How a diabetes drug unexpectedly redefined heart failure treatment| MEDICUS 2024 Issue 3

How a diabetes drug unexpectedly redefined heart failure treatment
By Dr Chua Li Min, Science writer

Credit: iStock.com / Vonschonertagen

Like other drugs for heart failure, SGLT2 inhibitors were originally developed to lower blood sugar levels in patients with diabetes. But this drug soon found its way into the heart of clinics that treat patients with heart failure when it was discovered that it lowered their risk of hospitalisation from heart failure.

While they were initially thought to work as diuretics that reduce fluid build-up in patients with heart failure, this assumption has recently been challenged by a study published in the Journal of the American College of Cardiology conducted by scientists from Duke-NUS, the National Heart Centre Singapore and Klinikum Nürnberg, Germany.

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“This study reinforces the fact that these (SGLT2 inhibitors) are disease-modifying drugs which improve healthspan rather than diuretics that relieve the symptoms of patients.”
Clin Assoc Prof David Sim

Heart failure develops when the heart is unable to pump sufficient blood around the body. This leads to sluggish blood flow, which forces fluids out of the bloodstream and into surrounding tissues, causing symptoms such as breathlessness and swelling in the legs and ankles. To relieve these symptoms, patients with heart failure are prescribed diuretics as part of their treatment regime.

Because SGLT2 inhibitors reduce blood sugar levels by causing large amounts of the sugar to be excreted in the urine, it was long assumed that this would lead to an increase in urine volume as more fluid is channelled to the bladder to dilute the sugar.

However, results from this latest research, spearheaded by Duke-NUS clinician-scientists, to investigate the evidence behind that assumption show that SGLT2 inhibitors did not, as anticipated, cause excess fluid to be drained from the body.

“We think that the drugs trigger some ancient and highly conserved evolutionary body survival signals that flip metabolic switches to improve heart and kidney function.”
Assoc Prof Jens Titze

“So they work by mechanisms other than diuresis,” explained cardiologist David Sim from the National Heart Centre Singapore, who was instrumental in running the randomised, placebo-controlled clinical trial component of this study, which involved 29 patients with chronic heart failure.

The team observed that when patients were given SGLT2 inhibitor dapagliflozin, their urine volume did not increase significantly after taking the drug. In fact, participants’ urine volume remained largely the same even after taking the drug for four weeks.

Instead, the researchers detected elevated levels of vasopressin, a hormone that signals the kidneys to conserve water, which the team believes to play a role in maintaining the urine volume.

“It seems that the brain’s internal hydration meter very quickly detects reduced hydration levels, and then forces the kidneys to further concentrate the urine to prevent body water loss. This suggests that we need to rethink our assumptions of how SGLT2 inhibitors benefit patients with heart failure, since decongestion by increased urine production doesn’t seem to be the answer,” said Associate Professor Jens Titze from the Duke-NUS Cardiovascular & Metabolic Disorders Programme, who conceptualised the study.

What this means, stressed Sim, is that in addition to SGLT2 inhibitors, patients should continue taking diuretics as part of their treatment regime for chronic heart failure.

“This study reinforces the fact that these (SGLT2 inhibitors) are disease-modifying drugs which improve healthspan rather than diuretics that relieve the symptoms of patients. So using the drug alone is not sufficient. We also need to give patients traditional diuretics to drive the excess fluid out. That is a very important take-home message,” added Sim.

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Failure to do so could result in inadequate diuresis and consequently water retention, which may lead to increased swelling in the body and even readmission for heart failure, he cautioned.

Following these initial findings, the team is planning to probe deeper into the mechanisms underlying the beneficial effects of SGLT2 inhibitors using a suite of new tools that will enable them to measure traces of the body’s metabolic pathways in urine.

At the same time, they are also expanding efforts to investigate the organ-protective benefits observed so far in people living with other chronic conditions, including kidney disease, diabetes or living with other ageing-related ailments.

“We are very excited because we finally have treatment options that will improve the outcomes for these chronically ill patients, but there clearly is much more to learn about how these drugs protect the heart and the kidneys, and maybe even improve longevity,” said first author of the study Dr Adriana Marton.

The consultant nephrologist and clinical investigator at Klinikum Nürnberg and its medical university, Paracelsus Medizinische Privatuniversität is currently conducting a follow-up clinical trial in patients with chronic kidney disease.

Added Titze: “We think that the drugs trigger some ancient and highly conserved evolutionary body survival signals that flip metabolic switches to improve heart and kidney function.”