New Clinical Trial Reveals Unexpected Benefits of Diabetes Drugs for Heart Failure Patients

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A randomized, placebo-controlled clinical trial led by a collaboration between Duke-NUS Medical School, National Heart Center Singapore (NHCS) and Klinikum Nürnberg, Germany, has revealed surprising new insights into how SGLT2 inhibitor drugs, originally developed for diabetes, benefit patients with heart failure. Contrary to common assumptions, these drugs may improve cardiac outcomes and heart health without acting as diuretics. 

This congestion strains the heart and causes symptoms like breathlessness and swelling. Reducing congestion is key to managing heart failure, as it reduces the workload of the heart and thereby eases pumping. 

SGLT2 inhibitor drugs are the new blockbuster treatment for chronic heart failure because they very quickly stabilize heart function and reduce hospitalizations and patient deaths. The drugs release more glucose into the urine, and thereby have the potential to pull more fluid from the body into the urine, alleviating the congestion experienced by patients with heart disease. Given this diuretic potential, leaflets accompanying the drugs list dehydration as a common side effect of their use. 

However, results from this clinical trial, published in the Journal of the American College of Cardiology, cast doubt on the presumed diuretic action of SGLT2 inhibitors in patients with heart failure. 

Conducted together with NHCS in Singapore, the double-blind, randomized, placebo-controlled trial, the gold standard of clinical trials, examined the SGLT2 inhibitor dapagliflozin in patients with chronic heart failure. 

As expected, the drug sharply increased urine glucose excretion. This increased concentration of glucose in urine creates an osmotic imbalance that should cause more water to be pulled into the urine and therefore increase urine volume. 

This minimized any rise in urine volume and even after 24 hours, patients’ urine volume remained stable despite persistent glucose excretion from dapagliflozin. These results, which are the first to be published from this international collaborative project, contradict the prevailing theory that SGLT2 inhibitors reduce congestion through diuresis or incrased urine production. 

One theory is that the process of energy and water conservation induced by these drugs induces metabolic changes in the body that improve organ function. Researchers think that the initial glucose and water loss caused by the SGLT2 inhibitors triggers some ancient and highly conserved evolutionary body survival signals that flip metabolic switches to improve heart and kidney function. 

In parallel to the clinical trial in Singapore, the team’s collaborators in Germany have developed methods that are now available to detect activation of these ancient metabolic pathways in patients’ urine. 

The team will use these to uncover the actual mechanisms behind these drugs’ organ-protective benefits and investigate how these changes may improve the healthspan not just of patients with heart failure but also with kidney disease, diabetes or living with other ageing-related ailments.  

Journal Reference – Adriana Marton et al, Water Conservation Overrides Osmotic Diuresis During SGLT2 Inhibition in Patients With Heart Failure, Journal of the American College of Cardiology (2024).

DOI: 10.1016/j.jacc.2024.02.020