Cohort studyindependent cross-checkabstract only checked★ key study I-ODD-09 in-depth review
SGLT2 drugs and ketoacidosis
Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Diabetic Ketoacidosis : A Multicenter Cohort Study.
Overview
Douros A et al.. Ann Intern Med 2020 · PMID 32716707 · DOI 10.7326/M20-0289
About 2 per 1,000 users per year developed ketoacidosis, nearly 3 times more than with DPP-4 drugs.
Does the study support the specific claim? Yes · Methodological quality: high
Plain-language summary
Study explained simply
- What did the researchers want to find out?
SGLT2 vs DPP-4 inhibitors and DKA risk
- How was the study done?
Multicentre population-based cohort (prevalent new-user design, propensity-matched)
- How many people, animals or samples were studied?
208,757 matched pairs; Type 2 diabetes new users
- What was actually found?
HR 2.85.
- How large was the observed effect?
HR 2.85 (1.99-4.08)
- What do the results mean in everyday life?
Rare but real; caution with fasting/illness.
- What are the study's limitations?
No lab data; Unmeasured confounding
- What does it say about Elawady's specific claim?
- Do the results apply to Germany and Europe?
UK data included.
- What can explicitly not be concluded from this study?
That the drugs are net harmful.
Scientific in-depth review
1. Full reference
- Authors
- Douros A et al.
- Journal
- Ann Intern Med
- Year
- 2020
- Identifier
- PMID 32716707 DOI 10.7326/M20-0289
- Verification
- verified – PubMed efetch 2026-10-25 (this agent)
- Retracted
- no
- Corrections
- none
- Extent checked
- abstract only
- Conflicts of interest and funding
CIHR funded.
2. Research question
SGLT2 vs DPP-4 inhibitors and DKA risk
3. Study design and population
- Study design
- Cohort study – Multicentre population-based cohort (prevalent new-user design, propensity-matched)
- Population
Type 2 diabetes new users
- Country
Canada (7 provinces) and UK
- Period
2013-2018
- Sample size
208,757 matched pairs
- Inclusion and exclusion criteria
As described in the abstract; details not available in abstract.
4. Methods and endpoints
- Exposure / intervention
SGLT2 inhibitors
- Comparator
DPP-4 inhibitors
- Endpoints
DKA
- Statistical methods
Cox, random-effects pooling
5. Actual results
- Results
521 DKA cases in 370,454 PY. Incidence 2.03 vs 0.75 per 1,000 PY; HR 2.85 (1.99-4.08); dapagliflozin 1.86, empagliflozin 2.52, canagliflozin 3.58; prior insulin appeared to decrease risk.
- Absolute risks
About 1.3 extra DKA cases per 1,000 person-years.
- Authors' conclusion
Almost 3-fold increased DKA risk; class effect.
6. Strengths
- Very large
- Active comparator
- Multinational
7. Weaknesses
- No lab data
- Unmeasured confounding
8. Risk of bias
- Orienting tool
- ROBINS-E
- Type of assessment
- simplified assessment (abstract only)
- Full formal assessment
- no
- Overall risk of bias
- some concerns
- Rationale
Well-designed pharmacoepidemiology.
9. Assessment of the statistical interpretation
Consistent relative increase; low absolute risk.
10. Relevance to the specific claim
Supports C-ODD-02; relevant to C-FAST-03.
11. Independent contrary findings
12. Transferability to Germany and Europe
UK data included.
13. Overall methodological judgement
Robust evidence of increased but rare DKA.
| Multidimensional assessment | |
|---|---|
| Authenticity of the source | verified |
| Methodological quality | high |
| Risk of bias | some concerns |
| Precision of results | high |
| 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
None beyond those stated.
15. Linked fact checks
- SGLT2 inhibitors such as dapagliflozin (Forxiga) can cause ketoacidosis, sometimes with normal or low blood glucose. – Studies supporting the claim
- 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