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

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 Declaration of financial interests For the last 3 years and the subsequent 12 months:

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

20 40 60 80 100 120 140 160

• 15 0

15 30 45 60 75 90 105120135150165180

Time (minutes) Plasma glucose (mg/dL)

25 g glucose

Plasma glucose during 25 g oral glucose in healthy subjects

Adapted from: Nauck et al. J Clin Endocrinol Metab 1986;63:492–498

• Small-intestinal glucose absorption

→ plasma glucose rises

• Elevated plasma glucose

→ insulin secretion

• Insulin facilitates glucose uptake

→ plasma glucose drops

20 40 60 80 100 120 140 160

• 15 0

15 30 45 60 75 90 105120135150165180

Time (minutes) Plasma glucose (mg/dL)

25 g glucose

20 40 60 80 100 120 140 160

• 15 0

15 30 45 60 75 90 105120135150165180

Time (minutes)

50 g glucose

Plasma glucose during 25 g oral glucose, 50 g glucose and 100 g glucose

Adapted from: Nauck et al. J Clin Endocrinol Metab 1986;63:492–498

100 g glucose

20 40 60 80 100 120 140 160

• 15 0

15 30 45 60 75 90 105120135150165180

Time (minutes)

20 40 60 80 100 120 140 160

• 15 0

15 30 45 60 75 90 105120135150165180

Time (minutes) Plasma glucose (mg/dL)

25 g glucose

20 40 60 80 100 120 140 160

• 15 0

15 30 45 60 75 90 105120135150165180

Time (minutes)

50 g glucose

25 g glucose 50 g glucose 100 g glucose

Plasma glucose during 25 g oral glucose, 50 g glucose and 100 g glucose

Adapted from: Nauck et al. J Clin Endocrinol Metab 1986;63:492–498

100 g glucose

20 40 60 80 100 120 140 160

• 15 0

15 30 45 60 75 90 105120135150165180

Time (minutes) Plasma glucose (mg/dL)

Plasma glucose during 25 g oral glucose, 50 g glucose and 100 g glucose

Adapted from: Nauck et al. J Clin Endocrinol Metab 1986;63:492–498

• 15 0

15 30 45 60 75 90 105120135150165180

Time (minutes) Plasma C-peptide (pM)

500 1000 1500 2000 2500

“Elevated plasma glucose → insulin secretion” (?)

20 40 60 80 100 120 140 160

• 15 0

15 30 45 60 75 90 105120135150165180

Time (minutes) Plasma glucose (mg/dL)

25 g glucose 50 g glucose 100 g glucose 25 g glucose 50 g glucose 100 g glucose

K cells L cells GIP GLP-1 GLP-1-positive endocrine L-cells in human small intestine (Knop et al. Unpublished)

Glu 7 37 Lys His Thr Thr Ser Phe Gly Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Gln Lys Phe Glu Ile Ala Trp Leu Gly Val Gly Arg Ala

Bell et al. Nature 19834 20 40 60 80

• 30

30 60 90 120 150 180 210 240 Meal Plasma GLP-1 (pM) Time (min) Knop et al. Am J Physiol Endocrinol Metab 20073

GIP-positive endocrine K cells in human jejunal mucosa (Knop et al. Unpublished)

Glu 1 ala Tyr Thr Ile Ser Phr Gly Asp Tyr ser Ile Ala Met Asp Lys His Gln Ile Gln Phe Asp Val Asn Trp Leu Gly Ley Gln Lys Leu Lys Asn Asp Typ Lys His Asn Ile Thr 42 Gln Ala

Brown & Dryburgh. Can J Biochem 19711 Jörnwall et al. FEBS Lett 19812 100 200 300

• 30

30 60 90 120 150 180 210 240 Meal Plasma GIP (pM) Time (min) Knop et al. Am J Physiol Endocrinol Metab 20073

The incretin hormones

Glucose-dependent insulinotropic polypeptide (GIP) Glucagon-like peptide-1 (GLP-1)

• 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 receptor expression in the human pancreas

GLP-1 receptors in pancreatic islets

GLP-1, glucagon-like peptide-1 Ørskov et al. Unpublished

OGTT IIGI

Time (min) Plasma glucose (mM)

4 8 12 16

• 20 10

40 70 100 130 160 190 220 250

Glucose

• 20 10

40 70 100 130 160 190 220 250

Plasma insulin (pM)

100 200 300 400

Time (min)

OGTT IIGI

Insulin

∫βSROGTT – ∫βSRIIGI ∫βSROGTT × 100% Incretin effect (%) =

Time (min)

GIP

GIP (pM)

20 40 60 80 100 120

• 20

40 100 160 220

GLP-1

Time (min)

10 20 30 40

• 20

40 100 160 220

GLP-1 (pM)

70%

OGTT and IGII in 10 healthy subjects – exposing the incretin effect

GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; OGTT, oral glucose tolerance test; IIGI, isoglycaemic intravenous glucose infusion; ∫βSR, 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

25 g 19% 100 g 61% 50 g 26%

Adapted from: Nauck et al. J Clin Endocrinol Metab 1986;63:492–498

• 15 0

15 30 45 60 75 90 105120135150165180

Time (minutes) Plasma C-peptide (pM)

500 1000 1500 2000 2500 20 40 60 80 100 120 140 160

• 15 0

15 30 45 60 75 90 105120135150165180

Time (minutes) Plasma glucose (mg/dL)

25 g glucose 50 g glucose 100 g glucose 25 g glucose 50 g glucose 100 g glucose

Time (min) Plasma glucose (mM)

4 8 12 16

• 20

10 40 70 100 130 160 190 220 250 T2DM OGTT IIGI CTRL OGTT IIGI

100 200 300 400

• 20

10 40 70 100 130 160 190 220 250

Plasma insulin (pM)

100 200 300 400

Plasma insulin (pM) Time (min)

T2DM OGTT IIGI CTRL OGTT IIGI

70% 35%

OGTT and IIGI in 10 patients with T2DM and 10 healthy controls

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

Effects on insulin and glucagon cease alongside the occurrence of normoglycaemia Time (min)

*p<0.05

Insulin (pM) Glucagon (pM) Glucose (mM) 150 5 250 200 100 50 20 15 10 60 120 180 240 15.0 12.5 10.0 7.5 5.0

Infusion of GLP-1 or placebo

* * * * * * * * * * * * * * Placebo (n=10) GLP-1 (n=10) * * * *

Alpha- and beta-cell effects of GLP-1 are glucose dependent – also in patients with type 2 diabetes

GLP-1, glucagon-like peptide 1; T2DM, type 2 diabetes mellitus Nauck MA et al. Diabetologia 1993;36:741–744

Rate ratio (95% CI) p-value Liraglutide Placebo N % N % Confirmed hypoglycaemia 0.80 (0.74 ; 0.88) <0.001 2039 43.7 2130 45.6 Severe hypoglycaemia 0.69 (0.51 ; 0.93) 0.016 114 2.4 153 3.3

Liraglutide: Hypoglycaemia reported in LEADER

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

Favours liraglutide Favours placebo

1 0 .5 1 .5

Hazard ratio (95% CI)

0.5 1.5 1

Effect of iv GLP-1 infusion in type 2 diabetes

GLP-1, glucagon-like peptide 1; iv, intravenous; T2DM, type 2 diabetes mellitus Rachman J et al. Diabetologia 1997;40:205–211

2 4 6 8 10 12 14 16 00:00 04:00 08:00 12:00 16:00 T2DM (n=7) - placebo Healthy controls (n=6) Plasma glucose (mM) Time of day T2DM - GLP-1 (1.2 pmol/kg/min) Snack Lunch Breakfast

GLP-1: Beyond glucose metabolism

Brain

Neuroprotection Neurogenesis Memory

Heart

Myocardial contractility Heart rate Myocardial glucose uptake Ischaemia-induced myocardial damage

Kidney

Natriuresis GLP-1

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

His Ala Thr Thr Ser Phe Glu Gly Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Gln Lys Phe Glu Ile Ala Trp Leu Gly Val Gly Arg Lys

Fat cells

Glucose uptake Lipolysis

Liver

Glycogen storage

Skeletal muscle

Glucose uptake

Blood vessel

Endothelium-dependent vasodilation

Pancreas

New β-cell formation β-cell apoptosis Insulin biosynthesis

DPP-4

GI tract

Motility

In the rodent and monkey brain, GLP-1R is abundantly expressed in many regions

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

LS LS AP+NTS ARH LS SFO NTS LS ARH ME AP

Mouse

NTS AP

Monkey

Autofluorescence liraglutide750

Targeting of discrete regions in the mouse brain following peripheral administration of acylated GLP-1R agonists

GLP-1R, glucagon-like peptide-1 receptor; s.c., subcutaneous Secher A et al. J Clin Invest 2014;124:4473–4488

Peripheral (s.c.)

• nce-daily injection
• f liraglutide750 to

mice for 4 days

GLP-1: Beyond glucose metabolism

Brain

Neuroprotection Neurogenesis Memory

Heart

Myocardial contractility Heart rate Myocardial glucose uptake Ischaemia-induced myocardial damage

Kidney

Natriuresis GLP-1

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

His Ala Thr Thr Ser Phe Glu Gly Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Gln Lys Phe Glu Ile Ala Trp Leu Gly Val Gly Arg Lys

Fat cells

Glucose uptake Lipolysis

Liver

Glycogen storage

Skeletal muscle

Glucose uptake

Blood vessel

Endothelium-dependent vasodilation

Pancreas

New β-cell formation β-cell apoptosis Insulin biosynthesis

DPP-4

GI tract

Motility

Liraglutide inhibits progression of early, low-burden atherosclerotic lesion development in mice

*p<0.05 vs vehicle by one-way ANOVA; data are mean ± SEM; performed in ApoE–/– mice with early, low-burden atherosclerotic lesions ApoE–/–, apolipoprotein E knockout; ANOVA, analysis of variance; Ex-9, exendin-9; IMR, intima:media ratio; Lira, liraglutide; SEM, standard error of the mean Gaspari T et al. Diab Vasc Dis Res 2013;10:353‒360

IMR

0.4 0.3 0.2 0.1 0.0

Vehicle Lira Lira + Ex-9

*

IMR analysis performed in the aortic arch

Intima:media ratio (IMR)

N=6‒10

% Lesion area

15 10 5

Vehicle Lira Lira + Ex-9

Oil red O staining performed in the aorta

Lipid deposition

N=13‒16

Vehicle Lira Lira + Ex-9

M M I M I

Lesion development

Haemotoxylin and eosin staining in the aortic arch

Semaglutide significantly attenuates aortic plaque lesions in LDLr-/- mice in a dose-independent manner

*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

Body weight (g)

7 14 21 28 35 42 49 56 63 70 77 84 91 98 105 112 119

15 20 25 30 35 40

Time (Experiment day)

Western diet (high fat, sugar + 0.2% cholesterol)

Plasma triglyceride

10 15 20

TG (mmol/L)

*

5

Vehicle, chow Vehicle, western diet Semaglutide (1 nmol/kg) Semaglutide (3 nmol/kg) Semaglutide (15 nmol/kg)

10 20 30

Aortic plaque lesions

**

Plaque area (%)

** **

Vehicle, chow Vehicle, western diet

Semaglutide

1 nmol/kg 3 nmol/kg 15 nmol/kg Semaglutide is an investigational product and not currently approved

• Analysis of macrophages for MΦ1 (pro-atherogenic) and MΦ2 (pro-resolving) macrophage markers,

showed that liraglutide modulates macrophage cell fate towards MΦ2 pro-resolving macrophages

• This coincided with decreased atherosclerotic

lesion formation

Liraglutide reduces atherosclerotic lesion formation via modulation of macrophage cell fate in ApoE-/- mice

Bruen R. et al. Cardiovasc Diabetol. 2017;16(1):143.

MΦ MΦ1 MΦ2

Macrophage Pro-atherogenic Pro-resolving Atherosclerotic lesion

Completed and ongoing CVOTs with GLP-1RAs

2019 2015 2020 2013 2014 2016 2017 2018 2021

SUSTAIN 6 (Semaglutide vs Pbo) n=3,297; duration ~2.8 yrs Q1 2016 – RESULTS ELIXA (Lixisenatide vs Pbo) n=6,000; duration 2.1 yrs Q1 2015 – RESULTS LEADER (Liraglutide vs Pbo) n=9,340; duration 3.8 yrs Q4 2015 – RESULTS FREEDOM-CVO (ITCA 650 Exenatide vs Pbo) n=4,000; duration ~2 yrs Q2 2016 – TOPLINE EXSCEL (Exenatide QW vs Pbo) n=14,000; duration ~7.5 yrs Q2 2017 - RESULTS PIONEER 6 (Oral semaglutide OD vs Pbo) n=3,176; duration ~2 yrs completion Q3 2018 HARMONY OUTCOME (Albiglutide QW vs Pbo) n~5,000; duration ~4 yrs completion Q2 2019 REWIND (Dulaglutide QW vs Pbo) n=9,622; duration ~6.5 yrs completion Q3 2018

Completed Ongoing 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.

CV outcomes with GLP-1 RA

0,4 0,6 0,8 1,0 1,2 1,4 1,6

HR (95% CI)

0,4 0,8 1,2 1,6 2,0 2,4 2,8

HR (95% CI)

Primary composite MACE

0.87 (0.78‒0.97) 0.74 (0.58‒0.95)

CV death

0.78 (0.66‒0.93)

Nonfatal MI Nonfatal stroke

0.61 (0.38‒0.99)

Unstable angina All-cause death

0.85 (0.74‒0.97) 0.86 (0.77‒0.97)

• Hosp. for HF

MACE HR upper bound 95%CI FREEDOM-CVO (ITCA 650 vs Pbo) (1.0‒1.8) non-inferior

0,4 0,6 0,8 1,0 1,2 1,4 1,6

HR (95% CI)

ELIXA1 LEADER2 SUSTAIN 63 EXSCEL4 Lixisenatide vs Pbo Liraglutide vs Pbo Semaglutide vs Pbo Exenatide OW vs Pbo

CI, confidence intervals; CV, cardiovascular; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HF, heart failure; Hosp., hospitalisation; HR, hazard ratio; MACE, major adverse cardiovascular events; MI, myocardial infarction; OW, once weekly; Pbo, placebo; vs, versus. 1. Pfeffer MA et al. NEJM 2015;373:2247-57. 2. Marso SP et al. NEJM 2016;375:311-22. 3. Marso SP et al. NEJM 2016; 375:1834-44. 4. Holman RR et al. NEJM 2017;377:1228-39.

0,2 0,4 0,6 0,8 1,0 1,2 1,4 1,6 1,8

HR (95% CI)

• Use a GLP-1RA with proven CVD benefits (liraglutide / semaglutide / exenatide)
• GLP-1 lowers blood glucose via pleiotropic mechanisms including strictly glucose-dependent

effects on pancreatic glucagon and insulin secretion (no hypo risk!)

• GLP-1 acts in the brain lowering appetite and food intake (body weight loss!)
• GLP-1RAs reduce systolic blood pressure (most likely via a natriuretic effect in the kidneys) –

and increase heart rate by 2-6 bpm (most likely via GLP-1Rs in the sinoatrial node)

• Most frequent are mild to moderate gastrointestinal side effects (e.g. nausea, vomiting) which

typically cease after 1-3 months of treatment

• Most GLP-1RAs can be used in patients with chronic kidney disease (eGFR down to 30)
• GLP-1RA treatment has few interactions and can be combined with other glucose-lowering

drugs (e.g. SGLT2is)

• Few contraindications: Type 1 diabetes, ketoacidosis, (CHF NYHA class IV)

When you prescribe a GLP-1RA in your high-risk type 2 diabetes patients, remember to / that…