Meta-analysisindependent cross-checkabstract checked★ key study I-ODD-103 in-depth review
SGLT2 drugs roughly double the rare risk of ketoacidosis
Sodium-Glucose Cotransporter-2 Inhibitors and Risk of Diabetic Ketoacidosis Among Adults With Type 2 Diabetes: A Systematic Review and Meta-Analysis.
Overview
Colacci M et al.. Can J Diabetes 2022 · PMID 34116926 · DOI 10.1016/j.jcjd.2021.04.006
RCTs: RR 2.46; absolute risk about 0.6-2.2 cases per 1,000 patient-years.
Does the study support the specific claim? Yes · Methodological quality: moderate
Plain-language summary
Study explained simply
- What did the researchers want to find out?
Quantify DKA risk with SGLT2 inhibitors.
- How was the study done?
Meta-analysis of trials and cohorts.
- How many people, animals or samples were studied?
About 360,000 participants.
- What was actually found?
Higher DKA risk in trials and cohorts.
- How large was the observed effect?
RR 2.46 (1.16-5.21) RCTs; RR 1.74 (1.07-2.83) cohorts.
- What do the results mean in everyday life?
Rare but real; patients need sick-day rules and ketone checks.
- What are the study's limitations?
Few trials, few events.
- What does it say about Elawady's specific claim?
Supports the ketoacidosis part of the claim.
- Do the results apply to Germany and Europe?
High.
- What can explicitly not be concluded from this study?
It does not show the drugs are net harmful.
Scientific in-depth review
1. Full reference
- Authors
- Colacci M et al.
- Journal
- Can J Diabetes
- Year
- 2022
- Identifier
- PMID 34116926 DOI 10.1016/j.jcjd.2021.04.006
- Verification
- verified – PubMed efetch 2026-10-26; Crossref works API 2026-10-26
- Retracted
- no
- Corrections
- none
- Extent checked
- abstract only
- Conflicts of interest and funding
Not stated in abstract.
2. Research question
How large is the risk of DKA with SGLT2 inhibitors in adults with type 2 diabetes?
3. Study design and population
- Study design
- Meta-analysis – Systematic review and meta-analysis of RCTs and cohort studies (random effects, Hartung-Knapp-Sidik-Jonkman)
- Population
Adults with type 2 diabetes
- Country
International
- Period
Searches to 15 April 2019
- Sample size
7 RCTs (42,375 participants; 4 pooled) and 5 cohort studies (318,636 participants)
- Inclusion and exclusion criteria
RCTs and observational studies quantifying DKA with an SGLT2 inhibitor vs other drugs or placebo; no language restriction
4. Methods and endpoints
- Exposure / intervention
SGLT2 inhibitors
- Comparator
Placebo or other glucose-lowering drugs
- Endpoints
Diabetic ketoacidosis
- Statistical methods
Random-effects RR; I2
5. Actual results
- Results
RCTs: absolute DKA rate 0.6-2.2 per 1,000 person-years with SGLT2 inhibitors; pooled RR 2.46 (95% CI 1.16-5.21; I2 0%). Observational: 0.6-4.9 per 1,000 person-years; RR 1.74 (1.07-2.83; I2 45%).
- Absolute risks
0.6-2.2 per 1,000 person-years in RCTs; 0.6-4.9 per 1,000 person-years in cohorts.
- Authors' conclusion
SGLT2 inhibitors increase the risk of DKA in adults with type 2 diabetes in both observational studies and large RCTs.
6. Strengths
- Combines randomised and observational evidence
- Absolute rates reported
- Cited by ADA Standards 2026
7. Weaknesses
- Only 4 RCTs pooled
- Search ended 2019 (before DAPA-CKD/EMPA-KIDNEY)
- Few events; wide CI
8. Risk of bias
- Orienting tool
- AMSTAR 2
- Type of assessment
- simplified assessment (abstract only)
- Full formal assessment
- no
- Overall risk of bias
- some concerns
- Rationale
Two independent reviewers; small number of pooled trials.
9. Assessment of the statistical interpretation
CIs log-symmetric (stats/C-ODD-02.py). Relative risk about doubled, but absolute risk remains around 1-2 per 1,000 person-years.
10. Relevance to the specific claim
Confirms the core of the claim that SGLT2 inhibitors can cause ketoacidosis.
11. Independent contrary findings
Palmer 2021 network meta-analysis judged no increase (moderate certainty); superseded by Shi 2023 (I-ODD-107) and SMART-C 2022 (I-ODD-106), both showing about doubled risk.
12. Transferability to Germany and Europe
High; same drugs and labels.
13. Overall methodological judgement
Supports a real but rare DKA risk.
| Multidimensional assessment | |
|---|---|
| Authenticity of the source | verified |
| Methodological quality | moderate |
| Risk of bias | some concerns |
| Precision of results | low |
| Directness | direct |
| Reproducibility | replicated |
| Consistency with the overall evidence | consistent |
| Regional transferability | high |
| Adequacy of the interpretation (by the archive) | not applicable |
14. Open questions
Risk under prolonged fasting or very-low-carbohydrate eating is not quantified in RCTs.
15. Linked fact checks
- SGLT2 inhibitors such as dapagliflozin (Forxiga) can cause ketoacidosis, sometimes with normal or low blood glucose. – Studies supporting the claim