The Influence of Type 2 Diabetes on Cardiovascular

Disease and Glycemic Treatment Options

Rocky Mountain/ACPInternal Medicine Conference

Banff, ABNovember 22, 2012

David C.W. Lau, MD, PhD, FRCPCDepts. of Medicine, Biochem. & Molec. Biol.

Julia McFarlane Diabetes Research CentreUniversity of Calgarydcwlau@ucalgary.ca

Program Faculty

• Dr. Ronald Goldenberg, MD, FRCPC, FACEConsultant Endocrinologist, North York General Hospitaland LMC Endocrinology Centers, Thornhill, Ontario

• Dr. Mansoor Husain MD, FRCPCDirector, Toronto General Hospital Research Institute and Heart and Stroke Richard Lewar Centre for ExcellenceSenior Scientist, Division of Experimental TherapeuticsProfessor of Medicine, University of Toronto

• Dr. David C. W. Lau MD, PhD, FRCPCProfessor of Medicine, Biochemistry and Molecular BiologyJulia McFarlane Diabetes Research CentreUniversity of Calgary

Disclosures: David C. W. Lau

Research funding:

• AHFMR, Alberta Cancer Board, CIHR, AstraZeneca, Boehringer-Ingelheim, BMS, Dainippon, Eli Lilly, Novo Nordisk, Pfizer and sanofi

Consultant or advisory board member:

• Abbott, Allergan, Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS, Eli Lilly, Merck, Novartis, Novo Nordisk, Pfizer, Roche, sanofi

Speaker bureau:

• CDA, HSFC, AstraZeneca, Abbott, Bayer, Boehringer-Ingelheim, BMS, Eli Lilly, Merck, Novo Nordisk, sanofi

Some slides are selected from accredited CHE programs sponsored by Novo Nordisk and AstraZeneca/BMS

Objectives

At the end of the presentation, the participant will be able to:• Understand the cardiovascular burden in diabetes• Review the mechanisms of actions of incretin-

based therapies for diabetes • Compare the cardiovascular effects of incretins and

other glucose-lowering agents• Review current and ongoing data on incretin-based

therapies and cardiovascular disease outcomes

Frequency of Diagnosed &Undiagnosed DM and IGT by Age

Rising Prevalence of Diabetes Mellitus

20-34 35-44 45-54 55-64 65-7405

10152025303540

IGTUndiagnosed diabetesDiagnosed diabetes

% ofpopulation

Adapted from M Harris. Diabetes Care 1993;16:642-52

Diabetes is a global disease!Estimated global prevalence of diabetes

International Diabetes Federation. IDF Diabetes Atlas. Fifth Edition. 2011

2000 2011 2030151 million 366 million 552 million

Diabetes Prevalence Rates in Canada, 2008/09

Canada 6.8%, N=2,359,252

Age- and sex-adjusted diabetes prevalence increased by 40% in the next 10 years, from 6.8%

in a population to 9.9% or 3.4 million in 2020!

Public Health Agency of Canada, Diabetes in Canada. Ottawa, 2011

Relative Risks for Fatal CAD in Diabetes

Huxley R et al., Br Med J 2006;332:73-78

Pooled RR = 1.7 from 37 studies; Meta-analysis of 22 studies

People with DM2 and CVD Derive Less Benefit from Preventive and Interventional Therapies

• Patients with diabetes treated with antiplatelet treatments continue to have a higher risk of adverse CV events compared with nondiabetic patients 1

Reduced antiplatelet drug responsiveness may play a role in these worse outcomes

• Diabetes may abolish the beneficial effect of primary percutaneous coronary intervention on long-term risk of reinfarction after acute ST-segment elevation MI 2

1. Angiolillo DJ. Diabetes Care 2009;32:531-540; 2. Madsen MM, et al. Am J Cardiol 2005;96:1469-1475. 9

CV, cardiovascular; CVD, cardiovascular disease; MI, myocardial infarction

Stratton IM, et al. BMJ 2000;321:405-412

1%A1C

reduction

21%reduction

21%reduction

14%reduction

14%reduction

12%reduction

37%reduction

19%reduction

43%reduction

16%reduction

Diabetes-related endpoints

Cataract extraction

Diabetes-related mortality

All-cause mortality

Fatal/non-fatal MI Fatal/non-fatal stroke Microvascular endpoints

Amputation/death from PVD

Heart failure

A1C Predicts Cardiovascular Disease:Reducti on Has Important Benefi ts

Glycemic Control and CVD Events

Mean A1C 0.9% • 9% major CV

events• 15% fatal/

nonfatal MI• No overall effect

on stroke, CHF or all-cause mortality

Turnbull FM et al. Diabetologia 2009;52:2288-2298

DCCT/EDIC: Glycemic Control Reduces the Risk CV Death, MI, Stroke in Type 1 Diabetes

Conventional treatment

Intensive treatment

*Intensive vs conventional treatment

Cum

ulati

ve in

cide

nce

of n

on-fa

tal M

I, st

roke

or

dea

th fr

om C

VD

Conventionaltreatment

Intensivetreatment

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21Years

0.06

0.04

0.02

0.00

DCCT (intervention period) EDIC (observational follow-up)

07

1 6

A1C

(%)

9

8

2 3 4 5 7 8 9 11 12 13 14 15 16 1710DCCT (intervention period) EDIC (observational follow-up)

Years

1. DCCT. N Engl J Med 1993;329:977–9862. DCCT/EDIC. JAMA 2002; 287:2563–25693. DCCT/EDIC. N Engl J Med 2005;353:2643–2653

CVD death, MI & StrokeRR 57% (p = 0.02, 95%CI 12-79%)

Legacy effect: Benefit of early aggressive glycemic

control on CVD outcomes

• Treatment goals and targets must be individualized with considerations given to individual risk factors

• Target 2-3 months for lifestyle management before initiating pharmacotherapy

Recommended Targets for Glycemic Control

Can J Diabetes 2008;32(Suppl 1):S29-S31

FPG(Fasting Plasma

Glucose)

4.0 – 7.0 mmol/L

2-hour PPG(Postprandial glucose)

5.0 – 10.0 mmol/L(5.0 – 8.0 if A1C targets

are not being met)

A1C

≤ 7.0%Type 1 and Type 2

Diabetes

2008 CDA Clinical Practice Guidelines

Initiate metformin

Initiate pharmacotherapy immediately without waiting for effect from lifestyle interventions: Consider initiating metformin concurrently with another agent from a different class; or insulin Initiate insulin

± metformin

If not at target

Add an agent best suited to the individual:• Alpha-glucosidase inhibitor• Incretin agent: DPP-4 inhibitor• Insulin• Insulin secretagogue: Meglitinide, Sulfonylurea• TZD• Weight loss agent

If not at target:• Add another drug from a

different class; or • Add bedtime basal insulin to

other agent(s); or • Intensify insulin therapy

2008 CDA Clinical Practice GuidelinesClinical Assessment - Lifestyle intervention (Nutrition therapy and physical activity)

A1C < 9.0% A1C ≥ 9.0% Symptomatic hyperglycemia with metabolic decompensation

2008 CDA CPGs. Can J Diabetes 2008;32(Suppl 1):S53–S61

How do glucose-lowering drugs work?

Main Classes ofGlucose-Lowering Medications

TZD = thiazolidinedione; DPP = dipeptidyl peptidase; GLP = glucagon-like peptide Krentz AJ, Bailey CJ. Drugs 2005;65:385-411

SUs and rapid-acting secretagogues

(stimulate insulin secretion)

Biguanides(reduce hepatic

glucose production and intestinal absorption of glucose; increase

peripheral glucose uptake)

α-glucosidase inhibitors (delay digestion and

absorption of intestinal carbohydrate)

TZDs (reduce insulin resistance

in target tissues)

DPP-4 inhibitors (prolong GLP-1 action, stimulate

insulin secretion, suppress glucagon release)

GLP-1 analogues (increase GLP-1 action, stimulate insulin

secretion, suppress glucagon release, decrease appetite, delay gastric emptying) Insulin

(improves insulin secretion and peripheral insulin sensitivity)

Food intake

Stomach

GI tract

Intestine

Increases and prolongs GLP-1 effect on alpha-cells:

Alpha-cells

Pancreas

Insulin release

Net effect: Blood glucose

Beta-cells

Increases and prolongs GLP-1 and GIP effects on beta-cells:

DPP-4 inhibitor

Glucagon secretion

Incretins

DPP-4

DPP-4 Inhibitors Enhance Incretin and Insulin Secretion

Adapted from: Barnett A. Int J Clin Pract 2006;60:1454-70 Drucker DJ, Nauck MA. Nature 2006;368:1696-705Idris I, Donnelly R. Diabetes Obes Metab 2007;9:153-65

GLP-1 receptor agonists improve glucose control through multiple mechanisms

Ussher J & Drucker DJ, Endocrine Rev 2012;33:187-215

Saxagliptin Canadian Product Monograph, Bristol Myers Squibb/Astra Zeneca, 2009; Sitagliptin Canadian Product Monograph, Merck Frosst, 2010.; Linagliptin Canadian Product Monograph, Boehringher Ingelheim (Canada) Ltd. July 26, 2011.; Liraglutide Canadian Product Monograph, Novo Nordisk Canada, 2011; Exenatide Canadian Product Monograph, Eli Lilly Canada, 2011. Drucker DJ, et al. Lancet 2006;368:1696-705 Slide Courtesy of Novo Nordisk sponsored accredited CHE program

GLP-1analogue:

Liraglutidemodified human

GLP-1

GLP-1 mimetic:

Exenatidemodified from Gila

monster lizard saliva

DPP-4 inhibitors:

LinagliptinSaxagliptinSitagliptin

Incretin Therapies Currently Available

Injectable Oral

Questions to consider when choosing a glucose-lowering agent

• What is the efficacy in A1C reduction?• What is the glycemic durability?• Is the patient at risk for hypoglycemia?• Is weight a concern?• What are the long-term side-effects?• Does the patient have a drug plan?• What is your prescribing comfort level?• What is your patient’s preference?

*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 vs. liraglutide 1.8 mg ;

Henry RR, et al. Endocr Pract 2011;17(6):907

Diabetes disease progression

≤7.5% >7.5% - 8.0% >8.0% to 8.5% >8.5% to 9.0% >9.0%

***

****

**

** ***

*

****

****

0.5

0

-0.5

-1.0

-1.5

-2.0Chan

ge in

A1C

from

bas

elin

e to

26

wee

ks (%

)

Exenatide

LiraglutideSitagliptin GlimepirideRosiglitazone

Glargine

Glucose Lowering Therapy in Diabetes: A1C Reduction by Baseline A1C

Kahn SE et al. N Engl J Med 2006;355:2427-2443

ADOPT: Kaplan-Meier Estimates of the Cumulative Incidence of Monotherapy Failure at 5 Years

Adverse Outcomes Among Patients with Type 2 Diabetes Experiencing Severe Hypoglycemia

25

No.

of a

dver

se o

utco

mes

Months from severe hypoglycemia to event

20

15

10

5

00–12 13–24 25–36 37–48

Macrovascular eventMicrovascular eventDeath from any causeCardiovascular deathNoncardiovascular death

Zoungas S, et al. N Engl J Med 2010;363(15):1410–18

The median time from hypoglycemic episode to related adverse event or death was ≤ 1.6 years!

N=11,140

Estimated Rates of Emergency Hospitalisations for Adverse Drug Events in Older U.S. Adults, 2007–2009

Budnitz DS, et al. N Eng J Med 2011;365:2002-12

14%

11%

Emergency Hospitalizations forAdverse Drug Events in Older Americans

Oral agents and insulin account for > 25% of hospitalizations in adults > 65 years!

Antihyperglycemic Drugs & Risk of Hypoglycemia

High• Insulin• Insulin secretagogues

SulfonyureasMeglitinides

Low• Metformin• DPP-4 inhibitors• GLP-1 receptor agonists• TZDs• Acarbose• Orlistat

Garber A et al. Lancet 2009;374:473-81 (LEAD-3); Marre M et al. Diabet Med 2009;26:268–78 (LEAD-1); Nauck M et al. Diabetes Care 2009;32:84–90 (LEAD-2); Zinman B et al. Diabetes Care 2009; 32:1224-30 (LEAD-4); Russell-Jones Det al. Diabetologia 2009;52:2046-55 (LEAD-5); Buse J et al. Lancet 2009;374:39-47 (LEAD-6); Pratley R et al. Lancet 2010;375:1447-1456 (Lira vs. sitagliptin)

LEAD 3Liraglutide

monotherapy vs SU

Diet/exerciseDiet/exercise

Met: metformin SU: sulfonylurea TZD: thiazolidinedione

+1 OAD+1 OAD +2 OAD+2 OAD +3 OAD or +2 OAD, Insulin

+3 OAD or +2 OAD, Insulin

LEAD 2Liraglutide+Met

vs SU+Met

LEAD 1Liraglutide+SU

vs TZD+SU

LEAD 6Liraglutide+met/SU/both

vs exenatide+met/SU/both

LEAD 4Liraglutide+met&TZD vs placebo+met&TZD

LEAD 5Liraglutide+Met&SUvs glargine+Met&SU

Type 2 diabetes treatment continuum

Liraglutide Effect and Action in Diabetes (LEAD) Clinical Trials

Liraglutide+Met vs sitagliptin+Met

-0.51%

-0.97%-1.00%-0.98%

-0.4%

-0.5%

-1.09%

-0.79%

-0.9%-0.84%*

-1.14%*-1.1%* -1.1%*

-1.5%* -1.5%*

-1.33%*

-1.12%*

-1.2%*

-1.5%*-1.60%

-1.40%

-1.20%

-1.00%

-0.80%

-0.60%

-0.40%

-0.20%

0.00%

Chan

ge in

A1C

% fr

om b

asel

ine

Liraglutide 1.2mg Liraglutide 1.8mg Glimepiride Rosiglitazone Placebo Glargine Exenatide Sitagliptin

MonotherapyLEAD-3

MET Combination

LEAD-2

SU Combination

LEAD-1

MET + TZD Combination

LEAD-4

MET + SU Combination

LEAD-5

MET ± SU Combination

LEAD-6

MET + SitagliptinNN2211-1860

p=0.0014

p<0.0001p<0.0001 p<0.0001

p=0.0015

p<0.0001

p<0.0001

p<0.0001p<0.0001 p<0.0001

Garber A et al, Lancet 2009;373:473–81 (LEAD-3); Nauck M et al, Diabetes Care 2009;32:84-90 (LEAD 2); Marre M et al. Diabetic Med 2009;26:268-78 (LEAD 1); Zinman B et al. Diabetes Care 2009;32:1224-30 (LEAD 4); Russell-Jones D et al. Diabetes 2009;52:2046-55 (LEAD 5); Buse J et al. Lancet 2009;374:39-47 (LEAD 6); Pratley R et al. Lancet 2010;375:1447-1456

*significant vs. comparator

LEAD Program: A1C Lowering with Liraglutide

Weight Reduction with Liraglutide in People with Type 2 Diabetes

Chan

ge in

bod

y w

eigh

t (kg

)

0.0

-0.5

-1.0

-1.5

-2.0 -1.8-2.0

51%43%

-2.5

-2.8

-2.5

-3.0-3.2

-3.5

2.5

2.0

1.5

1.0

0.5

-0.2

Exen

atide

-2.9

Plac

ebo

Glim

epiri

de

Rosi

glita

zone

Gla

rgin

e

Glim

epiri

de

+1.1

+1.6

+0.6+1.0

+2.1

Liraglutide 1.8 mg*Significant vs. comparator

-2.1

-2.6

0.3

-1.0

**

*

*

*

*

**

Liraglutide 1.2 mg

*

-2.9

-3.4

-1.0

Sita

glip

tin

**

LEAD 1SU combination

LEAD 2Met

combination

LEAD 4Met + TZD

LEAD 5Met + SU

combination

LEAD 3Monotherapy

LEAD 6Met ± SU

combination

Met combination(Lira vs sita)

Marre M et al. Diabetic Medicine 2009;26;268–78 (LEAD-1); Nauck M et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber A et al. Lancet 2009;373:473–81 (LEAD-3); Zinman B et al. Diabetes Care 2009;32:1224–30 (LEAD-4); Russell-Jones D et al. Diabetologia 2009;52:2046-2055 (LEAD-5); Buse J et al. Lancet 2009;374 (9683):39–47 (LEAD-6); Pratley R et al. Lancet 2010;375:1447-56 (Lira vs sitagliptin)

Exenatide: 3 AMIGOS TrialsA1C changes After 30 weeks

Chan

ge in

A1C

(%)

Placebo BID

-0.4*

-0.8*

-1

-0.5

0

0.5

0.1

Add-on to MET1

(n=336)

1. DeFronzo et al. Diabetes Care 2005

ITT population; Mean (SE); *p < 0.05 vs. placebo

Baseline 8.2%

Exenatide 5 µg BID

Add-on to SU2

(n=377)

*

0.1

-0.5*

-0.9

Baseline 8.6%

2. Buse et al. Diabetes Care 2004

Exenatide 10 µg BID

Add-on to MET+SU3

(n=733)

*

0.2

-0.5*

-0.8

Baseline 8.5%

3. Kendall et al. Diabetes Care 2005

Add-on to MET (n=336)

0 10 20

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

030

**

**

****

** **-3.5

*

Cha

nge

in w

eigh

t (kg

)

Time (weeks)

ITT population; Mean (SE); *p<0.05 vs. placebo; **p<0.001 vs. placebo

Exenatide: 3 AMIGOS TrialsWeight changes After 30 weeks

1. DeFronzo et al. Diabetes Care 2005

Add-on to SU(n=377)

0 10 20 30

*

Time (weeks)

2. Buse et al. Diabetes Care 2004

Placebo BIDExenatide 5 µg BIDExenatide 10 µg BID

Add-on to MET+SU(n=733)

0 10 20 30

*

*

*

** *

Time (weeks)

3. Kendall et al. Diabetes Care 2005

Changes in A1C and Body Weight: Liraglutide, Exenatide and Sitagliptin

= LEAD-6

= LEAD-6

= Lira-DPP-4

= Lira-DPP-4

Adapted from Niswender K et al, Diab Obes Metab 2012 doi: 10.1111/j.1463-1326.2012.01673.x

Glucose-lowering Drugs and CVD Risk

SUs May Increase CV Risk in Patients with T2DM:

34

In a meta analysis of 20 observational studies representing 1,311,090‐ patients (median follow-up , 4.6 years), SUs were associated with a

significantly increased risk of CV death and of a composite CV events compared with other oral diabetes drugs

Phung OJ, et al. Diabetes 2012;61:Suppl 1A. Abstract 2-LB

n = the total number of comparisons for that analysis; one study may contribute more than one comparison to the analysisCV composite = MI, stroke, CV-related hospitalization, or CV death

SUs May Increase Mortality and CV Risk versus Metformin

35

• In a Danish study (n=107,806), monotherapy with glimepiride, glibenclamide, glipizide, and tolbutamide was associated with significantly increased all-cause mortality vs metformin in patients with and without previous MI

• Results were similar for CV mortality and the composite CV end point

Schramm TK, et al. Eur Heart J. 2011;32:1900-1908

Hazard Ratio (95% confidence interval) Hazard Ratio (95% confidence interval)

No Previous MI Previous MI

Risk for All-Cause Mortality

Increased Mortality with Sulfonylureas in Patients with DM2 May Be Dose-related

In a retrospective cohort Canadian study of patients with newly diagnosed DM2 (n=12,272), first- or second-generation sulfonylurea monotherapy was

associated with increased mortality in a dose-related manner

Simpson SH, et al. CMAJ 2006;174:169-74 36

All-cause Mortality

a

a Either chlorpropamide or tolbutamide

Holman RR, et al. N Engl J Med 2008;359:1577-1589

UKPDS 10-year Follow-up:Kaplan-Meier Curves for Outcomes

Legacy effect; benefit of early

aggressive glycemic control on CVD

outcomes

Holman RR, et al. N Engl J Med 2008;359:1577-1589

Ins-SU

End-pt9%

MI15%

Micro24%

Death13%

Met

End-pt21%

MI33%

MicroNS

Death27%

Cardioprotective Effects of GLP-1

• GLP-1 improves cardiac function in heart failure 1,2

• GLP-1 increases myocardial glucose uptake 3 • GLP-1 improves functional recovery following

myocardial ischemia 4-6

• Incretins reduce infarct size 7-9

• GLP-1 improves endothelium dysfunction 10,11

1 Nikolaidis et al. Circulation 2004;110:955–61 2 Poornima I et al. Circ Heart Fail. 2008;1:153-1603 Zhao et al. J Pharmacol Exp Ther 2006;317:1106–13 4 Nikolaidis et al. J. Pharm Exp Ther 2005;312:303 5 Nikolaidis et al. Circulation 2004;109:962 6 Ban et al. Circulation 2008;117:2340 7 Bose A et al. Diabetes 2005;54:146 8 Noyan-Ashraf et al. Diabetes 2009;58:975 9 Sauve et al. Diabetes 2010;59:1063–73 10 Basu et al. Am J Physiol Endocrinol Metab 2007;293:E1289–95 11 Nyström et al. Am J Physiol Endocrinol Metab 2004;287:E1209–15

GLP-1 Actions on the Heart: Direct or Indirect?

Ussher J, Drucker DJ, Endocrine Rev. 2012 Apr;33(2):187-215.

GLP-1 Receptor Agonists Reduce BP

LEAD 6 Systolic blood pressure: Liraglutide vs. Exenatide

Buse J et al. Lancet 2009;374:39–47

n=60 per group

Liraglutide 200 µg/kg Placebo Sham operation

50 10 15 20 25 30

20

40

60

80

100

Surv

ival

(%)

20 4 6 8 10 12 14 16

DaysDays

Overall survival Death due to cardiac rupture

4

8

12

16

20

Dea

d m

ice

(n)

Liraglutide 75 µg/kg

Pre-treatment with Liraglutide Improves Survival Following MI

Noyan-Ashraf et al. Diabetes 2009;58:975–83. MI, myocardial infarction

Liraglutide Placebo

Arrows represent extent of infarct

Pre-treatment with Liraglutide Reduces Infarct Size

Noyan-Ashraf et al. Diabetes 2009;58:975–83

Infa

rct (

%)

0

10

20

30 P < 0.05

GLP-1 Reduced Infarct Size in Isolated Rat Hearts

44

a P < 0.001 vs control PC, ischemic pre-conditioning; VP, valine pyrrolidide (inhibitor of GLP-1 breakdown)

Infa

rct W

ithin

the

Risk

Zon

e, I/

R%

0

20

40

60

Control PC VP Before Ischaemia

GLP-1/VP as a PC Mimetic

VP at Reperfusion

a

GLP-1/VP at

Reperfusion

a a

Bose AK et al. Cardiovasc Drugs Ther 2005;19:9-11

3-month GLP-1 Treatment Prolongs 12-month Survival In SHHF Rats

Poornima I et al. Circ Heart Fail. 2008;1:153-160

Weeks of Treatment1 2 3 4 5 6 7 8 9 10 11 12

0

20

40

60

80

100

P<.005

(72%)

(44%)

Surv

ival

, %

Control

GLP-1

SHHF, spontaneously hypertensive heart failure- prone rat

45

Mechanisms Underlying Potential CV Benefits of DPP-4 Inhibitors

Fadini and Avogaro Vasc Pharmacol 2011

Mice Lacking DPP-4 Have Improved Outcomes After Experimental MI

Sauve et al. Diabetes 2010;59:1063–73

*

0 10 15 20 25 30Days post-MI

60

100

90

80

70

Surv

ival

(%)

50

Dpp4+/+ and -/- sham (n=26)

Dpp4-/- LAD (n=31)

Dpp4+/+ LAD (n=26)

DPP-4+/+ and DPP-4-/- mice

Normal chow diet (7% fat)

0 12 16

Age (weeks)

LAD ligation Endpoint: infarct size

5

20

15

10

Infa

rct (

%)

0

(n=10)(n=10)

Dpp4 genotype

+/+ -/-

*p < 0.05

MI, myocardial infarction; LAD, left anterior descending artery

Rieg T et al. Am J Physiol Renal Physiol 2012;303(7):F963-71 *P<0.05 vs. vehicle. n=5–6 per group

0.0

0.1

0.2

0.3

0.4

WT Mice

Urin

ary

flow

rate

(µl/

min

/g)

*

0

10

20

30

50

Urin

ary

flow

rate

(nm

ol/m

in/g

)40

Na K Cl

*

Vehicle Exendin-4

0.0

0.1

0.2

0.3

0.4

GLP-1r -/- Mice

Urin

ary

flow

rate

(µ/m

in/g

)

0

10

20

30

50

Urin

ary

flow

rate

(nm

ol/m

in/g

)

40

Na K Cl

Vehicle Exendin-4

0.0

0.1

0.2

0.3

0.4

Urin

ary

flow

rate

(µl/

min

/g)

*

0

10

20

30

40

Urin

ary

flow

rate

(nm

ol/m

in/g

)

Na K Cl

*

*

Vehicle Alogliptin

0.0

0.1

0.2

0.3

0.4

Urin

ary

flow

rate

(µl/

min

/g)

*

0

10

20

30

40

Urin

ary

flow

rate

(nm

ol/m

in/g

)

Na K Cl

*

Vehicle Alogliptin

Effects of GLP-1 RA and DPP-4ion Mouse Renal Function

Diabetic Mice with Pharmacological Inhibition of DPP-4 Have Increased

Expression of Cardioprotective Proteins

Sauve et al. Diabetes 2010;59:1063–73

0

Rela

tive

units

HFD/STZ Sitagliptin Metformin Liraglutide

HFD/STZ Sitagliptin Metformin Liraglutide

p-AKTHSP90

p-AKT

***

25

15

10

5

*

20

*P < 0.05 ***P < 0.001

HFD, high-fat diet; STZ, streptozotocin; p-AKT, phosphorylated cell survival kinase

Downregulation of BNP Gene Expression Following DPP-4 Inhibition in Rats

50Chaykovska L, et al. PLoS One 2011;6(11):e27861

Results suggest that DPP-4 inhibition leads to:• cardiac myocyte stress•Improved cardiac function

TGFb, TIMP, Col1α1 and Col3α1 are markers of fibrosis

*P<0.05; **P<0.001

Effects of DM2 on Endothelial Progenitor Cells (EPCs)

• The quantity and function of EPCs are diminished in patients with type 2 diabetes 1,2

EPCs play an important role in cardiac tissue repair following ischemic events 3

• Preclinical data in animals show the homing of EPCs to sites of vascular injury is impaired in diabetes 4

• In patients with ischemic heart disease, there are a decreased number of bone marrow-derived circulating progenitor cells with further reductions in those with diabetes 5

51

1. Hill JM, et al. N Engl J Med 2003;348:593-6002. Tepper OM, et al. Circulation 2002;106(22):2781-278663. Zaruba M-M, et al. Cell Stem Cell 2009;4:313-3234. Li M, et al. Circ Res. 2006 Mar 17;98:697-704 5. Bozdag-Turan I, et al. Cardiovasc Diabetol 2011;10(1):107

Mobilisation withG-CSF Treatment Ischemic myocardiumBone Marrow

Release ofSDF-1

CXCR + Stem cells

SDF-1CXCR4

DPP-4 (CD26)N-terminal Cleavage:Diminished Homing

DPP-4 (CD26)Inhibition

SDF-1CXCR4

Prevention of Cleavage-Enhanced Homing

Enhanced Homing by CD26 Inhibition

CXCR, chemokine receptor G-CSF, granulocyte colony-stimulating factorSDF-1, stromal cell-derived factor

52

Mechanism for DPP-4 Inhibition and SDF-1-mediated Improvements in Cardiac Function

Zaruba M-M, et al. Cell Stem Cell 2009;4:313-323

Risk ratio for major CV events1-5

1. Ratner R, et al. Cardiovascular Diabetology. 2011;10:22; 2. Johansen O-E., et al. ADA 2011 Late breaker 30-LB;3. www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4422b2-01-FDA.pdf Accessed Sept. 23, 2011;

4. Frederich R, et al. Postgrad Med. 2010;122(3):16–27; 16–27; 5. Williams-Herman D, et al. BMC Endocr Disord. 2010;10:7

Total patients in analysis

CV compositeendpoint

Comments

Incretin agent better Comparator better

10.50.250.125 2 4 8

MedDRA termsfor MACE

Post-hoc/No formal

adjudication

Sitagliptin5

0.680.41 1.12

MI, stroke, CV death Post-hoc/Independent adjudication

Saxagliptin4

0.430.23 0.80

No increased risk of CV events was observed in patients randomly treated with DPP-4

inhibitors or GLP-1R agonists

Exenatide1

0.70.38 1.31MedDRA terms for Stroke, MI, cardiac mortality, ACS,

revascularization

Post-hoc/No formal

adjudication

1.8

Liraglutide3

0.630.32 1.24

Post-hoc/No formal

adjudication

MedDRA termsfor MACE

CV death, MI, stroke,hospitalisation due to

angina pectoris

Pre-specified/independent adjudication

0.15 0.74

Linagliptin2

0.34

3,945

5,239

6,638

4,607

10,246

FDA Upper Bound 95%Criterion for Approvability

CV Meta-analyses of Individual Incretin Agents

1. Golden SH. Am J Cardiol 2011;108 (Suppl):59B-67B2. Fonseca V. Am J Cardiol 2011;108 (supp):52B–58Bl

3. Clinicaltrials.gov

Therapies N Population Endpoints Results

TECOS Sitagliptin/ Placebo

14,000 Established CVD CV death, NF MI or CVA, unstable angina hospital.

Dec 2014

SAVOR-TIMI 53 Saxagliptin/ Placebo

16,5003 CVD or ≥ 2 RF CV death, NF MI or ischemic stroke

June 2014

CAROLINA Linagliptin/ Glimepiride

6000 CVD or ≥ 2 RF CV death, NF MI or CVA, unstable angina hospital.

Sept 2018

LEADER Liraglutide/ Placebo

8754 CVD, PAD, CKD, CHF or RF if >60yrs

CV death, NF MI or stroke, revasc

Jan 2016

EXSCEL Exenatide LAR/Placebo

9500 Not specified CV death, NF MI or stroke

Mar 2017

Ongoing Cardiovascular Outcome Trials:DPP-4 Inhibitors and GLP-1 Agonists

Diabetes Cardiovascular Outcomes Trials2010 2011 2012 2013 2014 2015 2016 2017 2018 2019+

recruitment 11/09

canagliflozin (CANVAS)

3/13 completion

recruitment 9/09

alogliptin (EXAMINE)5/14 completion

recruitment 5/10

Aleglitazar (ALECARDIO)11/14 completion

9/03

Glargine (Lantus) (ORIGIN)12/12 completion

7/14 completion

Acarbose (GlucoBay) (ACE) recruitment 2/09

recruitment 5/10

Saxagliptin (Onglyza) (SAVOR-TIMI 53)4/14 completion

insulin

SGLT2

GLP1DPP4AGI

PPAR

recruitment 3/10

Exenatide (Byetta) (EXSCEL)3/17 completion

recruitment 12/08

Sitagliptin (Januvia) (TECOS)

12/14 completion

Empagliflozin

recruitment 12/10 7/18 completion

1/16 completionrecruitment 8/10

Liraglutide (Victoza) (LEADER)

10/13 completionrecruitment 6/10

lixisenatide (ELIXA)

recruitment 10/10

linagliptin (Trajenta) (CAROLINA)9/18 completion

N=12,500

N=4,500*

N=6,000

N=7,000

N=5,400

N=7,500

N=6,000

N=14,000

N=16,500

N=8,754

N=12,000

N=6,000

Assessed likely to deliver benefit

Diabetes and Atherosclerosis

CVD Management in Diabetes

Benefits of multiple CVD risk factor management on CVD outcomes

Steno 2: Effects on Combined CV Outcomes

Gaede P, et al, NEJM 2003;348(5):383-393

0 12 24 36 48 60 72 84 960

10

20

30

40

50

60P = 0.007

Conventional therapy

Intensive therapy

Months of Follow-up

80 72 70 63 59 50 44 41 13

80 78 74 71 66 63 61 59 19

No. at Risk

Conventional

Intensive Rx

20% absolute RRRRR 53%

CV Outcomes: Number Needed to Treat (NNT)

• NNT = 1/absolute risk reduction (AAR)• AAR = Event rate (control) – event rate (treatment)• Microvascular complications

UKPDS ( blood glucose) 39.2 UKPDS ( blood pressure) 12.2 Steno ( BG, BP, lipid and UAE) 5

• Major CHD HOT study 16 4S study 5 CARE study 12

• Screening for breast cancer 1000

Gaede P et al. N Engl J Med 2003;348:383-393

Intensive Therapy

Conventional Therapy

Num

ber o

f Car

diov

ascu

lar E

vent

s

AmputationRevascularization

PercutaneusCoronary

Intervention

Myocardial Infarction

StrokeDeath from

Cardiovascular Causes

Coronary Artery Bypass

Graft

Gaede P, et al. N Engl J Med 2003;358:580−591

0

5

10

15

20

25

30

35

40

STENO-2: Dramatic in Cardiovascular Events

0

20

40

60

80

100

120

140

160

180 Intensive Therapy

Conventional Therapy

BP V

alue

at 7

.8 Y

ears

FPG(mmol/L)

LDL-C(mmol/L)

HDL-C(mmol/L)

Systolic BP(mm Hg)

Diastolic BP(mm Hg)

7.2

9.8

2.15

3.27

1.22 1.17

131

146

73 78

A1C

7.9%

A1C

9.0%

P < .01

P < .01

P < .01 P < .01

Gaede P, et al. N Engl J Med 2008;358:580−591

BP = blood pressure; FPG = fasting plasma glucose; A1C = Hemoglobin A1C; HDL-C = high-density lipoprotein; LDL-C = low-density lipoprotein

STENO-2: Fasting Glucose, LDL-C, and BP at 7.8 Years With Intensive Treatment

Gaede P, et al. N Engl J Med 2008;358:580-591

STENO-2 13-year Follow-up:Kaplan-Meier Curves of the Risk of Death and CV Events

Absolute RR 20%

All causemortality

46%

CVDmortality

57%

Global CVD Risk Reduction in Diabetes

CVD risk estimates in diabetes should be patient-centred and not disease-based:1. Identify individual CVD risk factors 2. Consider all risk factors in estimating particular

patient’s CVD risk3. Appropriate therapies should be evidence-based4. Integrate all therapies to optimize best

management for global CVD risk reduction

Gerstein HC Diabetologia 2011;54:230–232

Guidelines on Vascular Protection: Summary of Diabetes Management

• Achieve healthy weight and exercise regularly• Treat to glycemic target

BG 4-10 mmol/L A1C ≤ 7%, ≤ 6.5% to reduce nephropathy in DM2 Regular surveillance for complications

• Treat lipid and BP to goal targets: LDL-C ≤ 2.0 mmol/L or 50% reduction, or ApoB < 0.8g/L TC/HDL-C ratio < 4 BP < 130/80 mmHg

• ACE inhibition (ACEi or ARB) for vascular protection• ECASA in patients with stable CAD• Smoking cessation and moderate alcohol intake

Can J Diabetes 2008;32(Suppl 1):S102-S118

Initiate metformin

Initiate pharmacotherapy immediately without waiting for effect from lifestyle interventions: Consider initiating metformin concurrently with another agent from a different class; or insulin Initiate insulin

± metformin

If not at target

Add an agent best suited to the individual:• Alpha-glucosidase inhibitor• Incretin agent: DPP-4 inhibitor/GLP-1 receptor agonist• Insulin• Insulin secretagogue: Meglitinide, Sulfonylurea• TZD• Weight loss agent

If not at target:• Add another drug from a

different class; or • Add bedtime basal insulin to

other agent(s); or • Intensify insulin therapy

2013 CDA Clinical Practice GuidelinesClinical Assessment - Lifestyle intervention (Nutrition therapy and physical activity)

A1C < 8.5% A1C ≥ 8.5% Symptomatic hyperglycemia with metabolic decompensation

2013 CDA draft CPGs. Can J Diabetes 2013

Summary

• Glycemic control reduces macro- and microvascular complications of both type 1 and type 2 diabetes

• In choosing antihyperglycemic agents, select drugs that do not cause hypoglycemia, as severe hypoglycemia is associated with adverse CV outcomes

• Metformin and incretins (DPP-4 inhibitors and GLP-1 receptor agonists) are associated with lower CV risk

• Sulfonylureas and TZDs are associated with increased CV risk

• Definitive CV effects of antihyperglycemic agents in DM2 will await the results of ongoing CV trials

“Superior Doctors Prevent the Disease.Mediocre Doctors Treat the Disease Before Evident.

Inferior Doctors Treat the Full Blown Disease.”

Huang Dee, 2600 B.C. In Nai Ching, 1st Chinese Medical Text

Thank you

Questions?