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

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 Zuckerberg San Francisco General 1 Disclosures § I have no financial disclosures. Zuckerberg San Francisco General Diabetes Medications and Heart Failure 2 2 1 | [footer text here]

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 Zuckerberg San Francisco General Diabetes Medications and Heart Failure 3 3 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 Zuckerberg San Francisco General Diabetes Medications and Heart Failure 4 4 2 | [footer text here]

The Beginning and Lessons Learned Zuckerberg San Francisco General 5 June 14, 2007 § 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) Zuckerberg San Francisco General Diabetes Medications and Heart Failure 6 6 3 | [footer text here]

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.” FDA. Guidance for Industry Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes Zuckerberg San Francisco General Diabetes Medications and Heart Failure 7 7 SAVOR- October 3, 2013 TIMI 53 § 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 SAVOR-TIMI 53. N Engl J Med 2013;369:1317-26 Zuckerberg San Francisco General Diabetes Medications and Heart Failure 8 8 4 | [footer text here]

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) SAVOR-TIMI 53. N Engl J Med 2013;369:1317-26 Zuckerberg San Francisco General Diabetes Medications and Heart Failure 9 9 Glucagon-Like Peptide 1 Receptor Agonists Zuckerberg San Francisco General 10 5 | [footer text here]

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) 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. Zuckerberg San Francisco General Diabetes Medications and Heart Failure 11 11 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) 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. Zuckerberg San Francisco General Diabetes Medications and Heart Failure 12 12 6 | [footer text here]

The SGLT2-Inhibitors Zuckerberg San Francisco General 13 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 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. Zuckerberg San Francisco General Diabetes Medications and Heart Failure 14 14 7 | [footer text here]

EMPA-REG November 26, 2015 OUTCOME § 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 m 2 of body-surface area - A1c 7-10% if had received stable glucose-lowering therapy for at least 12 weeks before randomization EMPA-REG OUTCOME. N Engl J Med 2015;373:2117-28. Zuckerberg San Francisco General Diabetes Medications and Heart Failure 15 15 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% Neal BMB, et al. N Engl J Med 2017; 377:644-657 Zuckerberg San Francisco General Diabetes Medications and Heart Failure 16 16 8 | [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 Glycemic Control Zuckerberg San Francisco General EMPA-REG OUTCOME. N Engl J Med 2015;373:2117-28. 18 9 | [footer text here]

EMPA-REG OUTCOME. N Engl J Med 2015;373:2117-28. Zuckerberg San Francisco General Diabetes Medications and Heart Failure 19 19 CANVAS August 17, 2017 Program § 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 Neal BMB, et al. N Engl J Med 2017; 377:644-657 Zuckerberg San Francisco General Diabetes Medications and Heart Failure 20 20 10 | [footer text here]

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) Neal BMB, et al. N Engl J Med 2017; 377:644-657 Zuckerberg San Francisco General Diabetes Medications and Heart Failure 21 21 DECLARE- January 24, 2019 TIMI 58 § 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. DECLARE-TIMI 58. N Engl J Med 2019;380:347-57. Zuckerberg San Francisco General Diabetes Medications and Heart Failure 22 22 11 | [footer text here]

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). DECLARE-TIMI 58. N Engl J Med 2019;380:347-57. Zuckerberg San Francisco General Diabetes Medications and Heart Failure 23 23 HHF HHF or MACE HHF HHF or MACE HHF HHF or HHF HHF or MACE MACE CV death CV death CV death CV death HHF: Hospitalization for HF MACE: Major adverse cardiovascular events Kluger AY et al. Cardiovasc Diabetol (2019) 18:99 Zuckerberg San Francisco General Diabetes Medications and Heart Failure 24 24 12 | [footer text here]

DAPA-HF Zuckerberg San Francisco General 25 September 19, 2019 DAPA-HF § 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 Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. NEJM. 9/19/19. Zuckerberg San Francisco General Diabetes Medications and Heart Failure 26 26 13 | [footer text here]