Why not everyone loses weight on tirzepatide drugs - endocrinologist

Despite the wide popularity of tirzepatide-based drugs (Mounjaro, Zepbound), clinical practice experience and new scientific data show that not all patients achieve the desired weight loss even with proper use. What is the reason?

This is told by Olena Davydenko, an endocrinologist and nutritionist with many years of clinical experience, specializing in metabolism, obesity and hormonal background. The material was based on data presented in May 2025 at the annual conference of the American Association of Clinical Endocrinology and in the journal American Diabetes Association.

How does tirzepatide work?

This is an injectable drug that combines two peptides - GIP and GLP-1. They mimic the action of intestinal hormones that regulate appetite, glucose levels and metabolic processes. The main advantage of tirzepatide is its resistance to the enzyme DPP-4, which allows the hormones to act longer in the body, suppressing hunger and improving glycemic control.

In most people, this provides a powerful weight loss effect. However, some patients do not lose weight, although blood sugar is well controlled.

What did the researchers find out?

According to Olena Davydenko, scientists identify two main reasons for the lack of a weight loss effect:
1. In some people, the GIP receptor works abnormally, and its stimulation can block the action of GLP-1. 
2. There may be increased sensitivity to GIP, which prevents normal metabolic adaptation.

A new strategy — blocking GIP

In case of ineffectiveness of tirzepatide, the future lies in drugs that block the GIP receptor. One of the most promising is MariTide (developed by Amgen). It combines:
• Monoclonal antibody to the GIP receptor (blocks it).
• GLP-1 component, which provides appetite control.

Advantages: injections once a month or even less often, with weight loss of up to 20%.
It is expected that MariTide will be released in doses of 70–420 mg and will become available in clinical practice after the completion of phase III studies in 2027.

“Individual response to incretin therapy is not the exception, but the rule. If there is no effect, a different approach is needed. Sooner or later we will be able to block GIP, and this will open a new era in the treatment of obesity,” notes Dr. Olena Davydenko.

Contacts for consultation with Elena Davydenko:

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