At least 68% of people >65 years with diabetes die of heart disease

Global CV Impact of T2DM

(N 820,900)

IDF Diabetes Atlas. 7th edn. 2015

Seshasal NEJM 2011;364:829

2015 2040

Years

Gregg NEJM 2014;370:1514–1523.

Disclosures

• Lectures for Merck, Pfizer, Amgen, Sanofi, Aegerion, Kowa, Danone

• Advisory boards: Danone, Merck, Amgen, Aegerion, Verseon

• No relevant research funding

CV Mortality in T2DMSwedish National Diabetes Register over 4.6 years

Tancredi N Engl J Med 2015;373:1720-32

Hazard Ratio (95% C)

Constantino et al (2013) Diabetes Care ePub

Long-Term Complications and Mortality

in Young-Onset DiabetesT2DM is more hazardous and lethal than T1DM

Diabetes, Fasting BG, BP andCholesterol on CHD Risk

Emerging Risk Factors Collaboration Lancet 2010; 375: 2215–22

Fasting Blood Glucose Total / non-HDL Cholesterol Systolic BP

CARDS: Cumulative Hazard for MI and CV death

Atorvastatin

Cu

mu

lati

ve H

azard

(%

)

Relative Risk -37% (95% CI: -52, -17)

P=0.001

Years

Placebo

0

5

10

15

0 1 2 3 4 4.75

Colhoun Lancet 2004; 364: 685-696

Time to First Major CV Event in Patients With Diabetes TNT Study : Lower

HR = 0.75 (95% CI 0.58, 0.97)

P=0.026

0 1 2 3 4 5 6

Time (years)

0.20

0.10

0.15

0.05

0

Cu

mu

lati

ve in

cid

en

ce o

f m

ajo

r card

iovascu

lar

even

ts

Relative risk reduction = 25%

Atorvastatin 80mg

Atorvastatin 10mg

Multiple Risk Factors and CVD Death in Diabetic and Non diabetic Men (MRFIT)

Stamler J et al Diabetes Care 1993;16:434.

Ag

e-a

dju

ste

d C

VD

death

rate

/10,0

00 p

ers

on

-years

140

120

100

80

60

40

20

0

No Diabetes

Diabetes

None One only Two only All three

Number of risk factors

Multifactorial Intervention in T2DM : Broader

Gaede N Engl J Med 2008;358:580-91

Benefit of Different Interventions per 200 Diabetes Pts Treated for 5 years

Per 0.9% lowerHbA1c

Per 4mmHg lower SBP

Per 1mmol/L

lower LDL-C

Ray Lancet 2009 Meta-analysis of intensive glucose-lowering trials

CV

Ev

en

ts

5

0

-5

-12.5-15

-20

-10 -8.2

-2.9

Using traditional Glucose lowering treatments

Intensive Glucose Lowering in T2DM: ACCORD Study : Earlier?

N Engl J Med 2008;358:2545-59

Primary Outcome Death from Any Cause

Adverse CV events led the FDA to require demonstration of CV safety for new glucose-lowering drugs

UGDP trial: tolbutamide discontinued due to increased CV mortality vs other treatments

1961

2005

2007

2008

2008

2012

Muraglitazar increases CV risk during FDA assessment

Rosiglitazone increased risk for MI and CV-related death

ACCORD trial: intensive glucose lowering increased all-cause mortality

FDA / EMA requirements

New diabetes drugs should

demonstrate CV safety with meta-

analysis and CV outcome trial

New Diabetes Treatments

Target CV disease mechanisms

Widely applicable

Safer ( eg Hypoglycaemia)

Weight loss

Lifetime CV risk management

Liraglutide and CV Outcomes in T2DM

Marso N Engl J Med 2016;375:311-22

Pati

en

ts w

ith

an

Even

t (%

)

Primary Outcome Death from Any Cause

Months since Randomisation

HR 0.87

P=0.01

HR 0.85

P=0.02

LEADER Trial

SGLT2 SGLT

1

Proximal tubule

S1

GlomerulusDistal tubule

Glucosefiltration

S3

Collecting duct

90%

10%

Loop of Henle

Glucosereabsorption

Wright EM. Am J Physiol Renal Physiol. 2001;280:F10-F18;

Lee YJ et al. Kidney Int Suppl. 2007;106:S27-S35;

Han S. Diabetes. 2008;57:1723-1729.

SGLT2 inhibitor Minimal

glucoseexcretion

SGLT2 Inhibition ReducesRenal Glucose Reabsorption

- 70-80 g/day ( - 280-320 Kcal/day)

Increasedglucose

excretion

Zinman N Engl J Med 2015;373:2117-28

Death from CV Causes

HR 0.62

P<0.01

Empagliflozin, CV Outcomes and Mortality in T2DM

Mechanisms for CV Benefit From SGLT2

Abdul-Ghani Diabetes Care 2016 May; 39(5): 717-725

Empagliflozin and Progression of Kidney Disease in T2DM

Wanner N Engl J Med 2016;375:323-34

Incident or Worsening Nephropathy Post Hoc Renal Composite Outcome

Empa

Placebo

Empa

Placebo

HR 0.61, P<0.001 HR 0.54, P<0.001

CV outcome trials for SGLT2 Inhibitors in Diabetes

CANVAS

(n = 4339)

2015 20172016 2018 2019

EMPA-REG

OUTCOME™

n = 7034

DECLARE-TIMI 58

(n = 17,150)

2020

Dapagliflozin

High risk for CVD

Established CVD

Triple MACE

1390 events

Canagliflozin

Established CVD

or > 2 CVD risk ff

Triple MACE

420 events

Empagliflozin

Established CVD

Triple MACE

691 events

CV mechanisms?

Safety?

Class effect?

Combination therapy?

Opportunity for Prevention?

New Era for CVD Management in DM:Some thoughts…

In addition to BP and Cholesterol lowering, CVD and renal benefit with two new diabetes drugs especially SGLT2 I

Has changed guidelines for DM care

Novel multiple mechanisms, especially with lack of hypoglycaemia may broaden indications towards early treatment, prevention, even without DM

Diabetologists Cardiologists