Endocrinology

Tirzepatide for diabetes and obesity: efficacy and mechanism of action

Marina Virko
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Tirzepatide (branded Munjaro) improves blood sugar metabolism in patients with obesity and type 2 diabetes. It is able to reduce body weight by up to 26.6% on average. This was evidenced by the results of SURMOUNT-3 and SURMOUNT- 4, two Phase 3 drug trials. Until now, the its effect on metabolism was not fully understood. Recently scientists have managed to uncover this mechanism.

Obesity: tirzepatide can achieve a more than 20% body weight reduction

Participants in the trial were adults with obesity (BMI ≥ 30 kg/m²) and overweight (BMI ≥ 27 kg/m²) with comorbidities. Patients with type 2 diabetes mellitus were excluded.

According to Munjaro manufacturer, the most commonly reported adverse events were gastrointestinal complaints, which were mostly mild to moderate.

The safety profile was consistent with data from other studies of tirzepatide and other incretins approved for the treatment of obesity.

Significant weight loss after lifestyle intervention

All the 806 participants in SURMOUNT-3 initially underwent a 12-week intensive lifestyle intervention program. It included a low-calorie diet, exercise, and weekly physician counseling. With an average initial weight of 109.5 kg, the average weight loss by the end of the lead-in period was 6.9%. Next, those who lost at least 5% (579 participants) were randomized in a 1:1 ratio into two groups; those in the first group took the subject medication and those in the second group took a placebo. This was followed by a 72-week double-blind phase (when neither doctors nor patients know what the subjects were taking).

During this time, tirzepatide demonstrated an additional average 21.1% reduction in body weight since randomization (the so-called co-primary endpoint).

In contrast, in the placebo group, the body weight increased by 3.3% over the same period.

Notably, 94.4% of those who got the drug rather than the inert substance lost more than 5% weight over the trial course (the second co-primary endpoint), while in the placebo group this was observed in only in 10.7% of participants.

In total, over the entire 84 weeks of the study (lead-in phase and follow-up after splitting into groups), with Munjaro the average body weight reduction amounted to 26.6%.

With long-term therapy, the effect is maintained

The SURMOUNT-4 study involved 783 participants, all of whom first received the drug for 36 weeks (open-label phase, i.e., not involving placebo). Then 670 of them were randomly divided in a 1:1 ratio into two groups; one continued taking the drug, those in the second group received a placebo. This double-blind phase lasted 52 weeks.

At the time of randomization, the mean weight loss of all participants was 21.1% and the average weight was 107.3 kg. Between weeks 36 and 88, tirzepatide reached the primary endpoint with better mean percentages than placebo. In terms of the efficacy measures evaluated, those taking the real drug had a further 6.7% reduction in body weight during the second phase, with the other group of subjects gaining weight again by an average of 14.8% during the same time period. Over the entire 88-week period, those who continued to take Munjaro after randomization lost weight by an average of 26.0%.

The full results of the SURMOUNT-3 study will be presented at the Obesity Week conference in October 2023, and the results of SURMOUNT-4 will be presented at the annual meeting of the European Association for the Study of Diabetes (EASD).

New insights into the mechanism of action

Tirzepatide is a molecule that activates the body's receptors for the metabolic hormones GIP and GLP-1 (natural incretins). Activation of both receptors stimulates the release of insulin. They are located in areas of the human brain relevant to appetite regulation. It has been found that the substance can modulate fat metabolism, but its effect on metabolism has not been fully understood until recently.

Decreased insulin production

Although Munjaro improves glycemic control in patients with type 2 diabetes compared to agonists acting only on the GLP-1 receptor, the mediating role of GIP in causing this effect was previously unknown.

But recently a group of researchers discovered that the signaling pathway through the GIP receptor in islet cells (islets of Langerhans) of the human pancreas is indeed crucial for stimulation of insulin secretion.

They were able to show that inhibition of the GIP receptor reduces the efficacy of tirzepatide on insulin secretion by islet cells.

Effect via the GIP receptor

At the same time, inhibition of the GLP-1 receptor had only a minor effect on insulin secretion induced by the new drug, which further confirms that signaling through the GIP receptor plays a crucial role in the novel drug mechanism of action, while the "mediating" role of the GLP-1 receptor is less important.

"These data are extremely exciting and indicate the importance of the GIP receptor in the effect of tirzepatide on metabolism," notes one of the study leaders, Dr. John Campbell.

Different algorithms in humans and animals

In addition, the scientists evaluated the pharmacological effects of the study substance on human and mouse receptors, and compared its mechanism of action in isolated mouse and human pancreatic islet cells.

"Similar to human GIP, tirzepatide shows less efficacy on the mouse GIP receptor, suggesting that it works differently in mice and humans," notes one of the study authors, Dr. Timo Müller.

While in mice it stimulates the release of insulin from islet cells via the GLP-1 receptor, in humans it acts predominantly via the GIP receptor, the scientist adds. Further tests will now be carried out to find out how important the GIP receptor is for the weight loss effect of tirzepatide.

More about the drug

Munjaro (tirzepatide) was approved by the European Commission in 2022 for the treatment of adults with type 2 diabetes.

It should be prescribed in addition to diet and exercise, either as monotherapy if metformin is not tolerated or contraindicated, or in addition to other antidiabetic drugs.

It is administered as subcutaneous injections.

References:

  1. El, K., Douros, J.D., Willard, F.S. et al. The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets. Nat Metab 5, 945–954 (2023). https://doi.org/10.1038/s42255-023-00811-0
  2. A Study of Tirzepatide (LY3298176) In Participants After A Lifestyle Weight Loss Program (SURMOUNT-3). https://www.clinicaltrials.gov/study/NCT04657016
  3. A Study of Tirzepatide (LY3298176) in Participants With Obesity or Overweight for the Maintenance of Weight Loss (SURMOUNT-4). https://www.clinicaltrials.gov/study/NCT04660643
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