The cardiovascular benefits beyond glucose control Filip K. Knop, MD - PowerPoint PPT Presentation

GLP-1 receptor agonists: The cardiovascular benefits beyond glucose control Filip K. Knop, MD PhD Professor of endocrinology, Consultant endocrinologist University of Copenhagen 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 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

Introduction to GLP-1 Role in physiology and type 2 diabetes pathophysiology Glucose-dependent pancreatic effects (implications for risk of hypo) Effects beyond glycaemic control Practical considerations

Plasma glucose during 25 g oral glucose in healthy subjects • 25 g glucose Small-intestinal glucose absorption → plasma glucose rises 160 Plasma glucose (mg/dL) 140 • Elevated plasma glucose 120 → insulin secretion 100 80 • Insulin facilitates glucose uptake 60 → plasma glucose drops 40 20 0 -15 0 15 30 45 60 75 90 105120135150165180 Time (minutes) Adapted from: Nauck et al. J Clin Endocrinol Metab 1986;63:492 – 498

Plasma glucose during 25 g oral glucose, 50 g glucose and 100 g 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: Nauck et al. J Clin Endocrinol Metab 1986;63:492 – 498

Plasma glucose during 25 g oral glucose, 50 g glucose and 100 g glucose 50 g glucose 25 g glucose 100 g glucose 25 g glucose 160 160 160 Plasma glucose (mg/dL) Plasma glucose (mg/dL) 50 g glucose 140 140 140 100 g glucose 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: Nauck et al. J Clin Endocrinol Metab 1986;63:492 – 498

Plasma glucose during 25 g oral glucose, 50 g glucose and 100 g glucose 2500 25 g glucose 25 g glucose 160 Plasma glucose (mg/dL) 50 g glucose 50 g glucose Plasma C-peptide (pM) 140 100 g glucose 100 g glucose 2000 120 1500 100 80 1000 60 40 500 20 0 0 -15 0 15 30 45 60 75 90 105120135150165180 -15 0 15 30 45 60 75 90 105120135150165180 Time (minutes) Time (minutes) “Elevated plasma glucose → insulin secretion ” (?) Adapted from: Nauck et al. J Clin Endocrinol Metab 1986;63:492 – 498

The incretin hormones Glucose-dependent insulinotropic polypeptide (GIP) Glucagon-like peptide-1 (GLP-1) Tyr Ala Glu Gly Thr Phr Ile Ser Asp Tyr 1 300 Meal 80 ser Meal Plasma GLP-1 (pM) Plasma GIP (pM) His Ala Glu Gly Thr Phe Thr Ser Asp Ile Val GIP 60 7 Ala Gln Gln His Ile Lys Asp Met Asp 200 Ser Phe 40 Lys Ala Ala Gln Gly Glu Leu Tyr Ser Val Glu 100 Asn Trp Leu Ley ala Gln Lys Gly Leu 20 Phe 37 Lys GLP-1 Ile Ala Trp Leu Val Lys Gly Arg Gly 0 42 Asn 0 Asp -30 0 30 60 90 120 150 180 210 240 Gln Thr Ile Asn His Lys Typ -30 0 30 60 90 120 150 180 210 240 Bell et al. Nature 1983 4 Time (min) Time (min) GIP-positive endocrine K cells in human GLP-1-positive endocrine L-cells in human Brown & Dryburgh. Can J Biochem 1971 1 Knop et al. Am J Physiol Endocrinol Metab 2007 3 Knop et al. Am J Physiol Endocrinol Metab 2007 3 jejunal mucosa (Knop et al. Unpublished) Jörnwall et al. FEBS Lett 1981 2 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

GLP-1 receptors in pancreatic islets GLP-1 receptor expression in the human pancreas GLP-1, glucagon-like peptide-1 Ørskov et al. Unpublished

OGTT and IGII in 10 healthy subjects – exposing the incretin effect Glucose Insulin 400 Plasma insulin (pM) Plasma glucose (mM) 16 300 12 OGTT OGTT 200 IIGI IIGI 70% 8 100 4 0 0 -20 10 40 70 100 130 160 190 220 250 -20 10 40 70 100 130 160 190 220 250 Time (min) Time (min) GIP GLP-1 120 40 100 GLP-1 (pM) GIP (pM) 30 80 60 20 ∫βSR OGTT – ∫βSR IIGI 40 × 100% Incretin effect (%) = 10 20 ∫βSR OGTT 0 0 -20 40 100 160 220 -20 40 100 160 220 Time (min) Time (min) GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; OGTT, oral glucose tolerance test; IIGI, isoglycaemic intravenous glucose infusion; ∫β SR, beta-cell secretory response Knop FK et al. Diabetologia 2007;292:E324 – 330

Healthy subjects are able to increase their incretin effect in response to increasing oral glucose loads …thereby preventing exaggerated glucose excursions 2500 25 g glucose 25 g glucose 160 Plasma glucose (mg/dL) 50 g glucose 50 g glucose Plasma C-peptide (pM) 140 100 g glucose 100 g glucose 2000 120 1500 100 80 1000 60 40 500 20 0 0 -15 0 15 30 45 60 75 90 105120135150165180 -15 0 15 30 45 60 75 90 105120135150165180 Time (minutes) Time (minutes) 25 g 50 g 100 g 19% 26% 61% Adapted from: Nauck et al. J Clin Endocrinol Metab 1986;63:492 – 498

OGTT and IIGI in 10 patients with T2DM and 10 healthy controls 400 Plasma insulin (pM) 300 OGTT T2DM IIGI 200 16 70% Plasma glucose (mM) OGTT CTRL OGTT IIGI CTRL IIGI 100 12 0 8 400 Plasma insulin (pM) 4 300 35% 0 200 OGTT -20 10 40 70 100 130 160 190 220 250 T2DM IIGI Time (min) 100 0 -20 10 40 70 100 130 160 190 220 250 Time (min) CTRL, healthy controls; OGTT, oral glucose tolerance test; IIGI, isoglycaemic intravenous glucose infusion; T2DM, type 2 diabetes mellitus Knop FK et al. Diabetologia 2007;292:E324 – 330

Alpha- and beta-cell effects of GLP-1 are glucose dependent – also in patients with type 2 diabetes Placebo (n=10) Glucose (mM) GLP-1 (n=10) 15.0 12.5 10.0 * 7.5 * * 5.0 * * * * Infusion of GLP-1 or placebo Insulin (pM) Effects on insulin and glucagon cease 250 alongside the occurrence of 200 * normoglycaemia * * * 150 * * * 100 50 Glucagon (pM) 20 15 * * 10 * * 5 * p <0.05 0 60 120 180 240 Time (min) GLP-1, glucagon-like peptide 1; T2DM, type 2 diabetes mellitus Nauck MA et al. Diabetologia 1993;36:741 – 744

Liraglutide: Hypoglycaemia reported in LEADER Liraglutide Placebo Rate ratio N % N % (95% CI) p -value 0.80 Confirmed hypoglycaemia <0.001 2039 43.7 2130 45.6 (0.74 ; 0.88) 0.69 Severe hypoglycaemia 0.016 114 2.4 153 3.3 (0.51 ; 0.93) 1 1.5 0.5 0 .5 1 1 .5 Hazard ratio (95% CI) Favours liraglutide Favours placebo Confirmed hypoglycaemia was defined as plasma glucose level of less than 56 mg per decilitre (3.1 mmol per litre) or a severe event. Severe hypoglycaemia was defined as hypoglycaemia for which the patient required assistance from a third party. Analysed using a negative binomial regression model %, percentage of group; CI, confidence interval; N, number of patients Marso SP et al. N Engl J Med 2016;375:311 – 322

Effect of iv GLP-1 infusion in type 2 diabetes T2DM (n=7) - placebo T2DM - GLP-1 (1.2 pmol/kg/min) 16 Healthy controls (n=6) 14 12 Plasma glucose (mM) 10 8 6 4 2 Breakfast Lunch Snack 0 00:00 04:00 08:00 12:00 16:00 Time of day GLP-1, glucagon-like peptide 1; iv, intravenous; T2DM, type 2 diabetes mellitus Rachman J et al. Diabetologia 1997;40:205 – 211

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 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

Targeting of discrete regions in the mouse brain following peripheral administration of acylated GLP-1R agonists Autofluorescence liraglutide 750 Peripheral (s.c.) once-daily injection of liraglutide 750 to mice for 4 days GLP-1R, glucagon-like peptide-1 receptor; s.c., subcutaneous Secher A et al . J Clin Invest 2014;124:4473 – 4488