Can one weekly injection do the job of two different hormones?
Yes, at least on blood sugar. In this 36-week trial, once-weekly zenagamtide lowered A1c by up to 1.7 percentage points in adults with type 2 diabetes, starting from a group average of 7.8%. At the top dose, that was 1.56 points better than placebo.
A1c is a blood test that reflects your average blood sugar over roughly the past three months. Zenagamtide, previously called amycretin, is one molecule that switches on three receptors at once: GLP-1, amylin, and calcitonin. GLP-1 is the target of drugs like semaglutide. Amylin is a separate hormone released alongside insulin. The idea being tested is whether combining those signals into a single weekly shot works better than hitting one of them alone.
What the data show
Researchers screened 915 people and randomly assigned 262 of them, with 225 getting zenagamtide and 37 getting placebo. Everyone was already taking metformin, some with an SGLT2 inhibitor added. The zenagamtide group was split again into six dose levels: 0.4, 1.5, 5, 10, 20, and 40 mg.
The response tracked the dose. At the lowest dose of 0.4 mg, A1c fell by 0.9 points, which was 0.77 points better than placebo. The true benefit is very likely somewhere between 0.28 and 1.26 points (95% CI -1.26 to -0.28), and there is only about a 2 in 1,000 chance that a difference this size came from luck alone (p=0.0021). At the 40 mg dose, A1c fell by 1.7 points, or 1.56 points better than placebo, very likely between 1.07 and 2.05 points (95% CI -2.05 to -1.07), with less than a 1 in 10,000 chance of being coincidence (p<0.0001).
For context, someone starting at the group average of 7.8% who drops 1.7 points lands near 6.1%. That is a large move for a single drug added on top of metformin.
Dr. Kumar’s Take
The dose-response curve here is what makes this trial worth reading. A drug that produces a bigger effect at every step up in dose, in a blinded trial with a matched placebo at each dose level, is behaving the way a real pharmacologic effect behaves. That is harder to fake than a single impressive number.
The limits are just as clear. This is a phase 2 dose-finding study, which exists to pick a dose for later trials, not to prove a drug is safe or useful over years. Thirty-six weeks is short for a disease people live with for decades. Only 37 people received placebo, which is a thin comparison group. Novo Nordisk funded the trial and several authors work for the company, and that is worth knowing when reading any drug trial.
The bigger open question is what happens to hard outcomes. Lowering A1c is a lab result, not a heart attack prevented or a kidney saved. Plenty of diabetes drugs have moved that number without changing what patients actually care about. Until phase 3 trials report, zenagamtide is a promising signal and nothing more.
Study snapshot
The trial ran at 83 hospital and clinic sites across 11 countries, with enrollment between August 7 and December 27, 2024. Adults aged 18 to 75 qualified if their A1c was between 7.0% and 10.0% and their BMI was 23.0 to under 50.0, and if they were on a stable dose of metformin with or without an SGLT2 inhibitor. Everyone started at 0.2 mg, with the dose stepping up every four weeks until they reached their assigned maintenance dose. Participants and staff were masked to whether they were getting drug or placebo. The main question was how much A1c changed from the start to week 36.
Safety, limits, and caveats
Most side effects were digestive and mild to moderate, which is the familiar pattern with GLP-1 based drugs: nausea, and stomach upset that tends to be worst when the dose goes up. Serious adverse events occurred in 21 of 261 treated participants, or 8%, and they did not cluster at the higher doses. One person on the 40 mg dose had a serious event, compared with four on the 0.4 mg dose and three on placebo. No one died during the trial.
That pattern is reassuring for a phase 2 study, but 261 people over 36 weeks cannot detect a rare harm. Uncommon problems show up in trials of thousands of people, or after a drug is on the market.
Practical takeaways
- Zenagamtide is not available by prescription. This was a phase 2 trial registered as NCT06542874, and the drug still needs large phase 3 studies before regulators will consider it.
- If you are on metformin and your A1c is still above target, the approved GLP-1 based options already on the market are the realistic conversation to have with your doctor now.
- Expect digestive side effects with any drug in this class, and know that slow dose escalation, which this trial used with steps every four weeks, is the standard way to reduce them.
- Judge any new diabetes drug on outcomes that matter to you, not on the A1c number alone, and ask what the long-term trials showed.
Related studies and research
- A weekly shot for type 2 diabetes that also drops 14% of body weight
- Creatine for type 2 diabetes: a placebo-controlled trial
- Single-dose psilocybin vs placebo: first double-blind depression trial
- Single-dose psilocybin shows rapid, sustained antidepressant effects
FAQs
How is zenagamtide different from semaglutide?
Semaglutide acts on the GLP-1 receptor. Zenagamtide is a single molecule that acts on the GLP-1, amylin, and calcitonin receptors together. Amylin is released by the same cells that make insulin and works through a different pathway than GLP-1, so the theory is that one molecule doing both jobs adds up to more than either alone. This trial did not compare zenagamtide against semaglutide or any other active drug, only against placebo, so nothing here tells you which is stronger.
Why do researchers test six different doses in one trial?
This is called a dose-finding study, and it is the standard job of a phase 2 trial. Testing a range from 0.4 mg up to 40 mg lets researchers see where the benefit levels off and where side effects start to outweigh it, which is how they pick the doses to carry into phase 3. It also produces a dose-response curve, and a clean curve is strong evidence that the drug itself is doing the work rather than chance or the placebo effect. The tradeoff is that each dose group is small, only 36 to 38 people here, so each individual comparison is less precise than a big single-dose trial.
Is a drop of 1.7 points in A1c a big change?
It is a substantial change for a drug added on top of metformin. Participants entered this trial with an A1c between 7.0% and 10.0%, averaging 7.8%, and the top dose brought the average down by 1.7 points over 36 weeks. What that means for any one person depends on where they started, since people with higher starting A1c usually have more room to fall. It also says nothing about whether the drop holds beyond nine months, which is the question phase 3 trials are built to answer.
Bottom line
In 262 adults with type 2 diabetes already taking metformin, once-weekly zenagamtide lowered A1c in a clear dose-dependent way over 36 weeks, from 0.9 points at the lowest dose to 1.7 points at 40 mg, with the strongest dose beating placebo by 1.56 points. Side effects were mostly mild to moderate digestive complaints, serious events occurred in 8% without a dose pattern, and no one died. This is an early, company-funded, dose-finding trial in a few hundred people, so the honest read is a promising blood sugar signal that now has to prove itself in larger and longer studies.
