Orforglipron

Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment.

Orforglipron, a small-molecule, nonpeptide oral glucagon-like peptide-1 (GLP-1) receptor agonist, is being investigated as a treatment for obesity. In this phase 3, multinational, randomized, double-blind trial, we examined the safety and efficacy of once-daily orforglipron at doses of 6 mg, 12 mg, or 36 mg, as compared with placebo (assigned in a 3:3:3:4 ratio) as an adjunct to healthy diet and physical activity for 72 weeks. All the patients had obesity without diabetes mellitus. The primary end point was the percent change in body weight from baseline to week 72, as assessed according to the treatment-regimen estimand in the intention-to-treat population. A total of 3127 patients underwent randomization. The mean change in body weight from baseline to week 72 was -7.5% (95% confidence interval [CI], -8.2 to -6.8) with 6 mg of orforglipron, -8.4% (95% CI, -9.1 to -7.7) with 12 mg of orforglipron, and -11.2% (95% CI, -12.0 to -10.4) with 36 mg of orforglipron, as compared with -2.1% (95% CI, -2.8 to -1.4) with placebo (P<0.001 for all comparisons with placebo). Among the patients in the orforglipron 36-mg group, 54.6% had a reduction of 10% or more, 36.0% had a reduction of 15% or more, and 18.4% had a reduction of 20% or more, as compared with 12.9%, 5.9%, and 2.8% of the patients, respectively, in the placebo group. Waist circumference, systolic blood pressure, triglyceride levels, and non-HDL cholesterol levels significantly improved with orforglipron treatment as compared with placebo. Adverse events resulted in treatment discontinuation in 5.3 to 10.3% of the patients in the orforglipron groups and in 2.7% of those in the placebo group. The most common adverse events with orforglipron were gastrointestinal effects, which were mostly mild to moderate. In adults with obesity, 72-week treatment with orforglipron led to significantly greater reductions in body weight than placebo; the adverse-event profile was consistent with that of other GLP-1 receptor agonists. (Funded by Eli Lilly; ATTAIN-1 ClinicalTrials.gov number, NCT05869903.).

Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist, in Early Type 2 Diabetes.

Orforglipron is a small-molecule, nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist in clinical development for type 2 diabetes and weight management. Additional data on the efficacy and safety of orforglipron are needed. In this phase 3, double-blind, placebo-controlled trial, we randomly assigned participants in a 1:1:1:1 ratio to receive orforglipron at one of three doses (3 mg, 12 mg, or 36 mg) or placebo once daily for 40 weeks. Participants had type 2 diabetes treated only with diet and exercise, a glycated hemoglobin level of at least 7.0% but no more than 9.5%, and a body-mass index (the weight in kilograms divided by the square of the height in meters) of at least 23.0. The primary end point was the change from baseline to week 40 in the glycated hemoglobin level. A key secondary end point was the percent change in body weight from baseline to week 40. A total of 559 participants underwent randomization. The mean glycated hemoglobin level at baseline was 8.0%. At week 40, the estimated mean change from baseline in the glycated hemoglobin level was -1.24 percentage points with the 3-mg dose, -1.47 percentage points with the 12-mg dose, -1.48 percentage points with the 36-mg dose, and -0.41 percentage points with placebo. All three doses of orforglipron were superior to placebo with respect to the primary end point; the estimated mean difference from placebo was -0.83 percentage points (95% confidence interval [CI], -1.10 to -0.56) with the 3-mg dose, -1.06 percentage points (95% CI, -1.33 to -0.79) with the 12-mg dose, and -1.07 percentage points (95% CI, -1.33 to -0.81) with the 36-mg dose (P<0.001 for all comparisons). The mean glycated hemoglobin level at week 40 was 6.5 to 6.7% with orforglipron. The percent change in body weight from baseline to week 40 was -4.5% with the 3-mg dose, -5.8% with the 12-mg dose, -7.6% with the 36-mg dose, and -1.7% with placebo. The most common adverse events were mild-to-moderate gastrointestinal events, most of which occurred during dose escalation. No episodes of severe hypoglycemia were reported. Permanent discontinuation of orforglipron or placebo due to adverse events occurred in 4.4 to 7.8% of participants receiving orforglipron and 1.4% of participants receiving placebo. In adults with early type 2 diabetes, orforglipron significantly reduced the glycated hemoglobin level over a period of 40 weeks. (Supported by Eli Lilly; ACHIEVE-1 ClinicalTrials.gov number, NCT05971940.).

Orforglipron (LY3502970), a novel, oral non-peptide glucagon-like peptide-1 receptor agonist: A Phase 1a, blinded, placebo-controlled, randomized, single- and multiple-ascending-dose study in healthy participants.

To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of orforglipron (LY3502970), an oral, non-peptide glucagon-like peptide-1 receptor agonist (GLP-1RA) in healthy participants. This was a double-blind, placebo-controlled, Phase 1 study. Overtly healthy adults aged 18 to 65&#x2009;years with body mass index of 20 to 40&#x2009;kg/m2 and glycated haemoglobin concentration of 47.5 mmol/mol (<6.5%) were eligible. In Part A, participants received single-dose orforglipron, with four cohorts receiving escalating doses (0.3-6&#x2009;mg). In Part B, participants received 4&#x2009;weeks of daily repeated oral orforglipron with doses escalating weekly to four different final target doses (2-24&#x2009;mg). Ninety-two participants enrolled and received at least one study drug dose (32 in Part A [mean age 43.4&#x2009;years] and 60 in Part B [mean age 42.5&#x2009;years]). The most common adverse events were gastrointestinal tract-related. Pharmacokinetics were approximately dose proportional, and the mean t1/2 was 24.6 to 35.3&#x2009;hours after a single dose (0.3-6&#x2009;mg). On Day 28, the mean t1/2 was 48.1 to 67.5&#x2009;hours across the dose range (2-24&#x2009;mg). Substantial reductions in body weight of up to 5.4&#x2009;kg were observed after 4&#x2009;weeks in orforglipron-treated participants, compared to a reduction of 2.4&#x2009;kg with placebo (P&#x2009;<&#x2009;0.05). Orforglipron decreased fasting glucose levels across Days 1 to 28, and gastric emptying was delayed on Day 28. Orforglipron's long half-life (25-68&#x2009;hours) allows once-daily oral dosing, without water and food restrictions. Orforglipron had a pharmacodynamic and safety profile similar to that of injectable GLP-1RAs, which supports continued clinical development.

Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity.

Obesity is a major risk factor for many leading causes of illness and death worldwide. Data are needed regarding the efficacy and safety of the nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist orforglipron as a once-daily oral therapy for weight reduction in adults with obesity. In this phase 2, randomized, double-blind trial, we enrolled adults with obesity, or with overweight plus at least one weight-related coexisting condition, and without diabetes. Participants were randomly assigned to receive orforglipron at one of four doses (12, 24, 36, or 45 mg) or placebo once daily for 36 weeks. The percentage change from baseline in body weight was assessed at week 26 (primary end point) and at week 36 (secondary end point). A total of 272 participants underwent randomization. At baseline, the mean body weight was 108.7 kg, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 37.9. At week 26, the mean change from baseline in body weight ranged from -8.6% to -12.6% across the orforglipron dose cohorts and was -2.0% in the placebo group. At week 36, the mean change ranged from -9.4% to -14.7% with orforglipron and was -2.3% with placebo. A weight reduction of at least 10% by week 36 occurred in 46 to 75% of the participants who received orforglipron, as compared with 9% who received placebo. The use of orforglipron led to improvement in all prespecified weight-related and cardiometabolic measures. The most common adverse events reported with orforglipron were gastrointestinal events, which were mild to moderate, occurred primarily during dose escalation, and led to discontinuation of orforglipron in 10 to 17% of participants across dose cohorts. The safety profile of orforglipron was consistent with that of the GLP-1 receptor agonist class. Daily oral orforglipron, a nonpeptide GLP-1 receptor agonist, was associated with weight reduction. Adverse events reported with orforglipron were similar to those with injectable GLP-1 receptor agonists. (Funded by Eli Lilly; GZGI ClinicalTrials.gov number, NCT05051579.).

Emerging pharmacotherapies for obesity: A systematic review.

The history of antiobesity pharmacotherapies is marked by disappointments, often entangled with societal pressure promoting weight loss and the prevailing conviction that excess body weight signifies a lack of willpower. However, categories of emerging pharmacotherapies generate hope to reduce obesity rates. This systematic review of phase 2 and phase 3 trials in adults with overweight/obesity investigates the effect of novel weight loss pharmacotherapies, compared to placebo/control or US Food and Drug Administration-approved weight loss medication, through searching Medline, Embase, and ClinicalTrials.gov (2012-2024). We identified 53 phase 3 and phase 2 trials, with 36 emerging antiobesity drugs or combinations thereof and 4 withdrawn or terminated trials. Oral semaglutide 50 mg is the only medication that has completed a phase 3 trial. There are 14 ongoing phase 3 trials on glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) (ecnoglutide, orforglipron, and TG103), GLP-1 RA/amylin agonist (CagriSema), GLP-1/glucagon RAs (mazdutide and survodutide), GLP-1/glucose-dependent insulinotropic polypeptide and glucagon RA (retatrutide), dapagliflozin, and the combination sibutramine/topiramate. Completed phase 2 trials on incretin-based therapies showed a mean percent weight loss of 7.4% to 24.2%. Almost half of the drugs undergoing phase 2 trials are incretin analogs. The obesity drug pipeline is expanding rapidly, with the most promising results reported with incretin analogs. Data on mortality and obesity-related complications, such as cardio-renal-metabolic events, are needed. Moreover, long-term follow-up data on the safety and efficacy of weight maintenance with novel obesity pharmacotherapies, along with studies focused on underrepresented populations, cost-effectiveness assessments, and drug availability, are needed to bridge the care gap for patients with obesity. SIGNIFICANCE STATEMENT: Obesity is the epidemic of the 21st century. Except for the newer injectable medications, drugs with suboptimal efficacy have been available in the clinician's armamentarium for weight management. However, emerging alternatives of novel agents and combinations populate the current obesity therapeutic pipeline. This systematic review identifies the state and mechanism of action of emerging pharmacotherapies undergoing or having completed phase 2 and phase 3 clinical trials. The information provided herein furthers the understanding of obesity management, implying direct clinical implications and stimulating research initiatives.

Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist.

Glucagon-like peptide-1 receptor (GLP-1R) agonists are efficacious antidiabetic medications that work by enhancing glucose-dependent insulin secretion and improving energy balance. Currently approved GLP-1R agonists are peptide based, and it has proven difficult to obtain small-molecule activators possessing optimal pharmaceutical properties. We report the discovery and mechanism of action of LY3502970 (OWL833), a nonpeptide GLP-1R agonist. LY3502970 is a partial agonist, biased toward G protein activation over &#x3b2;-arrestin recruitment at the GLP-1R. The molecule is highly potent and selective against other class B G protein-coupled receptors (GPCRs) with a pharmacokinetic profile favorable for oral administration. A high-resolution structure of LY3502970 in complex with active-state GLP-1R revealed a unique binding pocket in the upper helical bundle where the compound is bound by the extracellular domain (ECD), extracellular loop 2, and transmembrane helices 1, 2, 3, and 7. This mechanism creates a distinct receptor conformation that may explain the partial agonism and biased signaling of the compound. Further, interaction between LY3502970 and the primate-specific Trp33 of the ECD informs species selective activity for the molecule. In efficacy studies, oral administration of LY3502970 resulted in glucose lowering in humanized GLP-1R transgenic mice and insulinotropic and hypophagic effects in nonhuman primates, demonstrating an effect size in both models comparable to injectable exenatide. Together, this work determined the molecular basis for the activity of an oral agent being developed for the treatment of type 2 diabetes mellitus, offering insights into the activation of class B GPCRs by nonpeptide ligands.

Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study.

Orforglipron, an oral, non-peptide glucagon-like peptide-1 (GLP-1) receptor agonist, is in development for type 2 diabetes and obesity. We assessed the efficacy and safety of orforglipron versus placebo or dulaglutide in participants with type 2 diabetes. In this 26-week, phase 2, double-blind, randomised, multicentre study, participants were recruited from 45 centres (private clinics, hospitals, and research centers) in the USA, Hungary, Poland, and Slovakia. Adult participants aged 18 years or older with type 2 diabetes treated with diet and exercise, with or without metformin, and with a glycated haemoglobin (HbA1c) of 7&#xb7;0-10&#xb7;5%, and stable BMI of 23 kg/m2 or more, were randomly assigned (5:5:5:5:5:3:3:3:3) via an interactive web-response system to placebo, dulaglutide 1&#xb7;5 mg once per week, or orforglipron 3 mg, 12 mg, 24 mg, 36 mg (group 1), 36 mg (group 2), 45 mg (group 1), or 45 mg (group 2) once per day with no food or water restrictions. Two different dose escalation regimens were evaluated for each of the 36 mg and 45 mg cohorts. Participants were masked to the study drug, dulaglutide, and placebo. The primary efficacy outcome The primary efficacy outcome was mean change in HbA1c from baseline with orforglipron versus placebo at week 26. Efficacy was analysed in all randomly assigned participants who received at least one dose of study drug and excluded data after the permanent discontinuation of study drug or initiation of rescue medication. Safety was analysed in all participants who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT05048719) and is completed. Between Sept 15, 2021, and Sept 30, 2022, 569 participants were screened and 383 were enrolled and randomly assigned to a group. 352 (92%) completed the study and 303 (79%) completed 26 weeks of treatment. At baseline, the mean age was 58&#xb7;9 years, HbA1c was 8&#xb7;1%, BMI was 35&#xb7;2 kg/m2, 226 (59%) were men, and 157 (41%) were women. At week 26, mean change in HbA1c with orforglipron was up to -2&#xb7;10% (-1&#xb7;67% placebo adjusted), versus -0&#xb7;43% with placebo and -1&#xb7;10% with dulaglutide. HbA1c reduction was statistically superior with orforglipron versus placebo (estimated treatment difference -0&#xb7;8% to -1&#xb7;7%). Change in mean bodyweight at week 26 was up to -10&#xb7;1 kg (95% CI -11&#xb7;5 to -8&#xb7;7; 7&#xb7;9 kg placebo adjusted [-9&#xb7;9 to -5&#xb7;9]) with orforglipron versus -2&#xb7;2 kg (-3&#xb7;6 to -0&#xb7;7) for placebo and -3&#xb7;9 kg (-5&#xb7;3 to -2&#xb7;4) for dulaglutide. The incidence of treatment-emergent adverse events ranged from 61&#xb7;8% to 88&#xb7;9% in orforglipron-treated participants, compared with 61&#xb7;8% with placebo and 56&#xb7;0% with dulaglutide. The majority were gastrointestinal events (44&#xb7;1% to 70&#xb7;4% with orforglipron, 18&#xb7;2% with placebo, and 34&#xb7;0% with dulaglutide) of mild to moderate severity. Three participants receiving orforglipron and one participant receiving dulaglutide had clinically significant (<54 mg/dL [<3 mmol/L]) hypoglycaemia and no participants had severe hypoglycaemia. One death occurred in the placebo group and was not related to study treatment. In this phase 2 trial the novel, oral, non-peptide GLP-1 receptor agonist orforglipron at doses of 12 mg or greater showed significant reductions in HbA1c and bodyweight compared with placebo or dulaglutide. The adverse event profile was similar to other GLP-1 receptor agonists in similar stage of development. Orforglipron might provide an alternative to injectable GLP-1 receptor agonists and oral semaglutide, with the prospect of less burdensome administration to achieve treatment goals in people with type 2 diabetes. Eli Lilly and Company.

Gut hormones and appetite regulation.

Various gut hormones interact with the brain through delicate communication, thereby influencing appetite and subsequent changes in body weight. This review summarizes the effects of gut hormones on appetite, with a focus on recent research. Ghrelin is known as an orexigenic hormone, whereas glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), postprandial peptide YY (PYY), and oxyntomodulin (OXM) are known as anorexigenic hormones. Recent human studies have revealed that gut hormones act differently in various systems, including adipose tissue, beyond appetite and energy intake, and even involve in high-order thinking. Environmental factors including meal schedule, food contents and quality, type of exercise, and sleep deprivation also play a role in the influence of gut hormone on appetite, weight change, and obesity. Recently published studies have shown that retatrutide, a triple-agonist of GLP-1, GIP, and glucagon receptor, and orforglipron, a GLP-1 receptor partial agonist, are effective in weight loss and improving various metabolic parameters associated with obesity. Various gut hormones influence appetite, and several drugs targeting these receptors have been reported to exert positive effects on weight loss in humans. Given that diverse dietary and environmental factors affect the actions of gut hormones and appetite, there is a need for integrated and largescale long-term studies in this field.

Orforglipron (LY3502970), a novel, oral non-peptide glucagon-like peptide-1 receptor agonist: A Phase 1b, multicentre, blinded, placebo-controlled, randomized, multiple-ascending-dose study in people with type 2 diabetes.

To report the results of a Phase 1b trial evaluating the safety, pharmacokinetics and pharmacodynamics of orforglipron (LY3502970), an oral, non-peptide glucagon-like peptide-1 receptor agonist (GLP-1RA), in patients with type 2 diabetes (T2D). This was a double-blind, placebo-controlled Phase 1 study evaluating five different dosing regimens. The first group established that weekly dose escalation of the daily doses of orforglipron was generally well tolerated. This enabled a parallel-arm design for the four groups following. Participants were randomized 3:1 to daily doses of orforglipron or placebo for 12&#x2009;weeks. Eligible participants with T2D were aged 18 to 70&#x2009;years and had glycated haemoglobin (HbA1c) levels &#x2265;53.0 mmol/mol (7.0%) and &#x2264;91.3 mmol/mol (10.5%). A total of 51 participants received orforglipron and 17 received placebo. In the placebo and orforglipron groups, respectively, baseline HbA1c was 8.1% and 8.0%, and baseline body weight was 90.3 and 88.4&#x2009;kg. The most common adverse events were gastrointestinal-related, and occurred early in treatment, similar to findings with other GLP-1RAs. At Week 12, mean t1/2 ranged from 29 to 49&#x2009;hours. Mean HbA1c change ranged from -1.5% to -1.8% across orforglipron doses, versus -0.4% with placebo, and body weight change was -0.24 to -5.8&#x2009;kg across orforglipron doses, versus 0.5&#x2009;kg with placebo. Orforglipron treatment resulted in meaningful reductions in HbA1c and body weight, with an adverse event profile consistent with that of other GLP-1RAs. Orforglipron may provide a safe and effective once-daily oral treatment alternative to injectable GLP-1RAs or peptide oral formulations without water and food restrictions.

The pharmacological basis for nonpeptide agonism of the GLP-1 receptor by orforglipron.

Orally bioavailable, synthetic nonpeptide agonists (NPAs) of the glucagon-like peptide-1 receptor (GLP-1R) may offer an effective, scalable pharmacotherapy to address the metabolic disease epidemic. One of the first molecules in the emerging class of GLP-1R NPAs is orforglipron, which is in clinical development for treating type 2 diabetes and obesity. Here, we characterized the pharmacological properties of orforglipron in comparison with peptide-based GLP-1R agonists and other NPAs. Competition binding experiments using either [125I]GLP-1(7-36)NH2 or [3H]orforglipron indicated that orforglipron is a high-affinity [inhibition constant (Ki) = 1 nM], selective ligand of the human GLP-1R. Signal transduction assays showed that orforglipron has low intrinsic efficacy for effector activation and negligible &#x3b2;-arrestin recruitment. To evaluate GLP-1R engagement in vivo, mice expressing the human GLP-1R were administered orforglipron and subjected to a glucose tolerance test. Predicted receptor occupancy was calculated using the receptor Ki value of orforglipron and its unbound concentration in vivo that reduces hyperglycemia. These experiments revealed that low GLP-1R occupancy by orforglipron is sufficient to yield a full biological response. Moreover, in a model where CRISPR-Cas9 gene editing was used to sensitize the rat GLP-1R (Glp1rS33W) to GLP-1R NPAs, target engagement by orforglipron in the pancreas and brain was consistent with peptide-based GLP-1R agonists. Diet-induced obesity in Glp1rS33W rats enabled studies showing weight loss in animals orally administered orforglipron versus subcutaneous injection of GLP-1R agonist semaglutide. Furthermore, crossover studies indicated oral orforglipron can sustain efficacy initiated by parenteral semaglutide. The pharmacological properties of orforglipron may inform targeting of other peptide receptors with NPAs.

Seven glucagon-like peptide-1 receptor agonists and polyagonists for weight loss in patients with obesity or overweight: an updated systematic review and network meta-analysis of randomized controlled trials.

This study aimed to provide evidence-based support and a reference for the efficacy and safety of seven glucagon-like peptide-1 (GLP-1) receptor agonists and polyagonists for weight loss in patients with obesity or overweight through a network meta-analysis. Relevant randomized controlled trials (RCTs) with an intervention duration of at least 16&#xa0;weeks assessing seven GLP-1 receptor agonists and polyagonists (mazdutide, 6 or 4.5&#xa0;mg; retatrutide, 12 or 8&#xa0;mg; tirzepatide, 15 or 10&#xa0;mg; liraglutide, 3.0&#xa0;mg; semaglutide, 2.4&#xa0;mg; orforglipron, 45 or 36&#xa0;mg; and beinaglutide, 0.2&#xa0;mg) in patient with obesity or overweight was searched using three databases (Cochrane Library, PubMed, and Embase) from creation to August 30, 2024. The primary outcome was the percentage change in body weight from baseline. Secondary outcomes included changes in waist circumference, hemoglobin A1c, and fasting plasma glucose level from baseline; adverse events, serious adverse events, adverse event withdrawal, and hypoglycemic events. We conducted a frequentist random-effects network meta-analysis to analyze the data extracted from the RCTs using Stata 16.1 software. Twenty-seven RCTs of seven GLP-1 receptor agonists and polyagonists and 15,584 patients were included in the network meta-analysis. In terms of efficacy, compared with placebo, retatrutide 12&#xa0;mg (-22.10&#xa0;% in body weight and&#xa0;-&#xa0;17.00&#xa0;cm in waist circumference), retatrutide 8&#xa0;mg (-20.70&#xa0;% and&#xa0;-&#xa0;15.90&#xa0;cm), and tirzepatide 15&#xa0;mg (-16.53&#xa0;% and&#xa0;-&#xa0;13.23&#xa0;cm) were the three most efficacious treatments for reducing body weight and waist circumference. However, these treatments were less effective in patients with type 2 diabetes mellitus (T2DM). In addition, patients with a high body mass index (BMI) or longer treatment cycles exhibited significantly greater weight loss than those with a low BMI or shorter treatment cycles. In terms of safety, patients without T2DM had a higher incidence of adverse events than those with T2DM. None of the interventions increased the incidence of serious adverse or hypoglycemic events (&#x2c2;54&#xa0;mg/dL). There was no significant difference in the incidence of adverse event withdrawal for all interventions in head-to-head comparisons. In addition, disparities in race, BMI, and treatment cycles did not significantly increase the incidence of adverse events. Finally, the sensitivity and publication bias analyses indicated that the basic analysis results were reliable. Retatrutide (both doses) and tirzepatide exhibited superior efficacy compared to other GLP-1 receptor agonists and polyagonists in reducing body weight and waist circumference. Patients without T2DM, those with a high BMI, and individuals undergoing longer treatment cycles demonstrated significantly greater weight loss and reductions in waist circumference. Dual or triple receptor agonists (GLP-1 plus glucose-dependent insulinotropic polypeptide and/or Glucagon receptor) are more effective for weight loss than GLP-1 receptor agonists.

Efficacy and safety of once-daily oral orforglipron compared with oral semaglutide in adults with type 2 diabetes (ACHIEVE-3): a multinational, multicentre, non-inferiority, open-label, randomised, phase 3 trial.

Orforglipron is a novel non-peptide (GLP-1) receptor agonist designed for daily oral administration without food or water restrictions. This study aimed to compare the efficacy and safety of orforglipron with oral semaglutide in individuals with type 2 diabetes inadequately controlled with metformin. In this 52-week, randomised, open-label, active-controlled, multicentre, multinational, phase 3 study, we enrolled adults (&#x2265;18 years) with type 2 diabetes inadequately controlled with metformin (&#x2265;1500 mg per day), glycated haemoglobin (HbA1c) between 7&#xb7;0% and 10&#xb7;5% (53-91 mmol/mol), and BMI at least 25 kg/m2 from 131 medical research centres and hospitals in Argentina, China, Japan, Mexico, and the USA. Participants were randomly assigned (1:1:1:1) to orforglipron (12 mg or 36 mg) or semaglutide (7 mg or 14 mg); all groups had an up to 4-week lead-in period and 52-week treatment period, with the drugs administered orally once per day. The primary objective of the study was to assess non-inferiority of orforglipron 36 mg versus semaglutide 14 mg and orforglipron 12 mg versus semaglutide 7 mg for mean change at week 52 from baseline in HbA1c (with a non-inferiority margin of 0&#xb7;3%) in the intention-to-treat population. Hierarchical analysis for superiority was prespecified after attainment of non-inferiority. The treatment regimen estimand, based on data from all randomly assigned participants regardless of intercurrent events, was the primary estimand; the efficacy estimand was considered supportive. The safety endpoints used data from all participants who received at least one dose of the study drug. This trial was registered on ClinicalTrials.gov (NCT06045221) and is completed. From Sept 22, 2023, to Aug 22, 2025, 1698 participants were recruited and randomly assigned to orforglipron (n=424 on 12 mg and n=423 on 36 mg) or semaglutide (n=426 on 7 mg and n=425 on 14 mg). For the treatment regimen estimand, mean changes at week 52 from a baseline HbA1c of 8&#xb7;3% were -1&#xb7;71% (SE 0&#xb7;07) with orforglipron 12 mg, -1&#xb7;91% (0&#xb7;08) with orforglipron 36 mg, -1&#xb7;23% (0&#xb7;05) with semaglutide 7 mg, and -1&#xb7;47% (0&#xb7;06) with semaglutide 14 mg. Estimated treatment differences were -0&#xb7;48% (95% CI -0&#xb7;65 to -0&#xb7;31; p<0&#xb7;0001) for orforglipron 12 mg versus semaglutide 7 mg; -0&#xb7;44% (-0&#xb7;62 to -0&#xb7;26; p<0&#xb7;0001) for orforglipron 36 mg versus semaglutide 14 mg; -0&#xb7;24% (95% CI -0&#xb7;41 to -0&#xb7;072; p=0&#xb7;0050) for orforglipron 12 mg versus semaglutide 14 mg; and -0&#xb7;68% (-0&#xb7;85 to -0&#xb7;50; p<0&#xb7;0001) for orforglipron 36 mg versus semaglutide 7 mg. The primary objective of non-inferiority was met and both orforglipron doses showed superiority to both semaglutide doses, including orforglipron 12 mg versus semaglutide 14 mg. The most frequent adverse events were gastrointestinal events (orforglipron: 249 [59%] of 424 on 12 mg and 245 [58%] of 423 on 36 mg; semaglutide: 157 [37%] of 426 on 7 mg and 193 [45%] of 425 on 14 mg), most of which were mild to moderate in severity. More participants in the orforglipron groups (37 [9%] on 12 mg and 41 [10%] on 36 mg) discontinued study treatment due to adverse events than in the semaglutide groups (19 (4%) on 7 mg and 21 (5%) on 14 mg), and mean increase in pulse rate was greater in the orforglipron groups (12 mg 3&#xb7;7 bpm; 36 mg 4&#xb7;7 bpm) than in the semaglutide groups (7 mg 1&#xb7;0 bpm; 14 mg 1&#xb7;5 bpm). Four deaths occurred during the study: one in the orforglipron 12 mg group, one in the orforglipron 36 mg group, and two in the semaglutide 7 mg group. In individuals with type 2 diabetes inadequately controlled with metformin, orforglipron 12 mg and 36 mg was non-inferior and superior to semaglutide 7 mg and 14 mg with respect to the mean change in HbA1c from baseline to 52 weeks. Although the safety profiles of both orforglipron and semaglutide were generally consistent with the GLP-1 receptor agonist class, the incidence of gastrointestinal events, discontinuations due to adverse events, and mean increase in pulse rate were higher with orforglipron than oral semaglutide. Eli Lilly.

Medications for adults with type 2 diabetes: a living systematic review and network meta-analysis.

To provide up-to-date evidence on key benefits, harms, and uncertainties regarding medications for adults with type 2 diabetes. Living systematic review and network meta-analysis (NMA), using frequentist random effects and GRADE (grading of recommendations, assessment, development and evaluation) approaches. Updates are planned at least two times a year. Medline and Embase, searched up to 31 July 2024 for the current iteration. Randomised controlled trials of at least 24 weeks comparing one or more medications with standard treatment, placebo, or each other. The systematic review and NMA includes 493&#x2009;168 participants from 869 trials (adding 53 trials since October 2022) reporting data for 13 drug classes (63 drugs) and 26 outcomes of interest. Regarding benefits, moderate to high certainty evidence confirms the well established cardiovascular and kidney benefits of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and finerenone (the last for patients with established chronic kidney disease). The most effective drugs in reducing body weight were tirzepatide (mean difference (MD) -8.63 kg (95% confidence interval -9.34 to -7.93); moderate certainty) and orforglipron (MD -7.87 kg (-10.24 to -5.50); low certainty), followed by eight other GLP-1RAs (high to moderate certainty). Absolute benefits of medications vary substantially depending on the baseline risk of cardiovascular and kidney outcomes; risk-stratified absolute effects of medications are summarised using an interactive multiple comparisons tool (https://matchit.magicevidence.org/250709dist-diabetes/#!/). Regarding medication-specific harms, SGLT-2 inhibitors increase genital infections (odds ratio (OR) 3.29 (95% CI 2.88 to 3.77); high certainty) and ketoacidosis due to diabetes (OR 2.08 (1.45 to 2.99); high certainty), and probably increase amputations (OR 1.27 (1.01 to 1.61); moderate certainty); tirzepatide and GLP-1RAs probably increase severe gastrointestinal events (most increased risk with tirzepatide (OR 4.21 (1.87 to 9.49); moderate certainty)); finerenone increases severe hyperkalaemia (OR 5.92 (3.02 to 11.62); high certainty); and thiazolidinediones increase major osteoporotic fractures and probably increase hospitalisation for heart failure. Sulfonylureas, insulin, and dipeptidyl peptidase-4 inhibitors probably increase the risk of severe hypoglycaemia. There is low to very low certainty evidence for effects on other diabetes-related complications, including neuropathy and visual impairment. Despite interest in the issue, there is uncertainty about whether GLP-1RAs may reduce dementia (OR 0.92 (0.83 to 1.02); low certainty). This living systematic review provides a comprehensive summary of the cardiovascular, kidney, and weight loss benefits, as well as medication-specific harms of medications for adults with type 2 diabetes, including effects of SGLT-2 inhibitors, GLP-1RAs, finerenone and tirzepatide. PROSPERO number: CRD42022325948. A more detailed protocol is available at https://data.aliveevidence.org/records/q02rv-km486. This article is the first version of a living systematic review. It is linked to a living BMJ Rapid Recommendation and other living clinical practice guidelines, presenting risk stratified recommendations for patients with type 2 diabetes at lower, moderate, and higher risk of cardiovascular and kidney complications. The latest evidence will be made available via the BMJ Rapid Recommendation and via an interactive GRADE evidence summary (MATCH-IT: https://matchit.magicevidence.org/250709dist-diabetes/#!/). Major updates will be published in The BMJ.

Effect of Food Consumption on the Pharmacokinetics, Safety, and Tolerability of Once-Daily Orally Administered Orforglipron (LY3502970), a Non-peptide GLP-1 Receptor Agonist.

We assessed the effect of the prandial state on the pharmacokinetics, safety, and tolerability of single and multiple doses of orforglipron (LY3502970), an oral, non-peptide glucagon-like peptide&#xa0;1 receptor agonist (GLP-1 RA), in two studies (A and B). Study&#xa0;A and study&#xa0;B were phase&#xa0;1, randomized, crossover studies in healthy adults aged 18-65&#xa0;years and 21-70&#xa0;years, respectively. Participants received single (3&#xa0;mg, study&#xa0;A) or multiple (16&#xa0;mg, study&#xa0;B) oral doses of orforglipron under fasted and fed conditions. Blood samples were collected pre- and postdose to assess area under the concentration-time curve (AUC), maximum observed drug concentration (Cmax), time of Cmax (tmax), and half-life (t1/2) associated with terminal rate constant. AUC and Cmax were analyzed using a linear mixed-effects model. Treatment differences were presented as ratios of geometric least squares means (GLSM). Treatment-emergent adverse events (TEAEs), adverse events of special interest, and serious adverse events were assessed. Study&#xa0;A included 12 participants (mean age 45.0&#xa0;years; male 66.7%); study&#xa0;B included 34 participants (mean age 42.8&#xa0;years; male 88.2%). GLSM AUC and Cmax were lower by 23.7% and 23.2% in study&#xa0;A, and 17.6% and 20.9% in study&#xa0;B, in the fed versus fasted states, respectively. In both studies, t1/2 and median tmax were comparable between fed and fasted states. The majority of TEAEs in both studies were gastrointestinal tract-related conditions. No serious adverse events or deaths were reported in either study. The observed pharmacokinetic differences due to the prandial state are unlikely to contribute to clinically meaningful differences in the efficacy of orforglipron. The safety profile was consistent with the known profiles of other GLP-1 RAs. Given the absence of prandial restrictions, orforglipron may emerge as a convenient oral treatment option for patients with type&#xa0;2 diabetes or obesity. ClinicalTrials.gov identifiers, NCT03929744 and NCT05110794.

Orforglipron, an oral small-molecule GLP-1 receptor agonist, for the treatment of obesity in people with type 2 diabetes (ATTAIN-2): a phase 3, double-blind, randomised, multicentre, placebo-controlled trial.

Obesity is a chronic disease that significantly contributes to type 2 diabetes and its complications. We aimed to evaluate orforglipron, an oral small-molecule (non-peptide) GLP-1 receptor agonist, for obesity treatment in adults with type 2 diabetes. This 72-week, phase 3, double-blind, placebo-controlled trial was conducted across 136 sites in ten countries. Participants with a BMI of 27 kg/m2 or higher and glycated haemoglobin (HbA1c) of 7-10% (53-86 mmol/mol) were randomly assigned (1:1:1:2) to once-daily orforglipron 6 mg, 12 mg, 36 mg, or placebo. The primary endpoint was the mean percent change in bodyweight from baseline to week 72. The treatment regimen estimand (using data from all randomly assigned participants, regardless of intercurrent events) was the primary estimand, with the efficacy estimand considered supportive. Safety was assessed in all patients who received at least one dose of study drug. This trial was registered at ClinicalTrials.gov (NCT05872620) and is completed. From June 5, 2023, to Feb 15, 2024, 2859 participants were screened, and 1613 (757 [46&#xb7;9%] female) were randomly assigned, following a dose-escalation phase, to receive orforglipron 6 mg (n=329), 12 mg (n=332), 36 mg (n=322), or placebo (n=630), as an adjunct to lifestyle modification; 1444 (89&#xb7;5%) completed the study. Baseline bodyweight was 101&#xb7;4 kg (SD 22&#xb7;5), BMI 35&#xb7;6 kg/m2 (SD 6&#xb7;6), and HbA1c 8&#xb7;05% (SD 0&#xb7;75; 64&#xb7;4 mmol/mol [SD 8&#xb7;2]). For the treatment regimen estimand, the mean percent change in bodyweight from baseline to week 72 was -5&#xb7;1% (95% CI -6&#xb7;0 to -4&#xb7;2) with 6 mg (estimated treatment difference [ETD] -2&#xb7;7 [95% CI -3&#xb7;7 to -1&#xb7;6]; p<0&#xb7;0001), -7&#xb7;0% (-7&#xb7;8 to -6&#xb7;2) with 12 mg (ETD -4&#xb7;5 [-5&#xb7;5 to -3&#xb7;6]; p<0&#xb7;0001), and -9&#xb7;6% (-10&#xb7;5 to -8&#xb7;7) with 36 mg orforglipron (ETD -7&#xb7;1 [-8&#xb7;2 to -6&#xb7;1]; p<0&#xb7;0001), versus -2&#xb7;5% (-3&#xb7;0 to -1&#xb7;9) with placebo (all p<0&#xb7;0001 compared with placebo). All prespecified weight and cardiometabolic measures including HbA1c statistically significantly improved with orforglipron. Treatment discontinuations due to adverse events (mainly gastrointestinal-related) were higher for orforglipron (6&#xb7;1-9&#xb7;9%) versus placebo (4&#xb7;1%). The most common adverse events with orforglipron were mild-to-moderate gastrointestinal events, predominantly occurring during dose escalation. Ten deaths were reported during the study: six with orforglipron and four with placebo. Investigators deemed all deaths unrelated to the study treatment, except for one case in the placebo group and one case in the 12 mg orforglipron group. For the case in the orforglipron group, no treatment-related association was reported. In adults with obesity or overweight and type 2 diabetes, statistically superior reduction in bodyweight compared with placebo was demonstrated by once-daily orforglipron as an adjunct to lifestyle modification, with a safety profile similar to other GLP-1 receptor agonists. Eli Lilly and Company.

Novel GLP-1-based Medications for Type 2 Diabetes and Obesity.

The approvals of semaglutide and tirzepatide have set new benchmarks in the treatment of type 2 diabetes and obesity. Building on their success, novel glucagon-like peptide-1 (GLP-1)-based therapeutics are rapidly advancing. These next-generation agents engage not only GLP-1 receptors but also those for other gastro-entero-pancreatic hormones such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, amylin, and peptide YY to enhance energy uptake, storage, and expenditure through synergistic mechanisms. Both GIP receptor agonism and antagonism, particularly in combination with GLP-1 receptor agonism, have shown promise. Maridebart cafraglutide, combining GLP-1 receptor agonism with GIP receptor antagonism, exemplifies this innovative approach. Glucagon coagonists like survodutide and mazdutide have demonstrated significant weight loss and improved glycemic control. Amylin-based agents, including CagriSema (cagrilintide + semaglutide) and amycretin, enhance satiety and glycemic outcomes through complementary actions. Further innovation is seen in triple agonists such as retatrutide, which targets GIP, GLP-1, and glucagon receptors to amplify metabolic effects. Meanwhile, the emergence of orally active small-molecule GLP-1 receptor agonists like danuglipron and orforglipron, which are resistant to enzymatic degradation, marks a major advance in patient-friendly drug delivery. This review explores the mechanisms, clinical development, and therapeutic potential of these novel agents, excluding already approved drugs like liraglutide, semaglutide, and tirzepatide. We highlight how multireceptor agonists and oral GLP-1-based therapies may reshape the future landscape of obesity and type 2 diabetes treatment by offering more effective and better-tolerated options.

Orforglipron, a novel non-peptide oral daily glucagon-like peptide-1 receptor agonist as an anti-obesity medicine: A systematic review and meta-analysis.

Orforglipron is a novel once-daily oral non-peptide glucagon-like peptide-1 receptor agonist with several recently published randomized controlled trials (RCTs) evaluating its role in diabetes and obesity. No meta-analysis has analyzed the efficacy and safety of orforglipron; this meta-analysis aimed to address this knowledge gap. A systematic search was conducted in electronic databases to identify RCTs that included individuals with obesity who were administered orforglipron and compared to either a placebo or an active comparator. The primary outcome of interest was the percent change in body weight. From 12 initially screened articles, data from three RCTs involving 774 people were analyzed with a follow-up duration of up to 36&#xa0;weeks. Compared to placebo, patients receiving orforglipron 12&#xa0;mg/day (mean difference (MD), MD -5.48%, 95% CI [-7.64, -3.33], p&#xa0;<&#xa0;0.01), 24&#xa0;mg/day (MD -8.51%, 95% confidence interval (CI) [-9.88, -7.14], p&#xa0;<&#xa0;0.01), 36&#xa0;mg/day (MD -8.84%, 95% CI [-11.68, -6.00], p&#xa0;<&#xa0;0.01) and 45&#xa0;mg/day (MD -8.24%, 95% CI [-12.84, -3.63], p&#xa0;<&#xa0;0.01) had a significantly greater percent reduction in body weight. The percentage of patients being able to achieve >15% weight loss from baseline was significantly higher with orforglipron 24&#xa0;mg/day [Odds ratio (OR) 21.90 (95% CI [4.06, 118.15], p&#xa0;=&#xa0;0.0003), 36&#xa0;mg/day (OR 17.43, 95% CI [3.18, 95.66], p&#xa0;=&#xa0;0.001) and 45&#xa0;mg/day (OR 23.17, 95% CI [4.37, 123.03], p&#xa0;=&#xa0;0.0002). Total but not severe adverse events were significantly higher with all the doses of orforglipron compared to placebo, with the hazard ratios being higher with higher doses. Gastrointestinal side-effects were predominant side effects, being dose-dependent, with nausea, vomiting, constipation, and gastroesophageal reflux being the predominant ones. Orforglipron at 24-45&#xa0;mg/day doses is an effective weight loss medication. The efficacy versus side effect profile suggests that 24-36&#xa0;mg/day is the most optimal dose for orforglipron as an anti-obesity medicine.

Safety and efficacy of the new, oral, small-molecule, GLP-1 receptor agonists orforglipron and danuglipron for the treatment of type 2 diabetes and obesity: systematic review and meta-analysis of randomized controlled trials.

The present systematic review aimed to synthesize available data from recently published randomized trials (RCTs) investigating the efficacy and safety of the novel, orally administered, small-molecule glucagon-like peptide 1 receptor agonists (GLP-1RAs) orforglipron and danuglipron for the treatment of type 2 diabetes mellitus (T2DM), obesity or both. Literature search was performed through Medline (via PubMed), Cochrane Library and Scopus until August 16, 2023. Double-independent study selection, data extraction and quality assessment were performed. Evidence was pooled with random effects meta-analysis. Totally, 1037 patients among seven RCTs were analyzed. All RCTs had low risk of bias according to the Cochrane Collaboration tool (RoB2). Novel GLP-1RAs led to significant reduction in HbA1c in patients with T2DM compared to controls (MD&#xa0;=&#xa0;-1.03&#xa0;%; 95&#xa0;% CI&#xa0;=&#xa0;[-1.29, -0.77]; P&#xa0;<&#xa0;0.001). A significantly greater weight reduction was also noted both in patients with T2DM or obesity compared to controls (MD&#xa0;=&#xa0;-3.26&#xa0;kg; 95&#xa0;% CI&#xa0;=&#xa0;[-4.79, -1.72]; P&#xa0;<&#xa0;0.001 and MD&#xa0;=&#xa0;-7.52&#xa0;kg; 95&#xa0;% CI&#xa0;=&#xa0;[-14.63, -0.41]; P&#xa0;=&#xa0;0.038, respectively; P for subgroup differences&#xa0;=&#xa0;0.25). Regarding safety, novel GLP-1RAs showed a neutral effect on the odds of severe hypoglycemia or serious adverse events (OR&#xa0;=&#xa0;0.34; 95&#xa0;% CI&#xa0;=&#xa0;[0.09, 1.31]; P&#xa0;=&#xa0;0.11 and OR&#xa0;=&#xa0;0.95; 95&#xa0;% CI&#xa0;=&#xa0;[0.39, 2.34]; P&#xa0;=&#xa0;0.91, respectively) and significantly higher odds of gastrointestinal, treatment-emergent adverse events (OR&#xa0;=&#xa0;2.57; 95&#xa0;% CI&#xa0;=&#xa0;[1.49, 4.42]; P&#xa0;<&#xa0;0.001) and adverse events leading to discontinuation (OR&#xa0;=&#xa0;2.89; 95&#xa0;% CI&#xa0;=&#xa0;[1.22, 6.87]; P&#xa0;=&#xa0;0.016). Preliminary evidence supports that orforglipron and danuglipron are efficient in glycemic control and weight reduction in T2DM, obesity or both. More longitudinal research is warranted in order to provide deeper insights into their efficacy, safety and tolerability before their potential incorporation in the pharmacological arsenal against T2DM or obesity.

Disposition and Absolute Bioavailability of Orally Administered Orforglipron in Healthy Participants.

Orforglipron is a non-peptide, oral glucagon-like peptide 1 receptor agonist under development for glycemic control in adults with type 2 diabetes and weight management in people with obesity. Two phase 1, open-label studies evaluated the disposition and absolute bioavailability of orforglipron in healthy adults. Study A participants (N&#xa0;=&#xa0;10) received a 1-mg orforglipron oral capsule while fasting and an intravenous dose of &#x223c;21&#xa0;&#xb5;g of [14C]-orforglipron. Study B participants (N&#xa0;=&#xa0;6) received an oral solution of 3&#xa0;mg of orforglipron with &#x223c;200&#xa0;&#xb5;Ci of [14C]-orforglipron while fasting. In study A, total plasma radioactivity and [14C]-orforglipron were measured by accelerator mass spectrometry (AMS) and high-performance liquid chromatography (HPLC)/AMS, while orforglipron was measured by HPLC/MS. The mean absolute oral bioavailability of orforglipron was 79.1%&#xa0;&#xb1;&#xa0;16.8%. In study B, urine and feces were analyzed for total radioactivity. Metabolic radioprofiling was performed on selected plasma and fecal samples by HPLC/high-resolution MS. The primary route of elimination for [14C]-orforglipron-related radioactivity was via the feces (87%&#xa0;&#xb1;&#xa0;2.8%) with minimal urinary excretion (0.2%&#xa0;&#xb1;&#xa0;0.02%). Total recovery of administered radioactivity was 88% over 384&#xa0;hours after the dose. Metabolite profiling from study B showed that orforglipron underwent extensive oxidative metabolism, followed by microbial metabolism of the oxadiazolone ring. Orforglipron was the most abundant plasma component (93.3%) with minor oxidative metabolites M7 (3.3%) and M23 (1.6%).

Orforglipron: A Novel Oral GLP-1 Agonist for the Treatment of Obesity and Diabetes.

The therapeutic landscape for obesity and type 2 diabetes mellitus (T2DM) is being reshaped by glucagon-like peptide-1 receptor agonists (GLP-1 RAs). Orforglipron (LY3502970) represents a significant evolution in this class. Given the limitations of injectable GLP-1 RAs and the administration constraints of oral semaglutide, orforglipron offers a major convenience advantage: it is a small molecule with ~79% oral bioavailability that requires no food or water restrictions. Mechanistically, it acts by stimulating cyclic adenosine monophosphate without inducing &#x3b2;-arrestin recruitment, thus potentially limiting receptor desensitization and tachyphylaxis. Phase 3 trials demonstrated potent, dose-dependent efficacy. In the ACHIEVE-3 head-to-head trial (T2DM), orforglipron 36&#x2009;mg proved superior to oral semaglutide 14&#x2009;mg, delivering significantly greater reductions in hemoglobin A1c (-2.2% vs -1.4%) and body weight (-9.2% vs -5.3%). In the ATTAIN-2 trial (obesity and T2DM), the same dose achieved 10.5% mean weight loss. The safety profile is consistent with the GLP-1 RA class, dominated by manageable gastrointestinal events mitigated by slow dose escalation. A nondose-dependent heart rate increase and a small signal for mild pancreatitis were observed. A class-specific concern exists regarding increased ventricular arrhythmia risk in patients with heart failure with reduced ejection fraction treated with conventional GLP-1 RAs.

Orforglipron, an oral non-peptide glucagon-like peptide-1 receptor agonist, improves markers of &#x3b2;-cell function and insulin sensitivity in type 2 diabetes.

These participant-level exploratory analyses evaluated the effects of orforglipron, a once-daily, orally administered non-peptide glucagon-like peptide-1 receptor agonist, versus dulaglutide and placebo, on &#x3b2;-cell function and insulin sensitivity biomarkers. Participants (N&#x2009;=&#x2009;378) in this 26-week phase 2 study with inadequately controlled type 2 diabetes (T2D) were randomly assigned to orforglipron (3, 12, 24, 36, or 45&#x2009;mg), dulaglutide (1.5&#x2009;mg), or placebo. Treatment effects on &#x3b2;-cell function and insulin sensitivity markers were assessed, including homeostatic model assessment indices of &#x3b2;-cell function and insulin resistance (HOMA-B and HOMA-IR, respectively); fasting C-peptide, insulin, serum glucose, and glucagon; adiponectin; insulin-like growth factor binding protein 2; proinsulin; and the proinsulin/insulin ratio. Orforglipron doses of 12&#x2009;mg and higher were associated with improved &#x3b2;-cell function and insulin sensitivity. HOMA-B increased up to 123% (C-peptide) and 132% (insulin) with orforglipron doses of 12&#x2009;mg and higher from baseline to week 4 before stabilising. HOMA-B increases were greater with all orforglipron doses than with dulaglutide. Additional &#x3b2;-cell function biomarkers, such as fasting proinsulin and the proinsulin/insulin ratio, also improved with orforglipron doses of 12&#x2009;mg and higher compared with baseline and to a greater extent than seen with dulaglutide. HOMA-IR values decreased up to 16% (C-peptide) and 23% (insulin) with orforglipron by week 26. Reductions in HOMA-IR (insulin) were significant versus baseline only for the highest dose. IGFBP-2 and adiponectin, corollary biomarkers of insulin sensitivity, were generally improved with orforglipron. Increased HOMA-B and improved metabolic biomarkers suggest that treatment with the orally administered non-peptide GLP-1 receptor agonist orforglipron enhanced pancreatic &#x3b2;-cell function and insulin sensitivity in patients with T2D.

Orforglipron in type 2 diabetes mellitus and obesity: an overview.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used in the management of type 2 diabetes mellitus (T2DM) and obesity. An electronic search was conducted in Scopus, PubMed/MEDLINE, and Google Scholar databases. Orforglipron is a novel oral non-peptide GLP-1RA. In T2DM individuals, it has led to reductions in glycated hemoglobin (HbA1c) by up to 2.10%, in weight by up to 10.1&#x2009;kg and in waist circumference by up to 8.7&#x2009;cm. In studies on overweight or obesity, a weight loss up to 13.0&#x2009;kg has been reported. In meta-analyses, orforglipron was the most efficient GLP-1RA in terms of weight loss. Significant decreases in systolic blood pressure have also been found in individuals with and without T2DM. Untoward effects include mild-to-moderate vomiting and nausea, particularly in those receiving high doses and after rapid-dose escalation. Orforglipron is a promising treatment option for T2DM and overweight or obesity, in terms of glucose control and weight loss. The increased frequency of adverse events, particularly in those receiving high doses and after rapid-dose escalation, requires caution before widespread use.

Gastrointestinal adverse events associated with GLP-1 RA in non-diabetic patients with overweight or obesity: a systematic review and network meta-analysis.

Overweight and obesity are major global health issues, increasing disease risk and straining healthcare systems. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are effective for weight loss but cause gastrointestinal side effects, affecting adherence. Research often focuses on diabetics, leaving a gap in understanding their effects on non-diabetic individuals with overweight or obesity. This systematic review and dose-response network meta-analysis addresses this gap, analyzing gastrointestinal adverse events from GLP-1 RAs in non-diabetic subjects with overweight or obesity. We evaluated available evidence by searching PubMed and EMBASE databases, according to specific inclusion and exclusion eligibility criteria to evaluate gastrointestinal adverse events associated with GLP-1 RAs in non-diabetic individuals with overweight or obesity. Quality assessment of included studies was conducted using Cochrane Collaboration's tool. Thirty-nine articles were included in the review showing a total number of 33,354 individuals. Nausea, vomiting, diarrhea, and constipation were the most common gastrointestinal adverse effects. All evaluated GLP-1 RAs led to a significant increase in nausea risk, with orforglipron showing the highest risk, followed by exenatide, tirzepatide, semaglutide, and liraglutide. Additionally, liraglutide, orforglipron, semaglutide, and tirzepatide were associated with increased vomiting risk, while cagrilinitide and exenatide showed no significant increase. Exenatide, cagrilinitide, orforglipron were not associated with diarrhea risk. Finally, semaglutide and liraglutide were associated to increased constipation risk, while cagrilinitide and exenatide showed no significant increase. GLP-1 RAs showed several adverse gastrointestinal effects in non-diabetic patients with overweight or obesity. Understanding the different risk profiles of GLP-1 RAs helps clinicians make informed treatment decisions by balancing therapeutic benefits with potential side effects.

Orforglipron for maintenance of body weight reduction: the double-blind, randomized phase 3b ATTAIN-MAINTAIN trial.

Incretins have improved the management of obesity and its related complications, but maintaining these health benefits requires ongoing administration, which can be challenging. Orforglipron, a once-daily oral nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated weight loss efficacy, improvements in cardiometabolic risk factors, and safety generally similar to injectable GLP-1 receptor agonists. Here this double-blind, placebo-controlled trial randomized participants previously treated with tirzepatide (cohort 1: N&#x2009;=&#x2009;205) or semaglutide (cohort 2: N&#x2009;=&#x2009;171) during the SURMOUNT-5 study to orforglipron once daily or placebo. Cohort 1 participants who achieved body weight plateau maintained a model-based estimate (MBE) of 74.7% (s.e.m. 4.05) of body weight reduction with orforglipron compared with an MBE of 49.2% (s.e.m. 3.92) with placebo, resulting in an estimated treatment difference of MBE 25.5% (95% confidence interval 14.5 to 36.5); P&#x2009;<&#x2009;0.001; treatment-regimen estimand) at week 52. Cohort 2 participants who achieved body weight plateau maintained an MBE of 79.3% (s.e.m. 4.42) of body weight reduction with orforglipron compared with an MBE of 37.6% (s.e.m. 7.46) with placebo, resulting in an estimated treatment difference of MBE 41.7 (95% confidence interval 24.4 to 59.0); P&#x2009;<&#x2009;0.001; treatment-regimen estimand) at week 52. All key secondary endpoints were met. The most common adverse events were gastrointestinal effects, which were mostly mild to moderate in severity. These data demonstrate orforglipron's potential as a globally scalable option for minimizing weight changes after injectable therapy. Trial limitations include the absence of a comparator arm involving continued use of injectable obesity-management medications and the trial's 1-year duration. ClinicalTrials.gov registration: NCT06584916 .

Treatment with orforglipron, an oral glucagon like peptide-1 receptor agonist, is associated with improvements of CV risk biomarkers in participants with type 2 diabetes or obesity without diabetes.

Orforglipron, a novel oral, non-peptide glucagon like peptide-1 (GLP-1) receptor agonist, has demonstrated efficacy in improving body weight reduction and glycemic control. However, its potential benefits in improving cardiovascular (CV) risk factors have yet to be determined. We assessed the effect of orforglipron in participants with type 2 diabetes (T2D) and/or overweight or obesity on blood pressure, lipid, and inflammatory biomarkers associated with risk for major adverse cardiovascular events. Using data from participants with available samples from Phase 2 trials of orforglipron in participants with T2D (N&#x2009;=&#x2009;361) or with overweight or obesity without diabetes mellitus (N&#x2009;=&#x2009;234), we performed an exploratory analysis of changes in CV risk markers. For the T2D study, participants mean age 59&#xa0;years, 40% were assigned female at birth with a mean HbA1c of 8.1% and mean BMI of 35.3&#xa0;kg/m2; they received once daily orforglipron doses (3, 12, 24, 36, or 45&#xa0;mg) or once weekly subcutaneous dulaglutide 1.5&#xa0;mg, or placebo. In the obesity study, participants had a mean age 54&#xa0;years, 60% were assigned female at birth, and mean BMI was 37.9&#xa0;kg/m2; they received once daily orforglipron (12, 24, 36, or 45&#xa0;mg) or placebo. The change from baseline at 26&#xa0;weeks (T2D study) or 36&#xa0;weeks (obesity study) in blood pressure, lipids (cholesterol, triglycerides, Apolipoprotein B (ApoB), Apolipoprotein C3 (ApoC3), N-terminal pro-b-type natriuretic peptide (NT-pro-BNP), and inflammatory biomarkers (high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6)) were assessed. Significant placebo-adjusted decreases from baseline in blood pressure, low-density lipoprotein (LDL) cholesterol, triglycerides, ApoB, ApoC3, and hsCRP were observed following orforglipron treatment in participants with T2D and/or overweight or obesity. In both studies, improvements in blood pressure, lipid parameters, and most of the evaluated biomarkers were of similar magnitude after treatment with 12&#xa0;mg orforglipron as with 24, 36, and 45&#xa0;mg. Orforglipron treatment was associated with beneficial changes in CV risk markers in participants with T2D and in participants with overweight/obesity without T2D. (Clinicaltrials.gov: NCT05048719, NCT05051579).

[Glucagon-like peptide-1 receptor agonists: a new pharmacological treatment option for psychiatric illnesses?].

Albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, orforglipron and semaglutide are glucagon-like peptide&#x2011;1 (GLP-1) receptor agonists. Tirzepatide targets not only GLP&#x2011;1 but also glucose-dependent insulinotropic peptide (GIP) receptors and retatrutide is a&#xa0;triple GLP&#x2011;1, GIP and glucagon receptor agonist. The GLP&#x2011;1 receptor agonists increase insulin release but suppress glucagon release. They slow down the emptying of the stomach and thus prevent blood sugar spikes. They reduce appetite and food intake. In the brain GLP&#x2011;1 receptor agonists lead to a&#xa0;better glycemic control and they appear to have anti-inflammatory and neuroprotective effects. It has been reported that GLP&#x2011;1 receptor agonists reduce oxidative stress and apoptosis, lower the risk of ischemia and promote neurogenesis. The GLP&#x2011;1 receptor agonists can also influence dopaminergic signal transduction in the nucleus accumbens. Therefore, they could modify the effect of cocaine, alcohol and nicotine. Preliminary investigations provide indications of the therapeutic benefits of GLP&#x2011;1 receptor agonists for people with dementia, eating disorders, psychopharmacologically induced weight gain, depression, anxiety and substance use disorders. Typical accompanying adverse reactions are gastrointestinal side effects, such as nausea, vomiting, diarrhea, eructation and gastroesophageal reflux. More severe side effects include pancreatitis, allergic reactions, renal function disorders and possibly an increased risk of thyroid cancer.

Orforglipron (LY3502970), a novel, oral non-peptide glucagon-like peptide-1 receptor agonist: A Phase 1b, multicentre, blinded, placebo-controlled, randomized, multiple-ascending-dose study in people with type 2 diabetes.

Orforglipron Calcium.

Oral glucagon-like peptide-1 receptor agonists and combinations of entero-pancreatic hormones as treatments for adults with type 2 diabetes: where are we now?

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have changed the landscape of type 2 diabetes (T2D) management due to their cardio-renal benefits, their glucose-lowering efficacy and weight loss (WL) maintenance. However, the response to GLP-1 RA monotherapy is heterogeneous. Additionally, the majority of GLP-1 RAs are injectable treatments. Oral GLP-1 RAs and injectable combinations of GLP-1 with other entero-pancreatic hormones (glucose-dependent insulinotropic polypeptide (GIP), glucagon and amylin) are under development for T2D and obesity management. Herein, we review the data on (i) oral GLP-1 RAs (oral semaglutide 25/50&#x2009;mg and orforglipron) and (ii) dual/triple agonists (tirzepatide, cagrilintide 2.4&#x2009;mg/semaglutide 2.4&#x2009;mg, survodutide, mazdutide, retatrutide) that have recently completed phase 3 trials for T2D or are currently in phase 3 clinical trials. Tirzepatide is the first approved dual agonist (GLP-1/GIP) for T2D and obesity management. We are in a new era in T2D management where entero-pancreatic hormone-based treatments can result in&#x2009;&#x2265;15% WL and euglycemia for many people with T2D. Multiple molecules with different mechanisms of action are under development for T2D, obesity and other metabolic complications. Data on their cardio-renal benefits, long-term efficacy and safety as well as their cost-effectiveness will better inform their position in treatment algorithms.

Effects of once-daily oral orforglipron on weight and metabolic markers: a systematic review and meta-analysis of randomized controlled trials.

The aim of this study is to assess the effects of once-daily oral orforglipron on weight and metabolic markers in adult patients. PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were systematically searched until February 2024 for randomized controlled trials (RCTs) comparing orforglipron versus placebo or other anti-obesity medications in adult patients. Weighted mean differences (WMDs) for continuous outcomes and risk ratios (RRs) or risk differences for binary endpoints were computed, with 95% confidence intervals (CIs). Heterogeneity and risk of bias were assessed with I2 statistics and Rob-2, respectively. Statistical analyses were performed using R, version 4.2.2. A total of four studies were included, comprising 815 patients, of whom 620 (76.1%) were prescribed orforglipron. Compared with placebo, orforglipron reduced body weight (WMD -6.14 kg, 95% CI -9.62 to -2.66 kg), body mass index (WMD -2.87 kg/m2, 95% CI -4.65 to -1.10 kg/m2), and waist circumference (WMD -5.32 cm, 95% CI -9.13 to -1.51 cm). More patients treated with orforglipron than placebo achieved a weight loss of &#x2265; 5% (RR 3.31, 95% CI 2.23-4.93), &#x2265; 10% (RR 5.24, 95% CI 2.07-13.31), and &#x2265; 15% (RR 9.53, 95% CI 1.26-71.89). The most common adverse events were related to the gastrointestinal tract. In this meta-analysis, the use of once-daily oral orforglipron by adult patients was associated with a significant decrease in body weight, as compared with placebo, with an increase in non-severe gastrointestinal adverse events. Phase 3 RCTs are expected to shed further light on the efficacy and safety of once-daily oral orforglipron over the long term.

Comparison of the efficacy and safety of GLP-1 receptor agonists on cardiovascular events and risk factors: A review and network meta-analysis.

This study aims to systematically evaluate and perform a systematic review and network meta-analysis comparing the comprehensive cardiovascular protective effects of various glucagon-like peptide-1 receptor agonists (GLP-1RAs), focusing on cardiovascular events and risk factors. We searched PubMed, Embase, Cochrane Library and Web of Science from inception to December 15, 2024. Included studies were published randomized controlled trials (RCTs) comparing GLP-1RAs to placebo or other GLP-1RAs. Missing data were standardized, and network meta-analysis was performed using Stata 17.0. Study heterogeneity, publication bias and evidence quality were assessed using the Cochrane Risk of Bias tool and Confidence in Network Meta-Analysis (CINeMA). As of December 15, 2024, a total of 18&#x2009;313 articles were retrieved. Based on the inclusion and exclusion criteria, 156 high-quality studies were included, incorporating 144&#x2009;782 patients and 14 different GLP-1RAs. The network meta-analysis demonstrated low heterogeneity, ensuring the reliability of the results. Comprehensive analysis revealed the following: Efpeglenatide was the most effective in reducing major adverse cardiovascular events. Oral semaglutide shows more significant advantages in reducing all-cause mortality and cardiovascular mortality. Orforglipron excelled in glycaemic control and weight reduction. SC-Semaglutide showed the greatest efficacy in lowering both systolic blood pressure and diastolic blood pressure, Liraglutide showed the greatest efficacy in lowering total cholesterol, Noiiglutide in triglycerides and Taspoglutide in low-density lipoprotein cholesterol, but no GLP-1RAs in high-density lipoprotein cholesterol. GLP-1RAs did not significantly increase the incidence of adverse events, but Orforglipron and Taspoglutide significantly increased the incidence of gastrointestinal adverse events compared with placebo. This study compared the cardiovascular benefits of different GLP-1RAs, including reductions in cardiovascular events and improvements in multiple cardiovascular risk factors. However, due to limitations in the quantity and quality of the included studies, the conclusions should be interpreted with caution. Future large-scale, high-quality clinical trials are needed to validate these findings and further optimize comprehensive cardiovascular management strategies for patients.

Oral GLP-1 Receptor Agonists for Weight Loss.

With the increasing prevalence of obesity and the advent of new and highly effective antiobesity medications, there is renewed interest in novel antiobesity pharmacotherapy. Currently, the most effective medications for obesity are injectable medicines. There is a need to develop equally efficacious oral drugs to increase availability to patients. Oral semaglutide was approved by the Food and Drug Administration for type 2 diabetes in 2019. Herein, we review the current literature regarding the use of oral GLP-1 receptor agonists specifically for obesity including semaglutide, danuglipron, and orforglipron, with a focus on oral semaglutide as it is Food and Drug Administration-approved, although not for obesity alone. We also examine the future directions and impacts it will have on patients with obesity and overweight related to weight loss and cardiovascular disease.

Quantitative Comparison of Glucagon-Like Peptide-1 Receptor Agonists on Weight Loss in Adults: A Systematic Review and Model-Based Meta-Analysis.

The objective of this study is to quantitatively compare the weight loss effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in adult patients with no diabetes and type 2 diabetes (T2D). PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase have been used as data sources from database inception to January 6, 2024. A total of 137 trials, encompassing 310 treatment arms, 17 GLP-1RAs, and 56,683 patients, were included in the analysis. The included trials were divided into three groups based on the characteristics of the populations: nondiabetic overweight or obesity group (NDOOG), type 2 diabetes Caucasian group (T2DCG), and type 2 diabetes Asian group (T2DAG). The effects of covariates were further evaluated, patients with a higher baseline body weight tend to have better weight loss outcomes, and patients with a higher baseline glycated hemoglobin (HbA1c) tend to achieve better blood sugar control. Five mathematical models were subjected to longitudinal analysis. In terms of &#x394; body weight, retatrutide (12 mg qw) was the most effective treatment (mean difference = -26.56% [95% confidence interval: -43.89% to -3.01%]). Tirzepatide (15 mg qw) demonstrated good weight loss ability in all three &#x394;BW models, &#x394;BW-NDOOG (-22.76% [-26.45% to -18.50%]), &#x394;BW-T2DCG (-11.09% [-12.39% to -9.44%])), and &#x394;BW-T2DAG (-4.97% [-5.84% to -4.12%]). In the aspect of &#x394;HbA1c, tirzepatide (10 mg qw) and oral orforglipron (10 mg qd) were the most effective drug, respectively. GLP-1RAs demonstrated effective weight management in both nondiabetic and T2D populations. Retatrutide achieved the most pronounced weight reduction, followed by tirzepatide. GLP-1RAs also significantly improved glycemic control for patients with T2D, with tirzepatide performing the best for glycemic control.

Comparative efficacy and safety of GLP-1 receptor agonists for weight reduction: A model-based meta-analysis of placebo-controlled trials.

Obesity is a global epidemic. The FDA has approved glucagon-like peptide-1 (GLP-1) receptor agonists such as Liraglutide, Semaglutide, and the GLP-1/gastric inhibitory polypeptide (GIP) dual agonist Tirzepatide for the treatment of obesity. Clinical trials of GLP-1/GIP/glucagon(GCG) triple agonists are ongoing. This study compared the efficacy and safety profiles of different GLP-1 receptor agonists (GLP-1RAs) for weight reduction and explored the related influencing factors, providing quantitative information for the development of GLP-1RAs and their clinical use. This systematic review of public databases included placebo-controlled randomized clinical trials of GLP-1RAs. Time-course, dose-response, and covariate models were used to describe the efficacy characteristics and influencing factors of different GLP-1RAs. Subgroup analyses were performed to explore efficacy differences in receptor specificity. Meta-analyses compared the incidence of adverse event and dropout rates among different GLP-1RAs. Fifty-five studies involving 16,269 participants and 12 GLP-1RAs were included. Six drugs showed significant dose-response relationships. The maximum weight reduction effect ranged from 4.25&#xa0;kg (Liraglutide) to 22.6&#xa0;kg (Retatrutide). Reported onset times ranged from 6.4 weeks (Orforglipron) to 19.5 weeks (Tirzepatide). At 52 weeks, weight reduction effects were 7.03&#xa0;kg, 11.07&#xa0;kg, and 24.15&#xa0;kg for mono-agonists, dual-agonists, and tri-agonists, respectively. There was a significant negative correlation in the exponential pattern between age and weight reduction effect, whereas baseline weight and BMI had no significant impact. Common adverse events of GLP-1RAs, reported in the literature include nausea, vomiting, diarrhea, and constipation, with a significantly higher incidence of nausea than that of placebo. This study provides a quantitative evaluation of the efficacy and safety of GLP-1RAs and offers valuable insights into the assessment of new drugs for weight reduction.

Incretin-based therapies for the treatment of obesity-related diseases.

Obesity-related disability-adjusted life years (DALYs) are expected to increase by approximately 40% from 2020 to 2030. DALYs and mortality related to obesity are the consequence of multiple comorbidities such as cardiovascular (i.e., heart failure) and metabolic diseases (i.e. type 2 diabetes [T2D], metabolic dysfunction-associated steatotic liver disease [MASLD]). Lifestyle interventions represent the foundation of obesity treatment, yet an escalation to pharmacological and/or surgical interventions is often needed. Liraglutide, semaglutide and tirzepatide are incretin-based therapies currently approved by FDA for the management of obesity, while triple GIPR/GCGR/GLP-1R agonist retatrutide (LY3437943), the cagrilintide/semaglutide (CagriSema) 2.4&#x2009;mg combination, high-dose oral semaglutide, and oral orforglipron are in advanced stages of development. Incretin-based therapies have been associated with a body weight (BW) reduction of &#x2265;5% in at least half of patients in most randomized controlled trials (RCT) and real-world studies (RWS). Semaglutide and tirzepatide have also displayed a mean 60-69% 10-years relative risk reduction of T2D development. In line with evidence accrued in patients with T2D, incretin-based therapies produced a favorable effect on traditional cardiovascular risk factors, such as lipids and blood pressure, and even reduced the risk of major cardiovascular events and heart failure-related events in individuals with obesity, as recently demonstrated for the first time in the SELECT trial with semaglutide 2.4&#x2009;mg once-weekly. Moreover, incretin-based therapies have also been proven beneficial on obesity-related comorbidities, such as knee osteoarthritis (KOA), obstructive sleep apnea (OSA) syndrome, and MASLD. Further research is needed to improve our understanding of their effects on obesity-related comorbidities and the underlying mechanism, whether involving direct effects on target tissues or mediated by improvement in BW, glucose levels and other CV risk factors.

Orforglipron Added to Titrated Insulin Glargine in Type 2 Diabetes: The ACHIEVE-5 Randomized Clinical Trial.

The effects of orforglipron, an oral, nonpeptide glucagon-like peptide 1 receptor agonist, added to insulin glargine for treatment of type 2 diabetes have not been described. To assess efficacy and safety of orforglipron added to titrated insulin glargine in adults with type 2 diabetes and inadequate glycemic control. Randomized, double-blind, phase 3 study conducted at 72 sites across the US, Brazil, China, Japan, and Romania between November 10, 2023, and September 15, 2025, in adults with type 2 diabetes taking insulin glargine with or without metformin and/or sodium-glucose cotransporter 2 inhibitors over 40 weeks. Participants were randomized (1:1:1:1) to receive once-daily 3-mg (n&#x2009;=&#x2009;137), 12-mg (n&#x2009;=&#x2009;132), or 36-mg (n&#x2009;=&#x2009;136) dosages of orforglipron or placebo (n&#x2009;=&#x2009;141), in addition to titrated insulin glargine. The primary outcome was mean hemoglobin A1c (HbA1c) change from baseline to week 40 (for the 12-mg once daily and 36-mg once daily dosages of orforglipron). Key secondary outcomes were mean HbA1c change from baseline (for the 3-mg once daily dosage of orforglipron), proportion of participants achieving HbA1c targets of lower than 7.0% and 6.5% or lower, and mean body weight change and percentage change from baseline to week 40. Among 546 randomized participants (median age, 61.0 [IQR, 26-95] years; 52.9% male; median duration of type 2 diabetes, 14.6 [IQR, 0.1-40.7] years; mean HbA1c, 8.50% [SD, 0.95%]; mean body mass index, 30.8 [SD, 6.1]), 507 (92.9%) completed the trial. At week 40, the mean changes from baseline in HbA1c were -1.58%, -1.88%, and -1.82% with orforglipron, 3 mg, 12 mg, and 36 mg once daily, respectively, vs -0.79% with placebo. Each dosage of orforglipron was superior to placebo (estimated treatment differences: 3 mg once daily, -0.78% [95% CI, -1.02% to -0.55%]; 12 mg once daily, -1.08% [95% CI, -1.33% to -0.83%]; 36 mg once daily, -1.03% [95% CI, -1.28% to -0.77%]; P&#x2009;<&#x2009;.001 for all). All key secondary outcomes demonstrated statistically significant differences in favor of orforglipron compared with placebo. Mean percentage body weight change from baseline was -2.6%, -4.8%, and -5.4% with orforglipron, 3 mg once daily, 12 mg once daily, and 36 mg once daily, respectively, vs 0.2% with placebo. The most frequent adverse events with orforglipron were gastrointestinal (mild to moderate). Orforglipron did not increase the risk of clinically significant hypoglycemia vs placebo. In participants with type 2 diabetes inadequately controlled by insulin glargine, addition of oral orforglipron significantly improved glycemic control and body weight, without increasing hypoglycemia risk, compared with placebo. ClinicalTrials.gov Identifier: NCT06109311.

The efficacy and safety of danuglipron and orforglipron in patients with type 2 diabetes and obesity: a systematic review and meta-analysis.

This study assesses the efficacy and safety of the novel oral small molecule glucagon-like peptide-1 receptor agonists (GLP-1 RAs) danuglipron and orforglipron in the treatment of type 2 diabetes (T2DM) and obesity through systematic review and meta-analysis. Electronic databases (PubMed, Web of Science, Cochrane Library and Embase) were systematically searched up to 20 May 2025 to include randomised controlled trials evaluating danuglipron/orforglipron in patients with T2DM and/or obesity. Changes in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), fasting plasma insulin (FPI), weight and body mass index (BMI) compared with baseline post-treatment were evaluated using random-/fixed-effects models, alongside safety outcomes. Eight studies with low bias risk involving 1,454 participants were analysed. Meta-analysis results demonstrated that danuglipron significantly decreased HbA1c (mean difference [MD]: -0.90; 95% CI: -1.06, -0.74), FPG (MD: -24.66; 95% CI: -30.45, -18.86) and weight (MD: -2.17; 95% CI: -3.10,&#xa0;-1.23) and improved FPI (MD: 2.94; 95% CI: 1.50, 4.38). Orforglipron also showed significant positive effects on HbA1c (MD: -1.02; 95% CI: -1.18,&#xa0;-0.86), FPG (MD: -26.91; 95% CI: -31.05, -22.78), weight (MD: -6.28; 95% CI: -8.45, -4.11) and BMI (MD: -2.64; 95% CI: -3.38, -1.89). However, both danuglipron and orforglipron were associated with the occurrence of treatment-related adverse events and gastrointestinal adverse events (AEs). The oral GLP-1 RAs danuglipron and orforglipron are capable of improving blood glucose levels and reducing weight; however, they also pose an increased risk of gastrointestinal AEs. Further longitudinal studies are warranted to gain a deeper understanding of their efficacy, safety and tolerability.

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

Obesity 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). 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. Mean differences (MDs) and risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using random-effects models. Five RCTs comprising 4410 participants were included. Orforglipron demonstrated dose-dependent reductions in body weight from 2.48% at 3&#x2009;mg to 9.8% at 45&#x2009;mg, BMI from 0.89 to 3.62&#x2009;kg/m2, waist circumference from 1.57 to 6.9&#x2009;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&#x2009;mg or higher and treatment discontinuation rates were highest at 24&#x2009;mg (RR:4.61 [95% CI:1.6 to 13.33]) and 36&#x2009;mg (RR:3.68 [95% CI:2.48 to 5.44]) doses. Serious adverse events and mortality rates were comparable to those with placebo. Orforglipron 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.