Linagliptin Nephrologist perspective .pptx

use of linagliptin in ckd

1. Patient case Improving glycemic management in T2DM patient with CKD This patient case is hypothetical. Any data mentioned herein may be abbreviated and not exact

2. Confidential. For internal use only.

3. Confidential. For internal use only.

4. 55 years old female Working as a teacher . Complains of fatigue, tingling of toes and fingers, sleep problems Recurrent h/o uro - genital tract infection + ve T2D for 7 years Family history of CVD – not known B/L pedal edema + Meet Ms. Carol 4 Hypothetical patient case T2D, type 2 diabetes

5. Hypothetical patient case Her current medications 5 Metformin 1000 mg bid Atorvastatin 20 mg OD Telmisartan 40 mg OD

6. Hypothetical patient case ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; HbA 1c , glycated haemoglobin; LDL-C, low-density lipoprotein cholesterol; UACR, urine albumin-to-creatinine ratio Assessments of Ms. Carol 6 HbA 1c 7.8% eGFR 30 ml/min/1.73 m 2 UACR 130 mg/mmol Fasting glucose 135 mg/dl, PPBS- 210 mg/dl ECG Normal Blood pressure 106/70 mmHg LDL-C: 110 mg/dl

7. Hypothetical patient case HbA 1c , glycated haemoglobin Review of Ms. Carol’s treatment regimen 7 What is your main concern when considering your next steps? The need for HbA 1c reduction Kidney function decline Dose modification of the medication Recurrent uro - genital tract infection

8. Hypothetical case Review of Ms. Carol’s treatment regimen Why might Linagliptin be a good option for her ? ? 8

9. eGFR, estimated glomerular filtration rate Premaratne E et al . Diabetologia 2005;48:2486 Kidney function decline is inevitable with age 9 Age-stratified eGFR in 662 patients with T2D

10. Linagliptin is the globally available DPP-4 inhibitor with the lowest kidney excretion rate *Normal: eGFR ≥90 ml/min/1.73 m 2 ; † Mild: eGFR 60–<90 ml/min/1.73 m 2 ; ‡ Moderate: eGFR 30–<60 ml/min/1.73 m 2 ; § Severe: eGFR <30 ml/min/1.73 m 2 while not receiving chronic dialysis. 1,2 HbA1c, glycated haemoglobin; RCT, randomised controlled trial 1. Groop PH et al. Diabetes Obes Metab 2014;16:560; 2. McGill JB et al. Diabetes Care 2013;36:237; 3. Trajenta ® (linagliptin) India Pack Insert. Aug 2021 n 870 620 68 68 Mean baseline HbA 1c (%) 8.1 8.0 8.2 8.2 The efficacy of linagliptin remains consistent across all stages of kidney function 10 Adjusted mean HbA1c change from baseline versus placebo by degree of kidney function Mild kidney impairment † Normal*  Moderate kidney impairment ‡ Severe kidney impairment § Pooled analysis of three phase III trials 1 at 24 weeks RCT 2,3 at 52 weeks Adjusted mean change in HbA 1c (%) Linagliptin 5 mg qd -0.63 p <0.0001 -0.67 p <0.0001 -0.53 p <0.01 -0.72 p <0.0001   

11. *Adjusted for age, race, renal function, and pre-index HbA1c; ⴕ ANOVA; ‡ p -value across age or eGFR categories ANOVA, analysis of variance; eGFR, estimated glomerular filtration rate; HbA1c, glycated haemoglobin; LS, least square Hoogwerf BJ et al. Diabetes Ther 2020;11:1527 Linagliptin demonstrated glucose-lowering effectiveness across age and kidney function in a real-world setting 11 Change in HbA1c from a retrospective cohort study using the Optum database between July 2011 and March 2017 (N=11,001) n Baseline HbA1c Unadjusted change in HbA1c Adjusted LS mean change in HbA1c* Percentage of persons reaching HbA1c 7% (53 mmol/mol) mmol/mol mean (SD) % (SD) mmol/mol mean (SD) % (SD) mmol/mol mean % All 11,001 66 (17.7) 8.17 (1.62) -5.6 (16.0) -0.51 (1.46) 35.7 Age, years 40–54 2325 70 (20.2) 8.62 (1.85) -7.1 (18.0) -0.65 (1.65) -3.3 -0.30 30.3 55–64 3332 67 (18.3) 8.30 (1.67) -6.4 (16.8) -0.59 (1.54) -4.5 -0.41 35.6 65–74 3077 64 (15.8) 7.96 (1.45) -4.7 (14.9) -0.43 (1.36) -4.5 -0.41 37.9 ≥75 2267 62 (14.8) 7.80 (1.35) -3.9 (13.2) -0.36 (1.21) -4.6 -0.42 38.6 p -value ⴕ‡ <0.001 <0.001 ≤0.004 <0.001 eGFR, ml/min/1.73 m 2 <30 679 60 (16.4) 7.64 (1.50) -2.4 (16.0) -0.22 (1.46) -3.8 -0.35 46.7 30–44 1646 63 (16.7) 7.87 (1.53) -3.6 (14.6) -0.33 (1.34) -3.8 -0.35 38.9 45–59 1727 64 (16.9) 7.98 (1.55) -5.1 (15.5) -0.47 (1.42) -4.8 -0.44 40.2 60–89 3256 66 (17.1) 8.18 (1.56) -6.0 (15.7) -0.55 (1.44) -4.8 -0.44 35.7 ≥90 2603 70 (19.0) 8.57 (1.74) -7.7 (17.3) -0.70 (1.58) -4.7 -0.43 30.1 p -value ‡ <0.001 <0.001 0.010 <0.001

12. Mixed model for repeated measures analysis was performed Yamamoto F et al. Diabetes Ther 2020;11:523 Linagliptin monotherapy showed sustained HbA1c improvements regardless of kidney function in a real-world setting 12 Adjusted mean HbA1c over time by eGFR group from baseline to EOT in a 3-year Japanese post-marketing surveillance study (N=2130)

13. Pooled analysis of three 24-week studies of linagliptin as monotherapy or as an add-on to metformin ± SU Frequency of hypoglycaemia with linagliptin remains low in the presence of kidney impairment 13 * Classified according to the following definitions: asymptomatic hypoglycaemia: event not accompanied by typical symptoms of hypoglycaemia but with a measured plasma glucose concentration of ≤3.9 mmol/l (≤70 mg/dl); documented symptomatic hypoglycaemia with a measured plasma glucose concentration of ≥3.0 mmol/l (≥54 mg/dl) and ≤3.9 mmol/l (≤70 mg/dl), accompanied by typical symptoms of hypoglycaemia; documented symptomatic hypoglycaemia with a measured plasma glucose concentration of < 3.0 mmol/l ( < 54 mg/dl), accompanied by typical symptoms of hypoglycaemia but no need for external assistance. † Severe hypoglycaemic episode: event requiring assistance of another person to administer carbohydrate, glucagon or other resuscitative actions. SU, sulphonylurea Groop PH et al . Diabetes Obes Metab 2014;16:560 Proportion of patients, % Any investigator-reported hypoglycaemia* Severe hypoglycaemia †

14. Comparison of studies should be interpreted with caution due to differences in study design, populations and methodology. *Kidney safety refers to kidney safety investigated in a long-term randomised clinical trial with pre-specified, statistically powered, confirmatory tested for superiority, and adjudicated ‘hard’ kidney outcomes (e.g., composite of death due to kidney disease, progression to sustained ESKD or sustained eGFR decrease by ≥40%) in a population enriched for CKD (by specific CKD enrolment criteria). CKD, chronic kidney disease; CVOT, cardiovascular outcomes trial; DPP-4i, dipeptidyl peptidase-4 inhibitor; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease 1. Scirica BM et al. N Engl J Med 2013;369:1317; 2. White WB et al. N Engl J Med 2013;369:1327; 3. Green JB et al. N Engl J Med 2015;373:232; 4. Rosenstock J et al. JAMA 2019;321:69 CARMELINA is the only DPP-4i CVOT to assess ‘hard’ kidney outcomes* as a prespecified, statistically powered endpoint 14 Study drug Placebo HR (95% CI) HR (95% CI) p -value n with event/N analysed (%) SAVOR-TIMI 53 1 (saxagliptin) – – 229/7266 (3.1) – – EXAMINE 2 (alogliptin) – – 79/2679 (2.9) – – TECOS 3 (sitagliptin) – – 228/8212 (2.8) – – CARMELINA 4 (linagliptin) 327/3494 (9.4) 306/3485 (8.8) 420/3485 (12.1) 1.04 (0.89, 1.22) 0.62 ? Favours study drug Favours placebo

15. Linagliptin is not indicated for the treatment of albuminuria . Because both the parallel confirmatory tests for superiority of the primary outcome (3P-MACE) and the key secondary outcome (composite kidney outcome) in the overall population were not significant ( p =0.74 and p =0.62 for superiority, respectively), all subsequent analyses and outcomes are considered exploratory. Treated set, Kaplan–Meier estimate. HR and 95% CI based on Cox regression model with terms for treatment group ( p =0.0034) and region ( p <0.0001). *Change from normo- to micro- or macroalbuminuria, or from micro- to macroalbuminuria; † Two-sided 3P‑MACE, 3-point major adverse cardiovascular events; PY, patient-years Rosenstock J et al. JAMA 2019;321:69 Linagliptin was associated with a significant reduction in albuminuria progression 15 Time to first occurrence of albuminuria progression* HR 0.86 (95% CI 0.78, 0.95 ) Years Patients with event (%) 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 20 80 60 40 Placebo (n) 2129 1972 1434 1139 667 430 200 35 Linagliptin (n) 2162 2004 1554 1263 756 487 213 39 819 patients 763 patients p= 0.003 † Placebo Linagliptin Rate: 21.36/100 PY Rate: 24.54/100 PY No. at risk

16. * Results for 3P-MACE and HHF do not indicate that NRP is an effect modifier, all interaction p-values > 0.05. 1. Wanner C, et al. Clinical Kidney Journal, sfaa225, https://doi.org/10.1093/ckj/sfaa225. CI: confidence interval; CV: cardiovascular; HHF: hospitalization for heart failure; HR: Hazard Ratio; NRP: nephrotic-range proteinuria. Regardless of NRP-status, no significant difference between linagliptin vs placebo with respect to CV endpoints, consistent with the overall population* 1 (CARMELINA) 16 Linagliptin (N=3494) Placebo (N=3485) HR (95% CI) HR (95% CI) p-value n (%) Rate/100PY n (%) Rate/100PY 3P-MACE All Patients 434 (12.4) 4.69 420 (12.1) 5.63 1.02 (0.89, 1.17) 0.74 NRP (n=646) 79 (24.9) 12.49 69 (21.0) 10.31 1.21 (0.88, 1.67) 0.28 No NRP (n=6330) 354 (11.1) 5.14 350 (11.1) 5.16 1.00 (0.86, 1.15) HHF All Patients 209 (6.0) 2.77 226 (6.5) 3.04 0.90 (0.74, 1.08) 0.26 NRP (n=646) 40 (12.6) 6.41 37 (11.2) 5.70 1.31 (0.84, 2.06) 0.09 No NRP (n=6330) 169 (5.3) 2.45 188 (6.0) 2.78 0.86 (0.69, 1.05) Favors linagliptin Favors placebo Note: additional subgroup analyses shown in publication Bold p values are for overall analysis (i.e., all patients), while non-bold p values are for interaction “ Overall, regardless of NRP-status, there was no difference between linagliptin vs placebo with respect to 3P-MACE … or hospitalization for heart failure; the corresponding results do not indicate that NRP is an effect modifier, all interaction p-values > 0.05 .” 1

17. * Difference in HbA 1c over the full study duration based on least square means favored linagliptin vs placebo (-0.36 [95% CI; -0.42, -0.29] %), not indicating a different effect by NRP (-0.41 [95% CI; -0.63, -0.19]) and non-NRP (-0.35 [95% CI; -0.42, -0.29]). † Incidence rate and IRR (95% CI) of hypoglycaemic adverse events by severity; severe hypoglycaemia = requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative action. 1. Wanner C, et al. Clinical Kidney Journal, sfaa225, https://doi.org/10.1093/ckj/sfaa225. CI: confidence interval; IRR: incidence rate ratio; NRP: nephrotic-range proteinuria. Regardless of NRP-status, linagliptin significantly reduces HbA 1c without causing an increase in hypoglycaemia, compared to placebo 1 (CARMELINA) 17 Reduction of HbA 1C by linagliptin * IRR: 0.99 (0.76, 1.29) IRR: 0.87 (0.62, 1.23) IRR: 2.03 (0.95, 4.35) IRR: 0.98 (0.90, 1.08) IRR: 0.95 (0.84, 1.07) IRR: 0.85 (0.64, 1.14) Hypoglycaemia in Patients with NRP at Baseline † Hypoglycaemia in Patients without NRP at Baseline †

18. *Including metabolites and unchanged drug; excretion after single-dose administration of 14 C-labelled drug DPP-4, dipeptidyl peptidase-4 1. Trajenta ® (linagliptin) India Pack Insert. Aug 2021 ; 2. Merck. Januvia ® (sitagliptin) Prescribing Information. 2021; 3. Novartis Galvus ® (vildagliptin) summary of product characteristics . 2020; 4. AstraZeneca. Onglyza ® (saxagliptin) Prescribing Information. 2021; 5. Takeda. Nesina ® (alogliptin) Prescribing Information. 2021 Linagliptin is the globally available DPP-4 inhibitor with the lowest kidney excretion rate* 1–5 18 87% Sitagliptin 85% Vildagliptin 76% Alogliptin 75% Saxagliptin Linagliptin 5% No requirement for additional drug-related kidney function monitoring Dose adjustment required in patients with kidney impairment and/or drug-related kidney monitoring

19. *Saxagliptin recommended daily dose is 2.5 mg or 5 mg qd; † Alogliptin summary of product characteristics kidney impairment expressed in CrCl, ml/min. CKD, chronic kidney disease, CrCl, creatinine clearance; DPP-4i, dipeptidyl peptidase-4 inhibitor; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease 1. Trajenta ® (linagliptin) India Pack Insert. Aug 2021 ; 2 Merck. Januvia ® (sitagliptin) summary of product characteristics. 2021 ; 3. AstraZeneca. Onglyza ® (saxagliptin) summary of product characteristics. 2021 ; 4. Novartis. Galvus ® (vildagliptin) summary of product characteristics. 2020 ; 5. Takeda. Vipidia ® (alogliptin) summary of product characteristics. 2021 Linagliptin does not require dose reduction based on kidney function 19 Required DPP-4i doses with declining kidney function, as defined by prescribing information 1–5 Linagliptin 1 Sitagliptin 2 Saxagliptin* 3 Vildagliptin 4 Alogliptin † 5 When kidney function declines, there is no need for DPP-4i dose adjustment with linagliptin 1 100 mg qd 50 mg qd 25 mg qd 2.5 mg qd 50 mg bid 50 mg qd 25 mg qd 12.5 mg qd 6.25 mg qd 2.5 or 5 mg qd 5 mg qd eGFR CKD1 CKD2 CKD3a CKD3b CKD4 ESKD ≥90 ml/min/1.73 m 2 <90 to ≥60 ml/min/1.73 m 2 <60 to ≥45 ml/min/1.73 m 2 <45 to ≥30 ml/min/1.73 m 2 <30 to ≥15 ml/min/1.73 m 2 <15 ml/min/1.73 m 2

20. 82,332 patients with T2DM and CKD (Korean National Database) Inappropriate dosing: 1 out of 3 patients on DPP4-i (overall study) Inappropriate Renal Dose Adjustment of DPP-4i Is Associated With Poor Clinical Outcomes in T2DM Hong S. Mayo Clin Proc. January 2020;95(1):101-12 *Adjusted for age, sex, history of emergency department visits or severe hypoglycemia events, smoking and alcohol drinking status, systolic blood pressure, total cholesterol level, other antidiabetic drug treatment Inappropriate Dosing in Individual Agents: 2 out of 5 patients on Sitagliptin 1 out of 4 patients on Vildagliptin No patient on Linagliptin

21. Hypothetical patient case Ms. Carol’s new treatment regimen 21 Metformin 1000 mg bid | Linagliptin 5 mg qd Atorvastatin 20 mg OD Telmisartan 40 mg OD

22. DPP-4, dipeptidyl peptidase-4; HbA 1c , glycated haemoglobin; T2D, type 2 diabetes Please find references 3–6 at Ministry of Food and Drug Safety website. Available at: https://nedrug.mfds.go.kr/ (accessed Sep 2022) 1. American Diabetes Association. Diabetes Care 2022;45:S11; 2. Ministry of Food and Drug Safety Trajenta ® India Pack Insert, Aug 2021. ; 3 Merck. Januvia® (sitagliptin) prescribing information; 4. AstraZeneca. Onglyza® (saxagliptin) prescribing information; 5. Novartis. Galvus® (vildagliptin) prescribing information; 6. Takeda. Vipidia® (alogliptin) prescribing information What are the key learnings from this patient? 22 Risk of future kidney function decline should be considered when considering treatment options for patients with T2D and uncontrolled HbA 1c 1 Linagliptin can help simplify T2D management : one dose once daily , with consistent efficacy and safety profile for most patient types, including all stages of kidney function 2 Linagliptin is the DPP-4 inhibitor with the lowest rate of kidney excretion , and does not require dose adjustment if kidney function declines 2–6