New Incretin Co-agonists Could Change Obesity Therapy

Pharmacotherapy against obesity has a poor image in Germany. “Even truly effective medications, such as GLP-1 receptor agonist liraglutide, are only taken by a few thousand people,” reported Matthias Blüher, MD, member of the board of the German Obesity Society, at the Diabetes Congress in Berlin. Potent GLP-1 receptor agonists, as well as dual and even triple incretin agonists, may change the situation.

Some options for medicinal obesity therapy are already available in Germany. The lipase inhibitor orlistat, the combination product naltrexone/bupropion, and the GLP-1 receptor agonists liraglutide and semaglutide are all approved but must be paid for independently by the patient.

Questions of Reimbursement

“The German Social Code still equates medication used to treat obesity with treatments for erectile dysfunction and for promoting hair growth, and offers reimbursement through statutory health insurance,” said Blüher. Combined with the fact that the available medications only promise a moderate effect, many patients shy away from taking on the costs themselves.

An average weight loss of 3% to 5% can be achieved through the classic combination of nutrition, movement, and behavioral change. This increases by a further 3% to 6% with the approved medications. To date, obesity therapy physicians have been obliged “to make a virtue of necessity by informing patients that they will also benefit from significant health advantages with a 5% to 10% weight reduction,” said Blüher.

Pharmacotherapy Would Be Scalable

Pharmacological therapies are still not as effective as surgical interventions. “But not every obesity patient wants to have surgery,” stressed Blüher. Surgical capacities are simply not sufficient for the approximately 1 million people with a surgical indication in Germany.

Pharmacotherapy remains an extremely important cornerstone of the treatment of obesity, since “it is the only scalable therapy; medication could theoretically be prescribed to every person affected if it was fully subsidized by the health insurance funds,” said Blüher.

Approaching Surgical Efficacy

It is obvious that something needs to urgently change here politically, too, said Blüher. He assumes that the ever-more effective medications will be the basis for an important argument. The most potent of these drugs is the recently approved semaglutide. Together with liraglutide, it was associated with a total weight reduction of 12% in the SCALE studies, following a previous diet plan.

The STEP study program demonstrated that semaglutide was roughly twice as potent in weight reduction as liraglutide. In STEP 1, subjects taking semaglutide lost more than 16% on average. “That brings us close to the surgical levels of efficacy,” said Blüher.

What is also encouraging for clinical practice is that roughly every third subject managed to lose more than 20% with semaglutide. “That is what someone with, for example, a gastric band would achieve,” he said. “With this, a patient here and there could be kept from having surgery.”

Therapy Throughout Life

However, it must be made clear “that this is in an ideal scenario and it is a permanent treatment,” said Blüher. Long-term data for liraglutide show that the weight reduction quickly hits a plateau, and the weight also rapidly increases again if the medication is discontinued.

“Many patients discontinue liraglutide once they have lost a certain amount of weight,” said Blüher. “But obesity therapy does not differ here from the treatment for type 2 diabetes or high blood pressure. It only works if you are taking it.”

A Silver Lining

Despite numerous obstacles, Blüher has an optimistic view of the future, since ever better imitations of the hormonal changes achieved through surgical treatment of obesity are being made.

In fact, the success story has still not reached its conclusion. Two weeks ago, the dual GLP-1/GIP receptor agonist tirzepatide was approved in the USA for the treatment of type 2 diabetes. And even if approval for obesity therapy is still pending, the study data are promising.

Matthias Tschöp, MD, scientific managing director of the Helmholtz Center in Munich, reported at the Diabetes Congress that a weight loss of up to 23% had been achieved with the dual agonist. More than 60% of the subjects achieved a weight loss target of −20% in the SURMOUNT-1 study.

In terms of side effects, there appears to be “no significant differences between dual and mono-agonists,” added Tschöp. In this way, the first data indicate that tirzepatide may even be better at reducing cardiovascular risk than the previously most potent mono-agonist, semaglutide.

Dual and Triple Agonists

“This is in line with data from our laboratory, where we were able to improve dyslipidemia and atherosclerosis in mice with a GIP receptor agonist,” said Tschöp. “GIP seemed to do something that GLP-1 could not achieve and have a direct protective effect against atherosclerosis.”

If synergy can be achieved with two such substances, naturally the question is what would be possible with three active substances. “For many years, we have tried to manufacture a triple agonist that actually acts on all three receptors, including the glucagon receptor,” said Tschöp, who is credited as one of the pioneers of the dual-incretin co-agonist therapy principle.

This principle has now been put into practice, and the triple agonist has demonstrated “an unprecedented effect” on body weight, food intake, fat mass, glucose, insulin, and cholesterol in preclinical studies. “It was almost twice as good as the dual agonist we compared it against,” according to Tschöp.

Unpublished data from a phase 1b study suggests that these effects can be replicated in humans. “I believe that the future of obesity and type 2 diabetes therapy lies with dual and triple agonists. At some point, mono-agonists will no longer be able to keep up.”

This article was translated from the Medscape German edition.

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