Drug for heart failure associated with improved metabolism

Disease and treatment 3. sep 2021 2 min Associate Professor Nicolai J. Wewer Albrechtsen Written by Kristian Sjøgren

New research in Denmark reveals how a drug used for treating heart failure may improve metabolism.

The drug Entresto® (a combination of sacubitril and valsartan) turns out to have a surprising side-effect.

In addition to stabilizing the heart, researchers and doctors have observed that Entresto also improves blood glucose control among people with type 2 diabetes.

Now a new study in Denmark reveals how Entresto may improve metabolism and blood glucose control: it adjusts the amount of glucagon in the body and the body’s protein metabolism.

“Our study indicates that type 2 diabetes and heart disease are closely linked, and protecting the body’s glucagon system may improve health,” explains the senior researcher behind the study, Nicolai J. Wewer Albrechtsen, Associate Professor, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.

The research has been published in theJournal of the Endocrine Society.

Targets a glucagon-inhibiting enzyme

Nicolai J. Wewer Albrechtsen and colleagues investigated how Entresto affects metabolism in detail.

Entresto inhibits the enzyme neprilysin, and the researchers hypothesised that neprilysin reduces the amount of glucagon in the body by cleaving glucagon into fragments. Entresto thus increases the amount of glucagon by neutralising neprilysin.

Glucagon and insulin combine to regulate the body’s blood glucose. Insulin reduces blood glucose, whereas glucagon increases blood glucose but also positively affects health.

“Because of how glucagon improves health, researchers are working to develop drugs that affect glucagon. Our study shows that inhibiting neprilysin with Entresto more than doubles the concentration of glucagon, and this may help to improve metabolic health,” says Nicolai J. Wewer Albrechtsen.

Human trials show increased glucagon

The researchers examined how taking Entresto affects proteins among both mice and humans.

The researchers used mass spectrometry to analyse the content of proteins in blood samples to determine very accurately how taking Entresto changed the concentration of glucagon in the blood.

The results showed that Entresto doubled the concentration of glucagon by inhibiting neprilysin.

“Previous research has shown that neprilysin can inhibit glucagon and thus neutralise its effect. But these experiments were in a petri dish in the laboratory. However, now we have demonstrated the effect in animals and humans – among both normal-weight and overweight people,” explains Nicolai J. Wewer Albrechtsen.

Increased glucagon levels benefit the heart

Does doubling the concentration of glucagon increase blood glucose drastically?

Not according to Nicolai J. Wewer Albrechtsen, because although glucagon is associated with increased blood glucose, the effect is negligible compared with all the positive health effects associated with the hormone.

In general, Nicolai J. Wewer Albrechtsen thinks that the increased effect of glucagon provides a healthier body and healthier physiology, and this may be why the risk of heart failure declines and blood glucose control improves among people with type 2 diabetes.

“We know that various diseases are associated with a reduced effect of glucagon in the body, especially nonalcoholic fatty liver disease. Our study shows that medication can activate the body’s own mechanisms to regulate the concentration of glucagon, with increases leading to potential health benefits,” explains Nicolai J. Wewer Albrechtsen.

He adds that drug experiments have shown very great positive benefits based on a relatively small increase in glucagon, and doubling should therefore be assumed to be beneficial for health.

Bariatric surgery’s new potential effect on the heart

In addition to providing new insight into glucagon metabolism and ways to manipulate it, the new results also open up new pharmaceutical avenues for promoting health.

Nicolai J. Wewer Albrechtsen and colleagues are carrying out research showing that bariatric surgery can reduce the concentration of neprilysin in the body by 50% and thereby potentially reducing the risk of heart disease.

“In our new studies, we have discovered that bariatric surgery affects neprilysin to the same degree that Entresto does. This suggests that the surgery may contribute to improving health by inhibiting neprilysin,” concludes Nicolai J. Wewer Albrechtsen.

Neprilysin inhibition increases glucagon levels in humans and mice with potential effects on amino acid metabolism” has been published in the Journal of the Endocrine Society. Several authors are affiliated with the Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.

State-of the art analytical biochemistry is my scientific cornerstone. During my first years in academia at prof. Jens J. Holst laboratory, I develope...

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