Linagliptin and Metformin side effects: what 1,261 FDA adverse event reports show
Drug class
Dipeptidyl Peptidase 4 Inhibitor
Label matched
Linagliptin (Tradjenta)
Who reports
1,261 reports · 54% serious · 53 with death outcome · 54% female
Used for
TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus . TRADJENTA is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic con.
What it is
TRADJENTA tablets for oral use contain linagliptin, an inhibitor of the DPP-4 enzyme.
Boxed warning
None in the current label
Causality screen of the 20 strongest signals
What the badges mean
- Labeled adverse reaction The exact term appears in the label's warnings or adverse-reactions sections: a known, expected effect. The FAERS signal confirms the label rather than discovering anything.
- Labeled (related wording) The label describes this effect under different wording (e.g. 'neutropenia' for 'neutrophil count decreased'). Treated as known.
- Likely indication confounding The term appears in the label's indications: reports probably describe the disease being treated (or its progression), not a drug effect. Classic confounding by indication.
- Lab value / disease marker A laboratory result, investigation or disease-activity marker (antibody positive, CRP abnormal, swollen joint count) not described in the label. These usually mirror the monitored disease or testing protocol rather than a drug effect; not screened further.
- Not in label — unassessed Not found in the label text, not an artifact pattern. This is a genuine candidate for a formal causality assessment (Bradford Hill / WHO-UMC); it has NOT had one here.
Strongest disproportionality signals
Flagged terms (PRR ≥ 2, χ² ≥ 4, n ≥ 10), ranked by PRR; infinite PRRs (no comparator reports) excluded. The EBGM column is a second, shrinkage-based estimate (MGPS) with its 5th percentile EB05 and the BCPNN IC025; a pair flagged by PRR alone is marked PRR-only and should be read as fragile. The strata column recomputes the PRR on serious reports only and flags pairs whose reports are unusually skewed by sex or come mostly from consumers rather than clinicians. 5 further terms are in the interactive explorer. Reaction links open the term's cross-drug page.
| Reaction | Reports | PRR 95% CI · ROR · χ²/p | EBGM EB05 · IC025 | Label screen | Serious-only & strata | Trial cross-check |
|---|---|---|---|---|---|---|
| Blood glucose abnormal | 19 | 17.1 10.9–26.7ROR 17.3 · χ² 271 / p 3e-61 | 16.6 EB05 10.9 · IC025 +2.8 3/3 methods agree | Lab value / disease marker | serious PRR 16.5 | no trial data cached |
| Glycosylated haemoglobin increased | 23 | 15.2 10.1–22.8ROR 15.4 · χ² 291 / p 2e-65 | 14.7 EB05 10.0 · IC025 +2.8 3/3 methods agree | Lab value / disease marker | serious PRR 12.9 | no trial data cached |
| Lactic acidosis | 25 | 13.0 8.8–19.1ROR 13.2 · χ² 264 / p 1e-59 | 12.4 EB05 8.5 · IC025 +2.7 3/3 methods agree | Not in label — unassessed | serious PRR 13.9 · ♀ 76% (drug 54%) | no trial data cached |
| Hypercholesterolaemia | 7 | 12.2 5.8–25.5ROR 12.2 · χ² 61 / p 3e-15 | 9.1 EB05 4.0 · IC025 +1.5 3/3 methods agree | Not in label — unassessed | serious PRR 13.9 | no trial data cached |
| Pancreatitis acute | 14 | 10.4 6.2–17.6ROR 10.5 · χ² 110 / p 4e-26 | 8.9 EB05 5.3 · IC025 +2.1 3/3 methods agree | Labeled adverse reaction exact term | serious PRR 11.2 | no trial data cached |
| Diabetes mellitus inadequate control | 11 | 10.3 5.7–18.6ROR 10.4 · χ² 84 / p 3e-20 | 8.4 EB05 4.6 · IC025 +1.9 3/3 methods agree | Labeled (related wording) related wording | serious PRR 9.5 | no trial data cached |
| Pulmonary congestion | 8 | 10.0 5.0–20.0ROR 10.1 · χ² 56 / p 3e-14 | 7.5 EB05 3.7 · IC025 +1.5 3/3 methods agree | Not in label — unassessed | serious PRR 11.0 | no trial data cached |
| Diabetic ketoacidosis | 14 | 9.7 5.8–16.3ROR 9.8 · χ² 101 / p 5e-24 | 8.2 EB05 4.9 · IC025 +2.0 3/3 methods agree | Likely indication confounding shares a disease stem with the indications wording | serious PRR 10.5 | no trial data cached |
| Incontinence | 6 | 9.4 4.2–20.9ROR 9.5 · χ² 37 / p 6e-10 | 6.4 EB05 2.9 · IC025 +1.1 3/3 methods agree | Not in label — unassessed | serious PRR 11.4 | no trial data cached |
| Metabolic acidosis | 17 | 8.9 5.6–14.3ROR 9.0 · χ² 112 / p 2e-26 | 7.7 EB05 4.9 · IC025 +2.0 3/3 methods agree | Not in label — unassessed | serious PRR 9.6 | no trial data cached |
| Blood glucose increased | 100 | 8.8 7.3–10.6ROR 9.5 · χ² 688 / p 5e-152 | 8.6 EB05 7.2 · IC025 +2.7 3/3 methods agree | Labeled (related wording) related wording | serious PRR 7.9 · 73% consumer | no trial data cached |
| Polyneuropathy | 6 | 8.4 3.8–18.6ROR 8.4 · χ² 32 / p 8e-9 | 5.7 EB05 2.7 · IC025 +1.0 3/3 methods agree | Not in label — unassessed | serious PRR 9.1 | no trial data cached |
| Glomerular filtration rate decreased | 6 | 8.2 3.7–18.3ROR 8.3 · χ² 31 / p 1e-8 | 5.6 EB05 2.7 · IC025 +1.0 3/3 methods agree | Lab value / disease marker | serious PRR 5.5 | no trial data cached |
| Pancreatitis (pancreas inflammation) | 23 | 7.2 4.8–10.8ROR 7.3 · χ² 117 / p 1e-27 | 6.4 EB05 4.5 · IC025 +2.0 3/3 methods agree | Likely indication confounding term in indications; also in warnings | serious PRR 6.9 | no trial data cached |
| Hypoglycaemia (low blood sugar) | 21 | 7.2 4.7–11.0ROR 7.3 · χ² 106 / p 4e-25 | 6.4 EB05 4.3 · IC025 +1.9 3/3 methods agree | Labeled adverse reaction exact term | serious PRR 5.8 | no trial data cached |
| Proteinuria | 8 | 7.1 3.5–14.1ROR 7.1 · χ² 36 / p 1e-9 | 5.3 EB05 2.8 · IC025 +1.2 3/3 methods agree | Not in label — unassessed | serious PRR 7.4 | no trial data cached |
| Blood glucose decreased | 19 | 6.6 4.2–10.2ROR 6.6 · χ² 84 / p 2e-20 | 5.7 EB05 3.9 · IC025 +1.7 3/3 methods agree | Labeled (related wording) related wording | serious PRR 8.4 | no trial data cached |
| Pancreatic carcinoma | 7 | 4.0 1.9–8.4ROR 4.0 · χ² 13 / p 2e-4 | 3.3 EB05 1.8 · IC025 +0.4 | Likely indication confounding shares a disease stem with the indications wording | serious PRR 4.3 | no trial data cached |
| Suicide attempt | 10 | 2.7 1.5–5.1ROR 2.7 · χ² 9 / p 0.001 | 2.5 EB05 1.5 · IC025 +0.3 | Not in label — unassessed | serious PRR 2.9 | no trial data cached |
| Injection site haemorrhage | 10 | 2.1 1.1–3.9ROR 2.1 · χ² 5 / p 0.015 | 2.0 EB05 1.2 · IC025 -0.1 PRR-only: not supported by EBGM or IC | Not in label — unassessed | serious PRR 1.7 | no trial data cached |
Trial evidence (ClinicalTrials.gov)
Most frequently reported reactions
By raw co-report count, regardless of disproportionality. Common terms here are often the illness itself or generic outcomes.
| Reaction | Reports | PRR 95% CI · ROR · χ²/p | EBGM EB05 · IC025 | Label screen | Serious-only & strata | Trial cross-check |
|---|---|---|---|---|---|---|
| Blood glucose increased | 100 | 8.8 7.3–10.6ROR 9.5 · χ² 688 / p 5e-152 | 8.6 EB05 7.2 · IC025 +2.7 3/3 methods agree | Labeled (related wording) related wording | serious PRR 7.9 · 73% consumer | no trial data cached |
| Lactic acidosis | 25 | 13.0 8.8–19.1ROR 13.2 · χ² 264 / p 1e-59 | 12.4 EB05 8.5 · IC025 +2.7 3/3 methods agree | Not in label — unassessed | serious PRR 13.9 · ♀ 76% (drug 54%) | no trial data cached |
| Pancreatitis (pancreas inflammation) | 23 | 7.2 4.8–10.8ROR 7.3 · χ² 117 / p 1e-27 | 6.4 EB05 4.5 · IC025 +2.0 3/3 methods agree | Likely indication confounding term in indications; also in warnings | serious PRR 6.9 | no trial data cached |
| Glycosylated haemoglobin increased | 23 | 15.2 10.1–22.8ROR 15.4 · χ² 291 / p 2e-65 | 14.7 EB05 10.0 · IC025 +2.8 3/3 methods agree | Lab value / disease marker | serious PRR 12.9 | no trial data cached |
| Hypoglycaemia (low blood sugar) | 21 | 7.2 4.7–11.0ROR 7.3 · χ² 106 / p 4e-25 | 6.4 EB05 4.3 · IC025 +1.9 3/3 methods agree | Labeled adverse reaction exact term | serious PRR 5.8 | no trial data cached |
| Blood glucose decreased | 19 | 6.6 4.2–10.2ROR 6.6 · χ² 84 / p 2e-20 | 5.7 EB05 3.9 · IC025 +1.7 3/3 methods agree | Labeled (related wording) related wording | serious PRR 8.4 | no trial data cached |
| Blood glucose abnormal | 19 | 17.1 10.9–26.7ROR 17.3 · χ² 271 / p 3e-61 | 16.6 EB05 10.9 · IC025 +2.8 3/3 methods agree | Lab value / disease marker | serious PRR 16.5 | no trial data cached |
| Metabolic acidosis | 17 | 8.9 5.6–14.3ROR 9.0 · χ² 112 / p 2e-26 | 7.7 EB05 4.9 · IC025 +2.0 3/3 methods agree | Not in label — unassessed | serious PRR 9.6 | no trial data cached |
| Diabetic ketoacidosis | 14 | 9.7 5.8–16.3ROR 9.8 · χ² 101 / p 5e-24 | 8.2 EB05 4.9 · IC025 +2.0 3/3 methods agree | Likely indication confounding shares a disease stem with the indications wording | serious PRR 10.5 | no trial data cached |
| Pancreatitis acute | 14 | 10.4 6.2–17.6ROR 10.5 · χ² 110 / p 4e-26 | 8.9 EB05 5.3 · IC025 +2.1 3/3 methods agree | Labeled adverse reaction exact term | serious PRR 11.2 | no trial data cached |
| Diabetes mellitus inadequate control | 11 | 10.3 5.7–18.6ROR 10.4 · χ² 84 / p 3e-20 | 8.4 EB05 4.6 · IC025 +1.9 3/3 methods agree | Labeled (related wording) related wording | serious PRR 9.5 | no trial data cached |
| Injection site haemorrhage | 10 | 2.1 1.1–3.9ROR 2.1 · χ² 5 / p 0.015 | 2.0 EB05 1.2 · IC025 -0.1 PRR-only: not supported by EBGM or IC | Not in label — unassessed | serious PRR 1.7 | no trial data cached |
| Suicide attempt | 10 | 2.7 1.5–5.1ROR 2.7 · χ² 9 / p 0.001 | 2.5 EB05 1.5 · IC025 +0.3 | Not in label — unassessed | serious PRR 2.9 | no trial data cached |
| Proteinuria | 8 | 7.1 3.5–14.1ROR 7.1 · χ² 36 / p 1e-9 | 5.3 EB05 2.8 · IC025 +1.2 3/3 methods agree | Not in label — unassessed | serious PRR 7.4 | no trial data cached |
| Pulmonary congestion | 8 | 10.0 5.0–20.0ROR 10.1 · χ² 56 / p 3e-14 | 7.5 EB05 3.7 · IC025 +1.5 3/3 methods agree | Not in label — unassessed | serious PRR 11.0 | no trial data cached |
Unlabeled candidate signals
These flagged terms were not found in the FDA label text and do not match an artifact pattern. They are the pairs that would merit a structured assessment (temporality, dose-response, biological plausibility, consistency across databases, trial or cohort evidence). The screen has not done that; string-matching misses label wording, and a strong PRR can still be stimulated reporting, co-medication, or the disease itself.
- Lactic acidosis — n=25, PRR 13.0
✓ A hand-written Bradford Hill causality assessment exists for this drug: Linagliptin ↔ Pancreatitis.
Want to assess one of these properly? The runbook describes the Bradford Hill / trial-evidence workflow used on the assessment page, and handoff_top1000_signals.csv lists the strongest unassessed pairs across all drugs.
Common questions
What are the most reported side effects of Linagliptin and Metformin?
In FDA FAERS, the most frequently co-reported reaction terms for Linagliptin and Metformin are blood glucose increased, lactic acidosis, pancreatitis, glycosylated haemoglobin increased, hypoglycaemia, blood glucose decreased. These are report counts, not rates: FAERS has no denominator, reporting is voluntary and uneven, and a term can be reported because of the illness being treated rather than the drug.
Does Linagliptin and Metformin have an FDA boxed warning?
No. The FDA label retrieved for Linagliptin and Metformin has no boxed warning; see the label's Warnings and Precautions for the recognised risks.
Do FAERS signals prove that Linagliptin and Metformin causes these side effects?
No. A disproportionality signal (PRR, ROR) means a reaction is reported more often with this drug than with others in the database. That can reflect a real effect, but also the disease being treated, stimulated reporting after news or litigation, co-medications, or how reports are coded. Causality needs temporality, dose-response, biological plausibility, consistency across data sources and, ideally, trial or cohort evidence. This page screens each term against the FDA label and ClinicalTrials.gov results; it does not establish causation.
Sources & methods
- FDA label via openFDA (set ID dfe327e8-f6ab-41e5-bdef-d520118cd83a, effective 20250827; matched on
openfda.generic_name.exact:"LINAGLIPTIN") - Bayesian shrinkage measures computed offline over all 1,317,300 cached pairs: BCPNN information component (IC, with Norén closed-form IC025) and MGPS empirical-Bayes geometric mean (EBGM, EB05) with a two-component gamma prior fitted by maximum marginal likelihood (α₁=0.57, β₁=0.02, α₂=1.42, β₂=0.70, w=0.17); unstratified
- FAERS pair statistics from the OpenPV build of 2026-09-14 (openFDA
count=aggregation, fieldpatient.drug.openfda.generic_name.exact, 25 reaction terms, min 3 co-reports); PRR/ROR with 95% CI, chi-square with Yates correction - Serious-only and stratified counts (serious:1, patient.patientsex, primarysource.qualification) from openFDA count queries; serious-only PRR uses the drug serious report total and the term global serious total (N_serious=11,882,979); strata shown only when n ≥ 20
- Seriousness and sex counts from openFDA
count=serious,patient.patientsex,seriousnessdeath
Page generated 2026-10-08. Label and PubChem text are retrieved automatically and may lag the current label; always check the current prescribing information. OpenPV is a beta research tool of the Open Source Medicine Foundation.