Cardioprotective and Metabolic Effects of Metformin in Patients With Heart Failure and Diabetes

Phase 2

Completed

• Conditions: Insulin Resistance; Chronic Heart Failure
• Interventions: Drug: Metformini hydrochloridum (Siofor 1000 tbl, Berlin); Drug: placebo

• Registration Number: NCT01690091
• Lead Sponsor: Institute for Clinical and Experimental Medicine

Brief Summary

The aim of the study is to evaluate the effect of metformin on myocardial function, insulin resistance and selected metabolic markers in patients with type 2 diabetes and heart failure (HF+DM+) in a cross-over, randomized, placebo controlled trial.

Hypothesis:

Metformin treatment in HF+DM+ group will lead to better myocardial function and load tolerance in comparison to placebo. The degree of improvement will be linked to selected metabolic parameters.

Detailed Description

40 patients with HF and DM without previous diabetes treatment will be randomized into 2 groups (A succession: MET-placebo, B succession: placebo-MET) - stratified randomization with following parameters weighted: HF etiology (ischemic /non-ischemic), diabetes duration, gender, BMI, age, NYHA, smoker/non-smoker). After 3 months the treatment will be switched. All participants will undergo standardized selection of metabolic and cardiovascular tests (hyperinsulinemic euglycemic clamp with indirect calorimetry, measurement of endothelial function, echocardiography, spiroergometry, proton/phosphor MR spectroscopy, adipose tissue biopsy, selected cytokines in plasma and adipose tissue at the beginning and the end of each intervention period (3 times in total).

Study Timeline

• Study First Submitted: 2012-03-12
• Study First Submitted QC: 2012-09-20
• Study First Posted: 2012-09-21
• Study Start: 2012-11
• Primary Completion: 2016-05
• Study Completion: 2016-12
• Status Verified: 2018-03
• Last Update Submitted: 2018-03-28
• Last Update Posted: 2018-03-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

1. chronic heart failure will be defined by the following criteria (all must be included):

   • diagnosis of HF known for at least 6 months
   • medical history of hospitalization for cardiac decompensation with need for parenteral therapy for congestion - X-ray findings or swelling of lower extremities
   • stable drug therapy at least 1 month
   • treatment with diuretics (thiazide or furosemide)
   • LVEF below 50%

2. the presence of diabetes will be defined by:

   • diagnosis and treatment of type 2 diabetes in the medical history

   • screening blood sample:

     • the value of HbA1c(according to IFCC)≥ 4.8% + fasting glucose ≥ 7.0 mmol / l in venous plasma or
     • the value of HbA1c ≥ 4.8%(according to IFCC) + random blood glucose ≥ 11.1 mmol/l in venous plasma
     • or OGTT - blood glucose level at 120 min ≥ 11.1 mmol/l OGTT is indicated just in case of positivity of one of the criteria (fasting glucose + HbA1c or HbA1c + random blood glucose)

   • treatment of diabetes - by diet only

   • women and men aged 40-70 years

   • body mass index (kg/m2) in the range of 20-35

   • the range of HbA1c between 4-6,5% IFCC

   • signed informed consent

Exclusion Criteria

1. the planned cardiac intervention during the study that affect the function of the heart (revascularization including PCI, heart surgery, implantation of pacemaker, RF ablation; urgent candidate for OTS
2. metabolic disease, including: 1 type diabetes, decompensated thyreopathy (Note: patients with hypothyroidism and stable substitution (the last 3 months) of normal TSH levels may participate in the study
3. treatment with insulin or PAD one month before the recruitment(patients who were temporarily treated with insulin during hospitalization may participate in the study)
4. pregnancy (positive β-HCG test), breast feeding, trying to become pregnant
5. clinically significant anemia with hemoglobin below 100 g/l
6. renal insufficiency with eGF below 0.7 ml/s
7. atrial fibrillation - present during screening test
8. the presence of other medical condition, which occurs during physical examination, laboratory tests, ECG, including pulmonary, neurological or inflammatory disease, which would be considered by the examiner to distort the consistency of data

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Metformin	placebo	500 mg per day(1/2 tbl 1000 mg once a day - in the morning) after a week increase the dose to 1 tbl á 1000 mg after two weeks increase the dose to 2 x tbl 1000 mg (in the morning and in the evening), duration: 3 months
Metformin	Metformini hydrochloridum (Siofor 1000 tbl, Berlin)	500 mg per day(1/2 tbl 1000 mg once a day - in the morning) after a week increase the dose to 1 tbl á 1000 mg after two weeks increase the dose to 2 x tbl 1000 mg (in the morning and in the evening), duration: 3 months
Placebo	Metformini hydrochloridum (Siofor 1000 tbl, Berlin)	500 mg per day(1/2 tbl 1000 mg once a day - in the morning) after a week increase the dose to 1 tbl á 1000 mg after two weeks increase the dose to 2 x tbl 1000 mg (in the morning and in the evening), duration:3 months
Placebo	placebo	500 mg per day(1/2 tbl 1000 mg once a day - in the morning) after a week increase the dose to 1 tbl á 1000 mg after two weeks increase the dose to 2 x tbl 1000 mg (in the morning and in the evening), duration:3 months

Primary Outcome Measures

Name	Time	Method
insulin sensitivity	at baseline and after 3 months	change of glucose disposal during clamp

Secondary Outcome Measures

Name	Time	Method
endothelial function	at baseline and after 3 months	change in digital pulse amplitude tonometry
heart function	at baseline and after 3 months	change measured by echocardiography and spiroergometry
energy expenditure	at baseline and after 3 months	change of energy expenditure measured by indirect calorimetry

Trial Locations

Locations (1)

Diabetes Center, Institute of Clinical and Experimental Medicine; 🇨🇿 Prague, Czechia