OAD and Heart Failure

Putu Moda Arsana

RSSA, Malang, 2018
 Heart Failure

• Heart (or cardiac) failure is the state in

which the heart is unable to pump blood at
a rate commensurate with the
requirements of the tissues or can do so
only from high pressures

Braunwald 8th Edition, 2001

 Types of Heart Failure
• Systolic (or squeezing) heart failure
– Decreased pumping function of the heart, which
results in fluid back up in the lungs and heart failure

• Diastolic (or relaxation) heart failure

– Involves a thickened and stiff heart muscle
– As a result, the heart does not fill with blood
properly
– This results in fluid backup in the lungs and heart
failure
 Risk Factors for Heart Failure
• Coronary artery • Diabetes
disease • Congenital heart defects
• Hypertension (LVH) • Other:
• Valvular heart – Obesity
disease – Age
• Alcoholism – Smoking
• Infection (viral) – High or low hematocrit
level
– Obstructive Sleep Apnea

CAD=coronary artery disease; LVH=left ventricular hypertrophy.

 Pathologic Progression of CV Disease
Sudden
Coronary artery Death
disease

Hypertension Myocardial Pathologic Low ejection

injury remodeling fraction Death
Diabetes

Cardiomyopathy
Pump
Valvular disease failure

Symptoms:
• Neurohormonal Dyspnea
Chronic
heart
stimulation Fatigue
failure
• Myocardial Edema
toxicity

Adapted from Cohn JN. N Engl J Med. 1996;335:490–498.

How can Diabetes causes Heart
Failure?
Therapeutic implications of heart failure
in the diabetic population
• Glycemic Control
• HF therapy
 Glycemic Control
• Life style
• OAD
• Insulin
 OAD and Heart Failure
• Metformin
• Sulfonylurea
• Insulin
• Thiazolidinediones
• DPP-4 Inhibitor
• GLP-1 Agonis
• SGLT-2 Inhibitor
 Metformin
• Reduced mortality in metformin-treated
patients with heart failure.
• Recommended for Patients who suffering
from Heart failure and mild to moderate
Kidney disease
• Precaution in patients with acute or
unstable Heart Failure (potentially causes
lactic acidosis)
 Sulfonylurea
• No difference in heart failure events was
recorded in the UKPDS trial comparing
sulfonylureas or insulin treatment with
dietary intervention in 3867 newly
diagnosed patients with diabetes.
• Nevertheless, others found sulfonylurea
treatment to be associated with increased
heart failure risk when compared with
metformin in a retrospective cohort study.
 Insulin
• Retrospective studies have suggested that insulin
treatment worsens the prognosis of patients with
diabetes and heart failure.
• No increase in heart failure hospitalization or
cardiovascular events was observed in the Outcome
Reduction with an Initial Glargine Intervention (ORIGIN)
trial.
• A requirement of more than 100 units of insulin per day
was associated with increased cardiovascular mortality
(HR 2.65; 95% CI, 1.65-4.25) when compared with a
requirement of 25 units insulin per day or less. Still, no
association of higher insulin doses was found with heart
failure events.
 Thiazolidinediones
• Thiazolidinediones (glitazones) have fluid
retention potential, which leads to
increased heart failure events. Thiazo-
lidinediones are not recommended in
patients with symptomatic heart failure,
and initiation of therapy is contraindicated
in patients with established NYHA III/IV
heart failure.
 DPP-4 Inhibitor
• DPP-4 trials demonstrated cardiovascular safety in high-
risk populations of patients with diabetes,
 Saxagliptin (SAVOR- TIMI),
 Alogliptin (EXAMINE), and
 Sitagliptin (TECOS).
• The secondary endpoint of heart failure hospitalization
events was increased with saxagliptin in SAVOR-TIMI
• A similar, albeit not significant, trend was found with
alogliptin in the smaller EXAMINE trial
• whereas no difference in heart failure hospitalization was
found with sitagliptin in TECOS
 GLP-1 Reseptor Agonist
• Liraglutide and Semaglutide significantly
reduced cardiovascular events in high-risk
patients with diabetes
• Nonsignificant reductions in nonfatal
myocardial infarction, nonfatal stroke, and
heart failure hospitalization for liraglutide
• Significant reduction in CV Death for
liraglutide
 SGLT-2 Inhibitor
• Significant 14% relative risk reduction in the
primary endpoint of cardiovascular death,
myocardial infarction, and stroke (EMPAREG)
• Significant 35% relative risk reduction in
hospitalization for heart failure (EMPAREG)
• Potential mechanisms :weight loss, reduced
blood pressure, sodium depletion, reduced
oxidative stress, and arterial stiffness, reduction
in sympathetic nerve activation, increasing keton
bodies
Liraglutide
 EMPA-REG Outcomes Trial

Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction *95.02% CI

Zinman B, et al. N Engl J Med. 2015 0028-4793; Zinman B, et al. Cardiovasc Diabetol 2014;13:102; http://clinicaltrials.gov/ct2/show/NCT01131676?term=NCT01131676&rank=1 (Last accessed 24th
March 2017)
CANVAS Efficacy Endpoints

* P-Value for Superiority P = 0.0158

Neal B et al. New Eng J Med 2017 Jun 12. doi: 10.1056/NEJMoa1611925. [Epub ahead of print] 20
 Cardiovascular safety of Dapagliflozin: meta-
analysis of 21 phase 2b and 3 trials

DAPA DAPA
meta-analysis* Favours HR vs
Event rate/ Event rate/ DAPA  ●  Control Control
DAPA 100 p–y Control 100 p–y (95% CI)2
0.79
MACE plus UA 95/5699 1.46 81/3240 2.15
(0.58, 1.07)
0.77
MACE 72/5418 1.15 62/3101 1.69
(0.54, 1.1)
0.70
 Meta-analysis of 21
CV death 20/3825 0.37 18/2200 0.59
(0.36, 1.36) Phase 2b and 3 trials,
MI 30/5244 0.48 33/3014 0.91
0.57 n = 93392
(0.34, 0.95)  Findings supported
1.00 by later independent
Stroke 25/4227 0.45 18/2412 0.57
(0.54, 1.86)
meta-analysis (Wu et
Hospitalization 0.36
for heart failure
10/2576 0.15 16/1780 0.41
(0.16, 0.84) al) including other

Table adapted from Sonesson C et al.*

0.10 1.0 2.00
agents in the SGLT-2i
class

1 All Phase 2b and 3 Pool, ST + LT - 30MU; Stratified by study; Only trials with at least one positively adjudicated event
included in analysis;
Cox Proportional Hazards model. 2 Dapagliflozin n = 5936, control n = 3403)

*Sonesson C et al. Cardiovasc Diabetol. 2016;15:37. Wu JHY et al. Lancet Diabetes Endocrinol. 2016 May;4(5):411-9
Real World Evidence:
CVD-REAL
 Data sources

Truven MarketScan Claims & Encounters and linked Medicare

National full-population registries

National full-population registries All cause death

hHF
National full-population registries

Clinical Practice Research Datalink (CPRD) and

The Health Improvement Network (THIN)

Diabetes Patienten Verlaufsdokumentation (DPV) initiative

hHF – Hospitalisation for heart failure

Kosiborod M, et al. CIRCULATION 2017 [ePub ahead of print] doi. 10.1161/CIRCULATIONAHA.117.029190
 Baseline characteristics
SGLT-2 inhibitor* Other glucose-lowering drug*
(n=154,528) (n=154,523)

Age (years), mean (SD) 56.9 (10.0) 57.0 (10.6)

Women 68,420 (44.3) 68,772 (44.5)

Established cardiovascular disease 20,044 (13.0) 20,302 (13.1)

Acute myocardial infarction 3793 (2.5) 3882 (2.5)

Unstable angina 2529 (1.6) 2568 (1.7)

Heart failure 4714 (3.1) 4759 (3.1)

Atrial fibrillation 5632 (3.6) 5698 (3.7)

Stroke 6337 (4.1) 6394 (4.1)

Peripheral arterial disease 5239 (3.4) 5229 (3.4)

Microvascular disease 42,217 (27.3) 42,215 (27.3)

Chronic kidney disease 3920 (2.5) 4171 (2.7)

Frailty (yes) 11,982 (7.8) 12,731 (8.2)

Kosiborod M, et al. CIRCULATION 2017 [ePub ahead of print] doi. 10.1161/CIRCULATIONAHA.117.029190

 Primary analysis: Hospitalization for
heart failure

P-value for SGLT-2 inhibitor vs other glucose-

Heterogeneity
lowering drug: <0.001
p-value: 0.169

Data are on treatment, unadjusted

Kosiborod M, et al. CIRCULATION 2017 [ePub ahead of print] doi. 10.1161/CIRCULATIONAHA.117.029190

 Lower Risk of Events Consistent Across
Subgroups

* Diagnosis of AMI, unstable angina, stroke, HF,

transient ischemic attack, coronary revascularization,
or occlusive PAD prior to index drug initiation.

AMI; Acute Myocardial Infarction, PAD; Peripheral Artery Disease

Oral (377-OR) presentation at the 77th scientific sessions of the ADA; June 9 – 13th, 2017; San Diego, USA.
 Dapagliflozin is associated with lower
risk of hospitalization for heart failure,
major adverse cardiovascular events and
all-cause death compared to DPP-4i in
T2D patients: CVD-REAL Nordic

Norhammar A, Bodegard J, Nystrom, T, Nathanson D, Gulseth HL, Thuresson M, Fenici P,

Eriksson JW and Birkeland K

Poster (P3008) presented at European Society of Cardiology - Heart Failure meeting;

27
April 29 – May 2, 2017; Paris, France.
 Hospitalization for heart failure, MACE
and all-cause death
Dapagliflozin DPP-4 inhibitor Weighted average estimates
(n=8,582) (n=25,746) (n=34,328)

No of events Rate/100 P-Y No of events Rate/100 P-Y Hazard ratio 95% CI P-value

Hospitalization for heart

77 0.95 375 1.47 0.63 0.50–0.81 <0.001
failure

MACE 83 1.83 372 2.57 0.71 0.56–0.90 0.004

Non-fatal myocardial
40 0.88 170 1.17 0.75 0.53–1.06 0.102
infarction

Non-fatal stroke 37 0.81 147 1.01 0.80 0.56–1.15 0.222

CV mortality 18 0.39 77 0.53 0.74 0.44–1.23 0.241

All-cause death 106 1.04 468 1.44 0.73 0.59–0.91 0.004

Poster (P3008) presented at European Society of Cardiology - Heart Failure meeting; April 29 – May 2, 2017; Paris, France.
Real World Evidence:

CVD-REAL 2
 Lower Risk of Cardiovascular Events and
Death Associated with Initiation of SGLT-2
Inhibitors versus Other Glucose Lowering
Drugs - Real World Data Across Three Major
World Regions with More Than 400,000
Patients: The CVD-REAL 2 Study
Mikhail Kosiborod1, Carolyn Su Ping Lam 2, Shun Kohsaka3, Dae Jung Kim4,
Avraham Karasik5, Jonathan Shaw6, Navdeep Tangri7, Su-Yen Goh8, Marcus
Thuresson9, Hungta Chen10, Filip Surmont11, Niklas Hammar12,13, Peter Fenici14
on behalf of the CVD-REAL Investigators and Study Group
1Saint Luke's Mid America Heart Institute and University of Missouri-Kansas City, Kansas City, MO,
USA; 2National Heart Centre, Singapore and SingHealth Duke-NUS, Singapore; 3Keio University
School of Medicine, Tokyo, Japan; 4Department of Endocrinology and Metabolism, Ajou University
School of Medicine, Suwon, Republic of Korea; 5Tel Aviv University, Ramat Aviv, and Maccabi
Healthcare Israel; 6Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia; 7Department
of Medicine, University of Manitoba, Winnipeg MB, Canada; 8Singapore General Hospital, Singapore;
9Statisticon AB, Uppsala, Sweden; 10AstraZeneca, Gaithersburg, MD, USA; 11AstraZeneca, Luton, UK;
12Karolinska Institutet, Stockholm, Sweden; 13AstraZeneca, Gothenburg, Sweden; 14AstraZeneca,

Cambridge, UK
 Study Objectives

• To evaluate the relationship between the initiation of SGLT-2i vs.

other glucose-lowering drugs (oGLD) and a broad range of CV
outcomes (all-cause death, HHF, MI and stroke) in patients with T2D
from three major world regions: Asia-Pacific, Middle East, and North
America
 Countries and Data Sources

Australia – National Diabetes Services Scheme (NDSS)*

Canada – Manitoba Population Health Research Data Repository

Israel – The Maccabi Health Management Organization

Japan – Medical Data Vision

Singapore – SingHealth Diabetes Registry

South Korea – National Health Insurance Service (NHIS)

*Included in the ACD analysis only

 Inclusion/Exclusion Criteria

• Inclusion
– New users of SGLT-2i or oGLD
• Established type 2 diabetes on or prior to the index date
• ≥18 years old
• >1 year historical data available prior to the index date
• Exclusion
– Patients with type 1 diabetes or gestational diabetes
 Outcomes

• All-cause death
• Hospitalization for heart failure (HHF)
• All-cause death or HHF
• Myocardial infarction (MI)
• Stroke
 Patient Population
3,917,551 new user episodes of
SGLT-2i or oGLD fulfilling the
eligibility criteria

249,348 3,668,203
SGLT-2i oGLD

1:1 propensity match

14,284 (6%) excluded 3,433,139 (94%) excluded

235,064 235,064
SGLT-2i oGLD
 Baseline Characteristics
Baseline characteristic, n (%) SGLT-2i (N=235,064) oGLD (N=235,064) Standardized Difference

Age, years, mean (SD) 57 (12) 57 (13) 0.4%

Women 105,843 (45) 106,863 (46) 0.9%

Established cardiovascular disease* 59,222 (27) 56,576 (26) 2.7%

Acute myocardial infarction 7,624 (3) 7,479 (3) 0.4%

Unstable angina 12,480 (6) 12,235 (6) 0.5%

Heart failure 15,151 (7) 14,741 (7) 0.7%

Atrial fibrillation 6,026 (3) 5,843 (3) 0.5%

Stroke 20,983 (10) 20,153 (9) 1.3%

Peripheral arterial disease 2,446 (1) 2,384 (1) 0.3%

Microvascular disease† 116,370 (53) 114,630 (52) 1.6%

Chronic kidney disease 4,211 (2) 4,021 (2) 0.6%

*Myocardial infarction, unstable angina, stroke, heart failure, transient ischemic attack, coronary revascularization or occlusive peripheral artery disease; †diabetic mono-/polyneuropathy,
diabetic eye complications, diabetic foot/peripheral angiopathy, or diabetic kidney disease
Results
 All-Cause Death

ITT, unadjusted analysis

P-value for
SGLT2i vs. oGLD: p<0.001 Heterogeneity p-value: p<0.001
 Hospitalization for Heart Failure

ITT, unadjusted analysis

P-value for
SGLT2i vs. oGLD: p=0.001
Heterogeneity p-value: p<0.001
Conclusion ?
Thank You