Randomised controlled trialindependent cross-checkabstract checked I-ODD-122 standard review
Glimepiride vs linagliptin: same heart outcomes, far more low blood sugar
Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes: The CAROLINA Randomized Clinical Trial.
Overview
Rosenstock J et al.. JAMA 2019 · PMID 31536101 · DOI 10.1001/jama.2019.13772
MACE 12.0% vs 11.8%; hypoglycaemia 37.7% vs 10.6%.
Does the study support the specific claim? No · Methodological quality: high
Plain-language summary
Study explained simply
- What did the researchers want to find out?
Compare cardiovascular outcomes of glimepiride and linagliptin.
- How was the study done?
Blinded RCT.
- How many people, animals or samples were studied?
6,033 patients.
- What was actually found?
Equal cardiovascular events; more hypoglycaemia with glimepiride.
- How large was the observed effect?
HR 0.98 (0.84-1.14).
- What do the results mean in everyday life?
The main problem with sulfonylureas is low blood sugar, not heart attacks.
- What are the study's limitations?
No metformin comparison.
- What does it say about Elawady's specific claim?
Limits the claim.
- Do the results apply to Germany and Europe?
High.
- What can explicitly not be concluded from this study?
Comparison with metformin.
Scientific in-depth review
1. Full reference
- Authors
- Rosenstock J et al.
- Journal
- JAMA
- Year
- 2019
- Identifier
- PMID 31536101 DOI 10.1001/jama.2019.13772
- Verification
- verified – PubMed efetch 2026-10-26; Crossref works API 2026-10-26
- Retracted
- no
- Corrections
Erratum published (JAMA 2019;322:2138, 'Errors in Results Section'); content of erratum not reviewed.
- Extent checked
- abstract only
- Conflicts of interest and funding
Not stated in abstract.
2. Research question
Is linagliptin non-inferior to glimepiride for major cardiovascular outcomes?
3. Study design and population
- Study design
- Randomised controlled trial – Double-blind active-controlled non-inferiority RCT (CAROLINA)
- Population
Adults with relatively early type 2 diabetes and elevated CV risk
- Country
43 countries
- Period
2010-2018; median follow-up 6.3 years
- Sample size
6,042 randomised; 6,033 treated
- Inclusion and exclusion criteria
HbA1c 6.5-8.5% and elevated CV risk
4. Methods and endpoints
- Exposure / intervention
Glimepiride 1-4 mg (sulfonylurea)
- Comparator
Linagliptin 5 mg (DPP-4 inhibitor)
- Endpoints
3-point MACE; hypoglycaemia; pancreatitis
- Statistical methods
Cox model; non-inferiority margin 1.3
5. Actual results
- Results
MACE 356/3,023 (11.8%) linagliptin vs 362/3,010 (12.0%) glimepiride; HR 0.98 (95.47% CI 0.84-1.14). Hypoglycaemia 10.6% vs 37.7% (HR 0.23, 0.21-0.26). Adjudicated pancreatitis 0.5% in both.
- Absolute risks
MACE difference -0.25 percentage points (not significant); hypoglycaemia +27 percentage points with glimepiride (NNH about 4) (stats/C-ODD-11.py).
- Authors' conclusion
Linagliptin was non-inferior to glimepiride for the composite cardiovascular outcome.
6. Strengths
- Long-term blinded RCT
- Active comparator
7. Weaknesses
- Comparator is a DPP-4 inhibitor, not metformin
- Erratum
8. Risk of bias
- Orienting tool
- RoB 2
- Type of assessment
- simplified assessment (abstract only)
- Full formal assessment
- no
- Overall risk of bias
- low
- Rationale
Double-blind.
9. Assessment of the statistical interpretation
Event rates nearly identical; the main difference is hypoglycaemia.
10. Relevance to the specific claim
Shows a modern sulfonylurea (glimepiride) had the same cardiovascular event rate as a cardiovascularly neutral drug, while causing much more hypoglycaemia; indirect for the metformin comparison.
11. Independent contrary findings
Observational cohort A-ODD-07.
12. Transferability to Germany and Europe
High.
13. Overall methodological judgement
Argues against intrinsic cardiovascular toxicity of glimepiride; confirms hypoglycaemia as the main risk.
| Multidimensional assessment | |
|---|---|
| Authenticity of the source | verified |
| Methodological quality | high |
| Risk of bias | low |
| Precision of results | high |
| Directness | indirect |
| Reproducibility | partly replicated |
| Consistency with the overall evidence | consistent |
| Regional transferability | high |
| Adequacy of the interpretation (by the archive) | not applicable |
14. Open questions
Older sulfonylureas (glibenclamide).
15. Linked fact checks
- Sulfonylureas cause more myocardial infarctions, strokes and deaths than metformin (21% higher in 253,690 veterans). – Studies contradicting or limiting the claim