of new diabetes drugs? Filip Krag Knop, MD Copenhagen, Denmark - PowerPoint PPT Presentation

Session: Game changing clinical trials in T2DM & CVD: Novel insights & implications Translating mechanisms to benefits: How can we explain the cardiovascular benefits of new diabetes drugs? Filip Krag Knop, MD Copenhagen, Denmark Cardio Diabetes Master Class February 22-23, 2019 - Barcelona, Spain

Translating mechanisms to benefits: How can we explain the cardiovascular benefits of new diabetes drugs? Filip K. Knop, MD PhD Professor, Consultant Endocrinologist, Head of Clinical Metabolic Physiology Steno Diabetes Center Copenhagen, Gentofte Hospital University of Copenhagen Copenhagen, Denmark

Disclosures • Filip K. Knop 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

Pre-treatment HbA 1c decreased substantially over time (2000-2012) - more patients attain HbA1c goal Thomsen R et al., Diabetes, Obesity and Metabolism 2015

Glycaemic control reduces the risk of microvascular complications Neuropathy Retinopathy 20 Retinopathy 18 Nephropathy 16 Nephropathy Neuropathy Relative Risk 14 Microalbuminuria 12 10 8 6 (dialysis) 4 2 0 6 7 8 9 10 11 12 A1C (%) (amputations) 43 53 63 73 83 93 103 (blindness)

Number and rate* of adults who began treatment for end-stage renal disease attributed to diabetes, 2000 – 2014 *Rate per 100,000 persons with diabetes and age-standardized to the 2000 U.S. standard population, excluding Alaska, Vermont, and Wyoming because of the Burrows et al. Morbidity and Mortality Weekly Report 2017 small annual number (<50) of new ESRD-D cases during the study period.

Life expectancy is reduced by 12 years in diabetes patients with previous CVD* 60 years End of life No diabetes – 6 yrs Diabetes – 12 yrs Diabetes + MI In this case, CVD is represented by MI or stroke *Male, 60 years of age with history of MI or stroke CVD, cardiovascular disease; MI, myocardial infarction Emerging Risk Factors Collaboration et al. JAMA 2015;314:52 – 60

CVD is the leading cause of death in people with T2D 1. Seshasai et al. N Engl J Med 2011;364:829-41; 2. Centers for Disease Control and Prevention National Diabetes Fact Sheet 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf; 3. International Diabetes Federation. IDF Diabetes Atlas, 7th edition. Brussels, Belgium: International Diabetes Federation, 2015. http://www.diabetesatlas.org Presented at the American Diabetes Association 76 th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

Summary of glycaemic intervention studies Study Micro CVD Mortality DCCT UKPDS ACCORD ADVANCE VADT ACCORD, Action to Control Cardiovascular Risk in Diabetes; ADVANCE, Action in Diabetes and Vascular Disease Preterax and Diamicron MR; CVD, cardiovascular disease; DCCT, Diabetes Control and Complications Trial; UKPDS, UK Prospective Diabetes Study; VADT, Veterans Affairs Diabetes Trial

FDA guidance for industry • In December 2008, the US FDA issued guidance to industry for evaluating CV safety in diabetes drugs • Industry should demonstrate that new therapy will not result in an unacceptable increase in CV risk • The upper bound of the two-sided 95% CI of the risk ratio should be <1.8 CI, confidence interval; CV, cardiovascular; FDA, Food and Drug Administration. FDA. Guidance for Industry: Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. 2008. Available at: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf.

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 – TOPLINE 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 - TOPLINE 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) 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-1 RA 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+ *MACE+ White et al. N Engl J Med 2013; 369:1327 – 35; Pffefer et al. N Engl J Med 2015;373:2247 – 57; Intarcia press Scirica et al. N Engl J Med 2013;369:1317 – 26; release 06 May 2016; Marso et al. N Engl J Med 2016;375:311 – 22; Marso et al. N Engl J Med 2016;375:1834 – 44; Holman et al . N Green et al. N Engl J Med 2015;373:232 – 42; McGuire et al. Engl J Med 2017;377:1228 – 39; Hernandez et al . Lancet Zinman et al. N Engl J Med 2015; 373:2117- Presented at EASD 2018, Berlin 2018;doi:10.1016/S0140-6736(18)32261-X; Eli Lilly press release, 28; Neal et al. N Engl J Med 2017;377:644 – (https://www.easd.org/myeasd/home.html#!res November 2018 (https://investor.lilly.com/news-releases/news- Gerstein et al. N Engl J Med 2012;367: 57; Wiviott et al. N Engl J Med 2018; 319 – 28; Marso et al. N Engl J Med 2017;377:723 – ources/cardiovascular-outcomes-748e1b14- release-details/trulicityr-dulaglutide-demonstrates-superiority- doi: 10.1056/NEJMoa1812389 d08e-441d-b7d2-40b36cccea67) reduction) 32

GLP-1: beyond glucose metabolism Brain Heart Neuroprotection Myocardial contractility Liver Neurogenesis Heart rate Glycogen storage Memory Myocardial glucose uptake Ischaemia-induced DPP-4 myocardial damage GI tract Motility His Ala Glu Gly Thr Phe Thr Ser Asp Val GLP-1 Pancreas Ser New β -cell formation Fat cells Lys Ala Ala Gln Gly Glu Leu Tyr Ser β -cell apoptosis Glu Glucose uptake Insulin biosynthesis Lipolysis Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Skeletal muscle Kidney Glucose uptake Natriuresis Blood vessel Endothelium-dependent vasodilation DPP-4, dipeptidyl peptidase-4; GI, gastrointestinal; GLP-1, glucagon-like peptide-1 Adapted from Meier et al. Nat Rev Endocrinol 2012;8:728 – 42

In the rodent and monkey brain, GLP-1R is abundantly expressed in many regions Mouse Monkey LS LS LS LS AP NTS SFO AP NTS AP+NTS ARH ARH ME ARH, arcuate nucleus; AP, area postrema; GLP-1R, glucagon-like peptide-1 receptor; LS, septal nucleus; ME, median eminence; NTS, nucleus tractus solitarus Heppner et al. Endocrinology 2015;156:255 – 67