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

NOVEL THERAPEUTIC APPROACHES IN DIABETES: THE CARDIOVASCULAR BENEFITS BEYOND GLUCOSE CONTROL

Professor LINA BADIMON, BSc, PhD Cardiovascular Program-ICCC IR-Hospital de Sant Pau Barcelona, Spain WHF 2018 DUBAI

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:

Emerging Risk Factors Collaboration. Lancet 2010;375:2215

BMI, body mass index; CI, confidence interval; HR, hazard ratio; MI, myocardial infarction; SBP, systolic blood pressure HR, diabetes vs non-diabetes

Smooth Muscle Cells ↓ Vasodilation ↓ Response to vasoconstrictors ↑ Apoptosis ↑ MMP synthesis ↓ Collagen synthesis Platelets

Hemostatic changes Ca2+ ↑ Surface receptors

↑ Activation markers ↑ TxA2 production ↓ NO synthesis ↓ PGI2 synthesis Endothelium ↓ NO synthesis ↑ Vasoconstriction ↑ Adhesion molecules ↑ Chemokines ↑ Inflammation Coagulation / Fibrinolysis ↑ TF in circulation ↑ Activity TF ↑ vWF-FVIII ↑ Fibrinogen ↑ PAI-1 MicropartIcles ↑ Number ↑ p-MP

DIABETES AND ATHEROTHROMBOSIS

Badimon L et al 2012-2017

BM alterations

↑ Thrombotic risk

Obesity and insulin resistance

Hernandez Vera, Vilahur, et Badimon Thromb & Haemost 2013 Friedl, G., Acta Orthop, 2009. Khan, M.,, Stem Cells Dev, 2011

Obesity

Oñate, Vilahur, Ferrer et Badimon. FASEB Journal 2012

Resident ASC alterations

Hernandez Vera, Vilahur, et Badimon . Arterios Thromb Vasc Biol 2012

Type 2 diabetes Type 2 diabetes EPC

DIABETES AND THROMBOGENICITY

I I I II I I V

Badimon L et al 2012-2017

Hernandez Vera, Vilahur, et Badimon Thromb & Haemost 2014

Mitochondrial dysfunction Endothelial dysfunction Insulin resistance RAAS activation Inflammation

Heart failure

Neurohormonal activation Impaired contractility Cardiomyocyte apoptosis/fibrosis Shared pathological features

Diabetes

LV remodelling Hyperglycaemia Advanced glycated end- product toxicity ↓ Pancreatic beta-cell function Neuronal degeneration/ demyelination

CV death or HHF in patients with or without diabetes based on ejection fraction category 20 60 40 0.5 1 1.5 2 2.5 3 3.5

HFrEF: unadjusted HR 1.60 (95% CI 1.44, 1.77); p<0.0001 HFpEF: unadjusted HR 2.0 (95% CI 1.70, 2.36); p<0.0001 HFrEF HFpEF HFrEF HFpEF

Cumulative incidence (%) Follow-up (years)

No diabetes

Diabetes MacDonald MR et al. Eur Heart J 2008;29:1377

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 , 50 and 100 g oral glucose

Adapted from

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

15 30 45 60 75 90 105 120 135 150 165 180

Time (minutes) Plasma glucose (mg/dL)

25 g glucose 50 g glucose 100 g glucose

GLP-1

Plasma glucose during 25 , 50 and 100 g oral glucose

The incretin hormones

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

GIP K cells L cells

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

Daniel J. Drucker, Joel F. Habener, and Jens Juul Holst. JCI 2017

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.

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

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

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

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

GLP-1 METABOLIC EFFECTS Insulin secretion Β-cell function Gastric emptying Glucose output Appetite

Heart rate

INDIRECT CV EFFECTS DIRECT CV EFFECTS Endothelial dysfunction Vessel inflammation Atherosclerosis Cardiac function

GLP-1 effect on known risk factors for CVD

Dyslipidaemia Obesity Hypertension Glucose

Indirect and direct CV actions of GLP-1 in T2DM

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

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.

Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes

ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN 6 (semaglutide), EXSCEL (extended-release exenatide)

THREE POINT MACE: CARDIOVASCULAR MORTALITY, NON-FATAL MI AND NON-FATAL STROKE

Bethel et al. Lancet Diabetes Endocrinol Dec 6th, 2017

The phase 3a double-blinded PIONEER 6 trial achieved its primary endpoint by demonstrating non-inferiority of major adverse cardiovascular events (MACE) with oral semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), taken once daily 14 mg compared with placebo, both in addition to standard of care, in 3,183 adults with T2DM at high risk of CV events. The results are based on the accumulated occurrence of 137 MACE, with a median follow-up time of 16 months. The primary endpoint of the PIONEER 6 trial was defined as the MACE composite outcome of the first occurrence of CV death, non-fatal MI

• r non-fatal stroke and showed an non-significant HR of 0.79 in favor of oral semaglutide compared with placebo.

The MACE results demonstrated by oral semaglutide were driven by a statistically significant reduction in CV death of 51% (HR: 0.49, P=0.03), while non-fatal MI (HR: 1.18, non-significant) or non-fatal stroke (HR: 0.74, non-significant) were broadly similarly distributed between the two treatment arms. In addition, a statistically significant reduction in all-cause mortality

• f 49% (HR: 0.51, P=0.008) in favor of oral semaglutide was observed. The improvements in secondary endpoints including

HbA1c, body weight and blood pressure were similar to results reported throughout the PIONEER program for oral semaglutide. Furthermore, the safety profile of oral semaglutide in PIONEER 6 was consistent with the established safety profile observed in previous PIONEER clinical trials.

PIONEER 6 was an event-driven, pre-approval CV outcomes trial for oral semaglutide. It was a randomized, double-blinded, placebo-controlled trial evaluating the CV safety of oral semaglutide vs placebo when added to standard of care in 3,183 people with T2DM at high risk of CV events. The PIONEER phase 3a clinical development program for oral semaglutide is a global development program with enrolment of 8,845 people with T2DM across 10 clinical trials, which have all been completed in 2018.

GLP-1RA demonstrates CV safety and reduction in secondary mortality outcomes in T2DM

NEWS - NOV. 26, 2018

NEJM 373;22 November 26, 2015 EMPA-REG PRIMARY AND SECONDARY CARDIOVASCULAR OUTCOMES

SGLT2, Sodium- glucose co-transporter

STUDY DEVELOPMENT IN ANTI-DIABETIC DRUGS

• THE EVOLUTION OF REGULATORY GUIDANCE HAS ALTERED THE TRIAL

LANDSCAPE OF DRUG DEVELOPMENT IN T2DM >200,000 PATIENTS ENROLLED/PLANNED IN CV OUTCOMES TRIALS

• FIVE TRIALS HAVE REPORTED CV BENEFIT:
• LEADER: LIRAGLUTIDE ( reduced CV death and MI; no effect on stroke; no effect on

HF)

• SUSTAIN-6: SEMAGLUTIDE ( no effect on cv death and MI; reduce nonfatal stroke; no

effect on HF)

• EMPA-REG OUTCOME: EMPAGLIFLOZIN ( reduce MACE, reduce CV death and total

death and HF; no effect on MI/ stroke)

• CANVAS: CANAGLIFLOZIN Cardiovascular Assessment Study (reduced MACE
• DECLARE-TIMI 58: Dapagliflozin ( reduce HF only )

& CARDIAC EFFECTS

In summary: EFFECT OF ANTIHYPERGLYCEMIC AGENTS ON CARDIOVASCULAR OUTCOMES

HEMODYNAMIC CARDIAC BENEFICIAL EFFECTS ATHEROTHROMBOSIS & VASCULAR BENEFICIAL EFFECTS

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