From revolutionary GLP-1 receptor agonists to multi-target therapies, the obesity treatment field is evolving rapidly. Unibest's commitment to developing both generic semaglutide tablets and innovative drug delivery systems positions them as a key player in making these breakthrough treatments more accessible.

Obesity is a global health crisis affecting over 650 million people worldwide. But there's hope on the horizon. Recent breakthroughs in understanding how our gut and pancreatic hormones regulate appetite and blood sugar have led to the development of exciting new medicines to treat obesity and related conditions like type 2 diabetes (T2D).

Leading the charge is semaglutide, a once-weekly injectable medication approved in 2021 that mimics intestinal hormones to reduce appetite. In clinical trials, semaglutide helped people achieve an impressive 15-17% weight loss (WL) on average. While this doesn't quite match the results of bariatric surgery, it's a major step forward compared to previous obesity medications.

But semaglutide is just the beginning. Researchers are actively investigating a variety of other gut hormone-based therapies that may provide even greater weight loss and metabolic benefits. Some of the most promising candidates include combination treatments that target multiple pathways involved in hunger and metabolism.

In this article, we'll take a closer look at the latest developments in obesity pharmacotherapy. We'll explore the efficacy and safety data for drugs in the pipeline, with a special focus on treatments that leverage our gut-brain connection. Finally, we'll consider what implications these new medicines may have for the millions of people struggling with obesity and its complications. The era of truly effective medical treatments for obesity is on the horizon - and not a moment too soon.

Secretion and main actions of the gut hormones used in the pipeline obesity treatments. src: Melson, E., Ashraf, U., Papamargaritis, D. et al. What is the pipeline for future medications for obesity?. Int J Obes 49, 433–451 (2025). https://doi.org/10.1038/s41366-024-01473-y

Development of Single Target Therapy - GLP-1 receptor agonists

Oral Semaglutide

Oral semaglutide, containing an absorption enhancer, has been assessed in phase 3 trials for people with and without T2D.

• Oral semaglutide 50 mg resulted in 17.4% WL compared to 1.8% with placebo in people with obesity without T2D (OASIS-1 study).

• In people with T2D, oral semaglutide 50 mg led to 9.8% WL vs. 5.4% WL with 14 mg oral semaglutide and reduced HbA1c by -2.1% at 68 weeks compared to -1.3% with oral semaglutide 14 mg (PIONEER PLUS study).

Breakthrough and Significance

Oral semaglutide offers a non-injectable option for obesity management, potentially increasing patient adherence and acceptance. The higher dose of 50 mg demonstrates significant weight loss and improvements in cardiometabolic risk factors in people with and without T2D, expanding treatment options for obesity.

• Oral semaglutide requires specific administration instructions (taken in the morning with water, 30 min before meals) to ensure adequate absorption.

• Some people may still be reluctant to consider pharmacotherapy for obesity management.

Orforglipron

Orforglipron is a once-daily, oral, non-peptide GLP-1 RA that interacts with the GLP-1 receptor differently compared to native GLP-1. It is currently being assessed for the management of obesity and T2D and may provide a competitive alternative to oral semaglutide with less burdensome administration.

• In people with obesity, 36 weeks of orforglipron (12 to 45 mg) resulted in a dose-dependent weight loss up to -14.7% compared to -2.3% with placebo, along with improvement in cardiometabolic risk factors.

• In people with T2D, 48% of participants achieved ≥10% WL after 26 weeks of orforglipron 45 mg, with a mean HbA1c change of -2.1% vs. -0.4% with placebo and -1.1% with dulaglutide.

Breakthrough and Significance

Orforglipron, as a non-peptide GLP-1 RA, offers a novel approach to obesity and T2D management. Its oral administration and potential for less burdensome dosing compared to oral semaglutide may improve patient adherence and acceptability. The promising efficacy results in phase 2 trials suggest that orforglipron could be a competitive alternative to existing GLP-1 RAs.

Challenges

• Long-term safety and efficacy data for orforglipron are still needed.

• The optimal dosing regimen for orforglipron needs to be established in phase 3 trials.

• Comparative studies with other GLP-1 RAs, particularly oral semaglutide, are required to determine the relative efficacy and safety of orforglipron.

Danuglipron

Danuglipron is an oral, non-peptide, G-protein biased GLP-1 RA. A recent phase 2b study for people with obesity showed that danuglipron doses between 40 and 200 mg twice daily led to up to 11.7% WL compared to 1.4% weight gain with placebo after 32 weeks. In people with T2D and overweight/obesity, 16 weeks of danuglipron led to a placebo-adjusted WL up to -4.2 kg and a mean placebo-adjusted reduction of HbA1c up to -1.2% with the highest dose of 120 mg twice daily.

• In people with obesity, danuglipron doses between 40 and 200 mg twice daily led to up to 11.7% WL compared to 1.4% weight gain with placebo after 32 weeks.

• In people with T2D and overweight/obesity, 16 weeks of danuglipron led to a placebo-adjusted WL up to -4.2 kg and a mean placebo-adjusted reduction of HbA1c up to -1.2% with the highest dose of 120 mg twice daily.

Challenges

• Medication discontinuation rates were greater than 50% across all doses compared to ≈40% with placebo, with the most common adverse events being gastrointestinal in nature.

• The optimal dosing regimen for danuglipron needs to be established to balance efficacy and tolerability.

• Long-term safety and efficacy data for danuglipron are still needed.

Other entero-pancreatic hormones and combination of entero-pancreatic hormones in the management of obesity

Dual GLP1 and GIP Agonists

Tierpatide

Tirzepatide is a once-weekly, subcutaneous, unimolecular dual RA that activates both GLP-1 and GIP receptors. It has comparable GIP receptor binding affinity to native GIP and 5 times lower GLP-1 receptor affinity than native GLP-1. Tirzepatide has been approved for the management of T2D and chronic weight management.

• Mean HbA1c reduction ranged between 1.9% and 2.6% across trials

• 40–69% of participants achieved ≥10% weight loss with higher doses (10 and 15 mg)

• Subanalysis of SURPASS-3: Tirzepatide 10 and 15 mg resulted in a relative reduction in liver fat content by 40–47% compared to 11% with insulin glargine at 52 weeks

• Significant reduction in appetite and food intake compared to placebo

Efficacy in Weight Management (SURMOUNT Program)

• 72 weeks of tirzepatide induced mean weight loss of 16–22.5% in people without diabetes compared to 2.4% with placebo

• No sign of weight plateauing, suggesting potential for further weight loss with long-term use

• Mean weight loss up to 15.7% with tirzepatide 15 mg compared to 3.3% with placebo at 72 weeks for people with obesity and T2D

• Improvements in quality of life, physical function, and cardiometabolic risk factors

• After a 12-week intensive lifestyle intervention lead-in period (mean weight loss of 6.9%), participants randomized to tirzepatide achieved an additional 18.4% weight loss compared to 2.5% weight regain with placebo at 72 weeks

• 36-week open-label lead-in period with tirzepatide resulted in 21.1% mean weight loss

• Participants randomized to continue tirzepatide achieved an additional 5.5% weight loss, while those switched to placebo experienced a mean weight regain of 14% at 52 weeks

• At 88 weeks, 25.9% of the placebo group achieved ≥15% weight loss compared to 84.1% in the tirzepatide group

Adverse Events

The most commonly reported adverse events with tirzepatide were gastrointestinal, including nausea, diarrhea, and vomiting. Most were mild to moderate in severity and improved over time. Only 4-7% of participants in SURMOUNT-1 and -2 discontinued the medication due to adverse events.

GIP Antagonist

GIP antagonism has shown potential as an obesity treatment in preclinical studies, improving metabolic profile and reducing food intake. AMG133, a monoclonal antibody designed to antagonize the GIP receptor and activate the GLP-1 receptor, has demonstrated promising results in a phase 1 trial.

• Preclinical studies have shown that GIP antagonism improves metabolic profile and reduces food intake

• AMG133, a GIP receptor antagonist linked to modified GLP-1 peptides, demonstrated dose-dependent weight loss up to 14.5% compared to 1.5% with placebo by day 85 in a phase 1 trial

• Weight loss was maintained for a few months after the last injection of AMG133

Breakthrough and Significance

AMG133 represents a novel approach to obesity treatment by combining GIP receptor antagonism with GLP-1 receptor activation. The sustained weight loss observed after the last injection suggests a potential for long-term efficacy. This dual-action mechanism may offer a new therapeutic option for individuals with obesity.

Challenges

• The exact mechanisms underlying the similar effects on weight of both GIP agonism and antagonism need to be further elucidated, with a potential explanation being the desensitization of GIP receptors by GIP agonist exposure

• Adverse events, mainly nausea and vomiting, were observed in the phase 1 trial of AMG133, although they were transient

• The long-term safety and efficacy of AMG133 need to be established through ongoing clinical trials, such as the 52-week phase 2 trial in people with overweight and obesity (NCT05669599)

GLP-1 and Glucagon Co-agonists

Glucagon, secreted from pancreatic cells, primarily acts on the liver to regulate glucose production. It helps with weight loss by reducing food intake and increasing energy expenditure. When combined with GLP-1, it can improve weight loss outcomes while managing blood sugar levels. However, glucagon may also reduce amino acid levels and affect lean muscle mass, which requires further research to understand long-term effects.

Early studies in rodents showed promising results for combined GLP-1 and glucagon treatments, leading to the development of various co-agonist medications. Clinical trials have shown mixed results in terms of effectiveness and side effects, possibly due to varying ratios of GLP-1 to glucagon activity in different formulations.

Survodutide

Efficacy Highlights

• In a phase 2 trial, 46 weeks of survodutide once weekly (0.6 to 4.8 mg) resulted in a dose-dependent mean weight loss up to 18.7% compared to 2% with placebo in people with obesity

• For people with T2D, survodutide 1.8 mg twice weekly led to 9% weight loss compared to 5.4% with semaglutide 1 mg and 1.2% with placebo at 16 weeks (phase 2 trial)

• Higher doses of survodutide demonstrated superior HbA1c reduction compared to semaglutide 1 mg (1.9% vs. 1.5%, respectively)

Breakthrough and Significance

Survodutide's dual action as a GLP-1/glucagon co-agonist offers a novel approach to treating obesity and T2D. The drug's ability to induce significant weight loss and improve glycemic control highlights its potential as a game-changer in the management of these chronic conditions.

Challenges

• In the phase 2 trial for obesity treatment, 20-29% of participants discontinued the medication due to adverse events (AE), primarily gastrointestinal AE during the rapid escalation phase. This issue may be mitigated with more gradual dose escalation in phase 3 trials

• Despite similar serious adverse events (SAE) to semaglutide 1 mg, survodutide had higher rates of AE leading to drug discontinuation (10-30% compared to 4% with semaglutide 1 mg)

• Long-term safety and efficacy data are needed to fully assess the risk-benefit profile of survodutide in the treatment of obesity and T2D

Mazdutide

Mazdutide (IBI362 or LY3305677) is a once-weekly oxyntomodulin analogue that acts on both GLP-1 and glucagon receptors. It has shown promising results in phase 2 trials for the treatment of obesity and T2D in Chinese populations. Phase 3 studies using mazdutide as an obesity treatment in Chinese populations are ongoing, and early phase trials for MASH are in progress.

• In a phase 2 trial, mazdutide at doses of 3, 4.5, and 6 mg led to up to 11.3% weight loss after 24 weeks of treatment, compared to a 1% weight gain with placebo in a Chinese population with overweight/obesity

• A press release for another phase 2 trial using a higher dose of mazdutide (9 mg) for obesity revealed a placebo-adjusted weight loss of 15.4% after 24 weeks

• For people with T2D, a phase 2 trial with mazdutide (doses 3, 4.5, and 6 mg) demonstrated a reduction in HbA1c (up to −1.7%) and up to 7.1% weight loss at 20 weeks

Mazdutide's dual action on GLP-1 and glucagon receptors offers a novel approach to treating obesity and T2D. The drug's ability to induce significant weight loss and improve glycemic control in Chinese populations highlights its potential as a promising treatment option for these chronic conditions.

Pemvidutide

Pemvidutide (ALT-801) is a unimolecular once-weekly GLP-1/glucagon agonist currently undergoing phase 2 trials as an obesity treatment. It has shown promising results in terms of weight loss in phase 1 and phase 2 trials, as well as potential benefits for people with T2D and metabolic-associated fatty liver disease (MASLD).

• In a phase 1 trial, pemvidutide demonstrated up to 10.3% weight loss at 12 weeks

• A press release of the phase 2 obesity trial (MOMENTUM-1) reported a mean weight loss up to 15.6% (placebo-adjusted 13.4%) at 48 weeks with the 2.4 mg dose

• In people with T2D, a phase 1b study showed a placebo-adjusted weight loss of 8.5% after 12 weeks, although no improvement in HbA1c was observed

• In a phase 2 trial in people with MASLD, 24 weeks of pemvidutide resulted in a relative reduction in liver fat content up to 76% with the 2.4 mg dose vs. 14% with placebo

Breakthrough and Significance

Pemvidutide's dual action on GLP-1 and glucagon receptors offers a novel approach to treating obesity, T2D, and MASLD. The drug's ability to induce significant weight loss and reduce liver fat content highlights its potential as a promising treatment option for these chronic conditions.

Efinopegdutide

Efinopegdutide (JNJ-64565111; HM12525A) is a unimolecular once-weekly GLP-1 and glucagon agonist that has been investigated in people with obesity, T2D, and MASLD or MASH. It has shown promising results in terms of weight loss and reduction in liver fat content.

• In a phase 2 clinical trial for obesity, 26 weeks of efinopegdutide (doses 5 to 10mg) resulted in up to 11.8% weight loss in people with obesity (without diabetes) compared to 7.5% weight loss with liraglutide 3 mg and 1.8% weight loss with placebo

• For people with T2D, a phase 2 trial showed that 12 weeks of efinopegdutide achieved up to 7.9% weight loss (compared to 0.7% weight loss with placebo) without actual improvement in HbA1c

• In people with T2D and MASLD, 24 weeks of efinopegdutide 10 mg reduced liver fat content by 72.7% compared to 42.3% reduction with semaglutide 1 mg, despite similar weight loss achieved with both interventions

Breakthrough and Significance

Efinopegdutide's dual action on GLP-1 and glucagon receptors offers a novel approach to treating obesity, T2D, and MASLD/MASH. The drug's ability to induce significant weight loss and substantially reduce liver fat content highlights its potential as a promising treatment option for these chronic conditions, particularly for MASH.

Triple Agonism with GLP1, GIP and Glucagon

Retatrutide

Efficacy Highlights 

Obesity (without T2D)

• In a phase 2 study, retatrutide (doses 1 to 12 mg) led to a dose-dependent weight loss of up to 24.2% at 48 weeks, compared to 2.1% with placebo

• 36–48% of participants achieved ≥25% weight loss with the 8 mg and 12 mg doses, compared to no one in the placebo group

• Greater weight loss was observed in participants with BMI ≥35 kg/m2 and among females

• Marked improvements in lipid profile and blood pressure were also observed compared to placebo

Type 2 Diabetes

• In a phase 2 trial, retatrutide (0.5 to 12 mg) led to substantial reductions in bodyweight and HbA1c compared to both placebo and dulaglutide 1.5 mg

• After 36 weeks, retatrutide resulted in HbA1c reduction up to –2.2% vs. −1.4% with dulaglutide and −0.3% with placebo

• Bodyweight reduction was up to 16.9% with retatrutide vs. 2% with dulaglutide and 3% with placebo

• In a subgroup of 98 people with MASLD, fat content normalized in approximately 90% of those receiving the highest retatrutide doses

Amylin Agonists

Dual Agonism with GLP-1 and Amylin

Peptide YY Agonist

PYY, a hormone co-secreted with GLP-1 after eating, works through Y2R receptors in the brain to reduce food intake and increase satiety. While intravenous PYY agonists have shown promising results in reducing food intake, nasal delivery proved less effective. Currently, long-acting subcutaneous PYY receptor agonists are being tested both alone and in combination with GLP-1 receptor agonists.

Early trials of a PYY analogue (Y14 peptide) showed promising results, with participants losing 2.9-3.6 kg over 31 days and reducing food intake by 38-55% compared to placebo. A phase 2 trial combining PYY agonist NNC0165-1875 with semaglutide has been completed, though results are pending.

Unibest Commitment

Unibest offers a comprehensive development portfolio for T2D and obesity. Through the supply of intermediates of Semaglutide, Tirzepatide, Orforglipron, and more, to late-stage technology transfer of semaglutide generic tablets, innovative drug delivery systems for semaglutide, and early-phase assets in obesity and T2D pipelines, Unibest bridges Chinese innovation with the world. Visit our licensing list to learn more.

Reference

Melson, E., Ashraf, U., Papamargaritis, D. et al. What is the pipeline for future medications for obesity?. Int J Obes 49, 433–451 (2025). https://doi.org/10.1038/s41366-024-01473-y