NOVEL THERAPEUTIC APPROACHES IN DIABETES: THE CARDIOVASCULAR - PowerPoint PPT Presentation

NOVEL THERAPEUTIC APPROACHES IN DIABETES: THE CARDIOVASCULAR BENEFITS BEYOND GLUCOSE CONTROL WHF 2018 DUBAI Professor LINA BADIMON, BSc, PhD Cardiovascular Program-ICCC IR-Hospital de Sant Pau Barcelona, Spain

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 B From any institution YES II I have been a speaker or participant in accredited CME/CPD A From current sponsor(s) YES B From any institution YES III I have been a consultant/strategic advisor etc A For current sponsor(s) YES B For any institution YES IV I am a holder of (a) patent/shares/stock ownerships A Related to presentation NO B Not related to presentation YES

HR, diabetes vs non-diabetes BMI, body mass index; CI, confidence interval; HR, hazard ratio; MI, myocardial infarction; SBP, systolic blood pressure Emerging Risk Factors Collaboration. Lancet 2010;375:2215

DIABETES AND ATHEROTHROMBOSIS MicropartIcles ↑ Number ↑ p-MP Endothelium Coagulation / Fibrinolysis ↓ NO synthesis ↑ TF in circulation ↑ Vasoconstriction ↑ Activity TF ↑ Adhesion molecules ↑ vWF-FVIII ↑ Chemokines ↑ Fibrinogen ↑ Inflammation ↑ PAI-1 Platelets Smooth Muscle Cells Hemostatic changes Ca 2+ ↓ Vasodilation ↑ Surface receptors ↓ Response to vasoconstrictors ↑ Activation markers ↑ Apoptosis ↑ TxA2 production ↑ MMP synthesis ↓ NO synthesis ↓ Collagen synthesis ↓ PGI 2 synthesis Badimon L et al 2012-2017

DIABETES AND THROMBOGENICITY Type 2 diabetes Hernandez Vera, Vilahur, et Badimon . Arterios Thromb Vasc Biol 2012 ↑ Thrombotic risk BM alterations Obesity and insulin resistance Hernandez Vera, Vilahur, et Badimon Hernandez Vera, Vilahur, et Badimon Thromb & Haemost 2013 Thromb & Haemost 2014 I I Resident ASC I EPC alterations II I Obesity I V Type 2 diabetes Friedl, G., Acta Orthop, 2009. Oñate, Vilahur, Ferrer et Badimon. Khan, M., , Stem Cells Dev, 2011 FASEB Journal 2012 Badimon L et al 2012-2017

Heart failure Diabetes Shared pathological features Endothelial dysfunction Impaired contractility Hyperglycaemia ↓ Pancreatic Cardiomyocyte Insulin resistance apoptosis/fibrosis beta-cell function Mitochondrial dysfunction Advanced glycated end- Neurohormonal activation product toxicity RAAS activation Neuronal degeneration/ LV remodelling demyelination Inflammation No Diabetes diabetes Cumulative incidence (%) HF r EF: unadjusted HR 1.60 60 (95% CI 1.44, 1.77); p <0.0001 HF r EF HF p EF: unadjusted HR 2.0 CV death or HHF in patients with or without diabetes (95% CI 1.70, 2.36); p <0.0001 40 HF p EF HF r EF based on ejection fraction category 20 HF p EF 0 0 0.5 1 1.5 2 2.5 3 3.5 Follow-up (years) MacDonald MR et al. Eur Heart J 2008;29:1377

Plasma glucose during 25 , 50 and 100 g oral glucose 50 g glucose 25 g glucose 100 g glucose 160 160 160 Plasma glucose (mg/dL) 140 140 140 120 120 120 100 100 100 80 80 80 60 60 60 40 40 40 20 20 20 0 0 0 -15 0 15 30 45 60 75 90 105120135150165180 -15 0 15 30 45 60 75 90 105120135150165180 -15 0 15 30 45 60 75 90 105120135150165180 Time (minutes) Time (minutes) Time (minutes) Adapted from

Plasma glucose during 25 , 50 and 100 g oral glucose The incretin hormones Glucose-dependent insulinotropic polypeptide (GIP) Glucagon-like peptide-1 (GLP-1) 25 g glucose 160 50 g glucose Plasma glucose (mg/dL) 140 100 g glucose 120 100 80 GIP 60 40 20 GLP-1 K cells 0 L cells -15 0 15 30 45 60 75 90 105 120 135 150 165 180 Time (minutes) Nauck et al. J Clin Endocrinol Metab 1986;63:492 – 498; Brown JC, Dryburgh JR. Can J Biochem 1971;49:867 – 872; 2. Jörnwall H et al. FEBS Lett 1981;123:205 – 210; Knop FK et al. Am J Physiol Endocrinol Metab 2007;292:E324 – 330; 4. Bell GL et al. Nature 1983;304:368 – 371

PLEIOTROPIC LOCAL AND SYSTEMIC ACTIONS OF GLP-1 AND GLP-2 SECRETED IN RESPONSE TO NUTRIENTS, BACTERIAL METABOLITES, OR INFLAMMATORY TOXINS AND CYTOKINES, FROM ENTEROENDOCRINE L CELLS OF THE SMALL AND LARGE INTESTINE. Daniel J. Drucker, Joel F. Habener, and Jens Juul Holst. JCI 2017

GLP-1: Beyond glucose metabolism Brain Heart Neuroprotection Liver Myocardial contractility 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 Phe Lipolysis Ile Ala Trp Leu Val Lys Gly Arg Gly Skeletal muscle Kidney Glucose uptake Blood vessel Natriuresis Endothelium-dependent vasodilation DPP-4, dipeptidyl peptidase-4; GI, gastrointestinal; GLP-1, glucagon-like peptide-1 Adapted from Meier JJ et al. Nat Rev Endocrinol 2012;8:728 – 742

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; LS, septal nucleus; ME, median eminence; NTS, nucleus tractus solitarus Heppner et al. Endocrinology 2015, 156(1):255 – 267

Liraglutide resolves UPR in the neuroblastoma SH-SY5Y cell line Panagaki T et al Scientific REPorTS , 7: 16158 , 2017

GLP-1: Beyond glucose metabolism Brain Heart Neuroprotection Liver Myocardial contractility Neurogenesis Heart rate Glycogen storage Memory Myocardial glucose uptake Ischaemia-induced DPP-4 myocardial damage GI tract His Ala Glu Gly Thr Phe Thr Ser Motility Asp Val GLP-1 Pancreas Ser New β -cell formation Fat cells Lys Ala Ala Gln Gly Glu Leu Tyr Ser Glu β -cell apoptosis Glucose uptake Insulin biosynthesis Phe Lipolysis 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 JJ et al. Nat Rev Endocrinol 2012;8:728 – 742

Semaglutide is an investigational product and not currently approved Semaglutide significantly attenuates aortic plaque lesions in LDLr -/- mice in a dose-independent manner Body weight (g) Aortic plaque lesions 40 30 Vehicle, chow 35 Plaque area (%) Vehicle, western diet ** ** ** 30 20 Semaglutide (1 nmol/kg) Semaglutide (3 nmol/kg) 25 10 Semaglutide (15 nmol/kg) 20 Western diet (high fat, sugar + 0.2% cholesterol) 0 15 0 7 14 21 28 35 42 49 56 63 70 77 84 91 98 105 112 119 Semaglutide Time (Experiment day) Vehicle, Vehicle, chow 1 nmol/kg 3 nmol/kg 15 nmol/kg western diet Plasma triglyceride 20 TG (mmol/L) 15 * 10 5 0 * p <0.05; ** p <0.001, vs vehicle. LDLr, low-density lipoprotein receptor; TG, triglyceride Rakipovski G et al. Abstract submitted for the American Diabetes Association 77th Scientific Sessions; Jun 9 – 13, 2017; San Diego, USA

Indirect and direct CV actions of GLP-1 in T2DM GLP-1 METABOLIC DIRECT CV EFFECTS EFFECTS Β -cell function Insulin secretion INDIRECT CV EFFECTS Endothelial dysfunction Vessel inflammation Atherosclerosis Cardiac function Gastric emptying Glucose output Appetite GLP-1 effect on known risk factors for CVD Glucose Hypertension Heart rate Dyslipidaemia Obesity CV, cardiovascular; CVD, cardiovascular disease; GLP-1, glucagon-like peptide-1; T2DM, type 2 diabetes mellitus Meier JJ et al. Nat Rev Endocrinol 2012;8:728 – 742; Nyström T et al. Am J Physiol Endocrinol Metab 2004;287:E1209−E1215; Song X et al. ci Rep 2015;26:10202.

Completed and ongoing CVOTs with GLP-1RAs ELIXA FREEDOM-CVO PIONEER 6 (Lixisenatide vs Pbo) (ITCA 650 Exenatide vs Pbo) (Oral semaglutide OD vs Pbo) n=6,000; duration 2.1 yrs n=4,000; duration ~2 yrs n=3,176; duration ~2 yrs Q1 2015 – RESULTS Q2 2016 – TOPLINE completion Q3 2018 LEADER EXSCEL REWIND (Liraglutide vs Pbo) (Exenatide QW vs Pbo) (Dulaglutide QW vs Pbo) n=9,340; duration 3.8 yrs n=14,000; duration ~7.5 yrs n=9,622; duration ~6.5 yrs Q4 2015 – RESULTS Q2 2017 - RESULTS completion Q3 2018 SUSTAIN 6 HARMONY OUTCOME (Semaglutide vs Pbo) (Albiglutide QW vs Pbo) n=3,297; duration ~2.8 yrs n~5,000; duration ~4 yrs Q1 2016 – RESULTS completion Q2 2019 Completed Ongoing 2013 2014 2015 2016 2017 2018 2019 2020 2021 CVOT, cardiovascular outcome trial; Exe, exenatide GLP-1RA, glucagon-like peptide-1 receptor agonist; OD, once daily; Pbo, placebo; QW, once weekly; yrs, years. Adapted from Mannucci et al. Diabetes Care 2016;39(S2): S196-S204. Study completion dates sourced from https://clinicaltrials.gov. Last accessed: January 16, 2017.

Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes THREE POINT MACE: CARDIOVASCULAR MORTALITY, NON-FATAL MI AND NON-FATAL STROKE ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN 6 (semaglutide), EXSCEL (extended-release exenatide) Bethel et al . Lancet Diabetes Endocrinol Dec 6th, 2017