Efficacy and Safety of Orforglipron in Obese Adults With or Without Diabetes: A Systematic Review and Meta-Analysis.

Pandey RK, Jan M, Mohammad A, Jawaid KA, Naveed M, Abid MA, Amir AB, Ahmed S, Safiullah M, Bhatti MI, Iftikhar S, Saddique MN, Alfalh W, Omar RMB, Abu Dawood H

Endocrinology, diabetes & metabolism1 Nov 2025Cited by 7 (Europe PMC)

PMID41296780PMCIDPMC12653021DOI10.1002/edm2.70134PepBankPUB-41296780

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Summary

BackgroundObesity represents a major global health challenge, contributing substantially to cardiovascular disease and metabolic complications. Orforglipron, a novel oral non-peptide GLP-1 receptor agonist, has emerged as a promising therapeutic option for weight management and glycemic control. This meta-analysis evaluated the efficacy and safety of orforglipron in obese patients with or without type 2 diabetes mellitus (T2DM).MethodsA comprehensive literature search was conducted across PubMed, Embase, Cochrane Library and ClinicalTrials.gov from inception to October 2025 to identify randomised controlled trials (RCTs) evaluating orforglipron in obese patients. Mean differences (MDs) and risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using random-effects models.ResultsFive RCTs comprising 4410 participants were included. Orforglipron demonstrated dose-dependent reductions in body weight from 2.48% at 3 mg to 9.8% at 45 mg, BMI from 0.89 to 3.62 kg/m², waist circumference from 1.57 to 6.9 cm, and HbA1c from 0.76% to 1.04% compared with placebo. Favourable lipid changes included reductions in total cholesterol (MD: -4.51% [95% CI: -6.91 to -2.11]), LDL-C (MD: -5.34% [95% CI: -7.10 to -3.58]), and triglycerides (MD: -10.07% [95% CI: -12.33 to -7.80]), with increased HDL-C (MD: 2.94% [95% CI: 1.38 to 4.49]). However, gastrointestinal adverse events were significantly more frequent at doses of 12 mg or higher and treatment discontinuation rates were highest at 24 mg (RR:4.61 [95% CI:1.6 to 13.33]) and 36 mg (RR:3.68 [95% CI:2.48 to 5.44]) doses. Serious adverse events and mortality rates were comparable to those with placebo.ConclusionOrforglipron significantly improved glycemic and lipid parameters in patients with obesity, demonstrating dose-dependent efficacy with maximal benefits at higher doses. While gastrointestinal tolerability remains a clinically important limitation requiring mitigation strategies, orforglipron represents a promising oral therapeutic option for comprehensive obesity and metabolic management.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study14

14 results from studies that gave the peptide. 14 results from people.

01HumanSystematic reviewEfficacy outcome
In obese patients with or without diabetes, orforglipron 3 mg reduced weight by 2.48% compared with placebo.
In plain wordsOrforglipron 3 mg reduced weight by 2.48% compared with placebo in obese patients with or without diabetes.
Peptide
Orforglipron
Outcome
DecreaseBody weight
Study
n: not reported in source
Comparator
Placebo
Outcome group
Body weight · Metabolic and weight
Studied dose
3 mg · oralAs given in this study (human).
Measurements
Body weight reduction versus placebo
2.48%
orforglipron 3 mg
Source sentences
Summary
Orforglipron demonstrated dose-dependent reductions in body weight from 2.48% at 3 mg to 9.8% at 45 mg, BMI from 0.89 to 3.62 kg/m², waist circumference from 1.57 to 6.9 cm, and HbA1c from 0.76% to 1.04% compared with placebo.
2 context sentences(design, population, supporting numbers)
Summary · context
This meta-analysis evaluated the efficacy and safety of orforglipron in obese patients with or without type 2 diabetes mellitus (T2DM).
Summary · context
A comprehensive literature search was conducted across PubMed, Embase, Cochrane Library and ClinicalTrials.gov from inception to October 2025 to identify randomised controlled trials (RCTs) evaluating orforglipron in obese patients.
Show in the study text Report a problemFND-4129678001
02HumanSystematic reviewEfficacy outcome
In obese patients with or without diabetes, orforglipron 45 mg reduced weight by 9.8% compared with placebo.
In plain wordsOrforglipron 45 mg reduced weight by 9.8% compared with placebo in obese patients with or without diabetes.
Peptide
Orforglipron
Outcome
DecreaseBody weight
Study
n: not reported in source
Comparator
Placebo
Outcome group
Body weight · Metabolic and weight
Studied dose
45 mg · oralAs given in this study (human).
Measurements
Body weight reduction versus placebo
9.8%
orforglipron 45 mg
Source sentences
Summary
Orforglipron demonstrated dose-dependent reductions in body weight from 2.48% at 3 mg to 9.8% at 45 mg, BMI from 0.89 to 3.62 kg/m², waist circumference from 1.57 to 6.9 cm, and HbA1c from 0.76% to 1.04% compared with placebo.
2 context sentences(design, population, supporting numbers)
Summary · context
This meta-analysis evaluated the efficacy and safety of orforglipron in obese patients with or without type 2 diabetes mellitus (T2DM).
Summary · context
A comprehensive literature search was conducted across PubMed, Embase, Cochrane Library and ClinicalTrials.gov from inception to October 2025 to identify randomised controlled trials (RCTs) evaluating orforglipron in obese patients.
Show in the study text Report a problemFND-4129678002
03HumanSystematic reviewEfficacy outcome
In obese patients with or without diabetes, orforglipron reduced BMI by 0.89 to 3.62 kg/m² compared with placebo.
In plain wordsOrforglipron reduced BMI by 0.89 to 3.62 kg/m² compared with placebo in obese patients with or without diabetes.
Peptide
Orforglipron
Outcome
DecreaseBMI
Study
n: not reported in source
Comparator
Placebo
Outcome group
Body weight · Metabolic and weight
Studied dose
Dose not stated · oralAs given in this study (human).
Measurements
BMI reduction versus placebo
0.89 to 3.62 kg/m<sup>2</sup>
orforglipron, dose-dependent
Source sentences
Summary
Orforglipron demonstrated dose-dependent reductions in body weight from 2.48% at 3 mg to 9.8% at 45 mg, BMI from 0.89 to 3.62 kg/m², waist circumference from 1.57 to 6.9 cm, and HbA1c from 0.76% to 1.04% compared with placebo.
2 context sentences(design, population, supporting numbers)
Summary · context
This meta-analysis evaluated the efficacy and safety of orforglipron in obese patients with or without type 2 diabetes mellitus (T2DM).
Summary · context
A comprehensive literature search was conducted across PubMed, Embase, Cochrane Library and ClinicalTrials.gov from inception to October 2025 to identify randomised controlled trials (RCTs) evaluating orforglipron in obese patients.
Show in the study text Report a problemFND-4129678003
04HumanSystematic reviewEfficacy outcome
In obese patients with or without diabetes, orforglipron reduced waist circumference by 1.57 to 6.9 cm compared with placebo.
In plain wordsOrforglipron reduced waist circumference by 1.57 to 6.9 cm compared with placebo in obese patients with or without diabetes.
Peptide
Orforglipron
Outcome
DecreaseWaist circumference
Study
n: not reported in source
Comparator
Placebo
Outcome group
Body weight · Metabolic and weight
Studied dose
Dose not stated · oralAs given in this study (human).
Measurements
Waist circumference reduction versus placebo
1.57 to 6.9 cm
orforglipron, dose-dependent
Source sentences
Summary
Orforglipron demonstrated dose-dependent reductions in body weight from 2.48% at 3 mg to 9.8% at 45 mg, BMI from 0.89 to 3.62 kg/m², waist circumference from 1.57 to 6.9 cm, and HbA1c from 0.76% to 1.04% compared with placebo.
2 context sentences(design, population, supporting numbers)
Summary · context
This meta-analysis evaluated the efficacy and safety of orforglipron in obese patients with or without type 2 diabetes mellitus (T2DM).
Summary · context
A comprehensive literature search was conducted across PubMed, Embase, Cochrane Library and ClinicalTrials.gov from inception to October 2025 to identify randomised controlled trials (RCTs) evaluating orforglipron in obese patients.
Show in the study text Report a problemFND-4129678004
05HumanSystematic reviewEfficacy outcome
In obese patients with or without diabetes, orforglipron reduced HbA1c by 0.76% to 1.04% compared with placebo.
In plain wordsOrforglipron reduced HbA1c by 0.76% to 1.04% compared with placebo in obese patients with or without diabetes.
Peptide
Orforglipron
Outcome
DecreaseHbA1c
Study
n: not reported in source
Comparator
Placebo
Outcome group
Glycemic control · Metabolic and weight
Studied dose
Dose not stated · oralAs given in this study (human).
Measurements
HbA1c reduction versus placebo
0.76 to 1.04%
orforglipron, dose-dependent
Source sentences
Summary
Orforglipron demonstrated dose-dependent reductions in body weight from 2.48% at 3 mg to 9.8% at 45 mg, BMI from 0.89 to 3.62 kg/m², waist circumference from 1.57 to 6.9 cm, and HbA1c from 0.76% to 1.04% compared with placebo.
2 context sentences(design, population, supporting numbers)
Summary · context
This meta-analysis evaluated the efficacy and safety of orforglipron in obese patients with or without type 2 diabetes mellitus (T2DM).
Summary · context
A comprehensive literature search was conducted across PubMed, Embase, Cochrane Library and ClinicalTrials.gov from inception to October 2025 to identify randomised controlled trials (RCTs) evaluating orforglipron in obese patients.
Show in the study text Report a problemFND-4129678005
06HumanSystematic reviewEfficacy outcome
In obese patients with or without diabetes, orforglipron reduced total cholesterol compared with placebo.
In plain wordsOrforglipron reduced total cholesterol compared with placebo in obese patients with or without diabetes.
Peptide
Orforglipron
Outcome
DecreaseTotal cholesterol
Study
n: not reported in source
Comparator
Placebo
Outcome group
Lipids · Metabolic and weight
Studied dose
Dose not stated · oralAs given in this study (human).
Measurements
Mean difference
−4.51%
total cholesterol
95% CI of mean difference
−6.91 to −2.11%
total cholesterol
Source sentences
Summary
Favourable lipid changes included reductions in total cholesterol (MD: -4.51% [95% CI: -6.91 to -2.11]), LDL-C (MD: -5.34% [95% CI: -7.10 to -3.58]), and triglycerides (MD: -10.07% [95% CI: -12.33 to -7.80]), with increased HDL-C (MD: 2.94% [95% CI: 1.38 to 4.49]).
2 context sentences(design, population, supporting numbers)
Summary · context
This meta-analysis evaluated the efficacy and safety of orforglipron in obese patients with or without type 2 diabetes mellitus (T2DM).
Summary · context
A comprehensive literature search was conducted across PubMed, Embase, Cochrane Library and ClinicalTrials.gov from inception to October 2025 to identify randomised controlled trials (RCTs) evaluating orforglipron in obese patients.
Show in the study text Report a problemFND-4129678006
07HumanSystematic reviewEfficacy outcome
In obese patients with or without diabetes, orforglipron reduced LDL-C compared with placebo.
In plain wordsOrforglipron reduced LDL-C compared with placebo in obese patients with or without diabetes.
Peptide
Orforglipron
Outcome
DecreaseLDL-C
Study
n: not reported in source
Comparator
Placebo
Outcome group
Lipids · Metabolic and weight
Studied dose
Dose not stated · oralAs given in this study (human).
Measurements
Mean difference
−5.34%
LDL-C
95% CI of mean difference
−7.1 to −3.58%
LDL-C
Source sentences
Summary
Favourable lipid changes included reductions in total cholesterol (MD: -4.51% [95% CI: -6.91 to -2.11]), LDL-C (MD: -5.34% [95% CI: -7.10 to -3.58]), and triglycerides (MD: -10.07% [95% CI: -12.33 to -7.80]), with increased HDL-C (MD: 2.94% [95% CI: 1.38 to 4.49]).
2 context sentences(design, population, supporting numbers)
Summary · context
This meta-analysis evaluated the efficacy and safety of orforglipron in obese patients with or without type 2 diabetes mellitus (T2DM).
Summary · context
A comprehensive literature search was conducted across PubMed, Embase, Cochrane Library and ClinicalTrials.gov from inception to October 2025 to identify randomised controlled trials (RCTs) evaluating orforglipron in obese patients.
Show in the study text Report a problemFND-4129678007
08HumanSystematic reviewEfficacy outcome
In obese patients with or without diabetes, orforglipron reduced triglycerides compared with placebo.
In plain wordsOrforglipron reduced triglycerides compared with placebo in obese patients with or without diabetes.
Peptide
Orforglipron
Outcome
DecreaseTriglycerides
Study
n: not reported in source
Comparator
Placebo
Outcome group
Lipids · Metabolic and weight
Studied dose
Dose not stated · oralAs given in this study (human).
Measurements
Mean difference
−10.07%
triglycerides
95% CI of mean difference
−12.33 to −7.8%
triglycerides
Source sentences
Summary
Favourable lipid changes included reductions in total cholesterol (MD: -4.51% [95% CI: -6.91 to -2.11]), LDL-C (MD: -5.34% [95% CI: -7.10 to -3.58]), and triglycerides (MD: -10.07% [95% CI: -12.33 to -7.80]), with increased HDL-C (MD: 2.94% [95% CI: 1.38 to 4.49]).
2 context sentences(design, population, supporting numbers)
Summary · context
This meta-analysis evaluated the efficacy and safety of orforglipron in obese patients with or without type 2 diabetes mellitus (T2DM).
Summary · context
A comprehensive literature search was conducted across PubMed, Embase, Cochrane Library and ClinicalTrials.gov from inception to October 2025 to identify randomised controlled trials (RCTs) evaluating orforglipron in obese patients.
Show in the study text Report a problemFND-4129678008
09HumanSystematic reviewEfficacy outcome
In obese patients with or without diabetes, orforglipron increased HDL-C compared with placebo.
In plain wordsOrforglipron increased HDL-C compared with placebo in obese patients with or without diabetes.
Peptide
Orforglipron
Outcome
IncreaseHDL-C
Study
n: not reported in source
Comparator
Placebo
Outcome group
Lipids · Metabolic and weight
Studied dose
Dose not stated · oralAs given in this study (human).
Measurements
Mean difference
2.94%
HDL-C
95% CI of mean difference
1.38 to 4.49%
HDL-C
Source sentences
Summary
Favourable lipid changes included reductions in total cholesterol (MD: -4.51% [95% CI: -6.91 to -2.11]), LDL-C (MD: -5.34% [95% CI: -7.10 to -3.58]), and triglycerides (MD: -10.07% [95% CI: -12.33 to -7.80]), with increased HDL-C (MD: 2.94% [95% CI: 1.38 to 4.49]).
2 context sentences(design, population, supporting numbers)
Summary · context
This meta-analysis evaluated the efficacy and safety of orforglipron in obese patients with or without type 2 diabetes mellitus (T2DM).
Summary · context
A comprehensive literature search was conducted across PubMed, Embase, Cochrane Library and ClinicalTrials.gov from inception to October 2025 to identify randomised controlled trials (RCTs) evaluating orforglipron in obese patients.
Show in the study text Report a problemFND-4129678009
10HumanSystematic reviewSafety outcome
In obesity with or without diabetes, gastrointestinal adverse events were significantly more frequent with orforglipron at 12 mg or higher versus placebo.
In plain wordsIn obesity with or without diabetes, digestive adverse events were significantly more frequent with orforglipron at 12 mg or higher versus placebo.
Peptide
Orforglipron
Outcome
IncreaseGastrointestinal adverse events
Study
n: not reported in source
Comparator
Placebo
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Studied dose
12 mg or higher · oralAs given in this study (human).
Source sentences
Summary
However, gastrointestinal adverse events were significantly more frequent at doses of 12 mg or higher and treatment discontinuation rates were highest at 24 mg (RR:4.61 [95% CI:1.6 to 13.33]) and 36 mg (RR:3.68 [95% CI:2.48 to 5.44]) doses.
2 context sentences(design, population, supporting numbers)
Summary · context
This meta-analysis evaluated the efficacy and safety of orforglipron in obese patients with or without type 2 diabetes mellitus (T2DM).
Summary · context
A comprehensive literature search was conducted across PubMed, Embase, Cochrane Library and ClinicalTrials.gov from inception to October 2025 to identify randomised controlled trials (RCTs) evaluating orforglipron in obese patients.
Show in the study text Report a problemFND-4129678010
11HumanSystematic reviewSafety outcome
In obesity with or without diabetes, orforglipron 24 mg increased treatment discontinuation versus placebo (RR 4.61).
In plain wordsIn obesity with or without diabetes, treatment discontinuation was higher with orforglipron 24 mg than placebo (risk ratio 4.61).
Peptide
Orforglipron
Outcome
IncreaseTreatment discontinuation
Study
n: not reported in source
Comparator
Placebo
Outcome group
Adverse events · Whole body
Studied dose
24 mg · oralAs given in this study (human).
Measurements
Risk ratio
4.61
treatment discontinuation, 24 mg
95% CI of risk ratio
1.6 to 13.33
treatment discontinuation, 24 mg
Source sentences
Summary
However, gastrointestinal adverse events were significantly more frequent at doses of 12 mg or higher and treatment discontinuation rates were highest at 24 mg (RR:4.61 [95% CI:1.6 to 13.33]) and 36 mg (RR:3.68 [95% CI:2.48 to 5.44]) doses.
2 context sentences(design, population, supporting numbers)
Summary · context
This meta-analysis evaluated the efficacy and safety of orforglipron in obese patients with or without type 2 diabetes mellitus (T2DM).
Summary · context
A comprehensive literature search was conducted across PubMed, Embase, Cochrane Library and ClinicalTrials.gov from inception to October 2025 to identify randomised controlled trials (RCTs) evaluating orforglipron in obese patients.
Show in the study text Report a problemFND-4129678011
12HumanSystematic reviewSafety outcome
In obesity with or without diabetes, orforglipron 36 mg increased treatment discontinuation versus placebo (RR 3.68).
In plain wordsIn obesity with or without diabetes, treatment discontinuation was higher with orforglipron 36 mg than placebo (risk ratio 3.68).
Peptide
Orforglipron
Outcome
IncreaseTreatment discontinuation
Study
n: not reported in source
Comparator
Placebo
Outcome group
Adverse events · Whole body
Studied dose
36 mg · oralAs given in this study (human).
Measurements
Risk ratio
3.68
treatment discontinuation, 36 mg
95% CI of risk ratio
2.48 to 5.44
treatment discontinuation, 36 mg
Source sentences
Summary
However, gastrointestinal adverse events were significantly more frequent at doses of 12 mg or higher and treatment discontinuation rates were highest at 24 mg (RR:4.61 [95% CI:1.6 to 13.33]) and 36 mg (RR:3.68 [95% CI:2.48 to 5.44]) doses.
2 context sentences(design, population, supporting numbers)
Summary · context
This meta-analysis evaluated the efficacy and safety of orforglipron in obese patients with or without type 2 diabetes mellitus (T2DM).
Summary · context
A comprehensive literature search was conducted across PubMed, Embase, Cochrane Library and ClinicalTrials.gov from inception to October 2025 to identify randomised controlled trials (RCTs) evaluating orforglipron in obese patients.
Show in the study text Report a problemFND-4129678012
13HumanSystematic reviewSafety outcome
In obese patients with or without diabetes, serious adverse events with orforglipron were comparable to placebo.
In plain wordsSerious adverse events with orforglipron were comparable to placebo in obese patients with or without diabetes.
Peptide
Orforglipron
Outcome
No significant changeSerious adverse events
Study
n: not reported in source
Comparator
Placebo
Outcome group
Adverse events · Whole body
Studied dose
Dose not stated · oralAs given in this study (human).
Source sentences
Summary
Serious adverse events and mortality rates were comparable to those with placebo.
2 context sentences(design, population, supporting numbers)
Summary · context
This meta-analysis evaluated the efficacy and safety of orforglipron in obese patients with or without type 2 diabetes mellitus (T2DM).
Summary · context
A comprehensive literature search was conducted across PubMed, Embase, Cochrane Library and ClinicalTrials.gov from inception to October 2025 to identify randomised controlled trials (RCTs) evaluating orforglipron in obese patients.
Show in the study text Report a problemFND-4129678013
14HumanSystematic reviewSafety outcome
In obese patients with or without diabetes, mortality rates with orforglipron were comparable to placebo.
In plain wordsMortality rates with orforglipron were comparable to placebo in obese patients with or without diabetes.
Peptide
Orforglipron
Outcome
No significant changeMortality
Study
n: not reported in source
Comparator
Placebo
Outcome group
Mortality · Whole body
Studied dose
Dose not stated · oralAs given in this study (human).
Source sentences
Summary
Serious adverse events and mortality rates were comparable to those with placebo.
2 context sentences(design, population, supporting numbers)
Summary · context
This meta-analysis evaluated the efficacy and safety of orforglipron in obese patients with or without type 2 diabetes mellitus (T2DM).
Summary · context
A comprehensive literature search was conducted across PubMed, Embase, Cochrane Library and ClinicalTrials.gov from inception to October 2025 to identify randomised controlled trials (RCTs) evaluating orforglipron in obese patients.
Show in the study text Report a problemFND-4129678014

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Version history

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Version 2Current
14 Oct 2026, 05:02 UTC
Study results updated
Version 1
14 Oct 2026, 01:46 UTC
First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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Keywords

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