linagliptin in renal perspectives

1. MYTH BUSTERS- Linagliptin in renal perspective
DR LALIT KUMAR AGARWAL NEPHROLOGIST

2. • Diabetes is the most common reason
for progression to ESRD in many
parts of the world1−3
• CKD is the one of the strongest
predictor of mortality in patients
with diabetes4−6
• CKD occurs as a consequence of
multiple pathogenic pathways in the
diabetic kidney1
– Hyperglycaemia(glucotoxicity) plays a
major, but not exclusive role
CKD, chronic kidney disease; ESRD, end-stage renal disease; T2D, type 2 diabetes
1. Toth-Manikowski S & Atta MG. J Diabetes Res 2015;2015:697010;2. Stewart JH et al. Nephrology 2007;12:520; 3. Thomas MC et al. Nat Rev Nephrol 2016;12:73;
4. Reidy K et al. J Clin Invest 2014;124:2333; 5. United States Renal Data System. Am J Kidney Dis 2003;42:1; 6. Afkarian M et al. J Am Soc Nephrol 2013;24:302;
7. National Kidney Foundation. Diabetes. 2015. www.kidney.org/atoz/content/diabetes (Accessed Sep 2017)
Diabetes leads to micro and macrovascular complications
Approximately 50% of
those with T2D will
eventually suffer from
CKD3,7
~50%

3. 0
15
30
45
60
75
N=6,034 N=11,253 N=4,685 N=2,437
All-cause
mortality
rate
(per
1000
person-years)
3
Kidney disease is a stronger risk factor for mortality than a prior
CV event
CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; MI, myocardial infarction
Tonelli M et al. Lancet 2012;380:807-814
Previous MI
Diabetes + CKD
CKD
(eGFR <60)
Diabetes
2x

4. T2D, type 2 diabetes; GFR, glomerular filtration rate
Percentages indicate excess mortality above the reference group (individuals with no diabetes or kidney disease) Afkarian M et al. J Am Soc Nephrol 2013;24:302
Patients with T2D and kidney disease have higher mortality
rates than those without kidney disease
10
0
20
30
40
60
50
70
No kidney disease Albuminuria Impaired GFR Albuminuria &
impaired GFR
Reference group
Standardised
10-year
cumulative
incidence
of
mortality
(%)
4.1
17.8
23.9
47.0
Excess
mortality
Increased
mortality

5. T2D –CKD-CVD : The connecting link
5

6. CKD, chronic kidney disease
Moen MF et al. Clin J Am Soc Nephrol 2009;4:1121
Risk of hypoglycaemia is increased in CKD
8.4
4.1
1.6
1.0
1
0
2
4
3
5
8
7
6
9
+CKD/
+diabetes
–CKD/
+diabetes
+CKD/
–diabetes
–CKD/
–diabetes
Risk
of
severe
hypoglycaemia
(incidence
rate
ratio)
With declining renal
function, there is decreased
clearanceof insulin.

7. Challenges in optimising glycaemic control in CKD
The management of glucose levels is particularly challenging in these patients, with the
concomitant need to avoid hypoglycaemic events while managing renal comorbidities, often
accompanied by CVD and/or other significant comorbidities2
Dose adjustment or
cessation may be required
for oral antidiabetic agents
excreted by the kidney1
With declining renal
function, there is
decreased clearance of
insulin1
Need to avoid
hypoglycemia
Reduced renal gluconeogenesis
with declining renal mass1
CKD, chronic kidney disease; CVD cardiovascular disease.
1. KDOQI. Am J Kidney Dis 2012;60: 850–86. 2. Sherwin et al. J Clin Invest 1976;57: 722–31. 3. Defronzo et al. J Clin Invest 1978;62: 425–35.

8.  Concern regarding the long term CV and renal safety of anti-hyperglcemic
agents have been raised in several studies following publication of meta-
analysis in 2007 that ROSIGLITAZONE increased the risk of MI and in 2009,
RECORD trial showed that adding ROSIGLITAZONE increased the risk of heart
failure
 DDP4 Inhibitor – the net effect is a reduction in glucagon level and increased
INSULIN secretion.
 Most of the DPP4 inhibitors have neutral effects on CV events(proved by
many CVOT trials).
 LINAGLIPTIN is safe for CV and RENAL side effects.(CARMELINA TRIAL in
subjects with high cardio-renal risks)
ANTI HYPERGLYCEMIC AGENTS CHOICE: Concern on long term CV and renal safety -
8

9. 9
CARMELINA® was specifically designed and statistically powered
to evaluate both CV and Kidney Outcomes
CARMELINA: Pre-specified adjudicated composite renal endpoints
 Sustained ESRD
 Sustained reduction in eGFR >40%
 Renal Death
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. Cardiovasc Diabetol 2018;17:39
Renal safety and potential benefits of Linagliptin has been proven with
CARMELINA.
Perception : All DPP-4i are kidney safe, it is not exclusive to Linagliptin
What could be the clinical impact of a prespecified renal
endpoint safety evidence as recorded from the CARMELINA
trial?
EXPERT OPINION

10. Linagliptin has proven Safety and Effectiveness
Across the Spectrum of Chronic Kidney Disease
Mild RI1
Moderate RI1
Severe RI2
ESRD and
Hemodialysis3
New - Onset Diabetes
After Transplant4
-0.7%
-0.7%
-0.7%
-1%
-0.6%
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, J Jpn Soc Dial Ther 2013. 46 (Suppl 1):670. 4. Sanyal, et al Indian J Endocr Metab 2013;17:S203-5. 5. Bae J et al. Endocrinol Metab (Seoul). 2016 Jan 6. PMID: 26754588
HbA1c Reductions
with Linagliptin
Across CKD Spectrum
-1.4%
Diabetes in Renal
Transplant5
Preserved eGFR
over 1-year2

11. CV safety of DPP-4i in patients with kidney disease has been
appropriately studied in CARMELINA
11
Schernthaner, Guntram et al.Diabetes Research and Clinical Practice, Volume 153, 30 - 4
The safety of
linagliptin in
patients with kidney
disease, has been
appropriately
studied only in
CARMELINA: 74% of
trial population
were having
‘prevalent kidney
disease‘*
*Defined as eGFR <60 ml/min/1.73 m2 or macroalbuminuria (UACR ≥300 mg/g

12. CARMELINA demonstrated long-term kidney safety with
Linagliptin
CV, cardiovascular; CVOT, cardiovascular outcomes trial; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease;
VEGF, vascular endothelial growth factor
†ESKD, renal death, ≥50% decrease in eGFR, albuminuria progression, use of retinal photocoagulation or intravitreal injections of an anti-VEGF therapy for diabetic retinopathy, or vitreous haemorrhage or
diabetes-related-blindness
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. Boehringer Ingelheim. Data on file. 2018 12
HR (95% CI) HR (95% CI) p-value
Prespecified adjudicated kidney composite
outcome
Other DPP-4i CVOTs
1-3
Not studied
ESKD, renal death or ≥40% eGFR decrease
4
1.04 (0.89, 1.22) 0.6164
ESKD or renal death 0.87 (0.69, 1.10) 0.2371
Prespecified microvascular composite outcome
†
0.86 (0.78, 0.95) 0.0032
Albuminuria progression 0.86 (0.78, 0.95) 0.0034
0.5 1.0 2.0
Favours linagliptin Favours placebo
?

13. 13
UACR reduction ≥50%
14% Lower Risk of
Progression of Albuminuria
14%
RRR
15% Greater Likelihood of
Significant Regression in UACR
15%
Learnings from CARMELINA Trial:
Risk Reduction for Albuminuria with Linagliptin
Julio Rosenstock, Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High
Cardiovascular and Renal Risk The CARMELINA Randomized Clinical Trial, JAMA, nov 2018

14. Participants: Type 2 DM Plus CVD or Renal disease
Interventions: 5mg Linagliptin vs Placebo
Outcomes: 3P-MACE, Kidney outcome
Conclusion: Individuals with T2D and NRP having a high disease burden, Linagliptin reduces
their albuminuria burden and HbA1c, without affecting CV or kidney risk.
14

15. Reno-protective effects of linagliptin
1,2
 Inhibition of podocyte injury and apoptosis
 Inhibition of myofibroblast transformation
 Increased GLP-1 receptor expression
1. Mima A et al. Linagliptin affects IRS1/Akt signaling and prevents high glucose-induced apoptosis in podocytes. Sci Rep. 2020; 10: 5775.79-7
2. Sharkovska Y. J Hypertens. 2014 Nov;32(11):2211-23
Possible Mechanisms for Kidney Protection in Pre-clinical
Studies
• Linagliptin can inhibit endothelial to
mesenchymal transition (EndMT), thus
ameliorates diabetic kidney fibrosis and
progressive CKD
• Such effects of Linagliptin were drug-
specific, but not class effects

16.  Linagliptin did not affect glomerular filtration rate (GFR), effective renal plasma flow
(ERPF) or any intrarenal hemodynamic functions, compared to Glimepiride
 Linagliptin was associated with modest natriuresis, possibly mediated by SDF-1α, with
increase in fractional excretion of sodium (FENa) and potassium (FEK)
The RENALIS Study:
Effect of Linagliptin on Fasting Renal Hemodynamics
16
After 8 weeks of treatment in overweight T2D patients without renal impairment:
Muskiet MHA, et al. Diabetes Care 2020;dc200902 [DOI: 10.2337/dc20-0902]

17. With its unique mode of elimination, Linagliptin is the only available DPP-4 inhibitor
that does not require dose adjustment for any stage of renal impairment
Perception : Linagliptin is useful only in T2D with CKD Patients
Any opinion regarding the same?

18. Baseline Characteristics of DPP-4i CVOTs
18
Renal Risk
Cardiovascular
Risk
Low CV & Kidney Risk
High CV Risk High CV & Kidney Risk
With CARMELINA & CAROLINA,
linagliptin has been studied in
Patients across
Cardio-Renal Risk Continuum
Median T2D duration
6.3 years
Median T2D duration
14.75 years
Jennifer B. Green, Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes, n engl j med 373;3 nejm.org july 16, 2015. Benjamin M. Scirica,, Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus, n engl j med 369;14 nejm.org october 3,
2013. William B. White, Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes, n engl j med 369;14 nejm.org october 3, 2013. Julio Rosenstock, Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High
Cardiovascular and Renal Risk The CARMELINA Randomized Clinical Trial, JAMA. doi:10.1001/jama.2018.18269 Published online November 9, 2018. Julio Rosenstock, Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes
The CAROLINA Randomized Clinical Trial, JAMA. 2019;322(12):1155-1166. doi:10.1001/jama.2019.13772 Published online September 19, 2019.

19. CAROLINA® and CARMELINA® provide evidence across a
broad spectrum of T2D disease duration, CV and kidney risk
CV, cardiovascular; T2D, type 2 diabetes
1. Rosenstock J et al. ADA 2019; 2. Rosenstock J et al. JAMA 2019;321:69
19
Atherosclerosis
Chronic kidney disease
Target-organ damage
Risk
42%
Median T2D
duration
6.3 years
Had established
CV disease
Displayed ≥2
defined CV risk
factors
Had T2D for
≤5 years
Active-
comparator
Treatment
naïve
On insulin
On metformin
37%
40%
9%
0%
83% 74%
Mean T2D
duration
14.75 years
Prevalent kidney
disease
Had established
CV disease
Had established
CV disease and
prevalent kidney
disease
Placebo-
controlled
Treatment naïve
On metformin
On insulin
57%
33%
<3%
55%
58%
Early
disease
Advanced
disease
CAROLINA®1 CARMELINA®2
Asymptomatic Symptomatic

20. CAROLINA® Linagliptin, n/N (%) Glimepiride, n/N (%) HR (95% CI) p-value
3P-MACE 356/3023 (11.8) 362/3010 (12.0) 0.98 (0.84, 1.14)* 0.7625
HHF or CV death 236/3023 (7.8) 234/3010 (7.8) 1.00 (0.84, 1.20) 0.9671
All-cause mortality 308/3023 (10.2) 336/3010 (11.2) 0.91 (0.78, 1.06) 0.2263
Together CARMELINA and CAROLINA Demonstrate Long-term
Safety of Linagliptin in Patients Across Cardio-renal Risk Continuum
CARMELINA® Linagliptin, n/N (%) Placebo, n/N (%) HR (95% CI) p-value
3P-MACE 434/3494 (12.4) 420/3485 (12.1) 1.02 (0.89, 1.17) 0.7398
HHF or CV death 406/3494 (11.6) 422/3485 (12.1) 0.94 (0.82, 1.08) 0.3881
All-cause mortality 367/3494 (10.5) 373/3485 (10.7) 0.98 (0.84, 1.13) 0.7402
*95.47 CI. 3P-MACE, 3-point MACE; 4P-MACE, 4-point MACE; CV, cardiovascular; HF, heart failure;
HHF, hospitalisation for HF; MACE, major adverse CV events; MI, myocardial infarction
Rosenstock J et al. JAMA 2019;321:69; Rosenstock J et al. ADA 2019

21. Linagliptin has Proven CV and Renal Safety
Across the Spectrum of CKD in T2DM
*P value of subgroup-by-treatment interaction test.
Adapted: Perkovic V et al. Diabetes Care. 2020 May 22;dc200279
CARMELINA Study: Patients of T2DM with CVD and/or CKD

22. Linagliptin Placebo
HR (95% CI) HR (95% CI)
p-value for
treatment by age
interaction
n with event / N analysed (%)
3P-MACE 434/3494 (12.4) 420/3485 (12.1) 1.02 (0.89, 1.17) 0.0937
<65 years 154/1467 (10.5) 140/1501 (9.3) 1.11 (0.89, 1.40)
65 to <75 years 197/1405 (14.0) 182/1395 (13.0) 1.09 (0.89, 1.33)
≥75 years 83/622 (13.3) 98/589 (16.6) 0.76 (0.57, 1.02)
HHF 209/3494 (6.0) 226/3485 (6.5) 0.90 (0.74, 1.08) 0.9788
<65 years 67/1467 (4.6) 77/1501 (5.1) 0.87 (0.63, 1.21)
65 to <75 years 89/1405 (6.3) 99/1395 (7.1) 0.89 (0.67, 1.18)
≥75 years 53/622 (8.5) 50/589 (8.5) 0.92 (0.63, 1.35)
Kidney outcome* 327/3494 (9.4) 306/3485 (8.8) 1.04 (0.89, 1.22) 0.9968
<65 years 180/1467 (12.3) 173/1501 (11.5) 1.05 (0.85, 1.29)
65 to <75 years 113/1405 (8.0) 105/1395 (7.5) 1.06 (0.81, 1.38)
≥75 years 34/622 (5.5) 28/589 (4.8) 1.06 (0.64, 1.75)
Albuminuria progression 763/2162 (35.3) 819/2129 (38.5) 0.86 (0.78, 0.95) 0.4318
<65 years 289/816 (35.4) 308/829 (37.2) 0.93 (0.79, 1.09)
65 to <75 years 320/903 (35.4) 339/877 (38.7) 0.84 (0.72, 0.98)
≥75 years 154/443 (34.8) 172/423 (40.7) 0.78 (0.63, 0.97)
CARMELINA: No increased risk of cardio-renal events in older
patients
0.25 0.5 1 2 4
Favours linagliptin Favours placebo
*Death due to kidney disease, progression to end-stage kidney disease, or sustained decrease in estimated glomerular filtration rate from baseline of ≥40%
Cooper M et al. Diabetes Obes Metab 2020; Feb 9. doi: 10.1111/dom.13995 [Epub ahead of print]

23. Summary: Linagliptin has Broadest Clinical Evidence in DPP-4i
class
23
Uncertain
Proven safety
High CV risk Heart failure High kidney risk
Proven safety Proven safety
Safety Signal
Proven safety
Proven safety Uncertain
Proven safety
Uncertain
Uncertain
Safety signal
Uncertain‡ Uncertain Uncertain
Sitagliptin4, 5, 6
Teneligliptin3, 8
Linagliptin7
Saxagliptin2
Vildagliptin1
1. Novartis Europharm Ltd. Galvus® (vildagliptin) summary of product characteristics; 2. Scirica B et al. N Engl J Med 2013;369:1317; 3. Indian J Endocrinol Metab. 2017 Jan-Feb;21(1):11-17; 4. Green J et al. N Engl J Med
2015;373:232; 5. Engel SE et al. Diabetes Obes Metab 2017;19:1587; 6. Merck Sharp & Dohme Ltd. Januvia® (sitagliptin) summary of product characteristics; 7. Trajenta PI 9 April 2020. Boehringer Ingelheim. 8. Singh AK.
Efficacy and safety of teneligliptin. Indian J Endocr Metab 2017;21:11-7.
+ convenience of OD dosing without the need of dose adjustment

24. Summary : Simplifying T2DM Care with Linagliptin
24
Proven Effectiveness and Safety
Across Broad Range of Patients
No need for dose-adjustment, in
any stage of CKD
Long Half-life (>100 hours), Ensuring
Effective 24-hour Glycaemia Control
5mg one dose, once daily
independent of:
CV Risk
Trajenta PI Boehringer Ingelheim Pvt. Ltd. 09 Apr 2020

25. Thank You !