Promising New Drug, Maridebart Cafraglutide, Demonstrates Significant Weight Loss in obesity and Diabetes Trials
A once-monthly injection of maridebart cafraglutide resulted in considerable weight reduction in adults with obesity, nonetheless of whether they also had type 2 diabetes, according to findings from a phase 2 clinical trial.
Final data presented at the American diabetes Association Scientific Sessions and together published in The new England Journal of Medicine reveal the potential of this novel dual GLP-1/GIP receptor agonist, known as MariTide (Amgen), to address both weight management and metabolic health. Previous data from the phase 2 trial had already indicated positive effects on weight, blood pressure, cholesterol, and inflammation.
MariTide functions as a bispecific agent, simultaneously activating the GLP-1 receptor and antagonizing the GIP receptor. Researchers noted its unique mechanism of action, coupled with a prolonged half-life, supports the possibility of monthly or even less frequent management.
“To have something that is once-monthly or less frequent that both addresses their dysglycemia as well as address the root cause of their diabetes, which is obesity, is unique,” stated a leading endocrinologist during a press conference.
The double-blind,randomized controlled trial enrolled 592 adults with obesity or overweight and at least one obesity-related complication. Participants were divided into two cohorts: those with obesity alone and those with obesity and type 2 diabetes. Various dosing regimens of maridebart cafraglutide were tested, ranging from 140 mg to 420 mg every 4 or 8 weeks, with and without dose escalation, compared to a placebo. The primary endpoint was the change in body weight from baseline to one year.
Results: Obesity Without Diabetes
The cohort of 465 adults with obesity but without diabetes (mean age 47.9 years, 63% women, mean BMI 37.9 kg/m) experienced significant weight loss with MariTide. At one year, the mean percent change in body weight ranged from a 12.3% reduction to a 16.2% reduction in the MariTide groups, compared to a 2.5% reduction in the placebo group, based on the treatment policy estimand.
The efficacy estimand, which assumes full adherence to the treatment, showed even more pronounced results, with weight loss ranging from 16.3% to 19.9% compared to 2.6% with placebo. A researcher highlighted that the difference between these estimands was larger than observed in other obesity trials, possibly due to the study’s discontinuation rate.Approximately 16.8% of participants with obesity and without diabetes discontinued MariTide treatment due to adverse events.
Moreover, participants in the MariTide groups experienced reductions in fat mass ranging from 26.2% to 36.8% compared to 9.1% in the placebo group. Lean mass decreased by 8.6% to 11.6% versus 2.1% in the placebo group. Importantly, the lead researcher indicated that weight loss had not yet plateaued after one year.
“We don’t know the full efficacy of this agent until we look farther out,” she cautioned.
Results: Obesity with Type 2 Diabetes
The trial also included 127 adults with both obesity and type 2 diabetes (mean age 55.1 years, 42% women, mean BMI 36.5 kg/m). MariTide demonstrated significant weight loss in this group as well. The mean percent change in body weight, according to the treatment policy estimand, ranged from an 8.4% reduction to a 12.3% reduction, compared to a 1.7% reduction in the placebo group. The efficacy estimand showed even greater weight loss, ranging from 12.1% to 17% compared to 1.4% with placebo.
A researcher noted the notable magnitude of weight loss in the type 2 diabetes group, notably with the 420 mg dose of MariTide. “Individuals with type 2 diabetes usually lose less weight than those with obesity [alone],” she explained. “This was a very good result to see.”
Along with weight loss, MariTide led to a decrease in HbA1c levels, ranging from a 1.9 to 2.2 percentage point reduction in the efficacy estimand, compared to a 0.1 percentage point increase in the placebo group. Fat mass decreased between 17.4% and 33.7% with MariTide, while lean mass was reduced by 6.8% to 9.6%. The placebo group experienced a 4.3% decrease in fat mass and a 2.3% decline in lean mass.
Safety and Tolerability
At least 90% of participants receiving MariTide in both cohorts reported at least one adverse event, compared to 68% in the placebo group with obesity alone and 81% in the placebo group with obesity and type 2 diabetes.Gastrointestinal adverse events were the most common side effect associated with MariTide. These events were generally mild to moderate and more frequent in participants who did not receive dose escalation. Gastrointestinal issues were the primary reason for treatment discontinuation.
“The efficacy and safety of phase 2 support the examination of MariTide in phase 3,” a researcher concluded.
Optimizing Gastrointestinal Tolerability
researchers also presented findings from a phase 1 study evaluating lower starting doses of maritide to improve tolerability. This study involved 121 adults randomly assigned to starting doses of 21 mg, 35 mg, or 70 mg, with subsequent increases to 70 mg and then 350 mg. The study found that lower starting doses (21 mg) were associated with a lower prevalence of gastrointestinal adverse events during the initial 15 days. However,after dose increases,GI events became more similar across all groups.
A researcher explained that the initial increase in plasma concentrations with higher doses likely contributed to the increased incidence of GI events. Based on these findings, the researchers are planning a dose escalation strategy for a future phase 3 trial, starting at 21 mg, increasing to 35 mg at two weeks, and then to 70 mg at four weeks, followed by randomization to target doses at eight weeks.
“We think this is a great opportunity here and we’re really excited about that long half-life and the potential for monthly or even less frequent dosing,” she said.
Source: Seeley RJ, et al. once-monthly MariTide for the treatment of obesity in people with or without type 2 diabetes – A 52-week phase 2 study. Presented at: American Diabetes Association Scientific Sessions; June 20-23, 2025; Chicago.
Disclosures: Jastreboff reports receiving grant funding from Amgen, Boehringer Ingelheim, Eli Lilly, Novo Nordisk and Rhythm Pharmaceuticals; consulting for Amgen, AstraZeneca, Biohav
Following up on the promising results, potential long-term use and side effects of MariTide are vital considerations.While the weight loss and HbA1c reductions seen in the phase 2 trial are impressive, itS crucial to understand the potential downsides of this medication.
Long-Term Concerns and Unacceptable Side Effects
The most meaningful concerns about long-term MariTide use, as with any new medication, revolve around safety and durability of the effects.The 52-week data provides valuable insight, but longer-term studies are needed to assess the sustained efficacy, potential long-term side effects, and any unforeseen consequences of chronic use. here’s what to consider:
- Durability of Weight Loss: will the weight loss be maintained over several years? This is a key question. Weight regain is a common challenge with weight-loss medications, and it is currently unknown whether MariTide helps to prevent this.
- Cardiovascular Effects: although the initial data are promising, longer studies need to fully evaluate the cardiovascular impact. Some weight-loss drugs have shown cardiovascular benefits, but careful monitoring is crucial.
- Pancreatic Health: Because of the drug’s impact on GLP-1 receptors, there could be an increased risk of pancreatitis. Monitoring pancreatic enzyme levels might be required.
- Gastrointestinal Issues: As reported, GI issues are the most common side effects. The shift to lower starting doses aims to reduce these issues. However, consistent monitoring will be crucial.
- Lean Mass Loss: While MariTide led to substantial fat loss, a decrease in lean mass (muscle) was also observed. This is a common side effect of weight-loss medications. The long-term implications of lean mass loss should be watched.
What side effects would be unacceptable? severe,persistent gastrointestinal issues,such as unrelenting nausea,vomiting,or diarrhea,would be unacceptable for many patients. Any indication of serious complications, such as pancreatitis or clinically significant cardiovascular events, would also be of major concern.
Patient-Specific Considerations
Individual patient factors will play a vital role in determining the acceptability of side effects and the overall suitability of MariTide. For example, patients who are already burdened with gastrointestinal problems may find the side effects intolerable.
clinicians will need to discuss the potential benefits and risks with each patient. The decision to use MariTide will depend on factors such as the patient’s current health status, other medications they are taking, their history of adverse reactions, and their tolerance for side effects. Before widespread use, safety data will be vital, with continued rigorous monitoring in place, as well as full, thorough conversations with all patients.
The Road Ahead
Phase 3 trials are essential in assessing the long-term safety and efficacy of MariTide. They will involve larger and more diverse patient populations and will provide more data on side effects and long-term health outcomes. The growth of a dose escalation strategy is a positive step towards improving tolerability. Patient adherence also could be enhanced.
Ongoing research will also explore the ideal patient population for MariTide.For patients with obesity and Type 2 diabetes, balancing the benefits of weight loss and blood sugar control with potential risks is vital. For those with obesity that does not include diabetes, the risk-benefit ratio may look very diffrent and therefore could change patient-specific suitability.
ongoing, post-market surveillance will be crucial to identify any rare or delayed adverse effects that may not be apparent in clinical trials. Patients taking MariTide should be closely monitored, and any concerns about side effects should promptly be discussed with their healthcare provider. Is MariTide right for you? The long-term safety profile should and will be persistent through further study.
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