1. The Influence of Type 2 Diabetes on Cardiovascular Disease and Glycemic Treatment Options
Rocky Mountain/ACP
Internal Medicine Conference
Banff, AB
November 22, 2012
David C.W. Lau, MD, PhD, FRCPC
Depts. of Medicine, Biochem. & Molec. Biol.
Julia McFarlane Diabetes Research Centre
University of Calgary 1 1

2. Program Faculty Dr. Ronald Goldenberg, MD, FRCPC, FACE
Consultant Endocrinologist, North York General Hospital
and LMC Endocrinology Centers, Thornhill, Ontario
Dr. Mansoor Husain MD, FRCPC
Director, Toronto General Hospital Research Institute and
Heart and Stroke Richard Lewar Centre for Excellence
Senior Scientist, Division of Experimental Therapeutics
Professor of Medicine, University of Toronto
Dr. David C. W. Lau MD, PhD, FRCPC
Professor of Medicine, Biochemistry and Molecular Biology
Julia McFarlane Diabetes Research Centre
University of Calgary

3. 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

4. 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

5. Rising Prevalence of Diabetes Mellitus
Frequency of Diagnosed &Undiagnosed DM and IGT by Age
3 Million Canadians Have Diabetes Mellitus
According to data from the Heart and Stroke Foundation of Canada, overall, 4% of Canadian men and 5% of women report having diabetes mellitus, that is 1.5 million Canadians.1 They report an increasing prevalence of diabetes with age, ranging from 1-3% in the youngest (15-34 years) to 9-12% in the oldest (55-74 years) age groups.1
The true prevalence may be double that of self-reported diabetes, based on this U.S. study by Harris, which showed that 50% of adults with diabetes have not been diagnosed.2 The high incidence of impaired glucose tolerance (IGT) in the population is also a consideration. Although the data in this graph are from the U.S., the prevalence data for Canada are very similar.
Type 2 (noninsulin dependent) diabetes accounts for up to 95% of cases, while type 1 (insulin dependent) diabetes is much less frequent, affecting about 5-10% of the population with diabetes.2,3 By 1995, an estimated 110 million individuals worldwide had been diagnosed with diabetes, and the WHO projects this will double by the year
References:
1. Heart and Stroke Foundation of Canada. Heart Disease and Stroke in Canada, Ottawa, Canada, 1997.
2. Harris MI. Undiagnosed NIDDM: Clinical and public health issues. Diabetes Care 1993;16:
3. Plosker GL, Faulds D. Troglitazone. Drugs 1999;57(3):
4. Turner NC, Clapham JC. Insulin resistance, impaired glucose tolerance and non-insulin-dependent diabetes, pathologic mechanisms and treatment: current status and therapeutic possibilities. Prog Drug Res 1998;51:33-94.
Adapted from M Harris. Diabetes Care 1993;16:642-52

6. Diabetes is a global disease! Estimated global prevalence of diabetes
151 million
366 million
552 million
2000
2011
2030
International Diabetes Federation. IDF Diabetes Atlas. Fifth Edition. 2011

7. 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

8. Relative Risks for Fatal CAD in Diabetes
Pooled RR = 1.7 from 37 studies; Meta-analysis of 22 studies
Huxley R et al., Br Med J 2006;332:73-78

9. 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
Patients with T2DM and CVD derive less benefit from preventive and interventional therapies
Despite the availability of antiplatelet treatment strategies that have proven useful in improving outcomes, patients with diabetes continue to have a higher risk of adverse CV events compared with nondiabetic patients.1
It has been speculated that reduced responsiveness to antiplatelet drugs such as oral antiplatelet agents may play a role in these worse outcomes.1
Results from the DANAMI-2 trial, which included 1,572 consecutive patients who had ST-elevation MI who were randomized to percutaneous coronary intervention or fibrinolysis, suggest that diabetes may abolish the beneficial effect of primary percutaneous coronary intervention on long-term risk of reinfarction after acute ST-segment elevation MI.2
CV, cardiovascular; CVD, cardiovascular disease; MI, myocardial infarction; T2DM, type 2 diabetes mellitus.
References
Angiolillo DJ. Antiplatelet therapy in diabetes: efficacy and limitations of current treatment strategies and future directions. Diabetes Care. 2009;32:
Madsen MM, Busk M, Søndergaard HM, Bøttcher M, Mortensen LS, Andersen HR, Nielsen TT; DANAMI-2 Investigators. Does diabetes mellitus abolish the beneficial effect of primary coronary angioplasty on long-term risk of reinfarction after acute ST-segment elevation myocardial infarction compared with fibrinolysis? (A DANAMI-2 substudy). Am J Cardiol. 2005;96:
CV, cardiovascular; CVD, cardiovascular disease; MI, myocardial infarction
Angiolillo DJ. Diabetes Care 2009;32: ;
Madsen MM, et al. Am J Cardiol 2005;96: 9

10. A1C Predicts Cardiovascular Disease: Reduction Has Important Benefits
21%
reduction
21%
reduction
14% reduction
Diabetes-related endpoints
Diabetes-related mortality
All-cause mortality 1%
A1C reduction
14%
reduction
12%
reduction
37%
reduction
Notes to facilitator:
This slide highlights key findings from the UKPDS 351
In this trial, a 1% reduction in A1C was associated with risk reductions in microvascular and macrovascular outcomes as listed on this slide1
Later intervention for aggressive glycemic control will not prevent macrovascular complications (cardiovascular death, myocardial infarction, stroke) 2
This supports the need to achieve glycemic control early, to prevent long-term diabetes complications
References:
Stratton IM et al. BMJ 2000;321:
The Action to Control Cardiovascular Risk in Diabetes Study Group. New Engl J Med. 2008;358:
Fatal/non-fatal MI
Fatal/non-fatal stroke
Microvascular endpoints
19%
reduction
43%
reduction
16%
reduction
Cataract extraction
Amputation/death from PVD
Heart failure
Stratton IM, et al. BMJ 2000;321: 10

11. Diabetes Increases Mortality Following ACS
Cumulative Incidence of All-Cause Mortality Through 1 Year After ACS
Pooled data from 11 independent clinical 11 TIMI Study group clinical trials (1997–2006) of ACS patients suggest that, despite modern therapies for ACS, diabetes confers a significant adverse prognosis during the first year after an event
13.2%
P<.001
8.1%
7.2%
P<.001
3.1%
Diabetes increases mortality following ACS
Pooled data from 11 independent TIMI Study Group clinical trials conducted from 1997 to 2006 of ACS patients suggest that, despite modern therapies for ACS, diabetes confers a significant adverse prognosis during the first year after an event.1
A total of 62,036 patients were included in this analysis (46,577 presented with STEMI and 15,459 with UA/NSTEMI).1
As shown in the figure in this slide, mortality at 1 year was significantly higher among patients with diabetes than in patients without diabetes presenting with UA/NSTEMI (7.2% vs 3.1%; P<.001) or STEMI (13.2% vs 8.1%; P<.001).1
ACS, acute coronary syndrome; STEMI, ST-segment elevation myocardial infarction; UA/NSTEMI, unstable angina/non-STEMI
References
Donahoe SM, Stewart GC, McCabe CH, Mohanavelu S, Murphy SA, Cannon CP, Antman EM. Diabetes and mortality following acute coronary syndromes. JAMA. 2007;298:
ACS, acute coronary syndrome; STEMI, ST-segment elevation myocardial infarction; UA/NSTEMI, unstable angina/non-STEMI; TIMI, Thrombolysis in Myocardial Infarction
Donahoe SM, et al. JAMA 2007;298: 11 11

12. 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:

13. Benefit of early aggressive glycemic control on CVD outcomes
DCCT/EDIC: Glycemic Control Reduces the Risk CV Death, MI, Stroke in Type 1 Diabetes
*Intensive vs conventional treatment
Cumulative incidence of non-fatal MI, stroke or death from CVD
Conventional treatment
Intensive treatment
Years
0.06
0.04
0.02
0.00
DCCT (intervention period) EDIC (observational follow-up) 7 1 6
A1C (%) 9 8 2 3 4 5 11 12 13 14 15 16 17 10
DCCT (intervention period) EDIC (observational follow-up)
Years
Conventional treatment
Legacy effect:
Benefit of early aggressive glycemic control on CVD outcomes
Intensive treatment
CVD death, MI & Stroke
RR 57%  (p = 0.02, 95%CI 12-79%)
In the DCCT (Diabetes Control and Complications Trial), 1,441 patients with type 1 diabetes were randomized to intensive ( 3 daily insulin injections or insulin pump) or conventional treatment (1–2 daily insulin injections) for a mean follow-up period of 6.5 years.
At the end of the DCCT, participants receiving conventional treatment were offered intensive treatment. All patients returned to their own healthcare provider for diabetes care.
In total, 1,397 patients (96%) from the DCCT were followed in the observational EDIC (Epidemiology of Diabetes Interventions and Complications) study for a mean 17 years of follow-up.
As shown in the upper graph, in the DCCT the absolute difference in mean A1C between the intensive and conventional groups was ~2% (7.4% vs 9.1%; p < 0.01) at 6.5 years, which was sustained during the intervention period. During EDIC, differences in A1C narrowed in these groups (8.0% vs and 8.2%, respectively; p = 0.03) at 11 years.
As shown in the lower graph, changes in A1C associated with intensive treatment were accompanied by a reduction in risk of non-fatal MI, stroke or death.
In EDIC, patients who had received intensive treatment in DCCT had reduced the risk of non-fatal myocardial infarction (MI), stroke or death from cardiovascular disease (CVD) by 57% in patients with type 1 diabetes (95% CI, 12–79%; p = 0.02).
Intensive treatment also reduced the risk of any CVD event by 42% (95% CI, 9–63%; p = 0.02).
There are a number of potential mechanisms by which intensive glycemic control may reduce CVD risk, including a reduction in A1C.
Reference(s)
The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. New Engl J Med 1993;329:
The Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA 2002;287:
The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. New Engl J Med 2005;353:
DCCT. N Engl J Med 1993;329:977–986
DCCT/EDIC. JAMA 2002; 287:2563–2569
DCCT/EDIC. N Engl J Med 2005;353:2643–2653 13

14. 2008 CDA Clinical Practice Guidelines
Recommended Targets for Glycemic Control
A1C
≤ 7.0%
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)
Type 1 and Type 2 Diabetes
Key Message:
There are simple, accurate methods for assessing glycemic status.
Notes:
The CDA guidelines give us specific recommendations for what constitutes good glycemic control.
Poor control can also include excessive glucose excursions and episodes of hypoglycemia.
There may be some cases when these targets may be relaxed, e.g., in the elderly.
Evaluating the effect of treatment on glycemic control can be as simple as checking the A1C level every 3 months.
REFERENCE:
Canadian Diabetes Association Clinical practice guidelines for the prevention and management of diabetes in Canada. Canadian Journal of Diabetes 2008;32(Suppl 1):S29–31
1. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2003;27 (suppl 2):S19-S39.
Treatment goals and targets must be individualized with considerations given to individual risk factors
Target 2-3 months for lifestyle management before initiating pharmacotherapy
Can J Diabetes 2008;32(Suppl 1):S29-S31

15. 2008 CDA Clinical Practice Guidelines
Clinical Assessment - Lifestyle intervention (Nutrition therapy and physical activity)
A1C < 9.0%
A1C ≥ 9.0%
Symptomatic hyperglycemia with metabolic decompensation
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 CPGs. Can J Diabetes 2008;32(Suppl 1):S53–S61

16. How do glucose-lowering drugs work?

17. Main Classes of Glucose-Lowering Medications
α-glucosidase inhibitors (delay digestion and absorption of intestinal carbohydrate)
DPP-4 inhibitors (prolong GLP-1 action, stimulate insulin secretion, suppress glucagon release)
Biguanides (reduce hepatic glucose production and intestinal absorption of glucose; increase peripheral glucose uptake)
SUs and rapid-acting secretagogues (stimulate insulin secretion)
Type 2 diabetes is a multifaceted disease involving several pathophysiologic abnormalities.
Each of the main classes of antihyperglycemic agents has a mechanism or mechanisms aimed at achieving glucose control in the face of the pathophysiologic defects of type 2 diabetes.
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)
TZDs (reduce insulin resistance in target tissues)
TZD = thiazolidinedione; DPP = dipeptidyl peptidase; GLP = glucagon-like peptide
Krentz AJ, Bailey CJ. Drugs 2005;65:

18. DPP-4 Inhibitors Enhance Incretin and Insulin Secretion
Food intake
DPP-4 inhibitor
Increases and prolongs GLP-1 and GIP effects on beta-cells:
Beta-cells
DPP-4
Insulin release
Stomach
Net effect:
Blood glucose
Pancreas
GI tract
Speaker’s Notes
Incretin hormones are released by the intestine throughout the day and concentrations are increased in response to a meal. When blood glucose concentrations are elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. However, these hormones are rapidly inactivated by the enzyme DPP-4.
DPP-4 inhibitor acts in patients with type 2 diabetes by slowing the inactivation of incretin hormones, including GLP-1 and thus increasing the concentration of active GLP-1 incretin hormone. Alpha- and beta-cells in the pancreas respond to these higher levels of circulating hormones, leading to:
Increased glucose-dependent insulin release and decreased glucagon secretion from the pancreas
Increased peripheral uptake and disposal of glucose
Decreased hepatic glucose output — all of which contribute to glucose homeostasis
In patients with type 2 diabetes with hyperglycemia, these changes in insulin and glucagon levels may lead to lower glycosylated hemoglobin and lower fasting and postprandial glucose concentrations.
Incretins
Increases and prolongs GLP-1 effect on alpha-cells:
Glucagon secretion
Alpha-cells
Intestine
Adapted from: Barnett A. Int J Clin Pract 2006;60:
Drucker DJ, Nauck MA. Nature 2006;368: Idris I, Donnelly R. Diabetes Obes Metab 2007;9:153-65 18

19. Ussher J & Drucker DJ, Endocrine Rev 2012;33:187-215
GLP-1 receptor agonists improve glucose control through multiple mechanisms
Ussher J & Drucker DJ, Endocrine Rev 2012;33:

20. Incretin Therapies Currently Available
Injectable
Oral
GLP-1
analogue:
Liraglutide modified human GLP-1
DPP-4 inhibitors: Linagliptin
Saxagliptin
Sitagliptin
GLP-1 mimetic: Exenatide modified from Gila monster lizard saliva
Notes to facilitator:
Use this slide to distinguish between the GLP-1 receptor agonist and DPP-4 inhibitor sub-classes and to introduce the currently available incretin agents
It may also be important to further distinguish the agents within the GLP-1 receptor agonist sub-class of incretin therapies: “GLP-1 analogues and GLP-1 mimetics”
Slide background:
What is Glucagon Like Peptide-1 (GLP-1)?
GLP-1 is an incretin hormone released from the gut upon ingestion of a meal; GLP-1 increases insulin and decreases glucagon in a glucose-dependent manner.
GLP-1 is rapidly degraded and inactivated by the dipeptidyl peptidase-4 (DPP-4) enzyme
What is a DPP-4 inhibitor?
A DPP-4 inhibitor prevents breakdown of GLP-1, thus prolonging its availability and action. Linagliptin, saxagliptin and sitagliptin are all DPP-4 inhibitors.
What is a GLP-1 receptor agonist?
A GLP-1 receptor agonist is resistant to breakdown by the DPP-4 enzyme and thus increases the level of GLP-1 action
GLP-1 mimetic: exerts similar effects as native human GLP-1 but exhibits structural differences. Exenatide is a GLP-1 mimetic extracted from the Gila monster lizard.
GLP-1 analogue: native human GLP-1 with minor modifications which protect it from being degraded by the DPP-4 enzyme. Liraglutide is a GLP-1 analogue.
References:
1. Drucker et al. Diabetes Care 2003;26:
2. Drucker et al. Curr Pharm Des 2001;7:
3. Drucker et al. Mol Endocrinol 2003;17:
4. Degn et al. Diabetes 2004;53:1187–94. Mari et al. J Clin Endocrinol Metab 2005;90:4888–94.
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, Drucker DJ, et al. Lancet 2006;368: Slide Courtesy of Novo Nordisk sponsored accredited CHE program

21. 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?

22. Glucose Lowering Therapy in Diabetes: A1C Reduction by Baseline A1C
Diabetes disease progression
≤7.5%
>7.5% - 8.0%
>8.0% to 8.5%
>8.5% to 9.0%
>9.0% * **
***
****
0.5
-0.5
-1.0
-1.5
-2.0
Change in A1C from baseline to 26 weeks (%)
This slides highlights A1C reductions stratified by baseline A1C across commonly used antihyperglycemic agents1
As would be expected, glycemic reductions are greater at higher baseline A1C strata; however, it is evident that incretin therapies offer A1C reductions that are at least comparable, if not greater than those offered by conventional therapies1
Early achievement of glycemic control (as stated in the previous slide) is crucial in the management of type 2 diabetes2
Reference 1. Henry RR et al., Endocr Pract 2011; 17 (6); 907.
2. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2008 clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes 2008;32(suppl 1): S1-S201
Exenatide
Liraglutide
Sitagliptin
Glimepiride
Rosiglitazone
Glargine
*p<0.05, **p<0.01, ***p<0.001, ****p< vs. liraglutide 1.8 mg;
Henry RR, et al. Endocr Pract 2011;17(6):907

23. 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
Kahn SE et al. N Engl J Med 2006;355: 23

24. Adverse Outcomes Among Patients with Type 2 Diabetes Experiencing Severe Hypoglycemia
The median time from hypoglycemic episode to related adverse event or death was ≤ 1.6 years!
Zoungas 2010 p1414 Fig1B 25
Macrovascular event
N=11,140
Microvascular event 20
Death from any cause
Cardiovascular death 15
Noncardiovascular death
No. of adverse outcomes 10
Adverse Outcomes Among Patients With T2DM Experiencing Severe Hypoglycemia
Key message: Severe hypoglycemia has been associated with increased risk for diabetes-related complications. The median time from hypoglycaemic episode to related adverse event or death was ≤1.6 years.
This study evaluated the association between severe hypoglycemia and risk for diabetes-related complications in patients with T2DM (N=11,140).
Methods: Patients were recruited from 215 centers in 20 countries and were included if they had a diagnosis received after the age of 30 years with a history of microvascular or macrovascular disease or at least one other cardiovascular risk factor. Glucose control was not part of entry criteria, but patients were excluded if they had a clear indication for long-term insulin use at entry. Patients were randomized to receive blood-pressure lowering medication or placebo and either standard or intensive glucose control with extended-release localized or a standard guideline-based treatment strategy. Severe hypoglycemia was defined as blood glucose <50 mg/dL and transient dysfunction of the central nervous system, where patients were unable to treat themselves and required help from another person.
Results: During the follow-up period of 48 months, 2125 patients had a microvascular or macrovascular event, 1031 patients died (45 who reported severe hypoglycemia) and 87 patients reported severe hypoglycemia. The events are plotted on the chart above and the median times from severe hypoglycaemic episode to event were: first major macrovascular event, 1.56 years; first major microvascular event, 0.99 years; death, 1.05 years; death from a cardiovascular event, 1.31 years; death from a noncardiovascular cause, 0.74 years.
Reference
Zoungas S, Patel A, Chalmers J, et al; ADVANCE Collaborative Group. Severe hypoglycemia and risks of vascular events and death. N Engl J Med. 2010;363(15): 5
Zoungas 2010
P1410 A
P1411 B
P1411 C
0–12
13–24
25–36
37–48
Months from severe hypoglycemia to event
Zoungas S, et al. N Engl J Med 2010;363(15):1410–18
Zoungas p1414 Fig1B p F

25. Emergency Hospitalizations for Adverse Drug Events in Older Americans
Estimated Rates of Emergency Hospitalisations for
Adverse Drug Events in Older U.S. Adults, 2007–2009
14%
Oral agents and insulin account for
> 25% of hospitalizations in adults > 65 years!
On the basis of 5077 cases identified in the sample, there were an estimated 99,628 emergency hospitalizations (95% confidence interval [CI], 55,531 to 143,724) for adverse drug events in U.S. adults 65 years of age or older each year from 2007 through Nearly half of these hospitalizations were among adults 80 years of age or older (48.1%; 95% CI, 44.6 to 51.6). Nearly two thirds of hospitalizations were due to unintentional overdoses (65.7%; 95% CI, 60.1 to 71.3). Four medications or medication classes were implicated alone or in combination in 67.0% (95% CI, 60.0 to 74.1) of hospitalizations: warfarin (33.3%), insulins (13.9%), oral antiplatelet agents (13.3%), and oral hypoglycemic agents (10.7%). High-risk medications were implicated in only 1.2% (95% CI, 0.7 to 1.7) of hospitalizations.
Most emergency hospitalizations for recognized adverse drug events in older adults resulted from a few commonly used medications, and relatively few resulted from medications typically designated as high-risk or inappropriate. Improved management of antithrombotic and antidiabetic drugs has the potential to reduce hospitalizations for adverse drug events in older adults.
11%
Budnitz DS, et al. N Eng J Med 2011;365:

26. Antihyperglycemic Drugs & Risk of Hypoglycemia
High
Insulin
Insulin secretagogues
Sulfonyureas
Meglitinides
Low
Metformin
DPP-4 inhibitors
GLP-1 receptor agonists
TZDs
Acarbose
Orlistat

27. Liraglutide Effect and Action in Diabetes (LEAD) Clinical Trials
Type 2 diabetes treatment continuum
Diet/exercise
+1 OAD
+2 OAD
+3 OAD or
+2 OAD, Insulin
LEAD 3
Liraglutide
monotherapy vs SU
LEAD 1
Liraglutide+SU
vs TZD+SU
LEAD 4
Liraglutide+met&TZD
vs placebo+met&TZD
LEAD 2
Liraglutide+Met
vs SU+Met
LEAD 5
Liraglutide+Met&SU
vs glargine+Met&SU
Met: metformin
SU: sulfonylurea
TZD: thiazolidinedione
Liraglutide+Met
vs sitagliptin+Met
LEAD 6
Liraglutide+met/SU/both
vs exenatide+met/SU/both
Garber A et al. Lancet 2009;374: (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: (LEAD-4); Russell-Jones Det al. Diabetologia 2009;52: (LEAD-5); Buse J et al. Lancet 2009;374:39-47 (LEAD-6); Pratley R et al. Lancet 2010;375: (Lira vs. sitagliptin) 27 27

28. LEAD Program: A1C Lowering with Liraglutide
*significant vs. comparator
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: (LEAD 1); Zinman B et al. Diabetes Care 2009;32: (LEAD 4); Russell-Jones D et al. Diabetes 2009;52: (LEAD 5); Buse J et al. Lancet 2009;374:39-47 (LEAD 6); Pratley R et al. Lancet 2010;375:

29. Weight Reduction with Liraglutide in People with Type 2 Diabetes
LEAD 3
Monotherapy
LEAD 2
Met combination
LEAD 1
SU combination
LEAD 4
Met + TZD
LEAD 5
Met + SU combination
LEAD 6
Met ± SU
combination
Met combination (Lira vs sita)
2.5
+2.1
2.0
Rosiglitazone
+1.6
1.5
+1.1
+1.0
Glargine
1.0
+0.6
Glimepiride
Glimepiride *
0.5
0.3
Placebo
0.0
Exenatide
Change in body weight (kg)
51%
43%
-0.5
-0.2 *
-1.0
-1.0
-1.0
-1.5 *
Higher baseline body mass index (BMI), higher weight loss.
The effect of GLP-1 on weight:
GLP-1 affects the gastrointestinal system and delays absorption of food. This is caused by several means, including decreased gastric emptying and acid secretion. For example, the infusion of GLP-1 to generate plasma levels similar to those normally observed following meals delays gastric emptying (Wettergren et al. 1993).
Combined, these gastrointestinal effects reduce the meal-related increase in glucose. Prolonged presence of food in the stomach through delayed gastric emptying may also reduce energy intake by inducing satiety.
Additionally, GLP-1 receptors are present in several areas in the brain. The receptors in the brainstem (area postrema and subfornical organ) are believed to be involved in inducing satiety, regardless of the presence of food in the gastric system. This action therefore provides another means for decreasing energy intake.
Weight loss occurs irrespectively of GI side effects.
In LEAD-2 a quarter of patients loss as much as 7.7 kg on average.
-2.0
-1.8
Sitagliptin
-2.0
-2.1 *
-2.5 * *
-2.5 *
-2.6
-3.0 *
-2.8
-2.9
-2.9 *
-3.2 *
-3.5
-3.4 *
*Significant vs. comparator
Liraglutide 1.2 mg
Liraglutide 1.8 mg
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: (LEAD-5); Buse J et al. Lancet 2009;374 (9683):39–47 (LEAD-6); Pratley R et al. Lancet 2010;375: (Lira vs sitagliptin) 29

30. Exenatide: 3 AMIGOS Trials A1C changes After 30 weeks
Placebo BID
Exenatide 5 µg BID
Exenatide 10 µg BID
Add-on to MET1
(n=336)
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 SU2
(n=377) *
0.1
-0.5
-0.9
Baseline 8.6%
2. Buse et al. Diabetes Care 2004
0.5
Baseline 8.2%
0.1
Change in A1C (%)
-0.5
DISCUSSION
At week 30, compared to placebo, significant HbA1c reductions were seen in patients treated with exenatide across all three AMIGO studies
The percentage reduction in HbA1c was greater in patients who received an increased exenatide dose of 10 µg compared to those who received 5 µg exenatide throughout the study
Exenatide treatment was associated with reduced HbA1c independent of oral therapy (metformin [MET] and/or sulphonylurea [SFU] )
BACKGROUND
The three AMIGO studies were undertaken to evaluate the ability of exenatide to improve glycaemic control in patients with type 2 diabetes failing to achieve glycaemic control with maximally effective doses of MET, SFU or MET+SFU
Three 30-week, placebo-controlled, double-blind, phase 3 studies were completed in the US
This slide presents combined data
Subjects with type 2 diabetes (currently taking MET, SFU or MET+SFU) were randomised to placebo (PBO), 5 µg exenatide twice daily (BID) or 10 µg exenatide BID, n=1446. All subjects also continued current medication
MET study: PBO n=113, baseline HbA1c=8.2%; exenatide 5 µg n=110, baseline HbA1c=8.3%; exenatide 10 µg n=113, baseline HbA1c=8.2%
SFU study: PBO n=123, baseline HbA1c=8.7%; exenatide 5 µg n=125, baseline HbA1c=8.5%; exenatide 10 µg n=129, baseline HbA1c=8.6%
MET+SFU study: PBO n=247, baseline HbA1c=8.5%; exenatide 5 µg n=245, baseline HbA1c=8.5%; exenatide 10 µg n=241, baseline HbA1c=8.5%
The last observation carried forward (LOCF) method was applied to the data
Exenatide was associated with reduced HbA1c independent of disease duration
-0.4 * -1
-0.8 *
ITT population; Mean (SE); *p < 0.05 vs. placebo
1. DeFronzo et al. Diabetes Care 2005

31. Exenatide: 3 AMIGOS Trials Weight changes After 30 weeks
Add-on to MET (n=336)
Add-on to SU (n=377) 10 20 30 *
Time (weeks)
2. Buse et al. Diabetes Care 2004
Add-on to MET+SU (n=733) 10 20 30 *
Time (weeks)
3. Kendall et al. Diabetes Care 2005
Time (weeks) 10 20 30
-0.5 *
-1.0 *
-1.5 **
Change in weight (kg) *
-2.0
Mean baseline weight ranged from 95 kg to 101 kg across all trial arms.
Weight is reduced by up to 2.8 kg after 30 weeks of exenatide+MET therapy1-3.
Weight loss with exenatide is dose-dependent and is observed regardless of BMI1,2
References
DeFronzo RA et al. Diabetes Care. 2005;28:1092–100
Buse J et al. Diabetes Care. 2004;27:2628–35
Kendall D et al. Diabetes Care. 2005;28:1083–91 **
-2.5 **
-3.0 ** **
-3.5
Placebo BID
Exenatide 5 µg BID
Exenatide 10 µg BID
ITT population; Mean (SE);
*p<0.05 vs. placebo; *
*p<0.001 vs. placebo
1. DeFronzo et al. Diabetes Care 2005 31

32. Changes in A1C and Body Weight: Liraglutide, Exenatide and Sitagliptin
= LEAD-6
= Lira-DPP-4
Greatest reductions in A1C and body weight are with liraglutide
Patient-level data from two 26-week, randomized controlled trials were analyzed
Adapted from Niswender K et al, Diab Obes Metab 2012 doi: /j x 32

33. Glucose-lowering Drugs and CVD Risk

34. SUs May Increase CV Risk in Patients with T2DM:
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
SUs may increase CVD risk: Results of a systematic review and meta-analysis
Phung and colleagues1 recently performed a systematic review and meta-analysis to evaluate the association between sulfonylureas (SUs) and cardiovascular disease (CVD). These results were present at the American Diabetes Association’s 72nd Scientific Sessions in 2012.
A literature search in MEDLINE and Cochrane Central Registry of Controlled Trials (CENTRAL) was conducted through December 2011 to identify observational studies that reported the adjusted association between SU use and CVD events. Only studies comparing a SU group with a non-SU group were used.
This meta‐analysis included 20 observational studies, representing 1,311,090 patients who were followed over a median of 4.6 years.
Compared with other oral antidiabetic drugs, SUs were associated with a significantly increased risk of CV death (relative risk [RR], 1.26; 95% confidence interval [CI], 1.18‐1.34) in the cohort studies.
Additionally, SUs versus other oral antidiabetic drugs were associated with a significantly increased risk of composite CV event (myocardial infarction, stroke, CV-related hospitalization, or CV death) in all observational studies (RR, 1.11; 95% CI, 1.05‐1.18) as well as cohort studies (RR, 1.11; 95% CI, 1.05‐1.17).
Compared with metformin, SUs were associated with a significantly increased risk for CV mortality (RR, 1.26; 95%CI, 1.17‐1.35) and for the CV composite (RR, 1.18; 95%CI, 1.13‐1.24).
This analysis was limited by the high heterogeneity between treatment groups of the observational trials included. Nonetheless, compared with prior studies, this large meta‐analysis provides more precise estimates for CV mortality with SUs by expanding the pool of studies and using adjusted estimates, in addition to evaluating a composite CV event.
References:
Phung OJ, Allen RW, Schwartzman E, et al. Sulfonylureas associated with increased risk of cardiovascular disease: Results from meta-analysis. Diabetes. 2012;61:Suppl 1A. Abstract 2-LB. Available at: _Abstracts_2012.pdf. Accessed: July 30, Poster presented at ADA 2012.
n = the total number of comparisons for that analysis;
one study may contribute more than one comparison to the analysis
CV composite = MI, stroke, CV-related hospitalization, or CV death
Phung OJ, et al. Diabetes 2012;61:Suppl 1A. Abstract 2-LB 34

35. SUs May Increase Mortality and CV Risk versus Metformin
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
Risk for All-Cause Mortality
No Previous MI
Previous MI
SUs may increase mortality and CV morbidity: Results of a nationwide Danish study
A Danish study by Schramm et al1 assessed mortality and cardiovascular (CV) risk associated with monotherapy with different sulfonylureas (SUs) (glimepiride, glibenclamide, glipizide, and tolbutamide) compared with monotherapy with metformin in patients with type 2 diabetes mellitus (T2DM), with or without a previous myocardial infarction (MI).
The study included residents >20 years of age initiating single-agent SU or metformin between 1997 and 2006; individuals were followed for up to 9 years (median 3.3 years).
All-cause mortality, cardiovascular (CV) mortality, and the composite of MI, stroke, and CV mortality associated with individual SUs.
A total of 107,806 subjects were included, among whom 9,607 had previous MI.
Compared with metformin, glimepiride (hazard ratio; 95% confidence interval: 1.32; 1.24–1.40), glibenclamide (1.19; 1.11–1.28), glipizide (1.27; 1.17–1.38), and tolbutamide (1.28 ; 1.17–1.39) were associated with significantly increased all-cause mortality in patients without previous MI.
All-cause mortality was also significantly increased in patients with previous MI were with glimepiride (1.30; 1.11–1.44), glibenclamide (1.47 ; 1.22–1.76), glipizide (1.53; 1.23–1.89), and tolbutamide (1.47 ; 1.17–1.84).
All-cause mortality for gliclazide and repaglinide were not statistically different from metformin in both patients without and with previous MI.
Results were similar for CV mortality and for the composite CV endpoint (data not shown here).
These results suggest that monotherapy with glimepiride, glibenclamide, glipizide, and tolbutamide is associated with increased mortality and CV risk compared with metformin.
References:
Schramm TK, Gislason GH, Vaag A, et al. Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study. Eur Heart J. 2011;32(15):
Hazard Ratio (95% confidence interval)
Hazard Ratio (95% confidence interval)
Schramm TK, et al. Eur Heart J. 2011;32: 35

36. Simpson SH, et al. CMAJ 2006;174:169-74
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
All-cause Mortality a
Increased mortality with sulfonylureas in patients with T2DM may be dose related
In a Canadian retrospective cohort study of 12,272 patients with newly diagnosed T2DM, first- or second-generation sulfonylurea monotherapy was associated with increased mortality in a dose-related manner.
The first-generation sulfonylurea monotherapy and glyburide monotherapy higher-dose groups exhibited higher death rates than the lower-dose groups.
This statistical association was maintained after adjusting for age, sex, comorbidities, physician visits, and hospital admissions.
In contrast, higher daily doses of metformin were not associated with an increased mortality risk.
Similar patterns of association were noted for deaths attributable to an acute ischemic event.
These results suggest that higher exposure to sulfonylureas is associated with increased mortality among patients newly treated for T2DM.
T2DM, type 2 diabetes mellitus.
References
Simpson SH, Majumdar SR, Tsuyuki RT, Eurich DT, Johnson JA. Dose-response relation between sulfonylurea drugs and mortality in type 2 diabetes mellitus: a population-based cohort study. CMAJ. 2006;174:
a Either chlorpropamide or tolbutamide
Simpson SH, et al. CMAJ 2006;174:169-74 36

37. UKPDS 10-year Follow-up: Kaplan-Meier Curves for Outcomes
Ins-SU
End-pt 9% MI
15%
Micro
24%
Death
13%
Met
End-pt
21% MI
33%
Micro NS
Death
27%
Legacy effect; benefit of early aggressive glycemic control on CVD outcomes
Kaplan-Meier Curves for Four Prespecified Aggregate Clinical Outcomes. The proportions of patients in the United Kingdom Prospective Diabetes Study who had any diabetes-related end point (Panels A and B), myocardial infarction (Panels C and D), or microvascular disease (Panels E and F) or who died from any cause (Panels G and H) are shown for the sulfonylurea-insulin group versus the conventional-therapy group and for the metformin group versus the conventional-therapy group. Kaplan-Meier plots for cumulative incidence and log-rank P values are shown at 5-year intervals during a 25-year period from the start of the interventional trial.
Holman RR, et al. N Engl J Med 2008;359:
Holman RR, et al. N Engl J Med 2008;359:

38. 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– Poornima I et al. Circ Heart Fail. 2008;1:
3 Zhao et al. J Pharmacol Exp Ther 2006;317:1106–13
4 Nikolaidis et al. J. Pharm Exp Ther 2005;312: Nikolaidis et al. Circulation 2004;109:962
6 Ban et al. Circulation 2008;117:2340
7 Bose A et al. Diabetes 2005;54: Noyan-Ashraf et al. Diabetes 2009;58:975
9 Sauve et al. Diabetes 2010;59:1063– 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

39. Cardioprotective Effects of Incretins in People with Type 2 Diabetes
Increased GLP-1 may improve endothelial function and peripheral vascular tone in DM2
GLP-1 improves myocardial performance in heart failure and myocardial survival in ischemic heart disease
GLP-1 reduces infarct size and may have anti-atherogenic effects
Increased SDF1-α leading to a greater number of circulating EPCs and cardiac repair
Increased NO, which improves endothelial function
Antithrombotic effects and reduced levels of markers of inflammation
Increased BNP may exert beneficial CV effects in heart failure
The potential benefits of incretins on cardiovascular risk in T2DM include:
Increased GLP-1 may improve endothelial function and peripheral vascular tone in T2DM
GLP-1 improves myocardial performance in heart failure and myocardial survival in ischemic heart disease
GLP-1 may have anti-atherogenic effects
Increased SDF1-α leading to a greater number of circulating EPCs and cardiac repair
Increased NO, which improves endothelial function
Antithrombotic effects and reduced levels of markers of inflammation
Increased BNP may exert beneficial CV effects in heart failure 39

40. GLP-1 Actions on the Heart: Direct or Indirect?
Ussher J, Drucker DJ, Endocrine Rev Apr;33(2):

41. GLP-1 Receptor Agonists Reduce BP
LEAD 6 Systolic blood pressure: Liraglutide vs. Exenatide
Buse J et al. Lancet 2009;374:39–47

42. Pre-treatment with Liraglutide Improves Survival Following MI
Liraglutide 200 µg/kg
Liraglutide 75 µg/kg
Placebo
Sham operation
Overall survival
Death due to cardiac rupture
100 20 80 16
Dead mice (n) 60 12
Survival (%) 40 8 20 4 5 10 15 20 25 30 2 4 6 8 10 12 14 16
Days
Days
n=60 per group
Noyan-Ashraf et al. Diabetes 2009;58:975–83. MI, myocardial infarction

43. Pre-treatment with Liraglutide Reduces Infarct Size10 20 30
Arrows represent extent of infarct
P < 0.05
Liraglutide
Placebo
Noyan-Ashraf et al. Diabetes 2009;58:975–83

44. GLP-1 Reduced Infarct Size in Isolated Rat Hearts
Infarct Within the Risk Zone, I/R% 20 40 60
Control PC
VP Before Ischaemia
GLP-1/VP as a PC Mimetic
VP at Reperfusion a
GLP-1/VP at Reperfusion
GLP-1 Reduced Infarct Size in Isolated Rat Hearts
Treatment with GLP-1 as preconditioning or during reperfusion reduces infarct size and enhances recovery and survival following ischemic reperfusion injury in animal models [Bose 2005; Zhao 2006; Nikolaidis 2005; Noyan-Ashraf 2009; Timmers 2009]
This experimental protocol consisted of 35-minute regional ischemia followed by 120-minute reperfusion [Bose 2005].
The hearts were assigned to the following groups: (a) control hearts (35-min ischemia, 120-min reperfusion); (b) preconditioned hearts (2 times 5-min global normothermic ischemia interspaced with 10-min reperfusion before the 35-min lethal ischemia and 120-min reperfusion); (c) hearts pretreated with GLP-1 (and -VP, an inhibitor of GLP-1 breakdown) for 15 minutes followed by washout for 5 minutes before ischemia/reperfusion insult; (d) hearts treated with GLP-1 (and VP) for the first 15 minutes of reperfusion; (e) hearts treated only with VP before ischemia (as in group c) or (f) at reperfusion (as in group d).
The end point was the measurement of infarct size (using TTC staining) developed within the risk zone (using Evans blue dye), expressed as a percentage of the area at risk (I/R%).
The figure illustrates the benefit of GLP-1 when given either before ischemia (as a preconditioning mimetic) or when given at reperfusion [Bose 2005].
References
Bose AK, Mocanu MM, Carr RD, Yellon DM. Glucagon like peptide-1 is protective against myocardial ischemia/reperfusion injury when given either as a preconditioning mimetic or at reperfusion in an isolated rat heart model. Cardiovasc Drugs Ther. 2005;19:9-11.
Zhao T, Parikh P, Bhashyam S, et al. Direct effects of glucagon-like peptide-1 on myocardial contractility and glucose uptake in normal and postischemic isolated rat hearts. J Pharmacol Exp Ther. 2006;317:
Nikolaidis LA, Doverspike A, Hentosz T, et al. Glucagon-like peptide-1 limits myocardial stunning following brief coronary occlusion and reperfusion in conscious canines. J Pharmacol Exp Ther. 2005;312:
Noyan-Ashraf MH, Momen MA, Ban K, et al. GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes. 2009;58:
Timmers L, Henriques JP, de Kleijn DP, et al. Exenatide reduces infarct size and improves cardiac function in a porcine model of ischemia and reperfusion injury. J Am Coll Cardiol. 2009;53:
a P < vs control PC, ischemic pre-conditioning;
VP, valine pyrrolidide (inhibitor of GLP-1 breakdown)
Bose AK et al. Cardiovasc Drugs Ther 2005;19:9-11

45. 3-month GLP-1 Treatment Prolongs 12-month Survival In SHHF Rats4 5 6 7 8 9 10 11 12 20 40 60 80
100
P<.005
(72%)
(44%)
Survival, %
Control
GLP-1
SHHF, spontaneously hypertensive heart failure- prone rat
Three-month GLP-1 Treatment Prolongs 12-Month Survival in SHHF Rats
Infusions of GLP-1 improve cardiac function and survival in preclinical models of heart failure [Poornima 2008]
This preclinical study was conducted in part to determine the effects of 3-month continuous treatment with GLP-1 on SHHF rats [Poornima 2008]
The figure illustrates survival rates in 2 groups of SHHF rats including one group treated with a continuous intraperitoneal infusion of GLP-1 and another that served as a control group; GLP-treated animals had a significantly better survival compared with control (P<0.008).
The precise mechanism for increased survival was not reported but it thought to involve reduced apoptosis [Poornima 2008].
Reference
Poornima I, Brown SB, Bhashyam S, Parikh P, Bolukoglu H, Shannon RP. Chronic glucagon-like peptide-1 infusion sustains left ventricular systolic function and prolongs survival in the spontaneously hypertensive, heart failure-prone rat. Circ Heart Fail. 2008;1:
Weeks of Treatment
Poornima I et al. Circ Heart Fail. 2008;1: 45

46. Mechanisms Underlying Potential CV Benefits of DPP-4 Inhibitors
Fadini and Avogaro Vasc Pharmacol 2011

47. Mice Lacking DPP-4 Have Improved Outcomes After Experimental MI
DPP-4+/+ and DPP-4-/- mice
Normal chow diet (7% fat) 12 16
Age (weeks)
LAD ligation
Endpoint:
infarct size
100
Dpp4+/+ and -/- sham
(n=26)
(n=10) 90 20
(n=10) 80
Dpp4-/- LAD (n=31) 15
Survival (%) 70
Infarct (%) 10 * 60 5
Dpp4+/+ LAD (n=26) 50
+/+
-/- 10 15 20 25 30
*p < 0.05
Dpp4 genotype
Days post-MI
MI, myocardial infarction; LAD, left anterior descending artery
Sauve et al. Diabetes 2010;59:1063–73

48. Effects of GLP-1 RA and DPP-4i on Mouse Renal Function
0.0
0.1
0.2
0.3
0.4
WT Mice
Urinary flow rate (µl/min/g) * 10 20 30 50
Urinary flow rate (nmol/min/g) 40 Na K Cl
Vehicle
Exendin-4
0.0
0.1
0.2
0.3
0.4
GLP-1r -/- Mice
Urinary flow rate (µ/min/g) 10 20 30 50
Urinary flow rate (nmol/min/g) 40 Na K Cl
Vehicle
Exendin-4
0.0
0.1
0.2
0.3
0.4
Urinary flow rate (µl/min/g) * 10 20 30 40
Urinary flow rate (nmol/min/g) Na K Cl
Vehicle
Alogliptin
0.0
0.1
0.2
0.3
0.4
Urinary flow rate (µl/min/g) * 10 20 30 40
Urinary flow rate (nmol/min/g) Na K Cl
Vehicle
Alogliptin
The natriuretic response to exendin-4, but not to alogliptin, is blunted in awake mice lacking the GLP-1 receptor. Glp1r-/- and WT mice were randomized to application of exendin-4 (EX4; 10 μg/kg bw i.p.), alogliptin (10 mg/kg bw i.p.) or vehicle (2 μl/g bw of 0.85% NaCl), followed by oral gavage with isotonic saline (30 μl/g; ~30% of daily NaCl intake) and determination of urinary excretion in metabolic cages over 3 hours. A) EX4 increased urinary flow rate and Na+ excretion in WT but not in Glp1r-/- mice. B) The natriuretic effect of alogliptin was similar in both genotypes. *P<0.05 vs. vehicle. n=5-6 per group.
Rieg T et al. Am J Physiol Renal Physiol 2012;303(7):F963-71
*P<0.05 vs. vehicle. n=5–6 per group

49. Sauve et al. Diabetes 2010;59:1063–73
Diabetic Mice with Pharmacological Inhibition of DPP-4 Have Increased Expression of Cardioprotective Proteins
HFD, high-fat diet; STZ, streptozotocin; p-AKT, phosphorylated cell survival kinase
p-AKT
HSP90
HFD/STZ
Sitagliptin
Metformin
Liraglutide
p-AKT
*** 25
*P < 0.05
***P < 0.001 20 * 15
Relative units 10 5
HFD/STZ
Sitagliptin
Metformin
Liraglutide
Sauve et al. Diabetes 2010;59:1063–73

50. Chaykovska L, et al. PLoS One 2011;6(11):e27861
Downregulation of BNP Gene Expression Following DPP-4 Inhibition in Rats
TGFb, TIMP, Col1α1 and Col3α1
are markers of fibrosis
*P<0.05; **P<0.001
Results suggest that DPP-4 inhibition leads to:
 cardiac myocyte stress
Improved cardiac function
Downregulation of BNP Gene Expression Following DPP-4 Inhibition in Rats
In a preclinical models, the administration of a DPP-4 inhibitor resulted in the downregulation of BNP gene expression, suggesting that DPP-4 inhibition leads to decreased cardiac myocyte stress and improved cardiac function [Chaykovska 2011]
This study was conducted to explore the effects of linagliptin on biomarkers of cardiac and renal fibrosis.
The figures illustrate the cardioprotective reductions in four biomarkers of fibrosis (ie, TGF-β1, TIMP-1, Col1α1, and Col3α1) associated with the use of DPP-4 inhibition; the cardiac mRNA expression of BNP was also significantly reduced (data not shown) [Chaykovska 2011].
Reference
Chaykovska L, von Websky K, Rahnenführer J et al. Effects of DPP-4 Inhibitors on the heart in a rat model of uremic cardiomyopathy. PLoS One. 2011;6(11):e Epub 2011 Nov 18.
Chaykovska L, et al. PLoS One 2011;6(11):e27861

51. 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
Effects of T2DM on Endothelial Progenitor Cells (EPCs)
The quantity [Hill 2003] and function [Tepper 2002] of EPCs, which play an important role in cardiac tissue repair following ischemic events [Zaruba 2009], are diminished in patients with T2DM.
Data from a preclinical study show that homing of EPCs to sites of vascular injury is impaired in diabetic animals [Ii 2006].
The number of bone marrowderived circulating progenitor cells also is decreased in patients with ischemic heart disease, with further reductions in patients with diabetes [Bozdag-Turan 2011].
References
Hill JM, Zalos G, Halcox JP, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med. 2003;348:
Tepper OM, Galiano RD, Capla JM, et al. Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation. 2002;106(22):
Zaruba M-M, Thiess HD, Vallster M, et al. Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction. Cell Stem Cell. 2009;4:
Ii M, Takenaka H, Asai J, et al. Endothelial progenitor thrombospondin-1 mediates diabetes-induced delay in reendothelialization following arterial injury. Circ Res Mar 17;98:
Bozdag-Turan I, Turan RG, Turan CH, et al. Relation between the frequency of CD34+ bone marrow derived circulating progenitor cells and the number of diseased coronary arteries in patients with myocardial ischemia and diabetes. Cardiovasc Diabetol. 2011;10(1):107. [Epub ahead of print]
Hill JM, et al. N Engl J Med 2003;348:
Tepper OM, et al. Circulation 2002;106(22):
Zaruba M-M, et al. Cell Stem Cell 2009;4:
Li M, et al. Circ Res Mar 17;98:
Bozdag-Turan I, et al. Cardiovasc Diabetol 2011;10(1):107 51

52. Mechanism for DPP-4 Inhibition and SDF-1-mediated Improvements in Cardiac Function
Mobilisation with
G-CSF Treatment
Ischemic myocardium
Bone Marrow
Release of
SDF-1
CXCR + Stem cells
CXCR4
DPP-4 (CD26)
N-terminal Cleavage:
Diminished Homing
Inhibition
Prevention of Cleavage-
Enhanced Homing
Enhanced Homing by CD26 Inhibition
Mechanism for DPP-IV Inhibition and SDF-1-mediated Improvements in Cardiac Function
SDF-1, a chemotactic factor for endothelial and other circulating progenitor cells [Zaruba 2009], is expressed in the heart and vasculature [Zaruba 2009] and regulates homing of endothelial and other CXCR-4-positive stem cells [Ceradini 2004].
SDF-1  is cleaved and inactivated by CD26/dipeptidylpeptidase IV (DPP-IV) [Zaruba 2009].
Inhibition of DPP-IV with G-CSF-mediated stem cell mobilization after myocardial infarction in mice leads to increased myocardial homing of circulating CXCR-4+ stem cells and improved heart function and survival, as depicted in this figure.
Administration of SDF-1  has been shown to preserve cardiac function postischemia in animal models [Saxena 2008; Huang 2011].
References
Zaruba M-M, Thiess HD, Vallster M, et al. Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction. Cell Stem Cell. 2009;4:
Ceradini DJ, Kulkarni AR, Callaghan MJ, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med. 2004;10:
Saxena A, Fish JE, White MD, et al. Stromal cell-derived factor-1alpha is cardioprotective after myocardial infarction. Circulation. 2008;117::
Huang C, Gu H, Zhang W, Manukyan MC, Shou W, Wang M. SDF-1/CXCR4 mediates acute protection of cardiac function through myocardial STAT3 signaling following global ischemia/reperfusion injury. Am J Physiol Heart Circ Physiol. 2011;301:H1496-H1505.
CXCR, chemokine receptor G-CSF, granulocyte colony-stimulating factor
SDF-1, stromal cell-derived factor
Zaruba M-M, et al. Cell Stem Cell 2009;4: 52

53. CV Meta-analyses of Individual Incretin Agents6
CV Meta-analyses of Individual Incretin Agents
No increased risk of CV events was observed in patients randomly treated with DPP-4 inhibitors or GLP-1R agonists
Total patients in analysis
CV composite
endpoint
Comments
Exenatide1
0.7
0.38
1.31
MedDRA terms for Stroke, MI, cardiac mortality, ACS, revascularization
Post-hoc/
No formal adjudication
1.8
3,945
5,239
6,638
4,607
10,246
FDA Upper Bound 95%
Criterion for Approvability
CV death, MI, stroke,
hospitalisation due to angina pectoris
Pre-specified/
independent adjudication
0.15
0.74
Linagliptin2
0.34
Liraglutide3
0.63
0.32
1.24
Post-hoc/
No formal adjudication
MedDRA terms
for MACE
MI, stroke, CV death
Post-hoc/
Independent adjudication
Saxagliptin4
0.43
0.23
0.80
MedDRA terms
for MACE
Post-hoc/
No formal adjudication
Sitagliptin5
0.68
0.41
1.12
0.125
0.25
0.5 1 2 4 8
Incretin agent better
Comparator better
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. 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 53 53

54. Ongoing Cardiovascular Outcome Trials:
DPP-4 Inhibitors and GLP-1 Agonists
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
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
Notes:
Each DPP-4 inhibitors have trials coming in the next few years.
1. Golden SH. Am J Cardiol 2011;108 (Suppl):59B-67B
2. Fonseca V. Am J Cardiol 2011;108 (supp):52B–58Bl
3. Clinicaltrials.gov

55. Diabetes Cardiovascular Outcomes Trials
2010
2011
2012
2013
2014
2015
2016
2017
2018
2019+
9/03
Glargine (Lantus) (ORIGIN)
12/12 completion
N=12,500
Assessed likely to deliver benefit
N=4,500*
recruitment 11/09
canagliflozin (CANVAS)
3/13 completion
N=6,000
10/13 completion
recruitment 6/10
lixisenatide (ELIXA)
N=7,000
Empagliflozin
recruitment 12/10
7/18 completion
N=5,400
recruitment 9/09
alogliptin (EXAMINE)
5/14 completion
N=7,500
7/14 completion
Acarbose (GlucoBay) (ACE)
recruitment 2/09
N=6,000
recruitment 5/10
Aleglitazar (ALECARDIO)
11/14 completion
AGI
DPP4
GLP1
recruitment 12/08
Sitagliptin (Januvia) (TECOS)
12/14 completion
N=14,000
insulin
PPAR
N=16,500
recruitment 5/10
Saxagliptin (Onglyza) (SAVOR-TIMI 53)
4/14 completion
SGLT2
N=8,754
Liraglutide (Victoza) (LEADER)
recruitment 8/10
1/16 completion
N=12,000
recruitment 3/10
Exenatide (Byetta) (EXSCEL)
3/17 completion
N=6,000
recruitment 10/10
linagliptin (Trajenta) (CAROLINA)
9/18 completion

56. Diabetes and Atherosclerosis

57. CVD Management in Diabetes
Benefits of multiple CVD risk factor management on CVD outcomes

58. Steno 2: Effects on Combined CV Outcomes60
20% absolute RR
RRR 53%
P = 0.007 50
Conventional therapy 40
Intensive therapy 30 20 10
Significantly fewer primary endpoints (a composite of CV death, non-fatal stroke or MI, revascularization, or amputation) occurred in the Intensive treatment group. 12 24 36 48 60 72 84 96
No. at Risk
Conventional
Intensive Rx
Months of Follow-up
Gaede P, et al, NEJM 2003;348(5):

59. 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
CARE study 12
Screening for breast cancer 1000
Gaede P et al. N Engl J Med 2003;348:

60. STENO-2: Dramatic  in Cardiovascular Events
Intensive Therapy
Conventional Therapy
Number of Cardiovascular Events
STENO-2: No other clinical trial of patients with type 2 diabetes has shown such a dramatic reduction in cardiovascular events with a pharmacologic intervention
The patients in the STENO-2 study had fewer deaths from cardiovascular disease, had fewer strokes and myocardial infarctions, and had less need for bypass surgery or angioplasty and revascularization or amputations when compared to the patients randomized to the conventional-therapy group.
Reference:
Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:
Stroke
Revascularization
Death from Cardiovascular Causes
Myocardial Infarction
Coronary
Artery
Bypass
Graft
Percutaneus
Coronary
Intervention
Amputation
Gaede P, et al. N Engl J Med 2003;358:580−591

61. STENO-2: Fasting Glucose, LDL-C, and BP
at 7.8 Years With Intensive Treatment
9.8
Intensive Therapy
Conventional Therapy
146
131
7.2
3.27
BP Value at 7.8 Years
2.15 78
P < .01 73
1.22
A1C 7.9%
1.17
A1C 9.0%
STENO-2: Fasting Glucose, Low-Density Lipoprotein, and Blood Pressure at 7.8 Years With Intensive Treatment
When one looks at the absolute reductions across these parameters, fasting plasma glucose was reduced from 178 mg/dL in the conventional treatment group to 129 mg/dL in the intensive treatment group at the end of the study at 7.8 years. The concentration of hemoglobin A1c dropped from 9.0% to 7.9%. There were large reductions in low-density lipoprotein; for example, from 126 mg/dL to 83 mg/dL. There was also a reduction of systolic blood pressure from 146 to 131 mm Hg.
Reference:
Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:
P < .01
P < .01
P < .01
FPG (mmol/L)
LDL-C (mmol/L)
HDL-C (mmol/L)
Systolic BP (mm Hg)
Diastolic BP (mm Hg)
BP = blood pressure; FPG = fasting plasma glucose; A1C = Hemoglobin A1C;
HDL-C = high-density lipoprotein; LDL-C = low-density lipoprotein
Gaede P, et al. N Engl J Med 2008;358:580−591

62. 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 cause
mortality
46% 
CVD
57% 
Kaplan-Meier Estimates of the Risk of Death from Any Cause and from Cardiovascular Causes and the Number of Cardiovascular Events, According to Treatment Group. Panel A shows the cumulative incidence of the risk of death from any cause (the study's primary end point) during the 13.3-year study period. Panel B shows the cumulative incidence of a secondary composite end point of cardiovascular events, including death from cardiovascular causes, nonfatal stroke, nonfatal myocardial infarction, coronary-artery bypass grafting (CABG), percutaneous coronary intervention (PCI), revascularization for peripheral atherosclerotic artery disease, and amputation; Panel C shows the number of events for each component of the composite end point. In Panels A and B, the I bars represent standard errors.
Gaede P, et al. N Engl J Med 2008;358:

63. Global CVD Risk Reduction in Diabetes
CVD risk estimates in diabetes should be patient-centred and not disease-based:
Identify individual CVD risk factors
Consider all risk factors in estimating particular patient’s CVD risk
Appropriate therapies should be evidence-based
Integrate all therapies to optimize best management for global CVD risk reduction
Gerstein HC Diabetologia 2011;54:230–232

64. 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

65. 2013 CDA Clinical Practice Guidelines
Clinical Assessment - Lifestyle intervention (Nutrition therapy and physical activity)
A1C < 8.5%
A1C ≥ 8.5%
Symptomatic hyperglycemia with metabolic decompensation
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 draft CPGs. Can J Diabetes 2013

66. 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

67. “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 67

68. Thank you
Questions?