How do anti-diabetic drugs benefit patients with heart failure?

Professor David Kaye, Baker Heart and Diabetes Institute

2020 Vanguard Grant

Years funded: 2021-2022

Heart failure (HF) is one of the most disabling and life limiting forms of cardiovascular disease. HF patients have poor quality of life, frequent need for hospitalization and a markedly reduced life expectancy even with currently available treatments. Recently a novel approach for HF treatment using a class of drugs originally designed to treat diabetes ("SGLT2 inhibitors", SGLT2i) was unexpectedly shown to benefit HF patients, with favorable effects on survival, hospitalization and quality of life. The mechanism(s) responsible for the beneficial effect of these drugs in HF patients is not known. SGLT2i have been proposed to exert a range of actions across the cardiovascular and renal systems including improvements in energy metabolism, oxygen delivery and cardiac performance together with a reduction in blood pressure, sympathetic nervous system activity, inflammation, cellular stress and cell death but these have not been systematically studied in HF patients.

We will comprehensively investigate the mechanism of action of SGLT2i in HF patients. We will utilize methodology only available at Baker Heart and Diabetes Institute/Alfred Hospital to assess the effects of SGLTi (compared to placebo) on cardiac and renal sympathetic nerve activity (noradrenaline spillover), metabolite and oxygen flux and an assessment of regional release of biomarkers of inflammation (ie cytokines), oxidative stress and cellular death. These measurements are obtained by performing selective cardiac and renal blood sampling prior to and during SGLT2i or placebo treatment. In association we will assess the effects of treatment on cardiac performance (invasive hemodynamics and echocardiography), renal blood flow and renal function.

The objective of this study is to understand how SGLT2i benefit HF patients, with the aim of developing even more effective therapies for HF and to identify potential approaches to identify patients most likely to benefit from SGLT2i and related treatments.