Dapagliflozin plus calorie restriction for remission of type 2 diabetes: multicentre, double blind, randomised, placebo controlled trial.
Liu Y, Chen Y, Ma J, Lin J, Liu C, Li X, Xu Y, Kuang H, Shi L, Xue Y, Feng B, Zhu D, Wang G, Yang J, Xiao X, Yu X, Zhou J, Bao Y, Su Q, Lyu M, Li X, Zhang H, Li X
- DOI
- 10.1136/bmj-2024-081820
- Record issued
- 2026-08-15
- Engine
- 7.39.0
- Exported
- 2026-09-20
Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/aad5a84a-0f2d-484f-bea7-309fede4cb03 is authoritative.
How this rating was calculated
- IntegrityIntegrity concern ×2−1★
- ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
- ClaimsTreatment effect not shown to be clinically meaningful−0.5★
- ReportingData & code availability partially met−0.25★
- The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 52 reported means were read, and their group size is not stated where the values are printed (this source has no machine-readable table structure). These checks need the count the mean was averaged over, so none was performed.
- No data or code availability links were detected to verify.
- 01Efficacy rests on an unvalidated surrogate endpoint
The primary outcome is diabetes remission defined by glycated hemoglobin <6.5% and fasting plasma glucose <126 mg/dL in the absence of antidiabetic drugs for at least 2 months. This is a surrogate endpoint (glycemic control) rather than a hard clinical outcome. The paper does not provide evidence linking this surrogate to long-term clinical outcomes such as mortality or macrovascular complications, nor does it demonstrate target engagement at the tested dose beyond the mechanism of SGLT2 inhibition.
“Primary outcome: incidence of diabetes remission (defined as glycated haemoglobin <6.5% and fasting plasma glucose <126 mg/dL in the absence of all antidiabetic drugs for at least 2 months)”
- 02Treatment effect not shown to be clinically meaningful
The primary effect is a remission rate of 44% in the dapagliflozin group vs 28% in placebo, with a risk ratio of 1.56. While statistically significant, the absolute difference is 16 percentage points, and the effect size is not anchored to a minimal clinically important difference or long-term clinical benefit. The remission definition is based on a short-term surrogate (2 months off drugs) and may not reflect durable remission or improved clinical outcomes.
“Remission of diabetes was achieved in 44% (73/165) of patients in the dapagliflozin group and 28% (46/163) of patients in the placebo group (risk ratio 1.56, 95% confidence interval (CI) 1.17 to 2.09; P=0.002)”
This Kaimen Rigor review uses Kaimen Rigor reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.
This is a well-conducted and well-reported randomised controlled trial with rigorous design, clear reporting of methods and results, and appropriate ethical approvals. The main weakness is the vague data availability statement, which lacks a concrete access mechanism, and minor copyedit issues.
Both reviewers independently scored all eight dimensions and agreed on all statuses; no divergence was present. The statistics verification component checked only 2 tests (those with test statistics or effect estimates with CIs) and found them consistent; other reported statistics were not machine-verified. The citation check found no retracted or unresolved references.
Numerical inconsistencies
1 finding · worst lowValues that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.
- Internal contradictions in the reported numbersAssessed
Recomputed 2 tests: 2 consistent, 0 inconsistent; 1 recomputed directly from the reported test statistics, 1 via agent-written checks.
- CONSISTENTreported p = .002 · recomputed p = .003Recomputed risk ratio 1.56 (95% CI 1.17–2.09), reported p=0.002
“risk ratio 1.56, 95% confidence interval (CI) 1.17 to 2.09; P=0.002”
Taken as given: 1.17–2.09 is a two-sided 95% confidence interval for the risk ratio of 1.56, not a range, an IQR, or a different interval level; the risk ratio is a RATIO measure, so the interval is symmetric on the log scale; p=0.002 is the p for THIS estimate, not for another comparison in the same sentenceMethod: back the two-tailed p out of the log-scale CI width and compare it against the printed pHow we recomputed it: pCI(1.56, 1.17, 2.09, 1) - CONSISTENTreported p = .002 · recomputed p = .003Reviewers 1, 2Primary outcome risk ratio p-value from Cochran-Mantel-Haenszel test
“The risk ratio for diabetes remission stratified by whether participants were treated with metformin at baseline was 1.56 (95% CI 1.17 to 2.09) ... P=0.002”
Taken as given: The risk ratio is 1.56 with 95% CI 1.17 to 2.09.; The CI is two-sided at 95%.; The p-value is two-tailed.Method: Recomputed p-value from the reported risk ratio and 95% CI using the normal approximation for the log risk ratio.How we recomputed it: pCI(1.56, 1.17, 2.09, 1)
- lowinternal contradictionThe median intervention duration in the placebo group is reported as 12 months, which is the full trial duration, while the dapagliflozin group median is 9 months. This could be due to more early remissions in the dapagliflozin group, but the text does not explain the difference.
“The median duration of the intervention was 9 (IQR 4-12) months in the dapagliflozin group and 12 (4-12) months in the placebo group.”
ResultsFind in source - lowinternal contradictionThe abstract states '328 patients' while the results state '328 participants were enrolled and randomly assigned' — consistent. However, the CONSORT flow diagram is referenced but not shown in the text; no contradiction found.
Participants 328 patients with type 2 diabetes aged 20-70 years... Between 12 June 2020 and 31 January 2023, 328 participants were enrolled and randomly assigned
Abstractreviewer’s wording
Overstated conclusions
3 findings · worst highConclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.
- Efficacy rests on an unvalidated surrogate endpointAssessed
- Treatment effect not shown to be clinically meaningfulAssessed
- Conclusions only partially backed by the presented evidenceAssessed
5 major claims checked against the paper's own evidence: 1 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.
- partialReviewers 1, 2The combined regimen is a practical and effective strategy for diabetes remission.The trial shows efficacy, but 'practical' is supported by adherence data; generalisability is limited.Evidence: Adherence was high (91.5% vs 88.1% medication adherence), but limitations include short remission definition and lack of generalisability.
“Our findings provide an alternative and more practical strategy than intensive weight management to achieve remission for patients with early type 2 diabetes.”
ConclusionFind in source - supportedReviewers 1, 2Dapagliflozin plus calorie restriction achieved a higher rate of diabetes remission compared with calorie restriction alone.The primary outcome result directly supports this claim.Evidence: Primary outcome: 44% vs 28%, RR 1.56 (95% CI 1.17 to 2.09), P=0.002.
“Remission of diabetes was achieved in 44% (73/165) of patients in the dapagliflozin group and 28% (46/163) of patients in the placebo group (risk ratio 1.56, 95% confidence interval (CI) 1.17 to 2.09; P=0.002) over 12 months”
AbstractFind in source - supportedReviewer 1Dapagliflozin plus calorie restriction achieved greater weight loss than calorie restriction alone.Secondary outcome shows a significant difference in weight change.Evidence: Change in body weight: −5.0 vs −3.2 kg, difference −1.3 (95% CI −1.9 to −0.7), P<0.001.
“The mean weight loss from baseline to the final visit was greater in the dapagliflozin group than in the placebo group (5.0 (SD 4.5) v 3.2 (3.8) kg). We found a significant difference between the two groups in weight change (−1.3 (95% CI −1.9 to −0.7) kg).”
ResultsFind in source - supportedReviewer 1Dapagliflozin plus calorie restriction improved metabolic risk factors more than calorie restriction alone.Multiple secondary outcomes show significant improvements.Evidence: Significant differences in body fat, systolic BP, fasting glucose, HbA1c, HOMA-IR, HDL, triglycerides.
Metabolic risk factors were also significantly improved in the dapagliflozin group compared with the control group, including body fat mass, systolic blood pressure, fasting plasma glucose, HbA 1c , HOMA-IR, high density lipoprotein cholesterol, and triglycerides.
Resultsreviewer’s wording - supportedReviewer 2Dapagliflozin plus calorie restriction led to greater weight loss and improvement in insulin resistance.Secondary outcomes show significant differences in weight change and HOMA-IR.Evidence: Weight change difference -1.3 kg (95% CI -1.9 to -0.7); HOMA-IR difference -0.8 (95% CI -1.1 to -0.4).
“Changes in body weight (difference −1.3 (95% CI −1.9 to −0.7) kg) and homoeostasis model assessment of insulin resistance (difference −0.8, −1.1 to −0.4) were significantly greater in the dapagliflozin group than in the placebo group.”
AbstractFind in source
Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.
- INADEQUATESurrogate endpointThe primary outcome is diabetes remission defined by glycated hemoglobin <6.5% and fasting plasma glucose <126 mg/dL in the absence of antidiabetic drugs for at least 2 months. This is a surrogate endpoint (glycemic control) rather than a hard clinical outcome. The paper does not provide evidence linking this surrogate to long-term clinical outcomes such as mortality or macrovascular complications, nor does it demonstrate target engagement at the tested dose beyond the mechanism of SGLT2 inhibition.
“Primary outcome: incidence of diabetes remission (defined as glycated haemoglobin <6.5% and fasting plasma glucose <126 mg/dL in the absence of all antidiabetic drugs for at least 2 months)”
- INADEQUATEEffect sizeThe primary effect is a remission rate of 44% in the dapagliflozin group vs 28% in placebo, with a risk ratio of 1.56. While statistically significant, the absolute difference is 16 percentage points, and the effect size is not anchored to a minimal clinically important difference or long-term clinical benefit. The remission definition is based on a short-term surrogate (2 months off drugs) and may not reflect durable remission or improved clinical outcomes.
“Remission of diabetes was achieved in 44% (73/165) of patients in the dapagliflozin group and 28% (46/163) of patients in the placebo group (risk ratio 1.56, 95% confidence interval (CI) 1.17 to 2.09; P=0.002)”
Data authenticity concerns
None foundAn adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.
Checked — nothing surfaced.
Reporting gaps
1 finding · worst mediumRequired detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.
- Data/code availability incompleteAssessed
Prior research is cited (DiRECT trial, bariatric surgery, SGLT-2 inhibitor mechanisms) with strengths and limitations acknowledged (e.g., very low energy diet challenge, surgery risks). The rationale logically connects energy deficit from dapagliflozin plus calorie restriction to remission. Limitations of prior approaches are addressed by proposing a more practicable regimen.
“Thus, we hypothesised that dapagliflozin plus calorie restriction could achieve greater energy deficit and greater reduction of hyperglycaemia than calorie restriction alone and could lead to remission of diabetes in a generally acceptable way.”
“Thus, we hypothesised that dapagliflozin plus calorie restriction could achieve greater energy deficit and greater reduction of hyperglycaemia than calorie restriction alone and could lead to remission of diabetes in a generally acceptable way.”
“However, the strategy of a very low energy diet in routine care settings remains a challenge.”
Randomisation method (centralised IWRS, block size 4, stratified by metformin) and unit (participant) are reported. Blinding is described (identical tablets, masked investigators/patients). Power analysis is provided (80% power, 12.3% difference, 20% dropout). Inclusion/exclusion criteria are pre-specified. Outlier handling is addressed via ITT and multiple imputation for missing data. Controls are inherent (placebo group). Independent replication is not applicable for a single pivotal trial.
“Randomisation was achieved by an independent third party (Trial Data Pharmaceutical Technology; Shanghai, China) using a centralised interactive web based randomisation system (Trial Data IWRS) with block size of four and stratification according to metformin treatment at screening (yes or no).”
“Dapagliflozin and placebo tablets were identical in size, shape, colour, and appearance, were packaged in identical bottles, and were administered in the same dosage and route. The investigators, clinical staff, dietitian, and patients were masked to treatment throughout the study.”
“The sample size calculation suggested that 328 participants (164 per group) would provide 80% power to detect a significant difference (12.3%) in the remission rate between the dapagliflozin group and the placebo group at a significance level of 0.05 using a two tailed test, assuming an anticipated dropout rate of less than 20%.”
“Randomisation was achieved by an independent third party (Trial Data Pharmaceutical Technology; Shanghai, China) using a centralised interactive web based randomisation system (Trial Data IWRS) with block size of four and stratification according to metformin treatment at screening (yes or no).”
“The investigators, clinical staff, dietitian, and patients were masked to treatment throughout the study.”
“The sample size calculation suggested that 328 participants (164 per group) would provide 80% power to detect a significant difference (12.3%) in the remission rate between the dapagliflozin group and the placebo group at a significance level of 0.05 using a two tailed test, assuming an anticipated dropout rate of less than 20%.”
Sex is reported (66% male overall; 68% vs 65% per group). Age, weight, BMI, blood pressure, diabetes duration, and comorbidities (hypertension) are reported. Species/strain/housing are not applicable for a human trial. Demographics are adequately reported.
“The mean age of the participants was 46.7 years, 66% (218/328) were men, and the mean body mass index was 28.2.”
“No (%) hypertension | 90 (55) | 93 (57)”
“The mean age of the participants was 46.7 years, 66% (218/328) were men, and the mean body mass index was 28.2.”
“Mean (SD) age, years | 46.4 (10.4) | 47.1 (11.4)”
“No (%) hypertension | 90 (55) | 93 (57)”
The ethics statement names the approving bodies (ethics committees at each centre) and states written informed consent was obtained. Regulatory compliance is supported by trial registration (ClinicalTrials.gov NCT04004793) and adherence to ICMJE disclosure. The statement is adequate.
“The study protocol and amendments were reviewed and approved by the ethics committees at each centre. All the participants provided written informed consent.”
“Trial registration ClinicalTrials.gov NCT04004793 .”
“The study protocol and amendments were reviewed and approved by the ethics committees at each centre.”
“All the participants provided written informed consent.”
Dapagliflozin is identified by name and dose (10 mg/day); placebo is described as identical tablets. Protein shakes (Nutriease, Zhejiang Nutriease, China) are identified. SAS version 9.4 is identified. No antibodies, cell lines, or mycoplasma testing are applicable. The trial is scored because the investigational product is a key resource.
“Eligible participants were randomly assigned in a one-to-one ratio to receive 10 mg of dapagliflozin or placebo per day for 12 months”
“Participants were provided with protein shakes (Nutriease, Zhejiang Nutriease, China) twice a day for the first three months”
“We used SAS version 9.4 for all statistical analyses.”
“Eligible participants were randomly assigned in a one-to-one ratio to receive 10 mg of dapagliflozin or placebo per day for 12 months”
“Participants were provided with protein shakes (Nutriease, Zhejiang Nutriease, China) twice a day for the first three months”
“We used SAS version 9.4 for all statistical analyses.”
Primary analysis uses Cochran-Mantel-Haenszel test; secondary outcomes use mixed effects model with autoregressive correlation. Exact p-values are reported (e.g., P=0.002). Effect sizes with 95% CIs are reported for all outcomes. Assumptions are handled by design (mixed model, multiple imputation). Data presentation includes flow diagram, baseline table, and per-group n. Mathematical plausibility is not applicable for large-N continuous outcomes.
“For the primary outcome, we used a Cochran-Mantel-Haenszel test, stratified according to whether participants were treated with metformin at baseline, to estimate the risk ratio and corresponding 95% confidence interval (CI).”
“For the primary outcome, we used a Cochran-Mantel-Haenszel test, stratified according to whether participants were treated with metformin at baseline, to estimate the risk ratio and corresponding 95% confidence interval (CI).”
“Remission of diabetes was achieved in 44% (73/165) of patients in the dapagliflozin group and 28% (46/163) of patients in the placebo group (risk ratio 1.56, 95% confidence interval (CI) 1.17 to 2.09; P=0.002)”
“Change in body weight, kg | −5.0 (4.5) | −3.2 (3.8) | −1.3 (−1.9 to −0.7) | <0.001”
The data availability statement is present but lacks a concrete access mechanism (no repository, platform, or data-access committee). For patient-level data, managed access is acceptable, but the statement is too vague. No code sharing is reported, but no bespoke code is mentioned.
“Data from this study can be requested from the correspond”
“Data from this study can be requested from the correspond”
Methods are comprehensive (diet, exercise, drug discontinuation criteria). Trial registration number is provided. Limitations are explicitly discussed (generalisability, remission definition, DXA availability, energy expenditure). Conclusions are proportional to the results. Funding sources and COI are disclosed. No reporting guideline checklist is mentioned, but this is not a fail for a clinical trial.
“Trial registration ClinicalTrials.gov NCT04004793 .”
“Firstly, our findings cannot be generalised to patients with a duration of type 2 diabetes of more than six years or to populations of other races or ethnic groups.”
“Funding: This study was funded by grants from the National Nature Science Foundation of China (32241011, 82330024, 92357306) and National Nature Science Foundation of China for Distinguished Young Scholars (82325011), and partially by a grant from AstraZeneca (ESR-18-13952).”
“Trial registration ClinicalTrials.gov NCT04004793 .”
“The study had some limitations. Firstly, our findings cannot be generalised to patients with a duration of type 2 diabetes of more than six years or to populations of other races or ethnic groups.”
“Funding: This study was funded by grants from the National Nature Science Foundation of China (32241011, 82330024, 92357306) and National Nature Science Foundation of China for Distinguished Young Scholars (82325011), and partially by a grant from AstraZeneca (ESR-18-13952).”
Registered (1 ID: ClinicalTrials.gov). No reporting guideline cited.
Broken references and links
None found · partly checkedReferences checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.
Nothing surfaced — but not everything feeding this category ran (missing: data/code link verification), so read this as a partial clean bill.
Checked 16 references by DOI: 15 verified — 1 no DOI (shown, not verified).
- NO DOIIDF Diabetes AtlasNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
Copyediting
5 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 5 minor suggestions below.
5 copyedit issues flagged: mostly consistency, clarity, typo.
- MINORtypoAbstract, Objective“To assess the effect of dapagliflozin plus calorie restriction on remission of type 2 diabetes.”→ Consider adding 'the' before 'remission' for grammatical flow.Minor grammatical improvement.
- MINORconsistencyMethods, Statistical analysis“We considered a two sided P value <0.05 to indicate statistical significance.”→ Use 'two-sided' consistently with hyphenation.Hyphenation inconsistency.
- MINORclarityResults, Remission of diabetes“The median duration of the intervention was 9 (IQR 4-12) months in the dapagliflozin group and 12 (4-12) months in the placebo group.”→ Clarify why the median duration differs between groups.Potential reader confusion.
- MINORconsistencyMethods, Statistical analysis“We considered a two sided P value <0.05 to indicate statistical significance.”→ Use 'two-sided' consistently with hyphen.Hyphenation inconsistency.
- MINORclarityResults, Remission of diabetes“The median duration of the intervention was 9 (IQR 4-12) months in the dapagliflozin group and 12 (4-12) months in the placebo group.”→ Clarify that the placebo group median is 12 months, which may seem odd if the intervention was 12 months; consider explaining early discontinuation.Potential confusion for readers.
The published work is robust and well-reported; an informed reader should weigh the vague data availability statement and the minor copyedit issues as the only notable gaps. No erratum or re-analysis is warranted based on the evidence reviewed.
- 1.HIGHdata codeReplace the vague data availability statement with a concrete access mechanism, such as a named data-access committee or platform (e.g., YODA, Vivli) with conditions and timeframe.The current statement ('available from the corresponding author on reasonable request') lacks transparency and is a common reviewer concern.
- 2.MEDIUMreportingExplicitly state adherence to the CONSORT reporting guideline in the Methods or as a supplementary checklist.Referencing CONSORT strengthens reporting transparency and is expected for clinical trials.
- 3.MEDIUMethicsAdd a statement on regulatory compliance (e.g., Declaration of Helsinki) in the Ethics section.Explicitly naming the ethical standard enhances completeness, though approval is already stated.
- 4.MEDIUMdata codeIf bespoke analysis code was used, deposit it in a public repository (e.g., Zenodo, GitHub) with a DOI and reference it in the manuscript.Code sharing improves reproducibility and is increasingly expected.
- 5.MEDIUMreportingClarify the race/ethnicity breakdown of participants in the demographics, as the study is conducted in China but does not explicitly state ethnicity.Explicit demographic reporting improves generalisability assessment.
- 6.LOWcopyeditAdd 'the' before 'remission' in the Abstract Objective for grammatical flow.Minor grammatical improvement.
- 7.LOWcopyeditUse 'two-sided' consistently with hyphenation in the Methods, Statistical analysis section.Hyphenation inconsistency is a minor copyedit issue.
- 8.LOWcopyeditClarify why the median intervention duration differs between groups (9 vs 12 months) in the Results, Remission of diabetes section.Potential reader confusion; explain early discontinuation or other reasons.
The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”
- Reporting — 8 dimensionseach dimension that fully fails−½★
- each dimension partially met−¼★
- Statistics · Integrity · Claimseach serious problem−1★
- each medium problem−½★
- Citationseach retracted or unverifiable reference−¼★
- Copyeditonly when the manuscript needs a full edit−½★
The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.
The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.
Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.
This Kaimen Rigor review is model-assisted and is not a substitute for formal expert review. It complements human evaluation by surfacing potential methodological concerns — verify each finding against the source.