Meta-analysisindependent cross-checkfull text checked★ key study I-ODD-106 in-depth review
13 large trials: SGLT2 drugs protect kidneys and heart; ketoacidosis rare
Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials.
Overview
Nuffield Department of Population Health Renal Studies Group; SMART-C Consortium. Lancet 2022 · PMID 36351458 · DOI 10.1016/S0140-6736(22)02074-8
Kidney progression -37%, CV death -14%; DKA risk doubled from about 0.2 per 1,000 patient-years.
Does the study support the specific claim? Partly · Methodological quality: high
Plain-language summary
Study explained simply
- What did the researchers want to find out?
Pool all large placebo-controlled SGLT2 inhibitor trials.
- How was the study done?
Collaborative meta-analysis of 13 blinded RCTs.
- How many people, animals or samples were studied?
90,409 participants.
- What was actually found?
Clear kidney and heart benefits; DKA doubled but rare; amputation signal mainly from one trial.
- How large was the observed effect?
RR 0.63 kidney; RR 0.86 CV death; DKA RR 2.12.
- What do the results mean in everyday life?
For 1,000 people with diabetes and kidney disease treated for a year, about 26 serious events are avoided and about 2 caused.
- What are the study's limitations?
Summary data; industry trials.
- What does it say about Elawady's specific claim?
Confirms DKA risk, refutes net harm.
- Do the results apply to Germany and Europe?
High.
- What can explicitly not be concluded from this study?
Effects in people following prolonged fasting regimens.
Scientific in-depth review
1. Full reference
- Authors
- Nuffield Department of Population Health Renal Studies Group; SMART-C Consortium
- Journal
- Lancet
- Year
- 2022
- Identifier
- PMID 36351458 DOI 10.1016/S0140-6736(22)02074-8
- Verification
- verified – PubMed efetch 2026-10-26; Crossref works API 2026-10-26
- Retracted
- no
- Corrections
- none
- Extent checked
- full text
- Conflicts of interest and funding
UK Medical Research Council and Kidney Research UK; several authors report industry-funded trial work (declarations in full text).
2. Research question
What are the effects of SGLT2 inhibitors on kidney, cardiovascular and safety outcomes in people with and without diabetes?
3. Study design and population
- Study design
- Meta-analysis – Collaborative meta-analysis of large double-blind placebo-controlled trials (SMART-C)
- Population
Participants of 13 large SGLT2 inhibitor trials (82.7% with diabetes)
- Country
International
- Period
Trials published to 5 September 2022
- Sample size
90,409 participants in 13 trials
- Inclusion and exclusion criteria
Double-blind, placebo-controlled, >=500 per group, >=6 months, adults
4. Methods and endpoints
- Exposure / intervention
SGLT2 inhibitors
- Comparator
Placebo
- Endpoints
Kidney disease progression, AKI, CV death or HF hospitalisation, CV and non-CV death; safety: ketoacidosis, lower-limb amputation
- Statistical methods
Inverse-variance weighted meta-analysis of summary data (partly re-analysed by trial investigators); absolute effects per 1,000 patient-years
5. Actual results
- Results
Kidney disease progression RR 0.63 (0.58-0.69); AKI RR 0.77 (0.70-0.84); CV death or HF hospitalisation RR 0.77 (0.74-0.81); CV death RR 0.86 (0.81-0.92); non-CV death RR 0.94 (0.88-1.02). Ketoacidosis in diabetes RR 2.12 (1.49-3.04), baseline about 0.2 per 1,000 patient-years; one event among non-diabetic SGLT2i users in about 30,000 participant-years. Lower-limb amputation: CANVAS 6.3 vs 3.4 per 1,000 PY; other 12 trials RR 1.06 (0.93-1.21); all trials RR 1.15 (1.02-1.30). Per 1,000 patients with CKD and diabetes per year: 11 fewer kidney progression, 4 fewer AKI, 11 fewer CV death/HF hospitalisation, about 1 DKA and 1 amputation caused.
- Absolute risks
DKA excess about 0.22 per 1,000 patient-years (stats/C-ODD-02.py); benefit-harm balance about 26 events avoided vs 2 caused per 1,000 patient-years in CKD with diabetes.
- Authors' conclusion
Randomised data support SGLT2 inhibitors for reducing kidney progression and AKI in type 2 diabetes at high cardiovascular risk and in CKD or heart failure irrespective of diabetes; absolute benefits outweigh serious hazards of ketoacidosis or amputation.
6. Strengths
- Only large blinded RCTs
- Standardised kidney outcome
- Absolute benefit-harm estimates
- Hypothesis-testing analysis of amputation excluding CANVAS
7. Weaknesses
- Summary-level, not individual data
- Trials mostly industry-sponsored
- Ketoacidosis events few
8. Risk of bias
- Orienting tool
- AMSTAR 2
- Type of assessment
- simplified assessment (abstract only)
- Full formal assessment
- no
- Overall risk of bias
- low
- Rationale
Pre-registered (PROSPERO CRD42022351618); trials at low risk of bias.
9. Assessment of the statistical interpretation
All ratio CIs log-symmetric (stats/C-ODD-02.py, C-ODD-06.py). Significant heterogeneity for amputation (CANVAS vs others, p=0.0007) indicates the CANVAS signal was not replicated.
10. Relevance to the specific claim
Quantifies both the DKA harm (supporting C-ODD-02) and the net benefit (contradicting C-ODD-06); shows amputation signal mainly from CANVAS (limiting C-ODD-05).
11. Independent contrary findings
None of comparable quality showing net harm.
12. Transferability to Germany and Europe
High.
13. Overall methodological judgement
Pivotal high-quality evidence: SGLT2 inhibitors roughly double a rare DKA risk while preventing many more serious kidney and heart events.
| Multidimensional assessment | |
|---|---|
| Authenticity of the source | verified |
| Methodological quality | high |
| Risk of bias | low |
| 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
Risk under prolonged fasting/ketogenic diets.
15. Linked fact checks
- SGLT2 inhibitors such as dapagliflozin (Forxiga) can cause ketoacidosis, sometimes with normal or low blood glucose. – Studies supporting the claim
- Glucose-lowering drugs are net harmful and belong among the 'forbidden' items; dapagliflozin (Forxiga) is among the 'dirtiest' drugs and kills the brain; leg amputations happen only to people taking diabetes drugs and insulin. – Studies contradicting or limiting the claim
- Every major class of glucose-lowering drug (metformin, sulfonylureas, thiazolidinediones, DPP-4 inhibitors, SGLT2 inhibitors, GLP-1 agonists) carries a documented signal of serious harm in the peer-reviewed literature. – Studies contradicting or limiting the claim