREMIX I 1 Inclusion criteria Type 2 diabetes ≥6 months Previously treated with premixed or self-mixed insulin (OD or BID) ± OADs ≥3 months HbA 1c 7.0–10.0% BMI ≤40 kg/m 2 Age ≥18 years IDegAsp BID ± metformin ± DPP-4 ± pioglitazone (n=224) BIAsp 30 BID ± metformin ± DPP-4 ± pioglitazone (n=223)* Patients with type 2 diabetes (N=447) Insulin-experienced T2D BID: study designs BOOST INTENSIFY PREMIX I

10. Mean±SEM; FAS, LOCF a Calculated, not measured. Comparisons: estimates adjusted for multiple covariates. BIAsp 30, biphasic insulin aspart 30; BID, twice daily; CI, confidence interval; ETD, estimated treatment difference; FAS, full analysis set; IDegAsp, insulin degludec/insulin aspart; LOCF, last observation carried forward; NS, not significant; SEM, standard error of mean 1. Fulcher et al. Diabetes Care 2014;37:2084–90. HbA1c 1 HbA 1c (mmol/mol) a 63 51 60 75 69 57 45 72 66 54 48 ETD: -0.03% 95% CI [-0.18; 0.13] non-inferior 0.0 Time (weeks) HbA 1c & FPG over time BOOST INTENSIFY PREMIX I IDegAsp BID (n=224) BIAsp 30 BID (n=222) FPG (mg/dL) FPG 1 Time (weeks) 152 82 96 124 138 180 166 110 68 0.0 ETD: -1.14 mmol/L 95% CI [-1.53; - 0. 76], p <0.001 IDegAsp BID (n=224) BIAsp 30 BID (n=222)

11. BIAsp 30, biphasic insulin aspart 30; BID, twice daily; IDegAsp, insulin degludec/insulin aspart; U, unit 1. Fulcher et al. Diabetes Care 2014;37:2084–90. INTENSIFY PREMIX I 1 Mean insulin dose IDegAsp BID BIAsp 30 BID Number of patients, n 224 222 Morning dose, U Baseline 26 24 End of trial 38 44 Evening dose, U Baseline 28 27 End of trial 52 54 Total dose, U Baseline 54 51 End of trial 90 98 Post hoc analyses of trial demonstrated a statistically significant reduction in total daily insulin dose (estimated mean dose ratio: 0.89 [0.83; 0.96], p=0.002 ) Insulin dose BOOST INTENSIFY PREMIX I

12. SAS, safety analysis set; Comparisons: Estimates adjusted for multiple covariates. Severe hypoglycaemia occurred in 3.1% (7/224) of patients on IDegAsp (rate 0.09 episodes/PYE) compared with 7.2% (16/222) of patients on BIAsp 30 (rate 0.25 episodes/PYE), IDegAsp vs. BIAsp 30 rate ratio: 0.50 BIAsp 30, biphasic insulin aspart 30; BID, twice daily; ERR, estimated rate ratio; IDegAsp, insulin degludec/insulin aspart Fulcher et al. Diabetes Care 2014;37:2084–90 Confirmed hypoglycaemia Nocturnal confirmed hypoglycaemia Time (weeks) Time (weeks) 32% lower rate with IDegAsp ERR: 0.68 [0.52; 0.89], p =0.0049 73% lower rate with IDegAsp ERR: 0.27 [0.18; 0.41], p <0.0001 Hypoglycaemia BOOST INTENSIFY PREMIX I IDegAsp BID (n=224) BIAsp 30 BID (n=222)

13. Conclusions BIAsp 30, biphasic insulin aspart 30; IDegAsp, insulin degludec/insulin aspart; NS, not significant 1. Fulcher et al. Diabetes Care 2014;37:2084–90; 2. Kaneko et al. Diabetes Res Clin Pract 2015;107:139–47; 3. Christiansen et al. J Diabetes 2016;8:720–8. IDegAsp BIAsp 30 vs Significantly lower with IDegAsp 3 Non-inferiority confirmed 1,2 INTENSIFY PREMIX I 1 Total daily insulin dose Nocturnal-confirmed hypoglycaemia Confirmed hypoglycaemia HbA 1c Significantly lower (73%) with IDegAsp 1 Significantly lower (32%) with IDegAsp 1

14. Main Meal concept

15. Main Meal concept *Main meal is the meal with the highest carbohydrate content in the meal and not the portion size of the complete meal IDegAsp, insulin degludec/insulin aspart; OD, once daily; BID, twice daily. Mehta R, et al. Diabetes Obes Metab . 2020;10.1111/dom.14128. Main Meal Concept versus Adherence Strategy Main Meal concept - Most carbohydrate‐rich meal* OD BID 30 g carbohydrates 50 g carbohydrates 100 g carbohydrates 30 g carbohydrates 50 g carbohydrates 100 g carbohydrates 30 g carbohydrates 50 g carbohydrates 100 g carbohydrates BID With IDegAsp BID, the minimum interval between doses is determined by duration of action of the prandial component, and hence would need to be 4 hr.

16. IDegAsp, insulin degludec/insulin aspart Ryzodeg ® SmPC. October 2022. https://www.novo-pi.com/ryzodeg7030.pdf Device-IDegAsp is delivered in the prefilled pen Maximum dose/injection: 80 U Injection sites: Rotate frequently within the chosen area Storage: Opened pens – 2–8°C or room temperature for 4 weeks Unopened pens – 2–8°C until expiry date Needle: Do not re-use needles 70/30 – 3 ml prefilled pen

17. INITIATION SWITCHING BB, basal–bolus; BID, twice daily; IDegAsp, insulin degludec/insulin aspart; Ind. req., individual requirements; OAD, oral antidiabetic drug; OD, once daily; T2D, type 2 diabetes; U, units When using IDegAsp OD, changing to BID should be considered when higher dose is needed, e.g. to avoid hypoglycaemia Ryzodeg ® SmPC. October 2022 . https://www.novo-pi.com/ryzodeg7030.pdf Administer OD or BID with the main meal(s) Administer: alone or in combination with OADs or bolus insulin Recommended (total) daily starting dose 10 U Requires subsequent individual dosage adjustments Recommend using close glucose monitoring for first few weeks OD/BID 1:1 OD Basal/Premix IDegAsp BID/OD 1:1 ≥BID Basal/Premix IDegAsp IDegAsp Ind. req. BB Dosing of IDegAsp in T2D

18. Breakfast Lunch Dinner BASAL* 2 nd Main Meal 1 st Main Meal Mon - Sun Basal + Bolus Mon Wed Thu Fri Sat Sun Tue *Once-daily SMBG testing is recommended with current basal insulin analogues. 1-3 I nsulin degludec may be used with a simple monitoring and titration algorithm in patients with T2D: Once-weekly titration based on the average of 2 preceding FPG measurements 4,5 IDegAsp BID Mon Wed Thu Fri Sat Sun Tue KEY SMBG test strip IDegAsp Basal Bolus IDegAsp offers less complex dosing compared with basal–bolus BID, twice daily; FPG, fasting plasma glucose; IDegAsp, insulin degludec/insulin aspart; SMBG, self-measured blood glucose; T2D, type 2 diabetes 1.Starting patients on Levemir ® 2. Davies et al. Diabetes Care 2005;28:1282–8; 3. Titration guide for Lantus ® 4. Endocrinologic and Metabolic Drug Advisory Committee. Insulin degludec and insulin degludec/insulin aspart treatment to improve glycemic control in patients with diabetes mellitus: NDAs 203314 and 203313 briefing document. 5. Rodbard et al. Diabet Med 2013;30:1298–304 28 SMBGs/week 28 needles/week 6 SMBGs/week 14 needles/week

19. Management S witch to IDegAsp with a unit-for-unit dose conversion: IDegAsp 22 units BID 22 units in first meal of the day (around 11.00 am) 22  units in the evening (premeal dinner 6-8 pm)

20. 153 118 140 112 148 164 127 117 6/2 1 /2 7/2 8/2 5/2 2/2 3/2 4/2 126 117 148 139 124 138 149 146 153 136 90 108 99

21. Dose adjustments based on lowest of the 3 preceding FPG measurements FPG target should be individualised Do not increase dose if hypoglycaemia or symptoms suggestive of hypoglycaemia are present For twice-daily dosing, consider adjusting one dose at a time during weekly titration FPG, fasting plasma glucose; IDegAsp, insulin degludec/insulin aspart; T2D, type 2 diabetes 1. Gerety et al. Endocr Pract 2016;22:546–54; 2. Endocrinologic and Metabolic Drug Advisory Committee. Insulin degludec and insulin degludec/insulin aspart treatment to improve glycemic control in patients with diabetes mellitus: NDAs 203314 and 203313 briefing document. Published November 8, 2012 Suggested once-weekly titration schedule for IDegAsp in T2D At individualised target Below target Above target Below target At individualised target Above target +2 units Maintain dose -2 units

22. After 3 months, his HbA1c, FPG and postprandial blood glucose improved BW decreased with no further hypoglycaemic symptoms . Latest to IDegAsp dose was reduced to 0-18-16 units FPG (md/dl) HbA1C (%) Body Weight Aug 2022 164 9.0 61 Feb 2023 134 8.0 64 May 2023 156 7.8 65.7 Aug 2023 104 7.7 66.1 Nov 2023 145 8.7 66.8 Jan 2024 155 9.1 68.7 April 2024 109 7.3 65.9

23. Mrs. B ผู้ป่วยหญิงอายุ 78 ปี Long standing T2D ปี ,diagnosed diabetes at 55 yrs old, ongoing treatment at other hospital Current regimen : Lantus 4 units, glimepiride 6mg, vildagliptin 100mg per day, metformin 500mg per day. Referred due to Liver abscess, HbA1c 10.2%. During admission blood sugar was uncontrolled  Consult MED Multiple daily insulin injection (MDI) was started with regular human insulin (RI) for 3 times and Lantus once daily titrate per blood glucose monitoring Antibiotic+ drainage for Liver abscess  Clinical improved

24. Consult endocrine diurnal fluctuations of blood sugar + discharge planning BMI 21.09 kg/m 2 Medical problems Liver abscess : improved T2DM, long standing + difficult to control ( C-peptide 0.62ng/mL suggesting insulin deficiency) Hypertension H yperlipidemia Family meeting : Bio aspect : long standing T2D, insulin deficiency, OHA not enough Psycho & Social aspect : Refuse to change in diet อยู่คนเดียวเป็นส่วนใหญ่ ลูกกลับมาช่วงเย็น ทานข้าวไม่เป็นเวลา เน้นทานขนมบ่อยๆ ไม่สะดวกฉีดยา Basal bolus ไม่สะดวก SMBG

25. Danny Sugimoto, Juan Frias, Didier Gouet , Róbert Takács , Ting Jia , Petra Örsy , Stephen Bain Effects of insulin degludec/liraglutide (IDegLira) in patients with poorly controlled type 2 diabetes (T2D) with HbA 1c >9% : analyses from the DUAL program Sugimoto D et a l. Presented at the 78 th Scientific Sessions, American Diabetes Association, 22-26 June 2018, Orlando , FL, USA. Poster 1092-P.

26. Analyses from the following DUAL program *Metformin, SU, pioglitazone were the OADS that were used in both the treatment arms, DPP4i and glinides were discontinued at randomisation in both the arms. 1 patient in the IDegLira arm used α-GI . †GLP-1RA discontinued. ‡SU was discontinued at randomisation . α-GI, alpha-glucosidase inhibitor; ext., extension; GLP-1 RA, glucagon-like peptide-1 receptor agonist; IAsp , insulin aspart ; IGlar U100, insulin glargine U100; Met, metformin; OAD, oral anti-diabetic drug; Pio, pioglitazone; SGLT2i, sodium-glucose co-transporter 2 inhibitor; SU, sulphonylurea ; 1WT, once- weekly titration; 2WT, twice-weekly titration www.clinicaltrials.gov. Last accessed May 2019 Uncontrolled on basal insulin Uncontrolled on OADs DUAL II Basal insulin (20-40 U) + Met ± SU ‡ IDegLira Degludec DUAL V IGlar U100 IDegLira IGlar U100 (20-50 U) + Met DUAL I & ext. Met ± pio Degludec IDegLira Liraglutide DUAL VII IGlar U100+IAsp IDegLira IGlar U100 (20-50 U) + Met

27. Effects of IDegLira in patients with poorly controlled T2D with HbA 1c >9%: analyses from the DUAL program HbA 1c at baseline and EOT End of trial data based on full analysis set for all trials except DUAL VII (observed data; N-numbers for week 26). Arrows in graph indicate direction of change in HbA 1c from baseline to end of trial. Δ HbA 1c , change in HbA 1c from baseline to end of trial; EOT, end of trial; HbA 1c , glycated hemoglobin; IAsp, insulin aspart; IDegLira, insulin degludec/liraglutide; IGlar U100, insulin glargine 100 units/mL; Lira, liraglutide; T2D, type 2 diabetes. HbA 1c (%) DUAL I DUAL II DUAL V DUAL VII 9.7 9.5 9.6 6.8 7.6 9.5 9.6 7.7 8.3 6.9 7.8 9.6 9.6 9.4 7.1 7.3 9.4 7.2 IDegLira Degludec Lira IDegLira Degludec IDegLira IGlar U100 IDegLira IGlar U100 +IAsp N= 190 107 86 62 84 71 52 34 41 Δ HbA 1c (%) –2.7 –2.0 –1.9 –2.5 –1.2 –2.6 –1.8 –2.3 –2.2 EOT dose 38 ds 53 u 1.8 mg 45 ds 45 u 41 ds 66 u 40.4 ds 84.1 u Sugimoto D et a l. Presented at the 78 th Scientific Sessions, American Diabetes Association, 22-26 June 2018, Orlando , FL, USA. Poster 1092-P.

28. DUAL V BMI, body mass index; IGlar U100, insulin glargine U100; PG, plasma glucose; T2D, type 2 diabetes ; U, units Lingvay et al. JAMA 2016;315:898-907 Inclusion criteria Type 2 diabetes Metformin + IGlar U100 (20–50 units) HbA 1c 7–10% Age ≥18 years BMI ≤40 kg/m 2 Subjects with T2D uncontrolled on basal insulin (N=557) IDegLira Starting dose: 16 dose steps Maximum dose: 50 dose steps IGlar U100 Starting dose: Pre-trial dose Maximum dose: None Screening Randomisation 1:1 (open label) End of treatment Follow-up Titration algorithm: IDegLira and IGlar U100 mmol/L <4.0 4.0–5.0 >5.0 dose steps or U −2 +2 Mean fasting PG Dose change IGlar U100 + metformin (n=279) IDegLira + metformin (n=278) 27 –2 26 Week Study design

29. Characteristic IDegLira IGlar U100 Full analysis set, n 278 279 Female/Male, % 48.6/51.4 50.9/49.1 Age, years 58.4 (9.8 ) 59.1 ( 9.3) Weight, kg 88.3 ( ±17.5) 87.3 ( ±15.8) BMI, kg/m 2 31.7 ( 4.4) 31.7 ( 4.5) Duration of diabetes, years 11.6 ( 7.4) 11.3 ( 6.6) HbA 1c , % [HbA 1c , mmol/mol a ] 8.4 ( 0.9) [68.0 ( 9.8) ] 8.2 ( 0.9) [66.6 ( 9.6) ] FPG, mmol/L [mg/dL a ] 8.9 ( 2.6) [160.5 ( 47.5) ] 8.9 ( 2.9) [159.8 ( 52.0) ] Pre-trial insulin dose 31 (10) 32 (10) Baseline characteristics DUAL V Values are mean (SD) unless otherwise stated; aCalculated , not measured BMI, body mass index; FPG, fasting plasma glucose; IGlar U100, insulin glargine U100 Lingvay et al. JAMA 2016;315:898-907 IDegLira IGlar U100

30. Post hoc analysis of HbA 1c reductions at weeks 4, 8 and 12 DUAL V Mean observed values with error bars (95% CI) based on FAS and last observation carried forward-imputed data Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed last observation carried forward ---ADA/EASD HbA1c target <7.0%; AACE HbA1c target ≤6.5% AACE, American Association of Clinical Endocrinologists; ADA, American Diabetes Association; ANCOVA, analysis of covariance; EASD, European Association for the Study of Diabetes; EOT, end of trial; ETD, estimated treatment difference; FAS, full analysis set; IGlar U100, insulin glargine U100 Lingvay et al. JAMA 2016;315:898-907; Lingvay et al. Diabetes 2016;65 (Suppl.1):A63 (Abstract 239-OR) presented at ADA 76th Scientific Sessions IDegLira (n=278) IGlar U100 (n=279) HbA 1c over time 7.1% 6.6% HbA 1c (%) Time (weeks) EOT ETD ∆ Hb A 1c –1.81% –1.13% 0.0 –0.59% [–0.74; –0.45] 95% CI , for superiority p <0.001 –0.3% –0.7% ETD: –0.40% [–0.49;–0.30] 95% CI , p <0.0001 –0.6% ETD: –0.62% [–0.74; –0.50] 95% CI , p <0.0001 –1.3% –0.9% –1.7% ETD: –0.75% [–0.88; –0.62] 95% CI , P <0.0001 Post hoc analysis

31. DUAL V *p<0.001 Data are mean from observed values based on FAS with LOCF; p-values from ANCOVA analysis ANCOVA, analysis of covariance; EOT, end of trial; FAS, full analysis set; Lira, liraglutide; IGlar U100, insulin glargine U100; LOCF, last observation carried forward Sorli et al. Diabetes 2016;65(Suppl. 1):A238 (Abstract 925-P) Change in HbA 1c by baseline HbA 1c category 7.1 * 0.0 ≤7.5 >7.5–≤8.5 >8.5 Total trial population Baseline HbA 1c category HbA 1c (%) 278 279 N 8.4 6.6 8.2 9.2 7.5 113 97 9.3 6.8 * 102 118 8.1 * 63 64 7.2 6.2 7.1 6.7 * 6.5 7.1 8.1 IDegLira m ean baseline HbA 1c IDegLira m ean EOT HbA 1c IGlar U100 m ean baseline HbA 1c IGlar U100 m ean EOT HbA 1c

32. DUAL V Mean observed values with error bars (95% CI) based on FAS and LOCF imputed data Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF ANCOVA, analysis of covariance; CI, confidence interval; ETD, estimated treatment difference; FAS, full analysis set; IGlar U100, insulin glargine U100; LOCF, last observation carried forward Lingvay et al. JAMA 2016;315:898-907 Superiority confirmed ETD: – 3.20 kg [-3.77; -2.64] 95% CI , p <0.001 Change in body weight (kg) +1.8 kg –1.4 kg Change in body weight over time IDegLira (n=278) IGlar U100 (n=279) Time (weeks)

33. DUAL V *There was no maximum dose for IGlar U100 Mean observed values with error bars (95% CI) based on SAS and LOCF imputed data. T reatment difference is estimated from an ANCOVA analysis ANCOVA, analysis of covariance; CI, confidence interval; EOT, end of trial; ETD, estimated treatment difference; IGlar U100, insulin glargine U100; LOCF, last observation carried forward; SAS, safety analysis set; U, units Lingvay et al. JAMA 2016;315:898-907 Daily insulin dose Dose (units) 41 U 66 U ETD: –25.47 U [–28.90 ; –22.05] 95% CI , p <0.001 Time (weeks) At EOT approximately 40% of subjects on IDegLira received the maximum 50 dose steps, of which 68% achieved HbA 1c <7% IDegLira (n=278) IGlar U100 (n=279)

34. DUAL V Mean cumulative function based on SAS Treatment ratio is estimated from a negative binomial model based on FAS CI, confidence interval; ERR, estimated rate ratio; FAS, full analysis set; IGlar U100, insulin glargine U100; SAS, safety analysis set Lingvay et al. JAMA 2016;315:898-907 Number of episodes per subject IDegLira IGlar U100 HbA 1c at week 26 6.6 % 7.1 % Time (weeks) Superiority confirmed ERR: 0.43 [0.30; 0.61] 95% CI, p <0.001 Confirmed hypoglycaemia IDegLira (n=278) IGlar U100 (n=279)

35. DUAL V CI, confidence interval; EOT, end of trial; ETD, estimated treatment difference; ERR, estimated rate ratio; IGlar U100, insulin glargine U100 Lingvay et al. JAMA 2016;315:898-907 –0.8 2.0 Change in HbA 1c (%) Change in weight (kg) Hypoglycaemia rate (events/patient-year) IDegLira IDegLira IDegLira IGlar U100 up-titration HbA 1c Weight Confirmed hypoglycaemia Baseline HbA 1c 8.4% 8.2% EOT HbA 1c 6.6% 7.1% ETD: -0.59 [-0.74; -0.45] 95% CI, p <0.001 for superiority ERR: 0.43 [0.30; 0.61] 95% CI, p <0.001 for superiority ETD: -3.20 [-3.77; -2.64] 95% CI, p <0.001 for superiority Key clinical findings IGlar U100 up-titration IGlar U100 up-titration

36. DUAL V IGlar U100, insulin glargine U100 Lingvay et al. JAMA 2016;315:898-907 Conclusions Treatment with IDegLira was superior to IGlar U100 with regard to: change in HbA 1c change in body weight rate of confirmed hypoglycaemic events Significantly more subjects reached the HbA 1c targets and composite endpoints with IDegLira versus IGlar U100 Overall and serious adverse event rates were comparable in both arms

37. Patient is on any insulin regimen containing a basal component but A1c is still above 7%* consider start IDegLira at 16 dose steps Then titrate every 3 days until patient achieve target At individualised target Below target Above target Maintain dose -2 dose steps +2 dose steps FPG< 80 mg/dl FPG 80-130 mg/dl FPG> 130mg/dl * American Diabetes Association. Diabetes Care 2022 Jan Therapy with basal insulin should be discontinued prior to initiation of IDegLira Transfer from any insulin regimen containing a basal component 16 dose steps Intensify for the best outcome

38. Progress of blood glucose & treatment Date เช้า (mg/dl) กลางวัน (mg/dl) เย็น (mg/dl) ก่อนนอน (mg/dl) RI (unit) Lantus (unit) Xultophy (dose steps) Jan 16 172 179 277 244 3-3-5 4 23 118 213 234 220 2-4-4 6 29 111 203 176 215 2-4-3 7 30 66 138 178 239 0-2-3 8 31 101 168 140 214 2-3-2 8 Feb 1 112 204 197 228 10 4 99 157 201 239 10 8 124 177 10 11 108 170 10

39. Home medications Xultophy 10 dose steps Zanidip 10 mg/day Off Lantus/ glimepiride/vildagliptin/metformin Hold statin due to hepatits

40. Progress of blood glucose & treatment Date เช้า (mg/dl) กลางวัน (mg/dl) เย็น (mg/dl) ก่อนนอน (mg/dl) Xultophy (dose steps) Feb 16 145 12 25 135 14 Mar 1 125 14 7 119 14 14 124 14

41. FPG (md/dl) HbA1C (%) Body Weight /BMI Dec 2023 149 8.0 54.5 /22.11 Jan 2024 187 10.2 52.0/21.09 March 2024 104 8.9 51.7/20.97 Xultophy 14 doses step June 2024 112 7.7 51.4/20.8 Xultophy 16 doses step Current medications : Xultophy 16 doses steps hs Zanidip 10 mg/day, Atorvastatin 10 mg/day

42. Miss. C ผู้ป่วยหญิง อายุ 40 ปี อาชีพ ธุรกิจส่วนตัว ภูมิลำเนา กรุงเทพ OPD visit 20/11/2566 CC: ปรึกษาเรื่องเบาหวาน PI : Known case T2D diagnosed ปี 2560 presented ด้วย hyperglycemic symptoms admitted ที่ รพ เอกชน ใน จันทบุรี ช่วงแรกได้ยาฉีดและยารับประทาน แต่ฉีดยาแล้วเวียนศีรษะ ใจสั่น ไม่สุขสบายจึงหยุดยาฉีด เหลือแต่ยาเม็ด ไม่ทราบชนิด ย้ายมาอยู่เชียงราย 4 ปี รักษาที่ รพ เอกชน ปรับยา ล่าสุด Diamicron MR (60) 1 tab once daily Forxiga (10) 1 tab once daily Trajenta 1 tab once daily Glucophage XR (1000) 1 tab once daily

43. Miss. C ตรวจ lab ล่าสุด 24/10/2566 HbA1C 9.0 % ALT 97 AST 60 ค่าไต ไม่ได้ตรวจ พยายาม คุมอาหารแล้ว น้ำหนักลดเรื่อย ๆ (baseline ต้นปี 70 กก ) แต่ เจาะน้ำตาลที่บ้านก่อนอาหารเช้า ใกล้ๆ 200 ตลอด อ่อนเพลีย รู้สึกกังวล จึงมาปรึกษา Family history : ลูกคนเดียว ปู่ย่า ตายาย เป็นเบาหวาน Social history : ไม่ดื่มเหล้า ไม่สูบบุหรี่ Personal history : ทานอาหารเสริม Collagen/Glutathione PE: overweight BMI 25.31 kg/m 2

44. Laboratory profile BW FPG (md/dl) HbA1C (%) ALT AST GGT Cr Lipid Uric Urine albumin 24 Oct 2023 9.0 97 60 20 Nov 2023 63.2 157 11.2 128 103 48 0.53 TG 218 LDL 114 HDL 55 5.8 neg Young onset T2D, uncontrolled Overweight

45. ADA2023: Pharmacologic approaches American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment:Standards of Medical Care in Diabetes — 2023. Diabetes Care 2023;46(Suppl. 1)

46. Patient who did not receive injectable consider insulin as the first injectable, when A1C levels >9* or blood glucose levels ≥300 mg/dL start IDegLira at 10 dose steps Then titrate every 3 days until patient achieve target At individualised target Below target Above target Maintain dose -2 dose steps +2 dose steps FPG<80 mg/dl FPG 80-130 mg/dl FPG> 130mg/dl * American Diabetes Association. Diabetes Care 2022 Jan When IDegLira is added to SU therapy, a reduction in the dose of SU should be considered Add-on to OADs 10 dose steps Fix faster with fixed ratio combination

47. DUAL VIII * Dipeptidyl peptidase-4 (DPP-4) inhibitors and glinides discontinued at randomisation; †During the last 12 weeks of exposure; ‡Patients meeting criteria for treatment intensification discontinued the study drug. BG, blood glucose; BMI, body mass index; IDegLira , insulin degludec /liraglutide; OAD, oral antidiabetic drug; OD, once daily; T2D, type 2 diabetes Aroda VR, et al. Lancet Diabetes Endocrinol. 2019;7(8):596-605. Study design Open-label Treat-to-target (FPG 72–90 mg/dL) IGlar U100 OD + OAD(s) Duration 104 weeks Patients with T2D n=1012 (1:1) Week 104 End of Treatment visit IDegLira OD + OAD(s) Inclusion criteria Age ≥18 years A 1 % Insulin naїve OAD(s) HbA 1c 7.0–11.0% BMI ≥20 kg/m 2 Study drug was discontinued once a patient met the primary endpoint Week 26 n=481 (95.1%) Trial completers n=484 (95.7%) Trial completers N=506 N=506 V1 V2 Randomization Week 0 1 2 4 12 26 38 Weeks V12 V11 V10 V8 V7 V6 V4 V5 V9 P3 52 64 78 90 End of treatment Week 104 V13 V14 P15 104

48. DUAL VIII: Primary outcome – time to meeting criteria for need for treatment intensification† †HbA 1c ≥7% at two consecutive visits. Full analysis set. Treatment policy strategy. Kaplan–Meier curves. Test for no treatment difference is based on a stratified log-rank test (p-value: <0.0001) where treatment, baseline HbA 1c group and pre-trial OAD treatment group are included as strata in the model. Patients discontinuing treatment contribute to analyses as needing treatment intensification from time of discontinuation IDegLira , insulin degludec /liraglutide; IGlar U100, insulin glargine 100 units/mL; n, number of patients Aroda VR, et al. Lancet Diabetes Endocrinol. 2019;7(8):596-605 IDegLira (n=506) IGlar U100 (n=506) Time since randomization (weeks) Median time to need for treatment intensification was >2 years with IDegLira Median time to need for treatment intensification was ~1 year with IGlar U100 66.2% patients with IGlar U100 37.4% patients with IDegLira Met criteria for treatment intensification (% patients): H R -0.45

49. DUAL VIII: Insulin dose (U) over time Safety analysis set. Observed data. At week 104, 90 patients (27.36%) had max dose of IDegLira. 75.3% were at target <7%. Mean (symbol) and mean +/- standard error to the mean (error bars). Number of patients contributing to the data points appears in the bottom panel. IDegLira, insulin degludec/liraglutide; IGlar U100, insulin glargine U100; U, units Aroda VR, et al. Lancet Diabetes Endocrinol. 2019;7(8):596-605 IDegLira (n): 501 496 482 476 411 398 373 354 347 329 IGlar U100(n): 498 494 470 449 298 282 250 223 210 186 52 U 37 U IDegLira (n=506) IGlar U100 (n=504) Time since randomization (weeks) ETD [95% CI] LSMeans -14.94 [-17.41; -12.47] 95% CI p <0.0001

50. DUAL VIII: B ody weight over time Full analysis set. Trial product strategy. LSMeans from the MMRM model, error bars +/- standard error (of estimated LSMeans ) CI, confidence interval; ETD, estimated treatment difference; IDegLira , insulin degludec /liraglutide; IGlar U100, insulin glargine U100; LS, least squares; MMRM, mixed model repeated measurement Aroda VR, et al. Lancet Diabetes Endocrinol. 2019;7(8):596-605 Time since randomization (weeks) 3.39 kg 1.69 kg 4 26 52 78 104 12 ETD [95% CI] ∆Body weight (kg) LSMeans -1.70 [-2.47; -0.93] 95% CI p <0.0001 IDegLira (n=506) IGlar U100 (n=506) LSMean change in body weight (kg) IDegLira (N): 506 497 489 481 403 360 335 IGlar (N): 506 495 482 466 285 227 190

51. DUAL VIII: Cumulative severe or BG-confirmed symptomatic hypoglycemic episodes over time Safety analysis set. Observed data. ERR is estimated based on the trial product strategy (based on the FAS) Severe or BG confirmed symptomatic: an episode that is severe according to the ADA classification or BG confirmed by a plasma glucose value < 3.1 mmol/L (56 mg/L) with symptoms consistent with hypoglycemia. ADA: American Diabetes association; BG, Blood glucose; CI, confidence interval; conf., confirmed; ERR, estimated rate ratio; IDegLira , insulin degludec /liraglutide; IGlar U100, insulin glargine U100; symp ., symptomatic Aroda VR, et al. Lancet Diabetes Endocrinol. 2019;7(8):596-605 IDegLira (n=506) IGlar U100 (n=504) ERR: 0.44 [0.33; 0.60] 95% CI p< 0.0001 56% Rate reduction

52. Management Add ideg -Lira 10 dose steps Add atorvastatin 20 mg Off trajenta ลด diamicron to 0.5 tab once daily Continue Forxiga /Glucophage งด อาหารเสริมทุกชนิด นัด US liver

53. 167 138 164 10/12 22 /11 17/12 20/12 5/12 26/11 3/12 8/12 126 117 124 146 153 178 135 Xultophy 10 Xultophy 12 Xultophy 14

54. BW/BMI FPG (md/dl) HbA1C (%) ALT AST GGT Cr Lipid Uric Urine albumin 24 Oct 2023 9.0 97 60 20 Nov Xultophy 10 dose step 63.2/25.3 157 11.2 128 103 48 0.53 TG 218 LDL 114 HDL 55 9.28 neg 15 Jan 24 Xultophy 16 dose step ลด Diamicron 0.25 tab 60.0/24.0 125 9.1 80 62 37 TG 156 LDL 98 08 Apr 24 Xultophy 20 dose step Off diamicron 59.9/23.9 107 7.2 42 35 35 0.67 TG 118 LDL 77 7.2 17 Jun 24 Xultophy 20 dose step 60.0/ 24.0 112 6.8 22 30 Progress of blood glucose & treatment

55. The DUAL clinical programme *Mean change in HbA 1c from baseline to end of trial; †Severe or BG-confirmed (<3.1 mmol /L) symptomatic hypoglycaemia; 1WT, once-weekly titration; 2WT, twice-weekly titration; BG, blood glucose; GLP-1, glucagon-like peptide-1; OAD, oral anti-diabetic drug 1. Gough S et al. Diabetes Obes Metab 2015;17:965–73; 2. Buse J et al. Diabetes Care 2014;37:2926–33; 3. Linjawi et al. Diabetes Ther 2017;8:101-114; 4. Rodbard HW et al. Diabet Med . 2017;34(2):189-196; 5. Lingvay et al. JAMA 2016;315:898-907; 6. Harris et al. Diabetes Obes Metab . 2017;19(6):858-865; 7. Billings et al. Diabetes Care 2018;41(5):1009-1016; 8. Philis-Tsimikas et al. Diabetes Obes Metab . 2019. 21(6):1399-1408 9. # Sesti et al. Diabetes Obes Metab . 2020;22(5):873-878 End-of-treatment HbA 1c (%) Add to OAD(s) Basal insulin switch GLP-1 switch Add to OAD(s) Basal insulin switch GLP-1 switch Hypoglycaemia (events/subject-year) 6.4 8.3 6.0 8.1 6.4 7.9 8.2 6.1 6.4 7.8 6.6 8.4 8.7 6.9 8.2 6.7 8.2 6.3 0.2 1.8 3.5 0.8 1.5 2.2 2.8 1.1 0.4 DUAL I ext. DUAL IV DUAL IX DUAL III DUAL II DUAL V DUAL VII 1WT 2WT Add to OAD(s) Basal insulin switch GLP-1 switch Change in body weight (kg) –0.4 2.0 –2.0 –1.0 –2.7 –1.4 –0.9 DUAL I ext. DUAL IV DUAL II DUAL V DUAL VII DUAL III DUAL IX DUAL I ext. DUAL IV DUAL II DUAL V DUAL VII † DUAL III DUAL IX † DUAL VI 1WT 2WT DUAL VI † 1WT 2WT DUAL VI -1.8 * -1.5 * -2.0 * -2.0 * -1.9 * -1.3 * -1.9 * -1.8 * -1.5 * DUAL VIII # 8.4 6.4 -1.99* 0.5 0.5 DUAL VIII DUAL VIII 0.58