CARDIOMYOPATHY AND HEART FAILURE in DIABETES

W H. Wilson Tang, MD, and James B. Young, MD

ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA,

VOLUME 30 • NUMBER 4 • DECEMBER 2001

1. Introduction

2. Impact of cardiomyopathy and heart failure in diabetes

3. Heart failure caused by ischemic cardiomyopathy in diabetes

4. Heart failure caused by nonischemic cardiomyopathy in diabetes

5. Management of cardiomyopathy and heart failure in diabetes

6. Summary

I.INTRODUCTION

• 2/3 of the 16 million diabetic patients in the United States ( 6% of the population) will die of some form of heart or blood vessel diseases

• 1/3 of these patients will remain undiagnosed.• Although major medical advances have

improved overall cardiovascular mortality rates, diabetic patients have ? yet to experience the same degree of risk reductions as their nondiabetic counterparts.

CARDIOMYOPATHY (CM) andHEART FAILURE (HF)

• Heart failure

--A clinical syndrome with signs and symptoms of congestion and circulatory failure (regardless of cardiac function).

• Final common pathway of most end-stage cardiovascular complications.

• Cardiomyopathy

--functional pathology of heart muscle

--regardless of symptoms,

--often related to abnormalities in contraction (systolic dysfunction) or relaxation (diastolic dysfunction).

II. IMPACT OF CARDIOMYOPATHY and HEART FAILURE IN DIABETES

• Diabetes is observed in 15% to 25% of HF patients in major clinical trials.

• Among all patients hospitalized for heart failure, 25% to 30% patient have DM as a comorbid condition

• In large-scale mortality trials, in HF patients with systolic dysfunction, diabetes was an independent risk factor for death.

Framingham Study and SOLVD

• Framingham Study1. A direct association

between DM and HF was first demonstrated

2. Risk of developing symptomatic HF 2.4-fold in diabetic men 5-fold in diabetic women,

3. independent of coexisting hypertension or ischemic heart disease.

• Studies of Left Ventricular Dysfunction (SOLVD)

1. Registry of 6791 patients with heart failure,

2. 1310 diabetic patients were more likely to be hospitalized for HF exacerbation and likely to die.

DM and younger HF study

• Under 65 years old.– Four fold in diabetic men – Eight fold in diabetic women

• Gender-specific cardiovascular protective effects can be considered to be mitigated once overt diabetes develops in women.

Cardiomyopathy and Diabetes

• A distinctive entity of diabetic CM does exist as a vulnerable alteration to the myocardium– impaired glycemic

control– insulin resistance

• But direct, concrete evidence is lacking.

• Similar pathophysiologic processes – Endothelial dysfunction– Oxidative stress

• Lead to overt HF that is difficult to treat.1. coexisting risk factors

• hypertension

• dyslipidemia

2. major index events (such as myocardial infarction)

III. HEART FAILURE CAUSED BY ISCHEMIC CARDIOMYOPATHY IN DIABETES

• San Antonio Heart Study,1. 7-year follow-up of DM patients with no

history of coronary artery diseases (CAD). 2. Have a high risk of AMI as those with a prior

history of MI (20.2% versus 18.8%) 3. DM patients are more prone to silent MI (up

to 30% of cases) Presumably caused by alterations in pain

perception from autonomic neuropathy.• Diabetes as an independent risk factor for

CAD.

Framingham Study

• Patients who survived prior MI • DM women had a relative risk for HF

three times greater than that of non-DM women. – an observation that was not observed in men

• A clinical history of heart failure as well as the development of new-onset heart failure are more prevalent in the diabetic than in the nondiabetic population.

50% Post-infarction diabetic develop HF

1. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial,

• Postinfarction HF, a. 27% in the diabetic

group with insulin Tx vsb. 20% in the diabetic

group with no insulin vs c. 15% in nondiabetic

2. GUSTO-IIb trial -- Diabetics developing HF

following an acute coronary syndrome (ACS)

• 7.2% in diabetic vs• 3.8% in nondiabetic --Insulin therapy was not a

predictor of worse outcome • In insulin-treated patient

– older,– longer duration of diabetes, – more CV risk factors,– more often previous HF

Post-infarction Diabetic with HF carry a particularly poor long-term prognosis

• Studies of Left Ventricular Dysfunction (SOLVD), – diabetes aggravate

progression of ischemic CM to a greater extent than that of nonischemic cardiomyopathy.

• Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) trial, – HF accounted for 66%

of total mortality following AMI.

Post-infarction Diabetic HF and short-term prognosis

GUSTO-1 database • Unadjusted cardiac

mortality rate at 30 days

12.5% in insulin-Tx 9.7% in non insulin-Tx 6.2% in nondiabetic • Continued through 12

months of follow-up (14.5% versus 8.9%, respectively).

• The true impact of diabetic status on short-term prognosis was less clear

• Multivariate analyses based on short-term (30-day) mortality data from the Multicenter Investigation of the Limitation of Infarct Size (MILIS) study and GUSTO-1 did not include diabetic status.

• ???

Disease progression of diabetic HF

following an AMI.(1) • First, the pathogenesis of post infarction diabetic HF

may be independent of a LV (left ventricular) remodeling process.

• MILIS study—Post AMI1. 85 diabetic vs 415 nondiabetic. 2. 10 days postinfarction, Impairment in ventricular

function was more frequently in diabetic group.3. Long-term (3-month) ventricular dysfunction were

similar between diabetic and nondiabetic groups4. More diabetic patient presented with HF symptoms

following MI (27.6% versus 16.1%) .

MILIS study

• Independent of the initial degree of myocardial damage and long term LV remodeling.

1.Smaller infarct size --peak CPK levels,

2.Smaller area of CPK under the curve,

3.Smaller number of patient developing transmural infarction (new Q waves)

• Diabetic group had a much worse prognosis.– 4-year cardiac mortality rates of 25.9% versus 14.5%

for diabetic versus nondiabetic groups

Survival and Ventricular Enlargement (SAVE) trial

• Post-infarction HF in DM – over 2 years follow-up

a. 19.7% in DM

b. 9.8% in non-DM groups

– not associated with a greater propensity for left ventricular remodeling.

– LV enlargement was quantitatively less (instead of more) in diabetic than in nondiabetic patients.

Disease progression of diabetic heart failure following an AMI.(2)

• Second, Artery patency following infarction did not explain the increased incidence and worse outcomes in post-infarction HF in diabetics. – Similar degrees of early (90-minute) infarct-

related artery patency and regional and global ventricular function following thombolytic therapy have been observed up to 5 to 7 days after infarction in diabetic and nondiabetic patients .

GUSTO-1 angiographic substudy

• Diabetic with a blunted compensatory hyperkinesia in the noninfarcted zone.

• Lack of compensatory hyperkinesic response related extensive impairment of ventricular function may be an important contributing factor to the pathogenesis of diabetic HF. – extensive impairment of ventricular

function which is often seen as an early sign of myocardial ischemia

IV. HEART FAILURE caused by NONISCHEMIC CARDIOMYOPATHY in DM

• Some diabetic patients do not have obvious ischemic insults that lead to progressive HF.

• Every 1% increase in the baseline glycosylated hemoglobin level translates into a 15% increase in risk of developing HF.

• A number study challenged that Diabetic patients may have more diffuse and severe coronary insufficiency than nondiabetic patients.

• Hyperglycemia

abnormal glycosylation end products and overproduction of oxygen free radicals

impair endothelium-dependent relaxation with the inactivation of nitric oxide

inability of compensatory vasodilation during compromised myocardial blood flow

affect both epicardial and microcirculatory vascular tone.

• Alteration in functional rather than structural coronary insufficiency

1.Diabetic Cardiomyopathy

• An association between a distinctive heart muscle disease and diabetes was made as early as in 1881,

• Clinical entity—1. Diabetic angiopathy (by Lundback in 1954)2. Diabetic cardiomyopathy (by Rubler in 1972). • Manifest clinically-- systolic or diastolic dysfunction

with or without overt HF or CAD. • Gross anatomic, histologic, or ultrastructural morphology

Early diabetic cardiomyopathy are often indistinguishable from other forms of nonischemic cardiomyopathy.

Diabetic CM Histology

• Histologic findings1. Myocyte hypertrophy,2. Interstitial fibrosis and infiltration with periodic acid-

Schiff (PAS)-positive materials, 3. Alterations in the myocardial capillary basement

membranes 4. Intramyocardial microangiopathy.• Myocardial fibrosis correlated with increased risks for

neuropathy, nephropathy, and retinopathy.• Whether these nonspecific structural findings have an

underlying ischemic cause remains to be elucidated.

Alterations in the myocardium precede overt heart failure in DM patients

• In Framingham population

• Echocardiography-- – DM remains an

independent contributor to increased LV mass and wall thickness, esp. in women.

• Strong Heart Study and Cardiovascular Health Study.– DM patients with no

overt HF symptoms had higher LV mass and wall thickness.

Cardiovascular change in Diabetic CM

1. Greater arterial stiffness

2. Reduced systolic function at rest or during stress

3. Left ventricular end-diastolic pressures (LVEDP) elevated,

4. Stroke volume decreased

5. Wall stiffness increased( ratio of LVEDP to volume)

• Echocardiography1. Prolonged pre-ejection

period 2. Shortened ejection

time at rest or with stress

LVED volumes elevate and SV decrease.

Reductions in exercise tolerance.

2.Role of Insulin Resistance in Heart Failure

• Undiagnosed glucose abnormalities are common in patients with HF

• Randomized Evaluation of Strategies of Left Ventricular Dysfunction (RESOLVD)-2000

– Evaluate fasting plasma glucose and insulin levels, 43% had documented glucose abnormalities, 8% had previously undiagnosed DM 9% had impaired glucose tolerance.

• Presence of HF pose a higher risk to develop DM. – Risk increase with worsening severity of HF.

HF in an Elderly Italian population study

• 3-year follow-up. Excluding the

preexisting 30% DM patient,

Incidence of new-onset DM was 29%, compared with 18% in controls.

• Undiagnosed glucose abnormalities are common in patients with HF.

1. HF and overt DM share a common risks endothelial dysfunction insulin resistance

2. Increased adrenergic drive3. FFA (Free fatty acid) oxidation 4. NO (Nitric oxide) diminished5. LV afterload increase

– reduced peripheral blood flow– increased atherogenicity

impaired peripheral vasodilation and vascular activity

Insulin resistance (IR) and cardiovascular disease

• A higher degree of IR in– HF than in matched controls– in patients with CAD but without HF.– HF caused by valvular diseases(insulin sensitivity).

• Using positron emission tomography, --idiopathic dilated cardiomyopathy have impaired glucose uptake by dysfunctional myocardium. --use hyperinsulinemic glucose clamping, this

abnormal glucose uptake was reversed.

IV. MANAGEMENT OF CARDIOMYOPATHY AND HEART FAILURE IN DIABETES

• Treating heart failure and diabetes separately. • Limited understanding of the optimal combined

therapy for both diseases.• Special considerations

1. reduce polypharmacy

2. watch for adverse drug interactions

3. electrolyte abnormalities,

4. contraindications based on changing renal and hepatic functions in HF patients.

BP Control vs Risk Factor Modifications

• 50%-70% of DM have coexisting hypertension or dyslipidemia.

• Uncontrolled hypertension has a 2.5-fold increased risk for development of DM.

• Like hypertension patients, DM are more prone to develop HF when ischemic event despite equal or less myocardial damage.

1. lipid-lowering strategies,

2. weight reduction,

3. exercise training,

4. dietary restriction

5. aggressive blood pressure

6. glycemic control.

Blood pressure and HF

• United Kingdom Prospective Diabetes Study (UKPDS)

1. Atenolol is as effective as captopril in providing tight BP control and protection against microvascular diseases among type 2 DM

2. 56% reduction in the relative risk of developing new-onset HF.

• Hypertension Optimal Treatment (HOT) and Systolic Hypertension In the Elderly Program (SHEP) studies.

1. Aggressive blood pressure lowering were beneficial.

Drugs effect and Insulin sensitivity (IS)

• Decreased IS1. High-dose thiazide

diuretics are perhaps best avoided in DM patient . – Loop diuretics have

a lesser effect on glucose metabolism and are preferred to thiazide agents.

• Improve IS1. Angiotensin-

converting enzyme (ACE) inhibitors

2. Angiotensin-II receptor blockers (ARBs)

3. Vasodilators.

ACEI and ARBs

• In SOLVD, RESOLVD , and assessment of Treatment with Lisinopril and Survival trials,

--greater benefits with ACEI in diabetic subgroups. ( Captopril for stable type 2 DM with HF.)

• increase responsiveness to insulin

• reduction in HbAic.

• ACE inhibitors--first-line agent,

• ARBs and hydralazine and long-acting nitrate combinations should be prescribed only when ACEI cannot be tolerated.

• ARBs-equivocal results from Evaluation of Losartan in the Elderly (ELITE-II) and Valsartan Heart Failure Trial (Val HeFT)

Heart Outcomes Prevention Evaluation (HOPE)

• Cardioprotective effects • 3577 at-risk patients with

diabetes (among 9297 pts in original study population)

• receive either ramipril (Altace, Monarch Pharmaceuticals), vitamin E, both, or neither.

• ramipril-treated diabetic patients experienced

• a 25% relative-risk reduction (RRR) of the primary composite endpoint (MI, stroke, or cardiovascular death),

1. a 22% RRR in developing MI , 2. a 20% RRR in developing HF,3. a 33% RRR in developing stroke, 4. a 24% RRR in total mortality, 5. a 37% RRR in cardiovascular

deaths.

ACE inhibitor Therapy

• Without preexisting DM, a 23% reduced risk in developing HF

• 32% reduced risk in developing subsequent diabetes

• Caution

1.Hyperkalemia,

2.Hypoglycemia,

3.Worsening renal insufficiency.

Beta-Adrenergic Antagonists

• US Carvedilol Heart Failure Trials Program

1. Blood glucose– increased in both

diabetic and nondiabetic patients, but no difference in both group

2. LV ejection frsction and survival little change in placebo. improved significantly

with carvedilol in both diabetic and nondiabetic patients.

• Multicenter Oral Carvedilol Heart Failure Assessment (MOCHA)

1. Tx with three different doses ( from 6.25 mg to 25 mg two times/day).

2. Dose response curves for both mortality and the change in LV function with carvedilol were steeper for diabetic than for nondia betic patients

Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT HF)

• Patients with diabetic HF treated with metoprolol succinate

1. a significant 29% relative-risk reduction in mortality, equivalent to the reduction seen in their nondiabetic counterparts.

• Risk of adverse drug experience and drug discontinuation was lower in DM subgroup.

• Did not result in 1. increased incidence of

DM, 2. worsening glycemic

control, 3. masking of

hypoglycemic symptoms.

Glycemic Control with Insulin in Diabteic HF patient

1. Insulin can be safely used in DM pt with ischemia or HF.

2. Diabetic patients with AMI, admission blood glucose > 11.0 mmol/L, • an aggressive regimen of infusion of insulin and

glucose for at least 24 hours • followed by 3-month subcutaneous insulin Tx • an overall 1-year RRR in mortality 30%.

• Unwillingness to receive insulin therapy hindered this strategy.

Glycemic Control with OHA in Diabteic HF patient

• University Group Diabetes Program (UGDP) study

1. Increased incidence of cardiovascular events with first-generation sulfonylurea

2. a matter of controversy,

3. not validated from UKPDS.

In diabetic patients with heart failure

• Contraindicated in HF patients

1. Biguanides such as metformin (Glucophage, Bristol-Myers Squibb)

2. Thiazolidinediones (TZDs) such as – rosiglitazone (Avandia, SmithKlin Beecham)– pioglitazone (Actos, Takeda)

Oral antidiabteic agent (OAD) Adverse effect

• Biguanides1. Hepatotoxicity--used

by patients with already abnormal liver function

2. Lactic acidosis– at Renal dysfunction.

• TZDs. 1. Fluid retention2. weight gain3. pulmonary edema4. Hepatotoxicity

1. More with troghtazone (Rezulin, Parke-Davis)

2. Rezulin has been withdrawn from the market.

V.SUMMARY

• Patients with IR or type 2 DM have a high risk for HF and a poor prognosis once they develop HF.

• Choice of drugs for the management of HF in these patients should be directed at changing the natural history of the disease.

• Drugs for treatment of HF, including ACEI and beta-adrenergic blockers, are beneficial and should be given as first-line agents.

• Aggressive risk-factor modification and tight BP and glycemic control are crucial.

• Much work is needed to establish the safety and efficacy of various OADs, especially the TZDs, for which the theoretic benefits are substantial and overall morbidity and mortality impact remain ill defined.