failure: What have we learnt? John McMurray BHF Cardiovascular - - PowerPoint PPT Presentation

John McMurray BHF Cardiovascular Research Centre, University of Glasgow & Queen Elizabeth University Hospital, Glasgow.

New diabetes drugs and heart failure: What have we learnt?

Satellite symposium on: Heart failure, diabetes and renal dysfunction HFA Congress, Paris, 1 May 2017

Why are we talking about heart failure in diabetes?

• HF is one of the most common cardiovascular complications of type 2 diabetes
• HF is the most disabling and deadly complication of diabetes
• Most patients with HF have either diabetes or pre-diabetic dysglycaemia
• Diabetes is one of the most disabling and comorbidities complicating HF

So how should we treat diabetes in patients with HF?

• What do we know about treatments for diabetes and reducing

the risk of developing HF (incident HF)?

• What do we know about treatments for diabetes in patients

with established HF (prevalent HF)?

Outcome trials in T2DM: A timeline

1970 1998 2002 2005 2008

UGDP PROactive ACCORD ADVANCE VADT UKPDS

Major CV outcome trials in type 2 diabetes

2015 2017 2016 2018 2019 2013 2012 2014

CAROLINA N = 6041 MACE4

ELIXA* (n = 6000) 844 MACE4

: SGLT2i : DPP4i : GLP1 *lixisenatide (Sanofi, post-ACS). †liraglutide (Novo Nordisk). ‡semaglutide (Novo Nordisk). §exenatide (Amylin). §§albiglutide (GSK) ¶once-weekly DPP4i (Merck). #dulaglutide (Eli Lilly). TECOS (n = 14,723) 1300 MACE4

CANVAS (n = 4339) MACE3 DECLARE- TIMI 58 (n = 27,000) MACE3

SAVOR- TIMI 53 (n = 16,492) 1222 MACE3

SUSTAIN-6‡ (n = 3260) MACE3

EXAMINE (n = 5380) 621 MACE3

LEADER† (n = 9341) 611 MACE3 CANVAS-R (n = 5700) Alb.uria CREDENCE (n = 3627) Cardiorenal EXSCEL§ (n = 14000) MACE3 REWIND# (n = 9622) MACE3 Ertugliflozin CVOT (n = 3900) MACE3

ACS, acute coronary syndrome; CHF, congestive heart failure; CI, confidence interval; CV, cardiovascular; DPP4i, dipeptidyl peptidase-4 inhibitor; GLP1, glucagon-like peptide 1; HR, hazard ratio; SGLT2i, sodium glucose cotransporter 2 inhibitor; UL, upper limit.

CARMELINA N = 8300 MACE4 Omarigliptin¶ (n = 4000) Q42017 ? MACE4

EMPA-REG OUTCOME N = 7034 MACE3 FREEDOM§ (n = 4000) ? MACE4 HARMONY §§ (n = 9400) MACE3

Outcome trials in T2DM: A timeline

1970 1998 2002 2005 2008

UGDP PROactive ACCORD ADVANCE VADT UKPDS FDA guidance

Rosiglitazone increases risk of myocardial infarction?

United States FDA guidance

FDA guidance

Unacceptable harm must be excluded

FDA guidance – what endpoints?

The events should include cardiovascular

mortality, myocardial infarction and stroke

…and can include hospitalization for acute

coronary syndrome, urgent revascularization procedures

….and possibly other endpoints

FDA guidance – what endpoints?

The events should include cardiovascular

mortality, myocardial infarction and stroke

…and can include hospitalization for acute

coronary syndrome, urgent revascularization procedures

….and possibly other endpoints

“Fluid retention” or heart failure? HF in diabetes trials is real and deadly

RECORD: Design

Metformin

• r

Sulfonylurea add Rosiglitazone add Sulfonylurea or Metformin

Mean follow-up: 5.5 years Rescue therapy: Rosiglitazone group i) intensify to triple oral therapy ii) stop rosiglitazone and start insulin Metformin/SU group i) start insulin

Patients on monotherapy Randomized to dual therapy

RECORD: HF with rosiglitazone

Congestive Heart Failure (Adjudicated)

What happened to patients who developed HF in RECORD?

 Any heart failure (fatal or non-fatal): 29 control

patients vs. 61 rosiglitazone patients

 Survived first heart failure event: 29 control patients

• vs. 57 rosiglitazone patients

 Subsequent risk of death: 8 control patients (28%) vs.

17 rosiglitazone patients (30%)

Major CV outcome trials in type 2 diabetes

2015 2017 2016 2018 2019 2013 2012 2014

CAROLINA N = 6041 MACE4

ELIXA* (n = 6000) 844 MACE4

: SGLT2i : DPP4i : GLP1 *lixisenatide (Sanofi, post-ACS). †liraglutide (Novo Nordisk). ‡semaglutide (Novo Nordisk). §exenatide (Amylin). §§albiglutide (GSK) ¶once-weekly DPP4i (Merck). #dulaglutide (Eli Lilly). TECOS (n = 14,723) 1300 MACE4

CANVAS (n = 4339) MACE3 DECLARE- TIMI 58 (n = 27,000) MACE3

SAVOR- TIMI 53 (n = 16,492) 1222 MACE3

SUSTAIN-6‡ (n = 3260) MACE3

EXAMINE (n = 5380) 621 MACE3

LEADER† (n = 9341) 611 MACE3 CANVAS-R (n = 5700) Alb.uria CREDENCE (n = 3627) Cardiorenal EXSCEL§ (n = 14000) MACE3 REWIND# (n = 9622) MACE3 Ertugliflozin CVOT (n = 3900) MACE3

ACS, acute coronary syndrome; CHF, congestive heart failure; CI, confidence interval; CV, cardiovascular; DPP4i, dipeptidyl peptidase-4 inhibitor; GLP1, glucagon-like peptide 1; HR, hazard ratio; SGLT2i, sodium glucose cotransporter 2 inhibitor; UL, upper limit.

CARMELINA N = 8300 MACE4 Omarigliptin¶ (n = 4000) Q42017 ? MACE4

EMPA-REG OUTCOME N = 7034 MACE3 FREEDOM§ (n = 4000) ? MACE4 HARMONY §§ (n = 9400) MACE3

Glucagon-like peptide-1/ Incretin therapies

Incretins

• (GIP)
• GLP-1

Stimulate insulin release Inhibit glucagon release Reduce blood glucose

DPP4 Breakdown products DPP4 inhibitors (“gliptins”) GLP-1 agonists/analogues e.g. exenatide Inhibit renal re-absorption (SGLT2 inhibitors) Inhibit gastro- intestinal absorption (α-glucosidase inhib’s)

New approaches to reducing blood glucose

DPP-4 inhibitor Saxagliptin Alogliptin Sitagliptin Linagliptin Linagliptin Comparator Placebo Placebo Placebo SU Placebo

• No. of patients

16,492 5,380 14,723 6,041 ~8,3000 Trial initiation/ completion May 2010 May 2013

• Sept. 2009

June 2013

• Nov. 2008

June 2015

• Oct. 2010
• Sept. 2018

July 2013

• Jan. 2018

Excluded background therapy DPP-4i GLP-1 RA DPP-4i GLP-1 RA DPP-4i GLP-1 RA Rosiglitazone DPP-4i GLP-1 RA TZD DPP-4i GLP-1 RA SGLT-2i Patients CVD/CV risk factors (RF) ACS CVD CVD/ subclinical CVD/CVRF CVD & UACR/renal dysf.

1 2 3 4 5

Major DPP-4 inhibitor CV outcome trials

SAVOR-TIMI53

Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus

SAVOR-TIMI53

Design: T2DM aged ≥40 yr. with established CV disease or aged ≥55 yr. (≥60 yr. women) with ≥1 risk factor for CV disease. HbA1c 6.5-12.0%. Superiority design. Patients enrolled: 16,492 patients. Mean age 65 yr. 33% female. 79% CV disease. Mean HbA1c 8.0%. BMI 31 kg/m2. Median duration of diabetes 10.0 yr. Insulin treated 41%. Placebo-corrected decrease in HbA1c: 0.3% at 2 yr (0.2% end-of-study). Primary outcome: CV death, MI or ischaemic stroke. Intervention: Randomized 1:1 to placebo or saxagliptin 5mg/d (2.5 mg if eGFR ≤50 ml/min/1.73m2). Follow-up: Median 2.1 years.

NEJM 2013; 369:1317-1326

SAVOR-TIMI53: Primary outcome

NEJM 2013; 369:1317-1326

0,5 1 1,5 2 2,5 3 3,5 4

%

MI HF Stroke* CV death n = 141 228

SAVOR-TIMI53

* Ischaemic stroke

278 260

NEJM 2013; 369:1317-1326

0,5 1 1,5 2 2,5 3 3,5 4

%

MI HF Stroke* CV death saxagliptin n = 157 141 289 228 265 269

SAVOR-TIMI53

* Ischaemic stroke

278 260 p = 0.007

NEJM 2013; 369:1317-1326

It was real heart failure!

Placebo Saxagliptin HR Death 25.9% 26.3% 1.01 (0.72-1.43) Readmission for HF 25.0% 27.7% 1.06 (0.75-1.50)

Subsequent risk in patients hospitalized with heart failure

The DPP-4 inhibitor trials

DPP-4 inhibitor trials

First hospitalization for heart failure Cardiovascular death or hospitalization for heart failure

McGuire et al JAMA Cardiol. 2016;1:126-35.

More questions than answers?

 Is the increase in heart failure hospitalization with saxagliptin real or spurious? What about alogliptin?  If the effect in SAVOR-TIMI-53 is real, is it a drug- specific effect? How likely is it that one (or two) drugs in a class are different than the others?  If it is real, why does it occur? No plausible explanation to date.

Potential CV actions of DDP-4 inhibitors

Oyama & Node Circ J. 2014;78(4):819-24.

Incretins

• (GIP)
• GLP-1

Stimulate insulin release Inhibit glucagon release Reduce blood glucose

DPP4 Breakdown products DPP4 inhibitors (“gliptins”) GLP-1 agonists/analogues e.g. exenatide Inhibit renal re-absorption (SGLT2 inhibitors) Inhibit gastro- intestinal absorption (α-glucosidase inhib’s)

New approaches to reducing blood glucose

Major CV outcome trials in type 2 diabetes

2015 2017 2016 2018 2019 2013 2012 2014

CAROLINA N = 6041 MACE4

ELIXA* (n = 6000) 844 MACE4

: SGLT2i : DPP4i : GLP1 *lixisenatide (Sanofi, post-ACS). †liraglutide (Novo Nordisk). ‡semaglutide (Novo Nordisk). §exenatide (Amylin). §§albiglutide (GSK) ¶once-weekly DPP4i (Merck). #dulaglutide (Eli Lilly). TECOS (n = 14,723) 1300 MACE4

CANVAS (n = 4339) MACE3 DECLARE- TIMI 58 (n = 27,000) MACE3

SAVOR- TIMI 53 (n = 16,492) 1222 MACE3

SUSTAIN-6‡ (n = 3260) MACE3

EXAMINE (n = 5380) 621 MACE3

LEADER† (n = 9341) 611 MACE3 CANVAS-R (n = 5700) Alb.uria CREDENCE (n = 3627) Cardiorenal EXSCEL§ (n = 14000) MACE3 REWIND# (n = 9622) MACE3 Ertugliflozin CVOT (n = 3900) MACE3

ACS, acute coronary syndrome; CHF, congestive heart failure; CI, confidence interval; CV, cardiovascular; DPP4i, dipeptidyl peptidase-4 inhibitor; GLP1, glucagon-like peptide 1; HR, hazard ratio; SGLT2i, sodium glucose cotransporter 2 inhibitor; UL, upper limit.

CARMELINA N = 8300 MACE4 Omarigliptin¶ (n = 4000) Q42017 ? MACE4

EMPA-REG OUTCOME N = 7034 MACE3 FREEDOM§ (n = 4000) ? MACE4 HARMONY §§ (n = 9400) MACE3

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. NCT01243424. 6. NCT01394952

GLP-1 RA Lixisenatide Liraglutide Semaglutide Exenatide ITCA 650/ exenatide Dulaglutide Albiglutide Comparator Placebo Placebo Placebo Placebo Placebo Placebo Placebo

• No. of

patients 6068 9340 3297 ~14000 ~4000 ~9600 ~9400 Trial initiation/ completion June 2010 April 2015

• Sept. 2010
• Oct. 2015
• Feb. 2013
• Jan. 2016

June 2010 April 2018 March 2013 July 2018 July 2011 April 2019 June 2015

• Aug. 2019

Excluded therapy DPP-4i pramlintide DPP-4i pramlintide DPP-4i pramlintide

• ?
• GLP-1

agonists Patients ACS CVD/CV risk factors (RF) CVD/ subclinical CVD CVD/ CVRF CVD CVD/ subclinical CVD/CVRF CVD

Major GLP-1 RA CV outcome trials

REWIND

1 2 3 4 5 6 7

The GLP-1 receptor agonist trials

ELIXA

Evaluation of LIXisenatide in Acute coronary syndrome 6068 patients with T2DM and a recent ACS

ELIXA

Evaluation of LIXisenatide in Acute coronary syndrome Primary endpoint: CV death, MI, stroke, UA

Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER)

Published on June 13, 2016, at NEJM.org.

9340 patients with T2DM at high CV risk Median follow-up 3.8 years

GLP-1 agonist liraglutide – reduced incidence of primary composite endpoint

SUSTAIN-6

Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes 3297 patients with T2DM at high CV risk Median follow-up 2.1 years

SUSTAIN-6: Primary outcome

8.9% Semaglutide

Cardiovascular death, myocardial infarction or stroke

Placebo 6.6%

GLP-1R agonists: clinical pharmacology

Drug Exenatide bid Exenatide qw Lixisenatide

• d

Liraglutide

• d

Dulaglutide qw Albiglutide qw Structure (seq.homol) Exendin-4 (53%) Exendin-4 (53%) Exendin-4 plus extra Lys residues GLP-1 (97%) GLP-1 (91%) GLP-1 (97%) EC50 (nM) 0.55 0.55 1.4 0.11 NA 0.24 Dose 5, 10 μg 2 mg 20 μg 0.6, 1.2, 1.8 mg 0.75, 1.5 mg 30, 50 mg Cmax ~160-250 pg/ml SS ~300 pg/ml ~190 pg/ml SS ~34 nmol/L (1.8mg dose) 114 ng/ml (1.5mg dose) 4.4 μg/ml (50 mg dose) Tmax 2 - 3 h 2 – 6 weeks at SS 1.2 – 2.5 h 10 – 14 h 2 – 4 weeks at SS 3 – 5 days T½ ~3.5 h unspecified 2 – 4 h 11.6 – 13 h ~ 4.7 days ~ 5 days Elimination renal renal renal peptidases peptidases peptidases

SS = steady state Nat Rev Endo 2016, Tahrani et al

GLP-1 RA: HF hospitalization (as a marker of incident HF)

LEADER SUSTAIN-6

Marso et al N Engl J Med. 2016; 375: 311-22 Marso et al N Engl J Med. 2016; 375: 1834-1844

GLP-1 receptor agonists: hospitalization for heart

failure – lixisenatide (ELIXA)

Placebo (n=3034) Lixisenatide (n=3034) Hazard ratio (95% CI) No prior HF 58/2358 (2.5%) 56/2352 (2.4%) 0.97 (0.67-1.40) Prior HF 69/676 (10.2%) 66/682 (9.7%) 0.93 (0.66-1.30) Interaction P=0.87 HF = heart failure

Pfeffer N Engl J Med. 2015 Dec 3;373(23):2247-57

SUSTAIN-6: Change in heart rate

Functional Impact of GLP-1 for Heart Failure Treatment (FIGHT)

 300 patients with HFrEF  Hospitalized  Treated with placebo or liraglutide

1.8mg/d for 180 days

 Primary end point was a global rank

score

The GLP-1 receptor agonist trials

Incretins

• (GIP)
• GLP-1

Stimulate insulin release Inhibit glucagon release Reduce blood glucose

DPP4 Breakdown products DPP4 inhibitors (“gliptins”) GLP-1 agonists/analogues e.g. exenatide Inhibit renal re-absorption (SGLT2 inhibitors) Inhibit gastro- intestinal absorption (α-glucosidase inhib’s)

New approaches to reducing blood glucose

SGLT-2 inhibitors

Inhibit proximal tubular glucose reabsorption, cause diuresis and natriuresis, lower BP and reduce weight. Also renoprotective (in diabetes)?

EMPA-REG Outcome

7,020 patients with T2DM and CV disease/risk factors

EMPA-REG Outcome: Primary endpoint

The key findings in EMPA-REG OUTCOME

Heart failure Hospitalization Cardiovascular mortality

Zinman et al N Engl J Med. 2015; 373: 2117-28

What type of heart failure?

HFREF or HFPEF?

Normal HFREF HFPEF

Major CV outcome trials in type 2 diabetes

2015 2017 2016 2018 2019 2013 2012 2014

CAROLINA N = 6041 MACE4

ELIXA* (n = 6000) 844 MACE4

: SGLT2i : DPP4i : GLP1 *lixisenatide (Sanofi, post-ACS). †liraglutide (Novo Nordisk). ‡semaglutide (Novo Nordisk). §exenatide (Amylin). §§albiglutide (GSK) ¶once-weekly DPP4i (Merck). #dulaglutide (Eli Lilly). TECOS (n = 14,723) 1300 MACE4

CANVAS (n = 4339) MACE3 DECLARE- TIMI 58 (n = 27,000) MACE3

SAVOR- TIMI 53 (n = 16,492) 1222 MACE3

SUSTAIN-6‡ (n = 3260) MACE3

EXAMINE (n = 5380) 621 MACE3

LEADER† (n = 9341) 611 MACE3 CANVAS-R (n = 5700) Alb.uria CREDENCE (n = 3627) Cardiorenal EXSCEL§ (n = 14000) MACE3 REWIND# (n = 9622) MACE3 Ertugliflozin CVOT (n = 3900) MACE3

ACS, acute coronary syndrome; CHF, congestive heart failure; CI, confidence interval; CV, cardiovascular; DPP4i, dipeptidyl peptidase-4 inhibitor; GLP1, glucagon-like peptide 1; HR, hazard ratio; SGLT2i, sodium glucose cotransporter 2 inhibitor; UL, upper limit.

CARMELINA N = 8300 MACE4 Omarigliptin¶ (n = 4000) Q42017 ? MACE4

EMPA-REG OUTCOME N = 7034 MACE3 FREEDOM§ (n = 4000) ? MACE4 HARMONY §§ (n = 9400) MACE3

Anti-diabetes drugs and prevention of CV events

Months Years Decades

adapted from Tanaka A,Node K. J Cardiol.2017 Mar;69(3):501-507

Diuretic/ hemodynamic effect “Metabolic” effect Decrease in CV events

SGLT2 inhibitors: How do they work?

"The search for the sweet spot in heart failure: The metabolodiuretic promise of SGLT2 inhibition"

Recent data from animal models

The heart in heart failure plus diabetes: A “black box”

Diabetes: preferential oxidation of fatty acids Heart failure: preferential oxidation of glucose

Mitochondrial dysfunction? Microvascular dysfunction? Oxidative stress?

SGLT-2 inhibitors: Key questions

 Prevention of HF - how do they work?

– Diuretic/natriuretic effect (with less neurohumoral activation?)? – Improved myocardial metabolism? – Improved renal function? – What (pheno-)type of HF is prevented? – Can these explain reduced CV death as well as reduced HF hospitalization

 Can they be used to treat established HF?

– Existing trials largely about prevention of incident HF. What about patients with established HF? – Just HF patients with diabetes or all HF patients?

EMPA-REG Outcome: Heart failure

Experience with SGLT2 inhibitors in HF?

T2DM and NYHA class II-IV: dapagliflozin (N = 171) or placebo (N = 149). Placebo-adjusted reduction in HbA1c (−0.55%; −0.80,−0.30), weight (−2.67 kg; −3.88,−1.47), and SBP (−2.05 mmHg; −5.68, 1.57) over 52 weeks Post hoc; no LVEF.

Phase 3 mortality/morbidity trials with SGLT2 inhibitors in HFrEF

• Hypothesis: Empagliflozin will be superior to placebo,

added to SOC, in patients with symptomatic chronic HF- REF

• Population: 2850 patients; EF ≤40%; EF 36-40%/NT-

proBNP ≥2500 pg/ml; 31-35%/≥1000 pg/ml; ≤30% ≥600 pg/ml; eGFR ≥20 ml/min/1.73 m2 ; SBP ≥100 mmHg

• Primary endpoint: CV death or HF hospitalization

EMPEROR-Reduced1

• Hypothesis: Dapagliflozin will be superior to placebo,

added to SOC, in patients with symptomatic chronic HF- REF

• Population: 4500 patients; EF ≤40%; NT-proBNP ≥600

pg/ml; eGFR ≥30 ml/min/1.73 m2; SBP ≥95 mmHg

• Primary endpoint: CV death or worsening HF event

Dapa-HF2

1NCT03057977 2NCT03036124

Hypothesis: Empagliflozin will reduce morbidity and

mortality in patients with HF-PEF.

Population: 4126 patients; symptomatic HF; EF >40%; NT

pro BNP >300 pg/ml (> 900 pg/ml for patients with AF); structural heart disease or HF hospitalisation in prior 12 months.

Intervention: Empagliflozin 10 mg once daily vs. placebo. Primary endpoint: CV death or HF hospitalization

(Secondary - first and recurrent HF hospitalization )

Status: Enrolling

EMPEROR-Preserved

EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction NCT03057951

Diabetes and heart failure

 Heart failure is one of the most common

cardiovascular complications of diabetes.

 Heart failure is the most disabling and deadly

complication of diabetes.

 Treatments for diabetes may increase or decrease

the risk of developing heart failure.

 What is the effect of glucose-lowering therapy in

patients with established heart failure?