Rosiglitazone to Treat Patients With Heart Failure and Glucose Intolerance or Type II Diabetes
| Status: | Completed |
|---|---|
| Conditions: | Cardiology, Endocrine |
| Therapuetic Areas: | Cardiology / Vascular Diseases, Endocrinology |
| Healthy: | No |
| Age Range: | 22 - Any |
| Updated: | 4/21/2016 |
| Start Date: | July 2003 |
| End Date: | April 2007 |
Attenuating Insulin Resistance as a Therapeutic Target in the Management of Heart Failure
This study will evaluate the safety and effectiveness of the drug rosiglitazone for
improving heart function in patients with heart failure and glucose intolerance or type II
(adult-onset) diabetes, or both. Because of a lowered sensitivity to the hormone insulin,
patients with type II diabetes or glucose-intolerance do not regulate glucose (sugar)
effectively. Rosiglitazone is used to treat type II diabetes, but it is not commonly given
to patients with heart failure because it can cause leg swelling and, rarely, pulmonary
edema. However, patients with heart failure who also have glucose intolerance or type II
diabetes generally fare worse than those with heart failure alone, and therapies that
decrease insulin resistance may be beneficial to these patients.
Patients 21 years of age and older with heart failure and type II diabetes or glucose
intolerance, or both, may be eligible for this study. Patients must be stable on current
therapy for heart failure and must not have any planned surgeries for coronary artery
disease. Candidates will be admitted to the NIH Clinical Center for from 2 to 7 days for
screening procedures, which include a medical history and physical examination, blood and
urine tests, electrocardiogram (ECG), chest x-ray, magnetic resonance imaging (MRI),
exercise testing, and echocardiography (ultrasound test of the heart).
Participants will be randomly assigned to receive either rosiglitazone or placebo (an
identical-looking pill with no active ingredient). They will take one tablet a day for the
first month, one tablet twice a day for the second month, and then two tablets twice a day
from the third month to the end of the study at 6 months. During the treatment period,
patients will have a history, physical examination, and blood tests every 4 weeks, exercise
testing and echocardiography at 3 and 6 months, and urinalysis, electrocardiogram and MRI at
6 months. To check for fluid accumulation in the legs or lungs, patients will report their
weight and symptoms every 2 weeks throughout the study. After the 6-month treatment period,
patients will be put back on the diabetes medicines they were taking before the study. Their
physicians will be notified of possible modifications in treatment for maintaining optimum
glucose tolerance.
Six months after completing treatment (one year after beginning the study), patients will
return to the Clinical Center for blood tests to measure the long-term effects of
rosiglitazone and to evaluate progress. They will then be invited to return to the clinic
for annual checkups, if possible, or for yearly follow-up by mail or telephone to review
their health status.
improving heart function in patients with heart failure and glucose intolerance or type II
(adult-onset) diabetes, or both. Because of a lowered sensitivity to the hormone insulin,
patients with type II diabetes or glucose-intolerance do not regulate glucose (sugar)
effectively. Rosiglitazone is used to treat type II diabetes, but it is not commonly given
to patients with heart failure because it can cause leg swelling and, rarely, pulmonary
edema. However, patients with heart failure who also have glucose intolerance or type II
diabetes generally fare worse than those with heart failure alone, and therapies that
decrease insulin resistance may be beneficial to these patients.
Patients 21 years of age and older with heart failure and type II diabetes or glucose
intolerance, or both, may be eligible for this study. Patients must be stable on current
therapy for heart failure and must not have any planned surgeries for coronary artery
disease. Candidates will be admitted to the NIH Clinical Center for from 2 to 7 days for
screening procedures, which include a medical history and physical examination, blood and
urine tests, electrocardiogram (ECG), chest x-ray, magnetic resonance imaging (MRI),
exercise testing, and echocardiography (ultrasound test of the heart).
Participants will be randomly assigned to receive either rosiglitazone or placebo (an
identical-looking pill with no active ingredient). They will take one tablet a day for the
first month, one tablet twice a day for the second month, and then two tablets twice a day
from the third month to the end of the study at 6 months. During the treatment period,
patients will have a history, physical examination, and blood tests every 4 weeks, exercise
testing and echocardiography at 3 and 6 months, and urinalysis, electrocardiogram and MRI at
6 months. To check for fluid accumulation in the legs or lungs, patients will report their
weight and symptoms every 2 weeks throughout the study. After the 6-month treatment period,
patients will be put back on the diabetes medicines they were taking before the study. Their
physicians will be notified of possible modifications in treatment for maintaining optimum
glucose tolerance.
Six months after completing treatment (one year after beginning the study), patients will
return to the Clinical Center for blood tests to measure the long-term effects of
rosiglitazone and to evaluate progress. They will then be invited to return to the clinic
for annual checkups, if possible, or for yearly follow-up by mail or telephone to review
their health status.
The current medical management for heart failure invariably employs a 'one treatment fits
all' approach. The failure to appreciate specific genotypic/phenotypic features in heart
failure subjects is postulated to be a reason recent heart failure studies evaluating the
efficacy of tumor necrosis factor alpha antagonists and endothelin receptor blockers showed
no overall benefit. This experience suggests that the future improvement in the medical
management of patients with heart failure may require pre-prescription
genotyping/phenotyping to tailor drug therapy to the underlying mechanistic processes
orchestrating the development and progression of heart failure.
In this regard, the insulin-resistance syndrome has been recognized as a significant
associated factor with the development of cardiac hypertrophy and heart failure. A novel
class of agents has been developed that increase insulin sensitivity via the activation of
the transcription factor-peroxisomal proliferators activated receptor gamma (PPAR gamma).
These drugs, known as the thiazolidinediones are currently licensed for the treatment of
type II diabetes mellitus. Interestingly, at the preclinical level, PPAR gamma appears to
play a regulatory role in attenuating the development of cardiac hypertrophy and
thiazolidinedione therapy has been shown to attenuate the development of contractile
dysfunction in mice following myocardial infarction.
The hypothesis intrinsic to this proposal is that insulin resistance is commonly associated
with the development/progression of heart failure and that improving insulin sensitivity
will be of clinical benefit in this select group of patients with heart failure. The primary
objective of this study is to establish the safety and efficacy of thiazolidinedione therapy
in insulin-resistant heart failure subjects. The study is designed as a phase II,
randomized, double-blind, placebo-controlled dose escalation study. The primary outcomes
will be the safety of administration, and the evaluation of the modulation in contractile
function in heart failure subjects treated with thiazolidnediones. Moreover, changes in
functional capacity and the determination of the biochemical and genomic modification of
heart failure and insulin-resistance will be measured in response to thiazolidnedione
therapy in heart failure subjects.
all' approach. The failure to appreciate specific genotypic/phenotypic features in heart
failure subjects is postulated to be a reason recent heart failure studies evaluating the
efficacy of tumor necrosis factor alpha antagonists and endothelin receptor blockers showed
no overall benefit. This experience suggests that the future improvement in the medical
management of patients with heart failure may require pre-prescription
genotyping/phenotyping to tailor drug therapy to the underlying mechanistic processes
orchestrating the development and progression of heart failure.
In this regard, the insulin-resistance syndrome has been recognized as a significant
associated factor with the development of cardiac hypertrophy and heart failure. A novel
class of agents has been developed that increase insulin sensitivity via the activation of
the transcription factor-peroxisomal proliferators activated receptor gamma (PPAR gamma).
These drugs, known as the thiazolidinediones are currently licensed for the treatment of
type II diabetes mellitus. Interestingly, at the preclinical level, PPAR gamma appears to
play a regulatory role in attenuating the development of cardiac hypertrophy and
thiazolidinedione therapy has been shown to attenuate the development of contractile
dysfunction in mice following myocardial infarction.
The hypothesis intrinsic to this proposal is that insulin resistance is commonly associated
with the development/progression of heart failure and that improving insulin sensitivity
will be of clinical benefit in this select group of patients with heart failure. The primary
objective of this study is to establish the safety and efficacy of thiazolidinedione therapy
in insulin-resistant heart failure subjects. The study is designed as a phase II,
randomized, double-blind, placebo-controlled dose escalation study. The primary outcomes
will be the safety of administration, and the evaluation of the modulation in contractile
function in heart failure subjects treated with thiazolidnediones. Moreover, changes in
functional capacity and the determination of the biochemical and genomic modification of
heart failure and insulin-resistance will be measured in response to thiazolidnedione
therapy in heart failure subjects.
- INCLUSION CRITERIA:
Adult normal volunteers, age matched (55-75 years of age)
Adult patients greater than 21 years of age who meet the following criteria:
- Heart Failure due to ischemic heart disease or of idiopathic etiology
- Depressed LV systolic function, EF less than or equal to 0.45 by Radionuclide
Angiography (MUGA)
- New York Heart Association Functional Class II or III
- Patient stable on current heart failure therapy
- Evidence of insulin resistance or type II diabetes on insulin-sensitivity screening
- No predicted cardiac revascularization therapy requirements
EXCLUSION CRITERIA:
Pregnant or lactating
History of admission for acute heart failure exacerbation within last one month
Acute myocardial infarction within the last three months
Cardiac resynchronization pacemaker placement within the last three months
Genetic defect known to have induced heart failure
Serum creatinine greater than 2.5 mg/dL.
Liver transaminase levels greater than 2.5 x upper limit of normal
Requirement for insulin therapy to control blood glucose
Current use of thiazolidinedione for diabetic control or history of discontinuation of
thiazolidinedione therapy following development of side effects
Uncontrolled blood glucose levels or the use of insulin therapy to control diabetes
Immune compromise including chronic HIV, HBV, and HCV infection
Chronic systemic inflammatory disease such as SLE, rheumatoid arthritis, collagen vascular
disease
Participation in unrelated research involving investigational pharmacological agent 30
days before planned dosing
Current alcohol or drug abuse
Inability to provide informed consent
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