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MyDeficiencies

Saxagliptin

DPP-4 Inhibitor

Also sold as Onglyza.

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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.

Saxagliptin has no classical drug-nutrient depletion mechanism. Per its FDA label, it undergoes only limited hepatic metabolism (CYP3A4/5, to a half-potent active metabolite), does not induce or inhibit any of the eight CYP450 isoenzymes tested, is not a mineral chelator, shows no clinically significant antacid interaction, and is cleared predominantly by the kidney with roughly a quarter of the dose excreted unchanged. None of the mechanism classes that drive real drug-nutrient depletion (enzyme induction, absorption interference, renal electrolyte wasting, cofactor antagonism) are present. That absence of machinery is itself the headline result, not a gap in this review.

DPP-4 inhibitor (gliptin) · ATC A10BH03 · also sold as Onglyza and Kombiglyze XR (+metformin) and Qtern (+dapagliflozin) · 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 Saxagliptin 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 but bounded deficit: an exposure window, a subgroup, low frequency, or a functional rather than circulating deficit.
Yellow — Low
Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction.
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: Not gradeable under the rules above because nothing has been measured. Published as a documented gap, never as reassurance that there is no effect.

What the research found

Vitamin D, conflicting class-level signals, not saxagliptin-specific at either end

Yellow — Low

See study details

Class-level human data associate DPP-4-inhibitor use with higher, not lower, circulating vitamin D, while a separate narrative review reports saxagliptin-specific adverse bone-turnover marker effects in animal data; the two lines of evidence describe different endpoints and do not resolve into a depletion claim.

Full detail and limits

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. yellow

Limits on what this shows

  • Key negative/null findings: None located specific to saxagliptin and vitamin D blood levels.
  • At-risk subgroups: Not established.
  • Counter-evidence: Confounding by indication is not excluded in the cross-sectional study (Hard Rule 6): patients selected for DPP-4 inhibitors versus other agents may differ systematically in sun exposure, renal function, or supplement use. The primary saxagliptin-specific bone-turnover study cited by the Frontiers review could not be independently opened during this review (see access notes); the finding is reported here as the review states it, not independently verified at the primary-source level.

Regulatory status

Not addressed in the FDA label.

Population evidence

Barchetta et al. 2016 (Acta Diabetologica), cross-sectional, n=295 type 2 diabetes patients: DPP-4-inhibitor users had higher serum 25(OH)D than users of other antidiabetic therapies (18.4 ± 10.7 ng/mL vs 14.9 ± 8.6 ng/mL, p=0.004), association persisted after adjustment and correlated with treatment duration. Which specific DPP-4 inhibitors (including whether saxagliptin) made up the exposed group is not stated in the retrievable abstract/summary, so this is graded as Tier C class-level for saxagliptin under the mandatory cohort test. Separately, Yang et al. 2017 (Frontiers in Pharmacology, narrative review with drug-level stratification) reports that, in contrast to sitagliptin, saxagliptin decreased femoral osteocytic and osteoblastic density and increased osteoclastic tartrate-resistant acid phosphatase activity in animal data, via ERK-pathway suppression of osteocalcin expression and mineralization.

Mechanism

For the vitamin D association: unclear, proposed but not elucidated by the source study. For the bone-turnover finding: ERK-signaling-mediated suppression of osteoblast proliferation/mineralization and increased osteoclastic resorption markers, a direct bone-cell pharmacodynamic effect, not a vitamin D absorption or metabolism mechanism.

Counter-evidence held on record

Do not present this as evidence that saxagliptin depletes vitamin D; the direct human vitamin D data point the opposite way. Do not present the bone-turnover animal finding as a vitamin D or calcium deficiency per Hard Rule 2; it is a distinct, unverified, bone-cell pharmacodynamic signal that a clinician, not a supplement, would need to evaluate.

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, protective signal in diabetic vascular injury models, animal data only

Yellow — Low

See study details

Saxagliptin restores, rather than impairs, vascular mitochondrial function in two independent rodent models of diabetes; no evidence of saxagliptin-induced mitochondrial harm was found, and no human data exist either way.

Full detail and limits

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. yellow

Limits on what this shows

  • Key negative/null findings: No study measuring mitochondrial harm from saxagliptin in normoglycemic or human tissue was found.
  • At-risk subgroups: Not applicable; findings are in diabetic rodent vascular tissue, direction is protective.
  • Counter-evidence: None found suggesting saxagliptin impairs mitochondrial function; both located studies are directionally protective in disease-model tissue.

Regulatory status

Not addressed in the FDA label; no mitochondrial-function warning or monitoring requirement.

Population evidence

Two Tier B animal studies. (1) Keller et al. 2015, Goto-Kakizaki rats (type 2 diabetes model): saxagliptin "restored vascular mitochondrial exercise response," reversing an exercise-induced mitochondrial deficit seen in untreated diabetic rats. (2) Solini et al. 2016, db/db mice: saxagliptin reversed vascular hypertrophic remodeling and restored endothelial NOS dimer/monomer ratio (a marker of mitochondrial/endothelial redox coupling) that was decreased in untreated diabetic mice.

Mechanism

Proposed via improved incretin/GLP-1 signaling and reduced NADPH oxidase-driven uncoupling of endothelial nitric oxide synthase in diabetic vascular tissue; mechanism is protective/reparative in an injury model, not a depletion mechanism.

Counter-evidence held on record

This is a reverse-direction, protective finding in diseased animal vascular tissue, not evidence of a mitochondrial deficiency state, and not evidence that mitochondrial supplementation (e.g. CoQ10) is needed or beneficial in saxagliptin users. It should never be marketed as a depletion risk.

Oxidative Stress

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

Oxidative stress, reduced injury-model markers across three independent animal studies, reverse direction

Yellow — Low

See study details

In every drug-specific animal study located, saxagliptin lowered oxidative stress markers in diabetic or injured tissue rather than raising them; no evidence of saxagliptin causing oxidative stress was found, and no human oxidative-stress biomarker data exist for this drug.

Full detail, limits and 1 references

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. yellow

Limits on what this shows

  • Key negative/null findings: No animal or human study measuring an increase in oxidative stress markers attributable to saxagliptin was found.
  • At-risk subgroups: Not applicable; all located evidence is in diseased/injured rodent tissue and is directionally protective.
  • Counter-evidence: None found in the opposite direction. All three drug-specific studies located agree on direction (protective), though all are animal-only and in injury/disease models, which limits generalization to routine human use.

Regulatory status

Not addressed in the FDA label.

Population evidence

Three Tier B animal studies, saxagliptin dosed directly in each. Solini et al. 2016 (db/db mice): saxagliptin attenuated intravascular superoxide production (dihydroethidium staining) and NAD(P)H oxidase activity. Coskun 2020 (fructose-fed rats): saxagliptin ameliorated endoplasmic reticulum stress and associated oxidative injury in the liver. Tang et al. 2023 (diabetic rats with renal ischemia-reperfusion injury): saxagliptin showed a protective effect against oxidative renal injury.

Mechanism

Proposed via GLP-1/GIP pathway upregulation reducing NADPH oxidase activity and ER stress in injured tissue; a protective pharmacodynamic effect in disease models, not a nutrient-antioxidant depletion mechanism.

Counter-evidence held on record

Do not present this as grounds for an antioxidant-supplementation recommendation. The evidence describes saxagliptin's own protective pharmacology in injured tissue, not a nutrient-antioxidant deficiency it creates.

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 mechanism, no drug-specific or class-level study, and no circulating consumer claim linking saxagliptin to copper status was found.

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: Searched via PubMed search-listing pages, Crossref API, and general web queries ("saxagliptin copper," "DPP-4 inhibitor zinc copper trace element") across multiple phrasings; no Tier B or C evidence and no circulating claim were found, meeting both conditions for ungraded. The pharmacokinetic prescreen also found no chelation, absorption-interference, or renal-wasting mechanism that would plausibly implicate copper.

Access notes

Europe PMC's REST endpoint returned 403/429 responses throughout this review and could not be used for this category; PubMed and Crossref were used instead and returned no relevant results.

Iron

Not graded — disclosed evidence gap

See study details

The one Tier A trial that measured iron markers with saxagliptin in the cohort found no distinguishable saxagliptin-specific effect; no independent mechanism or circulating claim was found.

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: Koshino et al. 2023 (Cardiovascular Diabetology), DELIGHT trial, RCT in type 2 diabetes with chronic kidney disease (n=360 with biosamples of 461 randomized): dapagliflozin 10 mg alone reduced ferritin by 18.6% versus placebo (95% CI -27.5 to -8.7, p<0.001); dapagliflozin + saxagliptin 2.5 mg reduced ferritin by 18.4% versus placebo (95% CI -27.1 to -8.7, p<0.001); transferrin saturation showed a non-significant decreasing trend in both arms. The authors report "no clear difference" between the dapagliflozin-alone and combination arms on iron markers (p≥0.15), i.e., saxagliptin added no measurable independent effect once the SGLT2 inhibitor's own iron-mobilizing effect is accounted for. This is a genuine null finding for saxagliptin specifically, not an absence of research; it rules out yellow rather than failing to reach it, but no residual mechanism or circulating claim remains to grade, so it is recorded here as ungraded with the null trial data disclosed rather than omitted.

Access notes

None; this finding was retrieved successfully from the primary trial report.

Gut Microbiome Risk

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

Gut microbiome risk, modest, glycemia-dependent taxonomic shifts, mouse data only

Yellow — Low

See study details

Saxagliptin measurably alters specific gut bacterial genera in two independent mouse studies, with effects that differ between normoglycemic and hyperglycemic animals; no human microbiome data exist for saxagliptin.

Full detail and limits

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. yellow

Limits on what this shows

  • Key negative/null findings: Wang et al. found "no significant shift of the microbial composition" across the four principal saxagliptin/control comparison groups when analyzed in aggregate, despite the specific taxon-level and diversity differences reported above; saxagliptin's effect was consistently smaller than liraglutide's in both studies.
  • At-risk subgroups: Not established in humans; animal data suggest effect may depend on baseline glycemic state.
  • Counter-evidence: Both studies used mice, not humans; taxonomic shifts were modest relative to the comparator GLP-1 agonist and were not consistently in one direction (diversity fell in normoglycemic mice but was restored in hyperglycemic mice).

Regulatory status

Not addressed in the FDA label.

Population evidence

Two Tier B mouse studies. Wang et al. 2016 (Scientific Reports; ApoE-/- mice, n=9-10/group, normoglycemic and hyperglycemic, saxagliptin vs liraglutide vs control): saxagliptin decreased overall bacterial diversity in normoglycemic mice (Shannon p=0.009, Simpson p=0.015) but restored diversity toward normal in hyperglycemic mice; increased Lactobacillus (p=0.023), Allobaculum (p=0.017), Turicibacter (p=0.001); decreased Bacteroides (p=0.003) and Prevotella (p=0.018); affected only one obesity-linked phylotype versus liraglutide's broader effect. Tang et al. 2024 (BMJ Open Diabetes Research & Care; high-fat diet/streptozotocin diabetic mice, saxagliptin vs metformin vs repaglinide): saxagliptin altered phylum- and genus-level composition alongside glucose-lowering effect; combination regimens showed larger lipid-related shifts.

Mechanism

Not fully established; proposed link to altered incretin/GLP-1 signaling in the gut and downstream effects on bile acid and short-chain fatty acid-producing taxa. Mechanism class G (microbiome disruption) is plausible but not mechanistically proven at the molecular level for saxagliptin specifically.

Counter-evidence held on record

This is animal-only mechanistic evidence and should be presented as a research signal, not as an established human gut-health risk or a reason to recommend probiotics.

Oxygen and ATP Output

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

Oxygen delivery/utilization

Not graded — disclosed evidence gap

See study details

The same Tier A trial that measured hemoglobin with saxagliptin in the cohort found the hemoglobin rise was attributable to the co-administered SGLT2 inhibitor, not to saxagliptin.

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: Koshino et al. 2023 (Cardiovascular Diabetology), DELIGHT trial: dapagliflozin alone raised hemoglobin by 5.7 g/L versus placebo (95% CI 4.0-7.3, p<0.001); dapagliflozin + saxagliptin raised hemoglobin by 4.4 g/L versus placebo (95% CI 2.7-6.0, p<0.001), an overlapping, not larger, effect. Erythropoietin showed a numerical increase trend with dapagliflozin that was not statistically significant; saxagliptin's addition did not amplify it. No mechanism from the Step 1/2 screen (no effect on renal tubular handling, not a hypoxia-pathway drug) supports an independent saxagliptin effect on oxygen delivery, and no circulating consumer claim was found. Per Hard Rule 6, this is confounding-by-co-administration made explicit, not a saxagliptin signal.

Access notes

None; this finding was retrieved successfully from the primary trial report.

ATP production

Not graded — disclosed evidence gap

See study details

No study measuring saxagliptin's effect on cellular ATP synthesis specifically was found, and no circulating "low energy" claim tied to saxagliptin was identified.

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: Searched via Crossref API ("saxagliptin ATP synthesis mitochondrial function") and PubMed across multiple phrasings; all returned results concerned general ATP synthase biochemistry unrelated to saxagliptin, or were already captured under the Mitochondrial burden entry (which addresses mitochondrial structure/function, not ATP output specifically). No Tier B/C evidence and no circulating claim were found, meeting both conditions for ungraded.

Access notes

Semantic Scholar's API returned 429 responses throughout this review and could not be used for this category.

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.

  • Vitamin B12

    Where it comes from: Consumer conflation of gliptin/metformin fixed-dose combination products (e.g., Kombiglyze XR) with metformin's independently established, well-documented B12-depletion mechanism (intrinsic-factor-dependent absorption interference), attributed instead to the gliptin component.

    Why it fails: Saxagliptin's own pharmacokinetic profile has no absorption-interference or cofactor-antagonism mechanism that could affect B12 (Step 1/2 screen). A Tier C class-level study (Revista da Associação Médica Brasileira, 2023, PMID 37909618; one-year prospective comparison, n=118, vildagliptin or sitagliptin added to metformin vs metformin alone; saxagliptin not in this cohort) found B12 and ferritin declined similarly whether or not a gliptin was added to metformin, and folate decline was less pronounced with gliptin added. No gliptin class member shows evidence of worsening B12 status, and the mechanism that does cause B12 decline (metformin) is absent when saxagliptin is used without metformin.

All references used above
  1. ONGLYZA (saxagliptin) tablets, prescribing information — FDA label, accessed via accessdata.fda.gov and DailyMed (setid d45fc842-2563-4421-86af-a55b3191e19b). Regulatory label, Tier A.
  2. Barchetta I, Cimini FA, Bloise D, Cavallo MG. Dipeptidyl peptidase-4 inhibitors and bone metabolism: is vitamin D the link? — Acta Diabetologica. 2016;53(5):839-844. DOI 10.1007/s00592-016-0882-9. Cross-sectional, n=295. Tier C for saxagliptin (DPP-4-inhibitor class exposure group composition not confirmed to include saxagliptin specifically).Cohort not confirmed to include saxagliptin specifically; graded class-level.
  3. Yang Y, Zhao C, Liang J, Yu M, Qu X. Effect of Dipeptidyl Peptidase-4 Inhibitors on Bone Metabolism and the Possible Underlying Mechanisms. — Frontiers in Pharmacology. 2017. DOI 10.3389/fphar.2017.00487. Narrative review with drug-level stratification; saxagliptin-specific bone-turnover claim reported as the review states it. Tier C.Primary saxagliptin bone-cell study this review cites could not be independently located/opened during this review (Crossref API rate-limited on repeated attempts); reported here only as the secondary source states it.
  4. Solini A, Rossi C, Duranti E, Taddei S, Natali A, Virdis A. Saxagliptin prevents vascular remodeling and oxidative stress in db/db mice. Role of endothelial nitric oxide synthase uncoupling and cyclooxygenase. — Vascular Pharmacology. 2016;76:62-71. DOI 10.1016/j.vph.2015.10.002. PMID 26455387. Animal (db/db mice). Tier B.
  5. Keller AC, Knaub LA, Miller MW, Birdsey N, Klemm DJ, Reusch JEB. Saxagliptin Restores Vascular Mitochondrial Exercise Response in the Goto-Kakizaki Rat. — Journal of Cardiovascular Pharmacology. 2015;65(2):137-147. DOI 10.1097/FJC.0000000000000170. PMID 25264749. Animal (Goto-Kakizaki rats). Tier B.
  6. Coskun ZM. ER Stress Amelioration by Saxagliptin Protects the Liver Against Fructose-induced Insulin Resistance. — 2020. PMID 32223915. Animal (fructose-fed rats). Tier B.
  7. Tang et al. Protective effect of Saxagliptin on diabetic rats with renal ischemia reperfusion injury. — 2023. PMID 36435353. Animal (diabetic rats). Tier B.
  8. Wang L, Li P, Tang Z, Yan X, Feng B. Structural modulation of the gut microbiota and the relationship with body weight: compared evaluation of liraglutide and saxagliptin treatment. — Scientific Reports. 2016;6:33251. DOI 10.1038/srep33251. PMID 27633081. Animal (ApoE-/- mice, n=9-10/group). Tier B.
  9. Tang Y, Yan M, Fang Z, Jin S, Xu T. Effects of metformin, saxagliptin and repaglinide on gut microbiota in high-fat diet/streptozocin-induced type 2 diabetic mice. — BMJ Open Diabetes Research & Care. 2024. DOI 10.1136/bmjdrc-2023-003837. PMID 38719505. Animal (mice). Tier B.
  10. Koshino A, Neuen BL, Jongs N, Pollock C, Greasley PJ, Andersson EM, Hammarstedt A, Karlsson C, Langkilde AM, Wada T, Heerspink HJL. Effects of dapagliflozin and dapagliflozin-saxagliptin on erythropoiesis, iron and inflammation markers in patients with type 2 diabetes and chronic kidney disease: data from the DELIGHT trial. — Cardiovascular Diabetology. 2023. DOI 10.1186/s12933-023-02027-8. RCT, n=360 with biosamples (461 randomized). Saxagliptin 2.5 mg in the combination arm. Tier A.
  11. Effect of a combination of gliptin and metformin on serum vitamin B12, folic acid, and ferritin levels. — Revista da Associação Médica Brasileira. 2023. PMID 37909618. Prospective comparison, n=118 (vildagliptin/metformin n=35 or sitagliptin/metformin n=24 vs metformin alone, per secondary source review). Tier C for saxagliptin (not in cohort).Saxagliptin not in the studied cohort (vildagliptin and sitagliptin were); graded class-level (Tier C) for saxagliptin per the mandatory cohort test. PubMed Central full text (PMC10610761) and PubMed's individual article page returned bot-verification/CAPTCHA pages and could not be opened directly during this review; findings drawn from an accessible secondary summary of the same paper.
  12. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus (SAVOR-TIMI 53). — Cited via FDA label Adverse Reactions 6.1 (n=16,492); heart failure hospitalization HR 1.27, 95% CI 1.07-1.51. Tier A, saxagliptin in cohort. Clinical outcome, not a nutrient entry (Hard Rule 2).
  13. WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD Index, code A10BH03 (saxagliptin). — DDD 5 mg, oral. Regulatory classification reference.