A Novel Presentation of Euglycemic Diabetic Ketoacidosis Associated with SGLT2 Inhibitor and Weekly GLP-1 Agonist: Case Report

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The case report of diabetic ketoacidosis described by the author is one of the first reported in patients using SGLT2 inhibitor and weekly GLP-1 agonist (semaglutide) concomitantly. This certainly represents a very important contribution to science. As a reviewer, I have a few questions and suggestions for the author:

1. In the discussion, the author should focus more on comparing this case with earlier cases where patients used similar drugs, i.e., SGLT2 inhibitors and GLP-1 agonists, not necessarily the same ones:

e.g.: https://academic.oup.com/jcemcr/article/3/3/luaf028/8011175?login=true

2. During the treatment, both the SGLT2 inhibitor and the GLP-1 receptor agonist, were discontinued. Is it known whether the patient has resumed use of the GLP-1 agonist?
3. The author should emphasize more strongly in the conclusion the novelty of this case and, if it is indeed the first such report, clearly state that it is the first exactly of its kind.
4. There is no detailed physiological explanation of how the mechanisms of action of these drugs together influenced the development of ketoacidosis, and which, according to the author, was the more important/primary factor in causing this condition, and which only exacerbated it. The author touches on this topic, but I believe this section should be rewritten and expanded.

To make the discussion clearer, it should be noted that case reports are valuable not only for guiding physicians in daily practice, but also for providing insights to researchers investigating underlying mechanisms. What does the available literature say? What are the reported cases of ketoacidosis when these drugs are used individually?

5. Did the patient have any prior episodes of ketonuria or weight loss?
6. Along with intermittent fasting, did the patient follow a low-carbohydrate diet? High-protein/high-fat diet?
7. Was β-hydroxybutyrate measured in the blood, or was the diagnosis based solely on ketonuria and other parameters?
8. How was infection excluded, and was this done?
9. The table is incomplete — in the text, parameters are given that are not included in the table

Author Response

A Novel Presentation of Euglycemic Diabetic Ketoacidosis As-sociated with SGLT2 Inhibitor and Weekly GLP-1 Agonist: Case report

 

<Response to reviewers and summary of changes made>

 

             We thank the reviewers for their careful review of our manuscript. We found their comments and suggestions very helpful. We have tried to address all of the reviewers’ comments in our revised manuscript. Amended and newly added content is shown in red font.

 

Reviewer #1

The case report of diabetic ketoacidosis described by the author is one of the first reported in patients using SGLT2 inhibitor and weekly GLP-1 agonist (semaglutide) concomitantly. This certainly represents a very important contribution to science. As a reviewer, I have a few questions and suggestions for the author:

 

Comment 1) In the discussion, the author should focus more on comparing this case with earlier cases where patients used similar drugs, i.e., SGLT2 inhibitors and GLP-1 agonists, not necessarily the same ones:

e.g.: https://academic.oup.com/jcemcr/article/3/3/luaf028/8011175?login=true

 

We thank the reviewer for this insightful suggestion. In the revised Discussion, we have expanded our comparison with previously published cases of euDKA associated with SGLT2 inhibitors and GLP-1 receptor agonists. In our case, the patient was started on semaglutide for weight reduction and subsequently developed progressive gastrointestinal symptoms, including nausea and reduced appetite, which resulted in prolonged fasting. GLP-1 receptor agonists are known to delay gastric emptying and suppress appetite, thereby contributing to caloric restriction and ketone accumulation. This scenario is consistent with prior reports. For example, Louwagie et al. (2025) reported euDKA in a patient treated with empagliflozin and tirzepatide; however, that case differed from ours in several respects: the patient was not newly diagnosed with diabetes, tirzepatide is a dual GIP/GLP-1 receptor agonist rather than a pure GLP-1RA, and therapy was initiated primarily for glycemic control rather than weight reduction. Similarly, Alduraibi et al. described euDKA following GLP-1RA monotherapy (including semaglutide or dulaglutide), indicating that GLP-1RAs alone may precipitate ketone accumulation under certain conditions. These comparisons highlight that euDKA may arise not only from various combination regimens but also from monotherapy, particularly when precipitating factors such as fasting, dehydration, or gastrointestinal intolerance are present. Moreover, gastrointestinal side effects such as nausea and vomiting may mimic the early symptoms of DKA, potentially delaying recognition and treatment. We have revised the Discussion to incorporate these comparisons and provide a broader clinical context for our case.

 

Old manuscript (Page 5, Line 182-194)

New manuscript (Page 5-6, Line 200-213)

In this case, the patient was started on semaglutide for weight reduction and subsequently developed progressive gastrointestinal symptoms, including nausea and reduced appetite, which resulted in prolonged fasting. GLP-1RAs are known to delay gastric emptying and suppress appetite, which may contribute to caloric restriction and increase ketone produc-tion[12]. In this ketotic-prone state, the addition of an SGLT2 inhibitor may exacerbate ke-togenesis and overwhelm the patient’s compensatory metabolic capacity. Several reports have documented cases of euDKA in the setting of GLP-1RA use combined with pro-longed fastin[14,19]. Moreover, nausea and vomiting—common side effects of GLP-1RAs—may mimic early symptoms of DKA, potentially delaying diagnosis.

Comparison with previous reports Several recent case reports have described euDKA in the context of SGLT2 inhibi-tor or GLP-1RA therapy, or concomitant therapies. Louwagie et al. reported a case of euDKA in a patient treated with empagliflozin and tirzepatide [21]. However, this case differed from ours in several aspects: the patient was not newly diagnosed with dia-betes, tirzepatide was a dual GIP/GLP-1 receptor agonist rather than a pure GLP-1RA, and therapy was initiated primarily for glycemic control rather than weight reduction. Similarly, Alduraibi et al. described euDKA following GLP-1 agonist monotherapy, in-cluding semaglutide or dulaglutide [14, 22]. This suggests that even without SGLT2 in-hibitor use, GLP-1 receptor agonists alone may contribute to ketone accumulation un-der certain conditions. These comparisons emphasize that euDKA can occur not only with various combination regimens but also with monotherapy. In particular, the presence of additional precipitating factors such as fasting, dehydration, or gastroin-testinal intolerance may influence its occurrence. Moreover, nausea and vomiting, which are common side effects of GLP-1RAs, may mimic the early symptoms of DKA, potentially delaying the diagnosis.

 

Newly inserted reference

14.        Alduraibi, R. K.; Alrebdi, Y. M.; Altowayan, Y. F., Euglycemic diabetic ketoacidosis after the initiation of dulaglutide in patient with type 2 diabetes. Medicine 2023, 102, (23), e34027. 21.        Louwagie, E. J.; Diego, J. N.; Farooqi, C. S.; Kamal, M. M., Euglycemic Ketoacidosis Following Coadministration of an SGLT2 Inhibitor and Tirzepatide. JCEM Case Reports 2025, 3, (3), luaf028. 22.        Sood, N.; Bansal, O.; Garg, R.; Hoskote, A., Euglycemic Ketoacidosis From Semaglutide in a Patient Without Diabetes. JCEM Case Reports 2024, 2, (9), luae156.

 

 

Comment 2) During the treatment, both the SGLT2 inhibitor and the GLP-1 receptor agonist, were discontinued. Is it known whether the patient has resumed use of the GLP-1 agonist?

 

We appreciate the reviewer’s insightful question. In our case, both the SGLT2 inhibitor and the GLP-1 receptor agonist were discontinued during hospitalization. At discharge, semaglutide was not resumed because its gastrointestinal side effects, together with prolonged fasting, were considered potential contributing factors to the development of euDKA. Instead, the patient was transitioned to a conservative regimen consisting of basal insulin, metformin, and a DPP-4 inhibitor. At the two-week outpatient follow-up, she remained clinically stable on this regimen without recurrence of ketosis, and re-initiation of GLP-1RA therapy has not been attempted to date. We have clarified this point in the Case Presentation and Outpatient Follow-up sections.

 

Old manuscript (Page 4, Line 147-159)

Old manuscript (Page 4-5, Line 143-153)

At the two-week follow-up visit, the patient remained clinically stable, with no recurrence of ketosis. She had adapted well to the basal insulin regimen, and self-monitored blood glucose readings were within the target range. Intermittent fasting had been discontinued, and she had resumed a regular diet. No gastrointestinal symptoms or abdominal discomfort were reported, and overall health status had improved. The current plan is to maintain the regimen of basal insulin, metformin, and a DPP-4 inhibitor, with the possibility of cautiously introducing other antihyperglycemic agents if needed, under close monitoring. She continues to be followed regularly in the outpatient clinic and has maintained good glycemic control without further episodes of acidosis.

At the two-week follow-up visit, the patient remained clinically stable with no recurrence of ketosis. She adapted well to the basal insulin regimen, and self-monitored blood glucose values were within the target range. Intermittent fasting was discontinued, and the patient resumed a regular diet. No gastrointestinal symp-toms or abdominal discomfort were reported, and her overall health status improved. Semaglutide was not resumed because its gastrointestinal side effects combined with prolonged fasting were considered potential contributors to the development of eu-DKA. Instead, the patient was maintained on a conservative regimen comprising basal insulin, metformin, and a DPP-4 inhibitor. During three months of follow-up after discharge, she remained stable on this regimen, with good glycemic control and no further episodes of acidosis. A structured overview of the patient’s clinical course, in-cluding symptom onset, hospital management, and follow-up outcomes, is shown in Table 2.

 

 

Comment 3) The author should emphasize more strongly in the conclusion the novelty of this case and, if it is indeed the first such report, clearly state that it is the first exactly of its kind.

 

We thank the reviewer for this important comment. In the revised Conclusion, we have emphasized the novelty of our case. To the best of our knowledge, this is the first report of euglycemic diabetic ketoacidosis occurring in a newly diagnosed patient with type 2 diabetes following the combined use of semaglutide and enavogliflozin, in the context of prolonged intermittent fasting. We have revised the Conclusion to clearly highlight this point.

 

Old manuscript (Page 6, Line 233-239)

New manuscript (Page 6, Line 274-281)

SGLT2 inhibitors are beneficial for type 2 diabetes treatment but can induce euglycemic DKA. This case report presents a severe DKA episode following SGLT2 inhibitor use. Early recognition and aggressive management are crucial. Before initiating SGLT2 inhibitors, it is essential to assess for catabolic symptoms related to hyperglycemia and to avoid trig-gering factors such as fasting, dehydration, and infection. Patients should be advised to seek immediate medical attention if symptoms occur.

SGLT2 inhibitors are beneficial for the treatment of type 2 diabetes but can precip-itate euglycemic DKA. To the best of our knowledge, this case is unique in represent-ing the first reported episode of euDKA in a newly diagnosed patient with T2DM treated with a combination of semaglutide and enavogliflozin during prolonged inter-mittent fasting. Early recognition and aggressive management are crucial for achieving favorable outcomes. Before initiating SGLT2 inhibitors and GLP-1 receptor agonists, clinicians should carefully evaluate potential risk factors, such as fasting, dehydration, and gastrointestinal intolerance, and provide thorough patient education regarding the warning symptoms of DKA.

 

Comment 4) There is no detailed physiological explanation of how the mechanisms of action of these drugs together influenced the development of ketoacidosis, and which, according to the author, was the more important/primary factor in causing this condition, and which only exacerbated it. The author touches on this topic, but I believe this section should be rewritten and expanded.

 

We thank the reviewer for this insightful comment. In the revised Discussion, we have expanded the physiological explanation of how the mechanisms of action of SGLT2 inhibitors and GLP-1 receptor agonists may interact to precipitate ketoacidosis. We clarify that in our opinion the primary driver of ketogenesis in this case was SGLT2 inhibitor–induced relative insulin deficiency and increased glucagon secretion, while GLP-1RA–related gastrointestinal side effects and prolonged fasting served as significant exacerbating factors by reducing caloric intake and promoting a catabolic state. We have rewritten this section to provide a clearer mechanistic rationale and to highlight the interplay between these agents in the pathogenesis of euDKA.

 

Newly inserted description (Page 5, Line 176-187)

In contrast, GLP-1 receptor agonists may exacerbate ketone accumulation through gastrointestinal side effects. In our case, semaglutide prescribed for weight reduction induced progressive nausea, anorexia, and prolonged fasting. By delaying gastric emptying and suppressing appetite, GLP-1RAs can promote calorie restriction, further enhancing ketogenesis [12, 14]. The concomitant use of an SGLT2 inhibitor and GLP-1RA therefore creates a synergistic risk of euDKA, particularly under conditions of caloric restriction or dehydration. The close temporal relationship between drug ini-tiation and symptom onset, pharmacological plausibility, absence of alternative trig-gers, and prompt resolution after discontinuation strongly support a drug-associated mechanism. Although prolonged intermittent fasting may have contributed, the sever-ity of acidosis, temporal association, and rapid recovery with insulin–dextrose therapy point toward medication-induced euDKA rather than pure starvation ketoacidosis.

 

 

Comment 5) To make the discussion clearer, it should be noted that case reports are valuable not only for guiding physicians in daily practice, but also for providing insights to researchers investigating underlying mechanisms. What does the available literature say? What are the reported cases of ketoacidosis when these drugs are used individually?

 

We thank the reviewer for this important suggestion. In the revised Discussion, we explicitly outline how the mechanisms of SGLT2 inhibitors and GLP-1 receptor agonists may interact to precipitate ketoacidosis and specify which factor was primary in our case. Based on current literature, SGLT2 inhibitors are the principal drivers of euglycemic DKA through glycosuria-mediated reductions in insulin, relative hyperglucagonemia, lipolysis, and hepatic ketogenesis; euDKA risk in T2D appears increased (∼7-fold) with an overall incidence around 0.1% in trials/observational data. GLP-1RAs, while generally glucose-dependent insulinotropes, can exacerbate ketogenesis indirectly via gastrointestinal adverse effects leading to reduced caloric intake, dehydration, and catabolic stress; rare case reports describe ketoacidosis with GLP-1RA monotherapy (including dulaglutide and semaglutide), and tirzepatide has been implicated in ketoacidosis in both diabetic and nondiabetic settings. Accordingly, we consider the SGLT2 inhibitor the primary precipitant in our patient, with semaglutide-related gastrointestinal symptoms and prolonged fasting acting as exacerbating factors. We have added a concise literature synthesis on ketoacidosis reported with each drug class individually and clarified their interplay in the pathogenesis of euDKA.

 

Old manuscript (Page 6, Line 233-239)	New manuscript (Page 5, Line 171-175)
When additional precipitating factors such as decreased oral intake, dehydration, infection, or acute illness are present, this metabolic shift can be amplified, potentially leading to DKA even in the absence of significant hyperglycemia[7, 17, 18]	When combined with precipitating factors such as reduced oral intake, dehydration, infection, or acute illness, this metabolic shift may be amplified, predisposing patients to DKA even in the absence of significant hyperglycemia [7, 17, 18]. Reports of euglycemic DKA following SGLT2 inhibitor therapy support these proposed mecha-nisms [19, 20].

 

Newly inserted description (Page 5, Line 176-187)

In contrast, GLP-1 receptor agonists may exacerbate ketone accumulation through gastrointestinal side effects. In our case, semaglutide prescribed for weight reduction induced progressive nausea, anorexia, and prolonged fasting. By delaying gastric emptying and suppressing appetite, GLP-1RAs can promote calorie restriction, further enhancing ketogenesis [12, 14]. The concomitant use of an SGLT2 inhibitor and GLP-1RA therefore creates a synergistic risk of euDKA, particularly under conditions of caloric restriction or dehydration. The close temporal relationship between drug ini-tiation and symptom onset, pharmacological plausibility, absence of alternative trig-gers, and prompt resolution after discontinuation strongly support a drug-associated mechanism. Although prolonged intermittent fasting may have contributed, the sever-ity of acidosis, temporal association, and rapid recovery with insulin–dextrose therapy point toward medication-induced euDKA rather than pure starvation ketoacidosis.

 

Newly inserted reference

12.        Filippatos, T. D.; Panagiotopoulou, T. V.; Elisaf, M. S., Adverse effects of GLP-1 receptor agonists. The review of diabetic studies: RDS 2015, 11, (3), 202. 19.        Wang, K. M.; Isom, R. T., SGLT2 inhibitor–induced euglycemic diabetic ketoacidosis: A case report. Kidney Medicine 2020, 2, (2), 218-221. 20.        Alkatheeri, A.; Alseddeeqi, E., Euglycemic diabetic ketoacidosis induced by sodium-glucose cotransporter 2 inhibitor in the setting of prolonged fasting: a case report. Journal of Medical Case Reports 2022, 16, (1), 138.

 

Comment 6) Did the patient have any prior episodes of ketonuria or weight loss?

We thank the reviewer for this question. The patient had no documented history of ketonuria or prior episodes of ketoacidosis before this admission. Although she reported a modest reduction in appetite and some weight loss during the weeks following the initiation of semaglutide, there was no history of unintentional or progressive weight loss before starting antidiabetic therapy. We have clarified this information in the Case Presentation section.

 

Newly inserted description (Page 2, Line 85-88)

She had no history of ketonuria or ketoacidosis. Although she experienced a modest reduction in appetite and mild weight loss after starting semaglutide, there was no history of unintentional or progressive weight loss before initiating antidiabetic ther-apy.

 

 

Comment 7) Along with intermittent fasting, did the patient follow a low-carbohydrate diet? High-protein/high-fat diet?

We thank the reviewer for this question. The patient practiced intermittent fasting in combination with a low-carbohydrate, high-protein diet. Such a dietary pattern may promote ketone body production by restricting carbohydrate intake and, when combined with SGLT2 inhibitor therapy, can further increase the risk of ketoacidosis. We have clarified this point in the Case Presentation section.

 

Newly inserted description (Page 2, Line 81-83)

In addition, she adopted a low-carbohydrate, high-protein diet during the eating win-dow, which may have further restricted carbohydrate intake and promoted ketone body production.

 

Comment 8) Was β-hydroxybutyrate measured in the blood, or was the diagnosis based solely on ketonuria and other parameters?

We thank the reviewer for raising this point. In our case, serum β-hydroxybutyrate was not measured due to laboratory limitations at the admitting hospital. The diagnosis of euDKA was established based on high anion gap metabolic acidosis, strong ketonuria (+++), mild hyperglycemia, and the clinical context. We have clarified this limitation in the Case Presentation section.

 

Newly inserted description (Page 7, Line 263-265)

First, serum β-hydroxybutyrate was not measured due to laboratory constraints, and the diagnosis of euDKA was based on high anion gap metabolic acidosis, ketonuria, mild hyperglycemia, and the clinical context.

 

Comment 9) How was infection excluded, and was this done?

We thank the reviewer for this important point. Infection was considered as a possible precipitating factor; however, the patient had no fever, leukocytosis, or localizing signs of infection. In addition, her C-reactive protein (CRP) level was within the normal range, which made infection unlikely. We have clarified this information in the Case Presentation section.

 

Newly inserted description (Page 4, Line 133-135)

She was afebrile, had no leukocytosis or localizing signs, and her CRP level was within the normal range, making infection an unlikely precipitating factor.

 

Comment 10) The table is incomplete — in the text, parameters are given that are not included in the table

Old Table 1	New Table 1

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have presented an interesting case report of euglycemic DKA in a patient that was prescribed an SGLT2i together with a GLP1RA. although this is not an uncommon combination in clinical practice, what needs to be highlighted is the fact that the patient also decided to go on a very low-calorie diet.

What concerns me is the management of the patient following discharge. For safety reasons would it not have been better to be discharged on a basal-bolus regimen for 2-4 weeks and then switched to oral agents when the glucotoxicity has abated.

Author Response

A Novel Presentation of Euglycemic Diabetic Ketoacidosis As-sociated with SGLT2 Inhibitor and Weekly GLP-1 Agonist: Case report

 

<Response to reviewers and summary of changes made>

 

             We thank the reviewers for their careful review of our manuscript. We found their comments and suggestions very helpful. We have tried to address all of the reviewers’ comments in our revised manuscript. Amended and newly added content is shown in red font.

 

Reviewer #2

The authors have presented an interesting case report of euglycemic DKA in a patient that was prescribed an SGLT2i together with a GLP1RA. although this is not an uncommon combination in clinical practice, what needs to be highlighted is the fact that the patient also decided to go on a very low-calorie diet.

 

Comment 1) What concerns me is the management of the patient following discharge. For safety reasons would it not have been better to be discharged on a basal-bolus regimen for 2-4 weeks and then switched to oral agents when the glucotoxicity has abated.

 

We thank the reviewer for this valuable comment regarding post-discharge management. We agree that a basal–bolus insulin regimen could be considered a safe approach in the early recovery phase of DKA to ensure optimal glycemic control and prevent recurrence. In our patient, however, a basal–bolus regimen was not feasible because, due to her lifestyle, she was unable to administer lunchtime and dinnertime injections consistently. Therefore, a conservative regimen consisting of basal insulin once daily together with oral agents (metformin and a DPP-4 inhibitor) was initiated at discharge. This decision was further supported by her clinical stability, relatively preserved endogenous insulin secretion (C-peptide 0.88 ng/mL), and the absence of further ketosis during hospitalization. At two-week follow-up, she remained stable with no recurrence of ketosis and good glycemic control on this regimen. We have clarified this rationale in the Case Presentation and Outpatient Follow-up sections.

 

Old manuscript (Page 5, Line 150-155)

New manuscript (Page 4, Line 136-141)

At discharge, a conservative diabetes management regimen consisting of basal insulin, metformin, and a DPP-4 inhibitor was initiated. The patient was discharged in a clinically stable condition on hospital day 6.

Although a short-term basal–bolus regimen is often recommended following recovery from DKA, this approach was not feasible for our patient because of lifestyle con-straints that prevented consistent mealtime insulin administration. Therefore, she was switched to a conservative regimen of basal insulin, metformin, and a DPP-4 inhibitor. The patient remained clinically stable and was discharged on hospital day 6.

 

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript presents a clinically relevant case; however, it lacks sufficient novelty, comprehensive literature comparison, and critical analysis to justify publication. Methodological transparency, data interpretation depth, and adherence to case report guidelines require major revision.

1. How does this case add novel insights beyond previously published euDKA cases involving SGLT2 inhibitors and GLP-1 agonists, especially given several similar reports in recent literature?
2. Why was a standardized case report guideline (e.g., CARE) not explicitly followed, including a structured timeline of clinical events and interventions?
3. What objective criteria were used to attribute causality of euDKA to the combination of semaglutide and enavogliflozin, rather than other potential triggers like new-onset T2DM or baseline metabolic status?
4. Why is there no detailed discussion on the rarity or incidence rate of enavogliflozin-associated euDKA compared to other SGLT2 inhibitors?
5. Were ketone levels measured quantitatively in serum, and if not, how does the absent Why we’re confounding factors such as dehydration severity, electrolyte imbalances prior to therapy, or possible infection not systematically excluded?
6. How was fasting glucose of 137 mg/dL reconciled with the classification of “euglycemic” in the absence of continuous glucose monitoring data?
7. Why is there no discussion on the possibility of starvation ketoacidosis given the patient’s prolonged intermittent fasting?
8. Was the patient assessed for autoimmune diabetes (e.g., LADA) given low C-peptide levels, and if not, why was this potential differential diagnosis not considered?
9. Why was there no longer-term follow-up beyond two weeks to assess risk of recurrence or glycemic stability post-discharge?
10. How do the authors justify the lack of comparative discussion with other similar published cases regarding treatment duration, insulin infusion strategies, and patient education outcomes?

Comments on the Quality of English Language

English Language should be improve

Author Response

A Novel Presentation of Euglycemic Diabetic Ketoacidosis As-sociated with SGLT2 Inhibitor and Weekly GLP-1 Agonist: Case report

 

<Response to reviewers and summary of changes made>

 

             We thank the reviewers for their careful review of our manuscript. We found their comments and suggestions very helpful. We have tried to address all of the reviewers’ comments in our revised manuscript. Amended and newly added content is shown in red font.

 

Reviewer #3

The manuscript presents a clinically relevant case; however, it lacks sufficient novelty, comprehensive literature comparison, and critical analysis to justify publication. Methodological transparency, data interpretation depth, and adherence to case report guidelines require major revision.

 

We sincerely appreciate the reviewer’s insightful comments regarding the novelty, comprehensiveness, and methodological rigor of our case report. In the revised version, we have undertaken several major revisions to address these concerns. First, we expanded the literature review to include recently published reports of euDKA associated with SGLT2 inhibitors and GLP-1 receptor agonists, highlighting how our case differs in terms of clinical presentation, combination therapy, and precipitating factors. We also provided a more detailed comparison with prior cases to emphasize the clinical relevance and potential novelty of this report. Second, we strengthened the critical analysis by elaborating on the pathophysiological mechanisms, potential pharmacological implications of enavogliflozin’s potency, and unique diagnostic challenges. Third, we revised the structure and content to ensure full compliance with the CARE guidelines, including a clear timeline of clinical events and interventions. Finally, the entire manuscript has undergone professional English editing to improve clarity, readability, and overall quality. We believe these substantial revisions have significantly enhanced the scientific merit and clinical value of our report.

 

Reviewer only Figure

 

Comment 1) How does this case add novel insights beyond previously published euDKA cases involving SGLT2 inhibitors and GLP-1 agonists, especially given several similar reports in recent literature?

We thank the reviewer for this insightful suggestion. In the revised Discussion, we have expanded our comparison with previously published cases of euDKA associated with SGLT2 inhibitors and GLP-1 receptor agonists. In our case, the patient was started on semaglutide for weight reduction and subsequently developed progressive gastrointestinal symptoms, including nausea and reduced appetite, which resulted in prolonged fasting. GLP-1 receptor agonists are known to delay gastric emptying and suppress appetite, thereby contributing to caloric restriction and ketone accumulation. This scenario is consistent with prior reports. For example, Louwagie et al. (2025) reported euDKA in a patient treated with empagliflozin and tirzepatide; however, that case differed from ours in several respects: the patient was not newly diagnosed with diabetes, tirzepatide is a dual GIP/GLP-1 receptor agonist rather than a pure GLP-1RA, and therapy was initiated primarily for glycemic control rather than weight reduction. Similarly, Alduraibi et al. described euDKA following GLP-1RA monotherapy (including semaglutide or dulaglutide), indicating that GLP-1RAs alone may precipitate ketone accumulation under certain conditions. These comparisons highlight that euDKA may arise not only from various combination regimens but also from monotherapy, particularly when precipitating factors such as fasting, dehydration, or gastrointestinal intolerance are present. Moreover, gastrointestinal side effects such as nausea and vomiting may mimic the early symptoms of DKA, potentially delaying recognition and treatment.

In addition, we have strengthened the Conclusion to clearly highlight the novelty of our case. To the best of our knowledge, this is the first report of euglycemic diabetic ketoacidosis occurring in a newly diagnosed patient with type 2 diabetes following the combined use of semaglutide and enavogliflozin, in the context of prolonged intermittent fasting. By integrating early disease status, a specific drug combination, and well-characterized behavioral triggers, our case provides unique insights that contribute both to clinical awareness and to the literature on the mechanistic interplay of these therapies.

 

Old manuscript (Page 5, Line 182-194)

New manuscript (Page 6, Line 200-213)

In this case, the patient was started on semaglutide for weight reduction and subsequently developed progressive gastrointestinal symptoms, including nausea and reduced appetite, which resulted in prolonged fasting. GLP-1RAs are known to delay gastric emptying and suppress appetite, which may contribute to caloric restriction and increase ketone produc-tion[12]. In this ketotic-prone state, the addition of an SGLT2 inhibitor may exacerbate ke-togenesis and overwhelm the patient’s compensatory metabolic capacity. Several reports have documented cases of euDKA in the setting of GLP-1RA use combined with pro-longed fastin[14,19]. Moreover, nausea and vomiting—common side effects of GLP-1RAs—may mimic early symptoms of DKA, potentially delaying diagnosis.

Comparison with previous reports Several recent case reports have described euDKA in the context of SGLT2 inhibi-tor or GLP-1RA therapy, or concomitant therapies. Louwagie et al. reported a case of euDKA in a patient treated with empagliflozin and tirzepatide [21]. However, this case differed from ours in several aspects: the patient was not newly diagnosed with dia-betes, tirzepatide was a dual GIP/GLP-1 receptor agonist rather than a pure GLP-1RA, and therapy was initiated primarily for glycemic control rather than weight reduction. Similarly, Alduraibi et al. described euDKA following GLP-1 agonist monotherapy, in-cluding semaglutide or dulaglutide [14, 22]. This suggests that even without SGLT2 in-hibitor use, GLP-1 receptor agonists alone may contribute to ketone accumulation un-der certain conditions. These comparisons emphasize that euDKA can occur not only with various combination regimens but also with monotherapy. In particular, the presence of additional precipitating factors such as fasting, dehydration, or gastroin-testinal intolerance may influence its occurrence. Moreover, nausea and vomiting, which are common side effects of GLP-1RAs, may mimic the early symptoms of DKA, potentially delaying the diagnosis.

 

Old manuscript (Page 6, Line 233-239)

New manuscript (Page 6, Line 274-282)

SGLT2 inhibitors are beneficial for type 2 diabetes treatment but can induce euglycemic DKA. This case report presents a severe DKA episode following SGLT2 inhibitor use. Early recognition and aggressive management are crucial. Before initiating SGLT2 inhibitors, it is essential to assess for catabolic symptoms related to hyperglycemia and to avoid trig-gering factors such as fasting, dehydration, and infection. Patients should be advised to seek immediate medical attention if symptoms occur.

SGLT2 inhibitors are beneficial for the treatment of type 2 diabetes but can precip-itate euglycemic DKA. To the best of our knowledge, this case is unique in represent-ing the first reported episode of euDKA in a newly diagnosed patient with T2DM treated with a combination of semaglutide and enavogliflozin during prolonged inter-mittent fasting. Early recognition and aggressive management are crucial for achieving favorable outcomes. Before initiating SGLT2 inhibitors and GLP-1 receptor agonists, clinicians should carefully evaluate potential risk factors, such as fasting, dehydration, and gastrointestinal intolerance, and provide thorough patient education regarding the warning symptoms of DKA.

 

Newly inserted reference

14.        Alduraibi, R. K.; Alrebdi, Y. M.; Altowayan, Y. F., Euglycemic diabetic ketoacidosis after the initiation of dulaglutide in patient with type 2 diabetes. Medicine 2023, 102, (23), e34027. 21.        Louwagie, E. J.; Diego, J. N.; Farooqi, C. S.; Kamal, M. M., Euglycemic Ketoacidosis Following Coadministration of an SGLT2 Inhibitor and Tirzepatide. JCEM Case Reports 2025, 3, (3), luaf028. 22.        Sood, N.; Bansal, O.; Garg, R.; Hoskote, A., Euglycemic Ketoacidosis From Semaglutide in a Patient Without Diabetes. JCEM Case Reports 2024, 2, (9), luae156.

 

Comment 2) Why was a standardized case report guideline (e.g., CARE) not explicitly followed, including a structured timeline of clinical events and interventions?

We thank the reviewer for this important comment. We agree that adherence to standardized case report guidelines, such as the CARE guidelines, is essential to improve transparency and reproducibility. In the revised manuscript, we have explicitly indicated that the report was prepared in accordance with the CARE guidelines. Furthermore, we have added a structured timeline summarizing the sequence of clinical events, interventions, and outcomes, which is now included as a figure/table in the Case Presentation section. We believe this addition strengthens the methodological rigor and clarity of the report.

 

Newly inserted description (Page 2, Line 67-68)

This case report was prepared in accordance with the CARE (CAse REport) guidelines to ensure methodological transparency and completeness.

 

 

Old manuscript (Page 2, Line 73-77)	New manuscript (Page 2, Line 70-73)
A 38-year-old woman (height 165 cm, weight 70 kg, BMI 25.7 kg/m²) presented to our tertiary hospital with a 5-day history of progressive fatigue and decreased appetite. Apart from a recent diagnosis of diabetes, she had no significant past medical history.	A 38-year-old woman (height, 165 cm; weight, 70 kg; BMI, 25.7 kg/m²) presented to our tertiary hospital with a 5-day history of progressive fatigue and decreased appetite. Apart from a recent diagnosis of diabetes, she had no significant past medical history, prior surgeries, or regular medication use.

 

 

Newly inserted Table2

 

Comment 3) What objective criteria were used to attribute causality of euDKA to the combination of semaglutide and enavogliflozin, rather than other potential triggers like new-onset T2DM or baseline metabolic status?

We appreciate the reviewer’s thoughtful comment regarding causality. In this case, the temporal relationship was a key factor, as the patient developed euDKA shortly after the initiation of both semaglutide and enavogliflozin in the setting of prolonged intermittent fasting. The pharmacological plausibility of both drugs further supports causation: SGLT2 inhibitors promote ketogenesis by lowering circulating insulin levels, stimulating glucagon secretion, and enhancing lipolysis, while GLP-1 receptor agonists exacerbate this risk by inducing gastrointestinal intolerance, leading to prolonged fasting and reduced caloric intake that further facilitates ketone accumulation. Alternative triggers were carefully excluded, as the patient had no clinical or laboratory evidence of infection (normal CRP), no prior history of ketosis or significant weight loss, and no other comorbid metabolic or endocrine disorders. Furthermore, after discontinuation of both semaglutide and enavogliflozin, the patient remained free of recurrent ketoacidosis during follow-up while maintained on basal insulin, metformin, and a DPP-4 inhibitor. Collectively, these considerations strongly support the interpretation that the synergistic effects of enavogliflozin and semaglutide, in the context of prolonged fasting, were the most plausible precipitating factors for this patient’s euDKA, rather than new-onset diabetes or baseline metabolic status alone.

 

Newly inserted description (Page 5, Line 176-187)

In contrast, GLP-1 receptor agonists may exacerbate ketone accumulation through gastrointestinal side effects. In our case, semaglutide prescribed for weight reduction induced progressive nausea, anorexia, and prolonged fasting. By delaying gastric emptying and suppressing appetite, GLP-1RAs can promote calorie restriction, further enhancing ketogenesis [12, 14]. The concomitant use of an SGLT2 inhibitor and GLP-1RA therefore creates a synergistic risk of euDKA, particularly under conditions of caloric restriction or dehydration. The close temporal relationship between drug ini-tiation and symptom onset, pharmacological plausibility, absence of alternative trig-gers, and prompt resolution after discontinuation strongly support a drug-associated mechanism. Although prolonged intermittent fasting may have contributed, the sever-ity of acidosis, temporal association, and rapid recovery with insulin–dextrose therapy point toward medication-induced euDKA rather than pure starvation ketoacidosis.

 

 

 

 

Comment 4) Why is there no detailed discussion on the rarity or incidence rate of enavogliflozin-associated euDKA compared to other SGLT2 inhibitors?

We thank the reviewer for raising this important point. Currently, the incidence of enavogliflozin-associated euDKA has not been well established, and to our knowledge, no large-scale comparative data exist. However, enavogliflozin is known to be a potent and selective SGLT2 inhibitor. Pharmacokinetic and pharmacodynamic studies have shown that enavogliflozin produces greater urinary glucose excretion than dapagliflozin at equivalent doses in healthy adults, and clinical studies suggest superior glucose-lowering efficacy in patients with type 2 diabetes, even in the setting of mild renal impairment. This potent effect may theoretically predispose to a higher risk of ketogenesis compared with other SGLT2 inhibitors, although direct evidence regarding euDKA risk is lacking. Further studies are required to clarify whether the pharmacological potency of enavogliflozin translates into an increased incidence of euDKA.

 

Newly inserted description (Page 5-6, Line 188-198)

The incidence of enavogliflozin-associated euDKA has not been systematically reported, and no large-scale comparative data are currently available. Enavogliflozin is a potent and selective SGLT2 inhibitor that has been shown to induce greater urinary glucose excretion compared with dapagliflozin at equivalent doses, and clinical studies suggest superior glucose-lowering efficacy even in the presence of mild renal impair-ment[21-23]. This pharmacological potency may theoretically predispose patients to enhanced ketogenesis and a higher risk of euDKA compared with other SGLT2 inhibi-tors. However, direct clinical evidence supporting an increased incidence of enavogli-flozin-associated euDKA is lacking. Future studies are warranted to clarify whether the pharmacodynamic properties of enavogliflozin translate into a clinically meaning-ful difference in euDKA risk across the SGLT2 inhibitor class.

 

Newly inserted reference

21.        Louwagie, E. J.; Diego, J. N.; Farooqi, C. S.; Kamal, M. M., Euglycemic Ketoacidosis Following Coadministration of an SGLT2 Inhibitor and Tirzepatide. JCEM Case Reports 2025, 3, (3), luaf028. 22.        Sood, N.; Bansal, O.; Garg, R.; Hoskote, A., Euglycemic Ketoacidosis From Semaglutide in a Patient Without Diabetes. JCEM Case Reports 2024, 2, (9), luae156. 23.        Dhatariya, K. K.; Umpierrez, G. E., Guidelines for management of diabetic ketoacidosis: time to revise? Lancet Diabetes Endocrinol 2017, 5, (5), 321-323.

 

 

Comment 5) Were ketone levels measured quantitatively in serum, and if not, how does the absent Why we’re confounding factors such as dehydration severity, electrolyte imbalances prior to therapy, or possible infection not systematically excluded?

 

We thank the reviewer for this thoughtful comment. In this case, ketone bodies were assessed by urine dipstick, and quantitative serum β-hydroxybutyrate measurement was not performed, which is a limitation of our report. Nevertheless, the diagnosis of euDKA was supported by the presence of positive urine ketones, an elevated anion gap metabolic acidosis, and clinical response to insulin–dextrose therapy. Importantly, potential confounders were systematically evaluated and excluded: the patient had no prior history of ketonuria, was not dehydrated to a severe extent, had normal serum electrolytes at baseline apart from acidosis-related changes, and C-reactive protein levels were within the normal range, making infection unlikely. While we acknowledge that the lack of quantitative serum ketone measurement limits the precision of biochemical assessment, the overall clinical and laboratory context strongly supports the diagnosis of euDKA in this patient.

Newly inserted description (Page 3, Line 97-99)

She was afebrile, had no leukocytosis or localizing signs, and her CRP level was within the normal range, making infection an unlikely precipitating factor.

 

Newly inserted description (Page 7, Line 263-265)

This study has several limitations. First, serum β-hydroxybutyrate was not meas-ured due to laboratory constraints, and the diagnosis of euDKA was based on high an-ion gap metabolic acidosis, ketonuria, mild hyperglycemia, and the clinical context.

 

Comment 6) How was fasting glucose of 137 mg/dL reconciled with the classification of “euglycemic” in the absence of continuous glucose monitoring data?

Thank you for this important question. At presentation, the patient’s blood glucose was 137 mg/dL, which does not meet the threshold of ≥250 mg/dL typically used to define hyperglycemic diabetic ketoacidosis. According to the established definition, “euglycemic DKA” is characterized by the presence of ketoacidosis with blood glucose levels generally below 250 mg/dL. Although continuous glucose monitoring (CGM) data were not available in this case, the patient had experienced prolonged fasting prior to admission, and her blood glucose at presentation was relatively normal at 137 mg/dL. In addition, serial measurements of both capillary and venous glucose levels during hospitalization consistently remained below this threshold. Therefore, based on the clinical context of acidosis and ketosis along with repeatedly documented glucose levels, this case was classified as “euglycemic.”

 

Comment 7) Why is there no discussion on the possibility of starvation ketoacidosis given the patient’s prolonged intermittent fasting?

We appreciate the reviewer’s thoughtful comment. Given the patient’s history of prolonged intermittent fasting, we considered the possibility of starvation ketoacidosis as a differential diagnosis. However, several clinical features were more consistent with SGLT2 inhibitor– and GLP-1RA–associated euDKA rather than pure starvation ketoacidosis. First, the severity of metabolic acidosis observed in this case was greater than typically seen in starvation ketoacidosis, in which bicarbonate levels usually do not fall below 18 mmol/L. Second, the temporal association of ketoacidosis with the initiation of semaglutide and enavogliflozin, together with the pharmacological mechanisms by which these agents promote ketogenesis, strongly supports causality. Third, the resolution of ketoacidosis occurred only after discontinuation of the agents and initiation of insulin–dextrose therapy, which is generally not required in pure starvation ketoacidosis. Finally, the patient’s 20:4 dietary pattern (20 hours of fasting with a 4-hour eating window) does not represent extreme fasting and would be unlikely to cause ketoacidosis on its own. Therefore, while intermittent fasting may have acted as a precipitating factor, the overall clinical course was more consistent with drug-associated euDKA. This discussion has been incorporated into the revised manuscript’s Discussion section.

 

Newly inserted description (Page 6, Line 176-187)

In contrast, GLP-1 receptor agonists may exacerbate ketone accumulation through gastrointestinal side effects. In our case, semaglutide prescribed for weight reduction induced progressive nausea, anorexia, and prolonged fasting. By delaying gastric emptying and suppressing appetite, GLP-1RAs can promote calorie restriction, further enhancing ketogenesis [12, 14]. The concomitant use of an SGLT2 inhibitor and GLP-1RA therefore creates a synergistic risk of euDKA, particularly under conditions of caloric restriction or dehydration. The close temporal relationship between drug initiation and symptom onset, pharmacological plausibility, absence of alternative triggers, and prompt resolution after discontinuation strongly support a drug-associated mechanism. Although prolonged intermittent fasting may have contributed, the severity of acidosis, temporal association, and rapid recovery with insulin–dextrose therapy point toward medication-induced euDKA rather than pure starvation ketoacidosis.

 

Comment 8) Was the patient assessed for autoimmune diabetes (e.g., LADA) given low C-peptide levels, and if not, why was this potential differential diagnosis not considered?

We thank the reviewer for this important comment. In this case, the possibility of autoimmune diabetes, including latent autoimmune diabetes in adults (LADA), was considered due to the relatively low C-peptide level. However, several clinical features were more consistent with type 2 diabetes than with autoimmune diabetes. First, the patient had no personal or family history of autoimmune disease. Second, both GAD antibody and islet cell antibody tests performed at admission were negative. Third, glycemic control was successfully achieved with basal insulin in combination with oral agents (metformin and a DPP-4 inhibitor), and long-term intensive insulin therapy was not required during follow-up. These findings support type 2 diabetes rather than LADA. This explanation has been added to the Discussion to clarify that the likelihood of autoimmune diabetes was low.

 

Old manuscript (Page 4, Line 130-132)	New manuscript (Page 4, Line 130-132)
Electrolytes were closely monitored and adjusted as needed throughout treatment.	Electrolytes were closely monitored and adjusted as required. On admission, tests for type 1 diabetes–related antibodies, including GAD and islet cell antibodies, were nega-tive, suggesting a low likelihood of autoimmune diabetes such as LADA.

 

 

Comment 9) Why was there no longer-term follow-up beyond two weeks to assess risk of recurrence or glycemic stability post-discharge?

Thank you for this insightful comment. In our case, the patient was initially followed up for 2 weeks post-discharge, during which she remained clinically stable without recurrence of ketosis and maintained good glycemic control on basal insulin, metformin, and a DPP-4 inhibitor. Importantly, she has continued follow-up for 3 months after discharge at our institution, and remains stable to date on the same treatment regimen without any recurrence of ketoacidosis or deterioration of glycemic control. We agree that longer-term follow-up provides additional reassurance regarding recurrence risk, and we have updated the revised manuscript to reflect this extended follow-up.

 

Old manuscript (Page 4, Line 147-159)

Old manuscript (Page 4, Line 142-154)

At the two-week follow-up visit, the patient remained clinically stable, with no recurrence of ketosis. She had adapted well to the basal insulin regimen, and self-monitored blood glucose readings were within the target range. Intermittent fasting had been discontinued, and she had resumed a regular diet. No gastrointestinal symptoms or abdominal discomfort were reported, and overall health status had improved. The current plan is to maintain the regimen of basal insulin, metformin, and a DPP-4 inhibitor, with the possibility of cautiously introducing other antihyperglycemic agents if needed, under close monitoring. She continues to be followed regularly in the outpatient clinic and has maintained good glycemic control without further episodes of acidosis.

Outpatient Follow-up At the two-week follow-up visit, the patient remained clinically stable with no recurrence of ketosis. She adapted well to the basal insulin regimen, and self-monitored blood glucose values were within the target range. Intermittent fasting was discontinued, and the patient resumed a regular diet. No gastrointestinal symptoms or abdominal discomfort were reported, and her overall health status improved. Semaglutide was not resumed because its gastrointestinal side effects combined with prolonged fasting were considered potential contributors to the development of euDKA. Instead, the patient was maintained on a conservative regimen comprising basal insulin, metformin, and a DPP-4 inhibitor. During three months of follow-up after discharge, she remained stable on this regimen, with good glycemic control and no further episodes of acidosis. A structured overview of the patient’s clinical course, including symptom onset, hospital management, and follow-up outcomes, is shown in Table 2.

 

 

Comment 10) How do the authors justify the lack of comparative discussion with other similar published cases regarding treatment duration, insulin infusion strategies, and patient education outcomes?

We thank the reviewer for this important comment. In the revised Discussion, we have expanded our comparative analysis with other published cases of SGLT2 inhibitor– and GLP-1RA–associated euDKA, focusing on treatment duration, insulin infusion strategies, and patient education outcomes.

1) Treatment duration: Our patient required six days of hospitalization, with complete resolution of acidosis by day 5. This is within the range reported in other cases (typically 3–7 days).

2) Insulin infusion strategies: Unlike many prior case reports that only mentioned “standard DKA management,” we provided detailed information on our protocol. Specifically, we described initiating a continuous intravenous insulin infusion at 1–2 units/hr, accompanied by an 18% dextrose solution at 40 mL/hr and potassium chloride supplementation at 40 mEq/L (infused at 80 mL/hr). This explicit description of insulin–dextrose–potassium co-administration highlights the unique management considerations in euDKA, where the risk of hypoglycemia necessitates concurrent glucose infusion.

3) Patient education outcomes: We also offered a more comprehensive account of patient education compared to previous reports. Topics included sick-day management strategies, medication adherence, and the importance of maintaining adequate nutrition as core components of DKA prevention. In particular, we emphasized discontinuation of prolonged fasting practices and reinforced recognition of early warning symptoms, which helped our patient avoid recurrence during follow-up.

By incorporating these details, we aimed to strengthen the clinical applicability of our report and to provide a more transparent comparison with the published literature.

Newly inserted description (Page 6, Line 199-213)

Comparison with previous reports Several recent case reports have described euDKA in the context of SGLT2 inhibi-tor or GLP-1RA therapy, or concomitant therapies. Louwagie et al. reported a case of euDKA in a patient treated with empagliflozin and tirzepatide [24]. However, this case differed from ours in several aspects: the patient was not newly diagnosed with dia-betes, tirzepatide was a dual GIP/GLP-1 receptor agonist rather than a pure GLP-1RA, and therapy was initiated primarily for glycemic control rather than weight reduction. Similarly, Alduraibi et al. described euDKA following GLP-1 agonist monotherapy, in-cluding semaglutide or dulaglutide [14, 25]. This suggests that even without SGLT2 in-hibitor use, GLP-1 receptor agonists alone may contribute to ketone accumulation un-der certain conditions. These comparisons emphasize that euDKA can occur not only with various combination regimens but also with monotherapy. In particular, the presence of additional precipitating factors such as fasting, dehydration, or gastroin-testinal intolerance may influence its occurrence. Moreover, nausea and vomiting, which are common side effects of GLP-1RAs, may mimic the early symptoms of DKA, potentially delaying the diagnosis.

 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

No comments.

Reviewer 3 Report

Comments and Suggestions for Authors

I appreciate the author's efforts in revising the manuscript according to the reviewers' suggestions. It may be accepted in its current form, but a careful final check is recommended to ensure there are no remaining errors before publication.