tues 10 change of heart en v12 jan 21 cases 1 and 2 acc rockies of heart... · event...

Content Development Committee

Family Physicians:

Maureen Clement, MD, CCFPClinical Assistant Professor, University of British ColumbiaMedical Director, Vernon Diabetes Education CentreVernon (BC)

Pierre Filteau, MDFamily PhysicianFounding Member, Master Clinician Alliance Inc.Saint-Marc-des-Carrieres (QC)

Jeff Habert, MD, CCFP, FCFPAssistant Professor, Department of Family and Community Medicine, University of TorontoFounding Member, Master Clinician Alliance Inc.Toronto (ON)

2

Cardiologists:

Shaun Goodman, MD, MSc, FRCPC, FACC, FESC, FAHA, FCCS (Chair)Associate Head, Division of Cardiology, St. Michael’s HospitalProfessor, Department of Medicine, University of TorontoToronto (ON)

Richard Choi, MD, FRCPC (Cardiology)Staff Cardiologist, St. Joseph's Health Centre Lecturer, Department of Medicine, University of TorontoToronto (ON)

Disclosure

RELATIONSHIPS WITH COMMERCIAL INTERESTSGrants/Research Support:

Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-‐Myers Squibb, FerringPharmaceuticals, GlaxoSmithKline, Lilly, Luitpold Pharmaceuticals, Matrizyme, Merck, Novartis, Pfizer, Sanofi, Tenax Therapeutics

Speakers Bureau/Honoraria:

Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-‐Myers Squibb, FerringPharmaceuticals, Lilly, Merck, Novartis, Pfizer, Sanofi

Consulting Fees: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-‐Myers Squibb, Fenix Group International, Ferring Pharmaceuticals, Lilly, Merck, Pfizer, Sanofi

SPEAKER’S NAME and Credentials

Shaun Goodman, MD

3

Case Vignette 1: Sarah

4

Case Vignette 1: Sarah

• 56-year-old woman with type 2 diabetes who is new to your practice• She has come in to have her diabetes medications renewed• She is worried about her heart as her brother just had a heart attack, and wonders if better control of her “blood sugars” will reduce her chance of having another heart attack

5

History:• Medical:

• Diabetes for 13 years• Hypertension, obesity• MI 3 years ago

• Lifestyle: non-smoker;; sedentary job but walks her dog for 30 min per day

Physical exam:• BMI 32 kg/m2

• BP 132/78 mm/Hg

Laboratory:• A1C 8.1 %• eGFR 80 mL/min• LDL-C 1.8 mmol/L• ACR 5.0 mg/mmol

Medications:• ASA • Beta-blocker• ACEi at cardio-protective dose • Statin• Metformin/DPP-4i combination full dose

• Gliclazide full dose

MI: myocardial infarction;; ACEi: angiotensin-converting-enzyme inhibitor;; BMI: body mass index;; BP: blood pressure;; A1C: glycated hemoglobin;; eGFR: estimated glomerular filtration rate;; LDL-C: low-density lipoprotein cholesterol;; ACR: albumin to creatinine ratio;; ASA: acetylsalicylic acid;; DPP4i: dipeptidyl peptidase 4 inhibitor

Questions

1. Because she has diabetes, Sarah is at increased risk of another CV event. True or False?

2. Reducing Sarah’s A1C to <7% will reduce her risk of death from CVD. True or False?

3. Reducing Sarah’s A1C to <7% will reduce her risk of MI. True or False?

4. What A1C target would you choose for Sarah?

6

guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.caCopyright © 2013 Canadian Diabetes Association

20-30 31-40 41-45 46-50 51-55 56-60 61-65 66-70 71-75 76-80 81-85

Absolute Risk of MI is Higher in Patients with Diabetes

Age group

0.5

1.0

1.5

2.0

2.5

3.0

0

No. events per 100 person-years

Booth GL, et al. Lancet 2006;;368:29-36.

MI = myocardial infarction

Database 1994-2000

No diabetes (n=9,018,082) Men

Women

Diabetes (n=379,003)Men

Women

7

Event Risk Ratio (95% CI) P Value

Total mortality 0.98 (0.91–1.20) 0.69

CV mortality 1.00 (0.87–1.14) 0.99

MACE 0.92 (0.85–1.00) 0.04

MI 0.90 (0.82–0.98) 0.02

Stroke 0.94 (0.84–1.06) 0.33

CHF 1.19 (0.96–1.48) 0.11

Fang HJ, et al. Int J Cardiol. 2016;;218:50-58.

ACCORD, ADDITION-Europe, ADVANCE, Steno-2, TECOS, PROACTIVE, RECORD, UGDP, VACSDM, VADTT2DM: type 2 diabetes mellitus;; CV: cardiovascular;; RCTs: randomized controlled trials;; MACE: major adverse cardiovascular events;; MI: myocardial infarction;; CHF: congestive heart failure;; ACCORD: Action to Control Cardiovascular Risk in Diabetes;; ADDITION: Anglo-Danish-Dutch Study in General Practice of Intensive Treatment and Complication Prevention in Type 2 Diabetic Patients Identified by Screening;; ADVANCE: Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation;; TECOS: Trial Evaluating Cardiovascular Outcomes with Sitagliptin;; PROACTIVE: Prospective Pioglitazone Clinical Trial in Macrovascular Events;; RECORD: Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes;; UGDP: University Group Diabetes Program;; VADT: Veterans Affairs Diabetes Trial;; VASCDM: Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus

8

Effects of Intensive Glucose Lowering in T2DM on CV Outcomes: A Meta-analysis of Data from 58,160 Patients in 13 RCTs


Individualizing A1C Targets 2013

Consider 7.1-8.5% if:

9

Question

Using selected antihyperglycemic agents (AHA) can reduce Sarah’s risk of death from CVD. True or False?

10

Start metformin immediately

Consider initial combination with another antihyperglycemic agent

Start lifestyle intervention (nutrition therapy and physical activity) +/- Metformin

A1C <8.5% Symptomatic hyperglycemia with metabolic decompensationA1C ³8.5%

Initiate insulin +/-

metformin

If not at glycemic target (2-3 mos)

Start / Increase metformin

If not at glycemic targets

LIFESTYLE

Add another agent best suited to the individual by prioritizing patient characteristics:

Degree of hyperglycemiaRisk of hypoglycemiaOverweight or obesityCardiovascular disease or multiple risk factorsComorbidities (renal, CHF, hepatic)Preferences & access to treatment

See next page…

AT DIAGNOSIS OF TYPE 2 DIABETES

Consider relative A1C loweringRare hypoglycemiaWeight loss or weight neutralEffect on cardiovascular outcomeSee therapeutic considerations, consider eGFRSee cost column;; consider access

PATIENT CHARACTERISTIC CHOICE OF AGENTPRIORITY:Clinical Cardiovascular Disease

Antihyperglycemic agent with demonstrated CV outcome benefit (empagliflozin, liraglutide)

11/2016CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2016;;40:484–486.


Recommendation 4

4. In adults with type 2 diabetes with clinical cardiovascular disease in whom glycemic targets are not met, an antihyperglycemic agent with demonstrated cardiovascular outcome benefit should be added to reduce the risk of major cardiovascular events (Grade 1, Level 1A for empagliflozin ;; Grade 1, Level 1A for liraglutide if age ≥50 years;; Grade D, Consensus for liraglutide if age <50 years).

11/2016

12

CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2016;;40:484–486.

EMPA-REG OUTCOMEPrimary Outcome: CV Death, Non-fatal MI or Non-fatal StrokeEMPA-REG OUTCOME included adult patients (>18 years) with type 2 diabetes and established CVD who were receiving standard of care therapy for diabetes

0

5

10

15

20

0 6 12 18 24 30 36 42 48

Patients with event (%)

Months

Placebo

Empagliflozin

No. of patientsEmpagliflozinPlacebo

46872333

45802256

44552194

43282112

38511875

28211380

23591161

1534741

370166

Empagliflozin (pooled)HR 0.86

(95.02% CI 0.74, 0.99)p=0.04* for superiority

p<0.001 for noninferiority

Empagliflozin 25 mgHR 0.86 (95% CI 0.73, 1.02), p=0.09

Empagliflozin 10 mgHR 0.85 (95% CI 0.72, 1.01), p=0.07

13Cumulative incidence function. MACE: major adverse cardiovascular event;; HR: hazard ratio;; MI: myocardial infarction;; SGLT2: sodium glucose cotransporter 2*Two-sided tests for superiority were conducted (statistical significance was indicated if p≤0.0498)Note: Empagliflozin is an SGLT2 inhibitor. Data from: Zinman B, et al. N Engl J Med. 2015;; 373:2117-2128.

Patients with event/analyzed Hazard ratio (HR)(95% CI)

Empagliflozin Placebo HR (95% CI) p-value

3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.04

CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.001

Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.22

Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.16

EMPA-REG OUTCOME:CV Death, Non-fatal MI and Non-fatal Stroke

Favours empagliflozin Favours placeboCox regression analysis.* 95.02% CI;; for superiority

0.25 0.50 1.00 2.00

Data from: Zinman B, et al. N Engl J Med. 2015;; 373:2117-2128.

Note: Empagliflozin is an SGLT2 inhibitor

14MACE: major adverse cardiovascular event;; HR: hazard ratio;; CV: cardiovascular;; MI: myocardial infarction;; SGLT2: sodium glucose cotransporter 2

0

5

10

15

20

0 6 12 18 24 30 36 42 48 54

The primary composite outcome in the time-to-event analysis was the first occurrence of death from CV causes, non-fatal MI, or non-fatal stroke. The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the HRs with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval;; CV: cardiovascular;; CKD: chronic kidney disease;; HR: hazard ratio;; MI: myocardial infarction;; GLP-1RA: glucagon-like peptide-1 receptor agonistData from: Marso S, et al. N Engl J Med. 2016;; 375:311-322.

Patients with an event (%)

4668 4593 4496 4400 4280 4172 4072 3982 1562 4244672 4588 4473 4352 4237 4123 4010 3914 1543 407

LiraglutidePlacebo

Patients at risk Time from randomization (months)

HR 0.8795% CI (0.78 – 0.97)p=0.01 for superiority

p<0.001 for non-inferiority

LEADER included adults with type 2 diabetes aged ≥50 years with established CVD or CKD, or aged ≥60 years with an additional CV risk factor, who were receiving standard of care therapy for diabetes

LEADER: Primary Endpoint: CV Death, Non-fatal MI, or Non-fatal Stroke

15

Placebo

Liraglutide

Patients with event/analysed Hazard ratio (HR)(95% CI)

Liraglutide Placebo HR (95% CI) p-value

3-point MACE 608/4668 694/4672 0.87 (0.78–0.97) 0.01

CV death 219/4668 278/4672 0.78 (0.66–0.93) 0.007

Non-fatal MI 281/4668 317/4672 0.88 (0.75–1.03) 0.11

Non-fatal stroke 159/4668 177/4672 0.89 (0.72–1.11) 0.30

LEADER:CV Death, Non-fatal MI and Non-fatal Stroke

CV: cardiovascular;; MACE: major adverse cardiovascular event;; MI: myocardial infarction;; GLP-1RA: glucagon-like peptide-1 receptor agonist

Favours Liraglutide Favours Placebo

1.501.000.50

Data from: Marso S, et al. N Engl J Med. 2016;;375:311-322. 16

CANVAS Program: Primary Outcome: CV Death, Non-fatal MI or Non-fatal Stroke

17

No. of patientsPlaceboCanagliflozin

Years since randomization4347 4153 2942 1240 1187 1120 7895795 5566 4343 2555 2460 2363 1661

Data from: Neal B, et al. N Engl J Med. 2017;;377:644-57.

CANVAS included patients with type 2 diabetes aged >30 years with a history of symptomatic atherosclerotic CVD, or >50 years with >2 risk factors for CVD, who were receiving standard of care therapy for diabetes

Note: Canagliflozin is an SGLT2 inhibitor;; it is not currently indicated for cardiovascular protection in Canada

20

0

12

2

16

8

Patients with an event (%)

4

6

10

14

18

0 1 2 6543

Placebo

Canagliflozin

HR 0.86 (95% CI 0.75–0.97)p=0.0158 for superiorityp<0.0001 for non-inferiority

Intent-to-treat analysis

CANVAS Program: CV Death, Non-fatal MI and Non-fatal Stroke

Intent-to-treat analysis


Note: Canagliflozin is an SGLT2 inhibitor;; it is not currently indicated for cardiovascular protection in Canada18

Hazard ratio (95% CI)

Primary CV outcome 0.86 (0.75–0.97)CV death 0.87 (0.72–1.06)

Non-fatal MI 0.85 (0.69–1.05)

Non-fatal stroke 0.90 (0.71–1.15)

0.5 1.0 2.0

FavoursCanagliflozin

FavoursPlacebo

Choosing Between Empagliflozin and Liraglutide (as per Diabetes Canada’s Recommendation)* Depends on Patient/Agent Characteristics

Discuss with Sarah:Empagliflozin Liraglutide

Relative A1C lowering ¯¯ to ¯¯¯ ¯¯ to ¯¯¯

Remember to adjust gliclazide as needed for hypoglycemia Weight loss ¯¯ ¯¯

Hypoglycemia Rare RareSide effects Genital infections, UTI, hypotension, dose-related

changes in LDL-C, caution with renal dysfunction and loop diuretics

Gastrointestinal side effects

Route of administration Oral InjectableDosing Start at 10 mg OD;; increase to 25 mg OD if needed for

glycemic controlStart at 0.6 mg OD and then titrate up to

1.8 mg OD (as per LEADER trial)

Cost $$$ $$$$Reduction in MACE ↓14% ↓13%Reduction in CV death ↓38% ↓22%NNT 3y (CV mortality) 46 to prevent 1 CV death 104 to prevent 1 CV death

A1C: glycated hemoglobin;; UTI: urinary tract infection;; LDL-C: low-density lipoprotein cholesterol;; NNT: number needed to treat;; OD: once daily;; MACE: major adverse cardiac event *The Diabetes Canada recommendation to add empagliflozin or liraglutide in patients with diabetes and clinical CVD was released before the results of the CANVAS Program with canagliflozin became available.CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2016;;40:484–486. Zinman B, et al. N Engl J Med. 2015;; 373:2117-2128. Marso S, et al. N Engl J Med. 2016;;375:311-322.

19

Question

What if Sarah’s A1C is close to target (i.e., 7.2%) with her current antihyperglycemic regimen (i.e., metformin/DPP-4i combination and gliclazide), but she is experiencing episodes of hypoglycemia…

What, if any, changes would you make to her antihyperglycemic regimen?

20

ADVANCE: Severe Hypoglycemia Associated with Adverse Clinical Endpoints and Death

Numbers above sets of bars are HR (95% CI). aAdjusted for multiple baseline covariates. bPrimary endpoints: major macrovascular event = CV death, non-fatal myocardial infarction, or non-fatal stroke;; major microvascular event = new or worsening nephropathy or retinopathy;; ADVANCE: Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation;; HR: hazard ratio;; CV: cardiovascularData from: Zoungas S, et al. N Engl J Med. 2010;;363:1410–8.

25

0

15

5

20

10

Severe hypoglycemia (n=231)

No severe hypoglycemia (n=10,909)3.53 (2.41–5.17)a

Major macrovascular

eventb

15.9

10.2

2.19(1.40–3.45)a

Major microvascular

eventb

11.510.1

3.27(2.29–4.65)a

Death from any cause

19.5

9.0

3.79(2.36–6.08)a

CV disease

9.5

4.8

2.80(1.64–4.79)a

Non-CV disease

10.0

4.3

Patients with ≥ 1

hypoglycemic events (%)

21

Question

Reminder: Sara is currently prescribed ASA, a beta-blocker, an ACEi, a statin, a metformin/DPP-4i combination and gliclazide.

What if Sarah was also started on empagliflozin or liraglutide and then calls your office to tell you that she has a “really bad stomach flu” with vomiting and diarrhea…

What does Sarah need to know?

ACEi: angiotensin-converting-enzyme inhibitor;; ASA: acetylsalicylic acid;; DPP4i: dipeptidyl peptidase 4 inhibitor 22

Counsel all Patients About

Sick Day Medication

List

2015

Application to our Case Vignette: Treatment Plan(s)*

*Note that pathway options are based on Diabetes Canada’s most recent interim guideline update (CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes 2016;;40:484–486)A1C: glycated hemoglobin;; BP: blood pressure;; CVD: cardiovascular disease;; LDL: low-density lipoprotein;; ACEi: angiotensin-converting enzyme inhibitor;; OD: once daily;; SC: subcutaneously;; GI: gastrointestinal 24

Pathway:• Based on patient preference for oral AHA

à Empagliflozin 10 mg OD

• Counselling:• Possible weight loss• Possible hypoglycemia and need to titrate gliclazide• Possible genital mycotic infections • No need to adjust any of the other medications proactively

Pathway:• Based on preference for AHA that leads to possibility of increased satiety, no contraindications (pancreatitis) and acceptance of injectable:

à Liraglutide 0.6 mg SC daily for 1 week then titrated to 1.2 mg SC daily, as tolerated, and then 1.8 mg SC daily as tolerated

• Counselling:• Possible weight loss• Possible hypoglycemia and need to titrate gliclazide• Possible GI side effects• How to inject therapy

1. Ensure ABCDEs of CV protection:A: A1C – not at target B: BP at target C: LDL-cholesterol at target D: Cardioprotective drugs

(statin/ACEi) E: Exercise/diet S: Non-smoker

2. Twin goals for selection of antihyperglycemic agent (AHA)• Glycemic improvement • Reduce CV outcomes in a patient with clinical CVD

Case Vignette 2: Jake

25

Case Vignette 2: Jake

• 63-year-old metal recycling business owner with type 2 diabetes and peripheral arterial disease (PAD)• Jake is in to see you for a routine diabetes follow-up visit• He apologizes for not seeing you in 8 months as he and his wife spent the winter in Hawaii• He does recall that you discussed “changing meds” before Hawaii (A1C was high), but he declined • He feels well with no angina, dyspnea or symptoms of intermittent claudication

26

Case Vignette 2: Jake (continued)

PAD: peripheral arterial disease;; ACEi: angiotensin-converting-enzyme inhibitor;; BMI: body mass index;; BP: blood pressure;; A1C: glycated hemoglobin;; eGFR: estimated glomerular filtration rate;; LDL-C: low-density lipoprotein cholesterol;; ACR: albumin to creatinine ratio;; ASA: acetylsalicylic acid

27

History:

• Type 2 diabetes x 5 years

• PAD with percutaneous transluminal angioplasty (PTA) and stent of superficial femoral artery 3 years ago

• Hypertension

• 45 pack year smoking history: quit after the PTA

• Minimal exercise, but trying to walk more

Physical Exam:

• BP 128/78 mm Hg

• BMI 28 kg/m2

• Rest of exam unremarkable

Labs:

• A1C 7.8% (was 7.5% 8 months ago)

• LDL-C 1.79 mmol/L

• ACR 4.8 mg/mmol

• eGFR 64 mL/min/1.73 m2

Current Medications:

• Metformin 1 g bid

• Linagliptin 5 mg daily

• Perindopril 8 mg daily

• Rosuvastatin 20 mg daily

• ASA 81 mg daily

Question

Jake has worked hard all his life and now wants to enjoy his retirement, so he wants to know what he can do to help himself.

What will you tell Jake about his diabetes and CV disease?

28

Patients with Diabetes are More Likely to be Hospitalized for Many Conditions

Prevalence rate ratios† of complications among hospitalized individuals‡ aged >20 years, by diabetes status, Canada, 2008/09

† Rate ratios based on rates age-standardized to the 1991 Canadian population.‡ A person with diabetes hospitalized with more than one complication was counted once in each category, except for cases of acute myocardial infarction, where regardless of multiple counts in the acute myocardial infarction category, the individual was counted only once under the broader ischemic heart disease category.Source: Public Health Agency of Canada (August 2011);; using 2008/09 data from the Canadian Chronic Disease Surveillance System (Public Health Agency of Canada). 29

22

0

14

2

18

8Rate ratios

(with diabetes: without diabetes)

Cerebrovasculardisease (stroke)

Acute myocardialinfarction

(heart attack)

Ischemic heartdisease

Heartfailure

Chronic kidneydisease

End-stage renaldisease

Lower limbamputations

4

6

10

12

16

20

COMPLICATION

Clinical Approach to Jake

• Jake has CVD and diabetes and is at high risk of other CV events (e.g., stroke, MI)

• Review the ABCDs for vascular protection: A: A1C – his A1C is above target B: BP – his BP is well controlled C: Cholesterol – his cholesterol is at target D: Drugs to protect the heart – he is on an ACEi, statin and ASA

• Priorities will be getting Jake to target A1C to reduce risk of microvascular events, particularly given that he has evidence of early kidney disease, and using an antihyperglycemic agent with demonstrated CV benefits

30CVD: cardiovascular disease;; ACEi: angiotensin-converting-enzyme inhibitor;; BP: blood pressure;; A1C: glycated hemoglobin;; ASA: acetylsalicylic acid

Question

What would you do about Jake’s diabetes treatment?

1. Add canagliflozin 100 mg daily 2. Add dapagliflozin 5 mg daily 3. Add empagliflozin 10 mg 4. Add gliclazide MR 30-60 mg daily 5. Add dulaglutide 0.75 mg sc weekly 6. Add liraglutide 0.6 mg daily (titrating up to 1.8 mg)

31


PRIORITY:Clinical Cardiovascular Disease

11/2016

Add another agent best suited to the individual by prioritizing patient characteristics:

Degree of hyperglycemiaRisk of hypoglycemiaOverweight or obesityCV disease or multiple risk factorsComorbidities (renal, CHF, hepatic)Preferences & access to treatment

Consider relative A1C loweringRare hypoglycemiaWeight loss or weight neutralEffect on cardiovascular outcomeSee therapeutic considerations;; consider eGFR See cost column;; consider access

PATIENT CHARACTERISTIC CHOICE OF AGENTAntihyperglycemic agent withdemonstrated CV outcome benefit(empagliflozin, liraglutide)

PRIORITYClinical cardiovascular disease

Question

Jake has PAD with prior angioplasty/stenting of a superficial femoral artery 3 years ago.

Would this PAD history influence your choice of which antihyperglycemic/vascular protective agent he should receive next?

33

Amputations in CANVAS

34Data from: Neal B, et al. N Engl J Med. 2017;;377:644-57.

Event rate per 1000 patient-years Hazard ratio

(95% CI)Canagliflozin Placebo All amputations (n=187) 6.3 3.4 1.97 (1.41–2.75)Minor amputation (71%) 4.5 2.4 1.94 (1.31–2.88)Toe 3.4 2.2Transmetatarsal 1.0 0.3

Major amputation (29%) 1.8 0.9 2.03 (1.08–3.82)Ankle 0.04 0.07Below-knee 1.2 0.6Above-knee 0.6 0.2

0.25 0.5 1.0 2.0 4.0 8.0Favours

CanagliflozinFavoursPlacebo

CANVAS:Relationship to PAD History and Amputations


Effects of canagliflozin vs. placebo on atraumatic lower limb amputation in key subgroups in the CANVAS program

• 136 of 5795 subjects in the canagliflozin group and 102 of 4347 in the placebo group had a history of amputation• 1176 of 5795 subjects in the canagliflozin group and 937 of 4347 in the placebo group had a history of PAD

35

Canagliflozin per 1000

patient-years

Placebo per 1000

patient-years

Hazard ratio (95% confidence

interval)History of amputation Yes 96.30 59.16 2.15 (1.11–4.19)No 4.68 2.48 1.88 (1.27–2.78)

History of peripheral vascular diseaseYes 12.09 8.16 1.39 (0.80–2.40)No 5.20 2.41 2.34 (1.53–3.58)

The primary prevention cohort accounted for fewer primary MACE events and while subgroup analysis did not show heterogeneity, no conclusion can be made regarding the CV benefit in this group (HR 0.98;; 95% CI 0.74-1.30)

Canagliflozin in addition to standard of care reduced CV risk in adults with T2D and age ≥30 years with established CVD (66%) or age ≥50 yrs with ≥2 CV risk factors (34%)

33%

↓HFhospitalization(NNT 5y = 63)

14%

↓ CV death, non-fatal MI,non-fatal stroke

(P=0.02;;NNT 5y = 44)

40%

↓ eGFR, dialysis, renal death (NNT 5y = 58)

97%

↑ Lower extremity amputations(P<0.001;;

NNH 5y = 69)

26%

Fractures(P=0.02;;

NNH 5y = 58)

Canagliflozin is not currently indicated for cardiovascular or renal protection in Canada

36

CANVAS Program: Summary

CVD: cardiovascular disease;; HF: heart failure;; MI: myocardial infarction;; NNT: number needed to treat;; NNH: number needed to harm;;T2D: type 2 diabetesNeal B, et al. N Engl J Med. 2017;;377:644-57 ;; ADA Annual Meeting 2017. Slide courtesy of Dr. R. Goldenberg.

No increased risk of amputations was observed in EMPA-REG OUTCOME or LEADER

EMPA-REG OUTCOME: Summary

Empagliflozin in addition to standard of care reduced CV risk and improved overall survival in adults with T2D with established CVD

The overall safety profile of empagliflozin was consistent with previous clinical trials and current label information

Empagliflozin is not currently indicated for renal protection in CanadaCVD: cardiovascular disease;; MI: myocardial infarction;; NNT: number needed to treat;; T2D: type 2 diabetes;; HF: heart failure 37

↓ CV death(NNT 3y = 46)

38%

↓ All-cause mortality

(NNT 3y = 39)

32%

↓ HF hospitalizationsNNT 3y = 72

35% 39%

↓ New or worsening nephropathy(NNT 3y = 17)

14%

↓ CV death, non-fatal MI,

non-fatal stroke(NNT 3y = 63)

Zinman B, et al. N Engl J Med. 2015;;373:2117-28. Wanner C, et al . N Engl J Med. 2016;;375:323-334. Slide courtesy of Dr. R. Goldenberg.

LEADER: SummaryLiraglutide in addition to standard of care reduced CV risk and improved overall survival in adults with T2D and age ≥50 yrs with established CVD or

CKD or age ≥60 yrs with an additional risk factor

↓ CV death(NNT 3y = 104)

22%

↓ All-cause mortality

(NNT 3y = 98)

15%

↓ Fatal and non-fatal MI(NNT 3y = 127)

14%

The overall safety profile of liraglutide was consistent with previous clinical trials and current label information

22%

↓ New or worsening nephropathy(NNT 3y = 85)

13%

↓ CV death, non-fatal MI,

non-fatal stroke(NNT 3y = 66)

Marso S, et al. N Engl J Med. 2016;;375:311-322. Slide courtesy of Dr. R. Goldenberg.

LEADER: Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results – A Long Term Evaluation;; CVD: cardiovascular disease;; CKD: chronic kidney disease;; T2D: type 2 diabetes;; MI: myocardial infarction;; NNT: number needed to treatLiraglutide is not currently indicated for renal protection in Canada

38

Questions

What if Jake’s eGFR was 54 rather than 64 mL/min/1.73 m2…

What would you do about Jake’s diabetes treatment?• Add canagliflozin • Add dapagliflozin • Add empagliflozin • Add gliclazide • Add dulaglutide • Add liraglutide• Add another antihyperglycemic agent not listed above

What renal outcomes have been noted in LEADER, EMPA-REG and CANVAS? 39

SGLT2 inhibitors

GLP-1R agonists

sulfonylurea

Antihyperglycemic Agents and Renal Function

Contraindicated SafeCaution and/or reduce dose No dose adjustment but close monitoring of renal function Not recommended

eGFR (mL/min/1.73 m2): <15 15–29 30–59 60–89 ≥ 90CKD Stage: 5 4 3 2 1

Acarbose Not recommended 25

Dapagliflozin 60Empagliflozin

Thiazolidinediones 30

Canagliflozin 25 60*100 mg45

45 60*

Metformin 30 60

15Linagliptin

Sitagliptin 5030 50 mg25 mg

Saxagliptin 5015 2.5 mg

Alogliptin Not recommended 506.25 mg 12.5 mg30

Exenatide (BID/QW) 30 50Liraglutide

Lixisenatide†

15

Repaglinide

Gliclazide/Glimepiride 15 30Glyburide 30 50Insulin secretagogues

SGLT2 inhibitors

GLP-1R agonists

Alpha-glucosidase Inh.

Biguanide

DPP-4 inhibitors

Dulaglutide 50

40* = do not initiate if eGFR <60 ml/min †Approved but not yet available in CanadaAdapted from: Product Monographs as of December 2017;; Harper W, et al. Can J Diabetes. 2015;;39:250-52.

30 50

Differences in Renal Outcomes of Patients Treated in EMPA-REG OUTCOME, LEADER and CANVAS*

-50-45-40-35-30-25-20-15-10-50

EMPA-REG OUTCOME LEADER CANVAS

P<0.001

-39%

P<0.001

P=0.004

P=0.43

-26% -27%**(95% CI: -21% to -33%)

-38%

-44%

-11%

-46%

-22%

CAUTION: Cross-trial comparisons cannot be made due to differences in study designs, trial durations and patient populations.

Wanner C, et al . N Engl J Med. 2016;;375:323-334. Marso S, et al. N Engl J Med. 2016;;375:311-322. Neal B, et al. N Engl J Med. 2017;;377:644-57. Mann JFE, et al. N Engl J Med. 2017;;377:839-48.

*Empagliflozin, canagliflozin and liraglutide are not currently indicated for renal protection.**Exploratory outcome 41

New or worsening nephropathy

Progression to macroalbuminuraor progression of albuminuria

Doubling of serum creatinine

Doubling of serum creatinine, initiation of replacement therapy or death due to renal disease

40% reduction in eGFR, renal replacement therapy,

or renal deathEMPA-REG -39% -38% -44% -46% Not reportedLEADER -22% -26% -11% (NS) Not reported Not reportedCANVAS Not reported -27%** Not reported Not reported -40%**

-40%**(95% CI:

-23% to -53%)

P=0.003

P<0.001 P<0.001

Application to our Case Vignette: Treatment Plan(s)*

*Note that pathway options are based on Diabetes Canada’s most recent interim guideline update (CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2016;;40:484–486)42

Pathway:• Patient has private insurance plan• Motivated to prevent further CV risk • Add empagliflozin or liraglutide† as per Diabetes Canada guidelines

• Avoid canagliflozin due to history of PAD• All other meds adequate for CV protection

Pathway: low eGFR• Consider liraglutide† for CV protection to follow Diabetes Canada guidelines as eGFR <60 mL/min

• Empagliflozin and canagliflozin should not be initiatedin patients with an eGFR <60 mL/min• For patients already on empagliflozin, if eGFR falls between 45-60 mL/min, no dose adjustment but close monitoring of renal function is required

• For patients already on canagliflozin, if eGFR falls between 45-60 mL/min, the dose should be reduced to 100 mg daily

• Avoid canagliflozin due to history of PAD

• Reduce CV outcomes

• Improve glycemic control

• Consider implications with PAD

• Consider other factors:

§ Comfort with injectables

§ Coverage

§ Interaction with current meds

§ Patient/physician preference

†NOTE: Jake should be taken off DPP-‐4 inhibitor therapy (linagliptin) if adding a GLP-‐1RA (liraglutide).

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