Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Orforglipron is a small molecule activating the GLP-1 receptor by an allosteric mechanism. It holds much promise since it allows for an oral administration as opposed to direct agonists like semaglutide or liratglutide which have to be injected due to their peptide structure. Kansakar et al. provide a review dedicated to orforglipron highlighting its effects in patients sufferring from diabetes mellitus type 2 and/or obesity revealed in phase 1 – 3 clinical trials.

This reviewer recommends acceptance of the manuscript after consideration of few minor points detailed below.

• 2: Sounds as if there were no oral formulations of semaglutide – please see the paper below:

Efficacy of Semaglutide in a Subcutaneous and an Oral Formulation.

Meier JJ.Front Endocrinol (Lausanne). 2021 Jun 25;12:645617. doi: 10.3389/fendo.2021.645617. eCollection 2021.PMID: 34248838

• Although the GLP-1-R is already mentioned on p. 3, the reader learns only on p. 5 that this is a G protein-coupled receptor.
• Additional information about the exact sites of the GLP-1-R targeted by orforglipron would be interesting.
• Table 1: In lines 1 – 3, details with respect to the composition of the population should be given (Caucasians?, mixed population?).
• In Table 2, details to the duration of the treatment should be given.
• 8 (target glycemia below 7 %): I guess that the authors mean that the HbA1C was lower than 7 %.
• 12: If one reads that both formation of CYP metabolites and renal excretion play a minor role, one might wonder in which way elimination of orforglipron takes place. Does phase 2 metabolism play an important role (this aspect has not been considered)?
• 14: Semaglutide was reported to lead to pancreatitis and retinal attachment/ischemic optic neuropathy in rare instances. Such adverse events may be related to direct or indirect agonism at the GLP-1-R? Did these side effects also occur under the treatment with orforglipron?
• Abbreviations need to be explained, e.g. Tmax, Cmax, GI and AE in Table 1, N/A in Tables 3 and 4, SBP, DBP, LDL, HDL, TG and hsCRP in Table 5, SGLT-2 on p. 16 and HOMA-B and HOMA-IR.
• Please provide the regulatory status of orforglipron e.g. on January 16, 2026. Is the drug under review by the FDA or EMA?

Author Response

Orforglipron is a small molecule activating the GLP-1 receptor by an allosteric mechanism. It holds much promise since it allows for an oral administration as opposed to direct agonists like semaglutide or liratglutide which have to be injected due to their peptide structure. Kansakar et al. provide a review dedicated to orforglipron highlighting its effects in patients sufferring from diabetes mellitus type 2 and/or obesity revealed in phase 1 – 3 clinical trials.

This reviewer recommends acceptance of the manuscript after consideration of few minor points detailed below.

Thanks!

 

• 2: Sounds as if there were no oral formulations of semaglutide – please see the paper below:

Efficacy of Semaglutide in a Subcutaneous and an Oral Formulation.

Meier JJ.Front Endocrinol (Lausanne). 2021 Jun 25;12:645617. doi: 10.3389/fendo.2021.645617. eCollection 2021.PMID: 34248838

 

We rectified this issue and cited the suggested paper.

• Although the GLP-1-R is already mentioned on p. 3, the reader learns only on p. 5 that this is a G protein-coupled receptor.
• RE: We added a paragraph in the Intro to amend. Thanks.

 

• Additional information about the exact sites of the GLP-1-R targeted by orforglipron would be interesting.
• RE: We added a paragraph to discuss these aspects. Thanks.

 

 

• Table 1: In lines 1 – 3, details with respect to the composition of the population should be given (Caucasians?, mixed population?).
• We specify that the study in the last raw was conducted in Japanese patients.

 

 

• In Table 2, details to the duration of the treatment should be given.
• RE: Done.

 

 

• 8 (target glycemia below 7 %): I guess that the authors mean that the HbA1C was lower than 7 %.
• RE: Rectified.

 

• 12: If one reads that both formation of CYP metabolites and renal excretion play a minor role, one might wonder in which way elimination of orforglipron takes place. Does phase 2 metabolism play an important role (this aspect has not been considered)?
• RE: We added a paragraph to discuss these aspects. Thanks.

 

• 14: Semaglutide was reported to lead to pancreatitis and retinal attachment/ischemic optic neuropathy in rare instances. Such adverse events may be related to direct or indirect agonism at the GLP-1-R? Did these side effects also occur under the treatment with orforglipron?
• RE: We added a paragraph to discuss these aspects. Thanks.

 

 

• Abbreviations need to be explained, e.g. Tmax, Cmax, GI and AE in Table 1, N/A in Tables 3 and 4, SBP, DBP, LDL, HDL, TG and hsCRP in Table 5, SGLT-2 on p. 16 and HOMA-B and HOMA-IR.
• RE: Abbreviations have been spelled out, as requested.

 

 

• Please provide the regulatory status of orforglipron e.g. on January 16, 2026. Is the drug under review by the FDA or EMA?
• RE: As of January 16, 2026, orforglipron is not yet approved by major regulators such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA), but it is actively under regulatory review and expected to be decided in 2026:

Reviewer 2 Report

Comments and Suggestions for Authors

The authors present a comprehensive review on the properties of orforglipron, the first orally available GLP1 agonist likely to reach the market. The review is written in a somewhat rambling manner (for example, the advantages of oral vs. parenteral application are mentioned at least five times) and would possibly benefit from some shortening.

Furthermore, I believe that Fig. 2 is quite redundant to Fig. 1 and could be replaced with a scheme or even a structure showing the difference in binding to the GLP1 receptor between a peptide agonist and orforglipron (PDB 6XOX). The legend to Fig. 2 reads as if written by some kind of artificial intelligence. For example, for any organic compound, carbon atoms will constitute the bulk of the structure.

The ATTAIN trials are discussed in section 4.2. When reading this section, I wondered how orforglipron compared to peptidic agonists. Maybe a forward reference to section 6.3 could be included.

In section 6.1, the authors discuss quite nebulously that "certain racial and ethnic minorities" were underrepresented in the clinical trials. Is it not possible to be more specific?

Author Response

The authors present a comprehensive review on the properties of orforglipron, the first orally available GLP1 agonist likely to reach the market. The review is written in a somewhat rambling manner (for example, the advantages of oral vs. parenteral application are mentioned at least five times) and would possibly benefit from some shortening.

Thanks!

Furthermore, I believe that Fig. 2 is quite redundant to Fig. 1 and could be replaced with a scheme or even a structure showing the difference in binding to the GLP1 receptor between a peptide agonist and orforglipron (PDB 6XOX). The legend to Fig. 2 reads as if written by some kind of artificial intelligence. For example, for any organic compound, carbon atoms will constitute the bulk of the structure.

We have rewritten the legend of Figure 2. We respectfully believe that the ball-and-stick figure offers additional structural and 3D information compared to Figure 1.

The ATTAIN trials are discussed in section 4.2. When reading this section, I wondered how orforglipron compared to peptidic agonists. Maybe a forward reference to section 6.3 could be included.

Done, thanks for the suggestion.

In section 6.1, the authors discuss quite nebulously that "certain racial and ethnic minorities" were underrepresented in the clinical trials. Is it not possible to be more specific?

We have removed that sentence. Thanks.