Welcome and Introductions

Welcome and Introductions Shelley Zieroth MD, FRCPC, FCCS @ShelleyZieroth 2 Faculty Shelley Zieroth, MD, FRCPC, FCCS (chair) Cardiologist Associate Professor of Medicine University of MB President Canadian Heart Failure Society Winnipeg, MB @ShelleyZieroth Eileen O’Meara, MD Cardiologist Associate Professor of Medicine Université de Montréal Montreal Heart Institute Montreal, QC Lori Berard, RN, CDE Nurse Consultant Winnipeg, MB @ldb13 Navdeep Tangri, MD, PhD, FRCPC Nephrologist Associate Professor of Medicine Dept of Community Health Sciences Chronic Disease Innovation Center University of Manitoba Winnipeg, MB @NavTangri 3 Conflict of Interest Shelley Zieroth, MD, FRCPC, FCCS • Consulting Fees/Honoraria: Amgen, AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, Servier, Akcea, Cardiol Therapeutics • Clinical Trials: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis Eileen O’Meara, MD • Consulting Fees/Honoraria: Amgen, AstraZeneca, Bayer, BMS/Pfizer Alliance, Novartis, Servier • Clinical Trials: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck Lori Berard, RN, CDE • Consulting Fees/Honoraria: AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Johnson & Johnson, Merck, Sanofi, Novo Nordisk • Clinical Trials: N/A Navdeep Tangri, MD, PhD, FRCPC • Consulting Fees/Honoraria: AstraZeneca, Boehringer Ingelheim, Eli Lilly, Triceda Inc. • Clinical Trials: AstraZeneca, Johnson & Johnson 4 Disclosure of Commercial Support Specific details of relationship: • This program has received financial support from BI-Lilly Pharmaceuticals Canada in the form of an educational grant Potential for conflict(s) of interest: • Speakers have received honoraria from BI-Lilly Pharmaceuticals Canada • BI-Lilly is the manufacturer and benefits from the sale of empagliflozin 5 Mitigating Potential Bias Potential biases are acknowledged and are mitigated by presenting data supported by national and international guidelines, and as follows: • Information presented is evidence-based • Material has been developed and reviewed by a Planning Committee Off-label uses of drugs will be discussed and identified as such by the speaker 6 Learning Objectives After attending the symposium, participants will be able to: • Identify individualized treatment options for CV and renal protection in patients with T2DM • Explain the role of SGLT2 inhibitors in the prevention and treatment of heart failure • Describe practical recommendations and tips when starting SGLT2 inhibitors 7 Accreditation This event is an Accredited Group Learning Activity (Section 1) as defined by the Maintenance of Certification Program of the Royal College of Physicians and Surgeons of Canada and approved by the Canadian Cardiovascular Society. You may claim a maximum of 1 hour. 8 Agenda 9 TIME TOPIC SPEAKER 12:35 p.m. Welcome and Introductions Shelley Zieroth, MD 12:45 p.m. Diabetes Management: What Every Cardiologist Needs to Know Lori Berard, RN 1:05 p.m. Heart Failure Management Eileen O’Meara, MD 1:25 p.m. Chronic Kidney Disease Management Navdeep Tangri, MD 1:45 p.m. Closing Remarks Shelley Zieroth, MD #Cardiotwitter Question 10 ARS Question • Are you more likely to Rx SGLT2i’s for eligible patients with : • T2DM + CVD = 62% • T2DM + history of HF = 33% • I let endocrinologist start = 5% • I only prescribe GLP1-RA’s = 0% 11 #Cardiotwitter Answer 12 LEADER: Summary SUSTAIN-6: Summary LEADER: Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results – A Long Term Evaluation; CVD: cardiovascular disease; CKD: chronic kidney disease; T2D: type 2 diabetes; MI: myocardial infarction; NNT: number needed to treat Liraglutide is not currently indicated for renal protection in Canada. Marso S, et al. N Engl J Med. 2016;375:311-322. Slide courtesy of Dr. R. Goldenberg. Liraglutide in addition to standard of care reduced CV risk and improved overall survival in adults with T2D and age ≥50 yrs with established CVD or CKD or age ≥60 yrs with an additional risk factor ↓ CV death (NNT 3y = 104) 22% ↓ All-cause mortality (NNT 3y = 98) 15% ↓ Fatal and non-fatal MI (NNT 3y = 127) 14% The overall safety profile of liraglutide was consistent with previous clinical trials and current label information 22% ↓ New or worsening nephropathy (NNT 3y = 85) 13% ↓ CV death, non-fatal MI, non-fatal stroke (NNT 3y = 66) Semaglutide once weekly in addition to standard of care reduced CV risk in adults with T2D and age ≥50 yrs with established CVD or CKD or age ≥60 yrs with an additional risk factor 26% 39% 35% 76% 36% ↓ Nonfatal stroke (NNT 2y=91) ↓ Revascula- rization (NNT 2y=39) ↑ Retinopathy complications (NNH 2y=46) ↓ New or worsening nephropathy (NNT 2y=44) ↓ CV death, nonfatal MI, nonfatal stroke (NNT 2y =45) The overall safety profile of semaglutide was consistent with previous clinical trials and the GLP-1RA class, except for the retinopathy results SUSTAIN: Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes; CVD: cardiovascular disease; CKD: chronic kidney disease; T2D: type 2 diabetes; MI: myocardial infarction; NNT: number needed to treat; NNH: number needed to harm Semaglutide is not currently indicated for cardiovascular or renal protection in Canada and should not be used in patients with end stage renal impairment due to very limited clinical experience in this population.16. Marso S et al. N Engl J Med 2016;375:1834-44. (courtesy of Dr. R. Goldenberg) 13 The primary prevention cohort accounted for fewer primary MACE events and while subgroup analysis did not show heterogeneity, no conclusion can be made regarding the CV benefit in this group (HR 0.98; 95% CI 0.74-1.30) Canagliflozin in addition to standard of care reduced CV risk in adults with T2D and age ≥30 years with established CVD (66%) or age ≥50 yrs with ≥2 CV risk factors (34%) 33% ↓ HF hospitalization (NNT 5y = 63) 14% ↓ CV death, non-fatal MI, non-fatal stroke (P=0.02; NNT 5y = 44) 40% ↓ eGFR, dialysis, renal death (NNT 5y = 58) 97% ↑ Lower extremity amputations (P<0.001; NNH 5y = 69) 26% ↑ Fractures (P=0.02; NNH 5y = 58) CANVAS Program: Summary 14 No increased risk of amputations was observed in EMPA-REG OUTCOME or DECLARE indicated for slowing the progression of renal disease in patients with type 2 diabetes for use in patients with an eGFR of <45 mL/min/1.73m² CVD: cardiovascular disease; HF: heart failure; MI: myocardial infarction; NNT: number needed to treat; NNH: number needed to harm;T2D: type 2 diabetes Canagliflozin is not in Canada and contraindicated Neal B, et al. N Engl J Med. 2017;377:644-57 ; ADA Annual Meeting 2017. Slide courtesy of Dr. R. Goldenberg. EMPA-REG OUTCOME: Summary 15 Empagliflozin in addition to standard of care reduced CV risk and improved overall survival in adults with T2D with established CVD The overall safety profile of empagliflozin was consistent with previous clinical trials and current label information ↓ CV death (NNT 3y = 46) 38% ↓ All-cause mortality (NNT 3y = 39) 32% ↓ HF hospitalizations NNT 3y = 72 35% 39% ↓ New or worsening nephropathy (NNT 3y = 17) 14% ↓ CV death, non- fatal MI, non-fatal stroke (NNT 3y = 63) contraindicated in patients with eGFR less than 30 mL/min/1.73m2. CVD: cardiovascular disease; MI: myocardial infarction; NNT: number needed to treat; T2D: type 2 diabetes; HF: heart failure Empagliflozin is not currently indicated for renal protection in Canada and is Zinman B, et al. N Engl J Med. 2015;373:2117-28. Wanner C, et al . N Engl J Med. 2016;375:323-334. Slide courtesy of Dr. R. Goldenberg. DECLARE–TIMI 58: Summary 16 Dapagliflozin in addition to standard of care in patients with type 2 diabetes aged ≥40 years with established ischemic cerebrovascular disease, Ischemic heart disease or PAD, or aged ≥55 years (men) ≥66 (women) with ≥1 cardiovascular risk factor. The overall safety profile of dapagliflozin was consistent with previous clinical trials and current label information ↓ CV Death or HF hospitalizations (NNT 4yr = 108) 17% 24% ↓ 40% decrease in eGFR to <60 ml/min/1.73m2, ESRD or renal or CV death (NNT 4 yr -100) Non-significant reduction in CV death, non-fatal MI, non-fatal stroke 7% Dapagliflozin is not currently indicated for renal protection in Canada and is contraindicated in patients with eGFR less than 30 mL/min/1.73m2. CVD: cardiovascular disease; MI: myocardial infarction; NNT: number needed to treat; T2D: type 2 diabetes; HF: heart failure Note: Dapaglifozin is an SGLT2 inhibitor administered orally; it is not currently indicated for cardiovascular protection in Canada Adapted from: Wiviott S et al. N Engl J Med 2018;DOI: 10.1056/NEJMoa1812389 Mrs. P • 73 year old woman with NYHA 2, CCS 1 HFpEF • Patients’ Medical History: • Paroxysmal AF on DOAC • T2DM • Hypertension • Ex-smoker • MI 10 years ago • 1 hospitalization for HF in 2018 • MIBI 2017: LVEF 45%, fixed defect of inferior wall • Medications: • Metformin 1000 mg po BID • Lasix 40 mg po OD • Ramipril 2.5 mg po OD • Metoprolol 25 mg po BID • Rivaroxaban 20 mg po OD • Atorvastatin 80 mg po OD • Labs: • K 4.2, eGFR 72, hgb 130, hgbAIc 8.2, UACr neg • Exam: BP 132/70, HR 80 irreg, JVP 3, S4, trace edema, chest clear 17 Diabetes Management: What Every Cardiologist Needs to Know Lori Berard RN @ldb13 18 The Impact of Diabetes 19 Diabetes can reduce lifespan by up to15 years1 CV disease is the leading cause of morbidity and mortality in patients with T2DM 2 80% of Canadians with diabetes will die of CVD2 By 2020, diabetes is expected to cost the Canadian healthcare system $16.9 billion annually 3 1. The Emerging Risk Factors Collaboration. Association of Cardiometabolic Multimorbidity With Mortality. JAMA. 2015;314(1):52-60. 2. Diabetes Canada. Canada at the tipping point. 2017. https://www.diabetes.ca/CDA/media/documents/publications-and-newsletters/advocacy-reports/canada-at-the-tipping-point-english.pdf (Accessed Dec 12, 2018). 3. The cost of Diabetes in Canada. Diabetes Canada. (2017) Patients with Diabetes are More Likely to be Hospitalized for Many Conditions 20 Prevalence rate ratios† of complications among hospitalized individuals‡ aged >20 years, by diabetes status, Canada, 2008/0922 0 14 2 18 8 Rate ratios (with diabetes: without diabetes) Cerebrovascular disease (stroke) Acute myocardial infarction (heart attack) Ischemic heart disease Heart failure Chronic kidney disease End-stage renal disease Lower limb amputations 4 6 10 12 16 20 COMPLICATION † Rate ratios based on rates age-standardized to the 1991 Canadian population. ‡ A person with diabetes hospitalized with more than one complication was counted once in each category, except for cases of acute myocardial infarction, where regardless of multiple counts in the acute myocardial infarction category, the individual was counted only once under the broader ischemic heart disease category. Source: Public Health Agency of Canada (August 2011); using 2008/09 data from the Canadian Chronic Disease Surveillance System (Public Health Agency of Canada). ABCDES3 of Diabetes Care A • A1C – optimal glycemic control (usually ≤7%) B • BP – optimal blood pressure control (<130/80) C • Cholesterol – LDL <2.0 mmol/L or >50% reduction D • Drugs to protect the heart A – ACEi or ARB │ S – Statin │ A –ASA if indicated │SGLT2i/GLP-1 RA with demonstrated CV benefit if T2DM with CVD and A1C not at target E • Exercise / Healthy eating S • Screening for complications S • Smoking cessation S • Self-management, stress and other barriers 2018 Diabetes Canada CPG – The Essentials 2018 21 Beyond Metformin in the DC Algorithm 22 Add another agent best suited to the individual by prioritizing patient characteristics: Clinical CVD? YES NO Start antihyperglycemic agent with demonstrated CV benefit empagliflozin (Grade A, Level 1A) liraglutide (Grade A, Level 1A) canagliflozin (Grade C, Level 2) If not at glycemic target Add additional antihyperglycemic agent best suited to the individual based on the following: Clinical Considerations Choice of Agent Avoidance of hypoglycemia and/or weight gain with adequate glycemic efficacy DPP-4 inhibitor, GLP-1 receptor agonist or SGLT2 inhibitor Other considerations: Reduced eGFR and/or albuminuria Clinical CVD or CV risk factors Degree of hyperglycemia Other comorbidities (CHF, hepatic disease) Planning pregnancy Cost/coverage Patient preference See Appendix 7 See Table below. Adapted from Diabetes Canada Clinical Practice Guidelines Expert Committee. Can J Diabetes 2018; 42(Suppl1):S1-S325. Choosing Between SGLT2i and GLP-1 RA Drugs that Protect the Heart And Lower Glucose 23 A1C: glycated hemoglobin; CrCl: creatinine clearance; eGFR: estimated glomerular filtration rate; GLP-1RA: glucagon like peptide-1 receptor agonist; UTI: urinary tract infection; LDL-C: low-density lipoprotein cholesterol; NNT: number needed to treat; OD: once daily; SGLT2i: sodium glucose co-transporter-2 inhibitor; OD: once daily; QW: Once-daily *Superiority met ; **SUSTAIN-6 was not designed with pre-specified testing for superiority. However, the treatment effect of semaglutide and the accrual of more events than estimated resulted in a significantly lower risk of the primary outcome among patients in the semaglutide group.; #p<0.001; ##exploratory Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes. 2018;42(Suppl 1):S1-S325. . Zinman B et al. N Engl J Med 2015;373:2117; Neal B et al. N Engl J Med 2017;377:644; Marso et al., N Engl J Med. 2016 Jul 28;375(4):311-22; Marso et al., N Engl J Med. 2016 Nov 10;375(19):1834-1844; SGLT2i GLP-1RA Relative A1C lowering ↓↓ to ↓↓↓ ↓↓ to ↓↓↓ Remember to adjust sulfonylurea as needed for hypoglycemia Weight loss ↓↓ ↓↓ Hypoglycemia Rare Rare Side effects Genital infections, UTI, hypotension, dose-related changes in LDL-C, increased risk of fractures with canagliflozin; increased risk of lower extremity amputation with canagliflozin (avoid if prior amputation);caution with renal dysfunction, loop diuretics and the elderly; treatment should be withheld prior to major surgery or with serious illness or infection. Gastrointestinal side effects, rare cases of acute gallstone disease; contraindicated with personal/family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 Route of administration Oral Injectable Dosing Empagliflozin: Start at 10 mg OD; increase to 25 mg OD if needed for glycemic control Canagliflozin: Start at 100 mg OD; increase to 300 mg OD if needed for glycemic control Liraglutide: Start at 0.6 mg OD and then titrate up to 1.8 mg OD ; increase to 0.5 mg QW; increase to 1.0 mg in 4 weeks if needed for glycemic control Cost $$$ $$$$ Antihyperglycemic Agents and Renal Function Adapted from Diabetes Canada Clinical Practice Guidelines Expert Committee. Can J Diabetes 2018; 42(Suppl1):S1-S325, Novo Nordisk Canada Inc. Ozempic Product Monograph. Date of Approval: January 4, 2018; and Boehringer Ingelheim (Canada) Ltd. Jardiance Product Monograph. Date of Revision: April 11, 2019; AstraZeneca Canada Inc. Forxiga Product Monograph. Date of Revision: April 3, 2019. 24 ARS • What will be the most important self monitoring advice you can provide Mrs P when starting her on an SGLT2i to reduce her risk of CV events? • sick day protocol = 15% • management of yeast infections = 12% • monitor daily weights = 5% • all of the above = 68% 25 26 Heart Failure Management Eileen O’Meara MD 27 Lancet Volume 393, ISSUE 10166, P3-5, January 05, 2019 Pump, pipes, and filter: do SGLT2 inhibitors cover it all?, Verma, Juni, mazur SGLT2 inhibitors and CV disease 28 Renal protection Hospitalisation for heart failure Major adverse cardiovascular events Secondary prevention population SGLT2i prevent heart failure and renal disease, and reduce artherosclerotic events (major adverse cardiovascular events) Primary prevention population SGLT2i prevent heart failure and renal disease, but may not reduce major adverse cardiovascular events Diabetes and multiple risk factors Diabetes and established cardiovascular disease Cardiorenal efficacy of SGLT2i Figure: Cardiorenal benefits of SGLT2i in different patient populations SGLT2i = sodium-glucose cotransporter-2 inhibitors SGLT2 inhibition – Hypotheses for CV benefits 29 Verma, Connelly, Presented at AHA Nov 2018 Empa-Heart: Mechanistic clues to SGLT2i’s benefit 30 SGLT2i’s reduce HF Hospitalizations Zelniker TA et al, The Lancet Published online Nov 10, 2018. Patients Events Events per 1000 Patient-years Weight (%) HR HR (95% CI) Treatment (nN) Placebo (nN) Treatment Placebo Patients with atherosclerotic cardiovascular disease Patients with multiple risk factors Fixed effects model for atherosclerotic cardiovascular disease (p<0.0001) Fixed effects model for multiple risk factors (p=0.0634) EMPA-REG OUTCOME CANVAS Program DECLARE-TIMI 58 4687/7020 3756/6656 3474/6974 2333/7020 2900/6656 3500/6974 463 524 597 19.7 21.0 19.9 30.1 27.4 23.9 30.9 32.8 36.4 CANVAS Program DECLARE-TIMI 58 2039/3486 5108/10186 1447/3486 5078/10186 128 316 8.9 7.0 9.8 8.4 30.2 69.8 0.66 (0.55-0.79) 0.77 (0.65-0.92) 0.83 (0.71-0.98) 0.83 (0.58-1.19) 0.84 (0.67-1.04) 0.76 (0.69-0.84) 0.84 (0.69-1.01) 0.35 0.50 1.00 2.50 Favours treatment Favours placebo Meta-analysis of SGLT2i trials on hospitalisation for heart failure and cardiovascular death stratified by the presence of established atherosclerotic cardiovascular disease Atherosclerotic cardiovascular disease: Q statistic=3.49, p=0.17, I2=42.7%; multiple risk factors: Q statistic=0.0, p=0.96, I2=0%. The p value for subgroup differences was 0.41. Tests for subgroup differences were based on F tests in a random effect meta-regression estimated using restricted maximum likelihood and Hartung Knapp adjustment. HR=hazard ratio. SGLT2i=sodium-glucose cotransporter-2 inhibitors. †Broad definition HHF data shown 1:1 propensity score-matched cohorts; DPP-4i, dipeptidyl peptidase-4 inhibitor; HHF, hospitalisation for heart failure Patorno E et al. AHA 2018; poster 1112 EMPRISE Real World Data: Empagliflozin was associated with a reduced risk of HHF† in routine clinical practice compared with DPP-4i 32 Month HR 0.56 (95% CI 0.43, 0.73) p<0.0001 Cumulative incidence 0.05 0.04 0.03 0.02 0.01 0 0 3 6 9 12 15 18 21 24 DPP-4i Empagliflozin CVD REAL 33 All-Cause Death (ACD) Number of events: 5,216 Hospitalization for Heart Failure (HHF) Number of events: 5,997 HHF + ACD Number of events: 9,788 Kosiborod, M. et al. J Am Coll Cardiol. 2018;71(23):2628-39. Myocardial Infarction Number of events: 2,249 Stroke Number of events: 6,439 0.51 [0.37, 0.70] 0.64 [0.50, 0.82] 0.60 [0.47, 0.76] 0.81 [0.74, 0.88] 0.68 [0.55, 0.84] Favor SGLT-2i Favor oGLD 0.25 0.50 1.00 2.00 CENTRAL ILLUSTRATION: Lower Cardiovascular Risk Associated With SGLT-2 Inhibitors Recommendations CCS 2017 HF Guidelines: HF Prevention in Type 2 DM Ezekowitz, O’Meara et al, CJC 2017 34 • We recommend that diabetes should be treated according to the Canadian Diabetes Association’s national guidelines to achieve optimal control of blood glucose levels (Strong Recommendation, Moderate Quality Evidence) • We suggest that the use of empagliflozin, a SGLT-2 inhibitor, be considered for patients with type 2 diabetes and established cardiovascular disease for the prevention of HF-related outcomes (Weak Recommendation, Low Quality Evidence) Diabetes in Heart Failure Checklist Treat heart failure in people with diabetes the SAME as you would a person without diabetes METFORMIN recommended if eGFR >30 mL/min/1.73 m2 If eGFR <60 mL/min, use Renin Angiotensin Aldosterone system or sacubitril/valsartan blockade carefully Do NOT use thiazolidinediones Avoid saxagliptin in patients with heart failure and diabetes Connelly et al, 2018 Diabetes Canada CPG – Chapter 28. Treatment of Diabetes in People with Heart Failure 35 Proposed Management of Concomitant Diuretics When Initiating SGLT2 Inhibitors in Patients T2DM David Z.I. Cherney, and Jacob A. Udell Circulation. 2016 36 Mrs. P • 6 months ago following a routine Echo it was noted her LVEF had declined to 35%. You initiated her on triple therapy and she stable has NYHA 2 symptoms. She has not been hospitalized. • Her Cr is 90 with an eGFR of 55 • She is asking if SGLT2i is a good option for her (“she read in her favourite magazine about a new drug that can lower her sugars and help her lose weight”) 37 ARS • Would you prescribe a SGLT2i for patients: • Prevention of HF in T2DM patients with CVD = 12% • T2DM with HFpEF = 2% • T2DM with HFrEF = 2% • All of the above = 82% • I don’t know = 2% 38 What’s coming up with SGLT2s and heart failure? DAPA-HF: Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients with Chronic HF Duration is event driven: 844 events Powered for superiority Placebo + SoC Population: •≥18 years of age •Established documented diagnosis of symptomatic HFrEF (NYHA functional class II-IV) for ≥ 2 months •LVEF ≤40% •NTproBNP ≥ 600 pg/ml •eGFR ≥30 ml/min/ 1.73m 2 •Stable SoC HFrEF treatment Dapagliflozin 10 mg + SoC Randomization 1:1 N = ~4500 Study duration ~33 months Average follow-up ~24 months Primary endpoint: Time to first occurrence of any of the components of the composite: • CV death or hospitalization for HF or an urgent HF visit Secondary endpoints: • Time to first occurrence of CV death or hHF • Total number of (first and recurrent) hHF and CV death • Change from baseline in KCCQ at 8 months • Time to first occurrence of renal composite (≥50% sustained decline in eGFR, ESRD or renal death) Study Start: Feb 2017 Estimated Study Completion: BEFORE Fall 2019!  AHA 2019? CV, cardiovascular; eGFR, estimated glomerular filtration rate; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; N, number of patients; NTproBNP, N-terminal pro b- type natriuretic peptide; SCV, study closure visit; SED, study end date; SoC, standard of care https://clinicaltrials.gov/show/NCT03036124 39 What’s coming up with SGLT2s and heart failure? DAPA-HF and DELIVER 40 Aim: To investigate the safety and efficacy of dapagliflozin versus placebo on top of guideline-directed medical therapy in patients with heart failure with reduced or preserved ejection fraction Population: T2D and non-T2D, age ≥18 years, chronic HF (NYHA II–IV) DAPA-HF LVEF ≤40% DELIVER LVEF >40% Placebo qd + SoC† Dapagliflozin 10 mg qd + SoC† Screening Placebo qd + SoC Dapagliflozin 10 mg qd + SoC Screening *Based on blinded assessment of event rate; †Guideline-directed medical therapy LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; SoC, standard of care 1. ClinicalTrials.gov. NCT03057977; 2. Zannad F et al. ESC-HF 2018; poster P1755; 3. ClinicalTrials.gov. NCT03057951; 4. Butler J et al. ESC-HF 2018; poster P972 What’s coming up with SGLT2s and heart failure? EMPEROR-Reduced and EMPEROR-Preserved Phase III randomised double-blind placebo-controlled studies 41 Aim: To investigate the safety and efficacy of empagliflozin versus placebo on top of guideline- directed medical therapy in patients with heart failure with reduced or preserved ejection fraction Population: T2D and non-T2D, age ≥18 years, chronic HF (NYHA II–IV) EMPEROR-Reduced1,2 LVEF ≤40% EMPEROR-Preserved3,4 LVEF >40% Placebo qd + SoC† Empagliflozin 10 mg qd + SoC† Screening Placebo qd + SoC† Empagliflozin 10 mg qd + SoC† 30-day follow-up Screening 30-day follow-up Planned recruitment: 2850 patients Planned recruitment: 6000 Estimated follow-up ~38 months (event-driven) Estimated follow-up ~38 months (event-driven) Update on Mrs. P Started on SGLT2 inhibitor • Creatinine went from 120 to 144 mml/L: • Creatinine back to 130 mmol/L 2 weeks later • Last seen 08/4/2019, stable NYHA 2, NT-proBNP 2293 • Creatinine 130 mmol/L - eGFR 35 ml/min, Urine ACR 70 mg/mmol • Kidney Failure Risk – 12 % over 5 years Current meds: EF 35%, no ICD, NYHA 2 • Metformin 500 mg po BID • Empa 10 mg po OD • Lasix 80 mg po OD • Sac/valsartan 50 mg po BID • Metoprolol 25 mg po BID • Atorvastatin 80 mg po OD • Rivaroxaban dose 15 mg po OD 42 Chronic Kidney Disease Management Navdeep Tangri MD, PhD, FRCPC @NavTangri 43 Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004 Sep 23;351(13):1296-305. Erratum in: N Engl J Med. 2008;18(4):4. CKD is associated with adverse outcomes 44 Levin, Adeera, et al. "Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease." Kidney International Supplements 3.1 (2013): 1-150. KDIGO Heatmap 45 Importance of Albuminuria - Risk Tangri, Navdeep, et al. "A predictive model for progression of chronic kidney disease to kidney failure." Jama 305.15 (2011): 1553-1559. 46 NR, not reported; NS, not significant; * Progression to microalbuminuria; ** Progression of albuminuria. This was defined as more than a 30% increase in albuminuria and a change from either normoalbuminuria to microalbuminuria or macroalbuminuria, or from microalbuminuria to macroalbuminuria; §End-stage kidney disease, defined as dialysis, transplantation, or a sustained estimated GFR of <15 ml / min / 1.73 m2; ‡End-stage kidney disease, doubling of serum creatinine level, or renal death. 1. Zinman B, et al.. N Engl J Med 2015;373:2117-28. 2 Neal B. et al, N Engl J Med 2017;377:644-57. 3. Wiviott SD et al. N Engl J Med 2018;DOI:10.1056/NEJMoa1812389. 4. Marso S et al. N Engl J Med 2016;375:311-22. 5. Marso S et al. N Engl J Med 2016;375:1834-44. 6. Perkovic V, et al. N Engl J Med 2019; DOI: 10.1056/NEJMe1904740. Published CVOTs demonstrating superiority Secondary Renal Outcomes TRIAL SECONDARY OUTCOMES New or worsening nephropathy Doubling of SrCr Progression to MAU / of albuminuria Initiation of RRT Composite : 40% eGFR, RRT , renal death CV TRIALS EMPA-REG HR (95% CI) 0.61 (0.53, 0.70) 0.56 (0.39, 0.79) 0.62* (0.54, 0.72) 0.45 (0.40, 0.75) 0.54 (0.40, 0.75) CANVAS HR (95% CI) NR NR 0.73** (0.67, 0.79) NR 0.53 (0.33,0.84) DECLARE HR (95% CI) NR NR NR NR 0.53 Many Renal Effects of SGLT2 Inhibition Have Been Proposed Intraglomerular pressure Oxidant stress BP/arterial stiffness AlbuminuriaGlucose Intrarenal angiotensinogen upregulation Volume Inflammation/fibrosis And many others… 47 ARS • At what eGFR should we not prescribe SGLT2 inhibitors? • < 60 = 0% • < 45 = 4% • < 30 = 82% • It’s a moving target after Credence = 14% 48 Perkovic, Vlado., et al. “Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy." New England Journal of Medicine ePub Apr 2019 CREDENCE 49 Low Moderately increased High Very high <30 30-44 45-59 60-90C ≥90 Albuminuria categories (mg/g) A1: <30 A2: 30-300 A3: >300 DECLARE CANVAS Program EMPA-REG OUTCOME CREDENCE Median UACR (mg/g) 13 12 18 927 Mean eGFR (mL/min/1.73 m2) 85 76 74 56 Sustained RRT Events DECLARE Not reported CANVAS Program 18 EMPA-REG OUTCOME 11 CREDENCE 176 C DE D E C 50 Hazard ratio (95% CI) P value Primary 1. ESKD, doubling of serum creatinine, or renal or CV death 0.70 (0.59–0.82) 0.00001 Secondary 2. CV death or hospitalization for heart failure 0.69 (0.57–0.83) <0.001 3. CV death, MI, or stroke 0.80 (0.67–0.95) 0.01 4. Hospitalization for heart failure 0.61 (0.47–0.80) <0.001 5. ESKD, doubling of serum creatinine, or renal death 0.66 (0.53–0.81) <0.001 6. CV death 0.78 (0.61–1.00) 0.0502 7. All-cause mortality 0.83 (0.68–1.02) – 8. CV death, MI, stroke, hospitalization for heart failure, or hospitalization for unstable angina 0.74 (0.63–0.86) – Credence Summary Not formally tested Not formally tested ✔ ✔ ✔ ✔ ✔ Not significant 51 Published CVOTs demonstrating superiority Secondary Renal Outcomes 52 NR, not reported; NS, not significant; * Progression to microalbuminuria; ** Progression of albuminuria. This was defined as more than a 30% increase in albuminuria and a change from either normoalbuminuria to microalbuminuria or macroalbuminuria, or from microalbuminuria to macroalbuminuria; §End-stage kidney disease, defined as dialysis, transplantation, or a sustained estimated GFR of <15 ml / min / 1.73 m2; ‡End- stage kidney disease, doubling of serum creatinine level, or renal death. 1. Zinman B, et al.. N Engl J Med 2015;373:2117-28. 2 Neal B. et al, N Engl J Med 2017;377:644-57. 3. Wiviott SD et al. N Engl J Med 2018;DOI:10.1056/NEJMoa1812389. 4. Marso S et al. N Engl J Med 2016;375:311-22. 5. Marso S et al. N Engl J Med 2016;375:1834-44. 6. Perkovic V, et al. N Engl J Med 2019; DOI: 10.1056/NEJMe1904740. TRIAL SECONDARY OUTCOMES New or worsening nephropathy Doubling of SrCr Progression to MAU / of albuminuria Initiation of RRT Composite : 40% eGFR, RRT , renal death CV TRIALS LEADER HR (95% CI) 0.78 (0.67, 0.92) NR NR NR NR SUSTAIN-6 HR (95% CI) 0.64 (0.46, 0.88) NR NR NR NR What’s Coming Up with SGLT2i’s and CKD? 53 #Cardiotwitter Question 54 ARS Question • If you do prescribe SGLT2i’s is your recommendation for or against use influenced by: • Cost = 29% • CV benefits = 63% • Renal benefits = 6% • Presence of PVD = 2% 55 #Cardiotwitter Answer 56 Closing Remarks Shelley Zieroth MD, FRCPC, FCCS @ShelleyZieroth 57