Jarrell Weight Management Specialists

In my last blog, we discussed how many of the newer weight loss medications work, including GLP-1 and GIP. Today, we’re talking about one of the most potent weight loss medications ever studied: retatrutide. Like Zepbound, retatrutide is a GLP-1 and GIP agonist (remember, an agonist stimulates the receptor). But it adds a third piece: glucagon agonism.

How does glucagon help with weight loss?

This one is a little counterintuitive. Glucagon is made in the pancreas, and its main job is to raise blood sugar when it gets low by telling the liver to release stored sugar. So how would a hormone that raises blood sugar help with weight loss?

Think about when your body normally makes glucagon: overnight, or when you haven’t eaten in a while. Glucagon is the signal that says, “No food is coming in, so start using what’s in storage.” When glucagon is given as an injection, that signal stays turned on all the time, even while you’re resting. In theory, that means your body may burn more calories.

I want to be clear that this part is still unproven. No study has shown yet that retatrutide increases metabolism in people. We do have one small study in humans where an IV glucagon infusion raised calorie burn by about 15% (Salem et al., 2016). Glucagon may also help you feel full, which is similar to how GLP-1 works, so the effects may add together.

What about blood sugar? On its own, glucagon would raise it. That’s why it’s paired with GLP-1 and GIP, which boost insulin and keep blood sugar in check. In the trial, blood sugar actually improved.

The TRIUMPH-1 trial

In September, the New England Journal of Medicine published the results of TRIUMPH-1, the first large trial of retatrutide in people with obesity. The results were huge.

The trial included 2,339 adults with obesity, or overweight with a weight-related health problem. None of them had diabetes. Participants were assigned to one of three doses (4 mg, 9 mg or 12 mg) or a placebo, given as a weekly injection. Everyone started at 2 mg, and the dose was increased every 4 weeks until they reached their assigned dose. The main part of the trial lasted 80 weeks.

Here is the average weight loss with each dose:

People with a BMI of 35 or higher could continue in an extension to 104 weeks (532 people). Those on the 12 mg dose averaged 30.3% weight loss, about 85 pounds, at two years.

Benefits beyond the scale

The trial also looked at other health markers. On the highest dose at 80 weeks:

• Triglycerides fell 38%.
• Non-HDL (“bad”) cholesterol fell 21%.
• Systolic blood pressure dropped 10.4 mmHg.
• High-sensitivity CRP, a marker of inflammation, fell 63%.
• Knee arthritis pain dropped by up to 62%.
• Among people who started with prediabetes, more than 9 out of 10 had normal blood sugar by the end of the trial.

Side effects

Below is a table of the most important side effects. The most common were stomach-related (nausea, diarrhea, constipation and vomiting), similar to other medications in this class. Only 2 to 5% of patients stopped retatrutide because of these gastrointestinal side effects.

A few things stand out:

• Dysesthesia. This is the newest side effect to watch for. Dysesthesia is an abnormal skin sensation, like tingling or burning. It happened in about 1 in 8 people on the higher doses, compared with 1 in 100 on placebo. It was usually mild, most cases went away, and most people stayed on the medication.
• The 4 mg dose. To me, this is one of the most exciting findings. People on 4 mg lost about 18–19% of their body weight, yet the number who stopped because of side effects was no higher than placebo.
• Heart rate. Heart rate went up slightly, which the supplementary appendix to the study reports. The average starting heart rate was about 73 beats per minute. On the highest dose, it peaked around 81 beats per minute at about week 20, which is still well within the normal range. The rise happened while the dose was being increased. After that, heart rate drifted back down for the rest of the trial. By the end, the average heart rate was only about 2 to 3 beats per minute higher than at the start, similar to what we see with Zepbound and Wegovy.
• Losing too much weight. About 1 in 10 people on the 12 mg dose had their dose lowered because they were losing more weight than they needed to. This tells me many patients may not need the highest dose to reach their goals.

When will it be available?

The weight loss in TRIUMPH-1 is the most ever seen in a weight loss medication trial, and for many patients it’s comparable to bariatric surgery. Lilly plans to submit retatrutide to the FDA in early 2027. If it’s approved, we could have another tool for treating the disease of obesity by late 2027 or 2028.

Up next: cagrilintide

Next, I’ll be covering cagrilintide, an amylin agonist from Novo Nordisk that works through a completely different hormone than GLP-1. It’s being studied both on its own and combined with semaglutide (the active ingredient in Wegovy), a combination called CagriSema. As a refresher, here is the full table of medications currently in trials that I’ll be working through:

Seth Jarrell, MD

Sources

Jastreboff AM, Kaplan LM, Davies MJ, et al; TRIUMPH-1 Investigators. Retatrutide, a triple hormone receptor agonist, for treatment of obesity. N Engl J Med. Published online September 29, 2026. doi:10.1056/NEJMoa2604169. Supplementary Appendix available at NEJM.org.

Salem V, Izzi-Engbeaya C, Coello C, et al. Glucagon increases energy expenditure independently of brown adipose tissue activation in humans. Diabetes Obes Metab. 2016;18(1):72-81. doi:10.1111/dom.12585