Update on CVOTs:Is it time for a new approach?

Alice YY Cheng, MD, FRCPC

@AliceYYCheng

1

Learning ObjectivesUpon completion of this program, participants will be better able to:

1. Summarize the key findings from the major cardiovascular outcome trials in diabetes

2. Differentiate the patient populations for whom there are strong evidence to support certain antihyperglycemic therapies

3. Describe the similarities and differences between international consensus reports / guidelines regarding type 2 diabetes management and cardiorenal protection

2

3

GLP1 receptor agonist

SGLT2 inhibitors

For Patients with Cardiovascular Disease

GLP1: glucagon-like peptide-1; SGLT2: sodium-glucose linked transporter-2 4

GLP1 RA CVOTs in Diabetes Demonstrating Superiority

*Includes patients with chronic kidney disease; †p value for superiority; CI: confidence interval; CV: cardiovascular; CVOT: cardiovascular outcome trial; GLP1: glucagon-like peptide-1; hHF: hospitalization for heart failure; HR: hazard ratio; MACE: Major adverse cardiovascular events (MI, stroke, CV death); MI: myocardial infarction; NS: not significant; 1. Marso S, et al. N Engl J Med 2016; 375(4):311-22; 2. Marso S, et al. N Engl J Med 2016; 375:1834-44; 3. Gerstein HC, et al. Lancet 2019; 394;121-130.

StudyName Medication

% with NO

clinicalCVD*

Primary Outcome, HR (95% CI,

p value†)

Secondary Outcomes, HR (95% CI, p value)

CVDeath

Nonfatal MI

Nonfatal Stroke hHF

LEADER1 Liraglutide 18.7%MACE0.87

(0.78-0.97, p=0.01)

0.78 (0.66-0.93, p=0.007)

NS NS NS

SUSTAIN-62 Semaglutide(SC) 17.0%

MACE0.74

(0.58-0.95, p=0.02)

NS NS0.61

(0.38-0.99, p=0.04)

NS

REWIND3 Dulaglutide 68.5%MACE0.88

(0.79-0.99, p=0.026)

NS NS0.76

(0.61-0.95,p=0.017)

NS

5

SGLT2i CVOTs in Diabetes Demonstrating Superiority

CI: confidence interval; CV: cardiovascular; CVOT: cardiovascular outcome trial; GLP1: glucagon-like peptide-1; hHF: hospitalization for heart failure; HR: hazard ratio; MACE: Major adverse cardiovascular events (MI, stroke, CV death); MI: myocardial infarction; NS: not significant; 1. Zinman B, et al. N Engl J Med 2015; 373(22):2117-28; 2. Neal B, et al. N Engl J Med 2017; 377(7):644-57; 3. Wiviott SD, et al. N Engl J Med 2019; 380(4):347-57.

Studyname Medication

% with NO

clinical CVD

Primary Outcome, HR (95% CI, p value)

Secondary Outcomes, HR (95% CI, p value)

CVDeath

Nonfatal MI

Nonfatal Stroke hHF

EMPA-REG OUTCOME1 Empagliflozin 0

MACE0.86

(0.74-0.99, p=0.04)

0.62 (0.49-0.77,p<0.001)

NS NS0.65

(0.50-0.85, p=0.002)

CANVAS2 Canagliflozin 34.4%MACE0.86

(0.75-0.97, p=0.02)NS NS NS

0.67(0.52-0.87,

p not reported)

DECLARE3 Dapagliflozin 59.4%hHF/CV Mortality

0.83 (0.73-0.95, p=0.005)NS NS NS

0.73(0.61-0.88,

p not reported)MACE0.93 (0.84-1.03, p=0.17)

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Meta-analysis of SGLT2i CVOTs: Renal Outcomes Among Patients with CVD

Fixed effects model: considers the set of studies included in the meta-analysis and assumes that there is a single true value underlying all of the study results.; the assumption is that if all studies that address the same question were infinitely large and completely free of bias, they would yield identical estimates of the effect2ASCVD: atherosclerotic cardiovascular disease; CI: confidence interval; CVOT: cardiovascular outcome trial; HR: hazard ratio; pt-yrs: patient-years; SGLT2i: sodium-glucose linked transporter-2 inhibitor1. Zelniker TA, et al. Lancet 2019; 393(10166):31-9; 2. Guyatt G, et al (eds). Users' Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice, 3rd ed. American Medical Association, 2015.

Patients Events Events per 1000 patients-years HR HR (95% CI)

Treatment(n)

Placebo (n) Treatment Placebo

EMPA-REG OUTCOME 4645 2323 152 6.3 11.5 0.54

(0.40-0.75)

CANVAS Program 3756 2900 179 6.4 10.5 0.59

(0.44-0.79)

DECLARE-TIMI 58 3474 3500 183 4.7 8.6 0.55

(0.41-0.75)

FE MODEL for ASCVD (p<0.0001) 0.56(0.47-0.67)

0.35 0.50 1.00 2.50Favourstreatment

Favoursplacebo

7

MACE CV death Heart failure hospitalization

Renaloutcomes*

(lira)(empa)

Summary of Positive CVOTs for Patients with Pre-existing Cardiovascular Disease

*Composite renal endpoint: Doubling of serum creatinine, end-stage renal disease or renal death; †dulaglutide, liraglutide and semaglutide; ‡canagliflozin, dapagliflozin, empagliflozinCV: cardiovascular; CVOT: cardiovascular outcome trial; MACE: Major adverse cardiovascular events (MI, stroke, CV death); MI: myocardial infarction; SGLT2: sodium-glucose linked transporter-21. Marso S, et al. N Engl J Med 2016; 375(4):311-22; 2. Marso S, et al. N Engl J Med 2016; 375:1834-44; 3. Gerstein HC, et al. Lancet 2019; Jun 7 [epub before print];4. Zinman B, et al. N Engl J Med 2015; 373(22):2117-28; 5. Neal B, et al. N Engl J Med 2017; 377(7):644-57; 6. Wiviott SD, et al. N Engl J Med 2019; 380(4):347-57.7. Zelniker TA, et al. Lancet 2019; 393(10166):31-9.

= GLP1 Receptor agonists†1-3 = SGLT2 inhibitors‡4-7

8

SGLT2 Inhibitors

For Patients with CKD in Diabetes (↑ACR)

SGLT2: sodium-glucose linked transporter-2; ACR: albumin-creatinine ratio 9

Hazard ratio (95% CI) P value

Primary composite outcome 0.70 (0.59–0.82) 0.00001Doubling of serum creatinine 0.60 (0.48–0.76) <0.001ESKD 0.68 (0.54–0.86) 0.002

eGFR <15 mL/min/1.73 m2 0.60 (0.45–0.80) –Dialysis initiated or kidney transplantation 0.74 (0.55–1.00) –

Renal death 0.39 (0.08–2.03) –CV death 0.78 (0.61–1.00) 0.0502

ESKD, doubling of serum creatinine or renal death 0.66 (0.53–0.81) <0.001Dialysis, kidney transplantation or renal death* 0.72 (0.54–0.97) –

Favors Canagliflozin Favors Placebo

0.25 0.5 1.0 2.0 4.0

*Post hoc analysis.

CREDENCE: Canagliflozin in Patients with Diabetes and Established Nephropathy: Summary

eGFR: estimated glomerular filtration rate; ESKD: end stage kidney diseasePerkovic V, et al. N Engl J Med 2019; Apr 14 [Epub ahead of print]. 10

SGLT2i Renal Studies

11

DAPA-CKD EMPA-KIDNEYNo. of patients 4000 5000Treatment arms DAPA (5, 10 mg) vs. PBO EMPA vs. PBO

Patient population CKD ± T2DMay be taking ACEi/ARB

CKD ± diabetesMay be taking ACEi/ARB

Kidney function inclusion criteria(eGFR units: mL/min/1.73 m2)

eGFR ≥25 to <75 AND

UACR >22.6 mg/mmol

eGFR ≥20 to <45 OR

eGFR ≥45 to <90 with UACR ≥22.6 mg/mmol

Primary endpointComposite of ≥50%

sustained decline in eGFR, ESKD, CV or renal death

Composite of CV death, kidney disease progression (ESKD, renal

death or a sustained decline of ≥40% in eGFR)

Start 2017 2018

Completion 2020 2022

1. Heerspink HJL et al. Nephrol Dial Transplant 2020;35:274-82. 2. ClinicalTrials.gov Identifier: NCT03594110

Summary of Positive Antihyperglycemic Trials Among People with CKD in Diabetes ( ACR)

*Composite renal endpoint: Doubling of serum creatinine, end-stage renal disease or renal death†dulaglutide, liraglutide and semaglutide; ‡canagliflozin, dapagliflozin, empagliflozin; CV: cardiovascular; CVOT: cardiovascular outcome trial; MACE: Major adverse cardiovascular events (MI, stroke, CV death); MI: myocardial infarction; SGLT2: sodium-glucose linked transporter-21. Marso S, et al. N Engl J Med 2016; 375(4):311-22; 2. Mann JF, et al. N Engl J Med 2017; 377(9):839-48; 3. Marso S, et al. N Engl J Med 2016; 375:1834-44;4. Gerstein HC, et al. Lancet 2019; Jun 7 [epub before print]; 5. Gerstein HC, et al. Lancet 2019; Jun 7 [epub before print]; 6. Zinman B, et al. N Engl J Med 2015; 373(22):2117-28;7. Wanner C, et al. N Engl J Med 2016; 375(4):323-34; 8. Neal B, et al. N Engl J Med 2017; 377(7):644-57; 9. Wiviott SD, et al. N Engl J Med 2019; 380(4):347-57; 10. Perkovic V, et al. N Engl J Med 2019; Apr 14 [Epub ahead of print]. 11. Zelniker TA et al. Lancet 2019; 393(10166):31-9.

MACE CV death Heart failure hospitalization

Renaloutcomes*

12

(Cana) (Cana) (Cana)

= GLP1 receptor agonists†1-5 = SGLT2 inhibitors‡6-11

For Patients with CV Risk Factors

CV: cardiovascular; GLP1: glucagon-like peptide-1; SGLT2: sodium-glucose linked transporter-2 13

Cholesterolmeter

GLP1 Receptor Agonist

SGLT2 Inhibitor

REWIND: Dulaglutide in Patients with Multiple Risk Factors: Major Adverse Cardiovascular Events (MACE)*

*MI, stroke, death from cardiovascular causesGerstein HC, et al. Lancet 2019; Jun 7 [epub before print] (Cardiovascular publication). 14

HR 0.88 (95% CI 0.77, 0.99)P = 0.026HR 0.88 (95% CI 0.79, 0.99)P = 0.026

GLP-1 RA CVOT meta-analysis: MACE among those with no history of CVD

15Giugliano D et al. Diabetes Obes Metab 2019;21:2576-80.

Meta-analysis of SGLT2i CVOTs: Hospitalization for Heart Failure Among Patients with Multiple Risk Factors1

FE (fixed effects) Model considers the set of studies included in the meta-analysis and assumes that there is a single true value underlying all of the study results; the assumption is that, if all studies that address the same question were infinitely large and completely free of bias, they would yield identical estimates of the effect.2CI: confidence interval; CV: cardiovascular; CVOT: cardiovascular outcome trial; HR: hazard ratio; MRF: multiple risk factors; SGLT2i: sodium-glucose linked transporter-2 inhibitor1. Zelniker TA et al. Lancet 2019; 393(10166):31-9; 2. Guyatt G, et al (eds). Users' Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice, 3rd ed. American Medical Association, 2015.

Patients EventsTreatment Events Per 1000 Patient-

years

Placebo Events Per 1000 Patient-

years

HR [95% CI]

CANVAS Program 3486 45 2.6 4.2 0.64 [0.35,

1.15]

DECLARE-TIMI 58 10186 155 3.0 4.6 0.64 [0.46,

0.88]

FE MODEL for MRF (p=0.89) 1.64 [0.48, 0.85]

0.35 0.50 1.00 2.50Hazard Ratio

16

Patients Events Events Per 1000 Patient-years HR HR

(95% CI)

Treatment (n/N)

Placebo (n/N) Treatment Placebo

CANVAS Program 2039 1447 70 4.1 6.6 0.63

(0.39-1.02)

DECLARE-TIMI 58 5108 5078 182 3.0 5.9 0.51

(0.37-0.69)

FE MODEL for multiple risk factors (p<0.0001) 0.54(0.42-0.71)

Meta-analysis of SGLT2i CVOTs: Renal Outcomes Among Patients with Multiple Risk Factors1

FE (fixed effects) Model considers the set of studies included in the meta-analysis and assumes that there is a single true value underlying all of the study results; the assumption is that, if all studies that address the same question were infinitely large and completely free of bias, they would yield identical estimates of the effect.2CI: confidence interval; CVOT: cardiovascular outcome trial; HR: hazard ratio; SGLT2i: sodium-glucose linked transporter-2 inhibitor1. Zelniker TA et al. Lancet 2019; 393(10166):31-9; 2. Guyatt G, et al (eds). Users' Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice, 3rd ed. American Medical Association, 2015.

1.00 2.500.500.35

Favourstreatment

Favoursplacebo

17

Summary of Positive CVOTs in Patients with Multiple Risk Factors

*Composite renal endpoint: Doubling of serum creatinine, end-stage renal disease or renal death; †dulaglutide, liraglutide and semaglutide; ‡canagliflozin, dapagliflozin, empagliflozin CV: cardiovascular; CVOT: cardiovascular outcome trial; MACE: Major adverse cardiovascular events (MI, stroke, CV death); MI: myocardial infarction; SGLT2: sodium-glucose linked transporter-21. Marso S, et al. N Engl J Med 2016; 375(4):311-22; 2. Mann JF, et al. N Engl J Med 2017; 377(9):839-48; 3. Marso S, et al. N Engl J Med 2016; 375:1834-44;4. Gerstein HC, et al. Lancet 2019; Jun 7 [epub before print]; 5. Gerstein HC, et al. Lancet 2019; Jun 7 [epub before print]; 6. Zinman B, et al. N Engl J Med 2015; 373(22):2117-28;7. Wanner C, et al. N Engl J Med 2016; 375(4):323-34; 8. Neal B, et al. N Engl J Med 2017; 377(7):644-57; 9. Wiviott SD, et al. N Engl J Med 2019; 380(4):347-57; 10. Perkovic V, et al. N Engl J Med 2019; Apr 14 [Epub ahead of print]. 11. Zelniker TA et al. Lancet 2019; 393(10166):31-9.

MACE CV death Heart failure hospitalization Renal outcomes*

18

(dula)

= GLP1 receptor agonists†1-5 = SGLT2 inhibitors‡6-11

SGLT2 Inhibitors

For Patients with Heart Failure with reduced ejection fraction (HFrEF)

SGLT2: sodium-glucose linked transporter-2; ACR: albumin-creatinine ratio 19

DAPA-HF: Dapagliflozin in Patients with HFrEF (+/- diabetes)

McMurray JJV, et al. N Engl J Med 2019; 381:1995-2008. 20

EMPEROR-Reduced

EMPEROR-Preserved

SOLOIST-WHF

Intervention Empagliflozin 10 mg Empagliflozin 10 mg Sotagliflozin

Planned enrolment ~2850 ~4126 ~4000

Inclusion criteria LVEF ≤40%NT-proBNPeGFR ≥20 mL/min/1.73m2

± T2DM

LVEF >40%NT-proBNPeGFR ≥20 mL/min/1.73m2

± T2DM

T2DMAdmitted to hospital or urgent heart failure visit for worsening heart failurePrior diagnosis of HF (>3 mo)BNP ≥150 pg/mL

Primary Endpoint(Time to first event)

CV deathHospitalization for HF

CV death Hospitalization for HF

CV death or hospitalization for HF in patients with LVEF <50% CV death or hospitalization for HF total population

Duration Event driven Event driven 32 months

SGLT2i Heart Failure Studies

https://clinicaltrials.gov/show/NCT03036124. ; https://clinicaltrials.gov/show/NCT03057977 ; https://clinicaltrials.gov/show/NCT03057951ttps://clinicaltrials.gov/ct2/show/record/NCT03521934?term=SOLOIST&rank=3

CV, cardiovascular; eGFR, estimated glomerular filtration rate; HF, heart failure; LVEF, left ventricular ejection fraction; NT proBNP, N-terminal pro b-type natriuretic peptide;T2DM, Type 2 Diabetes Mellitus

Summary of Positive Antihyperglycemic Trials Among People with HFrER

*Composite renal endpoint: Doubling of serum creatinine, end-stage renal disease or renal death†dulaglutide, liraglutide and semaglutide; ‡canagliflozin, dapagliflozin, empagliflozin; CV: cardiovascular; CVOT: cardiovascular outcome trial; MACE: Major adverse cardiovascular events (MI, stroke, CV death); MI: myocardial infarction; SGLT2: sodium-glucose linked transporter-21. Marso S, et al. N Engl J Med 2016; 375(4):311-22; 2. Mann JF, et al. N Engl J Med 2017; 377(9):839-48; 3. Marso S, et al. N Engl J Med 2016; 375:1834-44;4. Gerstein HC, et al. Lancet 2019; 394(10193):121-30; 5. Gerstein HC, et al. Lancet 2019; 394(10193):131-8; 6. Zinman B, et al. N Engl J Med 2015; 373(22):2117-28;7. Wanner C, et al. N Engl J Med 2016; 375(4):323-34; 8. Neal B, et al. N Engl J Med 2017; 377(7):644-57; 9. Wiviott SD, et al. N Engl J Med 2019; 380(4):347-57; 10. Perkovic V, et al. N Engl J Med 2019; 380(24):2295-306; 11. Zelniker TA et al. Lancet 2019; 393(10166):31-9. 12. McMurray JJV, et al. N Engl J Med2019;381:1995-2008

MACE CV death Heart failure hospitalization

Renaloutcomes*

22

(Dapa) (Dapa)(Dapa)

= GLP1 receptor agonists†1-5 = SGLT2 inhibitors‡6-12

Co-morbidities MACE CV death hHF Renaloutcomes *

Cardiovasculardisease

eGFR with ACR

Risk factors(HTN, lipids and/or smoking)

Heart failure with reduced EF

Summary of Positive CVOTs Among Patient Types

*Composite renal endpoint: Doubling of serum creatinine, end-stage renal disease or renal death; †dulaglutide, liraglutide and semaglutide; ‡canagliflozin, dapagliflozin, empagliflozin. CV: cardiovascular; CVOT: cardiovascular outcome trial; MACE: Major adverse cardiovascular events (MI, stroke, CV death); MI: myocardial infarction; SGLT2: sodium-glucose linked transporter-21. Marso S, et al. N Engl J Med 2016; 375(4):311-22; 2. Mann JF, et al. N Engl J Med 2017; 377(9):839-48; 3. Marso S, et al. N Engl J Med 2016; 375:1834-44;4. Gerstein HC, et al. Lancet 2019; Jun 7 [epub before print]; 5. Gerstein HC, et al. Lancet 2019; Jun 7 [epub before print]; 6. Zinman B, et al. N Engl J Med 2015; 373(22):2117-28;7. Wanner C, et al. N Engl J Med 2016; 375(4):323-34; 8. Neal B, et al. N Engl J Med 2017; 377(7):644-57; 9. Wiviott SD, et al. N Engl J Med 2019; 380(4):347-57; 10. Perkovic V, et al. N Engl J Med 2019; Apr 14 [Epub ahead of print]. 11. Zelniker TA et al. Lancet 2019; 393(10166):31-9. 12. McMurray JJV, et al. N Engl J Med 2019;381:1995-2008 23

(cana) (cana) (cana)

(empa)

(lira)

(dula)

= GLP1 receptor agonists†1-5 = SGLT2 inhibitors‡6-12

(dapa) (dapa) (dapa)

Buse J et al. Diabetes Care 2019

2018

2019

2019

Added high risk primary prevention

More defined

Buse J et al. Diabetes Care 2019

Cosentino F et al. Eur Heart J 2019:00:1-69.

Cosentino F et al. Eur Heart J 2019:00:1-69.

Cosentino F et al. Eur Heart J 2019:00:1-69.

Type 2 diabetes(in absence of metabolic decompensation)

SELECT BELOW BASED ON MOST PROMINENT FEATURE

Clinical CVD No risk factors

Met + SGLT2ior

Met + GLP1RA

Met + GLP1RAor

Met + SGLT2i Metformin

Then add the other

Then add the other

Individualize

Individualize and add others until target achieved

Frail

Metformin

+ DPP4i

Adapted from Cheng AY et al. Can J Diabetes 2020; 44:1-3.

If not at glycemic target

CKD with ACR

Met + SGLT2i

Risk factors (HTN, dyslipidemia, smoking)

Individualize

HFrEF

Met + SGLT2i

Individualize

If not at glycemic target

Cheng AYY, Wolever T, Mancini GB.

Summary

• Recognize patient type –• CVD, CKD, CHF, multiple risk factors

• OUTCOME-REDUCING therapy regardless of A1C• Add other therapies as needed to still achieve MULTIFACTORIAL TARGETS

• Guidelines have updated accordingly

@AliceYYCheng