SEMAGLUTIDE PERSPECTIVES IN NASH 


Semaglutide

I spend a lot of time reading the various studies published on NASH and its future treatments and from time to time it seems to me that some treatment pathways seem more promising than others, such as semaglutide. I will explain here why I came to this conclusion.


Since the trial results presented two years ago on liraglutide (VICTOZA®) in the treatment of NASH, I look with interest to publications on GLP-1 analog.

This trial, targeting 58 obese patients with NASH, demonstrated that daily subcutaneous injection of 1.8mg liraglutide for 48 weeks allowed NASH resolution in 39% of cases (9/22) vs 9% of cases for Placebo (2/22).

These are excellent results compared to the FLINT study on the OCA that had not demonstrated NAS> = 4 resolution of NASH but a simple decrease of the NAS Score, and the GOLDEN study on The Elafibranor which had demonstrated on NAS patients> = 4 a resolution of NASH for 22.4% of patients vs. 12.7% for placebo.

In a NASH confirmed subpopulation, a post hoc analysis demonstrated in FLINT a resolution of the NASH (former definition) of 19% vs 8% p <0.05 for the OCA. 

A post hoc analysis of GOLDEN on balanced centers also demonstrated a NASH resolution of 29% vs 5% p = 0.001 for Elafibranor.

Another comparison was the PIVEN study on pioglitazone, which demonstrated a resolution of NASH (former definition) in 47% of patients vs 21%.

However, these comparisons should be balanced because the study carried out on liraglutide contained only a few patients and they were all obese, which makes it impossible to compare with homogeneous populations.

Moreover, Liraglutide is known for its ability to help patients to lose weight, and this loss of weight is one of the recognized treatments of NASH, so its action could have been indirect.

That said, one might wonder why NOVONORDISK did not extend its clinical studies on liraglutide in NASH.

The answer is simple, with its patent expiring in short time , liraglutide will become a generic drug and a lab is not launching expensive studies on such a drug .

One of the other problems posed by this drug is that it requires a daily subcutaneous injection that is highly penalizing for a supposed lifelong chronic treatment.

There is another commercialized molecule that is also a GLP-1 analog  prescribed in the treatment of diabetes, dulaglutide (TRULICITY) marketed by LILLY. The latter requires only a weekly injection which is more acceptable. 

To me, it is very curious that LiLLY has not yet launched a study on NASH with their TRULICITY (dulaglutide).

NOVONORDISK has therefore launched studies on NASH with its last molecule, semaglutide, another GLP-1 analog.

It is a wise choice, the results of a clinical study on T2D, that has just finished, shows its superiority in the treatment of diabetes compared to dulaglutide under similar weekly injection conditions. Semaglutide would also diminish cardiovascular risk.

This GLP-1 analog would therefore be more effective than the existing marketed drugs.

A clinical study (NCT02970942) is ongoing for the treatment of NASH, but on the basis of a daily injection. 

It should be noted that NOVONORDISK is developing worldwide, on the basis of a technology developed by ELIGEN, an oral version of this molecule which is also in clinical test in type 2 diabetes.

This oral version would open wide the path of easy chronic treatment. Presentations claims that the efficacy of daily oral treatment is equivalent with the one of weekly injected one. this need to be confirmed.

The effects of semaglutide are mainly centered on decreased glucagon secretion and stimulation of insulin secretion; hence its good effectiveness in type 2 diabetes, but it also has an important appetite suppressant effect that leads to weight loss.

It is not clear to me how he metabolic mechanisms of NASH are impacted by GLP-1 analogs, but their actions seem to target some of the metabolic disorder widely present in NASH patients (type 2 diabetes risk CV and obesity). Even if their effects are indirect, they cannot be neglected and could be a effective treatment.

That is why I consider that semaglutide is a serious candidate for the treatment of NASH, and that I will carefully follow the results of future clinical studies.

 



G.Divry

Notice that I am neither a physician nor a biologist, my point of view is only that of an enlightened amateur, so it must be taken for what it is, a questionable point of view!



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