Anders Larsen - Metformin and Heart Failure: cardiac uptake of metformin and effects of metformin treatment on myocardial efficiency in patients with heart failure

Heart failure (HF) is a common disease and there is a definite need for new treatment modalities for HF patients. Diabetes and insulin resistance is found in more than 40% of HF patients. Metformin is presently the most commonly prescribed oral anti-diabetic drug, and experimental data and registry studies show beneficial effects of metformin in HF, but human in vivo data are lacking.

A novel metformin tracer [¹¹C]-metformin has been developed at Aarhus University Hospital. It allows for precise determination of the biodistribution of metformin. This represents a major breakthrough as a research tool and by applying positron emission tomography (PET) it will for the first time be possible to investigate metformin action in human hearts in vivo, and determine mechanisms for metformin action.

Additionally, imaging techniques offer the possibility to assess myocardial efficiency, accurately. Efficiency reflects the ratio between mitochondrial oxygen consumption and cardiac work, and bears prognostic information in HF.

Interestingly, metformin has recently been found to affect mitochondrial activity. It is therefore relevant to further investigate the effect of metformin in HF patients. Finally, the safety of metformin in HF patients has been debated due to concerns about lactate acidosis, and the pharmacokinetics and -dynamics is unknown. 

Study 1: The expression of metformin transporter proteins will be measured in tissue samples from 25 explanted failing human hearts. Cardiac uptake of metformin will be studied in 8 pre-diabetic HF patients by [¹¹C]Metformin-PET.

Study 2: The pharmacokinetics and -dynamics of metformin will be determined in 12 metformin-treated HF patients and related to polymorphisms in genes encoding the metformin transporter proteins.

Study 3: In a double blinded study design, 36 pre-diabetic HF patients are randomized to 3 months metformin or placebo treatment. The primary endpoint is change in myocardial efficiency as determined by [¹¹C]acetate-PET.