Heart failure & diabetes: What is the goal of treatment? John - PowerPoint PPT Presentation

Heart failure & diabetes: What is the goal of treatment? John McMurray, MD Glasgow, United Kingdom May, 2019 - Athens, Greece

Translating Innovations to practice in HFpEF symposium, Athens 25 May 2019 HFpEF and diabetes: What are the goals of treatment? John McMurray BHF Cardiovascular Research Centre, University of Glasgow & Queen Elizabeth University Hospital, Glasgow.

Heart failure and type 2 diabetes • Prevention of heart failure – where we are today • Treatment of heart failure – the next step – Can these drugs be used to treat prevalent HF rather than just prevent incident HF? – Only patients with diabetes or everyone with HF? – HFrEF, HFpEF or both?

Heart failure and type 2 diabetes • Prevention of heart failure – where we are today – “Old” glucose lowering therapies (biguanides, sulfonylureas, insulins): No idea whether they reduce risk of heart failure or any other CV event (insulin safe?) . – DPP- 4 inhibitors don’t reduce the risk of any CV event (yet are the most widely prescribed of the “new” glucose lowering drugs!) – SGLT2inhibtors (definitely) and GLP-1 RAs (probably) reduce incident heart failure events

Do NOT believe non-randomized, observational analyses of outcomes related to treatment!

Heart failure and type 2 diabetes • Prevention of heart failure – where we are today – “Old” glucose lowering therapies (biguanides, sulfonylureas, insulins): No idea whether they reduce risk of heart failure. – DPP- 4 inhibitors don’t reduce the risk of any CV event (yet are the most widely prescribed of the “new” glucose lowering drugs - paradox! ) – SGLT2inhibtors (definitely) and GLP-1 RAs (probably) reduce incident heart failure events

Updated meta-analysis of DPP-4 inhibitor trials CV death/MI/stroke HF hospitalization

Heart failure and type 2 diabetes • Prevention of heart failure – where we are today – “Old” glucose lowering therapies (biguanides, sulfonylureas, insulins): No idea whether they reduce risk of heart failure or any other CV event (insulin safe?). – DPP- 4 inhibitors don’t reduce the risk of any CV event (yet are the most widely prescribed of the “new” glucose lowering drugs!) – SGLT2inhibtors (definitely) and GLP-1 RAs (probably) reduce incident heart failure events

SGLT-2 inhibitors: Large mortality/morbidity trials in type 2 diabetes (excluding CKD and HF trials) EMPA-REG CANVAS (-R) DECLARE VERTIS NCT01131676 NCT01032629 NCT01730534 NCT01986881 NCT01989754 SGLT2-i empaglifozin canagliflozin dapagliflozin ertugliflozin Comparator placebo placebo placebo placebo Patients CVD CV risk factors CV risk factors CVD enrolled /CVD /CVD Number of 7020 4430 17276 ~8000 patients 5812 Results 2015 2017 2019 2019?

Large SGTLT2 inhibitor RCTs: Effect on heart failure hospitalization Patients with atherosclerotic CV disease Patients with multiple risk factors Sabatine M et al Lancet 2019: 393:31-39

HF in diabetes with nephropathy

SGLT-2 inhibitors: Large mortality/ morbidity trials in CKD CREDENCE Dapa-CKD SCORED EMPA-Kidney NCT02065791 NCT03036150 NCT03315143 NCT03594110 sotagliflozin + SGLT2-i canagliflozin dapagliflozin empagliflozin Comparator placebo placebo placebo placebo Patients Type 2 DM Type 2 DM Type 2 DM Type 2 DM GFR ≥30 <90 & and no DM CV risk factors and no DM GFR ≥25 ≤75 & GFR ≥25 ≤60 GFR ≥20 <45 UACR >300 ≤5000mg/g UACR ≥200 GFR ≥45 <90 & ≤5000mg/g UACR ≥200 mg/g No. of patients 4,461 ~4000 10,500 ~5000 Results 2019 2020 2022 2022 + SGLT-1/2 inhibitor

CREDENCE Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation published on April 14, 2019, at NEJM.org CV death death or HF hospitalization CV death death or HF hospitalization: HR 0.69 (0.57,0.83), P<0.001 • CV death: HR 0.78 (0.61,1.00), P=0.05 • Hospitalization for HF: HR 0.61 (0.47,0.80), P<0.001

Summary of effect of GLP-1 RAs on HF in recent trials in T2DM J ACC HF 2018;6:823 – 30

Major GLP-1 RA CV outcome trials 4 2 3 5 6 1 7 REWIND ITCA 650/ GLP-1 RA Lixisenatide Liraglutide Semaglutide Exenatide Albiglutide Dulaglutide exenatide Comparator Placebo Placebo Placebo Placebo Placebo Placebo Placebo No. of 6068 9340 3297 ~14000 ~4000 ~9400 ~9600 patients Trial June 2010 Sept. 2010 Feb. 2013 June 2010 March 2013 June 2015 July 2011 initiation/ April 2015 Oct. 2015 Jan. 2016 April 2018 July 2018 Aug. 2019 April 2019 completion Excluded DPP-4i DPP-4i DPP-4i GLP-1 - ? - therapy pramlintide pramlintide pramlintide agonists CVD/ CVD/ CVD/CV risk CVD/ Patients ACS subclinical CVD CVD subclinical factors (RF) CVRF CVD CVD/CVRF 1 primary endpoint: cardiovascular (CV) death, nonfatal myocardial infarction (MI), nonfatal stroke, hospitalisation due to unstable angina pectoris. 2-6 primary endpoint: major adverse CV events (CV death, nonfatal MI, nonfatal stroke). ACS, acute coronary syndrome. Source: 1. NCT01147250. 2. NCT01179048. 3. NCT01720446. 4. NCT01144338. 5. NCT01455896. 6. NCT02465515 7. NCT01394952.

Harmony Outcomes Lancet . 2018; 392:1519-1529

17 Primary Outcome: Time to CV Death, MI or Stroke (MACE) Placebo (428 events) 16 Albiglutide (338 events) 14 HR: 0.78 (95% CI 0.68, 0.90) 12 Non-inferiority p<0.0001 Cumulative 10 Superiority p=0.0006 Incidence 8 (%) 6 Event rate per 100 person-years 4 Placebo 5.87 2 Albiglutide 4.57 0 0 4 8 12 16 20 24 28 Time (months) People at risk Placebo 4,732 4,460 3,074 1,030 Albiglutide 4,731 4,503 3,148 1,064

Major GLP-1 RA CV outcome trials 4 2 3 5 6 1 7 REWIND ITCA 650/ GLP-1 RA Lixisenatide Liraglutide Semaglutide Exenatide Albiglutide Dulaglutide exenatide Comparator Placebo Placebo Placebo Placebo Placebo Placebo Placebo No. of 6068 9340 3297 ~14000 ~4000 ~9400 ~9600 patients Trial June 2010 Sept. 2010 Feb. 2013 June 2010 March 2013 June 2015 July 2011 initiation/ April 2015 Oct. 2015 Jan. 2016 April 2018 July 2018 Aug. 2019 April 2019 completion Excluded DPP-4i DPP-4i DPP-4i GLP-1 - ? - therapy pramlintide pramlintide pramlintide agonists CVD/ CVD/ CVD/CV risk CVD/ Patients ACS subclinical CVD CVD subclinical factors (RF) CVRF CVD CVD/CVRF 1 primary endpoint: cardiovascular (CV) death, nonfatal myocardial infarction (MI), nonfatal stroke, hospitalisation due to unstable angina pectoris. 2-6 primary endpoint: major adverse CV events (CV death, nonfatal MI, nonfatal stroke). ACS, acute coronary syndrome. Source: 1. NCT01147250. 2. NCT01179048. 3. NCT01720446. 4. NCT01144338. 5. NCT01455896. 6. NCT02465515 7. NCT01394952.

Oral semaglutide: PIONEER-6 Peptide InnOvatioN for Early DiabEtesTreatment • 3183 patients with T2DM • Age ≥50 yr and CV disease or ≥60 yr and CV risk factors • Primary end point: CV death, MI or stroke (MACE) • Key secondary: primary endpoint, plus unstable angina or hospitalization for heart failure (and analysis of components)

More GLP-1 receptor agonist trials • Semaglutide oral: SOUL (n~9,600): T2DM and CV or renal disease. • Semaglutide oral: SELECT (n~17,500): obese/overweight and CV disease (diabetes excluded). • Semaglutide sc weekly: FLOW (n~3160): T2DM and CKD. eGFR decline ≥50%, ESRD or renal/CV death. • Semaglutide sc weekly: FOCUS (n~1500): T2DM ≥10 yr and retinopathy - ETDRS level of 10-75. Eye outcomes. • Liraglutide sc daily: LAMP (n~1708): T2DM minor stroke/high-risk TIA. Outcome: 90-day new stroke events. • Efpeglenatide sc weekly: AMPLITUDE-O (n=4,000): T2DM CV disease or men ≥50 yr /women ≥55 yr with eGFR ≥25 and <60 mL/min and ≥1 CV risk factor.

More GLP-1 receptor agonist trials • Semaglutide oral: SOUL (n~9,600): T2DM and CV or renal disease. • Semaglutide oral: SELECT (n~17,500): obese/overweight and CV disease (diabetes excluded). • Semaglutide sc weekly: FLOW (n~3160): T2DM and CKD. eGFR decline ≥50%, ESRD or renal/CV death. • Semaglutide sc weekly: FOCUS (n~1500): T2DM ≥10 yr and retinopathy - ETDRS level of 10-75. Eye outcomes. • Liraglutide sc daily: LAMP (n~1708): T2DM minor stroke/high-risk TIA. Outcome: 90-day new stroke events. • Efpeglenatide sc weekly: AMPLITUDE-O (n=4,000): T2DM CV disease or men ≥50 yr /women ≥55 yr with eGFR ≥25 and <60 mL/min and ≥1 CV risk factor.

What type of heart failure? HFrEF or HFpEF? Normal HFrEF HFpEF

Heart failure and type 2 diabetes • Prevention of heart failure – where we are today • Treatment of heart failure – the next step – It is wrong to assume that a drug that prevents/delays the development of HF will be beneficial in patients with established HF – Consider CCBs for hypertension or statins for CHD

Heart failure and type 2 diabetes • Prevention of heart failure – where we are today • Treatment of heart failure – the next step – It is wrong to assume that a drug that prevents/delays the development of HF will be beneficial in patients with established HF – Consider CCBs for hypertension or statins for CHD