and renal benefits of GLP-1 receptor agonists Filip Krag Knop, MD - PowerPoint PPT Presentation

The science behind vascular and renal benefits of GLP-1 receptor agonists Filip Krag Knop, MD Copenhagen, Denmark June 15, 2019 - Budapest, Hungary

The science behind cardiovascular and renal benefits of GLP-1 receptor agonists Filip K. Knop, MD PhD Professor, Consultant Endocrinologist, Head of Center for Clinical Metabolic Research Gentofte Hospital, University of Copenhagen Denmark

Contemporary CVOTs in diabetes ELIXA SUSTAIN 6 ACE REWIND AMPLITUDE-O SOLOIST-WHF (Lixisenatide, GLP-1RA) (Semaglutide, QW GLP-1RA) (Acarbose, AGI) (Dulaglutide, QW GLP-1RA) (Efpeglenatide, GLP-1RA) (Sotagliflozin, SGLT-1i & SGLT-2i) n=6068; follow-up ~2 yrs n=3297; duration ~2.8 yrs n=6522; duration ~8 yrs n=10,010; duration ~6.5 yrs n=4000*; duration ~2.7 yrs n=4000*; duration ~3 yrs Q1 2015 – RESULTS Q3 2016 – RESULTS Q2 2017 – RESULTS Q3 2018 – RESULTS Completion Q1 2021 Completion Q2 2021 TOSCA IT ALECARDIO EMPA-REG OUTCOME CANVAS PIONEER 6 SCORED (Aleglitazar, PPAR- αγ ) n=7226; (Pioglitazone, TZD) (Empagliflozin, SGLT-2i) (Canagliflozin, SGLT-2i) (Oral semaglutide, GLP-1RA) (Sotagliflozin, SGLT-1i & SGLT-2i) n=3028; duration ~10 yrs follow-up 2 yrs n=7000; duration up to 5 yrs n=4418; duration 4+ yrs n=3176*; duration ~1.5 yrs n=10,500*; duration ~4.5 yrs Q4 2017 † – RESULTS Termin. Q3 2013 – RESULTS Q3 2015 – RESULTS Q2 2017 – RESULTS Q4 2018 - RESULTS Completion Q1 2022 EXAMINE LEADER CANVAS-R HARMONY OUTCOMES VERTIS CV (Alogliptin, DPP-4i) (Liraglutide, GLP-1RA) (Canagliflozin, SGLT-2i) (Albiglutide, QW GLP-1RA) (Ertugliflozin, SGLT-2i) n=5380; follow-up ~1.5 yrs n=9340; duration 3.5 – 5 yrs n=5826; duration ~3 yrs n=9574; duration ~4 yrs n=8000*; duration ~6.3 yrs PPAR- αγ Q3 2013 – RESULTS Q2 2016 – RESULTS Q2 2017 – RESULTS Q2 2018 - RESULTS Completion Q3 2019 DPP-4i CREDENCE (cardio-renal) SAVOR-TIMI 53 EXSCEL DECLARE-TIMI 58 FREEDOM (Canagliflozin, SGLT-2i) GLP-1RA (Saxagliptin, DPP-4i) (Exenatide ER, QW GLP-1RA) (Dapagliflozin, SGLT-2i) (ITCA 650, GLP-1RA in DUROS) n=4401; duration 4.5 yrs n=16,492; follow-up ~2 yrs n=14,752; follow-up ~3 yrs n=17,276; duration ~6 yrs n=4000; duration ~2 yrs Q3 2018 – TERMINATED (+ve Q2 2013 – RESULTS Q3 2017 – RESULTS Q3 2018 – RESULTS Q2 2016 – TOPLINE RESULTS SGLT-2i efficacy) - RESULTS Insulin TECOS CARMELINA CAROLINA DEVOTE (Sitagliptin, DPP-4i) (Linagliptin, DPP-4i) (Linagliptin, DPP-4i vs SU) (Insulin degludec, insulin) TZD n=14,671; duration ~3 yrs n=7003; duration 4.5 yrs n=6072; duration ~8 yrs n=7637; duration ~2 yrs Q1 2015 – RESULTS Q2 2017 – RESULTS Q1 2018 - RESULTS Q3 2018 - RESULTS AGI 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 *Estimated enrolment; †Stopped early after a median follow -up of 57.4 months following futility analysis. Trials with filled boxes are completed. Trials with a white background are ongoing. ClinicalTrials.gov (August 2018)

Recent CVOTs with antidiabetic agents Primary composite endpoint: MACE DPP-4i SGLT2i GLP-1RA Insulin EXAMINE EMPA-REG Outcome ELIXA* ORIGIN Alo vs. Pbo Empa vs. Pbo Lixi vs. Pbo Glargine U100 vs. SOC DEVOTE SAVOR TIMI-53 CANVAS Program FREEDOM-CVO ? Degludec vs. Saxa vs. Pbo Cana vs. Pbo ITCA 650 vs. Pbo Glargine U100 TECOS* DECLARE-TIMI 58 LEADER Sita vs. Pbo Dapa vs. Pbo Lira vs. Pbo CARMELINA SUSTAIN-6 Lina vs. Pbo Sema vs. Pbo EXSCEL Exe OW vs. Pbo HARMONY Alb vs. Pbo REWIND Dul vs. Pbo 0,1 0,4 0,7 1,0 1,3 0,1 0,4 0,7 1,0 1,3 0,1 0,4 0,7 1,0 1,3 1,6 0,1 0,4 0,7 1,0 1,3 HR [95% CI] HR [95% CI] HR [95% CI] HR [95% CI] *MACE+ Pffefer et al. N Engl J Med 2015;373:2247 – 57; Intarcia press release 06 May 2016; Marso et al. N Engl J Med 2016;375:311 – 22; *MACE+ White et al. N Engl J Med 2013; 369:1327 – 35; Marso et al. N Engl J Med 2016;375:1834 – 44; Holman et al . N Zinman et al. N Engl J Med 2015; 373:2117- 28; Neal et al. N Engl J Med 2017;377:644 – Scirica et al. N Engl J Med 2013;369:1317 – 26; Engl J Med 2017;377:1228 – 39; Hernandez et al . Lancet. 2018 Oct Gerstein et al. N Engl J Med 2012;367: Green et al. N Engl J Med 2015;373:232 – 42; 319 – 28; Marso et al. N Engl J Med 2017;377:723 – 57; Wiviott et al. N Engl J Med. 2019 Jan 27;392(10157):1519-1529. ; Gerstein et al . Lancet . 2019 Jun 10. McGuire et al. JAMA . 2019 Jan 1;321(1):69-79. 24;380(4):347-357. http://dx.doi.org/10.1016/S0140-6736(19)31149-3 32

Renal outcomes in T2D CVOTs REWIND 3 New macroalbuminuria, 30% fall in eGFR or the need for continuous renal-replacement therapy SUSTAIN 6 2 LEADER 1 Macroalbuminuria, doubling of serum creatinine Macroalbuminuria, doubling of serum creatinine and eGFR ≤45 mL/min/1.73 m 2 per MDRD or the and eGFR ≤45 mL/min/1.73 m 2 per MDRD, need for continuous renal-replacement therapy 10 ESRD or renal death Patients with an event (%) 1 0 Patients with an event (%) Placebo HR: 0.64 HR: 0.78 8 8 Placebo HR: 0.85 95% CI (0.46; 0.88) 95% CI (0.67; 0.92) p =0.005 95% CI (0.78; 0.93) p =0.003 6 6 p =0.0004 Liraglutide 4 4 Semaglutide 2 2 0 0 0 8 16 24 32 40 48 56 64 72 80 88 96 104 0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 Time since randomisation (weeks) Time since randomisation (months) CI, confidence interval; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HR, hazard ratio; MDRD, 1. Mann JFE et al. N Engl J Med 2017;377:839 – 848; 2. Marso SP et al. N Engl J Med 2016;375:1834 – 1844; 3. Gerstein HC et al. Lancet 2019; Epub 2019 June 10

Introduction to the incretin hormone GLP-1

The incretin hormones Glucose-dependent insulinotropic polypeptide (GIP) Glucagon-like peptide-1 (GLP-1) 80 Meal Plasma GLP-1 (pM) His Ala Glu Gly Thr Phe Thr Ser Asp Val GIP 60 7 Ser 40 Lys Ala Ala Gln Gly Glu Leu Tyr Ser Glu 20 Phe 37 GLP-1 Lys Ile Ala Trp Leu Val Gly Arg Gly 0 -30 0 30 60 90 120 150 180 210 240 Bell et al. Nature 1983 4 Time (min) GLP-1-positive endocrine L-cells in human Knop et al. Am J Physiol Endocrinol Metab 2007 3 small intestine (Knop et al. Unpublished) K cells L cells 1. Brown JC, Dryburgh JR. Can J Biochem 1971;49:867 – 872; 2. Jörnwall H et al. FEBS Lett 1981;123:205 – 210; 3. Knop FK et al. Am J Physiol Endocrinol Metab 2007;292:E324 – 330; 4. Bell GL et al. Nature 1983;304:368 – 371

Potential modes of action for GLP-1 receptor activation to GLP-1 receptors are widely distributed in the human body impact CV and/or renal disease GLP-1, glucagon-like peptide-1 Drucker. Cell Metab 2016;24:15 – 30

Mechanism for CV/CKD risk reduction is likely to be multifactorial 1 – 3 Placebo Glucose (mM) n = 10 T2D GLP-1 15.0 12.5 10.0 * 7.5 * * * * * Infusion of GLP-1 Glycaemia or placebo Insulin (pM) Effects on insulin and glucagon Body weight 250 cease alongside the occurrence 200 * * of normoglycaemia * 150 * * * Blood pressure * 100 50 Blood lipids Glucagon (pM) 20 15 * 10 * * * GLP-1 receptor expression in the human pancreas 5 5 *p<0.05 0 0 60 120 180 240 Time (min) CV, cardiovascular; CKD, chronic kidney disease 1. Dalsgaard et al. Diabetes Obes Metab 2018;20:508 – 519; 2. Farr et al. Cardiovasc Haematol Disord Drug Targets 2014;14:126 – 36; 3. Yamamoto et al. J Clin Invest 2002;110:43 – 52

GLP-1R expression GLP-1R identified in 50+ regions GLP-1R, glucagon-like peptide-1 receptor GLP-1R Jensen et al. Endocrinology 2018;159:665 – 75

Brain access Cerebral nuclei 128 Hypothalamus Medulla 64 (liraglutide VT750 /vehicle) 32 Fold change 16 8 4 2 1 SF ARH DMH ME OV PVp SO AP NTS PVH SFO TU GLP-1R targeting in cerebral nuclei, hypothalamus and hindbrain Many untargeted GLP-1Rs *Significant difference between treatments analysed in individual brain regions using a false discovery rate value of 5% to correct for multiple comparisons AP, area postrema; ARH, arcuate hypothalamic nucleus; DMH, dorsomedial nucleus of the hypothalamus; GLP-1R, glucagon-like peptide-1 receptor; i.v., intravenous; ME, median eminence; OV, vascular organ of the lamina terminalis; NTS, nucleus of the solitary tract; PVH, paraventricular hypothalamic nucleus; PVp, periventricular hypothalamic nucleus, posterior part; SF, septofimbrial nucleus; SFO, subfornical organ; SO, supraoptic nucleus; TU, tuberal nucleus; VT 750 , VivoTag-S750 radiolabelled i.v. injection of 0.1 mg/kg liraglutide VT750 in mice, n=6 Salinas et al. Sci Rep 2018;8:10310

Brain activation Cerebral cortex Pons Cerebral nuclei Medulla Hypothalamus Thalamus 16 (liraglutide/vehicle) Fold change 16 4 2 1 BLA CeA ARHPSTN LC AP BST MTN PB NTS Potential direct activation in: • ARH (hypothalamus) • AP and NTS (medulla) Secondary activation in regions associated with control of food intake *Significant difference between treatments analysed in individual brain regions using a false discovery rate value of 20% to correct for multiple comparisons AP, area postrema; ARH, arcuate hypothalamic nucleus; BLA, basolateral amygdalar nucleus; BST, bed nuclei of the stria terminals; CeA, central amygdalar nucleus; LC, locus ceruleus; MTN, midline group of the dorsal thalamus; NTS, nucleus of the solitary tract; PB, parabrachial nucleus; PSTN, parasubthalamic nucleus s.c. injection of 0.4 mg/kg liraglutide in mice, n=6 c-Fos Salinas et al. Sci Rep 2018;8:10310