Emerging Role of GLP-1 Agonists in Obesity: A Comprehensive Review of Randomised Controlled Trials
Abstract
:1. Introduction
1.1. Prevalence of Obesity Globally
1.2. Complications of Obesity
1.3. The Emergence of Glucagon-Like Peptide 1 Receptor Agonists and the First Results Obtained upon Administration of Exenatide
2. Design of GLP1-RA
3. Involvement of the Incretin System in Obesity
4. Liraglutide
4.1. Evidence from Clinical Trials in Diabetics and Non-Diabetics
4.2. Liraglutide at A Dose of 3 mg/Day in Non-Diabetics
4.3. Long-Term Follow-Up Studies
4.4. Average Weight Loss
4.5. Indications and Contraindications
4.5.1. Directions
4.5.2. Contraindications and Precautions
5. Semaglutide
5.1. Weight Loss Evidence from Clinical Trials in Diabetics and Non-Diabetics
5.2. Semaglutide High Doses for Non-Diabetic Obese
5.3. Long-Term Follow-Up Studies
5.4. Average Weight Loss
5.5. Indications and Contraindications
5.6. Adverse Effects
6. Tirzepatide
6.1. Studies Completed on Tirzepatide
6.2. Average Weight Loss
6.3. Indications and Contraindications
6.4. Adverse Effects
7. Lixisenatide and Exenatide-STUDIES and Evidence
7.1. Lixisenatide
7.2. Exenatide
8. Conclusions and Future Prospects
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Study | Dosage/Number of Patients/Duration | Main Outcomes, Weight Reduction | Side Effects | Ref. |
---|---|---|---|---|
LEAD-1 | liraglutide 0.6, 1.2, or 1.8 mg/day with sulfonylurea versus placebo N = 1041, 26 weeks | −0.2 kg (baseline 83.0 kg) for 1.8 mg and +0.3 kg (baseline 80.0 kg) for 1.2 mg/day, better glycemic control | Hypoglycemia, nausea, vomiting, diarrhea | [66] |
LEAD-2 | liraglutide 0.6, 1.2, or 1.8 mg/day with metformin as a background treatment N = 1091, 26 weeks | Body weight decreased in all groups (1.8–2.8 kg), comparable glycemic control | Minor hypoglycemia, nausea | [67] |
LEAD-3 | liraglutide 1.2 mg/day [N = 251] or 1.8 mg/day [N = 247], versus glimepiride, 52 weeks | A1c decreased by 0.51% with glimepiride versus 0.84% with liraglutide 1.2 mg and 1.14% with liraglutide 1.8 mg | Vomiting | [68] |
LEAD-4 | liraglutide 1.2 or 1.8 mg/day versus placebo, N = 533, 26 weeks | Dose-dependent weight loss of 1–2 kg with 1.2 and 1.8 mg liraglutide versus weight gain of about 0.6 kg in placebo | Minor hypoglycemia, early gastrointestinal adverse events | [69] |
LEAD-5 | liraglutide 1.8 mg/day [N = 232], placebo [N = 115], and open-label insulin glargine [N = 234], all in combination with metformin (1 g/twice per day) and glimepiride (4 mg/day), 26 weeks | Average reduction of 1.8 kg in the liraglutide group versus 0.42 kg in the placebo group and a 1.6 kg increase in the glargine group. | Nausea (14%) reported in the liraglutide group | [67] |
LEAD-6 | liraglutide 1.8 mg/day [N = 233] or exenatide 10 μg twice/day [N = 231] open-label, parallel-group, multinational study (15 countries), 26 weeks | Average weight loss 3.24 kg (liraglutide group) and 2.87 kg (exenatide group) | Minor hypoglycaemia, less frequent in the liraglutide group compared to the exenatide one | [70] |
Study | Dosage/Number of Patients/Duration | Main Outcomes, Weight Reduction | Side Effects | Ref. |
---|---|---|---|---|
STEP-1 | Semaglutide 2.4 mg/week versus placebo N = 1961, 68 weeks | 14.9% reduction of body weight versus 2.4% in placebo | Nausea and diarrhea | [102] |
STEP-2 | Semaglutide 2.4 mg, or 1.0 mg once/week versus placebo N = 1210, 68 weeks | 9.64%, 6.99%, and 3.42% average body weight reduction with semaglutide 2.4 mg, 1.0 mg, and placebo, respectively. | Mild to moderate gastrointestinal adverse events more frequent with semaglutide 2.4 mg than with placebo | [103,115] |
STEP 3 | Semaglutide 2.4 mg once/week N = 611, 68 weeks | 16.0% average weight reduction versus 5.7% with placebo. The co-primary endpoint of at least a 5% reduction in body weight was met by 86.6% versus 47.6%. | Gastrointestinal adverse events more frequent with semaglutide vs. placebo | [104] |
STEP-4 | Semaglutide 2.4 mg/week for the first 20 weeks, followed by random semaglutide or placebo for the remaining 48 weeks. N = 902, 68 weeks | A total weight loss of 5.0% | Gastrointestinal events in 49.1% of participants in semaglutide group vs. 26.1% in placebo | [43] |
STEP-5 | Semaglutide 2.4 mg versus placebo N = 304, 104 weeks | Decreasing weight until week 60, maintained through week 104; average placebo-corrected weight loss of 12.6 % | Gastrointestinal disorders, nausea, diarrhea, vomiting, and constipation more frequent in semaglutide group | [105] |
STEP-6 | Semaglutide 2.4 or 1.7 mg/week versus placebo in Asian people N = 401, 20 weeks | Body weight reduction 13.2%, 9.6%and 2.1%, respectively, for 2.4 mg, 1.7 mg, and placebo | Mild to moderate gastrointestinal disorders predominantly in semaglutide 2.4 group | [106,108] |
STEP-7 | Semaglutide 2.4 mg or placebo N = 375, 44 weeks | Not yet published | Not yet published | |
STEP-8 | Semaglutide 2.4 mg vs. liraglutide1.8 mg/day. N = 338, 68 weeks | Significantly greater bodyweight reduction; 15.8% with semaglutide, compared to 6.4% with liraglutide | Gastrointestinal adverse events in 84.1% participants in semaglutide group and 82.7% in liraglutide | [107] |
Study | Dosage/Number of Patients/Duration | Main Outcomes, Weight Reduction | Side Effects | Ref. |
---|---|---|---|---|
SURPASS-1 | Tirzepatide 5, 10, and 15 mg/week. N = 705, 40 weeks | Dose-dependent bodyweight loss ranging from 7 to 9.5 kg | Transient gastrointestinal events, nausea, diarrhea, vomiting | [117] |
SURPASS-2 | Tirzepatide weekly doses (5, 10, and 15 mg) versus weekly injections of semaglutide 1.0 mg. N = 1879, 40 weeks | Greater reduction in body weight with tirzepatide than with semaglutide (−1.9 kg, −3.6 kg, and −5.5 kg, respectively) | Gastrointestinal events mild to moderate in both tirzepatide and semaglutide groups (nausea, diarrhea, vomiting) | [103] |
SURPASS-3 | Tirzepatide weekly (5, 10, and 15 mg) with daily insulin degludec in people with poorly controlled blood glucose despite stable treatment with metformin, with or without SGLT2 N = 1444, 52 weeks | Average loss of 7.5, 10.7, and 12.9 kg versus average weight gain of 2.3 kg in the degludec group | Mild to moderate gastrointestinal events | [119] |
SURPASS-4 | Tirzepatide 5 mg, 10 mg, or 15 mg/week or glargine 100 U/mL to reach fasting blood glucose < 100 mg/dLs N = 3045, 48 weeks | 74–88% of people taking tirzepatide achieved HbA1c below 7.0% without weight gain or severe hypoglycemia, versus13% in glargine group | Nausea, diarrhea, decreased appetite, and vomiting more frequent with tirzepatide than with glargine | [120] |
SURPASS-5 | Tirzepatide 5, 10, or 15 mg/week in people taking insulin glargine for T2DM, with or without metformin. N = 475, 40 weeks | Average reduced body weight by 6.2, 8.2, and 10.9 kg, respectively | Gastrointestinal events, decreased appetite in 7–14% participants in tirzepatide group compared to 1.7% in placebo group, potentially contributing to weight loss | [121] |
SURPASS-J-mono | Tirzepatide 5, 10, or 15 mg/week versus dulaglutide 0.75 mg/week in Japanese people with type 2 diabetes taking no other glucose-lowering medications during the study. N = 821, 96 weeks | Dose-dependent reduction of body weight in tirzepatide group (5.8 kg, 8.5 kg, and 10.7 kg, respectively), versus 0.5 kg reduction in dulaglutide group | Gastrointestinal events | [122] |
SURPASS J-combo | Tirzepatide (5, 10, or 15 mg/week) in addition to non-incretin-based antidiabetic medications N = 484, 52 weeks | Dose-dependent reduction in body weight with tirzepatide compared with dulaglutide | Nausea, constipation, and nasopharyngitis | [123] |
SURMOUNT-1 | Tirzepatide 5, 10, or 15 mg/week in obese people without diabetes N = 2539, 72 weeks | 15.0%, 19.5%, and 20.9%, respectively, body weight reduction in tirzepatide group, compared with just 3.1% in placebo | common gastrointestinal adverse events with tirzepatide | [124] |
Study | Dosage/Number of Patients/Duration | Main Outcomes, Weight Reduction | Side Effects | Ref. |
---|---|---|---|---|
Get-Goal Mono | Lixisenatide 20 μg/day in medication-naïve people N = 361, 12 weeks | 2 kg reduction regardless of treatment allocation. | Nausea | [130] |
Get-Goal-M | Lixisenatide 20 μg once daily, as add-on therapy in patients with T2DM insufficiently controlled with metformin alone. N = 680, 24 weeks | Mean body weight decreased to a similar extent in all groups. | Nausea and vomiting more frequently in Lixisenatide group | [131] |
Get-Goal-X | Lixisenatide 20 µg daily versus exenatide 10µg twice daily in T2DM inadequately controlled with metformin N = 1243, 24 weeks | 25.1% of Lixisenatide patients and 31.4% of exenatide patients had ≥5% weight loss from baseline to week 24 | Gastrointestinal symptoms, treatment discontinuation for 6.3% in the Lixisenatide group and 7.6% in exenatide group | [132] |
Get Goal F1 | (1) Lixisenatide one-step dose increase (10 μg once daily for two weeks, then 20 μg once daily; N= 161); (2) Lixisenatide two-step dose increase (10 μg once daily for one week, 15 μg once daily for one week, then 20 μg once daily; N = 161); (3) matching placebo one-step dose increase (N = 82); (4) matching placebo two-step dose increase (N = 80). N = 484, 24 weeks | Weight reduction between 2 kg and –2.7 kg in Lixisenatide group vs. 1.6 kg in placebo | Nausea and vomiting reported most frequently | [133] |
Get Goal -S | Lixisenatide 20µg/day versus placebo inT2DM patients inadequately controlled with sulfonylurea ± metformin N = 1438, 24 weeks | ≥5% weight loss from baseline to week 24 for 14.4% in Lixisenatide patients and 7.2% in placebo patients. Significant reduction in HbA1c at week 24 versus placebo in Lixisenatide group | Nausea in Lixisenatide group, mainly in the first month of treatment | [134] |
Get-Goal-P | Prandial Lixisenatide 20 µg/day versus placebo in T2DM patients insufficiently controlled by pioglitazone ± metformin. N = 484, 24 weeks | Average 0.2 kg reduction in body weight versus 0.2 kg increase in placebo group | Gastrointestinal disorders in Lixisenatide group | [135] |
Get-Goal-L | Adding Lixisenatide (20µg/day) to established basal insulin therapy alone or together with metformin in people with T2DM and elevated glycated hemoglobin (HbA1c). N = 495, 24 weeks | Body weight decreased by 1.8 kg with Lixisenatide and 0.5 kg with placebo between randomization and week 24 | Hypoglycemia and nausea were increased compared with placebo, but no excess of serious adverse events | [136] |
Get-Goal Duo 1 | Lixisenatide (20 µg/day) in patients with HbA1c still elevated after initiation of insulin glargine | Statistically significant bodyweight increase by an average of 0.3 and 1.2 kg in Lixisenatide and placebo groups, respectively | Increase in the frequency of gastrointestinal side effects and modestly increased rates of hypoglycemia | [137] |
Study | Dosage/Patients/Duration | Main Outcomes, Weight Reduction | Side Effects | Ref. |
---|---|---|---|---|
Duration-1 | Exenatide 2 mg/week, against the pre-existing 10 µg/twice per day version N = 295, 30 weeks | No increased risk of hypoglycaemia and similar reductions in body weight | Nausea reported in both treatments, but more often for 10 µg/twice per day formulation | [136] |
Duration-2 | Exenatide (2 mg once/week) versus maximum approved doses sitagliptin, thiazolidinedione, or pioglitazone, in patients treated with metformin | Average 2.3 kg weight loss in exenatide group, 0.8 kg reduction in sitagliptin group, and 2.8 kg weight gain with pioglitazone | Nausea and diarrhea in exenatide and sitagliptin groups | [137] |
Duration-3 | Exenatide (2 mg once/week) versus insulin glargine titrated to glucose targets N = 456, 84 weeks | Average 2.6 kg decrease in bodyweight with exenatide, compared with a 1.4 kg increase with glargine, accompanied by improved glycemic control | No evidence | [145] |
Duration-4 | Exenatide once weekly (EQW) compared with metformin, pioglitazone, and sitagliptin (SITA) N = 820, 26 weeks | 2.0 kg decrease with exenatide versus 0.8 kg reduction with sitagliptin and 1.5 kg increase with pioglitazone | Exenatide once weekly induced nausea and diarrhea | [146] |
Duration-5 | Exenatide (2 mg once/week)) versus exenatide twice daily (5 µg during 4 weeks followed by 10 µg during 20 weeks) in order to improve glycemic control, body weight, and safety. N = 252, 24 weeks | Similar reductions in mean body weight from baseline to wk 24 observed in both groups (−2.3 ± 0.4 kg and −1.4 ± 0.4 kg) | In both groups, the majority of nausea was transient and mild to moderate in intensity, while the incidence decreased over time | [138] |
Duration-6 | Exenatide once weekly (2 mg) versus liraglutide (1.8 mg) once daily in patients with T2DM. N = 911, 26 weeks | Better body weight reductions in liraglutide group (average 2.68–3.57 kg) | Nausea predominantly in exenatide group; diarrhea and vomiting more frequently in the liraglutide group and with decreasing incidence over time in both groups | [144] |
Duration-7 | Exenatide 2 mg once weekly or placebo in patients with T2DM inadequately controlled despite titrated insulin glargine ± metformin. N = 461, 28 weeks | Body weight reduction average of 1.5 kg with exenatide versus placebo. | Gastrointestinal and injection-site adverse events more frequent with exenatide + IG than with placebo + IG | [140] |
Duration Neo-1 | Exenatide 2 mg once/week, self-injectable Miglyol suspension (QWS-AI) versus exenatide 10 µg twice daily (BID), N = 375, 28 weeks | Significant body weight was reduced in both groups | Gastrointestinal adverse events were reported in 22.7% of patients within exenatide QWS-AI group and 35.6% in exenatide BID group | [141,142] |
Duration-Neo-2 | Exenatide 2 mg once-weekly Miglyol suspension for autoinjection (QWS-AI) versus sitagliptin (100 mg once/day oraly) or placebo. N = 364, 28 weeks | Average 1.12 kg and, respectively, 1.19 kg decrease of bodyweight in exenatide and sitagliptin groups versus 0.15 kg increase in the placebo | Gastrointestinal events and injection-site reactions | [142] |
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Popoviciu, M.-S.; Păduraru, L.; Yahya, G.; Metwally, K.; Cavalu, S. Emerging Role of GLP-1 Agonists in Obesity: A Comprehensive Review of Randomised Controlled Trials. Int. J. Mol. Sci. 2023, 24, 10449. https://doi.org/10.3390/ijms241310449
Popoviciu M-S, Păduraru L, Yahya G, Metwally K, Cavalu S. Emerging Role of GLP-1 Agonists in Obesity: A Comprehensive Review of Randomised Controlled Trials. International Journal of Molecular Sciences. 2023; 24(13):10449. https://doi.org/10.3390/ijms241310449
Chicago/Turabian StylePopoviciu, Mihaela-Simona, Lorena Păduraru, Galal Yahya, Kamel Metwally, and Simona Cavalu. 2023. "Emerging Role of GLP-1 Agonists in Obesity: A Comprehensive Review of Randomised Controlled Trials" International Journal of Molecular Sciences 24, no. 13: 10449. https://doi.org/10.3390/ijms241310449