Cardiac mechanisms of GLP-1 receptor agonists Filip K. Knop, MD PhD Professor, Consultant Endocrinologist, Director of Center for Clinical Metabolic Research Gentofte Hospital, University of Copenhagen Denmark
Faculty Disclosure Declaration of financial interests For the last 3 years and the subsequent 12 months: I I have received a research grant(s)/ in kind support A From current sponsor(s) YES NO B From any institution YES NO II I have been a speaker or participant in accredited CME/CPD A From current sponsor(s) YES NO B From any institution YES NO III I have been a consultant/strategic advisor etc A For current sponsor(s) YES NO B For any institution YES NO IV I am a holder of (a) patent/shares/stock ownerships A Related to presentation YES NO B Not related to presentation YES NO
Disclosures Professor Filip K. Knop, MD PhD, of Gentofte Hospital, University of Copenhagen, Denmark has served on scientific advisory panels and/or been part of speaker’s bureaus for, served as a consultant to and/or received research support from: • • Amgen MSD/Merck • • AstraZeneca Munidpharma • • Boehringer Ingelheim Norgine • • Carmot Therapeutics Novo Nordisk • • Eli Lilly Sanofi • • Gubra Zealand Pharma • MedImmune
Contemporary CVOTs in diabetes and obesity EXSCEL ACE REWIND (Exenatide ER, OW GLP- (Acarbose, AGI) (Dulaglutide, OW GLP-1RA) 1RA) n=6522; duration ~8 yrs n=9622; duration ~6.5 yrs n=14,752; follow-up ~3 yrs Q2 2017 – RESULTS Q2 2019 RESULTS Q3 2017 – RESULTS ALECARDIO SELECT TECOS DEVOTE CARMELINA PIONEER 6 AMPLITUDE-O (Aleglitazar, PPAR- αγ) (Semaglutide, OW GLP-1RA) (Sitagliptin, DPP-4i) (Insulin degludec, insulin) (Linagliptin, DPP-4i) (Oral semaglutide, GLP-1RA) (Efpeglenatide, OW GLP-1RA) n=7226; follow-up 2 yrs n=17,500 *; n=14,671; duration ~3 yrs n=7637; duration ~2 yrs n=7003; duration ~4 yrs n=3183; duration ~1.5 yrs n=4000*; duration ~3 yrs Termin. Q3 2013 – Duration: event driven, 1225 MACE Q4 2014 – RESULTS Q2 2017 – RESULTS Q3 2018 – RESULTS Q2 2019 RESULTS Completion Q2 2021 Completion Q3 2023 RESULTS SUSTAIN 6 CANVAS-R HARMONY OUTCOMES VERTIS CV SCORED ELIXA SOUL (Semaglutide, OW GLP- (Lixisenatide, GLP-1RA) (Canagliflozin, SGLT-2i) (Albiglutide, OW GLP-1RA) (Ertugliflozin, SGLT-2i) (Sotagliflozin, SGLT-1i & SGLT-2i) (Oral semaglutide, OD GLP-1RA) 1RA) n=12,546*; duration ~3.5 – 5 yrs n=6068; follow-up ~2 yrs n=5826; duration ~3 yrs n=9574; duration ~4 yrs n=8000; duration ~6 yrs n=10,500*; duration ~4.5 yrs n=3297; duration ~2.8 yrs Q1 2015 – RESULTS Q2 2017 – RESULTS Q3 2018 - RESULTS Completion Q3 2019 Completion Q1 2022 Completion Q2 2024 Q3 2016 – RESULTS FREEDOM CREDENCE (cardio-renal) SAVOR-TIMI 53 (ITCA 650, GLP-1RA in CANVAS CAROLINA (Canagliflozin, SGLT-2i) (Saxagliptin, DPP-4i) DUROS) (Canagliflozin, SGLT-2i) (Linagliptin, DPP-4i vs SU) n=4464; duration ~5.5 yrs SGLT-2i n=16,492; follow-up ~2 yrs n=4000; duration ~2 yrs n=4418; duration 4+ yrs n=6103; duration ~8 yrs Q3 2018 – CANCELLED Q2 2013 – RESULTS Q2 2016 – TOP-LINE Q2 2017 – RESULTS PPAR- αγ Q2 2019 RESULTS (+ve efficacy) RESULTS Insulin DPP-4i EXAMINE TZD TOSCA IT EMPA-REG OUTCOME LEADER DECLARE-TIMI 58 (Alogliptin, DPP-4i) (Pioglitazone, TZD) GLP-1RA (Empagliflozin, SGLT-2i) (Liraglutide, GLP-1RA) (Dapagliflozin, SGLT-2i) n=5380; n=3028; duration ~10 yrs n=9340; duration 3.5 – 5 yrs AGI n=7000; duration up to 5 yrs n=17,276; duration ~6 yrs follow-up ~1.5 yrs Q4 2017 † – RESULTS Q3 2015 – RESULTS Q2 2016 – RESULTS Q4 2018 – RESULTS Q3 2013 – RESULTS 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 * 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 AGI, alpha-glucosidase inhibitor; CVOT, cardiovascular outcomes trial; DPP-4i, dipeptidyl peptidase-4 inhibitor; ER, extended release; GLP-1RA, glucagon-like peptide-1 receptor agonist; ITCA 650, continuous subcutaneous delivery of exenatide; PPAR- αγ, peroxisome proliferator ‐ activated receptors- α and γ; OW, once weekly; SGLT -2i, sodium – glucose co-transporter 2 inhibitor; SU, sulphonylurea; TZD, thiazolidinedione ClinicalTrials.gov.
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
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
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