Inhibition of SGLT1: The Alternative Way Toward Incretin Protection

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Several sections imply direct causality between SGLT1 inhibition, microbiome changes, GLP-1 elevation, and reduced stroke risk. These relationships remain associative or hypothesis-driven, particularly in humans. The manuscript should more clearly distinguish: Gut-mediated SGLT1 inhibition; Renal SGLT1 compensation during SGLT2 blockade; Direct cardiac/brain SGLT1 effects. These are currently blended into a single mechanistic narrative. The reductions in stroke and MI with sotagliflozin should be discussed with greater nuance, including trial design considerations, secondary endpoint limitations, and comparison with GLP-1 receptor agonists and SGLT2 inhibitors.  I recommend a short paragraph explicitly addressing the GI side effects of SGLT1 inhibition and the variability in microbiome responses. 

Author Response

Dear Reviewer 1,

We appreciated your thoughtful comments and suggestions. Following we reported a point-to-point reply.

Thank you so much for your time.

• Several sections imply direct causality between SGLT1 inhibition, microbiome changes, GLP-1 elevation, and reduced stroke risk. These relationships remain associative or hypothesis-driven, particularly in humans. The manuscript should more clearly distinguish: Gut-mediated SGLT1 inhibition; Renal SGLT1 compensation during SGLT2 blockade; Direct cardiac/brain SGLT1 effects. These are currently blended into a single mechanistic narrative.

Thank you for your suggestion. We tried to distinguish the different mechanisms reported in the text. We added a new paragraph about the role of cardiac and cerebral SGLT1.

• The reductions in stroke and MI with sotagliflozin should be discussed with greater nuance, including trial design considerations, secondary endpoint limitations, and comparison with GLP-1 receptor agonists and SGLT2 inhibitors.

Thank you for your suggestion. We did not explain deeply the CVOTs with sotagliflozin to not mislead the reader from the goal of our article.

• I recommend a short paragraph explicitly addressing the GI side effects of SGLT1 inhibition and the variability in microbiome responses.

Thank you for your suggestion. We added a new paragraph about the safety profile of SGLT1 inhibition.

Reviewer 2 Report

Comments and Suggestions for Authors

Manuscript ID - diabetology-4095702

Title - Inhibition of SGLT1: the alternative way towards incretin protection

Comments and suggestions for Author

This review examines the role of SGLT1 inhibition in the modulation of the incretin pathway and its potential metabolic and cardiovascular implications. The topic is relevant in the context of current research on glucose-lowering therapies, particularly in light of the expanding interest in mechanisms that extend beyond glycemic control. The manuscript outlines the physiological role of SGLT1 and summarizes its expression in renal, intestinal, and extra-renal tissues.

The authors present and discuss experimental and clinical evidence suggesting that inhibition of SGLT1 may enhance endogenous incretin secretion, primarily GLP-1, through delayed intestinal glucose absorption and downstream intestinal and microbiome-related mechanisms. The sections focusing on dual SGLT1/2 inhibitors, including sotagliflozin, are generally well organized and supported by the cited literature. Overall, the review provides a coherent overview of current evidence in this area.

Major Comments for Authors

1. While the proposed mechanisms linking SGLT1 inhibition to incretin stimulation and cardiometabolic protection are biologically plausible and supported by experimental data, several clinical implications remain based on indirect evidence. The authors are encouraged to more clearly distinguish between mechanisms supported by clinical data and those that are primarily hypothesis-driven, particularly with regard to the reduction of stroke and myocardial infarction risk.
2. Given the expression of SGLT1 in multiple tissues, including the intestine, heart, and brain, a clearer distinction between intestinal-mediated effects (e.g., delayed glucose absorption and microbiome-related mechanisms) and potential direct tissue-specific effects of SGLT1 inhibition would improve conceptual clarity. A brief summarizing paragraph or schematic clarification may help readers better appreciate the relative contribution of these mechanisms.
3. The manuscript discusses the role of the gut microbiome in mediating the effects of SGLT1 inhibition; however, this aspect could benefit from a more structured synthesis. Clarifying which microbiome-related changes are supported by direct evidence versus inferred from related metabolic studies would strengthen this section and avoid overinterpretation.

Minor comments

1. Abbreviations such as GLP-1, GIP, and PYY should be consistently defined at first mention and used uniformly throughout the manuscript to improve clarity, particularly for readers who are not specialists in incretin physiology.
2. Minor language polishing could further improve readability in some sections of the discussion, especially those addressing microbiome-related mechanisms. Overall, the quality of the English language is good.
3. When discussing the effects of SGLT1 inhibition on GLP-1 secretion, it may be helpful to more explicitly specify whether circulating total GLP-1 or active GLP-1 is being referred to in the cited studies, as this distinction may have physiological and clinical relevance.

 

Comments for author File: Comments.pdf

Author Response

Dear Reviewer 2,

We appreciated your thoughtful comments and suggestions. Following we reported a point-to-point reply.

Thank you so much for your time.

 

• While the proposed mechanisms linking SGLT1 inhibition to incretin stimulation and cardiometabolic protection are biologically plausible and supported by experimental data, several clinical implications remain based on indirect evidence. The authors are encouraged to more clearly distinguish between mechanisms supported by clinical data and those that are primarily hypothesis-driven, particularly with regard to the reduction of stroke and myocardial infarction risk.

Thank you for your suggestion. We tried to improve the text to distinguish better the clinical and experimental data.

 

• Given the expression of SGLT1 in multiple tissues, including the intestine, heart, and brain, a clearer distinction between intestinal-mediated effects (e.g., delayed glucose absorption and microbiome-related mechanisms) and potential direct tissue-specific effects of SGLT1 inhibition would improve conceptual clarity. A brief summarizing paragraph or schematic clarification may help readers better appreciate the relative contribution of these mechanisms.

Thank you for your suggestion. We tried to distinguish the different mechanisms reported in the text. We added a new paragraph about the role of cardiac and cerebral SGLT1.

 

• The manuscript discusses the role of the gut microbiome in mediating the effects of SGLT1 inhibition; however, this aspect could benefit from a more structured synthesis. Clarifying which microbiome-related changes are supported by direct evidence versus inferred from related metabolic studies would strengthen this section and avoid overinterpretation.

Thank you for your suggestion. We explained the role of SCFA-producing microbiota on incretin pathway,  but we did not explain deeply this topic to not mislead the reader from the goal of our article.

• Abbreviations such as GLP-1, GIP, and PYY should be consistently defined at first mention and used uniformly throughout the manuscript to improve clarity, particularly for readers who are not specialists in incretin physiology.

Thank you for your suggestion. We corrected all the abbreviations.

 

• Minor language polishing could further improve readability in some sections of the discussion, especially those addressing microbiome-related mechanisms. Overall, the quality of the English language is good.

Thank you for your suggestion. We improved the readability.

• When discussing the effects of SGLT1 inhibition on GLP-1 secretion, it may be helpful to more explicitly specify whether circulating total GLP-1 or active GLP-1 is being referred to in the cited studies, as this distinction may have physiological and clinical relevance.

Thank you for your suggestion. We specified better in the text whether circulating total GLP-1 or active GLP-1 in the text.

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript addresses the role of SGLT1 inhibition in incretin stimulation and its potential cardiometabolic implications. The topic is clinically relevant and of growing interest, particularly in the context of dual SGLT1/SGLT2 inhibitors. However, several sections require clearer mechanistic explanation, more precise pharmacological characterization, and a more cautious distinction between established evidence and hypothesis. Strengthening structural coherence and scientific precision would substantially improve the clarity and impact of the manuscript.

lines 28–32
The statement regarding exceeded reabsorptive capacity and increased glucose delivery to distal nephron segments requires clearer mechanistic explanation and more precise anatomical terminology.

lines 45–47
The manuscript describes canagliflozin and sotagliflozin as “double SGLT1/2 inhibitors.” This requires clarification, as canagliflozin primarily targets SGLT2 and has only partial SGLT1 inhibitory activity. The pharmacological distinction should be accurately reflected.

Correct terminology and nomenclature (lines 26–27).

Use “sodium-glucose cotransporter 1 (SGLT1)” consistently.

Use “reabsorptive capacity” instead of “resorptive capacity.”

Improve wording and scientific precision (lines 39–41).

Replace “diabetic people” with “patients with diabetes.”

Replace “exaggerating glucosuria” with more precise scientific terminology.

Correct typographical errors (line 43).

“endocgenous” on “endogenous.”

Improve stylistic clarity (lines 23–25, 33–37).

Avoid generic expressions such as “It is known that…”

Replace vague phrases such as “many other tissues” with specific examples or references.

lines 49–50
The heading suggests a focused discussion on stimulation of the incretin pathway by canagliflozin; however, the section currently summarizes selected studies without clearly explaining how these data support the main hypothesis of the manuscript. The authors should explicitly state why these findings are central to the argument being developed.

lines 57–63:
The reported changes in GLP-1, GIP, and PYY are presented numerically, but the physiological interpretation is missing. The authors should explain how delayed intestinal glucose absorption leads to altered distal gut hormone secretion and whether this supports a causal SGLT1-mediated mechanism.

lines 51–55 vs. 56–66
The transition from rodent OGTT data to human crossover studies is abrupt. A bridging sentence explaining translational relevance is needed.

lines 77–80
The finding that GLP-1 and PYY levels increased in SGLT1-/- mice after glucose challenge requires deeper mechanistic discussion. If sotagliflozin acts primarily via SGLT1 inhibition, the observed incretin response in knockout animals raises important questions. The authors should address whether this suggests compensatory mechanisms, delayed glucose transit, or SGLT2-related effects.

lines 81–84
The healthy subject study includes only 12 individuals (10 active, 2 placebo). This very small placebo group raises concerns about statistical robustness. The authors should acknowledge this limitation.

line 70
Experimental evidence show” on “Experimental evidence shows”

Lines 91–94.
The mechanistic sequence linking SGLT1 inhibition to increased SCFAs and subsequent GLP-1 stimulation is overly condensed and requires clearer stepwise explanation. Please specify the exact intestinal segment involved and clarify whether the increase in SCFAs has been directly demonstrated following SGLT1 inhibition or is inferred.

Lines 114–117.
The description of TMAO dynamics in stroke patients is presented without a direct link to SGLT1 inhibition. Please clarify whether SGLT1 inhibitors have been shown to modulate TMAO levels or remove this speculative extension.

Lines 121–124.
The experimental findings on endothelial and cardiac SGLT1 expression should be better contextualized. It is not clear whether these data are directly translatable to human pathophysiology.

Lines 128–132.
The sentence stating that “there are several ways in which SGLT1 inhibition could favorably alter the risk of thrombosis” is overly broad. This claim should be reformulated in a more cautious and evidence-based manner.

Lines 165–167.
The conclusion that increased endogenous GLP-1 likely explains the observed cardiovascular benefits is speculative. This statement should be softened and clearly identified as a hypothesis rather than a demonstrated mechanism.

Lines 169–174.
The first paragraph largely repeats information already presented in earlier sections. The Conclusion should synthesize key insights rather than restate mechanistic details. Please shorten this part and focus on the most important take-home messages.

Lines 183–187.
The claim that moderate SGLT1 inhibition may improve glycemic control more effectively than highly selective SGLT2 inhibition requires cautious phrasing. It should be clarified whether this is supported by comparative outcome trials.

Lines 200–202.
The final sentence is grammatically incorrect and conceptually vague. The Conclusion should end with a concise, forward-looking statement defining the key unresolved mechanistic question and its clinical relevance.

Author Response

Dear Reviewer 3,

We appreciated your thoughtful comments and suggestions. Following we reported a point-to-point reply.

Thank you so much for your time.

 

• lines 28–32
• The statement regarding exceeded reabsorptive capacity and increased glucose delivery to distal nephron segments requires clearer mechanistic explanation and more precise anatomical terminology.

Thank you for your suggestion. We explained better the statement.

• lines 45–47
• The manuscript describes canagliflozin and sotagliflozin as “double SGLT1/2 inhibitors.” This requires clarification, as canagliflozin primarily targets SGLT2 and has only partial SGLT1 inhibitory activity. The pharmacological distinction should be accurately reflected.

Thank you for your suggestion. We corrected the statement.

• Correct terminology and nomenclature (lines 26–27).

Thank you for your suggestion. We corrected terminology and nomenclature.

• Use “sodium-glucose cotransporter 1 (SGLT1)” consistently.

Thank you for your suggestion. We used the suggested term in the text.

• Use “reabsorptive capacity” instead of “resorptive capacity.”

Thank you for your suggestion. We used the suggested term in the text.

• Improve wording and scientific precision (lines 39–41).

Thank you for your suggestion. We improved the wording in these lines.

• Replace “diabetic people” with “patients with diabetes.”

Thank you for your suggestion. We replaced the term.

• Replace “exaggerating glucosuria” with more precise scientific terminology.

Thank you for your suggestion. We replaced the term.

• Correct typographical errors (line 43).
• “endocgenous” on “endogenous.”

Thank you for your suggestion. We corrected typographical errors.

• Improve stylistic clarity (lines 23–25, 33–37).

Thank you for your suggestion. We improved stylistic clarity (lines 23–25, 33–37).

• Avoid generic expressions such as “It is known that…”

Thank you for your suggestion. We avoided generic expressions in the text.

 

• Replace vague phrases such as “many other tissues” with specific examples or references.

Thank you for your suggestion. We avoided vague phrases in the text.

• lines 49–50
• The heading suggests a focused discussion on stimulation of the incretin pathway by canagliflozin; however, the section currently summarizes selected studies without clearly explaining how these data support the main hypothesis of the manuscript. The authors should explicitly state why these findings are central to the argument being developed.

Thank you for your suggestion. We specified in the introduction the significance of the paragraphs.

• lines 57–63:
• The reported changes in GLP-1, GIP, and PYY are presented numerically, but the physiological interpretation is missing. The authors should explain how delayed intestinal glucose absorption leads to altered distal gut hormone secretion and whether this supports a causal SGLT1-mediated mechanism.

Thank you for your suggestion. We did not explain better because the data about this specific topic are yet limited.

• lines 51–55 vs. 56–66
• The transition from rodent OGTT data to human crossover studies is abrupt. A bridging sentence explaining translational relevance is needed.

Thank you for your suggestion. We added a bridging sentence.

• lines 77–80
• The finding that GLP-1 and PYY levels increased in SGLT1-/- mice after glucose challenge requires deeper mechanistic discussion. If sotagliflozin acts primarily via SGLT1 inhibition, the observed incretin response in knockout animals raises important questions. The authors should address whether this suggests compensatory mechanisms, delayed glucose transit, or SGLT2-related effects.

Thank you for your suggestion. We did not explain better because the data about this specific topic are yet limited.

• lines 81–84
• The healthy subject study includes only 12 individuals (10 active, 2 placebo). This very small placebo group raises concerns about statistical robustness. The authors should acknowledge this limitation.

Thank you for your suggestion. We highlighted the limits of the study.

• line 70
• Experimental evidence show” on “Experimental evidence shows”

Thank you for your suggestion. We corrected the term.

• Lines 91–94.
• The mechanistic sequence linking SGLT1 inhibition to increased SCFAs and subsequent GLP-1 stimulation is overly condensed and requires clearer stepwise explanation. Please specify the exact intestinal segment involved and clarify whether the increase in SCFAs has been directly demonstrated following SGLT1 inhibition or is inferred.

Thank you for your suggestion. We did not explain better because the data about this specific topic are yet limited.

• Lines 114–117.
• The description of TMAO dynamics in stroke patients is presented without a direct link to SGLT1 inhibition. Please clarify whether SGLT1 inhibitors have been shown to modulate TMAO levels or remove this speculative extension.

Thank you for your suggestion. We did not explain better because the data about this specific topic are yet limited. Thus we removed this speculative extension.

• Lines 121–124.
• The experimental findings on endothelial and cardiac SGLT1 expression should be better contextualized. It is not clear whether these data are directly translatable to human pathophysiology.

Thank you for your suggestion. We tried to distinguish better the clinical and experimental data.

• Lines 128–132.
• The sentence stating that “there are several ways in which SGLT1 inhibition could favorably alter the risk of thrombosis” is overly broad. This claim should be reformulated in a more cautious and evidence-based manner.

Thank you for your suggestion. We reformulated the statement.

• Lines 165–167.
• The conclusion that increased endogenous GLP-1 likely explains the observed cardiovascular benefits is speculative. This statement should be softened and clearly identified as a hypothesis rather than a demonstrated mechanism.

Thank you for your suggestion. We reformulated the statement.

• Lines 169–174.
• The first paragraph largely repeats information already presented in earlier sections. The Conclusion should synthesize key insights rather than restate mechanistic details. Please shorten this part and focus on the most important take-home messages.

Thank you for your suggestion. We shortened the conclusion section.

• Lines 183–187.
• The claim that moderate SGLT1 inhibition may improve glycemic control more effectively than highly selective SGLT2 inhibition requires cautious phrasing. It should be clarified whether this is supported by comparative outcome trials.

Thank you for your suggestion. We removed this statement.

• Lines 200–202.
• The final sentence is grammatically incorrect and conceptually vague. The Conclusion should end with a concise, forward-looking statement defining the key unresolved mechanistic question and its clinical relevance.

Thank you for your suggestion. We corrected this statement.

 

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

Dear Authors,

Thank you for your detailed and thoughtful responses to the comments. The revisions introduced in the manuscript address the concerns raised during the review process. The terminology has been corrected, the mechanistic descriptions have been clarified where possible, stylistic and grammatical issues have been improved, and speculative statements have been appropriately moderated or removed. In addition, the limitations of the cited studies have been acknowledged where necessary.

In its current revised form, the manuscript has improved in terms of clarity, scientific precision, and overall structure. The introduced changes sufficiently resolve the previously identified issues.

Therefore, in my opinion, the manuscript is suitable for publication.

Best regards

Author Response

Dear Reviewer 3,

We really appreciated your positive reply.

Best regards