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MyDeficiencies

Linagliptin

DPP-4 Inhibitor

Also sold as Tradjenta, Trajenta.

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Findings for this medication

Research about this medication, graded for how strongly each finding can be attributed to it. Nothing here describes your own levels.

Linagliptin has essentially no classical depletion machinery. Per its FDA label, about 90% of an oral dose is excreted unchanged, elimination is overwhelmingly biliary/fecal (about 80%) with under 7% renal, the drug does not induce any CYP450 enzyme, and no dosage adjustment is required in renal or hepatic impairment of any severity. None of the eight mechanism classes that typically drive drug-induced nutrient depletion (chelation, enzyme induction, renal wasting, cofactor antagonism, mitochondrial toxicity, hormonal dilution, microbiome disruption, altered intake) apply to linagliptin in the way they apply to, for example, metformin, PPIs, or loop diuretics. No nutrient in this review met the bar for a red or orange depletion grade.

DPP-4 inhibitor · ATC A10BH05 · also sold as Tradjenta and Trajenta and Jentadueto (+metformin) and Glyxambi (+empagliflozin) · reviewed 2026-09-20. This describes research about the medication. It does not say anything about your own levels or health.

How to read the evidence grades

These colours describe how strongly a finding can be attributed to the medication in the research. They are not a severity score and they say nothing about your own health.

Grades describe how strongly a finding can be attributed to Linagliptin in the research — not how common it is, how serious it would be, and not anything about you personally.

Red — Severe
two or more independent Tier A sources, this drug in the cohort, the nutrient directly measured, consistent direction, clinically meaningful magnitude, a named mechanism, no substantial contradicting Tier A evidence.
Orange — Moderate
at least one Tier A source with this drug in the cohort showing a real, bounded effect (exposure window, subgroup, low frequency, or functional rather than circulating measure).
Yellow — Low
mechanistic plausibility only (Tier B), class extrapolation with at least one class member supported (Tier C), or a context flag, including reverse-direction findings.
Not graded — disclosed evidence gap
Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result.Source definition: no Tier B or Tier C evidence exists to support even a yellow grade, and no circulating claim exists to rebut as white. A genuine literature gap, or a gap in what could be accessed during this review, not a finding of safety.

What the research found

Vitamin B12

Orange — Moderate

See study details

Linagliptin is associated with increased cobalamin retention and improved cobalamin-homeostasis markers relative to placebo, the opposite of a depletion effect.

Full detail and limits

What the grade means here: at least one Tier A source with this drug in the cohort showing a real, bounded effect (exposure window, subgroup, low frequency, or functional rather than circulating measure). orange

Limits on what this shows

  • Key negative/null findings: The authors describe the human effect as modest over the 6-month window and could not confirm CD320 protein-level changes in human tissue due to antibody limitations. MMA is a validated but imperfect functional surrogate, not a direct cobalamin measurement.
  • At-risk subgroups: None identified as being at elevated depletion risk from linagliptin. Patients already taking high-dose B12 supplements alongside linagliptin could theoretically see higher-than-expected B12/lower-than-expected MMA, though this has not been shown to cause harm.
  • Counter-evidence on record: No Tier A or Tier B source identified in this review shows linagliptin lowering B12. This is the only drug-specific human dataset found on this topic, and popular claims that "diabetes drugs deplete B12" generally trace to metformin, addressed separately in Fails Verification.

Regulatory status

Not addressed in the FDA label; this finding comes from independent post-marketing mechanistic research, not label-driven monitoring.

Population evidence

Tammen et al., 2023, Scientific Reports. Secondary analysis of the MARLINA-T2D randomized trial: 301 individuals, 1,092 plasma/urine samples, baseline and 6 months, using methylmalonic acid (MMA) as a cobalamin-status surrogate. In the medium-baseline-MMA subgroup, placebo patients had significantly higher (worse) MMA than linagliptin patients at study end (urine p<0.005, plasma p<0.05; Cohen's d 0.34 to 0.48, small to moderate). Supported by four independent mouse experiments (n=4-5 mice per group) showing 2-fold to 20-fold cobalamin accumulation in kidney, liver, and heart tissue with linagliptin, and an in vitro assay confirming DPP-4 cleaves the transcobalamin receptor CD320.

Mechanism

Named. DPP-4 normally cleaves the N-terminus of CD320, the cell-surface transcobalamin receptor. Linagliptin's DPP-4 inhibition is proposed to prolong CD320's half-life, enhancing cellular cobalamin uptake.

Counter-evidence held on record

This is a reverse-direction, protective signal, not a deficiency. It does not support recommending additional B12 intake, and B12 supplementation is not indicated by this finding.

The five body-system areas

Each finding is counted once, in a single area. Where a study is mentioned in a second area it is context only.

Mitochondrial Burden

Each finding below is counted once, in this area only.

Mitochondrial burden

Yellow — Low

See study details

Animal and in vitro data suggest linagliptin promotes mitochondrial biogenesis and preserves mitochondrial membrane integrity rather than damaging mitochondria; no human data exist for this category.

Full detail, limits and 2 references

What the grade means here: mechanistic plausibility only (Tier B), class extrapolation with at least one class member supported (Tier C), or a context flag, including reverse-direction findings. yellow

Limits on what this shows

  • Key negative/null findings: No study identified in this review found linagliptin causing mitochondrial damage, swelling, or biogenesis suppression at any tier.
  • At-risk subgroups: None identified.
  • Counter-evidence on record: None found suggesting mitochondrial harm; all drug-specific evidence located points toward a protective direction, though it is preclinical only.

Population evidence

PMID 38189391: linagliptin promoted mitochondrial biogenesis via the AMPK/PGC-1alpha/TFAM pathway in a rat model of diabetic kidney disease (Tier B, animal; shared with the ATP production entry below, see overlap map). PMID 31733186: linagliptin protected human chondrogenic ATDC5 cells against advanced-glycation-end-product-induced, mitochondria-dependent apoptosis, preserving mitochondrial membrane potential (Tier B, in vitro).

Mechanism

Named for the kidney model: AMPK/PGC-1alpha/TFAM pathway activation, the canonical mitochondrial-biogenesis axis. Not established as a unified mechanism across both studies.

Counter-evidence held on record

Animal and cell-culture findings only; this does not establish a clinical mitochondrial-protection benefit in humans and is not a basis for any supplement claim.

  • "Linagliptin improves diabetic kidney disease in rats by promoting mitochondrial biogenesis through the AMPK/PGC-1alpha/TFAM pathway." PMID 38189391. — Tier B, animal (rat), mechanistic. Cited in both Mitochondrial burden and ATP production entries; see Overlap map.
  • "Linagliptin protects human chondrogenic ATDC5 cells against advanced glycation end products (AGEs)-induced apoptosis via a mitochondria-dependent pathway." PMID 31733186. — Tier B, in vitro (human cell line).

Oxidative Stress

Each finding below is counted once, in this area only.

Oxidative stress

Yellow — Low

See study details

A human pilot study and multiple animal/in vitro studies indicate linagliptin lowers oxidative-stress markers rather than depleting antioxidant capacity; this review could not retrieve full effect-size data for the human study.

Full detail, limits and 1 references

What the grade means here: mechanistic plausibility only (Tier B), class extrapolation with at least one class member supported (Tier C), or a context flag, including reverse-direction findings. yellow

Limits on what this shows

  • Key negative/null findings: None identified; a dedicated search for null or contradicting oxidative-stress findings did not surface any in the sources this review was able to reach, itself a limitation of search depth given tool rate-limiting rather than confirmation of a uniformly positive literature.
  • At-risk subgroups: None identified.
  • Counter-evidence on record: None located within the sources reached; this entry should be revisited with fuller access to confirm the human pilot's sample size, exact markers, and statistical results.

Population evidence

PMID 31139534, "Effect of linagliptin on oxidative stress markers in patients with type 2 diabetes: a pilot study" (human, T2D, title and indexing confirm linagliptin as the study drug; full abstract text could not be retrieved during this review due to repeated tool rate-limiting, see access note below). Converging preclinical signal across seven animal/in vitro studies (PMIDs 41466876, 40109745, 24077249, 41713597, 32032367, 35134437, 41338293) spanning kidney, gastric, cardiovascular, hippocampal, and hepatic tissue models, consistently reporting reduced oxidative-stress markers (for example lower malondialdehyde, suppressed NADPH oxidase activity) with linagliptin treatment.

Mechanism

Not unified across studies; commonly cited mechanisms include NADPH oxidase suppression and reduced lipid peroxidation (malondialdehyde), with increased glutathione in some models.

Counter-evidence held on record

Predominantly preclinical, and the one human pilot's magnitude is unverified in this review; not a basis for antioxidant-supplement recommendations.

  • "Effect of linagliptin on oxidative stress markers in patients with type 2 diabetes: a pilot study." PMID 31139534. — Human pilot study; title and PubMed indexing confirm linagliptin as the study drug. Tier A by design, but treated conservatively as Tier B-equivalent in grading here.Full abstract text could not be retrieved during this review; repeated 429 rate-limiting from the fetch tool prevented opening the full record after multiple attempts across sessions and wait intervals. Title-level citation only.

Copper and Iron Balance

Copper and iron are assessed separately. Nothing here is counted twice.

Copper

Not graded — disclosed evidence gap

See study details

No evidence, at any tier, and no circulating consumer claim, was found linking linagliptin to copper status.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. ungraded

Limits on what this shows

  • Why no grade: Both conditions for ungraded were met: no Tier B or Tier C evidence supports even a yellow grade, and no circulating claim exists to rebut as white. Searches tried: PubMed "linagliptin copper" (0 results) and "DPP-4 inhibitor copper homeostasis" (0 results). No genuine mechanism from the Step 1/2 pharmacokinetic and mechanism screen implicates copper handling for this drug.

Access note

These two phrasings returned zero PubMed results cleanly (not blocked); this appears to be a genuine literature gap rather than a tooling failure, though it was not cross-checked against Europe PMC or Semantic Scholar directly due to rate-limiting on the fetch tool during this session.

Iron

Not graded — disclosed evidence gap

See study details

No evidence, at any tier, and no circulating consumer claim, was found linking linagliptin to iron status.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. ungraded

Limits on what this shows

  • Why no grade: Both conditions for ungraded were met: no Tier B or Tier C evidence supports even a yellow grade, and no circulating claim exists to rebut as white. Searches tried: PubMed "linagliptin iron deficiency anemia" (0 results) and "linagliptin iron status" (0 results). No genuine mechanism from the Step 1/2 screen implicates iron handling for this drug.

Access note

A plain "linagliptin iron" query (without additional qualifiers) was attempted but the fetch tool was rate-limited before it could complete; the two qualified searches above did complete cleanly with zero results. A future revision should re-run the plain, unqualified query to fully close this gap.

Gut Microbiome Risk

Each finding below is counted once, in this area only.

Gut microbiome risk

Yellow — Low

See study details

Limited evidence suggests linagliptin, generally studied together with metformin, is associated with changes in gut microbiota composition in prediabetes; linagliptin's independent contribution is not clearly isolated.

Full detail, limits and 2 references

What the grade means here: mechanistic plausibility only (Tier B), class extrapolation with at least one class member supported (Tier C), or a context flag, including reverse-direction findings. yellow

Limits on what this shows

  • Key negative/null findings: None identified; access limits prevented a full counter-evidence search for this category.
  • At-risk subgroups: None identified.
  • Counter-evidence on record: The human study combines linagliptin with metformin, which independently has well-documented gut microbiome effects; this confound means the available human evidence does not cleanly isolate linagliptin's own effect.

Population evidence

PMID 38678119, "Effect of metformin and metformin/linagliptin on gut microbiota in patients with prediabetes" (human; title and indexing confirm linagliptin as a studied arm alongside metformin; full abstract text could not be retrieved during this review due to repeated tool rate-limiting, see access note below). PMID 32698143, "Gut-liver axis modulation in fructose-fed mice: a role for PPAR-alpha and linagliptin" (Tier B, animal).

Mechanism

Not established for linagliptin specifically. DPP-4/incretin signaling affects a broad range of gut peptide substrates and could plausibly influence gut-hormone-microbiome crosstalk, but no validated pathway was identified in this review.

Counter-evidence held on record

Exploratory. The available human data cannot separate linagliptin's effect from that of concurrent metformin, and no direction (harmful or beneficial) is established for linagliptin alone.

  • "Effect of metformin and metformin/linagliptin on gut microbiota in patients with prediabetes." PMID 38678119. — Human study; title and indexing confirm linagliptin as a studied arm. Metformin co-administration is a confound for isolating linagliptin's independent effect.Full abstract text could not be retrieved during this review due to repeated fetch-tool rate-limiting. Title-level citation only.
  • "Gut-liver axis modulation in fructose-fed mice: a role for PPAR-alpha and linagliptin." PMID 32698143. — Tier B, animal (mouse).

Oxygen and ATP Output

Oxygen delivery and ATP production are assessed separately. Nothing here is counted twice.

Oxygen delivery/utilization

Orange — Moderate

See study details

In diabetic hemodialysis patients, adding linagliptin was followed by roughly a 50% reduction in the erythropoiesis-stimulating-agent dose needed to maintain hemoglobin, in a small, non-randomized pilot.

Full detail and limits

What the grade means here: at least one Tier A source with this drug in the cohort showing a real, bounded effect (exposure window, subgroup, low frequency, or functional rather than circulating measure). orange

Limits on what this shows

  • Key negative/null findings: Hemoglobin, white cell count, platelet count, ferritin, transferrin saturation, and hs-CRP were all unchanged with linagliptin.
  • At-risk subgroups: Hemodialysis patients on concurrent ESA therapy; if this finding is real, starting linagliptin in this population could warrant reassessing ESA dosing to avoid over-response.
  • Counter-evidence on record: Small (n=13 treated), single-center, non-randomized, unblinded pilot; the authors explicitly call it hypothesis-generating and ask for RCT confirmation. No larger confirmatory trial was identified in this review.

Regulatory status

Not addressed in the FDA label.

Population evidence

Aono & Sato, 2016, Renal Replacement Therapy. Prospective single-center cohort: 13 type 2 diabetic hemodialysis patients started on linagliptin 5 mg/day vs 16 insulin-only controls, followed 6 months. Darbepoetin alfa dose fell from a mean of 23.9 (SD 21.2) to 11.3 (SD 9.7) mcg/week, and the ESA-resistance index fell from 2.3 (SD 2.1) to 1.0 (SD 0.9) (p<0.05, Wilcoxon signed-rank). Hemoglobin itself did not change. The control group showed no significant change in ESA dose.

Mechanism

Proposed, not confirmed. DPP-4 inhibition may reduce N-terminal cleavage/inactivation of endogenous erythropoietin; the authors also speculate that reduced oxidative stress could improve red-cell survival (see overlap map).

Counter-evidence held on record

This is a favorable pharmacodynamic interaction (a possible ESA dose-sparing effect), not evidence of an oxygen-delivery deficiency caused by linagliptin. It should prompt a clinician to reassess ESA dosing, not a consumer to supplement anything.

ATP production

Yellow — Low

See study details

Preclinical work suggests linagliptin may increase mitochondrial ATP-generating capacity rather than impair it, through biogenesis and respiratory-reserve effects; there is no in vivo human ATP data.

Full detail, limits and 2 references

What the grade means here: mechanistic plausibility only (Tier B), class extrapolation with at least one class member supported (Tier C), or a context flag, including reverse-direction findings. yellow

Limits on what this shows

  • Key negative/null findings: No study identified in this review measured impaired ATP production with linagliptin.
  • At-risk subgroups: None identified.
  • Counter-evidence on record: None found suggesting depletion; evidence base is preclinical/ex vivo and has not been tested as a clinical human ATP endpoint.

Population evidence

PMID 38189391 (rat, diabetic kidney disease): AMPK/PGC-1alpha/TFAM-driven mitochondrial biogenesis, the pathway that governs ATP-synthesis capacity (Tier B; shared with Mitochondrial burden above, see overlap map). PMID 33328991: linagliptin modulated mitochondrial respiratory reserve in human platelets ex vivo, altering platelet activation and arterial thrombosis in an experimental model (Tier B, ex vivo human tissue).

Mechanism

AMPK/PGC-1alpha/TFAM biogenesis pathway (kidney model); direct modulation of platelet mitochondrial respiratory reserve (ex vivo platelet study), mechanism of the latter not fully characterized.

Counter-evidence held on record

Mechanistic and preclinical only; not a basis for energy or "low ATP" supplement claims in consumer-facing copy.

  • "Linagliptin improves diabetic kidney disease in rats by promoting mitochondrial biogenesis through the AMPK/PGC-1alpha/TFAM pathway." PMID 38189391. — Tier B, animal (rat), mechanistic. Cited in both Mitochondrial burden and ATP production entries; see Overlap map.
  • "Linagliptin Regulates the Mitochondrial Respiratory Reserve to Alter Platelet Activation and Arterial Thrombosis." PMID 33328991. — Tier B, ex vivo human platelets / experimental thrombosis model.

Claims checked and not supported

These circulate online for this medication. They are listed here only so they can be answered, never as findings, and they are not graded.

A claim with no supporting evidence is not necessarily disproven. Where evidence actually argues against a claim, that is stated below.

  • "Linagliptin depletes vitamin B12"

    Where it comes from: General consumer confusion conflating linagliptin with its common combination partner metformin (marketed together as Jentadueto); metformin has well-documented, class-specific B12 depletion evidence, and generic drug-interaction checkers sometimes list "gliptin plus B12" entries without distinguishing the mechanism.

    Why it fails: The only drug-specific evidence identified in this review runs the opposite direction: Tammen et al. (2023) found linagliptin associated with cobalamin accumulation via CD320 receptor protection, in both a human RCT-derived surrogate marker and mechanistic mouse/in vitro work. This is a factual reversal of the claimed direction for linagliptin specifically, not merely an absence of support.

All references used above
  1. TRADJENTA (linagliptin) tablets, full prescribing information. — Boehringer Ingelheim Pharmaceuticals, Inc., via DailyMed (U.S. National Library of Medicine). Regulatory label, Tier A.
  2. WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD Index, linagliptin, ATC code A10BH05. — Reference source for identity/classification.
  3. Tammen SA, et al. "Linagliptin treatment is associated with altered cobalamin (VitB12) homeostasis in mice and humans." Scientific Reports. 2023. — Secondary analysis of the MARLINA-T2D RCT (n=301, 1,092 samples) plus four independent mouse experiments and an in vitro CD320-cleavage assay. Tier A (human component) / Tier B (animal and in vitro components). DOI: 10.1038/s41598-023-27648-7.
  4. Aono M, Sato Y. "Dipeptidyl peptidase 4 inhibitor linagliptin can decrease the dosage of erythropoiesis-stimulating agents in patients on hemodialysis." Renal Replacement Therapy. 2016;2:58. — Prospective single-center pilot cohort, 13 linagliptin-treated vs 16 control diabetic hemodialysis patients, 6 months. Tier A (drug in cohort), bounded/pilot. DOI: 10.1186/s41100-016-0058-7.
  5. "Effect of linagliptin on oxidative stress markers in patients with type 2 diabetes: a pilot study." PMID 31139534. — Human pilot study; title and PubMed indexing confirm linagliptin as the study drug. Tier A by design, but treated conservatively as Tier B-equivalent in grading here.Full abstract text could not be retrieved during this review; repeated 429 rate-limiting from the fetch tool prevented opening the full record after multiple attempts across sessions and wait intervals. Title-level citation only.
  6. Seven Tier B animal/in vitro studies on linagliptin and oxidative-stress markers, identified via PubMed search listing. — PMID 41466876 (cisplatin nephro/cardiotoxicity, rat); PMID 40109745 (indomethacin gastric ulceration, mice); PMID 24077249 (telmisartan+linagliptin, blood pressure/oxidative stress, rats); PMID 41713597 (high-sugar diet, hippocampal oxidative stress, rats); PMID 32032367 (streptozotocin diabetic mice, cognitive impairment/NADPH oxidase); PMID 35134437 (thioacetamide hepatic encephalopathy, rats); PMID 41338293 (kidney cancer, AMPK/YAP/TAZ/HIF-1alpha, rats).Cited at title level from PubMed search-results listings; individual full abstracts were not separately opened due to fetch-tool rate-limiting, so exact effect sizes are not reported here.
  7. "Linagliptin improves diabetic kidney disease in rats by promoting mitochondrial biogenesis through the AMPK/PGC-1alpha/TFAM pathway." PMID 38189391. — Tier B, animal (rat), mechanistic. Cited in both Mitochondrial burden and ATP production entries; see Overlap map.
  8. "Linagliptin protects human chondrogenic ATDC5 cells against advanced glycation end products (AGEs)-induced apoptosis via a mitochondria-dependent pathway." PMID 31733186. — Tier B, in vitro (human cell line).
  9. "Linagliptin Regulates the Mitochondrial Respiratory Reserve to Alter Platelet Activation and Arterial Thrombosis." PMID 33328991. — Tier B, ex vivo human platelets / experimental thrombosis model.
  10. "Effect of metformin and metformin/linagliptin on gut microbiota in patients with prediabetes." PMID 38678119. — Human study; title and indexing confirm linagliptin as a studied arm. Metformin co-administration is a confound for isolating linagliptin's independent effect.Full abstract text could not be retrieved during this review due to repeated fetch-tool rate-limiting. Title-level citation only.
  11. "Gut-liver axis modulation in fructose-fed mice: a role for PPAR-alpha and linagliptin." PMID 32698143. — Tier B, animal (mouse).
  12. PubMed search, "linagliptin copper." — Zero results returned. Evidence-gap documentation for the Copper entry.
  13. PubMed search, "DPP-4 inhibitor copper homeostasis." — Zero results returned. Evidence-gap documentation for the Copper entry.
  14. PubMed search, "linagliptin iron deficiency anemia." — Zero results returned. Evidence-gap documentation for the Iron entry.
  15. PubMed search, "linagliptin iron status." — Zero results returned. Evidence-gap documentation for the Iron entry.