A review of potential therapeutic

targets impacting CV outcomes in

T2DM

Naveed Sattar, MDUniversity of Glasgow

United Kingdom

Asian Cardio Diabetes ForumApril 23 – 24, 2016 – Kuala Lumpur, Malaysia

Diagnosis

~ 5-15

years

CHD equivalent

CH

D R

ISK

Age

Diabetes and CVD risk: changing patterns over time

Sattar (2013) Diabetologia (several studies support concept)

Diabetes-related CV complications have declined with improved care, but substantial burden remains

0

50

100

150

1990 2000 2010

Eve

nts

pe

r 1

0,0

00

a

du

lt p

op

ula

tio

n w

ith

dia

be

tes

MI Stroke

Years

CV, cardiovascular; MI, myocardial infarction.

Adapted from Gregg EW, et al. N Engl J Med. 2014;370:1514–1523.

Glucose-lowering vs CVD

Knowns and unknowns

Many ways to lower sugar –

Method more important than glucose-lowering per

se?

– What do we know about

– Metformin / SU / TZDs?

– DPP4i and GLP-1?

Evolution of T2D agents

Adapted from 1. Kirby. Br J Diabetes Vasc Dis 2012;12:315–20. 2. Lantus® SPC.

1950 1960 1970 1980 1990 2000 2010 2012 2013

Lente class

of insulins

produced

SUs first used

Metformin

introduced

Recombinant

human insulin

produced

2nd generation

SUs available

Three new classes introduced:

-glucosidase inhibitors, meglitinides

and TZDs

Glimepiride:

3rd generation SU

DPP4

inhibitors

GLP1 receptor

agonists

SGLT2

inhibitors

Insulin

degludec

Older T2D agents Newer T2D agents

Insulin glargine

available2

5

Metformin

introduced

in the UK

Metformin: MOA

Adapted from 1. Bailey & Feher. Therapies for Diabetes 2004. 2. Batchuluun et al. J Endocrinol Diabetes Obes 2014;2:1035.

In addition to its glucose-lowering effects, metformin may have potential

effects on the CV system, e.g., improving plasma lipid profile2

6

Metformin1

Intestine Liver Skeletal muscle

Glucose utilisation Gluconeogenesis

Glycogenolysis

Fatty acid oxidation

Insulin-mediated

glucose uptake

Glycogenesis

Fatty acid oxidation

Hyperglycaemia

UKPDS 34 CV effects of metformin in overweight patients

1. UKPDS 34. Lancet 1998;352:854–65. 2. http://www.medicines.org.uk/emc/medicine/23244/SPC.

3. Holman et al. N Engl J Med 2008;359:1577–897

Significant reduction in MI maintained

over 10 years’ follow-up3

1997 1999 2001 2003 2005 2007

No. of events:

Conventionaltherapy 73 83 92 106 118 126

Metformin 39 45 55 64 68 81

Myocardial infarction

Metformin vs

conventional

p = 0.01

Time from randomisation (years)

0 3 6 9 12 15

0.0

10

20

30

Pro

po

rtio

n o

f p

atie

nts

with

eve

nts

(%)

Intensive (n = 951; events = 139)

Conventional (n = 411; events = 73)

Metformin (n = 342; events = 39)

Risk of MI is 39% lower with metformin vs

conventional therapy in obese patients1,2

1.4

1.2

1.0

0.8

0.6

0.4

HR

(9

5%

CI)

RR 0.611

p = 0.01

RR 0.67

p = 0.005

Overall values at study end in 1997

Annual values during 10-year post-trial monitoring period

0.4

Reproduced from 1. Gore and McGuire. Eur Heart J 2011;32:1832–4.

8

Sulphonylureas: MOA

Meta-analysis SU CV safety trials (≥ 6 months) no consistent association with MACE risk1

Monami et al. Diabetes Obes Metab 2013;15:938–53.

9

First author (year)

Birkeland 1996

Chou 2008

Perriello 2006

Gerstein 2010

UKPDS 33 1998

Hanefeld 2007

Seino 2010

Charbonnel 2005

Matthews 2005

Rubin 2008

Home 2009

Arechavaleta 2011

va der Laar 2004

Mazzone 2006

Riddle 1998

Giles 2010

Tolman 2009

Kahn 2006

Goke 2010

Garber 2009

Nissen 2008

Ristic 2007

Ferrannini 2009

Bakris 2006

Gallwitz 2012

Jain 2006

Johnston 1998

Nauck 2011

Seck 2010

Overall0.01 0.1 1 10 100

Favours SUs Favours comparators

MH-OR (95% CI)

• Overall MACE risk estimate: MH-OR 1.08 (0.86–1.36)

• Mortality MH-OR: 1.22 (1.01–1.49)

TZDs (PPAR-γ agonists): MOA

Adapted from Bailey & Feher. Therapies for Diabetes 2004.

10

TZD

Liver

Glucose uptake Gluconeogenesis

Adipogenesis

Fatty acid uptake

Lipogenesis

Glucose uptake

Hyperglycaemia

Adipose

Plasma FFA

Skeletal muscle

PPAR activation

In 2007, separate meta-analyses suggested

differing CV effects of drugs within the TZD class

1. Nissen & Wolski. N Engl J Med 2007;356:2457–71. 2. Lincoff et al. JAMA 2007;298:1180–8.

Rosiglitazone meta-analysis1

0,5 1.0 2.0

Favours

rosiglitazone

Favours control

MI

OR 1.43 (95% CI: 1.03‒1.98)

p = 0.03

CV death

OR 1.64 (95% CI: 0.98‒2.74)

p = 0.06

Pioglitazone meta-analysis2

0,5 1.0 2.0

Favours

pioglitazone

Favours control

MI

HR 0.81 (95% CI: 0.64‒1.02)

p = 0.08

Death

HR 0.92 (95% CI: 0.76‒1.11)

p = 0.38

11

No clinical trial directly compares the CV effects of pioglitazone and rosiglitazone

Rosiglitazone: RECORD study results showed no

increase in CV death

1. AVANDIA US Prescribing information. 2. Home et al. Lancet 2009;373:2125–35.

3. FDA Safety Information. 4. Rosenson et al. Am Heart J 2012;164:672–80.

Rosiglitazone N = 2220

Active control N = 2227

HR 95% CI

Primary endpoint

CV death or CV hospitalisation

321 323 0.99 0.85–1.16

Secondary endpoint

All-cause death 136 157 0.86 0.68–1.08

CV death 60 71 0.84 0.59–1.18

MI 64 56 1.14 0.80–1.63

Stroke 46 63 0.72 0.49–1.06

CV death, MI or stroke 154 165 0.93 0.74–1.15

Heart failure 61 29 2.10 1.35–3.27

CV outcomes for RECORD

trial (original data)1,2

• In 2013, FDA panel voted to reduce safety

restrictions on rosiglitazone3

U.S. National Institute of Neurological Disorders and Stroke

(Grant # U01NS044976)

Published on-line: February 17, 2016 DOI: 10.1056/NEJMoa1506930

IRIS Secondary OutcomesPioglitazone

(N=1939)

Placebo

(N=1937)

Outcome* % (No.) % (No.)

Hazard Ratio

(95% CI) P

Stroke 6.5 (127) 8.0 (154) 0.82 0.19

ACS 5.0 (96) 6.6 (128) 0.75 0.11

Stroke/MI/HF 10.6 (206) 12.9 (249) 0.82 0.11

DM 3.8 (73) 7.7 (149) 0.48 <.0001

Death 7.0 (136) 7.5 (146) 0.93 0.52

*ACS=Acute coronary syndrome (unstable angina or MI).

*HF=heart failure

Kernan WN et al. N Engl J Med, published on-line Feb 17, 2016 DOI: 10.1056/NEJMoa1506930

IRIS: Summary

Among insulin resistant, non-diabetic patients with

ischemic stroke/TIA, pioglitazone over 5 yrs prevented:

• Stroke or MI

Relative Risk Reduction 24%

Absolute Risk Reduction 2.9%

• Diabetes

Relative Risk Reduction 52%

Absolute Risk Reduction 3.9%

However, serious bone fracture was more common with

pioglitazone (5.1% vs. 3.2%)

Kernan WN et al. N Engl J Med, published on-line Feb 17, 2016 DOI: 10.1056/NEJMoa1506930

Summary on TZDs

Evidence for PIO and CVD (stroke and MI)

prevention exists

– But more fluid retention, weight gain, fractures, HF

– No evidence of CVD death benefit

Rosiglitazone likely no net CVD harm

Pio – good glycaemia effect – use lower doses to

minimise side effects?

EFFECT of Glucose lowering per se

Potentially independent of mode

Benefit of different interventions per 200 diabetes pts treated for 5 years

-12.5

-8.2

-2.9

-20

-15

-10

-5

0

5

CV e

vent

s

Per 0.9% lower

HbA1c

Per 4mmHg lower SBP

Per 1mmol/L

lower LDL-C

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

- lowers microvascular risk (better earlier in disease; later reduction less beneficial?)

- Slow burn benefit impact on CVD

- If lower too aggressively, potential harm (ACCORD)

- Glucose-lowering agents ≠ CVD

Totality of evidence: glucose lowering data

hard to decipher but lowering HbA1c per se

Uncertainty: guidelines - HbA1c targets vary by patient characteristics

Near diagnosis: 6.5% sensible

But 7 to 7.5% fine for most

Relax: elderly, long duration, frail, short

life expectancy, hypoglycaemia risk, CVD

– Inzucchi et al (2015) Diabetes Care

Incretins

•(GIP)

•GLP-1

Stimulate insulin

release

Inhibit glucagon

release

Reduce

blood glucose

DPP4

Breakdown

products DPP4 inhibitors

(“gliptins”)

GLP-1 agonists/analogues

e.g. exenatide

Inhibit renal

re-absorption

(SGLT2 inhibitors)

Inhibit gastro-

intestinal absorption

(α-glucosidase inhib’s)

New approaches to reducing blood glucose

CV safety trials: 5 down, many to come

Timings estimated from ClinicalTrials.gov.

CANVAS-R8

(n = 5700)Albuminuria

2013 2014 2015 2016 2017 2018 2019

SAVOR-TIMI 531

(n = 16,492)1,222 3P-MACE

EXAMINE2

(n = 5380)621 3P-MACE

TECOS4

(n = 14,724)≥ 1300 4P-MACE

LEADER6

(n = 9340)≥ 611 3P-MACE

SUSTAIN-67

(n = 3297)3P-MACE

DECLARE-TIMI 5815

(n = 17,150)≥ 1390 3P-MACE

EMPA-REG OUTCOME®5

(n = 7034)≥ 691 3P-MACE

CANVAS10

(n = 4365)≥ 420 3P-MACE

CREDENCE17

(n = 3700)Renal + 5P-MACE

CAROLINA®11

(n = 6000)≥ 631 4P-MACE

ITCA CVOT9

(n = 4000)4P-MACE

EXSCEL14

(n = 14,000)≥ 1591 3P-MACE

DPP4 inhibitor CVOTs

SGLT2 inhibitor CVOTs

GLP1 CVOTsErtugliflozin CVOT18

(n = 3900)3P-MACE

OMNEON13

(n = 4000)4P-MACE

CARMELINA12

(n = 8300)4P-MACE + renal

REWIND16

(n = 9622)≥ 1067 3P-

MACE

2021

ELIXA3

(n = 6068)≥ 844 4P-MACE

Incretins

•(GIP)

•GLP-1

Stimulate insulin

release

Inhibit glucagon

release

Reduce

blood glucose

DPP-4

Breakdown

products DPP-4 inhibitors

(“gliptins”)

GLP-1 agonists/analogues

e.g. exenatide

Inhibit renal

re-absorption

(SGLT2 inhibitors)

New approaches to reducing blood glucose

Therapy Trial N Population Follow-

up

duratio

n

HbA1c

difference

during follow-

up

Primary outcome

Saxagliptin

(DPP-4

inhibitor)

SAVOR-

TIMI 53

16,492 +CVD (80%) or

–CVD at high

risk (20%)

24

months

0.2-0.3% CVD death, NF

MI or stroke

Alogliptin

(DPP-4

inhibitor)

EXAMINE 5,380 MI or UA within

last 15-90 days

18

months

0.36% CVD death, NF

MI or stroke

Sitagliptin

(DPP-4

inhibitor)

TECOS 14,671 +CVD 36

months

0.3% CVD death, NF

MI or stroke,

hospitalization

for UA

Lixisenatide

(GLP-1R

agonist)

ELIXA 6,068 MI or UA within

last 180 days

25

months

0.27% CVD death, NF

MI or stroke,

hospitalization

for UA

Empagliflozin

(SGLT2

inhibitor)

EMPA-

REG

Outcomes

7,020 +CVD 37

months

0.3-0.5% CVD death, NF

MI or stroke

DPP-4 inh. GLP-1 agonist SGLT2 inh.

Hypo risk Low Low Low

Weight Neutral Lower Lower

BP Neutral Lower Lower

Lipids Neutral Improved HDL /LDL-c?

CVOT

results

Neutral CVD ELIXA

Neutral CVD ???Other points Small HF signal

SaxaWAIT FOR

LEADER

EXSCEL

Infections?

DKA?

Effects on other risk factors and CVD?

PRIMARY OUTCOMES for DPP4i trials all negative

No CVD benefit in major trials – EXAMINE,

SAVOR-TIMI, TECOS

Should we surprised? No

– HbA1c difference only 0.3%

– Median durations of follow-up short <2 years

– No other risk factors altered

Medications would have needed very strong

‘pleiotropic’ actions to yield CVD benefit

Cardiovascular outcome trials in T2D GLP-1 agents

Trial Treatment Inclusion

criteria

Primary

endpoint

Number of

patients

EXSCEL Placebo

ExenatideOnce weekly

T2D

HbA1c ≥ 7.0−<

10.0%

CVD in 60%

CV death, MI or

stroke

>14000

ELIXA Placebo

Lixisenatid

e

T2D

ACS

HbA1c ≥ 6.0−≤

10.0%

CV death, MI, UA

or stroke

6000

LEADER Placebo

Liraglutide

T2D

HbA1c ≥ 7.0%

≥ 50 years + CVD

≥ 60 years + CV

risk factors

CV death, MI or

stroke

8754

ACS, acute coronary syndrome; CV, cardiovascular; CVD, cardiovascular disease; GLP-1, glucagon-like peptide-1; HbA1c, glycosylated

haemoglobin; MI, myocardial infarction; T2D, Type 2 Diabetes; UA, unstable angina.

Small reductions in glucose alone for short time will not

lower CVD

– DPP4; ORIGIN (early insulin)

– Drugs must do more than just lower glucose

Proven for CVD benefit

– Metformin (UKPDS, less weight, no hypos)

– Pioglitazone (Stroke, MI, but increases HF, weight etc)

– Empagaflozin (hear later)

– Liraglutide (data coming)

Method, more than absolute glucose reduction may matter to CVD risks

Summary: CVD in DM: lipids, BP, smoking and specific diabetes agents?

Clear evidence CVD in DM over several decades

– Better management CVD risk factors big part

BP and LDL-c reduction >> glucose reduction

But many sub-optimally treated; high death rates if DM & CVD

Lower HbA1c targets early in disease but relax if CVD

or long duration or frail

Recent trial data enormously beneficial – not

necessarily how much we lower glucose, but how we

target it - “paradigm shift”?