renal benefits of linagliptin

1. Linagliptin: A renal friendly
gliptin for double trouble

2. Flow of Presentation
Diabetes
and CKD – A
double
trouble
Microalbuminuria
& eGFR: Early
markers
DPP4i:
Nephro-
protective
mechanisms
Linagliptin:
A Renal
friendly
drug
Evidences Summary

3. India Is
Facing
Double
Trouble
Condition
CKD

4. Indian Scenario: ‘I CaRe for Diabetes’ Survey
64.7%
53.1%
21.7%
0%
20%
40%
60%
80%
100%
CKD based on KDIGO definition (eGFR <90
mL/min/1.73sq.m OR Albuminuria +ve)
CKD based on Indian Reference Range for
eGFR (eGFR <77 mL/min/1.73sq.m OR
Albuminuria +ve)
Overt CKD in T2D (eGFR <60
mL/min/1.73sq.m OR Macroalbuminuria)
Prevalence of CKD Parameters in T2D
I CaRe for Diabetes Working Group. Presented at DiabetesIndia Conference, New Delhi, Feb 2017.
At-least 1 in 2 Patients of T2D had CKD

5. CKD
Identify the risk early to
protect early
Microalbuminura- an early
biomarker of a vicious cycle
Identify Early To Protect Early
Microalbuminuria- An Early Biomarker of Kidney
dysfunction

6. Prevalence of MAU in
double trouble population
Rev Port Cardiol. 2015;34:237---246

7. How impaired glycemic control affect microalbuminuria
Niger J Clin Pract. 2013;16(2):216-220.
Correlation of microalbumin levels to duration of T2DM Correlation of Microalbumin levels to HbA1c in cases
Microalbumin levels (g/day) were found to be highest day in diabetic subjects
with duration of diabetes more than four years (P < 0.001)

8. Microalbuminuria – A Marker of Progressive Renal Function Loss
Nephron Clin Pract 2009;111:c204–c211
The first three stages the risk to develop a CV
event is much higher than to develop a renal
event, the reverse is true in stages 4 and 5.
The risk to develop a renal event rises more
steeply than the risk to develop a CV event
already in the early stages, thus in the subjects
with microalbuminuria
Incidence rates (on a log scale) per CKD stage for
both CV endpoints and renal endpoints
Incidence of both endpoints in stage 1 or 2 CKD
is elevated as in stage 3 CKD compared to
subjects without CKD

9. eGFR and Diabetes
Duration of Diabetes ≈
eGFR
Buyadaa O, et al Scientific Reports. 2021 Jul 19;11(1):14705.

10. How to halt the progression of
double trouble?
Early detection and initiation
with nephron-protective agent

11. DPP4i: Potential Nephro-protective
Mechanisms
Diabetes Metab 2018 Mar;44(2):101-111.

12. Why Linagliptin?
The kidneys contain the highest levels of DPP-4, which is
increased in diabetic nephropathy.
Linagliptin is the only compound that is not predominantly excreted
in the urine. (excreted through hepato-biliary route).
Linagliptin is also the most potent DPP-4 inhibitor, has the highest
affinity for DPP4 protein, and has the largest volume of distribution.
These properties allow linagliptin to penetrate kidney tissue and
tightly bind resident DPP-4.
Clin Sci (Lond). 2018 Feb 28;132(4):489-
507

13. LINAGLIPTIN
CVOTs

14. Trial
EVALUATING THE IMPACT OF
LINAGLIPTIN VERSUS PLACEBO
ON CV AND KIDNEY SAFETY
Longer duration of DM
Renal risk marker +ve
Low eGFR

15. Key Features of CARMELINA
Trial
https://www.carmelinatrial.com/carmelina-trial.html
Relatively early T2D at increased CV risk

16. Proportion of trial population with kidney disease
(eGFR <60 ml/min/1.73 m2) in recent CVOTs
16
CARMELINA® includes the highest proportion of patients
with established CKD* within the modern diabetes CVOT
space
*KIDNEY DISEASE DEFINED AS EGFR <50 ML/MIN/1.73 M2
CKD, CHRONIC KIDNEY DISEASE; CVOT, CARDIOVASCULAR OUTCOMES TRIAL; EGFR, ESTIMATED GLOMERULAR FILTRATION RATE
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. PFEFFER MA ET AL. N ENGL J MED 2015;373:2247;(SUPPLEMENTARY APPENDIX); 4. GREEN JB ET AL. N ENGL J
MED 2015;373:232;(SUPPLEMENTARY APPENDIX); 5. ZINMAN B ET AL. N ENGL J MED 2015;373:2117 ; 6. MARSO SP ET AL. N ENGL J MED 2016;375:311; 7. MARSO SP ET AL. N ENGL J MED
2016;375:1834;(SUPPLEMENTARY APPENDIX);
8. BOEHRINGER INGELHEIM. DATA ON FILE. 2017
15.6*
29.1
23.2
9.3*
25.9
23.1
28.5
62.3
0
10
20
30
40
50
60
70
80
90
100
Proportion
of
patients
with
kidney
disease
(%)
SAVOR-TIMI 531
(Saxagliptin)
N=16,492
EXAMINE2
(Alogliptin)
N=5380
ELIXA3
(Lixisenatide)
N=6068
TECOS4
(Sitagliptin)
N=14,671
EMPA-REG
OUTCOME®5
(Empagliflozin)
N=7020
LEADER6
(Liraglutide)
N=9340
SUSTAIN-67
(Semaglutide)
N=3297
CARMELINA®8
(Linagliptin)
N=6980

17. The long-term kidney safety profile of linagliptin was
confirmed in the first prespecified adjudicated kidney
outcome data
LINAGLIPTIN EVENT RATE 4.89/100 PY PLACEBO EVENT RATE 4.66/100 PY
Treated set, Kaplan-Meier estimate. Hazard ratio and 95% CI based on Cox regression model with terms for treatment group (p=0.6164) and region (p<0.0001)
*Two-sided eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease
ROSENSTOCK J ET AL. JAMA 2018; DOI: 10.1001/JAMA.2018.18269
HR 1.04
(95% CI 0.89, 1.22)
Years
Patients
with
event
(%)
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
0
10
20
30
Placebo (n) 3,485 3,213 2,995 2,298 1,608 1,005 496 103
Linagliptin (n) 3,494 3,227 3,018 2,345 1,675 1,040 518 109
306 patients
327 patients
Time to death due to kidney disease, progression to ESKD or sustained eGFR
decrease of ≥40%
p=0.6164*
No. of patients
Placebo Linagliptin

18. Linagliptin significantly reduced the risk of
microvascular events
Linagliptin event rate: 25.72/100 PY Placebo event rate; 29.04/100 PY
Treated set, Kaplan-Meier estimate. Hazard ratio and 95% CI based on Cox regression model with terms for treatment group (p=0.0032), region (p<0.0001); 2-
sided p-value
ROSENSTOCK J ET AL. JAMA 2018; DOI: 10.1001/JAMA.2018.18269
HR 0.86
(95% CI 0.78, 0.95)
Patients
with
event
(%)
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
0
20
60
100
Years
Placebo (n) 2,129 1,965 1,425 1,128 659 425 196 33
Linagliptin (n) 2,160 1,999 1,546 1,244 747 479 211 37
No. of patients
40
80
843 patients
785 patients
Placebo Linagliptin
p=0.0032
Time to first occurrence of composite microvascular outcome

19. Learnings from CARMELINA Trial: Risk Reduction for
Albuminuria
19
Urine Albumin-Creatinine Ratio (uACR)

20. Medication Errors!!
Dose adjustment in RI may be a clinical challenge
Juliana Meyers et al. Postgraduate Medicine, Vol 123, issue 2, 2011
Inappropriate dose of Sitagliptin
Appropriate dose of Sitagliptin
Inappropriate dose of Metformin
Appropriate dose of Metformin
Source: U.S. Database (2000 - 2009)
• 3,44,770 T2DM patients
• 1,21,395 Renal insufficiency patients
84.89 %
15.11 %
99.89 %
0.11 %
Linagliptin – One dose fit for
all

21. Linagliptin: Demonstrated Safety and Efficacy
Evidence
Across the Spectrum of CKD
Mild RI1
Moderate RI1
Severe RI2
ESRD and
Hemodialysis3
Diabetes in Renal
Transplant4
-0.7%
-0.7%
-0.7%
-1%
-1.4%
1. Cooper M, et al. ADA 2011, Poster 1068-P.
2. McGill JB, et al. Diabetes Care. 2013;36:237–244.
3. Kono T et al. 58th Ann Mtg of the Japanese Society for Dialysis Therapy (JSDT), Fukuoka, 20 - 23 Jun 2013 J Jpn Soc Dial Ther 2013. 46 (Suppl 1):670.
4. Bae J et al. Endocrinol Metab (Seoul). 2016 Jan 6. PMID: 26754588
HbA1c Reductions
with Linagliptin
Across CKD Spectrum
Preserved eGFR
over 1-year2
RENAL SAFETY

22. requirement….
Linagliptin is best cost effective option
eGFR (mL/min
/1.73m2)
Linagliptin Sitagliptin Vildagliptin Liraglutide Dulaglutide Semaglutide
>90 Safe Safe Safe Use with
caution
No dose
adjustment
No dose
adjustment
60-90 Safe Safe Safe Use with
caution
No dose
adjustment
No dose
adjustment
45-59 Safe Safe Dose
adjustment-
50mg OD
Use with
caution
No dose
adjustment
No dose
adjustment
30-44 Safe Dose adjustment-
50mg OD
Dose
adjustment-
50mg OD
Use with
caution
No dose
adjustment
No dose
adjustment
15-29 Safe Dose adjustment-
25 mg OD
Dose
adjustment-
50mg OD
Use with
caution
No dose
adjustment
No dose
adjustment
<15 Safe Dose adjustment-
25 mg OD
Dose
adjustment-
50mg OD
Use with
caution
No dose
adjustment (use
with caution)
No dose
adjustment

23. Case-based presentation
Age: 35 yrs
BMI: 24 kg/m2
Duration of diabetes: 8 yrs
Comorbidities: Hypertension,
dyslipidemia
HbA1c: 8.3%
FPG: 130 mg/dl
PPG: 220 mg/dl
Current management:
Metformin(500 mg)/Linagliptin(5
mg) OD
SGLT2i
Basal insulin
Current investigation:
UACR ratio: 250 mg/g
eGFR: 25 ml/min/1.73 m2
Which medication should to be continue or discontinue?

24. Medication safe to be administered in renal impairment
Linagliptin- safe in any spectrum of CKD as only 5% of linagliptin excretes
through kidney
Insulin – safe in CKD
Medication need to be discontinue in renal impairment
SGLT2i as eGFR is gradually declining
Metformin as it is contraindication at eGFR < 30 ml/min/1.72m2
Risk of hypoglycemia
Linagliptin- Neutral
Basal insulin- may cause hypoglycemia
Is there any alternative approach for management?
Switch over from basal to premix insulin BID for better glycemic control
along with continuation of Linagliptin 5 mg

25. Summary: Simplifying T2DM care
with Linagliptin
25