Parts 1 and 2

Faculty/Presenter Disclosure

Faculty/Presenter: [insert name here]

Relationships with commercial interests:

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Disclosure of Commercial Support

• This program has received financial support from AstraZeneca Canada Inc. in the form of an educational grant

• This program has received in-kind support from AstraZeneca Canada Inc. in the form of logistical support

Potential for conflict(s) of interest:• [Faculty/speaker name] has received [payment/funding] from

[organization supporting the program AND/OR organization whose product(s) are being discussed in this program]

• AstraZeneca Canada Inc. markets or benefits from the sale of a product(s) that will be discussed in this program: exenatide (Byetta), saxagliptin (Onglyza)

Mitigating Potential Bias

Potential sources of bias identified in the preceding 2 slides have been mitigated as follows:• Information presented is evidence-based• Recommendations made are evidence- or

guidelines-based rather than personal recommendations of the presenter

• Material has been reviewed by an Educational Committee responsible for overseeing the program’s Needs Assessment and subsequent content development

Learning Objectives

After completing this program, participants will be able to:

• Articulate overall approaches to CV risk reduction in patients with type 2 diabetes (T2DM);

• Describe the impact of glycemic control on CV risk; and

• Cite evidence describing CV risks and/or benefits of various antihyperglycemic agents.

Part 1

Case Study 1: Paul

• 55-year-old male• Has been seen many times over

past years but has been poorlycompliant to follow-up

• Last visit 3 years ago: – noted to have “pre diabetes” (A1C 6.3%) – dietician follow-up booked; patient did not follow through

• Today’s visit: wants to “get his heart checked out” after his 59-year-old brother suffered a fatal MI

What investigations would you order in Paul’s case at this point?

Paul: Investigations

BP: 152/96 mmHg (confirmed on 2 office visits and HBP log)

All other blood parameters: normal

Lifestyle: sedentary, non-smoker

Family history: mother with T2DM; brother with fatal MI at age 59

Fasting blood sugar: 9.8 mmol/L

A1C: 8.6%

TC: 5.6 mmol/L, TG: 4.7 mmol/L,

HDL-C: 0.7 mmol/L

LDL-C: unable to calculate

BMI: 34 kg/m2

Discussion

1. Write a “problem list” for Paul.

2. Is his risk for CV events low, medium or high? What tools do you use to establish risk? Do you use any tools to communicate CV risk to patients?

3. What are your treatment priorities for Paul?

Problem List

How would you describe Paul’s risk for CV events?

What are your treatment priorities for Paul?

Metabolic Syndrome

*Other waist circumference (WC) cutoffs: ≥ 94 cm (men) or ≥ 80 cm (women) for Europids, whites, Sub-Saharan Africans, Mediterranean and Middle East (Arab) populations; ≥ 90 cm (men) or ≥ 80 cm (women) for Asian and ethnic South and Central American populations. Leiter LA, et al. Can J Cardiol 2011; 27(2):e1-e33.

• TG: ≥ 1.7 mmol/L (or receiving treatment)

• HDL-C: < 1.0 mmol/L (men) or < 1.3 mmol/L (women)

• Abdominal obesity: WC ≥ 102 cm (men) or ≥ 88 cm (women) in Canada/U.S./European populations*

• FBG: ≥ 5.6 mmol/L (or receiving treatment of elevated glucose)

• BP: ≥ 130/85 mmHg (or receiving treatment of previously diagnosed hypertension)

≥ 3 risk determinants are present:

CV Risk Assessment

• Not necessary to perform Framingham calculation to assess risk…

Patient is at HIGH RISK for CV disease

2013 CHEP Recommendations: Assessing Cardiovascular Risk to Improve Adherence

• Inform patients of their global risk to improve the effectiveness of risk-factor modification

• Use analogies that describe comparative risk, such as “Cardiovascular Age,” “Vascular Age” or “Heart Age” to inform patients of their risk status

What strategies would you use in discussing Paul’s CV risk with him?

Informing Patients of Their Global Risk Improves the Effectiveness of Risk-factor Modification

Grover SA, et al. J Gen Intern Med 2009; 24(1);33-9.

Case Study 1: Paul (cont’d)

• Paul agrees to see the diabetes nurse educator and start on lifestyle changes

• Adamant that he wants to reduce his CV risk, and comfortable with whatever therapies are necessary to achieve this

What evidence-based medical therapies would you recommend?

What evidence-based medical therapies would you recommend in Paul’s case?

CDA 2013 Guidelines: Vascular Protection Checklist

CDA: Canadian Diabetes Association.CDA 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2013;37(suppl 1):S1-S212.

A A1C – optimal glycemic control (usually ≤7%)

B BP – optimal blood pressure control (<130/80)

C Cholesterol – LDL ≤ 2.0 mmol/L if decided to treat

D Drugs to protect the heartA – ACEi or ARB │ S – Statin │ A – ASA if indicated

E Exercise / Eating healthily – regular physical activity, achieve and maintain healthy body weight

S Smoking cessation

CHEP Hypertension Recommendations: Vascular ProtectionStatins are recommended in high-risk hypertensive patients based on having established atherosclerotic disease or at least 3 of the following:

Hackam DG, et al. Can J Cardiol 2013; 29(5):528-42.

• Male gender

• 55 years or older

• Smoking

• T2DM

• TC:HDL-C ratio ≥ 6

• Family history of premature CV disease

• Previous stroke or TIA

• LVH

• ECG abnormalities

• Microalbuminuria or proteinuria

• Peripheral vascular disease

2012 CCS Dyslipidemia Guidelines Update: Recommendations in High Risk

Anderson TJ, Gregoire J, et al. Can J Cardiol 2013; 29(2):151-67.

• High risk: clinical atherosclerosis; all persons with diabetes aged > 40 years as well as younger persons with diabetes with additional sources of risk (e.g., diabetes > 15 years duration and age > 30 years); or adjusted Framingham Risk Score ≥ 20% (Strong Recommendation, High-Quality Evidence)

– now included in this category: abdominal aortic aneurysm, high-risk kidney disease (eGFR < 45) and high-risk hypertension (Strong Recommendation, Moderate-Quality Evidence)

• Treatment target for LDL-C: ≤ 2.0 mmol/L or ≥ 50% reduction for optimal risk reduction (Strong Recommendation, Moderate-Quality Evidence)

• ApoB (≤ 0.80 g/L) or non-HDL-C (≤ 2.6 mmol/L) considered as alternatives (Strong Recommendation, High-Quality Evidence)

STEP 2: What is the patient’s age?≥ 55 years

OR40-54 years

STEP 3: Does the patient…Have diabetes > 15 years AND age > 30 years?Warrant statin therapy based on the 2012 CCS Lipid Guidelines?

STEP 1: Does this patient have end-organ damage?Macrovascular disease

• Cardiac ischemia (silent or overt)• Peripheral arterial disease• Cerebrovascular/carotid diseaseORMicrovascular disease• Retinopathy• Nephropathy (ACR ≥ 2.0)• Neuropathy Statin

+ACEi or ARB

Statin

Does This Patient Require Vascular Protective Medications?

Canadian Diabetes Association. guidelines.diabetes.ca

YES

YES

YES

YES

NO

NO

Statin+

ACEi or ARB+

ASAClopidogrel if ASA-intolerant

YES

CDA 2013 Guidelines: Individualizing Antihyperglycemic Agents After Metformin

• The CDA guidelines suggest individualization of therapy based on patient characteristics

Complete the following table, looking at important characteristics of each class of

antihyperglycemic agents.

CDA: Canadian Diabetes Association.CDA 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2013;37(suppl 1):S1-S212.

Individualizing Antihyperglycemic Agents After Metformin (1)

Class Example medications

A1C-lowering

Effect on weight

Risk of hypo-glycemia

Leave blank

Alpha-glucosidase inhibitor

Biguanides

DPP-4 inhibitors

GLP-1 agonists

Insulin

Insulin secretagogues

TZDs

What would be your approach to individualizing antihyperglycemic therapy in Paul’s case?

Individualized T2DM Treatment Options After Metformin (CDA 2013)

*In alphabetical order.CDA 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2013;37(suppl 1):S1-S212.

Class*Relative A1C lowering Hypoglycemia Weight Other therapeutic considerations Cost

Alpha-glucosidase inhibitor (acarbose)

↓ Rare Neutral to ↓ Improved postprandial control, GI side effects $$

Incretin agents:

DPP-4 inhibitors

GLP-1 agonists

↓↓

↓↓ to ↓↓↓

Rare

Rare

Neutral to ↓

↓↓ GI side effects

$$$

$$$$

Insulin ↓↓↓ Yes ↑↑ No dose ceiling, flexible regimens $ to $$$$

Insulin secretagogue:

Meglitinide

Sulfonylurea

↓↓

↓↓

Yes

Yes

↑

↑

Less hypoglycemia in context of missed meals but usually requires tid to qid dosing

Gliclazide and glimepiride associated with less hypoglycemia than glyburide

$$

$

TZD ↓↓ Rare ↑↑ CHF, edema, fractures, rare bladder cancer (pioglitazone), cardiovascular controversy (rosiglitazone), 6-12 weeks required for maximal effect

$$

Weight loss agent (orlistat)

↓ None ↓ GI side effects $$$

Key Messages

1. Insulin resistance is progressiveand care should be taken to not lose patients with pre-diabetes to follow up.

2. Evaluate and treat all vascular risk factors in patients with DM.

3. Individualize the choice of antihyperglycemic agents based on patient characteristics

4. Recent evidence with saxagliptin and alogliptin reinforces the CV safety of DPP-4 Inhibitors

Part 2

Case Study 2: Russell

• 64-year-old male• T2DM for 10 years • Presents for annual health review

and medication renewal• Previously adequate A1C control

• Now has gained weight and reports a consistent elevation in fasting and 2-hour postprandial glucometer values

• Physical exam: negative (except for obesity)• Routine evaluations ordered

What investigations would you order in Russell’s case at this point?

Russell: Investigations

A1C: 7.5%

ECG: inferior changes consistent with previous MI (subsequent cardiac echo confirms inferior MI)

All other blood parameters: normal or “at target”

Russell: Current Medications

Simvastatin 40 mg od

EC-ASA 81 mg od

Ramipril 10 mg od

Metformin 1000 mg bid

Omeprazole 20 mg bid

What is the evidence for improving vascular outcomes by reducing A1C in patients with T2DM?

What new evidence exists?

Question 1

Is there evidence with traditional antihyperglycemic agents to help guide your choice of therapy for reducing CV risk in T2DM?

What We Know: Glycemic Control Prevents Microvascular Complications

aUKPDS results shown are for cumulative microvascular endpoints (renal failure or death; vitreous hemorrhage; retinal photocoagulation) in the respective treatment arms of the glucose control study.*Statistically significant.

Percent reduction compared with control

0 10 20 30 40 50 60 70 80

ADVANCE

Major Micro

Renal

Eye

ACCORDMicroalbumin

Macroalbuminuria

Retinopathy 3-step

UKPDSMetformina

Insulin/SUa

Final A1C values

6.5% vs. 7.3%

6.4% vs. 7.5%

7.0% vs. 7.9%

*

*

*

*

*

*

Conflicting Evidence: Glycemic Control and Reductions in Risk for CVD

CVD = cardiovascular disease.1. UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:837-53. 2. The ACCORD Study Group. N Engl J Med 2011; 364:818-28. 3. The ADVANCE Collaborative Group. N Engl J Med 2008; 358:2560-72. 4. Duckworth W, et al. N Engl J Med 2009; 360:129-39. 5. Holman RR, et al. N Engl J Med 2008; 359:1577-89. 6. Boussageon R, et al. BMJ 2011; 343:d4169. 7. Hemmingsen B, et al. BMJ 2011; 343:d6898.

• Long-term follow-up of the UKPDS study– benefit of metformin > SU / insulin

• Meta-analyses of individual studies

• Original UKPDS study• ACCORD• ADVANCE• VADT

Evidence of Benefit

No Evidence of Benefit

Effect of More- vs. Less-intensive Glycemic Control on CV Outcomes and Death in Patients with Diabetes: A Meta-analysis of Randomized, Controlled Trials

Adapted from: Turnbull FM, et al. Diabetologia 2009; 52(11):2288-98.

Hazard ratio(95% CI)

0.90 (0.78 – 1.04)0.94 (0.84 – 1.06)0.80 (0.62 – 1.04)0.90 (0.70 – 1.16)

0.91 (0.84 – 0.99)(Q = 1.32, p = 0.72, I2 = 0.0%)

TrialsMore intensive

Less intensive

ΔA1C(%)

No. of events (annual event rate, %)

Major cardiovascular event ACCORD ADVANCE UKPDS VADT

Overall

Myocardial infarction ACCORD ADVANCE UKPDS VADT

Overall

352 (2.11)557 (2.15)169 (1.30)116 (2.68)

1,194

371 (2.29)590 (2.28)87 (1.60)128 (2.98)

1,176

-1.01-0.72-0.66-1.16

-0.88

198 (1.18)310 (1.18)150 (1.20)72 (1.65)

730

245 (1.51)337 (1.28)76 (1.40)87 (1.99)

745

-1.01-0.72-0.66-1.16

-0.88

0.77 (0.64 – 0.93)0.92 (0.79 – 1.07)0.81 (0.62 – 1.07)0.83 (0.61 – 1.13)

0.85 (0.76 – 0.94)(Q = 2.25, p = 0.52,I2 = 0.0%)

Favors more intensive

0.5 2.01.0Hazard ratio (95% CI)

Favors less intensive

1.22 (1.01 – 1.46)0.93 (0.83 – 1.06)0.96 (0.70 – 1.33)1.07 (0.81 – 1.42)

1.04 (0.90 – 1.20)(Q = 5.71, p = 0.13,I2 = 47.5%)

All-cause mortality ACCORD ADVANCE UKPDS VADT

Overall

257 (1.41)498 (1.86)123 (0.13)102 (2.22)

980

203 (1.14)533 (1.99)53 (0.25)95 (2.06)

884

-1.01-0.72-0.66-1.16

-0.88

What key features would you look for in evaluating the meaningfulness of CV outcome studies in T2DM?

Recent FDA Guidance for Phase 2/3 T2DM Studies in Planning Stage

FDA. Guidance for Industry: Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. December 2008. Available at: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf.

• Establish independent committee to prospectively adjudicate CV events in a blinded fashion

• Include major events (CV mortality, MI, stroke)

• Can also include ACS hospitalization, urgent revascularization, etc.

• Design and conduct studies to enable future meta-analyses

• Include patients at higher risk of CV events

• Phase 3 trials should provide data on longer-term CV risk (e.g., minimum 2 years)

• Collect pre-specified CV outcomes data to exclude 80% increase in relative risk of the new agent

Two New Trials Released:SAVOR and EXAMINE

SAVOR: Baseline Characteristics and Medications

Scirica BM, et al. N Engl J Med 2013; 369(14):1317-26.

Placebo(n = 8,212)

Saxagliptin(n = 8,280)

CV Medications (%)

Aspirin 75 76

Statin 78 78

ACEi 55 54

ARB 28 28

Beta-blocker 62 62

Diabetes Medications (%)

Insulin 41 42

Sulfonylurea 40 41

TZD 6 6

Metformin 69 70

None 5 4

SAVOR: n = 16,492 patients (mean age 65 years) with type 2 diabetes (mean duration 10.3 years) and established CVD (78-79%) or multiple risk factors (21-22%).

Median duration of follow-up: 2.1 years.

SAVOR: Primary Efficacy Results*

*Primary endpoint: composite of CV death, non-fatal MI or non-fatal ischemic stroke.Scirica BM, et al. N Engl J Med 2013; 369(14):1317-26.

0

14

0

12

10

8

6

4

2

6 12 18 24Months

% o

f p

atie

nts HR 1.00

95% CI 0.89-1.12p (non-inferiority) < 0.001p (superiority) = 0.99

Saxagliptin

Placebo

SAVOR:Individual Endpoints

Scirica BM, et al. N Engl J Med 2013; 369(14):1317-26.

Endpoint

2-year KM rate (%)

HRp value for superiority

Placebo (n = 8,212)

Saxagliptin (n = 8,280)

CV death 2.9 3.2 1.03 (0.87-1.22) 0.72

MI 3.4 3.2 0.95 (0.80-1.12) 0.52

Ischemic stroke 1.7 1.9 1.11 (0.88-1.39) 0.38

Hosp. for cor. revasc. 5.6 5.2 0.91 (0.80-1.04) 0.18

Hosp. for UA 1.0 1.2 1.19 (0.89-1.60) 0.24

Hosp. for HF 2.8 3.5 1.27 (1.07-1.51) 0.007

All-cause mortality 4.2 4.9 1.11 (0.96-1.27) 0.15

SAVOR: Rates of Risk of Hospitalization for Heart Failure Over Time

0

8

0

6

4

180 360 540 720 900Days

Ho

spit

aliz

atio

n f

or

HF

(%

)

Saxagliptin

2

Placebo

n = 16,492

HR 1.80(1.29 – 2.54)

p = 0.001

Overall HR 1.27(1.07 – 1.51)

p = 0.007

HR 1.48(1.14 – 1.87)

p = 0.003

HR = hazard ratio1.1%

0.6%

1.9%

1.3%

3.5%

2.8%

• Saxagliptin neither increased nor decreased the risk of the 1° and 2° endpoints in these high-risk populations.

• There were no specific subgroups in which the RR associated with saxagliptin was particularly high or low.

• The absolute risk with saxagliptin was smallest in patients at low risk of HF and correspondingly larger in patients at highest risk.

Scirica BM, et al. Presented at AHA 2013, Dallas.

How can the data on CHF hospitalization from SAVOR be put into context, also taking into account the overall CV safety demonstrated in the trial?

EXAMINE: Baseline Characteristics and Medications

Placebo(n = 2,679)

Alogliptin(n = 2,701)

CV Medications (%)

Aspirin 91 91

Thienopyridine 81 80

Beta-blocker 82 82

Statin 90 91

CCB 23 22

RAS agents 83 82

Diabetes Medications (%)

Insulin 30 29

Metformin 67 65

TZD 2 3

Sulfonylurea 46 47

EXAMINE: n = 5,380 patients (median age 61 years) with type 2 diabetes (mean duration 7.1 to 7.3 years) and acute coronary syndrome within 15-90 days of randomization.

Median duration of follow-up: 18 months.

White WB, et al. N Engl J Med 2013; 369(14):1327-35.

EXAMINE: Primary Efficacy Endpoint*

*Primary endpoint: composite of CV death, non-fatal MI or non-fatal ischemic stroke.White WB, et al. N Engl J Med 2013; 369(14):1327-35.

0

24

0

18

12

6

6 12 24 30Months

Cu

mu

lati

ve i

nci

den

ce o

f p

rim

ary

end

-po

int

even

ts (

%)

HR 0.96(upper boundary of the one-sided repeated CI: 1.16)

18

Placebo

Alogliptin

EXAMINE: Other Endpoints

*Secondary endpoint: composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or urgent revascularization due to unstable angina within 24 hours after hospital admission.†Upper boundary of the one-sided repeated CI, at an alpha level of 0.01.

White WB, et al. N Engl J Med 2013; 369(14):1327-35.

EndpointPlacebo

(n = 2,679)Alogliptin(n = 2,701) HR (95% CI)

p value (superiority)

Components of primary endpoint

CV death 4.1 3.3 0.79 (0.6-1.04) 0.10

Nonfatal MI 6.5 6.9 1.08 (0.88-1.33) 0.47

Nonfatal stroke 1.2 1.1 0.91 (0.55-1.50) 0.71

Principal secondary endpoint* 13.4 12.7 0.95 (≤1.14)† 0.26

Death from any cause 6.5 5.7 0.88 (0.71–1.09) 0.23

SAVOR and EXAMINE: Safety Endpoints of Special Interest1,2

*Definite or possible.1. Scirica BM, et al. N Engl J Med 2013; 369(14):1317-26.2. White WB, et al. N Engl J Med 2013; 369(14):1327-35.3. Raz I, Bhatt DL. Presented at EASD 2013, Barcelona.

Adverse event

% of patients

SAVOR EXAMINE

Placebo(n = 8,212)

Saxagliptin(n = 8,280) p value

Placebo (n = 2,679)

Alogliptin(n = 2,701) p value

Pancreatitis, acute

0.2* 0.3* 0.77 0.3 0.4 0.50

Pancreatitis, chronic

0.1 <0.1 0.18 0.1 0.2 1.00

Pancreatic cancer

0.1 0.06 0.095 0 0 -

Hypoglycemia 13.4 15.3 < 0.001 6.5 6.7 0.74

• Incidences of acute and chronic pancreatitis were similar between treatment and placebo groups in these studies.1,2

• Further analysis of SAVOR results3 showed that pancreatitis frequency remained flat over the entire treatment period, suggesting that observed cases were natural history.

In terms of efficacy, were A1C levels adequately controlled in the SAVOR and EXAMINE studies?

What is the impact of hypoglycemia on CV risk?

Question 2

Link Between Hypoglycemia and Acute CV Events in T2DM• Retrospective, observational

study assessing association between hypoglycemia and acute CV events

• 3.1% patients had hypoglycemia during evaluation period

• Patients with hypoglycemia had 79% higher odds for acute CV events vs. patients with no hypoglycemia

Johnston SS et al. Diabetes Care 2011; 34:1164-70.

Hypoglycemia May Affect CV Events

Desouza CV, et al. Diabetes Care 2010; 33(6):1389-94.

Blood coagulationabnormalities

Inflammation

Endothelial dysfunction

Vasodilation

VEGF IL-6CRP

Neutrophil activation

Plateletactivation

Factor VIIHypoglycemia

Sympathoadrenal response

Rhythm abnormalities Hemodynamic changes

Adrenaline

Contractility

Oxygen consumption

Heart workload

Heart rate variability

Low Plasma Glucose Levels:

Acute Complications and Effects of Severe Hypoglycemia

1. Landstedt-Hallin L, et al. J Intern Med 1999; 246:299-307.2. Cryer PE. J Clin Invest 2007; 117(4):868-70.

• Abnormal prolonged cardiac repolarization - QTc

• Sudden death?

Increased Risk of Cardiac Arrhythmia1

• Cognitive impairment• Unusual behaviour• Seizure• Coma• Brain death?

Progressive Neuroglycopenia2

What is an appropriate A1C target for Russell?

What classes of antihyperglycemic agents may increase CV harm?

What is the impact on CV risk of various antihyperglycemic classes? (chart completion)

Question 3

What is an appropriate A1C target for Russell?

CDA 2013 Guidelines: Individualizing A1C Targets

A target A1C ≤ 6.5% may be considered in some patients with T2DM to further lower the risk of nephropathy and retinopathy, which must be balanced against the risk of hypoglycemia

Consider A1C target 7.1–8.5% if:• Limited life expectancy• High level of functional dependency• Extensive coronary artery disease at high risk

of ischemic events• Multiple comorbidities• History of recurrent severe hypoglycemia• Hypoglycemia unawareness• Longstanding diabetes and difficulty achieving

A1C ≤ 7% despite effective doses of multiple antihyperglycemic agents, including intensified basal-bolus insulin therapy

Most patients

with type 1 and type 2 diabetes

>7%≤7%

7%

CDA: Canadian Diabetes Association.CDA 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2013;37(suppl 1):S1-S212.

What classes of antihyperglycemic agents might increase CV risk?

Some Antihyperglycemic Therapies May Have Adverse CV Effects

1. Tzoulaki I, et al. BMJ 2009; 339:b4731. 2. Schramm TK, et al. Circulation 2008; 117:1945-54. 3. Nissen SE, Wolski K. N Engl J Med 2007; 356:2457-71. 4. Home PD, et al. Lancet 2009; 373:2125-35. 5. Dormandy JA, et al. Lancet 2005; 366:1279-89. 6. Wilcox R, et al. Am Heart J 2008; 155:712-17.

• Data suggest an increase in CV risk with certain oral antihyperglycemic agents

– Certain sulfonylureas,1,2 possibly mediated by:• increased CV risks associated with

hypoglycemia• effects on cardiac potassium ATP channels

(loss of beneficial ischemic pre-conditioning)

– Thiazolidinediones3-6

• increased risk of edema, CHF

What do we know about sulfonylureas and CV safety?

Individualizing Antihyperglycemic Agents After Metformin (2)

Class Example medications

A1C-lowering

Effect on weight

Risk of hypo-glycemia CV safety

Alpha-glucosidase inhibitor

Biguanides

DPP-4 inhibitors

GLP-1 agonists

Insulin

Insulin secretagogues

TZDs

What changes would you make to Russell’s medication regimen?

Question 4

What changes would you make to Russell’s medication regimen?

Key Messages

1. Evaluate all patients with diabetes for vascular risk

2. Avoid antihyperglycemic agents which put patients with established CV disease at risk for hypoglycemia

3. Individualize the choice of antihyperglycemic agents based on patient characteristics

4. Recent evidence with saxagliptin and alogliptin reinforces the CV safety of DPP-4 Inhibitors

Support Slides• Additional resources for program facilitators

2012 CCS Dyslipidemia Guidelines Update

Canadian Cardiovascular Society, 2013.

Points Age HDL-C Total cholesterol SBP not treated SBP treated Smoker Diabetic

-2 > 1.6 < 120

-1 1.3-1.6

0 30-34 1.2-1.3 < 4.1 120-129 < 120 No No

1 0.9-1.2 4.1-5.2 130-139

2 35-39 < 0.9 5.2-6.2 140-159 120-129

3 6.2-7.2 160+ 130-139 Yes

4 > 7.2 140-159 Yes

5 40-44 160+

6

7 45-49

8 50-54

9

10 55-59

11 60-64

12

13 65-69

14 70-74

15 75+ Total points

Pointsallotted

Estimation of 10-year risk of total CVD in men (Framingham Heart Study)

Multiplied by 2 when family history of premature CVD is positive

Points Risk Points Risk Points Risk

-3 or less < 1 % 5 3.9 % 13 15.6 %

-2 1.1 % 6 4.7 % 14 18.4 %

-1 1.4 % 7 5.6 % 15 21.6 %

0 1.6 % 8 6.7 % 16 25.3 %

1 1.9 % 9 7.9 % 17 29.4 %

2 2.3 % 10 9.4 % 18+ > 30 %

3 2.8 % 11 11.2 %

4 3.3 % 12 13.3 %

2012 CCS Dyslipidemia Guidelines UpdateEstimation of 10-year risk of total CVD in men (Framingham Heart Study)

Canadian Cardiovascular Society, 2013.

Cardiovascular Age Tables: Male Patients WITHOUT Diabetes

Total Cholesterol:HDL Ratio Total Cholesterol:HDL Ratio

3 4 5 6 7 3 4 5 6 7

120/80 28.1 28.4 28.9 29.5 30.2

Age30

33.1 33.7 34.7 35.7 36.8 120/80

130/85 29.1 29.4 30.0 30.8 31.5 34.2 34.9 36.0 37.1 38.3 130/85

140/90 30.0 30.4 31.2 32.0 32.9 35.3 36.0 37.3 38.5 39.7 140/90

150/95 31.0 31.4 32.3 33.2 34.2 36.4 37.2 38.5 39.8 41.1 150/95

120/80 37.3 37.6 38.1 38.8 39.5

Age40

42.2 42.8 43.8 44.8 45.9 120/80

130/85 38.2 38.6 39.2 40.0 40.8 43.3 43.9 45.1 46.2 47.3 130/85

140/90 39.2 39.6 40.3 41.2 42.1 44.3 45.1 46.3 47.5 48.7 140/90

150/95 40.1 40.6 41.5 42.4 43.4 45.4 46.2 47.5 48.8 50.0 150/95

120/80 47.1 47.3 47.9 48.5 49.2

Age50

51.7 52.3 53.2 54.2 55.1 120/80

130/85 47.9 48.3 48.9 49.6 50.4 52.7 53.3 54.4 55.4 56.4 130/85

140/90 48.8 49.2 50.0 50.8 51.7 53.7 54.4 55.5 56.6 57.6 140/90

150/95 49.7 50.2 51.0 51.9 52.9 54.6 55.4 56.6 57.7 58.7 150/95

120/80 57.4 57.6 58.1 58.6 59.2

Age60

61.5 62.0 62.7 63.5 64.3 120/80

130/85 58.2 58.5 59.0 59.6 60.3 62.4 62.9 63.7 64.5 65.3 130/85

140/90 59.0 59.3 60.0 60.6 61.4 63.2 63.8 64.6 65.4 66.2 140/90

150/95 59.8 60.2 60.9 61.6 62.4 64.0 64.6 65.5 66.2 66.9 150/95

120/80 68.2 68.4 68.7 69.1 69.5

Age70

71.4 71.7 72.2 72.7 73.2 120/80

130/85 68.8 69.0 69.4 69.9 70.3 72.1 72.4 72.9 73.4 73.9 130/85

140/90 69.5 69.7 70.1 70.6 71.1 72.7 73.0 73.6 74.0 74.4 140/90

150/95 70.1 70.4 70.8 71.3 71.8 73.3 73.6 74.1 74.5 74.9 150/95

Blo

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(mm

Hg

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mm

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Non-smokers Smokers

Cardiovascular Age Tables: Male Patients WITH Diabetes

Total Cholesterol:HDL Ratio Total Cholesterol:HDL Ratio

3 4 5 6 7 3 4 5 6 7

120/80 33.3 33.7 34.3 35.0 35.8

Age30

38.4 39.1 40.1 41.1 42.1 120/80

130/85 34.3 34.7 35.4 36.2 37.1 39.5 40.2 41.3 42.4 43.4 130/85

140/90 35.3 35.7 36.6 37.5 38.4 40.6 41.3 42.5 43.6 44.7 140/90

150/95 36.2 36.8 37.7 38.7 39.7 41.6 42.4 43.6 44.8 45.9 150/95

120/80 42.3 42.7 43.3 44.1 44.8

Age40

47.3 47.9 48.9 49.9 50.8 120/80

130/85 43.3 43.7 44.4 45.3 46.1 48.3 49.0 50.1 51.1 52.0 130/85

140/90 44.2 44.7 45.5 46.4 47.4 49.3 50.0 51.1 52.2 53.1 140/90

150/95 45.1 45.7 46.6 47.6 48.6 50.3 51.0 52.1 53.2 54.2 150/95

120/80 51.8 52.2 52.8 53.4 54.1

Age50

56.3 56.9 57.8 58.6 59.4 120/80

130/85 52.7 53.1 53.8 54.5 55.3 57.3 57.9 58.8 59.6 60.3 130/85

140/90 53.5 54.0 54.8 55.6 56.4 58.2 58.8 59.7 60.5 61.3 140/90

150/95 54.4 54.9 55.8 56.6 57.5 59.0 59.6 60.5 61.4 62.2 150/95

120/80 61.6 61.9 62.4 62.9 63.5

Age60

65.4 65.9 66.5 67.1 67.6 120/80

130/85 62.4 62.7 63.3 63.8 64.4 66.2 66.6 67.2 67.8 68.3 130/85

140/90 63.1 63.5 64.1 64.7 65.4 66.9 67.3 67.9 68.5 69.0 140/90

150/95 63.8 64.2 64.9 65.6 66.2 67.5 67.9 68.5 69.1 69.6 150/95

120/80 71.6 71.8 72.1 72.4 72.8

Age70

74.4 74.6 75.0 75.3 75.6 120/80

130/85 72.1 72.4 72.7 73.1 73.5 74.9 75.1 75.5 75.8 76.1 130/85

140/90 72.7 72.9 73.3 73.7 74.1 75.3 75.5 75.9 76.2 76.5 140/90

150/95 73.2 73.5 73.9 74.3 74.7 75.7 76.0 76.3 76.6 76.9 150/95

Blo

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Pre

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(mm

Hg

)Blo

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Pre

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re (

mm

Hg

)

Non-smokers Smokers

Total Cholesterol:HDL Ratio Total Cholesterol:HDL Ratio

3 4 5 6 7 3 4 5 6 7

120/80 33.3 33.7 34.3 35.0 35.8

Age30

38.4 39.1 40.1 41.1 42.1 120/80

130/85 34.3 34.7 35.4 36.2 37.1 39.5 40.2 41.3 42.4 43.4 130/85

140/90 35.3 35.7 36.6 37.5 38.4 40.6 41.3 42.5 43.6 44.7 140/90

150/95 36.2 36.8 37.7 38.7 39.7 41.6 42.4 43.6 44.8 45.9 150/95

120/80 42.3 42.7 43.3 44.1 44.8

Age40

47.3 47.9 48.9 49.9 50.8 120/80

130/85 43.3 43.7 44.4 45.3 46.1 48.3 49.0 50.1 51.1 52.0 130/85

140/90 44.2 44.7 45.5 46.4 47.4 49.3 50.0 51.1 52.2 53.1 140/90

150/95 45.1 45.7 46.6 47.6 48.6 50.3 51.0 52.1 53.2 54.2 150/95

120/80 51.8 52.2 52.8 53.4 54.1

Age50

56.3 56.9 57.8 58.6 59.4 120/80

130/85 52.7 53.1 53.8 54.5 55.3 57.3 57.9 58.8 59.6 60.3 130/85

140/90 53.5 54.0 54.8 55.6 56.4 58.2 58.8 59.7 60.5 61.3 140/90

150/95 54.4 54.9 55.8 56.6 57.5 59.0 59.6 60.5 61.4 62.2 150/95

120/80 61.6 61.9 62.4 62.9 63.5

Age60

65.4 65.9 66.5 67.1 67.6 120/80

130/85 62.4 62.7 63.3 63.8 64.4 66.2 66.6 67.2 67.8 68.3 130/85

140/90 63.1 63.5 64.1 64.7 65.4 66.9 67.3 67.9 68.5 69.0 140/90

150/95 63.8 64.2 64.9 65.6 66.2 67.5 67.9 68.5 69.1 69.6 150/95

120/80 71.6 71.8 72.1 72.4 72.8

Age70

74.4 74.6 75.0 75.3 75.6 120/80

130/85 72.1 72.4 72.7 73.1 73.5 74.9 75.1 75.5 75.8 76.1 130/85

140/90 72.7 72.9 73.3 73.7 74.1 75.3 75.5 75.9 76.2 76.5 140/90

150/95 73.2 73.5 73.9 74.3 74.7 75.7 76.0 76.3 76.6 76.9 150/95

Blo

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Pre

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(mm

Hg

)Blo

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Pre

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re (

mm

Hg

)

Non-smokers Smokers

Example: 30-year-old male with diabetes who smokes, BP 150/95 mmHg, TC:HDL-C ratio 5

• CV age: 43.6 years

• CV age vs. same profile but without diabetes: + 5 years

• CV age vs. healthy 30-year-old male: + 13.6 years

43.6

Cardiovascular Age Tables: Male Patients WITH Diabetes

Cardiovascular Age Tables: Female Patients WITHOUT Diabetes

Total Cholesterol:HDL Ratio Total Cholesterol:HDL Ratio

3 4 5 6 7 3 4 5 6 7

120/80 28.8 29.0 29.2 29.5 29.9

Age30

32.6 33.1 33.7 34.4 35.2 120/80

130/85 29.5 29.7 30.0 30.4 30.8 33.4 34.0 34.7 35.6 36.6 130/85

140/90 30.2 30.5 30.8 31.3 31.8 34.2 34.9 35.8 36.9 38.0 140/90

150/95 30.9 31.2 31.7 32.2 32.8 35.0 35.9 36.9 38.1 39.4 150/95

120/80 38.1 38.2 38.5 38.8 39.1

Age40

41.8 42.2 42.9 43.6 44.4 120/80

130/85 38.7 39.0 39.2 39.6 40.1 42.5 43.1 43.9 44.8 45.8 130/85

140/90 39.4 39.7 40.0 40.5 41.1 43.3 44.0 45.0 46.0 47.1 140/90

150/95 40.1 40.4 40.9 41.4 42.1 44.1 45.0 46.1 47.3 48.5 150/95

120/80 47.6 47.8 48.0 48.3 48.6

Age50

51.2 51.6 52.2 52.8 53.6 120/80

130/85 48.3 48.5 48.8 49.1 49.5 51.9 52.4 53.1 53.9 54.8 130/85

140/90 48.9 49.2 49.5 50.0 50.5 52.6 53.3 54.1 55.0 56.0 140/90

150/95 49.6 49.9 50.3 50.8 51.4 53.4 54.1 55.1 56.1 57.2 150/95

120/80 57.6 57.7 57.9 58.1 58.4

Age60

60.8 61.1 61.5 62.0 62.6 120/80

130/85 58.2 58.3 58.5 58.8 59.2 61.4 61.8 62.3 62.9 63.6 130/85

140/90 58.8 58.9 59.2 59.6 60.0 62.0 62.5 63.1 63.8 64.5 140/90

150/95 59.3 59.6 59.9 60.3 60.8 62.7 63.3 63.9 64.7 65.5 150/95

120/80 67.9 67.9 68.1 68.2 68.4

Age70

70.5 70.7 71.0 71.3 71.6 120/80

130/85 68.4 68.5 68.6 68.8 69.0 71.0 71.3 71.6 72.0 72.3 130/85

140/90 68.9 69.0 69.2 69.4 69.6 71.5 71.8 72.2 72.6 73.0 140/90

150/95 69.4 69.5 69.7 70.0 70.3 72.1 72.4 72.8 73.2 73.7 150/95

Blo

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(mm

Hg

)Blo

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Pre

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re (

mm

Hg

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Non-smokers Smokers

Cardiovascular Age Tables: Female Patients WITH Diabetes

Total Cholesterol:HDL Ratio Total Cholesterol:HDL Ratio

3 4 5 6 7 3 4 5 6 7

120/80 38.2 38.7 39.2 39.9 40.6

Age30

42.5 43.5 44.8 46.1 47.4 120/80

130/85 39.0 39.5 40.2 41.0 41.9 43.5 44.7 46.1 47.6 49.1 130/85

140/90 39.8 40.4 41.2 42.2 43.2 44.5 45.9 47.5 49.1 50.7 140/90

150/95 40.6 41.3 42.3 43.4 44.5 45.5 47.1 48.8 50.5 52.0 150/95

120/80 47.2 47.6 48.2 48.9 49.6

Age40

51.3 52.4 53.6 54.8 56.2 120/80

130/85 47.9 48.5 49.2 50.0 50.9 52.3 53.5 54.9 56.3 57.7 130/85

140/90 48.7 49.4 50.2 51.1 52.1 53.2 54.6 56.2 57.7 59.3 140/90

150/95 49.5 50.2 51.2 52.3 53.4 54.2 55.8 57.5 59.1 60.5 150/95

120/80 56.3 56.7 57.2 57.8 58.4

Age50

60.0 60.9 61.9 62.9 64.0 120/80

130/85 57.0 57.4 58.1 58.8 59.5 60.8 61.9 63.0 64.1 65.3 130/85

140/90 57.6 58.2 59.0 59.8 60.7 61.7 62.8 64.1 65.3 66.5 140/90

150/95 58.4 59.0 59.9 60.8 61.8 62.5 63.8 65.1 66.4 67.5 150/95

120/80 65.3 65.5 66.0 66.4 66.9

Age60

68.4 69.0 69.6 70.3 71.0 120/80

130/85 65.9 66.2 66.7 67.2 67.8 69.0 69.7 70.4 71.1 71.8 130/85

140/90 66.5 66.9 67.4 68.0 68.6 69.7 70.4 71.2 71.9 72.6 140/90

150/95 67.1 67.6 68.1 68.8 69.4 70.3 71.1 71.9 72.6 73.3 150/95

120/80 74.3 74.4 74.6 74.9 75.2

Age70

76.5 76.8 77.1 77.5 77.8 120/80

130/85 74.7 74.9 75.2 75.4 75.7 76.9 77.3 77.6 78.0 78.3 130/85

140/90 75.1 75.4 75.7 76.0 76.3 77.4 77.7 78.1 78.4 78.7 140/90

150/95 75.6 75.8 76.1 76.5 76.8 77.8 78.1 78.5 78.8 79.1 150/95

Blo

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(mm

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mm

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Non-smokers Smokers

Ongoing CV Outcome Trials: DPP-4 Inhibitors

Adapted from:1. Golden SH. Am J Cardiol 2011; 108(Suppl):59B-67B. 2. Fonseca V. Am J Cardiol 2011; 108(Supp):52B–58B. 3. www.clinicaltrials.gov

Trial Therapies # Population Primary endpoint End Date

EXAMINE Alogliptin/Placebo

5400 ACS 15-90 days before

Non-inferiority: time to occurrence of MACE

PUBLISHED

SAVOR Saxagliptin/Placebo

16,500 CVD or ≥ 2 RF Superiority efficacy, non-inferiority safety: composite CV death, NF MI, NF stroke

PUBLISHED

CARMELINA Linagliptin/Placebo

8,300 High risk of CV events

Time to first occurrence of composite CV outcome

Jan 2018

CAROLINA Linagliptin/ Glimepiride

6000 CVD or ≥ 2 RF Non-inferiority: time to first occurrence of any component of MACE composite outcome

Sept 2018

TECOS Sitagliptin/ Placebo

14,000 Established CVD Non-inferiority: time to first occurrence of composite CV outcome

Dec 2014

Ongoing CV Outcome Trials: GLP-1 Agonists

Adapted from:1. Golden SH. Am J Cardiol 2011; 108(Suppl):59B-67B. 2. Fonseca V. Am J Cardiol 2011; 108(Supp):52B–58B. 3. www.clinicaltrials.gov

Trial Therapies # Population Primary endpoint End Date

ELIXA Lixisenatide/ Placebo

6000 ACS leading to hosp ≤ 180 days before

Non-inferiority: CV death, NF MI, NF stroke, UA hospitalization.

Jan 2015

EXSCEL Exenatide LAR/ Placebo

9500 T2DM, A1C of 7.0-10.0%

Non-inferiority: Time to primary composite CV endpoint

Mar 2017

LEADER Liraglutide/ Placebo

8754 CVD, PAD, CKD, CHF or RF if age> 60 years

Superiority: Time to composite CV death, NF MI, NF stroke

Jan 2016

REWIND Dulaglutide/ Placebo

9622 CVD or ≥ 2 RF if age ≥ 60 years

Superiority: Time to composite CV death, NF MI, NF stroke

Apr 2019

SUSTAIN 6 Semaglutide/Placebo

3,260 T2DM, CVD or subclinical evidence of CVD if age ≥ 60 years

Time to first occurrence of MACE

Jan 2016