Can Treating Diabetes with SGLT2 inhibitors Prevent Heart Failure?

Transcription

1 UCSD Hawaii 2017 Symposium Can Treating Diabetes with SGLT2 inhibitors Prevent Heart Failure? Gregg C. Fonarow, MD, FACC, FAHA Elliot Corday Professor of Cardiovascular Medicine UCLA Division of Cardiology Director, Ahmanson UCLA Cardiomyopathy Center Co-Chief, UCLA Division of Cardiology

2 Presenter Disclosure Information Diabetes and Heart Failure Prevention I will not discuss off label use of medications DISCLOSURE INFORMATION: The following relationships exist related to this presentation: Gregg C. Fonarow, MD, FACC, FAHA Research: NIH, AHRQ, PCORI Consultant: Amgen, Janssen, Medtronic, Novartis

3 Diabetes and Survival 50-year-old with diabetes died, on average, 6 years earlier than those without diabetes (58% attributable to vascular, 9%, cancer, 30% other causes ) Reduction in life expectancy from long-term cigarette smoking ~10 years The Emerging Risk Factors Collaboration N Engl J Med 2011;364:829-41

4 Diabetes and Incident Heart Failure in the US Framingham study (risk of HF in diabetics) 2x diabetic males 5x diabetic females 4x young diabetic males 8x young diabetic females US HMO prevalence study With diabetes, incident HF developed at a rate of 3.3% per year Each 1% elevation in HbA 1c leads to a 15% increase in frequency of HF Kannel WB et al. JAMA. 1979;241: Nichols GA. Diabetologia. 2000;43(suppl A2):7. Chue CU et al. Circulation. 1998;98(suppl 1):721.

5 Prevalence of Diabetes in Patients with Heart Failure Clinical Trial Diabetics SOLVD 25.8% MERIT 24.5% ELITE II 24.0% Val HEFT 25.4% COPERNICUS 25.7% OPTIME (hospitalized) 44.2% VMAC (hospitalized) 47.0%

6 Mechanisms in Hyperglycemia/Diabetes Islet β-cell Impaired Insulin Secretion Decreased Incretin Effect Increased Lipolysis Islet α-cell Increased Glucagon Secretion Increased Glucose Reabsorption Increased HGP Neurotransmitter Dysfunction Decreased Glucose Uptake

7 Relationship Between DM and HF Incidence of HF: 13 / 1000 person-years in non-diabetics vs. 31 / 1000 person-years in diabetics Diabetes Mellitus Heart Failure

8 Insulin Resistance, Hyperglycemia, and Heart Failure Hyperglycemia oxidative stress altered intracellular signaling decreased vascular endothelial growth factor altered gene expression Insulin Myocardial hypertrophy Advanced Glycosylation Endproduct s (AGEs) sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase collagen cross-linking and reduce ventricular distensibility and vascular compliance Myocardial metabolism may become more dependent on free fatty acids uncoupling of oxidative phosphorylation

9 Etiology of HF in Patients with Diabetes Comorbidities Ischemic Heart Disease Hypertension Diabetic Cardiomyopathy Direct Myocardial Effects of hyperglycemia and Advanced glycation end products Fibrosis, diastolic dysfunction Altered calcium homeostasis, systolic dysfunction Free-radicals, oxidation, inflammation Lipotoxicity of myocardium Altered myocardial energetics Variable Combinations of above factors Bell, Diabetes Care 2003; 26:

10 Poor Glycemic Control in DM is Independently Associated with Increased HF Risk 10 n=48,858 men and women with Type II DM CHF Rate /year per p< < >10 Hemoglobin A 1c (percent) Iribarren et al. Circulation 2001;103:

11 Effect of Glycemic Control in Type 2 DM on Cardiovascular Outcomes

12 Cardiovascular Safety of Diabetes Medications The rates of heart failure events have actually exceeded that of acute myocardial infarction in many of the diabetes medication trials. When patients in trials developed heart failure hospitalizations, their subsequent risk of mortality greatly exceeded that of patients hospitalized with myocardial infarction. Yet, the FDA required cardiovascular safety trials for new diabetes medications do not require reporting on heart failure. McMurray JJ, et al. Heart failure: a cardiovascular outcome in diabetes that can no longer be ignored Lancet Diabetes Endocrinol. doi: /S (14)

13 Heart Failure Rates in Diabetes Glucose Control Trials Risk of HF events with glucose-lowering drugs or strategies versus standard care PPAR Agonists DPP-4 Inhibitors Intensive Control Insulin Weight loss Lancet Diabetes Endocrinol 2015 March 17,

14 Effects of Intensive Glucose Lowering in Type 2 Diabetes: ACCORD Heart Failure Endpoint HR 1.18 in the Intensive Therapy Group At 1 year, stable median glycated hemoglobin levels of 6.4% and 7.5% were achieved in the intensive-therapy group and the standard-therapy group, respectively ACCORD Study Group N Engl J Med 2008;358:

15 Major CV Outcome Trials in Type 2 Diabetes SAVOR- TIMI 53 (n = 16,492) 1222 MACE3 CAROLINA N = 6041 MACE4 Omarigliptin (n = 4000) Q42017? MACE4 : DPP4i : SGLT2i : GLP1 EXAMINE (n = 5380) 621 MACE3 TECOS (n = 14,723) 1400 MACE4 CARMELINA N = 8300 MACE *lixisenatide (Sanofi, post-acs). liraglutide (Novo Nordisk). semaglutide (Novo Nordisk). exenatide (Amylin). once-weekly DPP4i (Merck). #dulaglutide (Eli Lilly). ELIXA* (n = 6000) 805 MACE4 LEADER (n = 9341) 611 MACE3 EMPA-REG OUTCOME N = 7034 MACE3 SUSTAIN-6 (n = 3260) MACE3 EXSCEL (n = 14000) MACE3 CANVAS-R (n = 5700) Alb.uria CANVAS (n = 4339) MACE3 FREEDOM (n = 4000)? MACE4 REWIND# (n = 9622) MACE3 DECLARE-TIMI 58 (n = 27,000) MACE3 Ertugliflozin CVOT (n = 3900) MACE3 CREDENCE (n = 3627) Cardiorenal

16 SAVOR TIMI 53-Hospitalization for Heart Failure Time to the 1 st occurrence of any hospitalization for heart failure; 517 events 4% Saxagliptin Placebo HR 1.27 P= % Hospitalization for Heart Failure (%) 3% 2% 1% 0% HR 1.80 P= % 0.6% Scirica BM, et al. Circulation 2014; 130: HR 1.46 P= % 1.3% 2.8% Days from Randomization

17 Hospitalization for HF with Alogliptin: Observations from EXAMINE P interaction =0.068 HR: % CI: P-value: p=0.22 p=0.99 p=0.026 Zannad F. et al. Lancet 2015: 385 :

18 CV Effects of Lixisenatide: ELIXA Trial Results LEADER: Hospitalization for heart failure Pfeffer, M. A., et al. N Engl J Med : Marso SP et al. N Engl J Med. 2016;375:

19 Liraglutide in Systolic Heart Failure: The FIGHT Trial N=300: liraglutide (n = 154) vs. placebo (n = 146) Margulies KB et al. JAMA. 2016;316:

20 N=3297 T2DM w/ CVD/CV risk Semaglutide 0.5 or 1.0mg vs. placebo once weekly 104 Weeks Outcome # of events HR 95%CI semaglutide vs placebo CV Death/MI/Stroke 108 vs HF hospitalization 59 vs Marso SP, et al. NEJM 2016; DOI: /NEJMoa

21 SGLT2 Inhibitors Virtually all glucose filtered by the kidney is reclaimed in the proximal tubule. 1 Sodium glucose cotransporter 2 (SGLT2) is responsible for 90% of this reabsorption. Selective inhibitors of SGLT2 have been developed. 2 By reducing renal glucose reabsorption, SGLT2 inhibitors increases urinary glucose excretion. 3 In patients with type 2 DM, SGLT2 inhibitors leads to: 4 Significant reductions in HbA1c Weight loss Reductions in BP without increases in heart rate 1. Abdul-Ghani et al. Curr Diab Rep. 2012;12: Grempler et al. Diabetes Obes Metab.2012 ;14: Heise T et al. Diabetes Obes Metab 2013;15: Liakos A et al. Diabetes Obes Metab 2014;16:

22 Renal Glucose Re-absorption in Healthy Individuals Filtered glucose load 180 g/day SGLT2 ~ 90% SGLT1 ~ 10% Gerich JE. Diabet Med. 2010;27:

23 Renal Glucose Re-absorption in Patients with Hyperglycaemia Filtered glucose load > 180 g/day SGLT2 ~ 90% SGLT1 ~ 10% When blood glucose increases above the renal threshold (~ 10 mmol/l or 180 mg/dl), the capacity of the transporters is exceeded, resulting in urinary glucose excretion Gerich JE. Diabet Med. 2010;27:

24 Urinary Glucose Excretion via SGLT2 Inhibition Filtered glucose load > 180 g/day SGLT2 inhibitor SGLT1 SGLT2 inhibitors reduce glucose re-absorption in the proximal tubule, leading to urinary glucose excretion* and osmotic diuresis *Loss of ~ 80 g of glucose/day (~ 240 cal/day). Gerich JE. Diabet Med. 2010;27:

25 Mechanism of Action of SGLT2 Inhibitors Inhibition of SGLT2 Reversal of glucotoxicity Insulin sensitivity in muscle GLUT4 translocation Insulin signaling Other Insulin sensitivity in liver Glucose- 6-phosphatase Gluconeogenesis Decreased Cori cycle PEP carboxykinase β-cell function

26 EMPA-REG OUTCOME Trial design Placebo (n=2333) Screening (n=11531) Randomized and treated (n=7020) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) Study medication was given in addition to standard of care. The trial was to continue until 691 patients experienced an adjudicated primary outcome event. Key inclusion criteria: Adults with type 2 diabetes and established CVD BMI 45 kg/m 2 ; HbA1c 7 10%; egfr 30 ml/min/1.73m 2 (MDRD)

27 EMPA-REG OUTCOME Trial

28 Planned outcomes and analyses Primary outcome: 3-point MACE Further outcomes included: heart failure hospitalization or CV death, hospitalization for heart failure, all-cause mortality Analysis compared empagliflozin 10 mg and 25 mg (pooled) vs. placebo in patients treated with 1 dose of study drug (intent-to-treat population) Secondary analyses included comparisons of individual empagliflozin doses vs. placebo Subgroup analyses were based on baseline characteristics, including the presence/absence of investigator-reported heart failure

29 EMPA-REG OUTCOME Trial

30 EMPA-REG OUTCOME Study HF Hospitalization or CV Death HF Hospitalization or HF Death Empagliflozin is a highly selective inhibitor of Sodium-Glucose Cotransporter-2 Zinman B et al. N Engl J Med 2015 [Epub ahead of print] adults with type 2 diabetes and established CVD BMI 45 kg/m 2 ; HbA1c 7 10%; egfr 30 ml/min/1.73m 2 (MDRD)

31 Heart Failure Hospitalization or CV death Cumulative incidence function. CV, cardiovascular; HR, hazard ratio; CI, confidence interval. 31

32 Heart Failure Hospitalization or CV Death: Subgroup Analysis N analyzed Empagliflozin Placebo All patients Age (years) < egfr (ml/min/1.73m 2 ) < Insulin No Yes ACEIs/ARBs No Yes Diuretics No Yes Beta-blockers No Mineralocorticoid receptor antagonists Yes No Yes HR (95% CI) Favors empagliflozin Cox regression analysis. CV, cardiovascular; HR, hazard ratio; CI, confidence interval; ACEI, angiotensin-converting-enzyme inhibitor; ARB, angiotensin receptor blocker; egfr, estimated glomerular filtration rate. Favors placebo

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35 Heart Failure Hospitalization or CV Death in Patients with vs without HF at Baseline 25 HR 0.63 (95% CI 0.51, 0.78) HR 0.72 (95% CI 0.50, 1.04) Patients with 15 heart failure hospitalization or 10 CV death (%) Patients without heart failure at baseline Patients with heart failure at baseline Zinman B et al. N Engl J Med 2015 [Epub ahead of print].

36 Outcomes in Patients with vs without Heart Failure at Baseline Patients with event/analyzed Empagliflozin Placebo HR (95% CI) HF hospitalization or CV death All patients 265/ / (0.55, 0.79) Baseline HF: No 190/ / (0.51, 0.78) Baseline HF: Yes 75/462 49/ (0.50, 1.04) Hospitalization for HF All patients 126/ / (0.50, 0.85) Baseline HF: No 78/ / (0.43,0.82) Baseline HF: Yes 48/462 30/ (0.48, 1.19) CV death All patients 172/ / (0.49, 0.77) Baseline HF: No 134/ / (0.47, 0.77) Baseline HF: Yes 38/462 27/ (0.43, 1.16) All-cause mortality All patients 269/ / (0.57, 0.82) Baseline HF: No 213/ / (0.54, 0.81) Baseline HF: Yes 56/462 35/ (0.52, 1.20) Favors empagliflozin Favors placebo Cox regression analysis. HF, heart failure; CV, cardiovascular; HR, hazard ratio; CI, confidence interval.

37 Adverse Events in Patients with and without Heart Failure at Baseline Patients with heart failure at baseline Placebo (N=244) Empagliflozin (N=462) Patients without heart failure at baseline Placebo (N=2089) Empagliflozin (N=4225) At least one AE 230 (94.3) 413 (89.4) 1909 (91.4) 3817 (90.3) At least one severe AE 78 (32.0) 135 (29.2) 514 (24.6) 965 (22.8) At least one serious AE 126 (51.6) 202 (43.7) 862 (41.3) 1587 (37.6) Deaths 25 (10.2) 35 (7.6) 94 (4.5) 141 (3.3) At least one AE leading to discontinuation 62 (25.4) 99 (21.4) 391 (18.7) 714 (16.9) AE, adverse event. AEs that occurred during treatment or 7 days after the last intake of study medication.

38 Potential Mechanisms Involved in the Reduction of Cardiovascular Events

39 SGLT2 Inhibitors Empagliflozin 1 Dapagliflozin 2 Canagliflozin 3 Launch year 2014(EU/US) 2012 (EU) 2014 (US) 2013 (EU/US) MoA Molecular class Metabolism C-glycoside C-glycoside C-glycoside Dual renal and hepatic 50:50 Mainly hepatic 97:3 Mainly hepatic, no details reported Dosing Administration Oral Oral Oral Regimen Once daily Once daily Once daily Doses 10 mg and 25 mg 5 mg and 10 mg 100 mg and 300 mg

40 Component Analyses of MACE Events: Dapagliflozin S/ENDOCRINOLOGICANDMETABOLICDRUGSADVISORYCOMMITTEE/UCM Pdf

41 CV Outcome Trials with SGLT2 Inhibitors

42 Canagliflozin and Cardiovascular Events in Type 2 Diabetes: CANVAS DOI: /NEJMoa

43 Canagliflozin and Cardiovascular Events in Type 2 Diabetes: CANVAS DOI: /NEJMoa

44 2016 ESC Guidelines for the Diagnosis and Treatment of Acute & Chronic HF European Heart Journal (2016) 37,

45 Diabetes Medications and HF Risk Antihyperglycemic therapies/strategies influence risk for heart failure Increased risk: Intensification of glucose control Thiazolidinediones Saxagliptin and alogliptin Neutral risk: Glargine insulin; sitagliptin; lixisenatide; liraglutide, semaglutide Decreased risk: Empagliflozin; Canagliflozin, perhaps metformin Effects on HF risk of selected therapies appear independent of glycemic effects Empagliflozin, Canagliflozin (and potentially other SGLT2i s)

46 Conclusions Until 2015, no known T2 diabetes therapy known to improve CV outcomes Now 4 trials have shown improvement CV outcomes Importance of HF prevention Recognized but understudied Despite high risk for developing HF and subsequent adverse outcomes in patients with DM Little effort made to reduce HF in DM patients EMPA-REG Outcome trial data on HF prevention New option to reduce CV death and HF Compelling data Uses beyond diabetes?