The Influence of Type 2 Diabetes on Cardiovascular Disease and Glycemic Treatment Options
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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 [email protected]
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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• 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
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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
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How do glucose-lowering drugs work?
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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)
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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
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GLP-1 receptor agonists improve glucose control through multiple mechanisms
Ussher J & Drucker DJ, Endocrine Rev 2012;33:187-215
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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
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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?
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*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
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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
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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
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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!
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Antihyperglycemic Drugs & Risk of Hypoglycemia
High• Insulin• Insulin secretagogues
SulfonyureasMeglitinides
Low• Metformin• DPP-4 inhibitors• GLP-1 receptor agonists• TZDs• Acarbose• Orlistat
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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
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-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
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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)
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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
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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
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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
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Glucose-lowering Drugs and CVD Risk
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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
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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
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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
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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%
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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
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GLP-1 Actions on the Heart: Direct or Indirect?
Ussher J, Drucker DJ, Endocrine Rev. 2012 Apr;33(2):187-215.
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GLP-1 Receptor Agonists Reduce BP
LEAD 6 Systolic blood pressure: Liraglutide vs. Exenatide
Buse J et al. Lancet 2009;374:39–47
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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
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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
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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
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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
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Mechanisms Underlying Potential CV Benefits of DPP-4 Inhibitors
Fadini and Avogaro Vasc Pharmacol 2011
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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
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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
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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
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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
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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
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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
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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
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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
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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
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Diabetes and Atherosclerosis
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CVD Management in Diabetes
Benefits of multiple CVD risk factor management on CVD outcomes
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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%
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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
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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
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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
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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%
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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
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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
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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
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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
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“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
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Thank you
Questions?