Congestive Heart Failure, Insulin Resistance
Conditions
Keywords
Chronic Heart Failure, Insulin Resistance, Metformin, Peak VO2
Brief summary
Will metformin improve exercise capacity in chronic heart failure patients who has insulin resistance (pre-diabetic- means before they become diabetic)?
Detailed description
Exercise incapacity is one of the major debilitating symptoms of heart failure patients. Studies showed that heart failure patients will become insulin resistance (IR) or vice versa, severity of heart failure also correlates with the severity of insulin resistance. A recent study demonstrated that if we correct diabetic patient insulin resistance by giving them a drug to make them more sensitive to the effects of insulin, their exercise capacity improves. Therefore, we think that the same effects might happen in heart failure patients who have been identified to the insulin resistance by blood test. Insulin resistance means that they have not yet become diabetic and it is a stage the diabetic patients go through before they develop diabetes. Therefore, we plan to use a drug called metformin (a diabetic drug), give it to heart failure patients who also have IR for 4 months and examine the effects before and after 4 months of treatment. It is a double blind control study, therefore, neither the examiner nor the patient know which drug they receive (either active drug- Metformin, or a placebo). The main objective is to assess their exercise capacity using an exercise test called Innocor System. It is a bicycle based exercise test that involves patient breathing into a mouth piece before and during exercise in order for the machine to work out the maximum oxygen consumption and pumping power of the heart. The other objectives of the trial are looking at the possible mechanisms of improving exercise capacity. We aim to answer the following questions by doing the following tests: Does exercise capacity improve because of 1. The effect of metformin on the heart? We will answer this question by doing an ultrasound scan of the heart (Echocardiography) 2. The effects on the blood vessels? We plan to perform a test called flow-mediated dilatation, it is an ultrasound scan of the artery in the arm and also assess the blood flow in the skin using a test called Laser Doppler scan (small amount of medication will be delivered through a small electric current and the blood vessels response will be assessed using the laser doppler scan) 3. The effects on the muscle? We will do a muscle biopsy looking at the enzymes activities in the muscle before and after taking 4 months of medication.
Interventions
DRUGMetformin
Started at 500mg bd for 2 weeks. If well tolerated, increase to 1000mg bd for 14 weeks
Similar dosing regime as active comparator
Sponsors
University of Dundee
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
25 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Patients aged 25-80 yrs with compensated CHF in NYHA functional I-III with evidence of insulin resistance \[fasting insulin resistance index values of \> 2.7 are said to have insulin resistance\]. * Documented Left ventricular systolic dysfunction or LV ejection fraction \< 35%
Exclusion criteria
* Elderly patients (aged \>80 yrs); * Patients with decompensated CHF (NYHA functional class IV and /or signs of decompensated CHF); * Renal dysfunction (serum creatinine \> 160 mmol/L); * Patients who are unable to exercise including patients that will be excluded for reasons of safety or potential effects on exercise performance. Therefore, patients with angina or other cardiac or pulmonary symptoms potentially limiting exercise performance will be excluded. * Systolic blood pressure \>190 mmHg at rest or \>250 mmHg with exercise or diastolic blood pressure \>95 mmHg at rest or \>105 mmHg with exercise will also be a reason for exclusion; * Patients with underlying disease likely to limit life span and/or increase risk of interventions will be excluded i.e., cancer; cardiovascular disease .i.e., uncontrolled hypertension: SBP\>180 mmHg or DBP, recent stroke, any severe chronic disease (including renal and hepatic disease).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peak VO2 | 4 months | Peak VO2 after 4 months of intervention with either metformin or placebo. The Mean difference between baseline and after 4 months was analyzed using t-test comparing metformin and placebo. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Possible Mechanisms That Can Explain the Improvement of Exercise Capacity | 4 months | VE/VCO2 Slope, measurement of the abnormal ventilatory response to exercise identified by an increased slope of ventilation (L/min) vs. CO2 production (VE/VCO2) (L/min) to incremental workload |
Countries
United Kingdom
Participant flow
Recruitment details
Patients with symptomatic CHF were recruited from out patient cardiology clinics and local echocardiography database. Eligible patients were approached to have a fasting blood test to determine their fasting insulin resistance index (FIRI). CHF patients with a FIRI \>2.7 were considered to have IR and invited to participate in the study.
Pre-assignment details
127 patients were invited for screening.53 patients were excluded based on exclusion criteria.12 patients decided not to continue with the study after screening.62 patients were randomised using a computer generated sequence.Metformin was started at lower dose of 500mg bd for 2 weeks. Doses were up titrated if well tolerated to the target dose.
Participants by arm
| Arm | Count |
|---|---|
| Metformin Receiving Metformin for 4 months with a target dose of 1000mg twice a day | 39 |
| Placebo Matched Placebo for 4 months | 23 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 1 |
Baseline characteristics
| Characteristic | Placebo | Metformin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 14 Participants | 16 Participants | 30 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 23 Participants | 32 Participants |
| Age Continuous | 68 years STANDARD_DEVIATION 7 | 64 years STANDARD_DEVIATION 8 | 65 years STANDARD_DEVIATION 8 |
| Region of Enrollment United Kingdom | 23 participants | 39 participants | 62 participants |
| Sex: Female, Male Female | 1 Participants | 4 Participants | 5 Participants |
| Sex: Female, Male Male | 22 Participants | 35 Participants | 57 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 18 / 39 | 3 / 23 |
| serious Total, serious adverse events | 2 / 39 | 1 / 23 |
Outcome results
Primary
Peak VO2
Peak VO2 after 4 months of intervention with either metformin or placebo. The Mean difference between baseline and after 4 months was analyzed using t-test comparing metformin and placebo.
Time frame: 4 months
Population: .In the metformin group,3 patients were lost to follow up therefore excluded from analysis.5 patients were discontinued on medications due to side effects, however,were included in our intention to treat analysis.In the placebo group,1 patient was lost to follow up and was excluded from analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin Arm | Peak VO2 | -0.38 ml/kg/min | Standard Deviation 1.4 |
| Placebo | Peak VO2 | 3.6 ml/kg/min | Standard Deviation 3.9 |
Comparison: Null hypothesis: Metformin has no effect on peak VO2. We targetted 66 subjects and power calculation based on our previous observational study of CHF with insulin resistance with mean peak VO2 of 11.p-value: 0.08t-test, 1 sided
Secondary
Possible Mechanisms That Can Explain the Improvement of Exercise Capacity
VE/VCO2 Slope, measurement of the abnormal ventilatory response to exercise identified by an increased slope of ventilation (L/min) vs. CO2 production (VE/VCO2) (L/min) to incremental workload
Time frame: 4 months
Population: 39 patients were randomized with 3 dropped out. Therefore, 36 were included in the analysis. There was 1 patient who dropped out in the placebo arm and hence 22 patients were analysed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin Arm | Possible Mechanisms That Can Explain the Improvement of Exercise Capacity | -4.45 Unitless | Standard Deviation 10.72 |
| Placebo | Possible Mechanisms That Can Explain the Improvement of Exercise Capacity | -0.23 Unitless | Standard Deviation 3.54 |
Comparison: Null hypothesis: Metformin has no effect on the ratio between VCO2 (production of CO2) and VE (ventilation), it is also called the VE/VCO2 slopep-value: 0.034t-test, 1 sided