Case series / case reportindependent cross-checkfull text checked I-ODD-10 in-depth review
Ketoacidosis with normal blood sugar on SGLT2 drugs
Euglycemic Diabetic Ketoacidosis: A Potential Complication of Treatment With Sodium-Glucose Cotransporter 2 Inhibition.
Overview
Peters AL et al.. Diabetes Care 2015 · PMID 26078479 · DOI 10.2337/dc15-0843
Several patients developed ketoacidosis with near-normal sugar, so it was recognised late.
Does the study support the specific claim? Yes · Methodological quality: very low
Plain-language summary
Study explained simply
- What did the researchers want to find out?
Describe euglycaemic DKA with SGLT2 inhibitors
- How was the study done?
Case series
- How many people, animals or samples were studied?
9 individuals, 13 episodes; Patients with T1D or T2D on SGLT2 inhibitors
- What was actually found?
13 episodes in 9 patients on canagliflozin (7 with off-label type 1 diabetes); glucose often near normal, delaying diagnosis; all recovered with IV fluids and insulin.
- How large was the observed effect?
not applicable
- What do the results mean in everyday life?
Check ketones when unwell on SGLT2 drugs.
- What are the study's limitations?
Incidental case collection, no denominator, mostly off-label type 1 use, all on canagliflozin.
- What does it say about Elawady's specific claim?
- Do the results apply to Germany and Europe?
US.
- What can explicitly not be concluded from this study?
How often this happens; that every SGLT2 inhibitor (e.g. dapagliflozin) carries the same risk (inferred, not shown here).
Scientific in-depth review
1. Full reference
- Authors
- Peters AL et al.
- Journal
- Diabetes Care
- Year
- 2015
- Identifier
- PMID 26078479 DOI 10.2337/dc15-0843
- Verification
- verified – PubMed efetch 2026-10-25 (this agent)
- Retracted
- no
- Corrections
- none
- Extent checked
- full text
- Conflicts of interest and funding
J.B.B. supported by NIH/NCATS grant. A.L.P. investigator/speaker/consultant for many manufacturers including AstraZeneca, Janssen (canagliflozin maker), Lilly, Boehringer Ingelheim, Novo Nordisk, Sanofi; J.B.B. and I.B.H. report multiple industry contracts/grants.
2. Research question
Describe euglycaemic DKA with SGLT2 inhibitors
3. Study design and population
- Study design
- Case series / case report – Case series of incidentally identified cases aggregated from collaborators' practices (no systematic database or record search)
- Population
9 patients (8 women, 1 man; age 26-64) on canagliflozin: 7 with type 1 diabetes (off-label use, insulin pump or MDI) and 2 with type 2 diabetes (both postoperative)
- Country
USA (various practices; IRB review at USC and UNC Chapel Hill)
- Period
Cases up to 2015 (published September 2015)
- Sample size
9 individuals, 13 episodes of euDKA or ketosis
- Inclusion and exclusion criteria
Cases aggregated by the authors based on incidental clinical experience after one author learned of a case; no systematic case-finding criteria.
4. Methods and endpoints
- Exposure / intervention
SGLT2 inhibitor (all cases canagliflozin, 100-300 mg/day)
- Comparator
none
- Endpoints
euDKA/ketosis
- Statistical methods
Descriptive
5. Actual results
- Results
13 episodes of euDKA or ketosis in 9 patients; 3 had repeat episodes on rechallenge. Presenting glucose ~96-233 mg/dL (5.3-12.9 mmol/L); pH as low as 6.89; bicarbonate 5-18 mEq/L; anion gap 16-35 mEq/L; most episodes managed in ICU (one patient intubated and haemodialysed before euDKA was recognised). Precipitants included intercurrent infection, surgery, alcohol, prolonged exercise, reduced food intake and insulin dose reduction or omission; in some no trigger was found. All resolved with intravenous fluids and insulin (plus carbohydrate) once recognised; near-normal glucose delayed recognition by patients and clinicians.
- Absolute risks
not reported (case series; incidence unknown, as the authors state)
- Authors' conclusion
SGLT2 inhibitors associated with euglycaemic DKA; check ketones if nausea, vomiting, malaise; use with great caution in T1D.
6. Strengths
- Detailed clinical and biochemical description of each episode
- Rechallenge recurrences in 3 patients strengthen causal plausibility
- Clear mechanistic discussion (glycosuria lowers glucose despite low insulin, hyperglucagonaemia, volume depletion) and practical safety advice
7. Weaknesses
- Incidental, non-systematic case collection; no denominator, so incidence cannot be estimated
- 7 of 9 patients used the drug off-label in type 1 diabetes; frequent insulin reduction/omission, alcohol and illness as co-factors
- All cases on canagliflozin; class effect for other SGLT2 inhibitors (e.g. dapagliflozin) is the authors' inference
- No comparator group
8. Risk of bias
- Orienting tool
- none (case series; no standard RoB tool applies)
- Type of assessment
- structured assessment based on the full text by a single reviewer (no formal double review)
- Full formal assessment
- no
- Overall risk of bias
- high
- Rationale
Unchanged (high) as expected for a case series; adequate for signal detection, not for risk estimation. Single-reviewer structured judgement; a formal assessment would need two independent reviewers.
| Domain | Judgement | Rationale |
|---|---|---|
| Case selection | high | Incidental aggregation through personal networks; no systematic search or consecutive enrolment. |
| Exposure ascertainment | low | Canagliflozin use and dose documented for every patient. |
| Outcome ascertainment | low | Biochemical confirmation (ketones, anion gap, bicarbonate, pH) reported per episode. |
| Causality assessment | some concerns | Temporal association and rechallenge recurrence support causality, but co-factors (insulin reduction, alcohol, infection, surgery) present in most cases. |
| Generalisability | high | Mostly off-label type 1 diabetes; no denominator. |
Full-text review (25 October 2026): Added non-systematic case-finding method, that all cases were on canagliflozin and 7/9 off-label T1D, rechallenge recurrences, precipitants (insulin reduction, reduced intake, alcohol, surgery), biochemistry ranges, treatment with insulin/fluids, COI. Bias unchanged (high).
9. Assessment of the statistical interpretation
Descriptive only. Rechallenge recurrences and temporal association support a causal signal, but frequency and risk relative to non-users cannot be derived.
10. Relevance to the specific claim
Supports C-ODD-02; key for C-FAST-03 safety.
11. Independent contrary findings
12. Transferability to Germany and Europe
US cases; physiology and drug labelling equally relevant in the EU (EMA later issued similar warnings, not covered by this paper).
13. Overall methodological judgement
Seminal signal-generating case series establishing euglycaemic DKA as a serious SGLT2-inhibitor complication, mainly in off-label type 1 diabetes use and in the postoperative setting in type 2 diabetes; later confirmed by RCT data (e.g. CREDENCE). Also illustrates that reducing insulin or food intake can precipitate life-threatening ketoacidosis that is treated with insulin, fluids and carbohydrate.
| Multidimensional assessment | |
|---|---|
| Authenticity of the source | verified |
| Methodological quality | very low |
| Risk of bias | high |
| Precision of results | not applicable |
| 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
Incidence by drug, diabetes type and setting; perioperative withholding interval.
15. Linked fact checks
- SGLT2 inhibitors such as dapagliflozin (Forxiga) can cause ketoacidosis, sometimes with normal or low blood glucose. – Studies supporting the claim
- Insulin and diabetes drugs pull glucose out of the blood and out of the cells, producing an internal 'famine'. – Studies with mixed or unclear results
- Rising blood glucose and acetone (ketones) during fasting are evidence that the liver is working properly, not a danger; high glucose plus acetone is not insulin deficiency. – Studies contradicting or limiting the claim