The Influence of Metformin on Chronic Heart Failure Clinical Course in Patients With Prediabetes

Study Overview
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Brief Summary
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It is well known fact, that prediabetes is a predictor of high cardiovascular mortality, increasing the risk of developing such adverse cardiovascular events as myocardial infarction, stroke and sudden cardiac death. The key pathogenetic link in development of carbohydrates metabolism disorders (CMD) is insulin resistance (IR), which is one of the crucial mechanisms for the development and progression of chronic heart failure (CHF). IR disrupts the functioning of the myocardium due to endothelial dysfunction, inflammation, oxidative stress, remodeling and impaired myocardial metabolism. In condition of a combination of CMD and CHF the reverse development of hyperglycemia is also difficult due to hyperactivation of neurohormonal systems - renin-angiotensin-aldosterone system, in particular. So, drug therapy should neutralize the undesirable metabolic effects of hyperglycemia on the course of CHF, as well as prevent the development of micro- and macrovascular complications. The study will investigate the ability of metformin to impact on clinical and laboratory (neurohormonal, lipid profiles, renal function) parameters of ischemic etiology heart failure patients with prediabetes, as well as their quality of life and prognosis (incidence of adverse cardiovascular events). These tests will be assessed at the beginning and repeated after one year. At the end of the study we will investigate the difference between lifestyle modification effect and metformin treatment. The study is funded by Ministry of Education and Science of Kyrgyz Republic.

Detailed Description
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This is a single centre trial designed to investigate the benefit, if any, of 12-month metformin 2000 mg/day treatment on clinical course of chronic heart failure in 78 patients with coronary artery disease and impaired glucose tolerance. Participants will be seen in three occasions: screening, baseline randomization, 6 month, final 12 month, during which clinical and laboratory indicators will be assessed. There will also be three telephone visits at: month 1, month 3, month 9. At a screening visit an initial history will be performed during following informed consent. Participants will undergo a laboratory, clinical and instrumental screening in Chronic Heart Failure department of National Centre of cardiology and Internal Medicine named after academician M.Mirrakhimov. Among with anthropologic and clinical data, prior to metformin administration, blood samples were evaluated. Participants who meet all inclusion criteria will return for the randomization during hospitalization to either Metformin or Lifestyle modification alone. After 6 months of observation safety indicators will be evaluated, as well as fasting and postprandial glucose, creatinine, ECG. In the active arm, therapy will be metformin in an initial dose of 1000 mg/day (metformin 500 mg х2/day). Participants will continue on Metformin 500 mg x2/day for 2 weeks, following safety blood checks this dose will be increased to 2000 mg/day. If the higher dose cannot be tolerated it will be reduced to 1000 mg/day (or stopped if not tolerated). The target dose of Metformin at 2000 mg/day was chosen based on previous study of metformin in nondiabetic heart failure patients with IR

Official Title
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The Effect of Metformin on Clinical Course of Ischemic Etiology Chronic Heart Failure in Patients With Prediabetes: the Open-label Randomized Clinical Trial

Conditions
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Coronary Artery Disease, PreDiabetes, Chronic Heart Failure

Intervention / Treatment
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* Drug: Metformin Hydrochloride
* Other: lifestyle modification


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18 years or over (not older 65 y.o) Participant willing and able to give informed consent Documented Coronary artery disease (CAD): either angio-graphically documented CAD or a previous history of myocardial infarction/angina. Verified heart failure functional class III (Nt-proBNP levels, 6-min walking test) Fasting insulin resistance ≥ 2.5 (HOMA-IR) Receiving basic therapy for CAD and chronic heart failure (CHF) Able (in the investigators opinion) and willing to comply with all study requirements Exclusion Criteria: Cognitive impairments Type 1 or 2 Diabetes mellitus, antihyperglycemic therapy in anamnesis Unstable course of CAD Acute heart failure or CHF decompensation Malignancy (receiving active treatment) or other life threatening disease Renal dysfunction (stage 3B or worse) Thyroid dysfunction Pregnancy/lactating females Any other reason considered inappropriate by a study physician Participants who have participated in any other clinical trial within the previous 30 days

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: metformin<br>Metformin, 1000 mg b.i.d, 12 months | Drug: Metformin Hydrochloride<br>* patients were divided into 2 groups: 1st group was on lifestyle modification (LSM), 2nd group on regimen LSM+ metformin (1000 g b.i.d) during 12 months<br>|
| Active Comparator: lifestyle modification<br>Lifestyle modification Standard Principles | Other: lifestyle modification<br>* Lifestyle modification Standard Principles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events | Safety and efficacy of Metformin will be determined by monitoring changes from randomization till the end of the study or so long the patient remains in the study , whichever is earlier | 12 months | 
| Number of participants with newly diagnosed diabetes mellitus | Carbohydrate metabolism indicators will be determined by monitoring changes in fasting, postprandial glycemia and glycated hemoglobin | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Chronic heart failure patients Quality of Life | Minnesota Living with Heart Failure Questionnaire will be evaluated at baseline and at 12 months | 12 months | 
| 6-minute walking test results | The test is based on measuring the walking distance with turns along a long corridor (≥30 m) at the patient's own pace. Results will be evaluated at baseline and at 12 months | 12 months | 
| Insulin resistance by HOMA-IR | Improvement in insulin (insulin resistance by HOMA-IR) when treated with metformin compared to lifestyle modification in patients with ischemic etiology CHF and prediabetes using ELISA | 12 months | 
| Aldosterone levels | Improvement in aldosterone levels when treated with metformin compared to lifestyle modification in patients with ischemic etiology CHF and prediabetes using ELISA | 12 months | 
| Nt-proBNP levels | Improvement in Nt-proBNP levels when treated with metformin compared to lifestyle modification in patients with ischemic etiology CHF and prediabetes using ELISA | 12 months | 
| Renal function markers | Creatinine levels with estimated glomerular filtration rate and daily proteinuria at a baseline and at 12 months to assess safety and influence of metformin | 12 months | 
| Lipid profile markers | Improvement in lipid profile indicators (total cholesterol, high- and low-density lipoprotein cholesterol, triglycerides) when treated with metformin compared to lifestyle modification | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metformin, chronic heart failure, prediabetes, insulin resistance, clinical course