By Dr. Asnat Raziel, bariatric surgeon specializing in obesity treatment, metabolic health and healthy longevity; Director of the Multidisciplinary Center for Obesity Treatment, Assia Medical, Assuta Ramat HaChayal, Tel Aviv
New obesity drugs: a surgeon’s personal view
New obesity drugs are changing what I tell patients in my consulting room. For years, I explained a sentence that is both true and brutal: statistically, diet alone will not work. The reason is not a lack of willpower or laziness. Instead, the body simply fights back. Every kilogram you lose triggers a biological defense system: energy expenditure drops, ghrelin rises and leptin falls.
So for years I offered the only solution I knew worked over the long term: surgery. It worked, and it still works. However, surgery is not a solution for someone carrying fifteen extra kilos. Today I say completely different things. Honestly, there is also something unsettling about it. I am a surgeon watching medications move into indications that used to be mine alone. That is probably what it looks like when a profession meets far better medicine. You can find a detailed comparison in my article on bariatric surgery in the age of medications.
From lizard venom to a weekly injection
The history of weight-loss drugs is largely a history of disappointments. In 1997, the fen-phen combination left pharmacy shelves after damage to heart valves came to light. In 2008, regulators halted rimonabant because of depression and suicidality. Then, in 2010, sibutramine came off the market over cardiac risk. In other words, suppressing appetite through the brain exacted a price again and again.
The breakthrough came from an unexpected place. In the early 1990s, Dr. John Eng in New York studied the saliva of the Gila monster, a venomous desert lizard. He isolated a protein called Exendin-4, which resembles the human hormone GLP-1 but is far more durable. The human hormone breaks down within minutes. By contrast, the lizard protein survives for hours. This gave rise to exenatide and, later, to the entire drug family that transformed the field. The key difference is that these are not appetite suppressants. Rather, they are hormones the body makes anyway, in a version that lasts days instead of minutes.
New obesity drugs in the development pipeline
Semaglutide and tirzepatide changed the rules of the game. Looking back, though, we will probably see them as only the first generation. Today, companies are developing more than twenty molecules: dual and triple agonists, amylin analogues, monthly injections and pills. In some trials, weight loss is already approaching thirty percent. That is why it makes sense to review new obesity drugs by how close they are to market. The overview below is current as of October 2026.
Tier one: closest to market
CagriSema and the amylin connection
CagriSema combines semaglutide with cagrilintide, an amylin analogue. Researchers discovered amylin in 1987, in deposits in the pancreas of people with diabetes. The cells that produce insulin also release it, and it helps regulate fullness. The REDEFINE 1 trial included 3,417 adults without diabetes. After 68 weeks, those who stayed on treatment lost 22.7% of their body weight, compared with 2.3% on placebo. Digestive side effects were common, and 5.9% stopped because of side effects. Novo Nordisk submitted the drug to the FDA in December 2025, and a decision is expected in the last quarter of 2026. On the other hand, in the REDEFINE 4 trial it failed to show non-inferiority to tirzepatide: 23.0% versus 25.5%. The details are in my article on CagriSema versus tirzepatide.
Survodutide: glucagon switches sides
Survodutide represents a fascinating role reversal. Medical school taught us that glucagon is the opponent of insulin. Yet glucagon also raises energy expenditure and mobilizes fat from the liver. When you combine it with GLP-1, the result is a molecule that reduces eating and increases burning. In the SYNCHRONIZE-1 trial, weight loss reached up to 16.6% after 76 weeks, compared with 3.2% on placebo. Results from the fatty liver trials are expected later in 2026. You can read more in my article on survodutide.
Retatrutide: weight loss on a surgical scale
Retatrutide is the molecule that makes me stop and think about the future of my profession. It is a triple agonist of the GIP, GLP-1 and glucagon receptors. The TRIUMPH-1 trial included 2,339 people. After 80 weeks at the 12 mg dose, those who stayed on treatment lost 28.3% of their weight, and 45.3% crossed the thirty percent mark. As the trial continued to 104 weeks, weight loss reached 30.3%. That is exactly the range I expect after a sleeve gastrectomy. In addition, in the TRIUMPH-4 trial in patients with knee osteoarthritis, weight fell by up to 28.7%, and knee pain dropped by up to 75.8%. There is a price, too: 11.3% stopped because of side effects at the high dose. A filing for approval is expected in early 2027. I cover it in more depth in my article on retatrutide treatment.
Tier two: new obesity drugs in phase 3
MariTide mainly promises convenience. Its half-life is about 21 days, so patients inject it once a month. In a phase 2 trial, weight loss reached up to about 20% after 52 weeks, and about 17% in people with diabetes. I see patients drop out not because treatment fails, but because a weekly injection for years is exhausting. Interestingly, tirzepatide activates the GIP receptor, while MariTide actually blocks it. Both approaches reduce weight, and still nobody can explain why.
VK2735 is a dual GLP-1 and GIP agonist, available as both an injection and a pill. In phase 2, it produced up to 14.7% weight loss within 13 weeks. Its phase 3 program enrolled about 4,650 participants, above its target. Meanwhile, China already approved mazdutide in June 2025. It is the first dual glucagon and GLP-1 agonist approved for weight loss. At the 9 mg dose, weight loss reached 20.1% after 60 weeks. Finally, the Chinese drug ribupatide produced 23.6% weight loss after 36 weeks, and a global phase 3 trial began in January 2026.
Tier three: new obesity drugs in pills, amylin and monthly shots
Amycretin, recently renamed zenagamtide, is a single molecule that activates both the GLP-1 receptor and the amylin receptor. In an early injectable study, weight loss reached 24.3% after 36 weeks. The data still come from small studies, but the company moved straight to phase 3.
Orforglipron is no longer a drug of the future. The FDA approved it in April 2026 under the name Foundayo. It is a small molecule rather than a peptide, so manufacturers can produce it cheaply and at scale. Its efficacy is modest compared with the injections: 12.4% after 72 weeks. However, you can take it at any hour, with no food or water restrictions. Since September 2026 it has also been available here in Israel, as I described in my article on Foundayo in Israel.
Petrelintide stands out for its tolerability. The ZUPREME-1 trial included 493 people, and weight loss reached up to 10.7% after 42 weeks. That is a reasonable number, nothing more. But at the most effective dose there was no vomiting, and no one stopped because of digestive side effects. Obesity is a chronic disease, so a drug you can live with for a decade may beat a powerful drug people abandon after a year.
Eloralintide is a pure amylin agonist. In a phase 2 trial with 263 participants, weight loss was 9.5% to 20.1% after 48 weeks, compared with 0.4% on placebo. In other words, the amylin pathway stands on its own. I wrote about this family at length in my article on the next generation of amylin drugs. Lastly, Pfizer shelved its own pill over liver concerns and acquired the company Metsera. Its injection, PF-3944, produced up to 12.3% weight loss beyond placebo after 28 weeks, and the loss continued even after switching to monthly dosing.
Tier four: muscle, four receptors and maybe five
When a patient loses thirty kilos, not everything that comes off is fat. That is why pemvidutide stands out among new obesity drugs. It produced 15.6% weight loss after 48 weeks, and according to the company, 78.1% of the loss was fat. At the same time, Pfizer is developing a monthly amylin analogue, with the goal of combining it with PF-3944.
If a triple molecule reaches thirty percent, it is fair to ask how far we can go. Indeed, researchers presented molecules that activate four and even five receptors at 2026 conferences. All of them are still preclinical or at a very early stage. The more systems you activate, the deeper the weight loss. On the other hand, the range of side effects also grows, while our ability to predict them shrinks.
New obesity drugs and the patient sitting across from me
The market is splitting along two axes. On one axis is maximum efficacy: triple agonists that reach thirty percent. On the other is convenience and access: cheap pills and monthly injections. In addition, a family of amylin analogues is taking hold, and their advantage is tolerability.
But what worries me most is barely mentioned at conferences. All these impressive numbers are meaningless for someone who cannot afford the drug. In Israel, as around the world, the gap between what is medically possible and what is actually available is the central problem. Moreover, the data show that stopping treatment leads to weight regain. So this is long-term treatment, as I explained in my article on stopping medications and weight regain.
The bottom line on new obesity drugs
When I think of the patients who once heard from me that they did not have many options, I cannot help feeling that this is a rare moment. New obesity drugs are expanding our toolbox at a speed we have never seen. Still, comparisons across different trials are limited, and the numbers reflect trial conditions, not necessarily the clinic. Ultimately, our job as doctors is to know these tools in depth and match each person with what is right for them. Not the strongest option, but the one that fits best.
The information in this article is general and does not replace personal medical advice. Most of the drugs described here are not yet approved in Israel, so do not start, stop or change any treatment without a doctor.
References
Survodutide delivers 16.6% weight loss in major phase 3 obesity trial
Lilly’s triple agonist, retatrutide, delivered powerful weight loss in pivotal Phase 3 obesity trial
MariTide Shows Up to 20% Weight Loss in Phase II Trial for Obesity, Type 2 Diabetes
FDA approves Foundayo, an oral GLP-1, for adults with obesity
Some of the data are based on announcements by the developing companies and have not yet been fully published in a peer-reviewed journal.
