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 riskObesity 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

featuresDiabetes

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

0

60

40

0 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

HFpEFHFrEF

HFpEF

Cum

ula

tive

incid

en

ce (

%)

Follow-up (years)

No

diabetesDiabetes

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

0

20

40

60

80

100

120

140

160

-15 0 15 30 45 60 75 90 105120135150165180

Time (minutes)

Pla

sm

a g

luco

se (

mg

/dL

)

25 g glucose

0

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

0

20

40

60

80

100

120

140

160

-15 0 15 30 45 60 75 90 105120135150165180

Time (minutes)

0

20

40

60

80

100

120

140

160

-15 0 15 30 45 60 75 90 105 120 135 150 165 180

Time (minutes)

Pla

sm

a g

luco

se (

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 hormonesGlucose-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

HeartMyocardial contractility

Heart rate

Myocardial glucose uptake

Ischaemia-induced

myocardial damage

KidneyNatriuresis

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 SerPheGlu Gly AspVal

Ser

SerTyrLeuGluGlyAlaAla GlnLys

Phe

Glu

Ile Ala Trp Leu GlyVal Gly ArgLys

Fat cellsGlucose uptake

Lipolysis

LiverGlycogen storage

Skeletal muscleGlucose uptakeBlood vessel

Endothelium-dependent

vasodilation

PancreasNew β-cell formation

β-cell apoptosis

Insulin biosynthesis

DPP-4

GI tractMotility

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

LSLS

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

HeartMyocardial contractility

Heart rate

Myocardial glucose uptake

Ischaemia-induced

myocardial damage

KidneyNatriuresis

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 SerPheGlu Gly AspVal

Ser

SerTyrLeuGluGlyAlaAla GlnLys

Phe

Glu

Ile Ala Trp Leu GlyVal Gly ArgLys

Fat cellsGlucose uptake

Lipolysis

LiverGlycogen storage

Skeletal muscleGlucose uptake

Blood vesselEndothelium-dependent

vasodilation

PancreasNew β-cell formation

β-cell apoptosis

Insulin biosynthesis

DPP-4

GI tractMotility

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)

0 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

0

10

15

20

TG

(m

mo

l/L

)

*

5

Vehicle, chow

Vehicle, western diet

Semaglutide (1 nmol/kg)

Semaglutide (3 nmol/kg)

Semaglutide (15 nmol/kg)

0

10

20

30

Aortic plaque lesions

**

Pla

que a

rea (

%)

** **

Vehicle, chowVehicle,

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 emptyingGlucose 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

20192015 20202013 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

or 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

of 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

Thank you