DECLARE One Year On John Wilding Obesity & Endocrinology - - PowerPoint PPT Presentation

▶
declare one year on
SMART_READER_LITE
LIVE PREVIEW

DECLARE One Year On John Wilding Obesity & Endocrinology - - PowerPoint PPT Presentation

Sep 02, 2023 115 likes •647 views

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

slide-1
SLIDE 1

DECLARE One Year On

John Wilding Obesity & Endocrinology Clinical Research University of Liverpool & Aintree University Hospital Liverpool, UK

slide-2
SLIDE 2

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

slide-3
SLIDE 3

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 2 Adapted from: Abdul-Ghani MA, et al. Endocr Rev. 2011;32:515–31.

slide-4
SLIDE 4

Is Isch chaemic heart dis isease is is th the le leading cause of f mortality in in patients with ith T2D1

35% 15% 10%

40%

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

Non-cardiovascular causes Ischaemic heart disease Other heart disease (predominantly congestive) Stroke

slide-5
SLIDE 5

T2 T2D in increases th the ris risk of f developing heart failu ilure

  • 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. Heart

fail 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

  • f 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

slide-6
SLIDE 6

Trial Name (SGLT-2 Inhibitor) Target Enrollment Timing EMPA-REG OUTCOME (empagliflozin) N=7000 All 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=3700 Began 2014; Reported April 2019 VERTIS (ertugliflozin) N=8000 Began 2013- ending 2019

SGLT2i outcome trials in T2DM

slide-7
SLIDE 7

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 <12%, CrCl ≥60 ml/min, ≥55 yrs (m) or ≥60 yrs (f) with ≥1 CV risk factor OR ≥40 yrs with eASCVD

All other glucose-lowering agents per treating physician 1:1 double-blind

Study design

Single-blind PBO run-in (1–2 months) R

  • MACE
  • Composite of hospitalization for heart

failure or CV death

Dual Primary efficacy endpoints Primary safety endpoint

  • Composite of CV death, nonfatal MI, or

nonfatal ischemic stroke (MACE)

Secondary endpoints

  • Cardiorenal composite

endpoint

  • All-cause mortality

Raz I, et al. Diabetes Obes Metab 2018;20:1102–1110;. Wiviott SD, et al. Am Heart J 2018;200:83–89; 3. Wiviott SD, et al. N Engl J Med 2018 [Epub ahead of print]

slide-8
SLIDE 8
slide-9
SLIDE 9
slide-10
SLIDE 10
slide-11
SLIDE 11

5 10 15 20 25 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, MI or stroke

slide-12
SLIDE 12

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 %

Cumulative incidence

HR = 0.84 (95 % CI 0.72 to 0.99) HR = 1.00 (95 % CI 0.88 to 1.13)

slide-13
SLIDE 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 %

Cumulative incidence

HR = 0.81 (95 % CI 0.65 to 1.00) HR = 0.85 (95 % CI 0.72 to 1.00)

slide-14
SLIDE 14
slide-15
SLIDE 15

Hospitalisation for HF

14 2.5% vs 3.3% HR 0.73 (0.61-0.88) P<0.001

slide-16
SLIDE 16

DECLARE-TIMI-58 N=17,160* HFrEF EF <45% N=671 Not HFrEF N=16,489

Heart Failure: Ejection Fraction analysis - Methods

*EF available in 5202 pts

15

History of HF No history

  • f HF

HF without known rEF

EF≥45% n=808 EF unknown n=508

N=1,316 No HF N=15,173

slide-17
SLIDE 17

20 10 5 15

1 2 3 4

16

HFrEF: HR 0.64 [0.43, 0.95] Cumulative incident 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 15

P for interaction: 0.012

yrs

CV death

12.4% 7.2% 2.5% 2.3%

1 2 3 4

Not HFrEF: HR 1.08 [0.89, 1.31] Not HFrEF: HR 0.76 [0.62, 0.92] Dapagliflozin Placebo Dapagliflozin Placebo Not HFrEF: (N=16,489 ) HFrEF: (N=671)

HHF and CV Death

by HFrEF vs not HFrEF subgroups

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

slide-18
SLIDE 18

Distribution of eGFR Categories Amongst the DECLARE-TIMI 58 Population

eGFR ≥90 48% (n=8162) eGFR 60 to <90 45% (n=7732) eGFR <60 7% (n=1265) Total # of Patients:

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

slide-19
SLIDE 19

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

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

slide-20
SLIDE 20

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

Lancet Diabetes Endocrinol. 2019 Jun 10. pii: S2213-8587(19)30180-9 Renal composite 40% reduction in eGFR to < 60 ml/min/1.73 m2 end-stage renal disease renal dealh

slide-21
SLIDE 21

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

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

slide-22
SLIDE 22

The Renal-Specific Outcome Predefined Sub-Group Analyses (2)

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

slide-23
SLIDE 23

The Renal-Specific Outcome Predefined Sub-Group Analyses (3)

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

slide-24
SLIDE 24

Explo loratory ry renal outcomes in in SGLT2i CV outcomes tria 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

slide-25
SLIDE 25

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

5 10 15 20 25 26 52 78 104 130 156 182

Participants with an event (%) 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

Participants with an event (%)

slide-26
SLIDE 26

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.

slide-27
SLIDE 27

Baseline Characteristics

Characteristic Age < 65 Age ≥65-<75 Age ≥75 P-Trend

(N = 9253) (N = 6811) (N = 1096) Duration of diabetes (years), Median (IQR) 10.0* (5.0, 15.0) 12.0 (7.0, 18.0) 14.0 (8.0, 20.0) <.0001 Male Sex, N (%) 6203 (67.0) 3873 (56.9) 662 (60.4) <.0001 White, N (%) 7052 (76.2) 5639 (82.8) 962 (87.8) <.0001 Black, N (%) 351 (3.8) 222 (3.3) 30 (2.7) 0.0203 Asian, N (%) 1493 (16.1) 727 (10.7) 83 (7.6) <.0001 BMI, Median (IQR) 31.6* (28.0, 35.9) 31.1* (27.8, 35.0) 30.2* (27.4, 33.9) <.0001 Established ASCVD N (%) 3973 (42.9) 2519 (37.0) 482 (44.0) <.0001 History of HF, N (%) 886 (9.6) 682 (10.0) 156 (14.2) 0.0002 eGFR, Median (IQR) 94.0* (81.0, 100.0) 84.0 (70.0, 92.0) 75.0 (64.0, 84.0) <.0001 HbA1c, Median (IQR) 8.2* (7.5, 9.3) 7.9* (7.3, 8.7) 7.8* (7.2, 8.5) <.0001

*Data missing for up to 4 persons

slide-28
SLIDE 28

Baseline Characteristics

Characteristic Age < 65 Age ≥65-<75 Age ≥75 P-Trend

(N = 9253) (N = 6811) (N = 1096) Metformin, N (%) 7702 (83.2) 5572 (81.8) 794 (72.4) <.0001 SU, N (%) 3962 (42.8) 2882 (42.3) 478 (43.6) 0.9301 Insulin, N (%) 3779 (40.8) 2805 (41.2) 429 (39.1) 0.6789 Statin, N (%) 6772 (73.2) 5164 (75.8) 823 (75.1) 0.001 ACE Inhibitor/ARB, N (%) 7404 (80.0) 5629 (82.6) 917 (83.7) <.0001 Any diuretic, N (%) 3453 (37.3) 3000 (44.0) 514 (46.9) <.0001 Diuretics - loops, N (%) 832 (9.0) 791 (11.6) 183 (16.7) <.0001 Antiplatelet Therapy, N (%) 5605 (60.6) 4171 (61.2) 711 (64.9) 0.0203 Beta Blockers, N (%) 4854 (52.5) 3570 (52.4) 606 (55.3) 0.2689

slide-29
SLIDE 29

Metabolic Efficacy

slide-30
SLIDE 30

7.2 7.4 7.6 7.8 8 8.2 8.4 8.6 1 2 3 4

Adjusted Mean HbA1c (%) Years

<65, Placebo <65, Dapa 65-<75, Placebo

HbA1c Changes in the Age Groups

slide-31
SLIDE 31

80 82 84 86 88 90 92 94 0.5 1 1.5 2 2.5 3 3.5 4 Adjusted Mean Weight Years

<65, Placebo <65, Dapa 65-<75, Placebo

Weight Changes in the Age Groups

slide-32
SLIDE 32

129 130 131 132 133 134 135 136 137 138

1 2 3 4

Adjusted Mean Systolic Blood Pressure

Years

<65, Placebo <65, Dapa 65-<75, Placebo

Systolic BP in the Age Groups

slide-33
SLIDE 33

Cardiovascular and Renal Efficacy

slide-34
SLIDE 34

Efficacy Outcomes

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

slide-35
SLIDE 35

Efficacy Outcomes

slide-36
SLIDE 36

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 <65
  • 0.88 (0.81, 0.95) in age ≥65-<75
  • 1.02 (0.85, 1.21) in age ≥75

Interaction p value 0.2667

  • No heterogeneity across age groups was observed for any of the outcomes

assessed, although the number of events in the very elderly was often quite small yielding wide confidence intervals in this age category.

slide-37
SLIDE 37

Safety Outcomes

96 96 21 86 90 31

0.0% 1.0% 2.0% 3.0% 4.0% 5.0% 6.0% < 65 years ≥65-< 75 years ≥ 75 years

58 56 11 80 73 22

0.0% 0.5% 1.0% 1.5% 2.0% 2.5% 3.0% 3.5% 4.0% 4.5% < 65 years ≥65-< 75 years ≥ 75 years

HR 0.69 (0.49, 0.97) P=0.03

Volume depletion Acute kidney injury

Interaction P-value 0.6922 Interaction P-value 0.4046

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

slide-38
SLIDE 38

166 261 54 175 251 60

0.0% 2.0% 4.0% 6.0% 8.0% 10.0% 12.0% < 65 years ≥65-< 75 years ≥ 75 years

Safety outcomes

205 212 40 200 208 32

0.0% 1.0% 2.0% 3.0% 4.0% 5.0% 6.0% 7.0% 8.0% 9.0% < 65 years ≥65-< 75 years ≥ 75 years

Fractures Malignancies

Interaction P-value 0.7577 Interaction P-value 0.5245

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

Dapagliflozin Placebo

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=0.83 HR 1.04 (0.91, 1.18), p=0.59

slide-39
SLIDE 39

Safety outcomes

28 21 9 28 41 14

0.0% 0.5% 1.0% 1.5% 2.0% 2.5% 3.0% < 65 years ≥65-< 75 years ≥ 75 years

15 9 3 7 3 2

0.0% 0.2% 0.4% 0.6% 0.8% 1.0% < 65 years ≥65-< 75 years ≥ 75 years

HR 2.05 (0.84, 5.03) P=0.12

Major hypoglycemia Diabetic ketoacidosis*

Interaction P-value 0.8433 Interaction P-value 0.2107

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<0.01

Dapagliflozin Placebo

HR 2.89 (0.78, 10.69) P=0.11 HR 1.63 (0.27, 9.81) P=0.59

HR 2.18 (1.10, 4.30), p=0.02 HR 0.68 (0.49, 0.95), p=0.02

*Adjudicated as definite or probable

slide-40
SLIDE 40

37 35 4 6 1 2

0.0% 0.2% 0.4% 0.6% 0.8% 1.0% 1.2% 1.4% 1.6% < 65 years ≥65-< 75 years ≥ 75 years

Safety Outcomes

48 63 16 55 68 10

0.0% 0.5% 1.0% 1.5% 2.0% 2.5% 3.0% 3.5% < 65 years ≥65-< 75 years ≥ 75 years

Urinary tract infections

*

Genital infections*

Interaction P-value 0.1058 Interaction P-value 0.3066

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

Dapagliflozin Placebo

HR 6.07 (2.56, 14.38) P<0.01 HR 1.99 (0.36, 10.87) P=0.43 HR 34.55 (4.73, 252.17) P<0.01

HR 8.36 (4.19, 16.68), p<0.001 HR 0.93 (0.73, 1.18), p=0.54

*Serious or leading to drug discontinuation

slide-41
SLIDE 41

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.

slide-42
SLIDE 42

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 Double-blind

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 -14 Visit 2 (randomisation) Day 0 Visit 6, etc. Every 120 days Visit 5 Day 120 Visit 3 Day 14 Visit 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

slide-43
SLIDE 43

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

slide-44
SLIDE 44

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 <5.7% at Visits 1 and 2

History of diabetes (n=1983)

  • Provided by investigators

Undiagnosed diabetes (n=154)

  • HbA1c ≥6.5% at Visits 1 and 2 in

patients without diabetes history Prediabetes (n=1750)

  • HbA1c ≥5.7% at Visits 1 and 2 in

patients without known or undiagnosed diabetes

3 %

slide-45
SLIDE 45

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.

210 593 1096 1478 1917 2075 2163 2258 2371 Placebo 210 612 1146 1560 2002 2147 2221 2305 2373 DAPA 32 28 24 20 16 12 8 4 24 21 15 18 12 9 6 3

  • No. at Risk

Months from Randomisation Cumulative Percentage (%) 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

slide-46
SLIDE 46

Component of Primary Endpoint: Worsening HF Event

DAPA = Dapagliflozin; HF = Heart failure; HR = Hazard ratio. McMurray J. Presentation at: European Society of Cardiology Congress. September 1, 2019; Paris, France.

210 593 1096 1478 1917 2075 2163 2258 2371 Placebo 210 612 1146 1560 2002 2147 2221 2305 2373 DAPA

  • No. at Risk

Months from Randomisation 20 15 10 5 24 21 15 18 12 9 6 3 Cumulative Percentage (%)

45

DAPA Placebo HR 0.70 (0.59,0.83) p=0.00003

30% RRR

Absolute Risk Reduction [ARR]=3% Event rate/100 patient years: 7.1 vs 10.1; p=0.00003

slide-47
SLIDE 47

20 15 10 5 24 21 15 18 12 9 6 3 Cumulative Percentage (%)

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

234 664 1219 1636 2091 2230 2279 2330 2371 Placebo 232 671 1242 1664 2127 2248 2293 2339 2373 DAPA

  • No. at Risk

Months from Randomisation

HR 0.82 (0.69,0.98) p=0.029

18% RRR

Absolute Risk Reduction [ARR]=1.4% Event rate/100 patient years: 6.5 vs 7.9; p=0.029

slide-48
SLIDE 48

Primary Endpoint: Subgroup Analyses

47 *Defined as history of type 2 diabetes or HbA1c ≥6.5% at both enrollment and randomisation visits. McMurray J. Presentation at: European Society of Cardiology Congress. September 1, 2019; Paris, France. 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) 0.80 0.50 1.00 1.25 Placebo Better DAPA 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) 0.80 0.50 1.00 1.25 Placebo Better DAPA Better

Prespecified Subgroup Post-hoc Subgroup

slide-49
SLIDE 49

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

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

Patients exposed to at least

  • ne 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 <0.01

48

slide-50
SLIDE 50

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

slide-51
SLIDE 51

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