Saifuddin M. Bandukwala Lilavati Hospital and Research Centre Bandra West

Mumbai, India

Diabetes as a promoter of heart failure

Declared receipt of honoraria or consultation fees from Abbott Lab., Novartis, Johnson & Johnson

Declared to participate in a company sponsored speaker’s bureau in Aristo Pharmaceuticals LTD India

Dr. S. M. Bandukwala

MD, FCPS, FICA (USA), FCCP

Senior Consultant

Hon. Physician Lilavati Hospital & Research Centre

Visiting Diabetologist Dept. of Endocrinology Dr. L.H. Hiranandani Hospital, Powai

Diabetes as Promoter of Heart Failure

Cardiovascular disease and diabetes

Bell DSH. Diabetes Care. 2003;26:2433-41. Centers for Disease Control (CDC). www.cdc.gov.

T2DM = type 2 diabetes mellitus

Cardiovascular complications

of T2DM

~65% of deaths are due to CV disease

Coronary heart disease deaths 2- to 4-fold

Stroke risk 2- to 4-fold

Framingham Heart Study 30-Year Follow-Up: CVD Events in Patients With Diabetes (Ages 35-64)

10 9

20

11

9 6 38 19

3*

30

0

2

4

6

8

10

Age-adjusted annual rate/1,000

Men Women

Total

CVD

CHD Cardiac

failure

Intermittent claudication

Stroke

Risk

ratio

P<0.001 for all values except *P<0.05.

Wilson PWF, Kannel WB. In: Hyperglycemia, Diabetes and Vascular Disease. Ruderman N et al, eds.

Oxford; 1992.

Diabetes & HF Mortality & Morbidity

45%

24%

Diabetes & HF

Diabetes & No HF

Framingham Heart Study Mortality in diabetes patients 1 yr after diagnosis of HF was 34%

DIABHYCAR Incidence for hospitalisation due to HF was 10/1,000 person - years

Diabetes & HF Incidences Increase with Age

Lancet 2015; 385: 2107–17

Diabetes & Heart Failure Some Pertinent Facts

• HF is twice as common in men with diabetes and five times as common in women with diabetes as in age matched subjects without diabetes

• Overall prevalence of diabetes ( both type1 and 2) in HF is approximately 20 – 25%

• Patients with diabetes have a nearly 2 – fold risk for HF hospitalization and death

• Prevalence of HF in elderly subjects with diabetes is 39%

• 1% rise in HbA1 C is associated with a 12% increased risk of HF in elderly patients with diabetes

Diabetes amplifies the risk of Heart Failure

• Shared & Accelerated comorbid conditions

– Hypertension

– CAD

– Obesity

– Renal Sufficiency

– Aortic Stiffness

• Insulin resistance & hyperglycaemia may directly contribute to cardiac dysfunction

– Advanced glycation end

products

– Increased myocardial fibrosis

– Increased oxidative stress

– Increased local activation of

RAAS system

Diabetes & Cardiovascular Risk Diabetes – “ A cardiovascular risk equivalent”

Type 2 Diabetes

Endothelial dysfunction

Advanced Glycation Products

Prothrombosis

Fibrinogen↑

PAI -1 ↑

Hypertension

Dyslipidemia

Oxidative Stress Autonomic neuropathy

Impaired calcium homeostasis

Activation of RAS system

Diabetes is a promoter of Heart Failure The Mechanisms

Diabetes is a promoter of Heart Failure The Mechanisms

Microcirculation dysfunction

Impaired contraction &

relaxation

Diastolic Dysfunction Endothelial Dysfunction

Impaired Energetics

Diagnostic Flow chart

Blue : Echo First

Red : BNP First

Complex interplay among myocardium, arteries, metabolic and glycemic pathways

Management of Diabetes & Heart Failure

Diabetes in Heart Failure Heart failure in Diabetes

Management of Diabetes in Heart Failure

• Lifestyle measures • Glycemic control • Pharmacological

treatment of diabetes

Glycaemic control & Heart Failure Is Tight Control Mandatory ?

Lancet 2015; 385: 2107–17

Glycaemic control & Heart Failure Meta-analysis of major trials

Metformin monotherapy

Sulfonylurea monotherapy

Thiazolidinedione monotherapy

Insulin monotherapy

Combination Therapy with Insulin

Combination Therapy without Insulin

Managing Diabetes in Heart Failure

Mac Donald et al. Diabetes Care 2010

Diabetes Medication and Heart Failure Where Evidence Leads Us ?

JACC – Heart FailureVolume 3, Issue 2 February 2015, Pages 136–145

Heart Failure Rates in Diabetes Clinical Trials

Anti-glycemic treatment & Heart Failure

Metformin in Heart Failure Clinical Trials

Veterans Affairs

• 6,185 with CHF & DM

• Oral antihyperglycemic:

- With metformin (n=1,561)

- Without metformin

• Statistically adjusted for co-variables

Death: 0.76 (0.63-0.92) p < 0.01 CHF hospitalization: 0.93 (0.74-1.18) p = 0.56 Total hospitalization: 0.94 (0.83-1.07) p = 0.35

Surv

ival

est

imat

es

1.00

0.95

0.90

0.75

0.85

0.80

Time (days)

0 700 100 200 300 600 400 500

Metformin

No metformin

p = 0.01

Aguilar D, et al. Circ Heart Fail 2011;4:53-8.

Metformin Use in Heart Failure Patients

ACEi = Angiotensin-Converting Enzyme inhibitor; CHF = Chronic Heart Failure; MI = Myocardial Infarction; SU = Sulfonylurea

Tayside, Scotland

(population 400,000)

n=422 with CHF and diabetes

Antihyperglycemic therapy:

– Metformin alone n=68

– SU alone n=217

– Combination n=137 Cu

mu

lati

ve m

ort

alit

y

1.0

0.8

0.6

0

0.4

0.2

Time (days)

0 1000 2000 3000 4000 5000

Sulfonylurea monotherapy

Metformin monotherapy + combination

Evans JM, et al. Am J Cardiol 2010;106:1006-10.

Metformin Use in Heart Failure Patients

Risk of CHF Thiazolidinediones

Logo RM etal, Lancet 2007: 370: 1129 - 1136

Risk of CHF Sulfonylureas

Risk of CHF DPP-4 inhibitors

Risk of CHF DPP-4 inhibitors

Numbers of patients with events

Sitagliptin

n=7332

Placebo

n=7339

Hospitalization for heart failure† 228 (3.1%) 229 (3.1%)

1.07 per 100 pyrs 1.09 per 100 pyrs

ITT HR=1.00 (0.83, 1.20), p=0.98

Hospitalization for heart failure or

cardiovascular death†

538 (7.3%) 525 (7.2%)

2.54 per 100 pyrs 2.50 per 100 pyrs

ITT HR=1.02, (0.90, 1.15), p=0.74

Hospitalization for Heart Failure*

* Adjusted for history of heart failure at baseline † Prespecified analyses

Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

Risk of CHF GLP -1 Analogs

Risk of CHF SGLT2 Inhibitors

Lancet 2015; 385: 2107–17

The Effect of Insulin in Heart Failure

In Heart Failure what therapies are safe?

Oral

Meformin probably

Sulfonylureas ?

Glitazones No

DPP – 4 inhibitors Possibly not

SGLT2 inhibitors ?

Injected

GLP -1 RAs ?

Insulin ?

Drugs Commonly Used

Diuretics, Digoxin ?

Heart Failure Medications and Diabetes Where Evidence Leads Us ?

Trial Primary Outcome Subgroup of Patients With or Without DM

Average Follow-Up (Months)

Treatment Results RR or HR (95% CI)

SOLVD Mortality and hospitalization for worsening HF

HF patients with EF <35% 41.4 Enalapril vs. placebo

RR of 0.84 (0.74–0.95) in no DM vs. 1.01 (0.85–1.21) in DM

SAVE CV mortality Recent survivors of MI with EF ≤40%

42 Captopril vs. placebo

RR of 0.82 (0.68–0.99) in no DM vs. 0.89 (0.68–1.16) in DM

TRACE All-cause mortality

Patients with LVEF <35% after acute MI

26 Trandalapril vs. placebo

RR of 0.82 (0.69–0.97) in no DM vs. 0.64 (0.45–0.91) in DM (interaction analysis p = 0.3)

SMILE Progression to HF Patients with anterior acute MI not eligible for thrombolytic treatment

12 Zofenopril vs. placebo

RR of 0.79 (0.54–1.15) in no DM vs. 0.44 (0.22–0.87) in DM

ATLAS All-cause mortality

High-risk HF patients 46

Lisinopril high dose (32.5–35 mg day−1) vs. low-dose (2.5–5 mg day−1)

↓6% RR in no DM patients vs. ↓14% RR in DM high-dose vs. low dose (interaction analysis p = 0.3)

ACE Inhibitors in Heart Failure with Diabetes

Treatment of HF in Diabetes- ARB’s

Treatment with ARB in symptomatic HF patients with EF < 40% and DM improves LV function, patient well – being, reduces hospital admission for worsening HF ( Class I, level of evidence A) Treatment with ARB in HF patients who remain symptomatic despite optimal ACEI and beta blocker therapy reduces the risk of CV death ( Class IIa, level of evidence B) In patient intolerant to ACEI, ARB reduces the risk of CV death and reduces hospital admission for worsening HF ( Class I. level of evidence B)

CHARM-Added: CV Death or CHF Hospitalization

McMurray et al. Lancet 2003;362:767–71

0 1 2 3 3.5

50

40

30

20

10

0

Years

Placebo

Candesartan

%

HR 0.85 (95% CI 0.75–0.96), p=0.011

Adjusted HR 0.85, p=0.010

Number at risk

Candesartan 1,276 1,176 1,063 948 457

Placebo 1,272 1,136 1,013 906 422

538 (42%)

483 (38%)

NNT = 14

VALIANT: Valsartan is Effective at Reducing Cardiovascular Morbidity and Mortality

Hazard ratio (97.5% CI) p value

0.8 1 1.2

CV death (1,657 events)

0.62

CV death or HF (2,661 events)

0.51

CV death or MI (2,234 events)

0.25

CV death, MI, or HF

(3,096 events) 0.20

Favours valsartan Favours captopril

Pfeffer et al. N Engl J Med 2003;349:1893–906

First hospitalisation

**p<0.001

Cohn et al. N Engl J Med 2001;345:1667–75

Placebo (n=2,499)

Val-HeFT: Valsartan Significantly Reduces Heart Failure-related

Hospitalisations

27.5% Risk reduction**

Valsartan (n=2,511)

Time (months)

100

95

90

85

80

75

70

65

0 0 3 6 9 12 15 18 21 24 27

Pro

bab

ility

of

eve

nt-

fre

e s

urv

ival

Treatment of HF in Diabetes- Beta-Blockers

Treatment of HF in Diabetes- Beta-Blockers

Treatment of HF in Diabetes Beta-Blockers in patients with HF and DM vs without DM

Relative risk of Beta blocker versus placebo Inpatients with diabetes mellitus and heart failure

Relative risk of Beta blocker versus placebo Inpatients without diabetes mellitus but with heart failure

Treatment of HF in Diabetes Influence of diabetes on prognosis in pts > 70 yrs. With HF & effects of Nebivolol (SENIORS)

Treatment of HF in Diabetes EPHESUS: Eplerenone increases probability of survival by 15%

Stages in the development of HF and recommended therapy by stage.

Clyde W. Yancy et al. Circulation. 2013;128:e240-e327

Prominent people with heart failure

Take Home Message

• Heart Failure is the frequent, forgotten, and often fatal complication of

diabetes

• Patients with diabetes have a nearly 2 – fold risk for HF hospitalization and

death.

• Patients with concomitant HF and DM have diverse pathophysiologic,

metabolic, and neurohormonal abnormalities that potentially contribute to

worse outcomes than those without comorbid DM.

• Several retrospective studies suggest worse prognosis for patients with

heart failure with diabetes whose HbA1c is less than 7%. Less intensive

therapy is therefore preferred.

• Metformin is not only safe, but is also associated with improved survival in

patients with DM and HF.

• Sulfonylureas are associated with hypoglycemia and weight gain, and these

potential effects need to be monitored .

• Thiazolidinediones are contraindicated in patients with NYHA class III/IV HF.

• Risk of Heart Failure is not a class effect with DPP4 inhibitors.

• Further studies are required to assess the safety and efficacy of DPP4

inhibitors and GLP – 1 Analogs in patients with DM and HF.

• Antiheart failure therapies such as angiotensin-converting-enzyme inhibitors,

β blockers and mineralocorticoid-receptor antagonists work similarly well in

individuals with diabetes as in individuals without the disease.

Take Home Message

Don’t be satisfied with stories, how things

have gone with others. Unfold your own myth

Rumi – Persian Poet

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