Table 1 Clinical trials for obesity and obesity-related diseases
From: Recent advances in targeting obesity, with a focus on TGF-β signaling and vagus nerve innervation
Mechanism of Action | Product Name | Condition and Phase | Primary Endpoint(s) | Duration (wk) | Ref. |
|---|---|---|---|---|---|
GLP-1receptor agonist | Semaglutide | Obesity, Type 2 Diabetes | Mean weight loss − 14.9% in the semaglutide group as compared with − 2.4% with placebo (P < 0.001) | 68 | (Wilding et al. 2021) |
GIP and GLP-1 receptor agonist | Tirzepatide | Obesity, phase II | Weight loss − 15.0% in 5-mg doses, -19.5% in 10-mg doses, and − 20.9% in 15-mg doses and − 3.1% in placebo (P < 0.001); -20.9%, glucose tolerance, Resolution of MASH, and no worsening of fibrosis | 72 | (Jastreboff et al. 2022) |
GIP and GLP-1 receptor agonist | Tirzepatide | Type 2 Diabetes, phase III | HbA (1c) decrease was − 2.01%, -2.24%, and − 2.30% in 5, 10, and 15 mg of tirzepatide, respectively, and − 1.86% in semaglutide, which is not a significant difference | 40 | (Frias et al. 2021) |
GIP and GLP-1 receptor agonist | Tirzepatide | MASH, and F2-F3 fibrosis, phase II | Resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44%, 56% and 62% in the 5, 10, 15-mg group (P < 0.001). Improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55%, 51% and 51% in the 5, 10, 15-mg group | 52 | (Loomba et al. 2024) |
GLP-1 receptor agonist with Amylin analogue | CagriSema | Obesity, Type 2 Diabetes; phase II | Weight loss − 15.6%, greater than semaglutide (-5.1%) and cagrilintide (-8.1%); HbA (1c) decrease − 2.2%, greater than cagrilintide (-0.9%) | 32 | (Frias et al. 2023) |
GLP-1 receptor agonist | Orforglipron | Obesity; pahse II | Weight loss at 24 week − 8.6% to -12.6% and at 36 week − 9.4% to -14.7% | 36 | (Wharton et al. 2023) |
THR-β agonist | Resmetirom | MASH with F1B, F2, or F3 Liver Fibrosis; phase III | NASH resolution with no worsening of fibrosis was achieved in 25.9% of 80-mg and 29.9% of 100-mg group, as compared with 9.7% of placebo group (P < 0.001). Fibrosis improvement by at least one stage with no worsening of the NAFLD activity score was achieved in 24.2% of the 80-mg group and 25.9% of 100-mg group, as compared with 14.2% of placebo group (P < 0.001) | 52 | (Harrison et al. 2024; Harrison, Taub, Harrison et al. 2023a, b) |
Dual glucagon/GLP-1 receptor agonist | Survodutide | MASH with F1B, F2, or F3 Liver Fibrosis; phase II | Improvement in MASH with no worsening of fibrosis occurred in 47% of 2.4-mg group, 62% of 4.8-mg group, and 43% of 6.0-mg group, as compared with 14% of placebo group (P < 0.001); Decrease liver fat content in 63% of 2.4-mg group, 67% of 4.8-mg group, 57% of 6.0-mg group, and 14% of placebo group; improvement in fibrosis by at least one stage occurred in 34%, 36%, 34%, and 22%, respectively | 48 | (Sanyal et al. 2024) |
GIP, GLP-1, and Glucagon receptor agonist | Retatrutide | Obesity, Type 2 Diabetes, phase II | Weight loss − 8.7% in the 1-mg group, -17.1% in the combined 4-mg group, -22.8% in the combined 8-mg group, and − 24.2% in the 12-mg group, as compared with − 2.1% in the placebo group. In the diabetes trial, with a decrease HbA (1c) -2.02% and weight loss up to -16.94% | 48 (Obesity), 36 (Diabetes) | |
FGF21 analogue | Efruxifermin | MASH and F2-F3 fibrosis, pahse IIb | Improvement in fibrosis of at least 1 stage and no worsening of NASH, at week 24, 15 (36%) of 42 in the 28 mg group (p = 0.033) and 14 (33%) of 43 in the 50 mg group (p = 0.123) versus eight (19%) of 43 patients in the placebo group met this endpoint | 96 | (Harrison et al. 2023) |
pan-PPAR agonist | Lanifibranor | MASH, pahse IIb | A decrease of at least 2 points in the SAF-A score without worsening of fibrosis is higher in the 1200-mg dose than placebo (1200-mg dose vs. placebo, 55% vs. 33%); also a decrease in ALT, AST, etc. | 24 | (Francque et al. 2021) |
GLP-1 receptor agonist | Liraglutide | Obesity, phase III | Weight loss a mean of 8.4 kg in liraglutide group, and 2.8 kg in placebo group | 56 | (Pi-Sunyer et al. 2015) |
Pancreatic Lipase inhibitor | Orlistat | Obesity, phase NA | Weight reduction at year 1 end more than the placebo group (10.2% [10.3 kg] vs. 6.1% [6.1 kg]; at year 2 end patients switched from placebo to orlistat lost an additional 0.9 kg, compared with a mean regain of 2.5 kg in patients who continued on placebo | 104 | (Sjostrom et al. 1998) |
Opioid antagonist and norepinephrine reuptake inhibitor | Bupropion / Naltrexone | Obesity, phase III | Weight loss − 6.1% in the naltrexone 32 mg plus bupropion group and − 5.0% in the naltrexone 16 mg plus bupropion group | 56 | (Greenway et al. 2010) |
Norepinephrine-releasing agent and GABA receptor modulator | Phentermine / Topiramate | Obesity, phase III | Weight reduction − 8.1 kg and − 10.2 kg in the phentermine 7.5 mg plus topiramate 46.0 mg, and phentermine 15.0 mg plus topiramate 92.0 mg, respectively | 56 | (Gadde et al. 2011) |
MC4R agonist | Setmelanotide | Obesity, phase II | Average reduction in BMI of 15%, a mean reduction in hunger score of 45% | 16 | (Roth et al. 2024) |
Amylin analogue | Pramlintide acetate | Type 2 Diabetes, phase NA | A sustained reduction from baseline in HbA1c (− 0.68 and − 0.62% at weeks 26 and 52, respectively); a mean weight loss (− 1.4 kg vs. +0.7 kg with placebo at week 52) | 52 | (Hollander et al. 2003) |
Biguanide | Metformin | Type 2 Diabetes, phase NA | Lowered fasting plasma glucose (19 mg/dL at 500 mg dosage to 78 mg/dL at 2000 mg dosage) and HbA1c (0.9% at 500 mg dosage to 2.0% at 2000 mg dosage) | 14 | (Garber et al. 1997) |
ALK5 inhibitor | Galunisertib | Hepatocellular carcinoma, phase II | Combination of Galunisertib and sorafenib, the median OS Is 18.8 months, TGF-β1 responders (decrease of > 20% from baseline) vs. nonresponders have longer OS (22.8 vs. 12.0 months, P = 0.038) | > 104 | (Kelley et al. 2019) |
Bifunctional fusion protein (TGF-β trap/anti-PD-L1) | Bintrafusp alfa | Hepatocellular carcinoma, phase I | Median OS and PFS are 13.8 and 1.5 months in the dose-escalation cohort and 13.5 and 1.4 months in the dose-expansion cohort | 180 | (Lim et al. 2025) |
TGF-β monoclonal antibody | SAR439459 | Hepatocellular carcinoma and other cancers, phase I | Relatively safe and tolerable, discontinued due to the unclear efficacy and bleeding risk | 52 | (Baranda et al. 2024) |
TGF-β monoclonal antibody | NI5793 | Hepatocellular carcinoma and other cancers, phase I | No dose-limiting toxicities were observed | 208 | (Bauer et al. 2023) |
αvβ1 inhibitor | PLN-1474 | MASH; phase I, recruiting | - | - | (Slack et al. 2022) |
ActRII antibody | Bimagrumab | Obesity, Type 2 Diabetes phase II | Weight loss − 6.5% | 48 | (Heymsfield et al. 2021) |
GDF8/Activin A inhibitor | KER-065 | Obesity, muscular dystrophy; phase I, recruiting | - | - | (Keros, 2024) |
VNS, left cervical vagus | NCP model 101 stimulator | Obesity with depression, phase NA | At one-year average weight loss was 7 kg, at two-year loss of approximately 3.7 kg/year for individuals with an initial BMI of 32 kg/m2 | 104 | |
Anterior gastric wall | Transcend implantable gastric stimulator | Obesity, LOSS trail, phase NA | EWL was: 8.6% at 1 month, 15.8% at 3 months, 17.8% at 6 months, 21.0% at 10 months, and 21.0% at 15 months. | 65 | (De Luca et al. 2004) |
Anterior gastric wall | Transcend implantable gastric stimulator | Obesity, SHAPE trail, phase NA | Control group lost 11.7% of excess weight and the treatment group lost 11.8% (P = 0.717) | 52 | (Shikora et al. 2009) |
VNS, gastroesophageal junction | vBloc (Maestro Rechargeable System) | Obesity, ReCharege trail, phase NA | The mean EWL at 24 months was 21% (8% of body weight loss) | 104 | (Apovian et al. 2017; Ikramuddin et al. 2014; Shikora et al. 2015) |
VNS, gastroesophageal junction | vBloc (Maestro Rechargeable System) | Obesity, EMPOWER trail, phase NA | At 12-month, EWL was 17 ± 2% for the treated and 16 ± 2% for the control group | 52 | (Sarr et al. 2012) |
VNS, gastroesophageal junction | vBloc (Maestro Rechargeable System) | Type 2 Diabetes, Obesity, phase NA | At 12-month, EWL was 25 ± 4% (P < 0.0001), HbA1c declined 1.0 ± 0.2% (P = 0.02) | 52 | (Shikora et al. 2013) |
VNS, greater occipital nerves | Multiprogram Trial Stimulator System | Obesity, a pilot study | Average body mass decrease of 8.7 kg | 8 | (Sobocki et al. 2013) |
Anterior gastric wall | Gastric Electrical Stimulation | Obesity, a pilot study | The mean weight loss in individuals with a mean BMI of 40.8 ± 0.7 kg/m2 was 14.2 ± 4.5% | 52–720 | (Cigaina 2002) |
Gastroesophageal junction | Transcend Implantable Gastric Stimulator | Obesity, a pilot study | Excess BMI lost was 30 ± 24% or 16 ± 12 Kg | 36 | (D’Argent 2002) |
Anterior gastric wall | Gastric Electrical Stimulation | Obesity, phase NA | Excess weight lost 11.8% ± 17.6%, but no difference compared to control group | 52 | (Shikora et al. 2009) |
VNS, transcutaneous auricular | Huatuo Ear vagus nerve stimulator | Type 2 Diabetes, a pilot study | Decreased glucose tolerance from 9.7 mmol/L to 7.5 mmol/L | 12 | (Huang et al. 2014) |
PENS of dermatome T7 | PC Neuromodulation System | Type 2 Diabetes, Obesity, phase NA | Decrease in glycemic levels of 62.1 mg/dL. | 12 | (Ruiz-Tovar et al. 2015) |