Survodutide (GLP1/glucagon agonist) shows promise for weight management and MASH/MASLD ('fatty liver' disease)

As blogged previously, survodutide is a dual GLP1/glucagon receptor agonist that is being developed as a weight management medication and also as a potential treatment of MASH/MASLD (‘fatty liver’ disease). Stimulation of the GLP1 and glucagon receptors together mimics a natural human hormone called oxyntomodulin, and may provide health benefits beyond the benefits of GLP1 alone (read more on the potential benefits of stimulating GLP1 and glucagon together, here).

The SYNCHRONIZE-1 trial, published in the New England Journal of Medicine (disclosure, I am an author of this publication, and the Canadian National Lead Investigator of this trial) was a phase 3 weight management study including 725 participants in 14 countries with obesity (without diabetes). Participants were randomized to receive survodutide 3.6mg weekly, 6mg weekly, or placebo, alongside a reduced calorie diet and physical activity. At baseline, the average age was 47, average weight was 108.8kg, average BMI 37.9, and 41% of participants were men (59% women). At 76 weeks, we found:

weight loss of 12.2% with survodutide 3.6mg
weight loss of 13% with survodutide 6mg
weight loss of 5.4% with placebo

Discontinuation rates of study medication were higher than ideal in this study. By the end of the study, 35.3% (survodutide 3.6mg group), 34.3% (survodutide 6mg group), and 40.1% (placebo group) had stopped treatment (more on discontinuations below). For those who took the treatment as prescribed throughout the trial:

weight loss of 15.3% with survodutide 3.6mg
weight loss of 16.6% with survodutide 6mg
weight loss of 3.2% with placebo

Waist circumference and eating behavior scores improved with survodutide, alongside a small reduction in A1c (-0.3% with both doses of survodutide vs +0.1% with placebo – remembering people in this study did not have diabetes). Systolic blood pressure was improved by -7.5-7.9mmHg for those taking survodutide as intended through the study (vs -3.2mmHg decrease with placebo).

We also looked at body composition with MRI in a subset of participants. We found significant reductions in total body fat of up to 27.8% with survodutide (vs 9.5% with placebo), visceral (central) fat was reduced by up to 34%, (vs 11.8% with placebo) and liver fat by up to 63.1% (vs 24.5% with placebo). What is particularly interesting to me is that there was a greater liver fat reduction in the 6mg group (63%) than the 3.6mg group (46%) without much difference in weight between these two groups. This suggests that there may be a weight loss independent benefit to reduce liver fat, which is exciting given that the majority of people with obesity have MASLD (‘fatty liver’), and 1 out of every 3 people with obesity have inflammation of the liver related to liver fat (MASH).

The most common side effects were gastrointestinal (nausea, vomiting, diarrhea, constipation, typically mild to moderate in severity). Gastrointestinal side effects were a leading reason for stopping study medication (17.8% of the survodutide 3.6mg group and 20.2% of the 6mg group stopped treatment for these reasons, vs 2.9% in the placebo group). It is important to note that in this study, there was limited flexibility in dosing of survodutide until very late in the trial. Greater flexibility in dosing may have reduce GI side effects and allowed more people to tolerate treatment.

A substantial number of people (16.5%) in the placebo group started GLP1 treatment during the trial, which is likely responsible for a greater weight loss than is typically seen in the placebo group. This reflects the challenges (and ethics) in conducting placebo-controlled trials with increasing access/decreasing prices of GLP1 medications. Placebo controlled studies are still required by regulators – it is high time that the world (and its regulators) moves away from having placebo arms in these studies and uses other medications as comparators instead.

In the phase 3 SYNCHRONIZE-MASLD study, 216 adults with obesity and MASLD (38% with type 2 diabetes, 62% without diabetes) in USA and Spain were randomized 2:1 to receive survodutide 6mg weekly or placebo for 48 weeks. Researchers found that at least 30% reduction in liver fat (assessed by MRI-proton density fat fraction (PDFF)) was achieved by 84.2% of the survodutide group vs 24.3% of the placebo group , when treatment was taken as prescribed, alongside 12.2% weight loss with survodutide vs 1% with placebo. Liver fat content was completely normalized in 61% of people taking survodutide vs 5.7% of people taking placebo. Improvements in waist, blood pressure and blood sugars were also seen. Again the most common side effects were gastrointestinal, most often during dose escalation, and mild to moderate in severity. Treatment was discontinued in 41.1% of the survodutide group (about half of which were due to gastrointestinal side effects) and 40% of the placebo group. Again in this study, there was limited flexibility in dosing of survodutide until very late in the trial. Greater flexibility in dosing may have reduce GI side effects and allowed more people to tolerate treatment. The LIVERAGE study is currently underway to further evaluate survodutide as a treatment of MASH/MASLD.

BOTTOM LINE: Survodutide is emerging to become a promising addition to the next generation of obesity medications, demonstrating clinically meaningful weight loss, with robust loss of fat from the liver suggesting benefits potentially independent of weight loss. A more flexible dosing approach may help to improve gastrointestinal side effects.

Disclaimer: I am an investigator in clinical trials of survodutide. I receive honoraria as a continuing medical education speaker and consultant from the makers of survodutide (Boehringer Ingelheim).

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