← All causality assessments
Contested: signal not confirmed by large randomized trials
Causality assessment · Contested: signal not confirmed by large randomized trials
Canagliflozin and Amputation: is the FAERS signal real?
A written Bradford Hill assessment of one drug–event pair. The grade is a judgement about the signal, not a statement that this drug causes this event in any one person; FAERS counts are reports, not rates.
Canagliflozin ↔ Amputation
n=2,195 co-reports · PRR 535.9 · ROR 578.5
Canagliflozin is an SGLT2 inhibitor; in the CANVAS trial it was associated with an increased risk of lower-limb amputation, predominantly toe and mid-foot, prompting a boxed warning (2,195 co-reports here, PRR 535.9). The biological mechanism is uncertain and the finding was not clearly replicated across other SGLT2-inhibitor trials, so the label advises caution in patients at high amputation risk rather than attributing a proven causal mechanism.
Regulatory basis: canagliflozin (Invokana) prescribing information — boxed warning for lower-limb amputation; CANVAS trial.
| Bradford Hill viewpoint | Status | Note |
|---|---|---|
| Temporality (necessary) | met | Amputations occurred on treatment |
| Strength | met | PRR 535.9, an extreme signal |
| Consistency | partial | Signal seen mainly in CANVAS |
| Specificity | partial | Concentrated in at-risk patients |
| Biological gradient | not established | Mechanism uncertain |
| Plausibility | partial | Biologically debated, not established |
| Coherence | not established | Not consistently found across the class |
| Experiment | met | CANVAS trial showed the imbalance |
| Analogy | partial | Limited analogy to other SGLT2 inhibitors |
This table is this page's own qualitative read of the literature cited above, not an automated or citation-gated assessment — see the note at the bottom of this page.
✗ No ClinicalTrials.gov results-posting trial in the top search hits for canagliflozin captured amputation as a tracked adverse event in a usable structure. Amputation was captured as a serious adverse event in CANVAS, but other SGLT2-inhibitor trials used different reporting structures.