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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
UGDPPROactive
ACCORD
ADVANCE
VADTUKPDS
Major CV outcome trials in type 2 diabetes
2015 20172016 2018 201920132012 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
UGDPPROactive
ACCORD
ADVANCE
VADTUKPDS
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
or
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 20172016 2018 201920132012 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/
completionMay 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
PatientsCVD/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-TIMI53Saxagliptin 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
0,5
1
1,5
2
2,5
3
3,5
4% MI HF Stroke* CV death
n = 141228
SAVOR-TIMI53
* Ischaemic stroke
278 260
NEJM 2013; 369:1317-1326
0
0,5
1
1,5
2
2,5
3
3,5
4% MI HF Stroke* CV death saxagliptin
n = 157141289228265 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 20172016 2018 201920132012 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 ExenatideITCA 650/
exenatideDulaglutide Albiglutide
Comparator Placebo Placebo Placebo Placebo Placebo Placebo Placebo
No. of
patients6068 9340 3297 ~14000 ~4000 ~9600 ~9400
Trial initiation/
completionJune 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
therapyDPP-4i
pramlintide
DPP-4i
pramlintide
DPP-4i
pramlintide- ? -
GLP-1
agonists
Patients ACSCVD/CV risk
factors (RF)
CVD/
subclinical
CVD
CVD/
CVRFCVD
CVD/
subclinical
CVD/CVRF
CVD
Major GLP-1 RA CV outcome trials
REWIND1 2 3 4 5 6 7
The GLP-1 receptor agonist trials
ELIXAEvaluation of LIXisenatide in Acute coronary syndrome
6068 patients with T2DM and a recent ACS
ELIXAEvaluation 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-6Trial 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
od
Liraglutide
od
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 HeartFailure 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 HospitalizationCardiovascular 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 20172016 2018 201920132012 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” effectDecrease 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-PreservedEMPagliflozin 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?
