Advances in Non-CPAP Management of Obstructive Sleep Apnea: Spotlight on Pharmacological Therapies

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

I would like to thank you for the opportunity to review this manuscript.

General Assessment

This manuscript provides a comprehensive and timely narrative review of non-CPAP management strategies for obstructive sleep apnea, with a particular focus on emerging pharmacological therapies. The topic is highly relevant given the well-recognized limitations of CPAP adherence and the growing interest in phenotype- and endotype-driven treatment approaches.

The review is generally well structured, scientifically sound, and supported by an extensive and up-to-date reference list. The sections dedicated to pharmacological interventions are detailed and informative, and the authors demonstrate strong familiarity with recent clinical trials and mechanistic frameworks.

However, several minor issues related to clarity, balance, and structure should be addressed to further improve the manuscript’s readability, clinical applicability, and methodological transparency.

Specific Comments

1. Title (Lines 1–3)
   The title is clear and informative. The authors may consider specifying that this is a narrative reviewto better set reader expectations and distinguish it from systematic reviews.
2. Abstract (Lines 15–29)
   The abstract accurately summarizes the scope and conclusions of the review.
   Minor suggestion: briefly indicate that this is a narrative review and explicitly mention the concept of phenotype/endotype-driven pharmacological management, which represents a key unifying theme of the manuscript.
3. Introduction – Epidemiology and Background (Lines 33–45)
   The epidemiological overview is appropriate and well referenced.
   Some sentences are relatively long and could benefit from minor language editing to improve clarity and readability.
4. Introduction – Pathophysiology and PALM Framework (Lines 46–50)
   The PALM framework is correctly introduced.
   Consider adding one brief sentence explaining how this framework directly informs the therapeutic strategies discussed later in the manuscript.
5. CPAP Adherence and Rationale for Alternatives (Lines 56–68)
   The discussion of CPAP adherence is clear and clinically relevant.
   The authors may wantto briefly emphasize that alternative therapies should generally be considered complementary or second-line, depending on patient phenotype.
6. Non-CPAP Therapy Overview (Lines 69–78)
   This section provides a concise overview of non-CPAP options.
   Consider adding a short summary statement at the end highlighting patient selection criteriafor non-CPAP approaches within a personalized treatment framework.
7. Oral Appliances (Lines 79–92)
   The discussion of MADs is balanced and well supported by evidence.
   Minor stylistic suggestion: some repetition regarding efficacy versus CPAP could be streamlined for conciseness.
8. Surgical Therapies (Lines 93–116)
   Surgical options are appropriately described.
   The authors may consider breaking this long paragraph into shorter sections to improve readability and to clearly distinguish resective versus reconstructive procedures.
9. Hypoglossal Nerve Stimulation (Lines 120–128)
   The indications for HNS are clearly stated.
   Consider briefly commenting on real-world limitations such as cost, availability, and candidacy constraints.
10. Positional and Behavioral Therapy (Lines 129–138)
    This section is clear and concise.
    A brief statement reinforcing the role of these strategies as part of multimodal therapywould enhance clinical applicability.
11. Pharmacological Therapy – General Overview (Lines 139–147)
    The categorization of pharmacological approaches is logical and well structured.
    Consider explicitly stating that no pharmacological agent currently replaces CPAP as first-line therapy.
12. Figure 1 (Lines 148–149)
    Figure 1 is helpful.
    The legend could be expanded to clarify which treatments are disease-modifying versus symptomatic.
13. Weight Loss Medications – General (Lines 173–185)
    The rationale for targeting obesity-related OSA is well explained.
    A brief mention of limitations (e.g., variability in response, long-term adherence) would improve balance.
14. Tirzepatide and SURMOUNT-OSA Trials (Lines 186–204)
    This section is detailed and up to date.
    Consider clarifying whether FDA approval applies broadly or specifically to obesity-related OSA phenotypes.
15. Other Anti-Obesity Agents (Lines 205–216)
    The discussion is appropriate.
    The authors may wantto emphasize the relatively limited and heterogeneous evidence for agents beyond GLP-1/GIP agonists.
16. Upper Airway Muscle Modulators – General (Lines 217–224)
    This is a strong and well-written section.
    Consider briefly summarizing which patient endotypes are most likely to benefit from noradrenergic–antimuscarinic combinations.
17. AD109 and MARIPOSA Trial (Lines 235–243)
    The trial is clearly described.
    A short comment on regulatory status and availability would enhance clinical relevance.
18. Alternative Pharmacological Combinations (Lines 249–260)
    The emerging combination strategies are interesting and well presented.
    The authors may consider emphasizing that evidence remains preliminary and largely short-term.
19. Loop Gain Modulation – Carbonic Anhydrase Inhibitors (Lines 266–302)
    The physiological rationale and clinical evidence are clearly explained.
    It would be helpful to explicitly note that long-term safety and efficacy data are still lacking.
20. Section Heading Duplication (Lines 303–304)
    The subsection title “Modulators of ventilatory stability (loop gain)” is repeated and may cause confusion.
    Please revise the heading of Section 3.4 to reflect its focus on arousal threshold modulation.
21. Arousal Threshold Modulation (Lines 304–345)
    The discussion is balanced and clinically relevant.
    Consider reinforcing caution when using sedative agents in patients with severe anatomical obstruction.
22. Other Experimental Compounds (Lines 347–361)
    This section is forward-looking and interesting.
    A brief statement emphasizing the preclinical natureof many of these approaches would avoid overinterpretation.
23. Residual Excessive Daytime Sleepiness – Overview (Lines 362–368)
    The prevalence and clinical impact of rEDS are clearly described.
    The authors may consider adding a concise summary table comparing wake-promoting agents.
24. Wake-Promoting Agents – Comparative Discussion (Lines 373–501)
    This section is thorough and well referenced.
    Minor suggestion: streamline some repetitive descriptions of mechanisms of action for readability.
25. Future Directions and Challenges (Lines 506–522)
    This section is appropriate but could be strengthened by explicitly listing unresolved issues such as long-term outcomes, combination therapy strategies, and cost-effectiveness.
26. Language and Terminology
    Minor grammatical and stylistic issues are present.
    Please standardize terminology (e.g., CPAP vs. PAP, OSA vs. OSAS) and consider a final language edit.
27. References

References are appropriate and up-to-date

Recommendation

This is a high-quality and informative review that addresses an important and evolving area in sleep medicine. The points raised above are minor and primarily relate to clarity, balance, and presentation rather than scientific validity. I therefore recommend Minor Revision.

Comments on the Quality of English Language

Language and Terminology
Minor grammatical and stylistic issues are present.
Please standardize terminology (e.g., CPAP vs. PAP, OSA vs. OSAS) and consider a final language edit.

Author Response

Reviewer 1

I would like to thank you for the opportunity to review this manuscript.

General Assessment

This manuscript provides a comprehensive and timely narrative review of non-CPAP management strategies for obstructive sleep apnea, with a particular focus on emerging pharmacological therapies. The topic is highly relevant given the well-recognized limitations of CPAP adherence and the growing interest in phenotype- and endotype-driven treatment approaches.

The review is generally well structured, scientifically sound, and supported by an extensive and up-to-date reference list. The sections dedicated to pharmacological interventions are detailed and informative, and the authors demonstrate strong familiarity with recent clinical trials and mechanistic frameworks.

However, several minor issues related to clarity, balance, and structure should be addressed to further improve the manuscript’s readability, clinical applicability, and methodological transparency.

 

Response: We thank the Reviewer for her/his appreciation.

 

Specific Comments

1. Title (Lines 1–3)
   The title is clear and informative. The authors may consider specifying that this is a narrative reviewto better set reader expectations and distinguish it from systematic reviews.

 

Response: We thank the Reviewer for this suggestion. We have now specified that the manuscript is a narrative review to better set reader expectations. This change has been made on page 1, lines 1–3.

 

2. Abstract (Lines 15–29)
   The abstract accurately summarizes the scope and conclusions of the review.
   Minor suggestion: briefly indicate that this is a narrative review and explicitly mention the concept of phenotype/endotype-driven pharmacological management, which represents a key unifying theme of the manuscript.

 

Response: We agree with the Reviewer. The Abstract has been revised to explicitly state that this is a narrative review and to emphasize the phenotype- and endotype-driven pharmacological management framework. Changes are reported on page 1, lines 26-30.

 

3. Introduction – Epidemiology and Background (Lines 33–45)
   The epidemiological overview is appropriate and well referenced.
   Some sentences are relatively long and could benefit from minor language editing to improve clarity and readability.

 

Response: We thank the Reviewer for this comment. Minor language editing was performed to improve clarity and readability without altering content.

 

4. Introduction – Pathophysiology and PALM Framework (Lines 46–50)
   The PALM framework is correctly introduced.
   Consider adding one brief sentence explaining how this framework directly informs the therapeutic strategies discussed later in the manuscript.

 

Response: We agree and have added a sentence clarifying how the PALM framework directly informs therapeutic strategies discussed later in the manuscript. This addition appears at lines 57-58.

 

5. CPAP Adherence and Rationale for Alternatives (Lines 56–68)
   The discussion of CPAP adherence is clear and clinically relevant.
   The authors may wantto briefly emphasize that alternative therapies should generally be considered complementary or second-line, depending on patient phenotype.

 

Response: We have clarified that non-CPAP therapies should generally be considered complementary or second-line options, depending on patient phenotype. This clarification is reported at lines 71-74.

 

6. Non-CPAP Therapy Overview (Lines 69–78)
   This section provides a concise overview of non-CPAP options.
   Consider adding a short summary statement at the end highlighting patient selection criteriafor non-CPAP approaches within a personalized treatment framework.

 

Response: A concise summary statement highlighting patient selection within a personalized treatment framework has been added. See lines 89–93.

 

7. Oral Appliances (Lines 79–92)
   The discussion of MADs is balanced and well supported by evidence.
   Minor stylistic suggestion: some repetition regarding efficacy versus CPAP could be streamlined for conciseness.

 

Response: We agree and have streamlined repetitive statements regarding efficacy versus CPAP for conciseness. Revisions are shown at lines 94-99.

 

8. Surgical Therapies (Lines 93–116)
   Surgical options are appropriately described.
   The authors may consider breaking this long paragraph into shorter sections to improve readability and to clearly distinguish resective versus reconstructive procedures.

 

Response: The section has been restructured into shorter paragraphs to improve readability and to distinguish resective from reconstructive approaches. Changes are located at lines 105–129.

 

9. Hypoglossal Nerve Stimulation (Lines 120–128)
   The indications for HNS are clearly stated.
   Consider briefly commenting on real-world limitations such as cost, availability, and candidacy constraints.

 

Response: We have added a brief comment addressing real-world limitations, including cost, availability, and candidacy constraints. This revision is at lines 141-144.

 

10. Positional and Behavioral Therapy (Lines 129–138)
    This section is clear and concise.
    A brief statement reinforcing the role of these strategies as part of multimodal therapywould enhance clinical applicability.

 

Response: We agree and have reinforced the role of these strategies within a multimodal treatment approach. See lines 151–154.

 

11. Pharmacological Therapy – General Overview (Lines 139–147)
    The categorization of pharmacological approaches is logical and well structured.
    Consider explicitly stating that no pharmacological agent currently replaces CPAP as first-line therapy.

 

Response: We have explicitly stated that no pharmacological agent currently replaces CPAP as first-line therapy. This clarification appears at lines 160-161.

 

12. Figure 1 (Lines 148–149)
    Figure 1 is helpful.
    The legend could be expanded to clarify which treatments are disease-modifying versus symptomatic.

 

Response: The figure legend has been expanded to distinguish disease-modifying from symptomatic treatments. Changes are reported at lines 177-181.

 

13. Weight Loss Medications – General (Lines 173–185)
    The rationale for targeting obesity-related OSA is well explained.
    A brief mention of limitations (e.g., variability in response, long-term adherence) would improve balance.

 

Response: We have added a brief discussion of limitations, including variability of response and long-term adherence. See lines 205-213.

 

14. Tirzepatide and SURMOUNT-OSA Trials (Lines 186–204)
    This section is detailed and up to date.
    Consider clarifying whether FDA approval applies broadly or specifically to obesity-related OSA phenotypes.

 

Response: We have clarified that FDA approval applies specifically to adults with obesity-related OSA. This clarification is reported at lines 237-239

 

15. Other Anti-Obesity Agents (Lines 205–216)
    The discussion is appropriate.
    The authors may wantto emphasize the relatively limited and heterogeneous evidence for agents beyond GLP-1/GIP agonists.

 

Response: We agree and have emphasized the limited and heterogeneous evidence beyond GLP-1/GIP agonists. Revisions are at lines 214-221.

 

16. Upper Airway Muscle Modulators – General (Lines 217–224)
    This is a strong and well-written section.
    Consider briefly summarizing which patient endotypes are most likely to benefit from noradrenergic–antimuscarinic combinations.

 

Response: We have added a brief summary of patient endotypes most likely to benefit from noradrenergic–antimuscarinic combinations. See lines 252-254.

 

17. AD109 and MARIPOSA Trial (Lines 235–243)
    The trial is clearly described.
    A short comment on regulatory status and availability would enhance clinical relevance.

 

Response: A short comment on investigational status and regulatory considerations has been added. Changes appear at lines 267-270.

 

18. Alternative Pharmacological Combinations (Lines 249–260)
    The emerging combination strategies are interesting and well presented.
    The authors may consider emphasizing that evidence remains preliminary and largely short-term.

 

Response: We have reinforced that current evidence remains preliminary and largely short-term. See lines 283-286; 295-300.

 

19. Loop Gain Modulation – Carbonic Anhydrase Inhibitors (Lines 266–302)
    The physiological rationale and clinical evidence are clearly explained.
    It would be helpful to explicitly note that long-term safety and efficacy data are still lacking.

 

Response: We have explicitly noted that long-term safety and efficacy data are currently lacking. This addition is found at lines 303-308.

 

20. Section Heading Duplication (Lines 303–304)
    The subsection title “Modulators of ventilatory stability (loop gain)” is repeated and may cause confusion.
    Please revise the heading of Section 3.4 to reflect its focus on arousal threshold modulation.

 

Response: Done. Line 325.

 

21. Arousal Threshold Modulation (Lines 304–345)
    The discussion is balanced and clinically relevant.
    Consider reinforcing caution when using sedative agents in patients with severe anatomical obstruction.

 

Response: We have reinforced caution regarding sedative use in patients with severe anatomical obstruction. Revisions appear at lines 373-375.

 

22. Other Experimental Compounds (Lines 347–361)
    This section is forward-looking and interesting.
    A brief statement emphasizing the preclinical natureof many of these approaches would avoid overinterpretation.

 

Response: We have emphasized the predominantly preclinical nature of these approaches to avoid overinterpretation. See lines 395-397.

 

23. Residual Excessive Daytime Sleepiness – Overview (Lines 362–368)
    The prevalence and clinical impact of rEDS are clearly described.
    The authors may consider adding a concise summary table comparing wake-promoting agents.

 

Response: A comparative summary table of wake-promoting agents has been added and integrated into the text. See lines Table 2.

 

24. Wake-Promoting Agents – Comparative Discussion (Lines 373–501)
    This section is thorough and well referenced.
    Minor suggestion: streamline some repetitive descriptions of mechanisms of action for readability.

 

Response: Done.

 

25. Future Directions and Challenges (Lines 506–522)
    This section is appropriate but could be strengthened by explicitly listing unresolved issues such as long-term outcomes, combination therapy strategies, and cost-effectiveness.

 

Response: This section has been expanded to explicitly address unresolved issues, including long-term outcomes, combination strategies, and cost-effectiveness. See lines 538–571.

 

26. Language and Terminology
    Minor grammatical and stylistic issues are present.
    Please standardize terminology (e.g., CPAP vs. PAP, OSA vs. OSAS) and consider a final language edit.

 

Response: Terminology has been standardized throughout the manuscript, and minor grammatical issues have been corrected during a final language revision.

 

27. References

References are appropriate and up-to-date

Response: Thank you.

Reviewer 2 Report

Comments and Suggestions for Authors

This review addresses an important and rapidly evolving area in sleep medicine: non-CPAP therapies for obstructive sleep apnea, with particular attention to emerging pharmacological strategies. The topic is timely, clinically relevant, and aligns with current trends in phenotype- and endotype-driven management. The manuscript is generally well organized and contains substantial detail, but it reads more like an extensive encyclopedic compilation than a critical appraisal. The narrative often prioritizes listing findings over synthesizing them. The absence of a clear conceptual hierarchy—particularly regarding the relative weight of evidence, clinical applicability, safety considerations, and translational readiness—weakens the overall impact. While the authors demonstrate wide coverage, the depth of analysis is uneven. Certain sections devote disproportionate emphasis to early-phase or proof-of-concept studies without adequately contextualizing limitations, effect sizes, or real-world applicability. The manuscript would benefit from a sharper focus on clinical decision-making, a clearer distinction between established and experimental therapies, and a more rigorous interpretative framework.

 

Major comments

The manuscript requires stronger critical synthesis. Many statements describe effects or trial outcomes without evaluating methodological quality, sample size limitations, or the clinical significance of the reported changes. Pharmacological approaches are sometimes presented in a way that could be misinterpreted as more mature or widely applicable than current evidence supports. This is particularly true of noradrenergic–antimuscarinic combinations and trazodone-based strategies, which remain investigational. The text would benefit from explicit discussion of why these promising physiological effects have not yet translated into long-term clinical adoption, including concerns regarding tolerability, nighttime cardiovascular risk, and the scarcity of robust longitudinal data.

The structure of the review should more clearly separate established therapies, such as mandibular advancement devices and hypoglossal nerve stimulation, from investigational modalities. At present, all modalities are given equal weight, which may mislead readers about comparative evidentiary maturity. The pharmacology sections could be strengthened by explicit discussion of target populations, contraindications, and plausible integration with PAP and behavioural strategies in real-world settings. Similarly, weight-loss medications are discussed at length, but the authors should clarify that improvements in sleep-disordered breathing largely correlate with the magnitude of weight reduction rather than with direct mechanistic effects on upper-airway physiology. The tirzepatide trials, while important, are based on 52-week outcomes, and the durability of benefit beyond one year remains uncertain; this should be acknowledged more clearly.

The discussion of wake-promoting agents is informative yet overly descriptive. The authors should contextualize the clinical relevance of ESS reductions of two to three points and the relatively modest improvements in neurocognitive outcomes. It would also be important to address controversies surrounding the cardiovascular safety signals reported in post-marketing surveillance for modafinil and armodafinil. Given that many patients with OSA have hypertension or cardiometabolic disease, a more nuanced examination of risk–benefit balance is needed. Conversely, pitolisant is presented favorably, but the text could better explore limitations, including weight gain, insomnia, and the need for careful titration.

The section on future directions lacks depth. The authors briefly mention endotype-based pharmacotherapy but do not fully engage with challenges related to phenotyping in routine clinical practice, including cost, availability of polysomnographic trait analyses, and limitations of using drug-induced sleep endoscopy as a surrogate for mechanism. A more rigorous appraisal of implementation barriers, as well as potential ethical and economic considerations, would strengthen the manuscript.

 

Minor comments

Certain sections would benefit from stylistic refinement and redundancy reduction. The introduction repeats epidemiological data that could be summarized more succinctly. Some transitions between paragraphs feel abrupt, and the narrative occasionally shifts between descriptive and mechanistic perspectives without a clear unifying thread. The manuscript contains scattered typographical inconsistencies, such as fluctuating use of acronyms at first mention and occasional grammatical lapses. The table of ongoing trials is useful but would benefit from clearer integration with the narrative discussion; at present, it appears appended rather than integrated. The conclusion could be strengthened by emphasizing gaps in the evidence, particularly the limited availability of long-term outcomes data for most pharmacological interventions.

Author Response

This review addresses an important and rapidly evolving area in sleep medicine: non-CPAP therapies for obstructive sleep apnea, with particular attention to emerging pharmacological strategies. The topic is timely, clinically relevant, and aligns with current trends in phenotype- and endotype-driven management. The manuscript is generally well organized and contains substantial detail, but it reads more like an extensive encyclopedic compilation than a critical appraisal. The narrative often prioritizes listing findings over synthesizing them. The absence of a clear conceptual hierarchy—particularly regarding the relative weight of evidence, clinical applicability, safety considerations, and translational readiness—weakens the overall impact. While the authors demonstrate wide coverage, the depth of analysis is uneven. Certain sections devote disproportionate emphasis to early-phase or proof-of-concept studies without adequately contextualizing limitations, effect sizes, or real-world applicability. The manuscript would benefit from a sharper focus on clinical decision-making, a clearer distinction between established and experimental therapies, and a more rigorous interpretative framework.

 

Response: We thank the Reviewer for this thoughtful and constructive assessment. In response, we have strengthened the interpretative framework throughout the manuscript by explicitly differentiating established from investigational therapies, clarifying the relative weight of evidence, and integrating clinical applicability, safety considerations, and translational readiness, particularly within the pharmacological sections. These revisions aim to shift the narrative from a predominantly descriptive overview toward a more clinically oriented and critically synthesized appraisal.

 

Major comments

The manuscript requires stronger critical synthesis. Many statements describe effects or trial outcomes without evaluating methodological quality, sample size limitations, or the clinical significance of the reported changes. Pharmacological approaches are sometimes presented in a way that could be misinterpreted as more mature or widely applicable than current evidence supports. This is particularly true of noradrenergic–antimuscarinic combinations and trazodone-based strategies, which remain investigational. The text would benefit from explicit discussion of why these promising physiological effects have not yet translated into long-term clinical adoption, including concerns regarding tolerability, nighttime cardiovascular risk, and the scarcity of robust longitudinal data.

Response: We thank the Reviewer for this important comment. We have revised the manuscript to strengthen critical synthesis throughout, explicitly contextualizing methodological limitations (e.g., small samples, short duration), clinical significance, and real-world applicability—particularly for investigational pharmacological approaches. In addition, we have more clearly framed noradrenergic–antimuscarinic and trazodone-based strategies as investigational, emphasizing tolerability considerations, cardiovascular caution, and the current lack of robust longitudinal outcome data.

The structure of the review should more clearly separate established therapies, such as mandibular advancement devices and hypoglossal nerve stimulation, from investigational modalities. At present, all modalities are given equal weight, which may mislead readers about comparative evidentiary maturity. The pharmacology sections could be strengthened by explicit discussion of target populations, contraindications, and plausible integration with PAP and behavioural strategies in real-world settings. Similarly, weight-loss medications are discussed at length, but the authors should clarify that improvements in sleep-disordered breathing largely correlate with the magnitude of weight reduction rather than with direct mechanistic effects on upper-airway physiology. The tirzepatide trials, while important, are based on 52-week outcomes, and the durability of benefit beyond one year remains uncertain; this should be acknowledged more clearly.

Response: We agree and have strengthened the conceptual hierarchy of the review by more explicitly separating established non-CPAP therapies (e.g., oral appliances, HNS, surgery, positional/behavioral strategies) from emerging/investigational pharmacological modalities, so that evidentiary maturity is not perceived as equivalent across options (revised Section 2 vs Section 3). We also expanded the clinical framing by clarifying candidate profiles/contraindications and the intended adjunctive integration with PAP and behavioral strategies where appropriate. Finally, we have explicitly stated that improvements with weight-loss medications largely correlate with the magnitude (and maintenance) of weight reduction, and we acknowledged uncertainty regarding durability beyond the 52-week horizon of pivotal trials (revised Section 3.2)

The discussion of wake-promoting agents is informative yet overly descriptive. The authors should contextualize the clinical relevance of ESS reductions of two to three points and the relatively modest improvements in neurocognitive outcomes. It would also be important to address controversies surrounding the cardiovascular safety signals reported in post-marketing surveillance for modafinil and armodafinil. Given that many patients with OSA have hypertension or cardiometabolic disease, a more nuanced examination of risk–benefit balance is needed. Conversely, pitolisant is presented favorably, but the text could better explore limitations, including weight gain, insomnia, and the need for careful titration.

Response: We thank the Reviewer and agree that this section required more clinical contextualization. We have revised the wake-promoting agents section to better interpret the clinical meaning of typical ESS reductions (often ~2–3 points) and the comparatively modest/variable neurocognitive effects, rather than listing trial outcomes in isolation (revised Section 3.7). We also strengthened discussion of cardiovascular safety considerations for modafinil/armodafinil (especially in cardiometabolic risk profiles) and balanced the pitolisant appraisal by highlighting practical limitations (e.g., insomnia, weight gain, titration needs), and we added a comparative summary table to support clinical decision-making (Table 2).

The section on future directions lacks depth. The authors briefly mention endotype-based pharmacotherapy but do not fully engage with challenges related to phenotyping in routine clinical practice, including cost, availability of polysomnographic trait analyses, and limitations of using drug-induced sleep endoscopy as a surrogate for mechanism. A more rigorous appraisal of implementation barriers, as well as potential ethical and economic considerations, would strengthen the manuscript.

Response: We agree and have substantially expanded the “Future Directions and Challenges” section to address implementation barriers to endotype-driven care, including access and cost constraints, limited availability of trait estimation pipelines in routine PSG, and uncertainty about trait stability across time and clinical contexts (revised Section 4). We also clarified that DISE can guide anatomical interventions but should be interpreted cautiously as a surrogate for mechanistic endotyping, and we added explicit discussion of economic and scalability considerations relevant to real-world adoption.

 

Minor comments

Certain sections would benefit from stylistic refinement and redundancy reduction. The introduction repeats epidemiological data that could be summarized more succinctly. Some transitions between paragraphs feel abrupt, and the narrative occasionally shifts between descriptive and mechanistic perspectives without a clear unifying thread.

 

Response: We thank the Reviewer for these suggestions. We have edited several sections to reduce redundancy (particularly in the Introduction and mechanistic descriptions), improve transitions, and maintain a consistent narrative thread linking mechanisms to clinical decision-making across modalities.

 

 

The manuscript contains scattered typographical inconsistencies, such as fluctuating use of acronyms at first mention and occasional grammatical lapses.

 

Response: We have performed a consistency edit to standardize terminology and acronyms (e.g., OSA, CPAP/PAP usage) and corrected minor grammatical/typographical issues throughout the manuscript.

 

 

The table of ongoing trials is useful but would benefit from clearer integration with the narrative discussion; at present, it appears appended rather than integrated.

 

Response: We agree and have more clearly integrated the table of ongoing trials into the narrative by explicitly referencing it in the relevant pharmacology/future directions discussion, so it functions as a structured complement rather than an appended list.

 

 

The conclusion could be strengthened by emphasizing gaps in the evidence, particularly the limited availability of long-term outcomes data for most pharmacological interventions.

 

Response: We have strengthened the concluding emphasis on remaining evidence gaps, particularly the limited availability of long-term outcomes and safety data for most pharmacological interventions and the need for outcomes-focused, longer-duration trials.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

I thank the authors for their thorough and thoughtful engagement with all prior comments. The manuscript has been substantially strengthened.