Cardiac Friendly Drugs for Disclosures Type-2 Diabetes · 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 Follow-up (Months) 0 6 12 18 24 30 36 42 48 54 60 66 7.3 % Mean HbA 1c at final visit 6.5%

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Cardiac Friendly Drugs for

Type-2 Diabetes

John AthertonDepartment of Cardiology, Royal Brisbane and Women’s

Hospital; Heart Lung Stream Metro North HHS; University of Queensland School of Medicine

• AstraZeneca: Hyperkalaemia advisory board

• Bayer*

• Bristol-Myers Squibb*

• Boehringer Ingelheim* and Eli Lilly Alliance: Specialist advisory

board

• GE Healthcare: Research funding

• Menarini*

• Novartis*: Heart failure advisory board

Disclosures*Honoraria and/ or sponsorship Consultancy (listed)

T2DM Cardiac Friendly Drugs

• Is diabetes associated with increased risk

of cardiovascular events?

• What is the evidence for more intense

glucose lowering?

• What is the cardiovascular safety and

effectiveness for glucose lowering drugs?

Diabetes vs. no diabetes in Framingham HS over 20 yrs

Kannel WB and McGee DL. JAMA 1979;241:2035-8.

2-4X

Framingham Heart Study: 20 yr follow-up

Kannel WB and McGee DL. JAMA 1979;241:2035-8.Ojji D et al. J Natl Med Assoc 2008;100:1066-72.

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Ojji D et al. J Natl Med Assoc 2008;100:1066-72.

Two approaches in RCTs to improve

clinical outcomes in T2DM

• Compare aggressive vs. conventional

glucose lowering strategies aiming for a

lower HbA1c level.

• Compare different glucose lowering

strategies (drugs), but aim for similar

HbA1c levels in patients in the placebo/

active comparator limb.





glucose lowering?



T2DM Glucose lowering trials

Study Duration

(yrs)

N Glycaemia

Target Achieved

A1c

UKPDS 10 3,867 FPG <6.0 7.0 vs. 7.9%

ACCORD 3.5 10,251 A1c <6.0% 6.4 vs. 7.5%

ADVANCE 5 11,140 A1c <6.5% 6.5 vs. 7.3%

VADT 6.3 1,791 A1c <6.0% 6.9 vs. 8.4%

UKPDS- Lancet 1998;352:837-53. ACCORD- NEJM 2011; 364:818-28.

ADVANCE- NEJM 2008;358:2560-72. VADT- NEJM 2009;360:129-39.

UKPDS 33

3,867 patients with newly diagnosed T2DM:

• Conventional diabetic control (diet)

– FBG less than 15 mmol/L

• Intensive control

– FBG less than 6 mmol/L• Insulin (Ultralente)

• Sulphonylureas (Chlorpropamide, Glibenclamide)

• Biguanides (Metformin)

Lancet 1998; 352: 837–53 ukpds

UKPDS: HbA1c

cohort, median values

06

7

8

9

0 2 4 6 8 10

HbA

1c (

%)

Years from randomisation

ChlorpropamideConventional GlibenclamideInsulin Metformin

overweight patients

Lancet 1998; 352: 837–53

HbA1c 7.9% vs. 7.0%:

- 12% RRR diabetes-related EPs, P=0.029

- 10% RRR microvascular EPs, P=0.0099

10 years follow-up

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ukpds

0.0

0.1

0.2

0.3

0.4

0 3 6 9 12 15

Pro

port

ion o

f patien

ts w

ith

even

t


Conventional (896)

Chlorpropamide (619)

Glibenclamide (615)

Insulin (911)

UKPDS: Myocardial Infarction

C v G v I

p = 0.66

Lancet 1998; 352: 837–53

0.052

10 years follow-up

ukpds

UKPDS: Myocardial Infarction

M v I

p=0.12

overweight

patients

0.0

0.1

0.2

0.3

0.4

0 3 6 9 12 15

Pro

port

ion o

f patie

nts

with

even

ts


Conventional (411)

Intensive (951)

Metformin (342)

M v C, p=0.010- 39% RRR myocardial infarction, P=0.01

- 36% RRR all-cause mortality, P=0.01

- Less weight gain

- Less hypoglycaemic episodes

Lancet 1998;352(9131):854-65.

10.7 years follow-up

UKPDS Conclusions:

• No evidence of harm of

– insulin

– sulphonylureas

– metformin

• No evidence of benefit of lowering BGL on CVD

• Possible benefit of Metformin monotherapy (342

patients) in addition to its effect on BGLs

Hemoglobin A1c

Δ 0.67% (95% CI 0.64 - 0.70); p<0.001

Me

an

Hb

A1

c(%

)

5.0

5.5

6.0

6.5

7.0

7.5

8.0

8.5

9.0

9.5

10.0

Follow-up (Months)

0 6 12 18 24 30 36 42 48 54 60 66

7.3 %

Mean HbA1c

at final visit

6.5%

Standard

Intensive

N Engl J Med 2008;358:2560-72

5 yrs follow-up

N=11,140

Major macrovascular events

Follow-up (months)

25

20

15

10

5

0

Standard

Intensive

0 6 12 18 24 30 36 42 48 54 60 66

Relative risk reduction

6%: 95% CI: -6 to 16%

p=0.32

N Engl J Med 2008;358:2560-72

5 yrs follow-up

N=11,140

N Engl J Med 2008; 358:2545-2559 N Engl J Med 2008; 358:2545-2559

N Engl J Med 2008;358:2545-59

6.4% vs. 7.5% a 1 year

N=10,251

ACCORD

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N Engl J Med 2008;358:2545-59

HR 0.90, 95% CI 0.78-1.04, P=0.16

MI, Stroke, CV death

3.5 yrs follow-up

ACCORD

N=10,251

N Engl J Med 2008;358:2545-59

HR 1.22, 95% CI 1.01-1.46, P=0.04

460 deaths

3.5 yrs follow-up

ACCORD

Nonfatal MI

All-cause mortalityRay KK et al.

Lancet 2009;

373:1765-72.

HbA1c 0.9% lower

Holman RR et al. N Engl J Med 2008;359:1577-1589.

UKPDS Legacy EffectSulphonylurea-InsulinFollow-up: 16.8 yrs (8.5 yrs post-RCT)

MetforminFollow-up: 17.7 yrs (8.8 yrs post-RCT)





glucose lowering?



Glucose lowering drugs and CV outcome trials

Drug RCT evidence Summary

Sulphonylurea

Metformin

Insulin

TZDs

GLP-1 RA

DPP-4 inhibitors

SGLT-2 inhibitors

No RCT data with same HbA1c

UKPDS (safe, legacy effect)

Safe

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Systematic review of observational studies comparing

metformin vs. other ADD in T2DM + CHF

Crowley MJ et al. Ann

Intern Med 2017;166:191-

200.

11 studies, N=35,410



Sulphonylurea No RCT data with same HbA1c


Safe

Metformin

Insulin

TZDs

GLP-1 RA

DPP-4 inhibitors

SGLT-2 inhibitors

No RCT data with same HbA1c

UKPDS (may decrease MI)

Safe (observational data including HF)

Safe





Safe

Metformin No RCT data with same HbA1c



Safe

Insulin

TZDs

GLP-1 RA

DPP-4 inhibitors

SGLT-2 inhibitors

ORIGIN (neutral)

UKPDS (safe, legacy effect)Safe

NEJM 2007

NEJM 2007

Lago RM et al. Lancet 2007;370:1129-36.

Heart Failure

CV death

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Lancet 2009;373:2125-35.





Safe




Safe

Insulin ORIGIN (neutral)


Safe

TZDs

GLP-1 RA

DPP-4 inhibitors

SGLT-2 inhibitors

PROACTIVE, RECORD (neutral)

Increased HF events

Safe

Avoid in CHF

GLP-1 RA CV outcome RCTs

Trial Pop’n Drug Result

ELIXA

(n=6,068)

ACS Lixisenatide No effect on CV death/ MI/ CVA/

unstable angina hosp.

LEADER

(n=9,340)

High CV risk Liraglutide 13% RRR CV death/ MI/ CVA, P=0.01

22% RRR CV death, P=0.007

15% RRR all-cause mortality, P=0.02

Less nephropathy events, P=0.003

More retinopathy events, P=0.33

SUSTAIN-6

(n=3,297)

High CV risk Semaglutide 26% RRR CV death/ MI/ CVA, P=0.02

39% RRR nonfatal CVA, P=0.04

Less nephropathy events, P=0.005

More retinopathy events, P=0.02

EXSCEL

(n=14,752)

High CV risk Exanatide No effect on CV death/ MI/ CVA

Effect of liraglutide in heart failure with reduced LVEF

Margulies KB et al. JAMA 2016;316:500-8. Jorsal A et al. Eur J Heart Fail 2017;19:61-7.

FIGHT LIVE

Increased serious cardiac events (12 vs. 3), P=0.04

HR: + 7 bpm

N=300N=241

No difference in HR





Safe




Safe



Safe

TZDs PROACTIVE, RECORD (neutral)

Increased HF events

Safe

Avoid in CHF

GLP-1 RA

DPP-4 inhibitors

SGLT-2 inhibitors

LEADER and SUSTAIN-6 (decrease CV events)

ELIXA and EXSCEL (neutral)

Benefit (2 trials)

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

5,380 T2DM with ACS

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

SAVOR-TIMI 53

16,492 T2DM with high CV risk

Green JB et al. N Engl J Med 2015;373:232-242.

TECOS

14,671 T2DM patients with CV disease

Meta-analysis of DPP-4I RCTs in T2DMEffect on heart failure hospitalisation

Li L et al. BMJ 2016;352:bmj.i610

Moderate quality of evidence (using GRADE) due to imprecision. 1,174 events in 37,028 patients: OR: 1.13 (1.00 – 1.26).

8 events (0-16) per 1,000 patients over 5 years.





Safe




Safe



Safe


Increased HF events

Safe

Avoid in CHF

GLP-1 RA LEADER and SUSTAIN-6 (decrease CV events)


Benefit (2 trials)

DPP-4 inhibitors

SGLT-2 inhibitors

EXAMINE, SAVOR-TIMI 53, TECOS (neutral)

Increased HF hosp. with saxagliptin (SAVOR-TIMI 53)Safe

SGLT-2 Inhibitors:

Increased urinary excretion

of excess glucose (~70 g/day)

Glucose

filtration

SGLT2

SGLT2

InhibitorGlucose

SGLT-2I

Reduced glucose

reabsorption

Distal

tubule

Loop of

Henle

GlomerulusProximal

tubule

Primary Results of

EMPA-REG OUTCOME®

Summary of primary results. Please refer to manuscript for full details

42Zinman B et al. N Engl J Med 2015;373:2117-28

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Key inclusion and exclusion criteria

• Key inclusion criteria

– Adults with type 2 diabetes

– BMI ≤45 kg/m2

– HbA1c 7–10%*

– Established cardiovascular disease

• Prior myocardial infarction, coronary artery disease, stroke, unstable

angina or occlusive peripheral arterial disease

• Key exclusion criteria

– eGFR <30 mL/min/1.73m2 (MDRD)

43

BMI, body mass index; eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease*No glucose-lowering therapy for ≥12 weeks prior to randomisation or no change in dose for ≥12 weeks prior to randomisation or, in the case of insulin, unchanged by >10% compared to the dose at randomisation

Zinman B et al. N Engl J Med 2015;373:2117-28

Primary outcome: CV death/ MI/ CVA

3-point MACE

44

HR 0.86

(95.02% CI 0.74, 0.99)p=0.0382*

Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio. * Two-sided tests for superiority were conducted (statistical significance was indicated if p≤0.0498)

772 events


EMPA-REG OUTCOME

3-point MACE

45

Empagliflozin 10 mg

HR 0.85(95% CI 0.72, 1.01)

p=0.0668

Empagliflozin 25 mg

HR 0.86(95% CI 0.73, 1.02)

p=0.0865


Patients with event/analysedEmpagliflozin Placebo HR (95% CI) p-value

3-point MACE 490/4687 282/2333 0.86(0.74,

0.99)*0.0382

CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001

Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.2189

Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.1638

CV death, MI and stroke

46

Favours empagliflozin Favours placebo

Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction*95.02% CI


All-cause mortality

47

HR 0.68

(95% CI 0.57, 0.82)p<0.0001

Kaplan-Meier estimate. HR, hazard ratio

463 deaths


Hospitalisation for heart failure

48

HR 0.65

(95% CI 0.50, 0.85)p=0.0017

Cumulative incidence function. HR, hazard ratio


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EMPA-REG OUTCOME Adverse Events

49Zinman B et al. N Engl J Med 2015;373:2117-28

These results are not explained by improved glycaemic control1

The exact reason is unknown...1

1. Zinman B et al. N Engl J Med 2015; 373:2117–28.

Effects on arterial stiffness

Cardiac function

Cardiac oxygen demand

Cardio-renal effects

Uric acid reduction

Albuminuriareduction

Low risk ofhypoglycaemia

Reduction in weight

Effects on diuresis

Two subsequent studies:-

1. CANVAS programProspective randomised placebo controlled CVD

outcome study with canagliflozin in type 2 diabetes

patients with and without CVD

2. CVD-REALCross sectional analysis of HHF and death in

several countries assessing outcomes in patients with type 2 diabetes who are taking SGLT2Is or other hypoglycaemic agents.

EMPA-REG

OUTCOME

CANVAS

CV death/ MI/ CVA 0.86 (0.74-0.99) 0.86 (0.75-0.97)

CV death 0.62 (0.49-0.77) 0.87 (0.72-1.06)

Nonfatal MI 0.87 (0.7-1.09) 0.85 (0.69-1.05)

Nonfatal CVA 1.24 (0.92-1.67) 0.90 (0.71-1.05)

Death 0.68 (0.57-0.82) 0.87 (0.74-1.01)

HF hosp 0.65 (0.50-0.85) 0.67 (0.52-0.87)

CV death/ HF hosp 0.66 (0.55-0.79) 0.78 (0.67-0.91)

SGLT-2 Inhibitor Outcome RCTs

Zinman B et al. N Engl J Med 2015. Neal B et al. N Engl J Med 2017.





Safe




Safe



Safe


Increased HF events

Safe

Avoid in CHF

GLP-1 RA LEADER and SUSTAIN-6 (decrease CV events)


Benefit (2 trials)

DPP-4 inhibitors EXAMINE, SAVOR-TIMI 53, TECOS (neutral)

Increased HF hosp. with saxagliptin (SAVOR-TIMI 53)

Safe

SGLT-2 inhibitors EMPA REG OUTCOME, CANVAS (decrease CV events) Benefit

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• T2DM is an independent RF for CV events.

• Glucose lowering decreases microvascular events and probably major CV events.– Need to consider age and comorbidities.

• Glucose lowering therapies are generally safe including SU, metformin, insulin, glitazones, DPP-4 inhibitors, GLP-1 RA, and SGLT-2 inhibitors.– Metformin can be used in patients with HF.

– Increased risk of HF events with glitazones.

– Consider non-glycaemic effects.

• SGLT-2 inhibitors decrease CV events in patients with CV disease.

Documents

Cardiac Friendly Drugs for Disclosures Type-2 Diabetes · 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 Follow-up (Months) 0 6 12 18 24 30 36 42 48 54 60 66 7.3 % Mean HbA 1c at final visit 6.5%