2. efectos castelao...improved(diabetes(care(has(notyetsucceeded(in(reducing(renal(complicaons(0 50...

Efectos vasculares y renales de los Inhibidores de DPP4

Alberto Mar+nez-‐Castelao Consultor emérito Hospital Universitari Bellvitge, IDIBELL Hospitalet. Barcelona. REDinREN , InsDtuto Salud Carlos III.

DISCLOSURE

•  Honoraria from Amgen, Bayer, Boëhringer-‐Ingelheim, Fresenius, Gambro, Janssen-‐Cilag, NovarDs, Roche, Shire.

•  Advisory boards for Abbvie, Amgen, Boëhringer-‐Ingelheim, MSD.Roche.

Improved diabetes care has not yet succeeded in reducing renal complicaDons

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MI Stroke ESRD

MI, myocardial infarcDon Adapted from Gregg EW et al. N Engl J Med 2014;370:1514

3

Year

Albuminuria: early marker for poor outcome in complex pathology of vascular disease

Adapted from Chade A, et al. Hypertension. 2005;45:1042–1049.

CV risk factors* *e.g., diabetes, hypertension, dyslipidaemia

Atherosclerosis Albuminuria

CV and renal disease

Inflammation Oxidative stress

Endothelial dysfunction

Vascular damage

Major previous placebo-‐controlled trials with renal outcomes in paDents with Type 2 Diabetes and CKD

ACEi, angiotensin-‐converDng enzyme inhibitor; ARB, angiotensin receptor blocker; CKD, chronic kidney disease; Cr, creaDnine; CV, cardiovascular; eGFR, esDmated glomerular filtraDon rate; ESRD, end-‐stage renal disease;

na, not applicable; Nrf2, transcripDon factor called nuclear factor (erythroid-‐derived 2)-‐like 2; RAAS, renin-‐angiotensin-‐aldosterone system; UACR, urinary albumin-‐to-‐creaDnine raDo.

1. Lewis EJ, et al. N Engl J Med. 2001;345:851–860; 2. Brenner BM, et al. N Engl J Med. 2001;345:861–869; 3. Fried LF, et al. N Engl J Med. 2013;369:1892–1903; 4. Parving HH, et al. N Engl J Med. 2012;367:2204–2213; 5. de Leeuw PW. Ann Intern Med. 2013;158:JC7; 6. Mann JF, et al. J Am Soc Nephrol. 2010;21:527–535; 7. de Zeeuw D, et al. N Engl J

Med. 2013;369:2492–2503; 8. Pfeffer MA, et al. N Engl J Med. 2009;361:2019–2032. Source: Groop P-‐H, et al. Diab Vasc Dis Res.2015; pii: 1479164115579002

Trial Study drug Concept Mean study

duration Reason for early

termination Key results

IDNT1 Irbesartan Single RAAS

blockade (ARB) 2.6 years na •  20% reduction in risk of doubling serum

Cr, ESRD and death

RENAAL2 Losartan Singe RAAS

blockade (ARB) 3.4 years na •  16% reduction in risk of doubling serum

Cr, ESRD and death

VA NEPHRON-D3

Losartan + Lisinopril

Dual RAAS blockade (ARB +

ACEi) 2.2 years

Excess risk of hyperkalaemia

and acute kidney injury

•  No benefit in eGFR decline, ESRD or death

ALTITUDE4, 5 Aliskiren

Dual RAAS blockade (renin inhibitor + ARB

or ACEi)

2.7 years

Excess risk of hyperkalaemia

and hypotension

•  No significant differences in renal composite outcome (ESRD, renal death and doubling of serum Cr)

•  14% reduction in UACR

ASCEND6 Avosentan Endothelin antagonist 4 months

Excess risk of CV events •  45–50% reduction in UACR

BEACON7 Bardoxolone methyl

Antioxidant (Nrf2 activator) 9 months

Excess risk of CV events

•  No reduction in the risk of ESRD or CV death

TREAT8 Darbepoetin Erythropoiesis-

stimulating agent

2.4 years na •  No reduction in the risk of ESRD or death •  Excess risk of stroke, thromboembolic

complications and cancer deaths

Major ongoing, Phase 3, randomised, placebo-‐controlled clinical trials with renal outcomes in paDents with Type 2 Diabetes and CKD

CKD, chronic kidney disease; Cr, creaDnine; CV, cardiovascular; DPP4, dipepDdyl pepDdase 4 inhibitor; eGFR, esDmated glomerular filtraDon rate; ESRD, end-‐stage renal disease; SGLT2, sodium glucose cotransporter 2.

Source: Groop P-‐H, et al. Diab Vasc Dis Res.2015; pii: 1479164115579002

Trial Drug Target Estimated enrollment

Estimated treatment duration (months)

Predefined renal outcomes

Estimated completion date

CARMELINA®™ NCT01897532 Linagliptin

DPP4 inhibition 8300 48

ESRD, sustained decrease of eGFR ≥ 50%, renal death

January 2018

CREDENCE NCT02065791 Canagliflozin

SGLT2 inhibition 3627 66

ESRD, doubling of serum Cr,

renal or CV death February 2019

SONAR NCT01858532 Atrasentan

Endothelin receptor

antagonist 4148 48

ESRD, doubling of serum Cr March 2017

PIONEER NCT02156843 Pyridorin

Vitamin B6 600 42

ESRD, doubling of serum Cr March 2018

DPP-‐4 inhibitors and albuminuria

•  The following slides report findings from studies that evaluated changes in albuminuria for the following DPP-‐4 inhibitors: –  SitaglipDn –  AloglipDn

•  SitaglipDn/aloglipDn crossover –  VildaglipDn –  SaxaglipDn –  LinaglipDn –  TeneliglipDn (Japón, Corea y ArgenDna)

•  Comparisons of paDent populaDons, background medicaDons and changes in eGFR and HbA1c are noted between trials

7

Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2015:8 ; 339-‐345.

An:-‐atherosclero:c effects of sitaglip:n in pa:ents with type 2 diabetes mellitus Omoto S, Taniura T, Nishizawa T, Tamaki T, Shouzu A, Nomura S

Conclusion: SitaglipDn shows an adiponecDn-‐dependent an:-‐atherothrombo:c effect, which may be beneficial for primary prevenDon of atherothrombosis, in paDents with type 2 diabetes.

DiabeDc paDents eligible for sitaglipDn monotherapy or combinaDon therapy (eg, sitaglipDn plus a sulfonylurea) were administered sitaglipDn (50 mg/day) for 6 months. Levels of soluble P-‐selecDn (sP-‐selecDn), soluble E-‐selecDn (sE-‐selecDn), soluble vascular cell adhesion molecule-‐1 (sVCAM-‐1), MCP-‐1, sRAGEs, and adiponecDn were measured by ELISA at baseline and aler 3 and 6 months of treatment.

RESULTS: reducDons in sP-‐selecDn, sE-‐selecDn, sVCAM-‐1, and MCP-‐1 during sitaglipDn therapy were significantly greater in responders, defined as paDents with a significant increase in adiponecDn levels, than in nonresponders.

Renal Effects of DPP-‐4 Inhibitors: A Focus on Microalbuminuria. Haluzik M; Rychlik I InternaDonal Journal of Endocrinology 2013 (7085):895102 ·∙ September 2013 DOI: 10.1155/2013/895102 ·∙ One of the recently emerged interesDng features of dipepDdyl pepDdase-‐4 (DPP-‐4) inhibitors is its possible protecDve effect on the diabeDc kidney disease. Here, we review the renal effects of DPP-‐4 inhibitors with special focus on its influence on the onset and progression of microalbuminuria, as presence of microalbuminuria represents an important early sign of kidney damage and is also associated with increased risk of hypoglycemia and cardiovascular complicaDons. Mechanisms underlying possible nephroprotec:ve proper:es of DPP-‐4 inhibitors include:

reducDon of oxida&ve stress and inflamma&on improvement of endothelial dysfunc&on. Effects of DPP-‐4 inhibitors may be both glucagon-‐like pep&de-‐1 (GLP-‐1) dependent and independen

Numerous ongoing long-‐term cardiovascular trials with DPP-‐4 inhibitors can bring novel crucial informaDon about relaDonships among glucose control and macrovascular and microvascular complicaDons and further elucidate the role of albuminuria in these processes

Systema:c Literature Review of DPP-‐4 Inhibitors in Pa:ents with Type 2 Diabetes Mellitus and Renal Impairment.

Thomas MC1, PaldániusPM2, AyyagariR3, Ong SH2,4, Groop PH5,6,7. RESULTS: Seven trials of ≤52-‐54 weeks duraDon were retrieved, which included one study each on vildaglip:n, saxaglip:n, and sitaglip:n, two on linaglip:n, and the remaining two were extension studies of vildaglipDn and saxaglipDn. Majority of paDents were on insulin at baseline (53-‐86%), except in the sitaglipDn study, where approximately 11% received insulin during the placebo-‐controlled phase. Aler 52 weeks, vildaglipDn and saxaglipDn reduced HbA1c levels by 0.6-‐0.7% (baseline 7.8-‐8.4%) versus placebo in the overall populaDon. HbA1c reducDons were similar at weeks 12 and 52. In the 12-‐week, placebo-‐controlled phase, sitaglipDn and linaglipDn reduced mean HbA1c by approximately 0.4% (baseline 7.7-‐8.1%) versus placebo. Rates of HEs with DPP-‐4 inhibitors were not significantly different versus placebo in any study. Rates of adverse events (AEs) and changes involving renal funcDon were similar in the acDve-‐ and placebo-‐treated groups. CONCLUSION: These results suggest that DPP-‐4 inhibitors have the poten&al to improve glycemic control in pa&ents with RI without increasing the risk of HEs or overall AEs.

Diabetes Ther. 2016 Sep;7(3):439-‐54. doi: 10.1007/s13300-‐016-‐0189-‐4. Epub 2016 Aug 8.

TFGb

Groop P-‐H, et al. Diab Vasc Dis Res.2015; pii: 1479164115579002

DPP-‐4 inhibitors and renal outcomes: overview of completed and ongoing trials

Please note that each flag is hyperlinked to the corresponding study slide *No compleDon dates available Dates indicate study compleDon or, when available, primary compleDon

13

2010 2016 2017

Company-‐sponsored InvesDgator-‐sponsored Has published results

2011

SitaglipDn

Study populaDons

*e.g. mesormin, glinide or α-‐glucosidase inhibitor; †Data available for per protocol populaDon (N=277) OAD, oral anD-‐diabeDc 1. Green JB et al. N Engl J Med 2015;373:232; 2. Hawori S et al. Endocr J 2011;58:69; 3. Katsuno T et al. Endocr J 2013;60:733; 4. Mori H et al. J Diabetes Invest 2014;5:313; 5. Arjona Ferreira JC et al. Diabetes Care 2013;36:3460067; 6. Harashima SI et al. Int J Clin Pract 2012;66:465

15

Sitaglip:n

Study N Comparator

TECOS1 14,671 Placebo

Hawori et al2 36 None

Katsuno et al3 71 None

Mori et al4 85 OADs*

Arjona Ferreira et al5 423 Glipizide

Harashima et al6 82 None

67,9

22,3

9,8

TECOS Caucasian Asian Other

100 (Japan)

HaZori

100 (Japan)

Mori

100 (Japan)

Katsuno

100 (Japan)

Harashima

29,6

53,3

17,1

Arjona Ferreira†

Trial Evaluate Outcomes Sitag

Study Popula:on Baseline At endpoint Significance TECOS1 UACR, median mg/gCr (range)

Mixed 10.3 (3.5, 34.6) Month 48: Change:

–1.06 (–1.94, –0.09)2 p=0.0342

Hawori et al3 UACR, mean mg/gCr ± SD

Japanese

Normo (n=13): 11.6±8.4 Micro (n=11): 98.4±79 Macro (n=6): 1263±492

Month 6: 4.5±5.0 24.9±20 561±89

Overall: –20.6±24.6

p=0.0012 p=0.0152 p=0.0211 p=0.0014

Katsuno et al4 Glycoalbumin, mean % ± SE

Japanese p<0.001

Albuminuria (1/2)

*p<0.01 vs Week 0 N/A, not applicable; NR, not reported; SD, standard deviaDon; SE, standard error 1. Green JB et al. N Engl J Med 2015;373:232; 2. Penno G et al. Nutr Metab Cardiovasc Dis 2016;26:361; 3. Hawori S et al. Endocr J 2011;58:69; 4. Katsuno T et al. Endocr J 2013;60:733

16

Sitaglip:n

18 18,5 19

19,5 20

20,5 21

21,5 22

22,5 23

0 4 8 12

Glycoalbu

min, m

ean % ± SE

Week

p<0.001 for whole curve

* * *

X

eGFR (mL/min/1.73 m2) (1/2)

NS, not significant *MDRD formula 1. Green JB et al. N Engl J Med 2015;373:232; 2. Hawori S et al. Endocr J 2011;58:69; 3. Katsuno T et al. Endocr J 2013;60:733

17

Sitaglip:n

Study Popula:on Baseline At endpoint Significance

TECOS1 Mean ± SD* Mixed 74.9±21.3 Month 48:

Change: −4.0±18.4 NR

Hawori et al2 Mean ± SD Japanese 73.3±16.3 Month 6:

77.0±19.4 NS

Katsuno et al3 Japanese NR

Diabetes Care 2016 Nov; 39(11): 2042-‐2050. hwps://doi.org/10.2337/dc16-‐1371

To invesDgate the effects of sitaglipDn or liragluDde on renal hemodynamics, tubular func:ons, and markers of renal damage in overweight paDents with type 2 diabetes without chronic kidney disease (CKD).

CONCLUSIONS Twelve-‐week treatment with sitaglipDn or liragluDde does not affect measured renal hemodynamics. No sustained changes in tubular func:ons or altera:on in renal damage markers were observed. The validity and clinical relevance of the slight sitaglipDn-‐induced PGLO reducDon remains speculaDve.

RESULTS At week 12, GFR was not affected by sitaglipDn (−6 mL/min/1.73 m2 [95% CI −14 to 3], P = 0.17) or liragluDde (+3 mL/min/1.73 m2 [−5 to 11], P = 0.46), compared with placebo. SitaglipDn modestly reduced esDmated glomerular hydraulic pressure (PGLO; P = 0.043). ERPF, other intrarenal hemodynamic variables, renal damage markers, and PRC did not change for both treatments. Both agents reduced HbA1c. Only at week 2, sitaglipDn increased FENa and FEU (P = 0.005).

Renal Effects of DPP-‐4 Inhibitor Sitaglip:n or GLP-‐1 Receptor Agonist Liraglu:de in Overweight Pa:ents With Type 2 Diabetes: A 12-‐Week, Randomized, Double-‐

Blind, Placebo-‐Controlled Trial. LTonneijck, MM Smits, MHA.Muskiet Hoekstra, MHH.Kramer, AH Jan Danser, P M. ter

Wee, MDiamant JA.Joles and DH. van Raalte

AloglipDn

Study populaDons

1. White WB et al. New Engl J Med 2013;369:1327; 2. Sakata K et al. Diabetes Metab Res Rev 2013;29:624

20

Aloglip:n

Study N Comparator

EXAMINE1 5380 Placebo

Sakata et al2 61 None 72,7

20,2

7,1

EXAMINE

Caucasian Asian Other

100 (Japan)

Sakata

Albuminuria

1. White WB et al. New Engl J Med 2013;369:1327; 2. Sakata K et al. Diabetes Metab Res Rev 2013;29:624

21

Aloglip:n


EXAMINE1 Mixed NR

Sakata et al2 Median mg/gCr (range)

Japanese

31.6 (6.8–145.7)

26.5 (5.6–125.1)

p=0.04

26.7 (6.1–116.1)

22.3 (5.7–86.9)

p=0.23

All pa:ents

Aloglip:n monotherapy (n=26)

eGFR (ml/min/1.73 m2)

*MDRD formula 1. White WB et al. New Engl J Med 2013;369:1327 (Suppl); 2. Sakata K et al. Diabetes Metab Res Rev 2013;29:624

22

Aloglip:n


EXAMINE1 Mean change from baseline*

Mixed

≥90: 60–89: 31–59:

<30:

104.8 74.6 48.5 22.6

≥90: 60–89: 31–59:

<30:

–6.7 0.6 1.1 0.2

NR

Sakata et al2 Mean ± SD Japanese

75.6±19.2

72.7±18.2

p=0.01

71.2±14.5

69.0±13.2

p=0.21

All pa:ents

Aloglip:n monotherapy (n=26)

SitaglipDn/aloglipDn crossover

Study populaDon

Fujita H et al. Clin J Am Soc Nephrol 2014;9:64 24

Sitaglip:n/Aloglip:n crossover

Study N Comparator

Fujita et al 12 Crossover study 100 (Japan)

Asian

SitaglipDn Week –4 AloglipDn Week

0 SitaglipDn Week 4

Albuminuria, eGFR, HbA1c

Fujita H et al. Clin J Am Soc Nephrol 2014;9:64 25

Sitaglip:n/Aloglip:n crossover

Fujita et al

Baseline At endpoint Significance

UACR mg/gCr

Microalbuminuria (30–300 mg/g)

Sita→Alo: p<0.01 Alo→Sita: NS

eGFR ml/min/1.73 m2

Mean ± SD 66.2±9.3 NS

HbA1c, % Mean ± SD 7.0±0.4 NS

VildaglipDn

Study populaDon

1. Tani S et al. Am J Cardiovasc Drugs 2013;13:443; 2. Hong AR et al. Diabetes Res Clin Pract 2015;109:141

27

Vildaglip:n

Study N Comparator

Tani et al1 47 None

VISUAL2 344 SU (dose increasing)

100 (Japan)

Tani

Asian

100 (Korea)

VISUAL

Albuminuria

*Not significant vs comparator (SU dose-‐increasing) 1. Tani S et al. Am J Cardiovasc Drugs 2013;13:443; 2. Hong AR et al. Diabetes Res Clin Pract 2015;109:141

28

Vildaglip:n


Tani et al1 UACR, median mg/gCr (range)

Japanese 27.0 (17.3, 67.8) Week 8: 15.0 (9.1, 60.0) p<0.0001

VISUAL2 Log UACR, mg/gCr Mean ± SE

Korean 2.8±1.5 Week 24: 2.9±1.5 NR*

eGFR (mL/min/1.73 m2)

*MDRD formula 1. Tani S et al. Am J Cardiovasc Drugs 2013;13:443; 2. Hong AR et al. Diabetes Res Clin Pract 2015;109:141

29

Vildaglip:n


Tani et al1 Mean ± SD* Japanese 69.0±12.5 Week 8:

69.3±13.2 p=0.748

VISUAL2 Korean NR

SaxaglipDn

Study populaDon

Mosenzon O et al. Diabet Met Res Rev 2013;29:417 31

Saxaglip:n

Study N Comparator

*SAVOR-‐TIMI 53 16,496 Placebo 74,8

10,7

14,5 Caucasian

Asian

Other

*SaxaglipDn Assessment Vascular Outcomes Recorded Thrombolysis In Myoc. InfacDon


*Significant vs placebo (p<0.001); †MDRD formula Scirica BM et al. New Engl J Med 2013;369:1317

32

Saxaglip:n

SAVOR-‐TIMI 53

Baseline At Year 1 Significance

UACR mg/mmol Cr

Median (range) 1.8 (0.7–7.5) NR*

eGFR ml/min/1.73 m2

Mean ± SD† 72.5±22.6 NR N/A

HbA1c, % Mean ± SD 8.0±1.4 7.6±1.4 NR*

X

Summary

•  In SAVOR-‐TIMI 53, a large cardiovascular outcomes trial, albuminuria levels remained unchanged in the majority of the populaDon (78.8%), with reducDons and elevaDons reported in 11.8% and 9.4% of paDents, respecDvely –  eGFR remained generally unchanged

33

Effect of Saxaglip:n on Renal Outcomes in the SAVOR-‐TIMI 53 Trial.

Mosenzon O1, Leibowitz G2, Bhaw DL3, et al.

Diabetes Care. 2017 Jan;40(1):69-‐76. doi: 10.2337/dc16-‐0621. Epub 2016 Oct 17. •  N= 16,492 paDents with DM-‐2 followed for a median of 2.1 years

•  RESULTS: At baseline normoAlbª 9,696 (58.8%)

micro Albª 4,426 (26.8%) macroAlbª 1,638 (9.9%)

•  Treatment with saxaglipDn was associated with improvement in and/or less deterioraDon in ACR categories from baseline to end of trial (P = 0.021 normo, P < 0.001 micro and P = 0.049 macroalbuminuria.

•  At 2 years mean ACR change between saxaglipDn and placebo arms was -‐ 19.3 mg/g (P = 0.033) for eGFR >50 mL/min/1.73 m2,

-‐105 mg/g (P = 0.011) for 50 ≥ eGFR ≥ 30 mL/min/BSA, -‐245.2 mg/g (P = 0.086) for eGFR <30 mL/min/BSA. ACR reducDon with saxaglipDn 1 year, P < 0.0001 2 years, P = 0.0143

The change in eGFR was similar in the saxaglipDn and placebo Safety renal outcomes, including doubling of serum creaDnine, iniDaDon of chronic dialysis, renal

transplantaDon, or serum creaDnine >6.0 mg/dL, were similar as well.

Effect of Saxaglip:n on Renal Outcomes in the SAVOR-‐TIMI 53 Trial.

Mosenzon O1, Leibowitz G2, Bhaw DL3, et al.

Diabetes Care. 2017 Jan;40(1):69-‐76. doi: 10.2337/dc16-‐0621. Epub 2016 Oct 17. CONCLUSIONS:

•  Treatment with saxaglipDn improved ACR, even in the normoalbuminuric range, without affecDng eGFR.

•  The beneficial effect of saxaglipDn on albuminuria could not be explained by its effect on glycemic control.

LinaglipDn

Effect of linaglip:n on albuminuria: pooled analysis

Groop PH, et al. Diabetes Care. 2013;36:1–9.

Effect of linagliptin on albuminuria on top of recommended standard treatment in patients with Type 2 Diabetes and

renal dysfunction

Study populaDons

1. Groop P-‐H et al. Diabetes Care 2013;36:3460; 2. Cooper ME et al. Am J Kidney Dis 2015;66:441

39

Linaglip:n – pooled analyses

Study N (Lina) Comparator

Groop et al1 (T2M paDents with renal dysfuncDon at BL)

162 Placebo

Cooper et al2 (Pooled analysis of renal endpoints)

3505 Placebo 69,8

25,9

4,3 Groop

64,2

33,6

2,2 Cooper

Caucasian Asian Other

Phase III clinical trials included in the pooled analysis

ClinicalTrials.gov registration number

Background treatment

Treatment groups Pooled analysis set Linagliptin Placebo n = 162 n = 55

NCT006211401 None Linagliptin: placebo 16 (9.9%) 10 (18.2%)

NCT007981612 None Linagliptin: placebo 10 (6.2%) 4 (7.3%)

NCT006012503 Metformin Linagliptin: placebo 47 (29.0%) 14 (25.5%)

NCT006024724 Metformin + sulphonylurea

Linagliptin: placebo 89 (54.9%) 27 (49.1%)

1. Del Prato S, et al. Diabetes Obes Metab. 2011;13:258–267; 2. Haak T, et al. Diabetes Obes Metab. 2012;14:565–574. data from other treatment groups (metformin, linagliptin + metformin) were not included in this analysis; 3. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65–74; 4. Owens DR, et al. Diabet Med. 2011;28:1352–1361.

Source: Groop PH, et al. Diabetes Care. 2013;36:1–9.

All four Phase III trials: •  Assessed safety and efficacy of linagliptin in patients with T2D •  Were randomized, double-blind, placebo-controlled •  Had identical study duration, primary endpoint definition and safety

assessments

Study design: paDent inclusion and analysis endpoint

*For at least 4 weeks prior to study conduct and from baseline to date of last UACR on-‐treatment measurement within the 24-‐week treatment period.


Placebo n = 55

Linagliptin n = 162

Baseline: •  30 <UACR ≤3,000 mg/g Cr •  eGFR ≥30 mL/min per 1.73 m2

n = 564

Pooled analysis set with stable ACE inhibitor/ARB therapy*

n = 217

Pooled population n = 2,472

Excluded (n = 1,908) •  Baseline UACR ≤30 mg/g Cr •  Baseline UACR >3,000 mg/g Cr •  Baseline eGFR <30 •  Missing UACR value

Excluded (n = 347) •  No ACE inhibitor/ARB therapy at baseline •  Unstable ACE inhibitor/ARB therapy

Primary endpoint: Percentage change in geometric mean UACR from baseline to Week 24

Percentage change in UACR

*p < 0.05 versus baseline.

†Adjusted for baseline UACR and trial effect; ‡Median UACR at baseline were: linaglipDn 73.8 (30.1–2534.4) mg/g Cr; placebo 80.5 (30.9–1538.2) mg/g Cr. Groop PH, et al. Diabetes Care. 2013;36:1–9.

-6 -6 -29* -32* -60

-40

-20

0

20

40 Placebo Linagliptin

Week 12 Week 24‡

Percentage change in UACR from baseline to 12 and 24 weeks Adjusted† geometric mean (95% CI)

55 n 170 56 162

Linagliptin placebo-corrected: -25% (95% CI -46 to 3), p = 0.0750

Linagliptin placebo-corrected: -28% (95% CI -47 to -2), p = 0.0357

•  After 24 weeks, the percentage change in UACR from baseline was significantly higher with linagliptin compared with placebo; change in UACR was independent of glucose lowering effects

•  The magnitude of the albuminuria-lowering effect of linagliptin was seen after 12 weeks of treatment

Change in UACR by HbA1c reducDon

*Adjusted for baseline UACR and trial effect. Groop PH, et al. Diabetes Care. 2013;36:1–9.

-32 -36

-26 -33

-60

-50

-40

-30

-20

-10

0

Adjusted* geometric mean percentage change in UACR by quartiles of HbA1c reduction in the linagliptin group

Perc

enta

ge c

hang

e in

UA

CR

fr

om b

asel

ine

to W

eek

24

(mea

n, 9

5% C

I)

Quartiles of HbA1c reduction from baseline to Week 24 (%) <0.10 n = 37

0.10–0.59 n = 41

0.60–0.99 n = 37

≥1.0 n = 47

Percentage changes in UACR for linagliptin across quartiles of HbA1c reduction were not statistically significantly different

Change in UACR by SBP change

*Adjusted for baseline UACR and trial effect. Groop PH, et al. Diabetes Care. 2013;36:1–9.

-35 -13

-35 -60 -50 -40 -30 -20 -10

0 10 20 30 40

Adjusted* geometric mean percentage change in UACR by categories of SBP change in the linagliptin group

Perc

enta

ge c

hang

e in

UA

CR

fr

om b

asel

ine

to W

eek

24

(mea

n, 9

5% C

I)

SBP change from baseline to last value on treatment (mmHg) Increase >1 mmHg

n = 66

Stable ± 1 mmHg

n = 25

Decrease >1 mmHg

n = 71

Percentage changes in UACR for linagliptin across categories of SBP change were not statistically significantly different

Albuminuria

1. Groop P-‐H et al. Diabetes Care 2013;36:3460; 2. Cooper ME et al. Am J Kidney Dis 2015;66:441

45

Linaglip:n – pooled analyses

Study Popula:on Baseline At endpoint (W 24) Significance

Groop et al1 UACR, median mg/gCr (range)

Mixed 73.8 (30.1–2534.4) NR

Cooper et al2 UACR, mean mg/gCr ± SE

Mixed 311.7±26.2 Change: –17.0 mg/g ±21.3

-‐60 -‐40 -‐20 0 20 40 Reduc:on in UACR Increase in UACR

Linaglip:n beZer Placebo beZer p-‐value

Change in UACR from baseline 0.0357

Placebo corrected change in UACR

White paDents

Asian paDents

Mean baseline HbA1c <8.25%

Mean baseline HbA1c ≥8.25%

X

0,1 1 10 Favours linaglip:n Favours placebo

p-‐value N of pa:ents with events

Overall popula:on 0.02 754 Age <65 0.003 510 ≥65 0.9 244

Race White 0.04 487 Asian 0.5 251 Black 0.4 16

Without ACEi/ARB 0.06 373 With ACEi/ARB 0.1 381

X

Conclusion

§  LinaglipDn significantly reduced albuminuria from baseline by 28% compared with placebo aler 24 weeks of treatment –  The magnitude of effect was seen aler 12 weeks of treatment

§  Albuminuria-‐lowering effect of linaglipDn was consistently found in relevant paDent subgroups (e.g., categorized by race, baseline HbA1c and baseline SBP)

§  Neither changes in blood pressure nor in HbA1c influenced the albuminuria-‐lowering effect of linaglipDn

§  This analysis suggests that linaglipDn may have direct effects on the kidney in T2D, warranDng prospecDve trials to test this hypothesis


LinaglipDn and albuminuria effect beyond glycaemic control

Source: Groop P-‐H, et al. Diab Vasc Dis Res.2015; pii: 1479164115579002

Dipeptidyl peptidase-4 inhibition with linagliptin and effects on hyperglycemia and albuminuria in patients

with Type 2 Diabetes and renal dysfunction: Rationale and design of the MARLINA–T2D™ trial

Study populaDon

Groop P-‐H et al. ADA 76th ScienDfic Sessions 2016. Poster 17-‐LB

48

Linaglip:n: MARLINA-‐T2D™

Study N Comparator

MARLINA-‐T2D™ 360 Placebo

30,3

66,4

3,3

Caucasian

Asian

Other

Study design

BMI, body mass index; Cr, creaDnine; EOT, end of treatment; HbA1c, glycosylated haemoglobin; OAD, oral anD-‐diabetes drug; RAAS, renin-‐angiotensin-‐aldosterone system; SGLT2, sodium glucose cotransporter 2 ; T2D, Type 2 Diabetes;

UACR, urinary albumin-‐to-‐creaDnine raDo. *RandomisaDon straDfied by HbA1c level (< 8.5% vs ≥ 8.5%) at screening and UACR level (< 300 mg/g Cr vs ≥ 300 mg/g Cr)

at start of run-‐in period. †Based on ModificaDon of Diet in Renal Disease formula at screening (Day –14). Source: Groop P-‐H, et al. Diab Vasc Dis Res.2015; pii: 1479164115579002

Screening Placebo run-in period

Linagliptin 5 mg once daily Plus background therapy

Placebo once daily Plus background therapy

Study week -3

Day -14

Follo

w-u

p

EOT+4

Exclusion criteria •  Non-diabetic renal disease •  Mealtime insulin use •  Dual/triple RAAS blockade •  Previous exposure to DPP4 inhibitors,

GLP1 receptor agonists or SGLT2 inhibitors

Visit 1 Visit 2 Visit 3

-2 Day -1

Visit 8

0

Visit 3.1 1:1 Randomisation*

24

Visit 7 EOT

6

Visit 4

12

Visit 5

18

Visit 6

The MARLINA–T2D™ study

Inclusion criteria •  HbA1c 6.5–10.0% •  Renal dysfunction •  Age 18–80 years •  BMI ≤ 40 kg/m2 •  Treatment-naïve or treated with 1–2 OADs and/or basal insulin

NOT EXHAUSTIVE


*CKD-‐EPI formula gCV, geometric coefficients of variaDon; gMean, geometric mean Groop P-‐H et al. ADA 76th ScienDfic Sessions 2016. Poster 17-‐LB

50

Linaglip:n: MARLINA-‐T2D™

MARLINA-‐T2D™

Baseline At Week 24 Significance

UACR mg/gCr

gMean (gCV) 126.1 (159.4) p=0.1954

eGFR (cysta:n C) ml/min/1.73 m2

Mean ± SD* 98.7 ± 46.8 N/A

HbA1c, % Mean ± SE 7.84 ± 0.88 p<0.0001

0,6

0,7

0,8

0,9

1,0

1,1

0 6 12 18 24

Adjusted

gMean Ra

Do (9

5% CI)

Week

Placebo (n=173) (gMean baseline UACR: 132.2 mg/gCr)

X

-‐10,0

-‐5,0

0,0

5,0

0 6 12 18 24

Adjusted

mean (SE) change from

baseline in eGF

R (CKD

-‐EPI, cystaDn

C)

(mL/min/1.73 m

2 )

Week

Placebo (n=173) (mean baseline eGFR: 93.8 mL/min/1.73 m )

2

2

X

-‐0,8

-‐0,6

-‐0,4

-‐0,2

0

0,2

Adjusted

mean (SE) cha

nge from

ba

selin

e in HbA

1c (%

)

Mean baseline 7.79 7.87

p<0.0001

n 172 171

-‐0.03

-‐0.63 -‐0.60

LinaglipDn

Placebo

Placebo-‐adjusted

X

Linaglip:n and its effects on hyperglycaemia and albuminuria in pa:ents with type 2 diabetes and renal dysfunc:on: the randomized MARLINA-‐T2D trial.

Groop PH1,2,3, Cooper ME3, Perkovic V4, Hocher B5,6,7, Kanasaki K8,9, Haneda M10, et

al. . Diabetes Obes Metab. 2017 Nov;19(11):1610-‐1619. doi: 10.1111/dom.13041. Epub 2017 Jul 31. Baseline x HbA1c and 7.8% ± 0.9% (62.2 ± 9.6 mmol/mol)

x geometric UACR 126 mg/g 73.7% of parDcipants had microAlbª 20.3% of parDcipants had macroAlbª Aler 24 weeks, the placebo-‐adjusted x change in HbA1c from baseline was P < .0001).

Efectos de la linaglipDna sobre el control glucémico y la albuminuria en la DM2 ( estudio MARLINA)

Cambios en albuminuria

DM Dpo 2, HbA1c: 6-‐10%, IMC < 40, FG > 30, ACR; 30-‐3000 mg/g 24 semanas de duración End point 1º: cambios en HbA1c, End point 2º: cambios en albuminuria

Groop PH1,2,3 et al. . Diabetes Obes Metab. 2017 Nov;19(11):1610-‐1619. doi: 10.1111/dom.13041. Epub 2017 Jul 31.

Estudio MARLINA: Cambios desde la base en la albuminuria en los disDntos grupos a las 24 semanas

Groop PH1,2,3 et al. . Diabetes Obes Metab. 2017 Nov;19(11):1610-1619. doi: 10.1111/dom.13041. Epub 2017 Jul 31.

Summary •  Pooled analyses of phase III studies show that linaglipDn

significantly reduces new onset of moderately elevated albuminuria by 18%

•  In MARLINA-‐T2D™ (N=360), linaglipDn significantly improved glycaemic control but did not significantly lower albuminuria. There was no significant change in placebo-‐adjusted eGFR.

•  DetecDon of clinically relevant renal effects of linaglipDn may require longer treatment, as its main experimental effects in animal studies have been to reduce intersDDal fibrosis rather than alter glomerular haemodynamics..

•  The ongoing CARMELINA® trial is invesDgaDng cardiovascular and renal outcomes with linaglipDn in paDents with T2D and advanced CKD

54

Summary of albuminuria changes with DPP-‐4 inhibitors

55

Sitaglip:n TECOS (N=14,671, mixed popula:on): Marginally improved UACR values with sitaglipDn

compared with placebo (-‐1.0 mg/g creaDnine) in the subset of 3669 paDents with data available

Aloglip:n No effect as monotherapy (Japanese paDents). Data are limited, but consistent

Vildaglip:n No effect in the study examined (Korean paDents). Data are limited, but consistent

Saxaglip:n SAVOR-‐TIMI (N=16,492, mixed popula:on; 2-‐years data based on N=6,553):

Reduced UACR in 11.1% and unchanged UACR in 76.0% of paDents. Exploratory analysis

Linaglip:n Reduced in two pooled analyses with mixed populaDons

No significant changes in the dedicated MARLINA-‐T2D™ trial (2/3 of paDents of Asian descent)

DPP-‐4i, dipepDdyl pepDdase-‐4 inhibitor Penno G et al. Nutr Metab Cardiovasc Dis 2016;26:361

N=213 ≥30 years of age with T2D and moderate or severe chronic renal insufficiency/ESRD; HbA1c: 7–10% (no glucose-‐lowering therapy); 6.5–9% (1 glucose-‐lowering agent); 7.5–10% (+ FPG >130 mg/dl with insulin)

Randomised, double blind, parallel assignment, safety/efficacy

Global

Merck Sharp & Dohme

Prior treatment: single oral glucose-‐lowering agents or low-‐dose dual oral combinaDon Comparator: placebo

Primary: change from BL in HbA1c at Week 24; proporDon of paDents who experienced ≥1 AE; proporDon of paDents who disconDnued the study due to an AE Secondary: change from BL in FPG (Week 24 and 54) and HbA1c (Week 54); eGFR (Week 24 and 54)

FPG, fasDng plasma glucose Study NCT01698775. hwps://clinicaltrials.gov/ct2/show/NCT01698775 (Accessed April 2016)

Omariglip:n: phase III study in paDents with CKD or kidney failure on dialysis

Oct 2012 Jan 2016 NCT01698775

56

N=88 20–70 years of age with T2D; HbA1c 7–9%; 24 h UAE 30–300mg

Randomised, open label, parallel assignment, efficacy

China

The Second Hospital of Nanjing Medical University

Prior treatment: stable mesormin (1000–2550 mg/day) or acarbose (100–300 mg/day) for ≥ 60 days Comparator: glimepiride

Primary: microalbuminuria improvement at Week 52 Secondary: incidence of hypoglycaemia at Week 52

Study NCT02462369. hwps://clinicaltrials.gov/ct2/show/NCT02462369 (Accessed April 2016)

Saxaglip:n: phase IV study on microalbuminuria improvements

Jun 2015 Oct 2017 Apr 2017 NCT02462369

57

N=129 ≥30 years of age with T2D and on dialysis; HbA1c 7–9%


Global

Merck Sharp & Dohme

Prior treatment: N/A Comparator: glipizide

Primary: change from BL in HbA1c at Week 54; number of paDents with clinical AEs Secondary: number of paDents with symptomaDc hypoglycaemic AEs (Week 54 + 28 days); change from BL in FPG; change from BL in HbA1c

Study NCT00509236. hwps://clinicaltrials.gov/ct2/show/NCT00509236 (Accessed April 2016); Arjona-‐Ferreira JC et al. Am J Kidney Dis 2013;61:579

Sitaglip:n: phase III study in paDents with end-‐stage renal disease

NCT00509236 Oct 2007 Mar 2011 ü

58

N=556 ≥25 years of age with T2D, mild renal impairment, and inadequate glycaemic control on mesormin


Global (excluding Japan)

Merck Sharp & Dohme

Prior treatment: mesormin monotherapy ≥1500 mg/day for ≥8 weeks Comparator: dapagliflozin

Primary: change from BL in HbA1c at Week 24; number of paDents who experienced ≥1 AE; number of paDents who disconDnued the study due to an AE Secondary: change in incremental 2-‐hour PPGE; change in 2-‐hour PPG; change in post-‐prandial glucagon AUC; change in post-‐prandial insulin AUC; change in post-‐prandial insulin AUC to glucagon AUC raDo, proporDon of paDents with HbA1c <7%; change in FPG; all endpoints at Week 24

AUC, area under the curve; PPG, post-‐prandial glucose; PPGE, post-‐prandial glucose excursion Study NCT02532855. hwps://clinicaltrials.gov/ct2/show/NCT02532855 (Accessed April 2016)

Sitaglip:n: phase III study in paDents with mild renal impairment

Oct 2015 May 2017 NCT02532855

59

N=32 18–70 years of age with T2D; HbA1c 6.5–9%; SBP 120–160 mmHg

Randomised, double blind, parallel assignment

Canada

Merck Sharp & Dohme and University Health Network, Toronto

Prior treatment: N/A Comparator: placebo

Primary: fracDonal sodium excreDon 3 hours aler single dose and at Day 28 Secondary: eGFR, ERPF, FF, RBF, RVR, plasma volume, plasma neurohormones, urinary vasoacDve mediators, markers of free radical stress, site of tubular sodium excreDon. All 3 hours aler single dose and at Day 28 Other: glycaemic control; blood cholesterol; albumin:creaDnine raDo

SBP, systolic blood pressure Study NCT02406443. hwps://clinicaltrials.gov/ct2/show/NCT02406443 (Accessed April 2016)

Sitaglip:n: phase IV study on outcomes on renal sodium excreDon (INDORSE)

Mar 2015 Dec 2016 Jun 2016 NCT02406443

60

N=110 18–75 years of age with T2D; HbA1c 7–9%, BP <145/90 mmHg on treatment with ACEi or ARB for >3 months; UACR 30–299 mg/dl; eGFR ≥60 ml/min/1.73 m2

Randomised, double blind, parallel assignment, efficacy

US

Merck Sharp & Dohme and University of Missouri-‐Columbia

Prior treatment: ACEi or ARB Comparator: placebo

Primary: decrease in microalbuminuria levels at Month 6 Secondary: none

*Recruitment status of this study is unknown because the informaDon has not been verified recently (last Jan 2014) Study NCT02048904. hwps://clinicaltrials.gov/ct2/show/NCT02048904 (Accessed April 2016)

Sitaglip:n: phase IV study on UACR in paDents with overt kidney disease

Jan 2014 ???* Jan 2016 NCT02048904

61

N=70 Caucasian, 35–75 years of age with T2D; HbA1c 6.5–9%; BMI 25–40 kg/m2

Randomised, double blind, parallel assignment, safety

The Netherlands

VU University Medical Center & EU FP7: SAFEGUARD consorDum

Prior treatment: stable dose of oral glucose-‐lowering agents (either mesormin alone, SU alone or a combinaDon of mesormin and SU) for ≥3 months Comparator: placebo*

Primary: changes from BL with GLP-‐1RA (acute effects and at Week 12) or sitaglipDn (Week 12) in pancreaDc exocrine funcDon Secondary: effect of GLP-‐1RA (acute) and GLP-‐1RA or DPP-‐4i (Week 12) on: CV parameters;† renal parameters (i.e. ERPF, renal tubular funcDon, renal damage); and gastrointesDnal parameters†

*The agents tested are not compared with each other; †See notes for detailed list of CV and gastrointesDnal outcomes BMI, body mass index; GLP-‐1RA, glucagon-‐like pepDde-‐1 receptor agonist Study NCT01744236. hwps://clinicaltrials.gov/ct2/show/NCT01744236 (Accessed April 2016); Smits MM et al. BMJ Open 2015;5:e009579

Sitaglip:n, exenaDde, or liragluDde: phase IV SAFEGUARD study

NCT01744236 Apr 2013 Aug 2015 ü

62

N=148 18–85 years of age with T2D and severe renal impairment, not undergoing dialysis; glucose ≤270 mg/dl (≤15 mmol/l)


US

NovarDs

Prior treatment: N/A Comparator: sitaglipDn

Primary: safety and tolerability in paDents with T2D and severe renal impairment (Week 24) Secondary: relaDonship between renal funcDon and concentraDon levels of vildaglipDn and its metabolites aler repeated administraDon (Week 24) Other: HbA1c and FPG reducDon from baseline (Week 24)

Study NCT00616811. hwps://clinicaltrials.gov/ct2/show/NCT00616811 (Accessed April 2016); Kothny W et al. Diabetologia 2015;58:2020

Vildaglip:n: phase III study in paDents with severe renal impairment

NCT00616811 Jan 2008 Oct 2010 ü

63

N=525 18–85 years of age with T2D and moderate or severe renal impairment; glucose ≤270 mg/dl (≤15 mmol/l)


Global (excluding US, China and Japan)

NovarDs

Prior treatment: N/A Comparator: placebo

Primary: safety and tolerability in paDents with T2D and moderate or severe renal impairment (Week 24) Secondary: concentraDon levels of vildaglipDn and its metabolites and efficacy of vildaglipDn in the invesDgated populaDon; both at Week 24

Study NCT00646542. hwps://clinicaltrials.gov/ct2/show/NCT00646542 (Accessed April 2016) Kothny W et al. Diabetes Obes Metab 2012;14:1032

Vildaglip:n: phase III study in paDents with moderate or severe renal impairment

NCT00646542 Mar 2005 Oct 2010 ü

64

CARDIOVASCULAR OUTCOME TRIALS

CARMELINA® Trial Baseline CharacterisDcs: A Cardiovascular and Renal Outcome Trial With LinaglipDn in PaDents With Type 2 Diabetes at High Vascular Risk

PublicaDon Summary Slides: ADA 2017 poster

Source: Rosenstock J., et al. ADA 2017, Poster 1284-‐P

CARMELINA® trial design

67

LinaglipDn 5 mg/day (in addiDon to standard of care)

Placebo (in addiDon to standard of care)

RScreening Visit 1

R RandomizaDon (1:1) at visit 2 (week 0)

Week −2

Week 0

Trial conDnues unDl 611 primary outcome events accrue

End of Treatment*

+30 days

Follow-‐up

§  The protocol also encourages the invesDgators and paDents’ HCPs to treat all CV risk factors (e.g. lipid levels, blood pressure, albuminuria, hyperglycaemia, smoking) according to an opDmal level of local/regional standard of care

CV, cardiovascular; HCP, healthcare provider. *PaDents who stop treatment early are observed unDl study end (not just unDl their treatment stop + 30 days). Source: Rosenstock J., et al. ADA 2017, Poster 1284-‐P

§  MulD-‐naDonal, randomized, double-‐blind, placebo-‐controlled clinical trial (ClinicalTrials.gov: NCT01897532)

Key inclusion criteria

68

Patients wirisk of CV events defined asth documented diagnosis of T2DM at high :

Age ≥18 years HbA1c of ≥6.5% and ≤10.0%

BMI ≤45 kg/m2

and/or

Impaired kidney func:on with or without albuminuria

•  eGFR:15−<45 mL/min/1.73 m2

•  eGFR ≥45−75 mL/min/1.73 m2 with UACR >200 mg/g creaDnine or >200 mg/L or >200 μg/min or >200 mg/24 h

Albuminuria (UACR >30 mg/g*) and previous macrovascular disease, defined as ≥1 of the following:

•  Confirmed history of MI •  Advanced CAD†

•  High-‐risk single-‐vessel CAD •  History of ischaemic or haemorrhagic

stroke •  Presence of caroDd artery disease •  Presence of peripheral artery disease BMI, body-‐mass index; CAD, coronary artery disease; CT, computed tomography; CV, cardiovascular; eGFR, esDmated glomerular filtraDon rate; HbA1c, glycated haemoglobin A1c; MI, myocardial infarcDon; MRI,

magneDc resonance imaging; T2DM, type 2 diabetes; UACR, urinary albumin-‐to-‐creaDnine raDo. *Albuminuria was also defined as ≥30 μg albumin/min or ≥30 mg albumin/24 h. †Any 1 of the following: ≥50% narrowing of the luminal diameter in ≥2 major coronary arteries by coronary angiography, MRI

angiography or CT angiography; lel main stem coronary artery with ≥50% narrowing of the luminal diameter by coronary angiography, MRI angiography or CT angiography; prior percutaneous or surgical

revascularizaDon of ≥2 major coronary arteries ≥2 months prior to Visit 1 (screening); the combinaDon of prior percutaneous or surgical revascularizaDon of 1 major coronary artery ≥2 months prior to Visit 1, and

≥50% narrowing of the luminal diameter by coronary angiography, MRI angiography or CT angiography of ≥1 addiDonal major coronary artery. Source: Rosenstock J., et al. ADA 2017, Poster 1284-‐P

The primary endpoint is 3P-‐MACE: i.e., the Dme to first occurrence of CV death, non-‐fatal MI or non-‐fatal stroke

The key secondary endpoint is the Dme to first occurrence of kidney death, sustained end-‐stage kidney disease or sustained decrease of ≥40% in eGFR

Endpoints

3P-‐MACE, 3-‐component composite endpoint of major adverse CV events; CV, cardiovascular; eGFR, esDmated glomerular filtraDon rate;

HbA1c, glycated haemoglobin A1c; MI, myocardial infarcDon. Source: Rosenstock J., et al. ADA 2017, Poster 1284-‐P 69

§  All CV and renal events are adjudicated by an independent and blinded Clinical Event Commiwee §  HospitalisaDon for heart failure is an adjudicated, pre-‐specified endpoint §  Glycaemia-‐related endpoints include change from baseline in levels of HbA1c and fasDng plasma glucose

H0(MACE) H0(Kidney)

TesDng Hierarchy 3P-‐MACE

non inferiority

3P-‐MACE Kidney Composite

α=2.5% one-‐sided

0.2α=0.5%

0.8α=2.5%

superiority superiority

3P-‐MACE, 3-‐component composite endpoint of major adverse CV events (cardiovascular death, nonfatal myocardial infarcDon or non-‐fatal stroke). Source: Rosenstock J., et al. ADA 2017, Poster 1284-‐P

Sequen:ally rejec:ve mul:ple test procedure: §  First is a non-‐inferiority test of linaglipDn versus placebo for 3P-‐MACE:

§  if non-‐inferiority is demonstrated, the second step will test separately for superiority of 3P-‐MACE and for superiority of the kidney composite endpoint

Baseline characterisDcs, overall and by renal and CV risk categories at baseline (1)

PaDents with no kidney risk and no CV risk: n=59. PaDents with missing kidney risk and missing CV risk: n=5. CV, cardiovascular disease; eGFR, esDmated glomerular

filtraDon rate; HbA1c, glycated haemoglobin A1c; MDRD, ModificaDon of Diet in Renal Disease study equaDon; SD,

standard deviaDon; UACR, urinary albumin-‐to-‐creaDnine raDo. *eGFR 15 to <45 mL/min/1.73 m2 or eGFR ≥45 to 75 mL/min/

1.73 m2 with UACR >200 mg/g; †albuminuria and previous macrovascular disease without evidence of impaired renal

funcDon; ‡albuminuria and previous macrovascular disease plus eGFR 15 to <45 mL/min/1.73 m2 or eGFR ≥45 to 75 mL/

min/1.73 m2 with UACR >200 mg/g. Source: Rosenstock J., et al. ADA 2017, Poster 1284-‐

P

71

Total (n=6980)

Kidney* only (n=2927)

CV only† (n=2728)

Kidney + CV‡

(n=1261)

Age, years, mean (SD) 65.8 (9.1) 67.2 (9.2) 63.8 (8.7) 66.9 (8.6)

Male, n (%) 4390 (62.9) 1604 (54.6) 1863 (68.0) 889 (70.3)

Race, n (%)

White 5595 (80.2) 2230 (75.9) 2297 (83.8) 1015 (80.2)

Asian 641 (9.2) 303 (10.3) 205 (7.5) 129 (10.2)

Black/African American 411 (5.9) 244 (8.3) 86 (3.1) 77 (6.1)

Region

Europe 2833 (40.6) 1104 (37.6) 1260 (46.0) 453 (35.8)

South America 2310 (33.1) 933 (31.8) 950 (34.7) 412 (32.6)

North America 1180 (16.9) 606 (20.6) 293 (10.7) 252 (19.9)

Asia 657 (9.4) 284 (9.7) 225 (8.2) 144 (11.4)

eGFR (MDRD), mL/min/1.73 m2, mean (SD) 54.6 (25.0) 38.3 (13.6) 75.7 (21.6) 46.1 (18.3)

eGFR (MDRD), n (%)

≥90 mL/min/1.73 m2 728 (10.4) 5 (0.2) 684 (25.0) 30 (2.4)

≥60−<90 mL/min/1.73 m2 1903 (27.3) 235 (8.0) 1391 (50.7) 248 (19.6)

≥45−<60 mL/min/1.73 m2 1349 (19.3) 543 (18.5) 490 (17.9) 299 (23.6)

≥30−<45 mL/min/1.73 m2 1937 (27.8) 1331 (45.3) 134 (4.9) 464 (36.7)

<30 mL/min/1.73 m2 1063 (15.2) 813 (27.7) 29 (1.1) 220 (17.4)

HbA1c, %, mean (SD) 7.9 (1.0) 7.9 (1.0) 8.0 (1.0) 8.0 (1.0)

Diabetes duraDon, mean (SD) 14.7 (9.5) 16.0 (9.6) 12.6 (9.0) 16.5 (9.4)

Prognosis of CKD in CARMELINA® populaDon by eGFR and albuminuria categories*

72 CKD, chronic kidney disease; eGFR, esDmated glomerular filtraDon rate; KDIGO, Kidney Disease: Improving Global Outcomes organisaDon; UACR, urinary albumin-‐to-‐creaDnine raDo. Source: Rosenstock J., et al. ADA

2017, Poster 1284-‐P

*Based on KDIGO categories. Reprinted from Kidney Int, 80, Levey et al, The definiDon, classificaDon, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report, 17–28, Copyright 2011, with permission from Elsevier

Prognosis of CKD Low risk Moderate risk High risk Very high

risk

CARMELINA® populaDon at baseline; n (%) 484 (6.9) 1561 (22.4) 1902 (27.2) 3033 (43.5)

UACR (mg/g)

eGFR (mL/min/1.73 m2) <30 30−300 >300

>60

45−59

30−44

<30

CARMELINA® (LinaglipDn) N=6980

SAVOR-‐TIMI 581 (SaxaglipDn) N=16,492

EXAMINE2 (AloglipDn) N=5380

TECOS3 (SitaglipDn) N=14,671

EMPA-‐REG OUTCOME®4

(Empagliflozin) N=7020

ELIXA5 (LixisenaDde)

N=6068

LEADER6 (LiragluDde) N=9340

SUSTAIN-‐67 (SemagluDde)

N=3297

62,3

15.6* 29,1

9.3*

25,9 23,2 23,1 28,5

0 10 20 30 40 50 60 70 80 90

100

Prop

or:o

n of pa:

ents with

kidn

ey disease (%

)

•  In CARMELINA®, 62.3% of paDents had an eGFR <60 mL/min/1.73 m2, compared with 9.3% to 29.1% of paDents in other CVOTs1-‐7

ProporDon of CVOT populaDons with kidney disease (eGFR <60 mL/min/1.73 m2)

CVOT, cardiovascular outcomes trial; eGFR, esDmated glomerular filtraDon rate. 1. Scirica BM, et al. N Engl J Med. 2013;369:1317–1326; 2. White WB, et al. N Engl J Med. 2013;369:1327–1335; 3. Green JB, et al. N Engl J Med. 2015;373:232–242; 4. Zinman B, et al. N Engl J Med. 2015;373:2117–2128; 5. Pfeffer MA, et al. N Engl J Med. 2015;373:2247–2257; 6. Marso SP, et al. N Engl J Med.

2016;375:311–322; 7. Marso SP, et al. N Engl J Med. 2016;375:1834–1844. *Kidney disease defined as eGFR <50 mL/min/1.73 m2.

Source: Rosenstock J., et al. ADA 2017, Poster 1284-‐P

•  CARMELINA® is designed to assess the addiDon of the DPP-‐4 inhibitor linaglipDn versus placebo to standard care in paDents with T2DM

•  In comparison to other recent outcome trials in T2DM, CARMELINA® includes the highest number of paDents with reduced kidney funcDon (n=4190), including those with very low eGFR (<30 mL/min/1.73 m2, n=1063). These paDents: –  are at a high cardio-‐renal risk –  face limited glucose-‐lowering treatment opDons –  mark an under-‐represented populaDon in CVOTs in T2DM

•  CARMELINA® will add evidence to the long-‐term clinical safety profile of linaglipDn by including paDents at advanced stages of kidney disease

Summary at Baseline

CVOT, cardiovascular outcomes trial; DPP-‐4, dipepDdyl pepDdase-‐4; eGFR,

esDmated glomerular filtraDon rate; T2DM, type 2 diabetes mellitus. Source:

Rosenstock J., et al. ADA 2017, Poster 1284-‐P

74

iDPP-‐4. MENSAJES PARA CASA. •  Perfil de seguridad y tolerabilidad en pacientes con DM-‐2 y ERC, los iDPP4 requieren ajuste de dosis según FGe, excepto para lina/teneliglipDna.

•  Efecto anDproteinúrico demostrado en “pooled analysis” con linaglipDna y ocasionalmente con otros iDPP4, solo parcialmente pero no global en el estudio MARLINA y en SAVOR-‐TIMI renal outcomes.

•  Mantenimiento ( no efecto sobre) del FGe. •  En espera confirmación resultados en diversos estudios “ongoing” y efectos CV/renales del estudio CARMELINA y CAROLINA (linaglipDna).

Efectos vasculares y renales de los Inhibidores de DPP4

Alberto Mar+nez-‐Castelao Consultor emérito Hospital Universitari Bellvitge, IDIBELL Hospitalet. Barcelona. REDinREN , InsDtuto Salud Carlos III.

MUCHAS GRACIAS

POR VUESTRA ATENCION

Study Popula:on Baseline At endpoint Significance Mori et al1 UACR, mean mg/g ± SD

Japanese 61.4±154.3 Month 6: 42.2±126.4 p<0.05

Arjona Ferreira et al2 UACR, mean mg/g ± SE

Mixed NR

Harashima et al3 UACR, mean mg/g ± SD

Japanese 76.2±95.6 Week 52: 33.0±48.1 p<0.001

Albuminuria (2/2)

BL, baseline 1. Mori H et al. J Diabetes Invest 2014;5:313; 2. Arjona Ferreira JC et al. Diabetes Care 2013;36:3460067; 3. Harashima SI et al. Int J Clin Pract 2012;66:465

78

Sitaglip:n

-‐0,10 -‐0,06 -‐0,02 0,02 0,06 0,10 0,14 0,18 0,22 0,26 0,30

Albu

min:crea:

nine

Ch

ange from

baseline (M

ean ± SE)

BL Week 6 Month 6 Year 1 Time

SitaglipDn Glipizide

X


Mori et al1 Mean ± SD Japanese 77.1±18.9 Month 6:

73.7±16.0 p<0.05

Arjona Ferreira et al2 Mean ± SD Mixed NR

Harashima et al3 Japanese NR

eGFR (mL/min/1.73 m2) (2/2)

1. Mori H et al. J Diabetes Invest 2014;5:313; 2. Arjona Ferreira JC et al. Diabetes Care 2013;36:3460067; 3. Harashima SI et al. Int J Clin Pract 2012;66:465

79

Sitaglip:n

-‐5

-‐4

-‐3

-‐2

-‐1

0

1

eGFR

, mean chan

ge ± SE

0 6 12 18 30 42 54

SitaglipDn Glipizide

Week

X

Summary

•  Albuminuria outcomes with vildaglipDn are so far only available in Asian paDents –  Marginal UACR reducDons were observed in Japanese paDents (N=47) –  No effect on UACR levels was observed in a larger (N=344) Korean study –  Data are limited, but consistent

80

Time points of key biochemical and clinical parameters assessed

ABPM, ambulatory blood pressure measurement; BP, blood pressure; eCrCl, esDmated creaDnine clearance; eGFR, esDmated glomerular filtraDon rate; EOT, end of treatment; HbA1c, glycosylated haemoglobin; KIM-‐1, kidney injury molecule-‐1; LFABP, liver fawy acid binding protein; NGAL, neutrophil

gelaDnase-‐associated lipocalin; UACR, urinary albumin-‐to-‐creaDnine raDo. *EsDmated using Cockrol-‐Gault formula. †EsDmated using either the MDRD (ModificaDon of Diet in Renal Disease) or

CKD-‐EPI (Chronic Kidney Disease Epidemiology CollaboraDon) equaDon. Source: Groop P-‐H, et al. Diab Vasc Dis Res.2015; pii: 1479164115579002

Study week -3

Day -14 EOT+4

Visit 1 Visit 2 Visit 3

-2 Day -1

Visit 8

0

Visit 3.1 Randomisation

24

Visit 7 EOT

6

Visit 4

12

Visit 5

18

Visit 6

Screening

Placebo run-in period Treatment period

Follow-up

•  Albuminuria will be determined by the geometric mean UACR value from 3 urine samples taken on 3 consecutive days at each visit (first void morning spot urine samples). At least 2 out of the requested 3 samples have to be available at each time point.

HbA1c (%) ü ü ü ü ü UACR (mg/gCr) ü ü ü ü ü ü ü ü eCrCl (mL/min)* + eGFR (mL/min/1.73 m2)† ü ü ü ü ü ü ü BP (ABPM) (mmHg) ü ü Markers of tubular damage (KIM-1, LFABP, and NGAL) (ng/mL)

ü ü ü

Baseline characterisDcs, overall and by renal and CV risk categories at baseline (2)

PaDents with no kidney risk and no CV risk: n=59. PaDents with missing kidney risk and missing CV risk: n=5. ACE, angiotensin-‐converDng enzyme; ARB, angiotensin-‐receptor blocker; CV, cardiovascular disease; DBP, diastolic blood pressure; HDL, high-‐density lipoprotein; LDL, low-‐density lipoprotein; SBP, systolic blood

pressure; SD, standard deviaDon; UACR, urinary albumin-‐to-‐creaDnine raDo. *eGFR 15 to <45 mL/min/1.73 m2 or eGFR ≥45 to 75 mL/min/1.73 m2 with UACR >200 mg/g; †albuminuria and previous macrovascular

disease without evidence of impaired renal funcDon; ‡albuminuria and previous macrovascular disease plus eGFR 15 to <45 mL/min/1.73 m2 or eGFR ≥45 to 75 mL/min/1.73 m2 with UACR >200 mg/g; §Includes direct

LDL. Source: Rosenstock J., et al. ADA 2017, Poster 1284-‐P

82

Total (n=6980)

Kidney* only (n=2927)

CV only† (n=2728)

Kidney + CV‡

(n=1261)

UACR, mg/g, median (25th−75th percenDle) 162.0 (44.0−727.0) 251.0 (34.0−1156.0) 98.0 (41.0−267.0) 353.0 (96.0−1120.4)

UACR, n (%)

<30 mg/g 1390 (19.9) 694 (23.6) 530 (19.3) 138 (10.9)

30−300 mg/g 2896 (41.5) 866 (29.5) 1564 (57.1) 446 (35.3)

>300 mg/g 2691 (38.6) 1365 (46.5) 633 (23.1) 677 (53.5)

SBP, mmHg, mean (SD) 140.5 (17.9) 142.3 (19.1) 138.2 (16.0) 141.6 (18.1)

DBP, mmHg, mean (SD) 77.8 (10.5) 77.4 (10.8) 78.9 (9.7) 76.6 (11.1)

LDL cholesterol§, mg/dL, mean (SD) 91.1 (39.6) 93.6 (39.9) 90.2 (39.3) 87.6 (39.4)

HDL cholesterol, mg/dL, mean (SD) 44.5 (12.9) 45.5 (13.8) 43.9 (12.0) 43.7 (12.6)

Glucose-‐lowering therapy, n (%) 6802 (97.4) 2837 (96.6) 2668 (97.3) 1235 (97.6)

Mesormin 3823 (54.8) 1121 (38.2) 2084 (76.0) 572 (45.2)

Sulphonylurea 2434 (34.9) 923 (31.4) 1131 (41.3) 355 (28.1)

Insulin 4039 (57.9) 1934 (65.8) 1216 (44.4) 860 (68.0)

AnDhypertensives 6637 (95.1) 2815 (95.8) 2557 (93.3) 1206 (95.3)

ACE inhibitors or ARBs 5655 (81.0) 2396 (81.6) 2218 (80.9) 996 (78.7)

β-‐blockers 4144 (59.4) 1547 (52.7) 1701 (62.1) 861 (68.1)

DiureDcs 3711 (53.2) 1837 (62.5) 1116 (40.7) 732 (57.9)

Calcium antagonists 2870 (41.1) 1393 (47.4) 882 (32.2) 571 (45.1)

Aspirin 4764 (68.3) 1592 (54.2) 2132 (77.8) 1009 (79.8)

2. efectos castelao...improved(diabetes(care(has(notyetsucceeded(in(reducing(renal(complicaons(0 50...

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