Diabetes Treatment and Heart Failure From Preventing Harm to - - PDF document

▶
diabetes treatment and heart failure
SMART_READER_LITE
LIVE PREVIEW

Diabetes Treatment and Heart Failure From Preventing Harm to - - PDF document

Jan 17, 2023 230 likes •601 views

Diabetes Treatment and Heart Failure From Preventing Harm to Increasing Survival Jonathan D Davis, MD, MPHS Director, Heart Failure Program Assistant Clinical Professor | Division of Cardiology Zuckerberg San Francisco General Hospital

slide-1
SLIDE 1

1 | [footer text here]

Zuckerberg San Francisco General

Diabetes Treatment and Heart Failure

From Preventing Harm to Increasing Survival Jonathan D Davis, MD, MPHS

Director, Heart Failure Program Assistant Clinical Professor | Division of Cardiology Zuckerberg San Francisco General Hospital Department of Medicine | University of California, San Francisco jonathan.davis@ucsf.edu | @JonathanDavisHF December 6, 2019

1

Zuckerberg San Francisco General

Disclosures

§ I have no financial disclosures.

Diabetes Medications and Heart Failure 2

2

slide-2
SLIDE 2

2 | [footer text here]

Zuckerberg San Francisco General

Overview

A Journey From Preventing Harm to Increasing Survival § The Beginning and Lessons Learned

  • Rosiglitazone, the FDA, and Saxaglitptin

§ GLP1-RA § SGLT2-I and Cardiovascular Outcomes

  • Canagliflozin, Empagliflozin, Dapagliflozin

§ National Society Recommendations § Practical Tips for Everyday Practice

Diabetes Medications and Heart Failure 3

3

Zuckerberg San Francisco General

Since I was asked to give this talk…

§ September

  • European Society of Cardiology Conference

§ DAPA-HF & DEFINE-HF results released

  • ACC/AHA Primary Prevention of Cardiovascular Disease

Guideline Update

§ October

  • FDA fast tracks dapagliflozin for heart failure

§ November

  • AHA Annual Meeting

Diabetes Medications and Heart Failure 4

4

slide-3
SLIDE 3

3 | [footer text here]

Zuckerberg San Francisco General

The Beginning and Lessons Learned

5

Zuckerberg San Francisco General

Diabetes Medications and Heart Failure 6

§ Meta-analysis of 42 trials with rosiglitazone vs. placebo § Mean age ~56 years, and the mean baseline Hgb A1c

~8.2%

§ For rosiglitazone as compared to placebo:

  • Odds ratio for MI: 1.43 (95% CI, 1.03 to 1.98; P=0.03)
  • Odds ratio for death from cardiovascular causes: 1.64 (95%

CI, 0.98 to 2.74; P=0.06) June 14, 2007

6

slide-4
SLIDE 4

4 | [footer text here]

Zuckerberg San Francisco General

Changes to the FDA – December 2008

§ “To establish the safety of a new antidiabetic therapy to

treat type 2 diabetes, sponsors should demonstrate that the therapy will not result in an unacceptable increase in cardiovascular risk.”

Diabetes Medications and Heart Failure 7

  • FDA. Guidance for Industry Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes

7

Zuckerberg San Francisco General

§ Selective dipeptidyl peptidase 4 (DPP-4) inhibitor § 16,492 patients with Type 2 DM (A1c 6.5-12%) who had a

history of, or were at risk for, cardiovascular events

§ Randomized to saxagliptin or placebo § Followed for a median of 2.1 years

Diabetes Medications and Heart Failure 8

SAVOR-TIMI 53. N Engl J Med 2013;369:1317-26

October 3, 2013 SAVOR- TIMI 53

8

slide-5
SLIDE 5

5 | [footer text here]

Zuckerberg San Francisco General

SAVOR-TIMI 53: Saxagliptin vs. Placebo

§ No difference in primary end point of composite of

cardiovascular death, myocardial infarction, or ischemic stroke

  • Hazard ratio 1.00 (95% CI, 0.89 to 1.12; P=0.99 for superiority)

§ More patients in the saxagliptin group were hospitalized

for heart failure (3.5% vs. 2.8%; hazard ratio, 1.27; 95% CI, 1.07 to 1.51; P=0.007)

Diabetes Medications and Heart Failure 9

SAVOR-TIMI 53. N Engl J Med 2013;369:1317-26

9

Zuckerberg San Francisco General

Glucagon-Like Peptide 1 Receptor Agonists

10

slide-6
SLIDE 6

6 | [footer text here]

Zuckerberg San Francisco General

Glucagon-Like Peptide 1 Receptor Agonists (GLP-1RAs)

§ GLP-1 is a peptide hormone released from the distal

ileum and colon after oral nutrient intake

§ Increased levels of GLP-1 increase glucose-dependent

insulin secretion, decrease glucagon secretion, and delay gastric emptying (leads to satiety)

Diabetes Medications and Heart Failure 11 2018 ACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease. JACC. 2018.

11

Zuckerberg San Francisco General

Liraglutide

§ Only GLP-1 that has definitively demonstrated

significantly reduce CV events.

  • 3-point MACE composite was reduced by 13% (HR: 0.87;

95% CI: 0.78 to 0.97; p = 0.01 for superiority)

Diabetes Medications and Heart Failure 12 2018 ACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease. JACC. 2018.

12

slide-7
SLIDE 7

7 | [footer text here]

Zuckerberg San Francisco General

The SGLT2-Inhibitors

13

Zuckerberg San Francisco General

SGLT2-Inhibitor Mechanism of Action

§ Sodium-glucose cotransporter in the proximal tubule of

the nephron

  • Responsible for ~90% of urinary glucose reabsorption

§ Inhibition of SGLT2 results in glucose lowering through

induction of glucosuria

  • Effect is more pronounced in the setting of hyperglycemia

Diabetes Medications and Heart Failure 14 2018 ACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease. JACC. 2018.

14

slide-8
SLIDE 8

8 | [footer text here]

Zuckerberg San Francisco General

§ 7020 patients for median observation time of 3.1 years § Primary composite outcome: death from cardiovascular

causes, nonfatal myocardial infarction, or nonfatal stroke

§ Inclusion:

  • eGFR ≥ 30 ml per minute per 1.73 m2 of body-surface area
  • A1c 7-10% if had received stable glucose-lowering therapy

for at least 12 weeks before randomization

Diabetes Medications and Heart Failure 15

EMPA-REG OUTCOME. N Engl J Med 2015;373:2117-28.

EMPA-REG OUTCOME November 26, 2015

15

Zuckerberg San Francisco General

EMPA-REG Baseline Characteristics

§ Mean age 63 years ± 8.7 § Hemogloblin A1c 8.1% § 99% with Cardiovascular disease

  • Coronary artery disease – 75%
  • Prior myocardial infarction – 46%
  • Heart Failure – 10%

§ ACE/ARB – 80%; Beta-blocker – 64%; MRA – 6%

Diabetes Medications and Heart Failure 16

Neal BMB, et al. N Engl J Med 2017; 377:644-657

16

slide-9
SLIDE 9

9 | [footer text here]

Zuckerberg San Francisco General

Diabetes Medications and Heart Failure 17 EMPA-REG OUTCOME. N Engl J Med 2015;373:2117-28.

17

Zuckerberg San Francisco General

EMPA-REG OUTCOME. N Engl J Med 2015;373:2117-28.

Glycemic Control

18

slide-10
SLIDE 10

10 | [footer text here]

Zuckerberg San Francisco General

Diabetes Medications and Heart Failure 19

EMPA-REG

  • OUTCOME. N Engl

J Med 2015;373:2117-28.

19

Zuckerberg San Francisco General

§ 10,142 participants with type 2 diabetes and high

cardiovascular risk

§ Primary Outcome: Composite of death from

cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke

§ Mean age 63.3 years, 35.8% were women, the mean

duration of diabetes was 13.5 years, and 65.6% had a history of cardiovascular disease

Diabetes Medications and Heart Failure 20

Neal BMB, et al. N Engl J Med 2017; 377:644-657

CANVAS Program August 17, 2017

20

slide-11
SLIDE 11

11 | [footer text here]

Zuckerberg San Francisco General

Canagliflozin – CANVAS Program

§ Primary outcome: 26.9 vs. 31.5 events per 1000 patient-

years (HR, 0.86; 95% CI, 0.75 to 0.97;P=0.02 for superiority)

§ No statistical significance for the 3 components of the

primary outcome — death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke.

§ Increased risk of amputation (6.3 vs. 3.4 participants per

1000 patient-years; HR, 1.97; 95% CI, 1.41 to 2.75)

Diabetes Medications and Heart Failure 21

Neal BMB, et al. N Engl J Med 2017; 377:644-657

21

Zuckerberg San Francisco General

§ 17,160 patients, including 10,186 without atherosclerotic

cardiovascular disease, followed for a median of 4.2 years

§ Primary safety outcome: composite of major adverse

cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke.

Diabetes Medications and Heart Failure 22

DECLARE-TIMI 58. N Engl J Med 2019;380:347-57.

DECLARE- TIMI 58 January 24, 2019

22

slide-12
SLIDE 12

12 | [footer text here]

Zuckerberg San Francisco General

DECLARE-TIMI 58, cont.

§ Dapagliflozin did not lower rate of MACE (8.8% vs. 9.4%;

HR 0.93; 95% CI, 0.84 to 1.03; P=0.17)

§ Lower rate of CV death or hospitalization for HF (4.9% vs.

5.8%; HR 0.83; 95% CI, 0.73 to 0.95; P=0.005)

  • Reflected a lower rate of hospitalization for HF (HR, 0.73;

95% CI, 0.61 to 0.88);

  • No between-group difference in CV death (HR, 0.98; 95% CI,

0.82 to 1.17).

Diabetes Medications and Heart Failure 23

DECLARE-TIMI 58. N Engl J Med 2019;380:347-57.

23

Zuckerberg San Francisco General

Diabetes Medications and Heart Failure 24

Kluger AY et al. Cardiovasc Diabetol (2019) 18:99

HHF HHF HHF HHF MACE MACE MACE MACE HHF or CV death HHF or CV death HHF or CV death HHF or CV death HHF: Hospitalization for HF MACE: Major adverse cardiovascular events

24

slide-13
SLIDE 13

13 | [footer text here]

Zuckerberg San Francisco General

DAPA-HF

25

Zuckerberg San Francisco General

§ Dapagliflozin 10 mg vs. placebo, 4744 patients § New York Heart Association class II, III, or IV § Ejection fraction of 40% or less § 60% of enrolled WITHOUT Diabetes § Primary outcome was a composite of worsening HF

(hospitalization or an urgent visit resulting in IV therapy for HF) or CV death

Diabetes Medications and Heart Failure 26

Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. NEJM. 9/19/19.

DAPA-HF September 19, 2019

26

slide-14
SLIDE 14

14 | [footer text here]

Zuckerberg San Francisco General

Diabetes Medications and Heart Failure 27

DAPA-HF. NEJM. 9/19/19.

Characteristic Dapagliflozin (N = 2373) Placebo (N = 2371) Age – years 66.2 ± 11.0 66.5 ± 10.8 Female – No. (%) 564 (23.8) 545 (23.0) Race – No. (%) White 1662 (70) 1671 (70.5) Black 122 (5.1) 104 (4.4) Asian 552 (23.3) 564 (23.8) NYHA Class – No. (%) II 1606 (67.7) 1597 (67.4) III 747 (31.5) 751 (31.7) IV 20 (0.8) 23 (1.0) Principal Cause of HF – No. (%) Ischemic 1316 (55.5) 1358 (57.3) Nonischemic 857 (36.1) 830 (35.0)

27

Zuckerberg San Francisco General

Diabetes Medications and Heart Failure 28

DAPA-HF. NEJM. 9/19/19.

Characteristic Dapagliflozin (N = 2373) Placebo (N = 2371) HF Medication – No. (%) ACE Inhibitor 1332 (56.1) 1329 (56.1) ARB 675 (28.4) 632 (26.7) Sacubitril-valsartan 250 (10.5) 258 (10.9) Beta-blocker 2278 (96.0) 2280 (96.2) MRA 1696 (71.5) 1674 (70.6) Diuretic 2216 (93.4) 2217 (93.5) Digitalis 445 (18.8) 442 (18.6) Device Therapy – No. (%) ICD 622 (26.2) 620 (26.1) CRT 190 (8.0) 164 (6.9)

~96%

28

slide-15
SLIDE 15

15 | [footer text here]

Zuckerberg San Francisco General

Diabetes Medications and Heart Failure 29 DAPA-HF. NEJM. 9/19/19.

29

Zuckerberg San Francisco General

Similar Outcomes Regardless of Diabetes Status

Diabetes Medications and Heart Failure 30

DAPA-HF. NEJM. 9/19/19.

30

slide-16
SLIDE 16

16 | [footer text here]

Zuckerberg San Francisco General

Diabetes Medications and Heart Failure 31

DAPA-HF. NEJM. 9/19/19. Variable Dapagliflozin Placebo P Value (N=2373) (N=2371)

31

Zuckerberg San Francisco General

Dapagliflozin and Quality of Life (QoL)

The DEFINE-HF Trial § 263 patients randomized to dapagliflozin 10 mg daily or

placebo for 12 weeks

§ Kansas City Cardiomyopathy Questionnaire

  • Increased in proportion of patients experiencing clinically

meaningful improvements in HF-related health status (42.9 vs 32.5%, adjusted OR 1.73, 95% CI 0.98–3.05)

Diabetes Medications and Heart Failure 32

Nassif, M et al. Circulation. 2019;140:00–00

32

slide-17
SLIDE 17

17 | [footer text here]

Zuckerberg San Francisco General

Mechanism of Action & Risks

33

Zuckerberg San Francisco General

Proposed Mechanism of Cardiorenal Protection

Diabetes Medications and Heart Failure 34

Verma S, et al. JAMA Cardiol. 2017;2(9):939-940.

34

slide-18
SLIDE 18

18 | [footer text here]

Zuckerberg San Francisco General

“Euglycemic” Diabetic Ketoacidosis

§ Consider if patient feels unwell or nauseous

  • Esp. if inappropriate reduction of insulin doses or anything

increasing insulin demand (e.g., stress, acute illness, alcohol)

§ Check for blood and urine ketones! § Temporarily stop the SGLT2 inhibitor § Contact medical provider § Maintain vigorous fluid intake & consume carbohydrates

Diabetes Medications and Heart Failure 35 Rosenstock J and Ferrannini E. Diabetes Care 2015 Sep; 38(9): 1638-1642.

35

Zuckerberg San Francisco General

Euglycemic Diabetic Ketoacidosis

§ Pooled rate in EMPA-REG, DECLARE, DAPA-HF:

  • 0.22% (34/15634) in SGLT2-i vs. 0.10% (13/13273) in placebo

§ As of May 2015, a total of 101 reported cases worldwide

in T2D patients treated with SGLT2-I, with an estimated exposure over 250,000 patient-years

Diabetes Medications and Heart Failure 36

Peters AL, et al. Diabetes Care 2015 Sep; 38(9): 1687-1693. Rosenstock J and Ferrannini E. Diabetes Care 2015 Sep; 38(9): 1638-1642.

36

slide-19
SLIDE 19

19 | [footer text here]

Zuckerberg San Francisco General

Societal Recommendations and The FDA

37

Zuckerberg San Francisco General

2019 ACC/AHA Guideline: Primary Prevention of Cardiovascular Disease

“If medication is indicated, metformin is first-line therapy, followed by consideration of a sodium-glucose cotransporter 2 inhibitor or a glucagon-like peptide-1 receptor agonist”

Diabetes Medications and Heart Failure 38

Arnett DK, et al. J Am Coll Cardiol. 2019 Sep, 74 (10) 1376-1414.

38

slide-20
SLIDE 20

20 | [footer text here]

Zuckerberg San Francisco General

Diabetes Medications and Heart Failure 39

American Diabetes Association. Diabetes Care 2019 Jan; 42(Supplement 1): S90-S102.

39

Zuckerberg San Francisco General

FDA Fast Track Designation for HF

§ Empagliflozin: June 26, 2019 for chronic HF § Dapagliflozin: October 16, 2019 for worsening HF

Diabetes Medications and Heart Failure 40

Peters AL, et al. Diabetes Care 2015 Sep; 38(9): 1687-1693. Rosenstock J and Ferrannini E. Diabetes Care 2015 Sep; 38(9): 1638-1642.

40

slide-21
SLIDE 21

21 | [footer text here]

Zuckerberg San Francisco General

Summary and Future Directions

41

Zuckerberg San Francisco General

Diabetes Medications and Heart Failure 42

42

slide-22
SLIDE 22

22 | [footer text here]

Zuckerberg San Francisco General

Diabetes Medications and Heart Failure 43

43

Zuckerberg San Francisco General

HFpEF Overview 44

44

slide-23
SLIDE 23

23 | [footer text here]

Zuckerberg San Francisco General

Quadruple Therapy for HF with Reduced EF?

Beta-blocker

+

ACE/ARB/ARNI

+

Mineralocorticoid Receptor Antagonist

+

SGLT2-I (?)

Diabetes Medications and Heart Failure 45

45

Zuckerberg San Francisco General

Quadruple Therapy for HF with Reduced EF

Beta-blocker

+

ARNI

+

Mineralocorticoid Receptor Antagonist

+

SGLT2-I

Diabetes Medications and Heart Failure 46

46

slide-24
SLIDE 24

24 | [footer text here]

Zuckerberg San Francisco General

Trials in Progress

Type II Diabetes NOT an inclusion criterion § Dapagliflozin

  • DELIVER - dapagliflozin 10 mg versus placebo in HFpEF

§ Empagliflozin 10 mg in EMPEROR program

  • EMPEROR-Reduced
  • EMPEROR-Preserved

Diabetes Medications and Heart Failure 47

47

Zuckerberg San Francisco General

In Conclusion

§ Must view SGLT2-I as a cardiac medication rather than a

diabetes medication

§ SGLT2-I as a class reduce HF admission § FOR NOW

  • WITH DIABETES: Empagliflozin over dapagliflozin for

reducing mortality

§ EMPA-REG OUTCOME vs. DECLARE-TIMI 58

  • WITHOUT DIABETES: Dapagliflozin for reducing mortality in

HFrEF without diabetes based on DAPA-HF

Diabetes Medications and Heart Failure 48

48

slide-25
SLIDE 25

25 | [footer text here]

Zuckerberg San Francisco General

Thank you!

jonathan.davis@ucsf.edu @JonathanDavisHF

49

Zuckerberg San Francisco General

Extra Slides

Diabetes Medications and Heart Failure 50

50

slide-26
SLIDE 26

26 | [footer text here]

Zuckerberg San Francisco General

Future Impacts of Rosiglitazone

§ Joint meeting of the Endocrinologic and Metabolic Drug

Advisory Committee and the Drug Safety and Risk Management Advisory Committee of the FDA

  • Concluded that rosiglitazone, an insulin-sensitizing agent

used in treating type 2 diabetes mellitus, was associated with an increased risk of myocardial ischemia

Diabetes Medications and Heart Failure 51

Rosen CJ. N Engl J Med 2010; 363:803-806

51

Zuckerberg San Francisco General

Changes to the FDA

Diabetes Medications and Heart Failure 52

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/diabetes-mellitus-evaluating- cardiovascular-risk-new-antidiabetic-therapies-treat-type-2-diabetes. Last Accessed 10/17/19.

52

slide-27
SLIDE 27

27 | [footer text here]

Zuckerberg San Francisco General

Requirements of Trial Sponsors

§ Independent cardiovascular endpoints committee § Phase 2 and phase 3 clinical trials must be designed and

conducted to facilitate future meta-analysis and perform them!

Diabetes Medications and Heart Failure 53

  • FDA. Guidance for Industry Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes

53

Zuckerberg San Francisco General

SAVOR-TIMI 53: Saxagliptin vs. Placebo

§ Established cardiovascular disease:

  • At least 40 years old and have a history of a clinical event

associated with atherosclerosis involving the coronary, cerebrovascular, or peripheral vascular system.

§ Multiple risk factors for cardiovascular disease:

  • At least 55 years of age (men) or 60 years of age (women) with at

least one of the following additional risk factors:

§ dyslipidemia, hypertension, or active smoking

Diabetes Medications and Heart Failure 54

SAVOR-TIMI 53. N Engl J Med 2013;369:1317-26

54

slide-28
SLIDE 28

28 | [footer text here]

Zuckerberg San Francisco General

EMPA-REG OUTCOME Baseline

Diabetes Medications and Heart Failure 55

EMPA-REG OUTCOME. N Engl J Med 2015;373:2117-28.

Characteristic Placebo (N = 2333) Pooled empagliflozin (N = 4687) Hemoglobin A1c (%) 8.1 ± 0.8 8.1 ± 0.9 CV Risk Factor – No. (%) 2307 (98.9) 4657 (99.4) Coronary artery disease 1763 (75.6) 3545 (75.6) History of MI 1083 (46.4) 2190 (46.7) History of Stroke 553 (23.7) 1084 (23.1) Peripheral Vascular Disease 479 (20.5) 982 (21.0) Cardiac Failure 244 (10.5) 462 (9.9) DM Medications Metformin 1734 (74.3) 3459 (73.8) Insulin 1135 (48.6) 2252 (48.0) CV Medications ACE/ARB 1868 (80.1) 3798 (81.0) Beta blocker 1498 (64.2) 3056 (65.2) MRA 136 (5.8) 305 (6.5)

55

Zuckerberg San Francisco General

EMPA-REG OUTCOME Cont.

10 mg empagliflozin group § A1c lowered by 0.54% (95% CI, −0.58 to −0.49) § Primary outcome occurred in a significantly lower

percentage of patients in the empagliflozin group (10.5%) than in the placebo group (12.1%) (HR, 0.86; 95% CI, 0.74 to 0.99; P=0.04 for superiority)

Diabetes Medications and Heart Failure 56

EMPA-REG OUTCOME. N Engl J Med 2015;373:2117-28.

56

slide-29
SLIDE 29

29 | [footer text here]

Zuckerberg San Francisco General

Key Results

10 mg empagliflozin group § A1c lowered by 0.54% (95% CI, −0.58 to −0.49) § Significantly lower risk of death from cardiovascular

causes (HR, 0.62; 95% CI, 0.49 to 0.77; P<0.001)

§ Significantly lower risk of death from any cause (HR,

0.68; 95% CI, 0.57 to 0.82, P<0.001)

§ Significantly lower risk of hospitalization for heart failure

(HR, 0.65; 95% CI, 0.50 to 0.85; P=0.002)

Diabetes Medications and Heart Failure 57

EMPA-REG OUTCOME. N Engl J Med 2015;373:2117-28.

57

Zuckerberg San Francisco General

Key Results

10 mg empagliflozin group § A1c lowered by 0.54% (95% CI, −0.58 to −0.49) § Significantly lower risk of:

  • Hospitalization for heart failure (HR, 0.65; 95% CI, 0.50 to

0.85; P=0.002)

  • Death from cardiovascular causes (HR, 0.62; 95% CI, 0.49 to

0.77; P<0.001)

  • Death from any cause (HR, 0.68; 95% CI, 0.57 to 0.82,

P<0.001)

Diabetes Medications and Heart Failure 58

EMPA-REG OUTCOME. N Engl J Med 2015;373:2117-28.

58

slide-30
SLIDE 30

30 | [footer text here]

Zuckerberg San Francisco General

Diabetes Medications and Heart Failure 59

Neal BMB, et

  • al. N

Engl J Med 2017; 377:644- 657

59

Zuckerberg San Francisco General

Diabetes Medications and Heart Failure 60 DECLARE-TIMI 58. N Engl J Med 2019;380:347-57.

60

slide-31
SLIDE 31

31 | [footer text here]

Zuckerberg San Francisco General

DECLARE-TIMI 58, cont.

§ A renal event occurred in 4.3% in the dapagliflozin group

and in 5.6% in the placebo group (HR, 0.76; 95% CI, 0.67 to 0.87)

§ Death from any cause occurred in 6.2% and 6.6%,

respectively (HR, 0.93; 95% CI, 0.82 to 1.04)

Diabetes Medications and Heart Failure 61

DECLARE-TIMI 58. N Engl J Med 2019;380:347-57.

61

Zuckerberg San Francisco General

Diabetes Medications and Heart Failure 62

DECLARE-TIMI 58. N Engl J Med 2019;380:347-57.

62

slide-32
SLIDE 32

32 | [footer text here]

Zuckerberg San Francisco General

Diabetes Medications and Heart Failure 63

DAPA-HF. NEJM. 9/19/19.

63

Zuckerberg San Francisco General

Diabetes Medications and Heart Failure 64

DAPA-HF. NEJM. 9/19/19.

64

slide-33
SLIDE 33

33 | [footer text here]

Zuckerberg San Francisco General

Proposed Mechanism of Cardiorenal Protection of SGLT2-Inhibitors

Diabetes Medications and Heart Failure 65

2018 ACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease. JACC. 2018.

65

Zuckerberg San Francisco General

EMPA-REG OUTCOME DAPA-HF DECLARE-TIMI 58 Cumulative Empagliflozin 10 mg Placebo Dapagliflozin 10 mg Placebo Dapagliflozin 10 mg Placebo SGLT2-i Placebo Total Rate in SGLT2-i Rate in Placebo Difference 2345 2333 2373 2371 8574 8569 13292 13273 26565 Hypoglycemia (any) 656 650 4 4 58 83 718 737 1455 5.40% 5.55%

  • 0.15%

Genital infection 153 42 76 9 229 51 280 1.72% 0.38% 1.34% Volume Depletion 115 115 178 162 213 207 506 484 990 3.81% 3.65% 0.16% Acute Kidney Failure or Injury 147 192 153 170 125 175 425 537 962 3.20% 4.05%

  • 0.85%

DKA 3 1 3 27 12 33 13 46 0.25% 0.10% 0.15% Amputation 13 12 123 113 136 125 261 1.02% 0.94% 0.08% Diabetes Medications and Heart Failure 66

66

slide-34
SLIDE 34

34 | [footer text here]

Zuckerberg San Francisco General

Diabetes Medications and Heart Failure 67

Rosenstock J and Ferrannini E. Diabetes Care 2015 Sep; 38(9): 1638-1642.

§ euDKA is

pathophysiologically similar to DKA

§ SGLT2-induced glycosuria

“artificially” lowers plasma glucose levels and predisposes to increased ketogenesis

Euglycemic Diabetic Ketoacidosis

67

Zuckerberg San Francisco General

“Euglycemic” Diabetic Ketoacidosis

§ Long-standing T2D patients with marked β-cell

insufficiency

§ Adults with latent autoimmune diabetes with rapid

evolution toward T1D

§ Stress:

  • E.g., prolonged starvation, after surgery, concurrent illness

Diabetes Medications and Heart Failure 68

Rosenstock J and Ferrannini E. Diabetes Care 2015 Sep; 38(9): 1638-1642.

68

slide-35
SLIDE 35

35 | [footer text here]

Zuckerberg San Francisco General

Diabetes Medications and Heart Failure 69

Rosenstock J and Ferrannini E. Diabetes Care 2015 Sep; 38(9): 1638-1642.

69

Zuckerberg San Francisco General

FDA Grants Fast Track Designation to Empagliflozin for Treatment of Chronic HF

June 26, 2019

§ “Fast Track designation to empagliflozin for the

reduction of the risk of cardiovascular death and hospitalization for heart failure in people with chronic heart failure.”

Diabetes Medications and Heart Failure 70

https://www.boehringer-ingelheim.us/press-release/us-fda-grants-fast-track-designation-empagliflozin-treatment-chronic-heart-failure

70

slide-36
SLIDE 36

36 | [footer text here]

Zuckerberg San Francisco General

Diabetes Medications and Heart Failure 71 https://www.healio.com/cardiology/hf-transplantation/news/print/cardiology-today/%7B9503736c-fd71-451f-8e84- 1a7003a6923f%7D/fda-grants-fast-track-designation-to-dapagliflozin-for-worsening-heart-failure. 10/16/19

71

Zuckerberg San Francisco General

HFpEF Overview 72

72