DECLARE One Year On · 2020. 7. 21. · R •MACE •Composite of hospitalization for heart failure...

DECLARE One Year On

John Wilding

Obesity & Endocrinology Clinical Research

University of Liverpool &

Aintree University Hospital

Liverpool, UK

Outline

• SGLT2 inhibitors for diabetes treatment

• Cardiovascular & heart failure risk in diabetes

• DECLARE TIMI-58 – reminder of key results

• DECLARE – outcomes in patients with prior MI and

prior heart failure

• DECLARE – renal outcomes

• DECLARE – efficacy and safety in older patients

• DAPA-HF – CV outcomes in heart failure with and

without diabetes

Increased glucose excretion

Increased sodium excretion

Reduced sodium load

Blood pressure reduction

Loss of energy (calories)

Weight loss

Reduced glycaemia HbA1c reduction

Expected clinical effects of SGLT2 inhibition based on the mode of action

HbA1c, glycated haemoglobin; SGLT2, sodium–glucose co-transporter 2Adapted from: Abdul-Ghani MA, et al. Endocr Rev. 2011;32:515–31.

Ischaemic heart disease is the leading cause of mortality in patients with T2D1

35%

15%10%

40%

1. Low Wang CC et al. Circulation 2016;133:2459–502

Non-cardiovascular causes

Ischaemic heartdisease

Other heart disease(predominantly

congestive)

Stroke

T2D increases the risk of developing heart failure

1. Nichols GA et al. Diabetes Care 2004;27:1879–84; 2. Faden G et al. Diabetes Res Clin Pract 2013;101:309–16; 3. Ahmed A et al. Heartfail clin 2008;4:387-399; 4. Cubbon RM et al. Diab Vasc Dis Res 2013;10:330; 5. MacDonald MR et al. Eur Heart J 2008;29:1377

2–3 fold increased risk of heart failure vs patients

without T2D1

68% of patients with T2D had evidence of left ventricle

dysfunction 5 years after diagnosis2

~29% of all patients with heart failure also have T2D5

Survival outcomes in patients with diabetes and

HF are worse than those for patients with heart failure

and no diabetes4,5

Over half of all patients with heart failure may have

moderate to severe chronic kidney disease3

Trial Name(SGLT-2 Inhibitor) Target Enrollment Timing

EMPA-REG OUTCOME(empagliflozin)

N=7000All prior CVD

Began 2010; reported Sept 2015

CANVAS

(canagliflozin)

CANVAS-R

(canagliflozin)

N=5700

N=4330

66% prior CVD

Began 2009; reported June 2017

Began 2013; reported June 2017

DECLARE

(dapagliflozin)

N=17,160

41% prior CVD

Began 2013; reported Nov 2018

CREDENCE(canagliflozin)

N=3700Began 2014; Reported April 2019

VERTIS

(ertugliflozin)N=8000 Began 2013- ending 2019

SGLT2i outcome trials in T2DM

DECLARE-TIMI 58 Study Design

S

Placebo daily

Dapagliflozin 10 mg daily

Event-driven duration: ≥1390 MACE

Median follow-up: 4.2 years

17,160 patients

T2DM

6.5%≤ HbA1c

0

5

10

15

20

25

0 5 10 15 20 25 30 35 40

Patients with prior cardiac ischaemic event are more likely to have adverse

CV outcomes

Cavender et al. Circulation 2015;132:923

MACE in REACH registry (n = 19,699) across the spectrum of atherothrombotic risk

Adj K-M

(%)

Months

Diabetes + only risk

factors

Diabetes + ASCVD

without prior ischemic

event

Diabetes + ASCVD

with prior ischemic

event

CV

death

, M

I or

str

oke

10%

5%

0%360 24 36 48

15%

Prior MI – Placebo (N = 1,807) Prior MI – Dapagliflozin (N = 1,777)

No Prior MI – Placebo (N = 6,771) No Prior MI – Dapagliflozin (N = 6,805)

Patients with prior MI

% with events: 17.8 % vs. 15.2 %

Patients without prior MI

% with events: 7.1 % vs. 7.1 %

20%

Months

ARR = 2.6 %

P-int HR = 0.11

P-int ARR = 0.048

CV outcomes with dapagliflozin

MACE – CV death, MI or ischemic stroke

12

ARR = 0.0 %Cum

ula

tive

in

cid

en

ce

HR = 0.84 (95 % CI 0.72 to 0.99)

HR = 1.00 (95 % CI 0.88 to 1.13)

10%

5%

0%

7.5%

2.5%

12 24 36 48

12.5%

Patients with prior MI

% with events: 10.5 % vs. 8.6 %

Patients without prior MI

% with events: 4.5 % vs. 3.9 %

Months

P-int ARR = 0.01

P-int HR = 0.69

CVD or HF hospitalization

HF outcomes with dapagliflozin by prior MI

ARR = 1.9 %

Prior MI – Placebo (N = 1,807) Prior MI – Dapagliflozin (N = 1,777)

No Prior MI – Placebo (N = 6,771)

No Prior MI – Dapagliflozin (N = 6,805)

ARR = 0.6 %Cu

mu

lati

ve

in

cid

en

ce

HR = 0.81 (95 % CI 0.65 to 1.00)

HR = 0.85 (95 % CI 0.72 to 1.00)

Hospitalisation for HF

14

2.5% vs 3.3%HR 0.73 (0.61-0.88)P

DECLARE-TIMI-58N=17,160*

HFrEFEF

20

10

5

0

15

0 1 2 3 4

16

HFrEF:HR 0.64

[0.43, 0.95]

Cu

mu

lati

ve in

cid

ent

rate

(%

) P for interaction: 0.449

HFrEF:HR 0.55

[0.34, 0.90]

HHF

19.0%

13.5%

2.7%

2.1%

yrs

20

10

5

0

15

P for interaction: 0.012

yrs

CV death

12.4%

7.2%

2.5%

2.3%

0 1 2 3 4

Not HFrEF:HR 1.08

[0.89, 1.31]

Not HFrEF:HR 0.76

[0.62, 0.92]

DapagliflozinPlacebo

DapagliflozinPlacebo

Not HFrEF:(N=16,489)

HFrEF:(N=671)

HHF and CV Deathby HFrEF vs not HFrEF subgroups

Not HFrEF defined as pts with HF without known reduced EF and pts without hx of HF

Distribution of eGFR Categories Amongst the DECLARE-TIMI 58 Population

eGFR ≥90 48% (n=8162)

eGFR 60 to

Mean eGFR change with Dapagliflozin vs. Placebo in the Total Population

Lancet Diabetes Endocrinol. 2019 Jun 10. pii: S2213-8587(19)30180-9

The Renal Composite Outcomes and their Components in the DECLARE-TIMI 58 Trial


Renal composite

40% reduction in eGFR to < 60 ml/min/1.73 m2

end-stage renal diseaserenal dealh

The Renal-Specific Outcome Predefined Sub-Group Analyses (1)


Exploratory renal outcomes in SGLT2i CV outcomes trials

aProgression to macroalbuminuria, doubling of serum creatinine and eGFR ≤ 45 mL/min/1.73 m2, initiation of RRT or renal death; bp value not assessed due to statistical hierarchy; cplus eGFR ≤ 45 mL/min/1.73 m2. CI, confidence interval; CV, cardiovascular; eGFR, estimates glomerular filtration rate; HR, hazard ratio; RRT, renal replacement therapy; SGLT2i, sodium–glucose co-transporter 2 inhibitor. 1. Neal B, et al. N Engl J Med. 2017;377:644–57; 2. Wanner C, et al. N Engl J Med. 2016;375:323–34; 3. Wiviott SD et al. N Engl J Med 2019;380:347–57 2

3

0.2 0.7 1.2

Favours SGLT2i Favours placebo

HR 0.60; 95% CI: 0.47–0.77b

HR 0.73; 95% CI: 0.67–0.79b

HR 0.61; 95% CI: 0.53–0.70; p < 0.001

HR 0.54; 95% CI: 0.40–0.75; p < 0.001

HR 0.53; 95% CI: 0.67–0.79b

Renal composite:1

• 40% reduction in eGFR• requirement for RRT• renal death

Renal composite:2

• doubling of serum creatininec

• requirement for RRT• renal death

Renal composite:3

• 40% reduction in eGFR to < 60 ml/min/1.73 m2

• end-stage renal disease• renal deal

CANVAS Program (canagliflozin)1

Renal composite

Renal composite

Renal composite

Progression of albuminuria

Incident or worsening nephropathya

EMPA-REG (empagliflozin)2

DECLARE-TIMI 58 (dapagliflozin)3

Primary Outcome:ESKD, Doubling of Serum Creatinine, or Renal or CV Death

0

5

10

15

20

25

0 26 52 78 104 130 156 182

Parti

cip

an

ts w

ith

an

even

t (%

)

Months since randomization

Hazard ratio, 0.70 (95% CI, 0.59–0.82)P = 0.00001

6 12 18 24 30 36 42

340 participants

245 participants

Placebo

Canagliflozin

No. at risk

Placebo 2199 2178 2132 2047 1725 1129 621 170

Canagliflozin 2202 2181 2145 2081 1786 1211 646 196

Parti

cip

an

ts w

ith

an

even

t (%

)

Background

• Type 2 Diabetes Mellitus (T2DM) is a prevalent disorder in the elderly with approximately one quarter of people age >65 with T2DM.

• Limited therapeutic experience and insufficient long-term safety data in very elderly patients, age ≥75 years, led some authorities not to recommend initiation of SGLT2i therapy at this age.

• The DECLARE-TIMI 58 study included 7907 elderly patients (age ≥ 65) of whom 1096 were very elderly (≥75 years).

• We studied the efficacy and safety of dapagliflozin in elderly and very elderly patients with T2DM.

Baseline Characteristics

Characteristic Age < 65 Age ≥65-

Metabolic Efficacy

7.2

7.4

7.6

7.8

8

8.2

8.4

8.6

0 1 2 3 4

Ad

just

ed M

ean

Hb

A1

c (%

)

Years

80

82

84

86

88

90

92

94

0 0.5 1 1.5 2 2.5 3 3.5 4

Ad

just

ed M

ean

Wei

ght

Years

129

130

131

132

133

134

135

136

137

138

0 1 2 3 4

Ad

just

ed M

ean

Sys

tolic

Blo

od

P

ress

ure

Years

Cardiovascular and Renal Efficacy

Efficacy Outcomes

CVD – Cardiovascular death; HHF – Hospitalization for heart failure; MACE – Major Adverse Cardiovascular events

Efficacy Outcomes

Safety Outcomes

• The incidence of serious adverse events (SAE’s) was lower with dapagliflozin vs.

placebo in the overall study population with no age based treatment interaction.

• HR (95% CI) for SAE’s:

• 0.93 (0.86, 1.00) in age

Safety Outcomes

96 96 2186 90 310.0%

1.0%

2.0%

3.0%

4.0%

5.0%

6.0%

< 65 years ≥65-< 75 years

≥ 75 years

58 56 1180 73 220.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

3.5%

4.0%

4.5%


≥ 75 years

HR 0.69 (0.49, 0.97)P=0.03

Volume depletion Acute kidney injury

Interaction P-value0.6922


HR 1.07 (0.80, 1.44)P=0.63

HR 0.70 (0.40, 1.23)P=0.22

HR 1.06 (0.79, 1.41)P=0.71

Dapagliflozin Placebo

HR 0.75 (0.53, 1.07)P=0.11

HR 0.52 (0.25, 1.08)P=0.08

HR 1.00 (0.83, 1.21), p=0.99 HR 0.69 (0.55, 0.87), p=0.002

166 261 54175 251 600.0%

2.0%

4.0%

6.0%

8.0%

10.0%

12.0%


≥ 75 years

Safety outcomes

205 212 40200 208 320.0%

1.0%

2.0%

3.0%

4.0%

5.0%

6.0%

7.0%

8.0%

9.0%


≥ 75 years

Fractures Malignancies



HR 1.02 (0.84, 1.24)P=0.86

HR 1.36 (0.85, 2.17)P=0.20

HR 1.02 (0.84, 1.23)P=0.87


HR 1.03 (0.87, 1.23)P=0.70

HR 0.95 (0.66, 1.38)P=0.79

HR 0.94 (0.76, 1.16)P=0.58

HR 0.99 (0.87, 1.12), p=0.83HR 1.04 (0.91, 1.18), p=0.59

Safety outcomes

28 21 928 41 140.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%


≥ 75 years

15 9 37 3 20.0%

0.2%

0.4%

0.6%

0.8%

1.0%


≥ 75 years

HR 2.05 (0.84, 5.03)P=0.12

Major hypoglycemia Diabetic ketoacidosis*



HR 0.97 (0.58, 1.64)P=0.91

HR 0.68 (0.29, 1.57)P=0.36

HR 0.50 (0.29, 0.84)P

37 35 46 1 20.0%

0.2%

0.4%

0.6%

0.8%

1.0%

1.2%

1.4%

1.6%


≥ 75 years

Safety Outcomes

48 63 1655 68 100.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

3.5%


≥ 75 years

Urinary tract infections*

Genital infections*



HR 0.84 (0.57, 1.24)P=0.39

HR 1.60 (0.73, 3.54)P=0.24

HR 0.90 (0.64, 1.27)P=0.57


HR 6.07 (2.56, 14.38)P

Conclusions

• DECLARE-TIMI 58 confirms the efficacy results for the overall

population with cardiovascular and renal benefits regardless of age.

• This sub-analysis also confirms the safety of dapagliflozin which was

consistent across all age groups studied.

• Dapagliflozin provides clinically relevant benefits to patients with

T2DM regardless of age.

Assessing Dapagliflozin in Patients with Chronic HFrEF With or Without T2D1-4

41

CV = cardiovascular; eGFR = estimated glomerular filtration rate; ESRD = end stage renal disease; HbA1c = glycated haemoglobin; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; hHF = hospitalisation for heart failure; KCCQ = Kansas City Cardiomyopathy Questionnaire; LVEF = left ventricular ejection fraction; NT-proBNP = N-terminal pro B-type natriuretic peptide; NYHA = New York Heart Association; SoC = standard of care; T2D = type 2 diabetes.1. McMurray JJV et al. Article and supplementary appendix. Eur J Heart Fail. 2019;21:665-675; 2. McMurray J. Presentation at: European Society of Cardiology Congress. September 1, 2019; Paris, France; 3. Study NCT03036124. ClinicalTrials.gov website. Accessed August 19, 2019. 4. McMurray JJV et al. Eur J Heart Fail. 2019;doi: 10.1002/ejhf.1548. Accessed July 16, 2019.

Target primary endpoint events: 8441

Median follow-up: 18.2 months2

Completion: July 20193

Placebo + standard of care

Dapagliflozin 10 mg + standard of care

1:1

Do

ub

le-b

lin

d

4744 patients• ≥18 years of age

• With or without T2D

• Diagnosis of symptomatic HFrEF (NYHA class II-IV) for ≥ 2 months

• LVEF ≤40% within last 12 months

• Elevated NT-proBNP

• eGFR ≥30 ml/min/1.73 m2

• Stable SoC HFrEF treatment

Visit 1 (enrollment)

Day -14Visit 2 (randomisation)

Day 0Visit 6, etc.

Every 120 days

Visit 5

Day 120

Visit 3

Day 14Visit 4

Day 60

Secondary Endpoints

• Time to first occurrence of either of the components of the composite: CV death or hHF

• Total number of (first and recurrent) hHF and CV death• Change from baseline measured at 8 months in the total symptom score of

the KCCQ• Time to first occurrence of any of the components of the composite: ≥50%

sustained decline in eGFR or reaching ESRD or renal death• Time to death from any cause

Primary Endpoint

• Time to first occurrence of any of the

components of the composite: CV

death or hHF or an urgent HF visit

DAPA-HF Key Baseline Characteristics

a Includes 82 dapagliflozin and 74 placebo patients with previously undiagnosed diabetes i.e. two HbA1c ≥6.5% (≥48 mmol/mol).

BP = blood pressure; eGFR = estimated glomerular filtration rate; NT pro BNP = N-terminal pro-B-type natriuretic peptide; NYHA = New York Heart Association; LVEF = left ventricular ejection fraction; T2D = type 2 diabetes.

McMurray J. Presentation at: European Society of Cardiology Congress. September 1, 2019; Paris, France.

Characteristic Dapagliflozin

(n=2373)

Placebo

(n=2371)

Mean age (yr) 66 67

Male (%) 76 77

NYHA class II/III/IV (%) 68/31/1 67/32/1

Mean LVEF (%) 31 31

Median NT pro BNP (pg/mL) 1428 1446

Mean systolic BP (mmHg) 122 122

Ischaemic aetiology (%) 55 57

Mean eGFR (mL/min/1.73m2) 66 66

Prior diagnosis T2D (%) 42 42

Any baseline T2D (%)a 45 45

42

Distribution of Patients by Glycaemic Status

43

HbA1c = glycated haemoglobin.

1. McMurray JJV et al. Article and supplementary appendix. Eur J Heart Fail. 2019;doi: 10.1002/ejhf.1548. Accessed July 16, 2019.

42%

3%

37%

18%History of

diabetes

Euglycaemi

c

Prediabete

s

Undiagnosed diabetes

N=4744

Euglycaemic (n=857)

• HbA1c

Primary Endpoint: CV Death or hHF or an Urgent HF Visit1

44

DAPA = dapagliflozin; HF = heart failure; hHF = hospitalisation for heart failure; HR = hazard ratio; NNT = number needed to treat.

1. McMurray J. Presentation at: European Society of Cardiology Congress. September 1, 2019; Paris, France.

2105931096147819172075216322582371Placebo

2106121146156020022147222123052373DAPA

32

28

24

20

16

12

8

4

0

242115 18129630No. at Risk Months from Randomisation

Cu

mu

lati

ve

Pe

rce

nta

ge

(%

)

36

HR 0.74 (0.65, 0.85)

p=0.00001

NNT = 21

DAPA

Placebo 26% RRR

Absolute Risk Reduction

[ARR]=4% Event rate/100 patient

years:

11.6 vs 15.6; p=0.00001

Component of Primary Endpoint: Worsening HF Event

DAPA = Dapagliflozin; HF = Heart failure; HR = Hazard ratio.


2105931096147819172075216322582371Placebo

2106121146156020022147222123052373DAPA

No. at Risk Months from Randomisation

20

15

10

5

0

242115 18129630

Cu

mu

lati

ve

Pe

rce

nta

ge

(%

)

45

DAPA

Placebo

HR 0.70 (0.59,0.83)

p=0.00003

30% RRR


[ARR]=3% Event rate/100 patient

years:

7.1 vs 10.1; p=0.00003

20

15

10

5

0

242115 18129630

Cu

mu

lati

ve

Pe

rce

nta

ge

(%

)

Component of Primary Endpoint: Cardiovascular Death

DAPA = Dapagliflozin; HR = Hazard ratio.

McMurray J. Presentation at: European Society of Cardiology Congress. September 1, 2019; Paris, France.46

DAPA

Placebo

2346641219163620912230227923302371Placebo

2326711242166421272248229323392373DAPA

No. at Risk Months from Randomisation

HR 0.82 (0.69,0.98)

p=0.029

18% RRR


[ARR]=1.4%

Event rate/100 patient years:

6.5 vs 7.9; p=0.029

Primary Endpoint: Subgroup Analyses

47

*Defined as history of type 2 diabetes or HbA1c ≥6.5% at both enrollment and randomisation visits.


Characteristics

Dapagliflozin

(n=2373)

Placebo

(n=2371) HR (95% CI) HR (95% CI)

All Patients 386/2373 502/2371 0.74 (0.65, 0.85)

Type 2 Diabetes at Baseline*

Yes 215/1075 271/1064 0.75 (0.63, 0.90)

No 171/1298 231/1307 0.73 (0.60, 0.88)

0.800.50 1.00 1.25Placebo BetterDAPA Better

Characteristics

Dapagliflozin

(n=2373)

Placebo

(n=2371) HR (95% CI) HR (95% CI)

All Patients 386/2373 502/2371 0.74 (0.65, 0.85)

Angiotensin Receptor Neprilysin Inhibitor (ARNI)

Yes 41/250 56/258 0.75 (0.50, 1.13)

No 345/2123 446/2113 0.74 (0.65, 0.86)

0.800.50 1.00 1.25Placebo BetterDAPA Better

Prespecified Subgroup

Post-hoc Subgroup

Safety/Adverse Events

+Volume depletion serious AEs in 29 dapagliflozin patients (1.2%) and 40 placebo patients (1.7%), p=0.23‡Renal serious AEs in 38 dapagliflozin patients (1.6%) and 65 placebo patients (2.7%), p=0.009


Patients exposed to at least

one dose of study drug

Dapagliflozin

(n=2368)

Placebo

(n=2368) p-value

Adverse events (AE) of interest (%)

Volume depletion+ 7.5 6.8 0.40

Renal AE‡ 6.5 7.2 0.36

Fracture 2.1 2.1 1.00

Amputation 0.5 0.5 1.00

Major hypoglycaemia 0.2 0.2 -

Diabetic ketoacidosis 0.1 0.0 -

AE leading to treatment discontinuation (%) 4.7 4.9 0.79

Any serious adverse event (incl. death) (%) 38 42

Summary and conclusions

• SGLT2i reduce HbA1c, weight and blood pressure in T2DM

• Three major CV outcome trials show that SGLT2i reduce cardiovascular events,

especially heart failure in T2DM

• There is clear evidence that SGLT2i reduce MACE for those with established

cardiovascular disease

• Heart failure events are reduced independent of baseline ejection fraction, but

those with reduced ejection fraction may have greatest benefit

• SGLT2i improve renal outcomes in T2DM

• Cardiovascular benefit also seen in older people, without an increase in adverse

effects

• DAPA-HF shows SGLT2i also effective in people with HF without diabetes

• SGLT2i should be considered in patients with type 2 diabetes: known

cardiovascular disease and / or heart failure, diabetic nephropathy

Future Landscape for SGLT2i

• Ongoing trials in HF including HFpEF with and without

diabetes

• Trials in other chronic kidney disease ongoing

Likely widespread use in HF and kidney disease if

benefits confirmed

• Recent approval for dapagliflozin in type 1 diabetes

Likely more widespread use if renal benefits also

shown in T1DM

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DECLARE One Year On · 2020. 7. 21. · R •MACE •Composite of hospitalization for heart failure...

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