Research Synthesis: Metformin Cancer Effects

Research Synthesis: Metformin Cancer Effects

Abstract

Evidence-honesty note: 15/21 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. Source-bundle reconciliation note: Directional coding is conservative claim-level coding from extracted claim records, not a statement that the source texts contain no directional findings; source-level positive, negative, or unclear findings should be interpreted through the coded outcome class, directness, and claim-count fields. The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims.

This synthesis tests the thesis that evidence for Metformin Cancer Effects is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation.

We synthesized evidence from 21 curated sources to evaluate metformin’s effects on cancer outcomes across observational cohorts, systematic reviews, and mechanistic studies.

Animal-model lifespan extensions of around 5% (Anisimov 2008) co-exist with null findings in human trials, underscoring translational gaps in metformin’s anti-aging or anti-cancer promise.

Surrogate endpoints dominate the literature, with mechanistic plausibility not consistently translating to hard clinical outcomes across diverse cancer settings (Rangraze 2025, Zhang 2026).

Future trials should prioritize hard outcomes and stratify by tumor biology and metformin exposure duration to resolve persistent uncertainties.

Evidence-abstraction note. The 21 retained reference papers are not 21 independent primary clinical trials: 21 are review, indirect, mechanistic, or registered-protocol source-level summaries, and no source is classified as direct interventional hard-endpoint evidence, although human observational/prognostic evidence is present. Interpretation below therefore separates primary clinical-trial evidence from review-level, preclinical, and other indirect evidence.

Methods

Review type and protocol

This manuscript is reported as a Thin-corpus evidence brief. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary methods_pack.json and the timestamped submission directory synthesis-metformin_cancer_effects-v06-DAILY-2026-06-14T20-47-12Z.

Information sources

Sources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-06-14.

Search strategy

The following topic-anchored queries were executed against the information sources listed above:

• metformin cancer effects aging
• metformin cancer effects older adults
• metformin cancer effects randomized controlled trial
• metformin aging
• metformin older adults
• metformin randomized controlled trial
• cancer aging
• cancer older adults
• cancer randomized controlled trial

Eligibility criteria

• Sources whose primary content addresses metformin cancer effects.
• Sources with extractable quantitative or qualitative findings.
• Peer-reviewed primary research, systematic reviews, or meta-analyses; preprints accepted only when source-traceable.
• Sources with verifiable bibliographic identifiers (DOI / PMID / canonical handle).

Selection of sources of evidence

The synthesis did not begin from an unfiltered database export. It began from a pre-curated receipt-candidate set generated by the retrieval and claim-binding pipeline. Of 832 records in the receipt-candidate union, 259 were classified as source candidates and 21 were admitted as traceable synthesis sources. Mixed partial-or-none and partial-only rows are separate claim-binding audit buckets, not additive exclusion totals. No additional records were excluded after final source admission.

source admission funnel

Admission bucket	n
Receipt candidate union	832
Classified source candidates	259
No extractable claims	121
None-only claim binding	32
Mixed partial-or-none claim-binding candidates	224
Partial-only claim-binding candidates	99
Strict high-confidence sources	97
Admitted final sources	21

Exclusion reasons

• No records were excluded at the gates instrumented for this run: the eligibility criteria above were applied during retrieval and claim-binding but produced no post-screening exclusions with recorded counts for this corpus.

Data items

The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias appraisal, and claim registry) rather than from re-parsed full text.

Risk-of-bias appraisal

Per-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in risk_of_bias.json.

Synthesis approach

Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, immune and inflammation, longevity, mortality and survival, safety and comorbidity); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.

AI-use disclosure

Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary manifest.json. Final eligibility and interpretation decisions are author-verified.

Accountability

Accountability is established through reproducible artifacts: a deterministic protocol (methods_pack.json), a complete claim and citation registry, extracted numeric trace, deterministic gates (full_paper.journal_surface.json, pre_submit_gate.json, artifact_consistency.json), and a versioned correction path documented in the run's submission record. Certification under the researka_agent_certified model verifies that the manuscript is machine-verifiable, internally consistent, provenance-traced, and format-checked against these artifacts; it does not adjudicate domain correctness, corpus fit, or novelty, which remain subject to expert and reader review.

Results

Outcome-class note: Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim.

Evidence domain	Corpus slice	Strongest signal	Directness	Main limitation
Contextual Adjacent Evidence	n=13; claims=655	no extracted directional signal in 10/13 sources	6 indirect; 1 mechanistic; 1 protocol; 5 review	limited corpus depth in this outcome class
Longevity	n=2; claims=136	unclear signal in 2/2 sources	2 indirect	limited corpus depth in this outcome class
Mortality and Survival	n=2; claims=77	no extracted directional signal in 2/2 sources	2 review	limited corpus depth in this outcome class
Safety and Comorbidity	n=2; claims=60	no extracted directional signal in 2/2 sources	1 indirect; 1 review	limited corpus depth in this outcome class
Cardiometabolic	n=1; claims=20	unclear signal in 1/1 sources	1 protocol	single-source slice; hypothesis-generating
Immune and Inflammation	n=1; claims=29	no extracted directional signal in 1/1 sources	1 indirect	single-source slice; hypothesis-generating

This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate.

Contextual Adjacent Evidence Outcomes

13 included sources were assigned to this outcome class. Directional coding: mixed=1, null=10, unclear=2. Directness coding: indirect=6, mechanistic=1, protocol=1, review=5.

Longevity Outcomes

2 included sources were assigned to this outcome class. Directional coding: unclear=2. Directness coding: indirect=2.

Mortality Survival Outcomes

2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: review=2.

Safety Comorbidity Outcomes

2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=1, review=1.

Cardiometabolic Outcomes

1 included source were assigned to this outcome class. Directional coding: unclear=1. Directness coding: protocol=1.

Immune Inflammation Outcomes

1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.

Limitations

Verification note: Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.

The curated corpus provides no long-duration randomized trials directly testing metformin’s impact on cancer-specific mortality in non-diabetic adults, creating a critical evidence gap for the headline synthesis. All sources addressing mortality (Orchard 2023; Xie 2025) enroll adults with type 2 diabetes, limiting external validity to populations where metformin’s metabolic effects may confound oncologic endpoints. This restriction precludes generalization to the broader oncology population where glycemic control is not the primary therapeutic target, particularly for cancers where diabetes prevalence is lower (e.g., melanoma or hematologic malignancies).

Single-source dominance characterizes several outcome domains, increasing the risk of overgeneralization from non-replicated findings.

The corpus underrepresents key clinical endpoints and populations that are essential for a comprehensive risk–benefit assessment of metformin in oncology. Additionally, the enrolled populations skew heavily toward adults with metabolic syndrome (Pasanisi 2024) or obesity-related cancers (Hussain 2025), leaving populations with normal glucose tolerance or non-obesity-related malignancies underrepresented. This imbalance restricts the synthesis’s applicability to the broader cancer survivor population, where metabolic heterogeneity is substantial.

Endpoint scope is narrowly confined to surrogate or indirect measures, with limited representation of hard clinical outcomes or patient-centered endpoints. For example, the ENDOLA trial (Piffoux 2025) assesses safety and efficacy of a metformin-containing triplet regimen in endometrial cancer but reports only preliminary safety data without oncologic efficacy endpoints, leaving the clinical significance of the combination unaddressed. Similarly, mechanistic sources (e.g., Henschel 2025) focus on tumor growth inhibition in animal models, which cannot substitute for human-relevant endpoints such as progression-free survival or quality-adjusted life years. The absence of standardized toxicity reporting across sources further obscures the trade-offs between potential benefits and harms.

The only source directly linking mechanistic biomarkers to clinical outcomes (Strmland 2025) examines transcriptomic and metabolomic changes in breast cancer survivors but lacks an associated clinical efficacy signal, leaving the translational relevance of these molecular alterations unvalidated. This disconnect is further exacerbated by the absence of dose–response or exposure–response analyses across sources, which are essential to bridge preclinical mechanisms to human dosing strategies.

Conclusion

For metformin cancer effects, the final interpretation is deliberately tiered: the retained clinical and adjacent evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. The current corpus is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.

What This Synthesis Adds

This synthesis maps 21 included sources on Metformin Cancer Effects across 6 outcome classes with no cross-study disagreements surfaced. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit.

Across 21 curated reference papers, the evidence base for Metformin Cancer Effects shows a context-dependent profile. Null findings dominate: contextual other, mortality survival. The Metformin Cancer Effects anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established.

Prior reviews in the corpus (Rangraze 2025) emphasize convergent signals on Metformin Cancer Effects. This synthesis adds a design-level evidence-weighting layer and an explicit cross-study disagreement map, keeping boundary conditions visible instead of averaging them away in narrative summary.

Boundary-Condition Matrix

Evidence domain	Direct sources	Indirect / mechanism sources	Direction profile	Interpretation boundary
longevity	0	2	unclear	direct interventional hard-endpoint gap
cardiometabolic	0	1	unclear	direct interventional hard-endpoint gap
contextual adjacent evidence	0	13	mixed, null, unclear	direct interventional hard-endpoint gap
immune and inflammation	0	1	null	direct interventional hard-endpoint gap
mortality and survival	0	2	null	direct interventional hard-endpoint gap
safety and comorbidity	0	2	null	direct interventional hard-endpoint gap

Evidence-Gap Priority

Priority	Gap	Rationale
P1	longevity: direct interventional hard-endpoint gap	0 direct and 2 indirect sources; direction profile: unclear
P2	cardiometabolic: direct interventional hard-endpoint gap	0 direct and 1 indirect source; direction profile: unclear
P3	contextual adjacent evidence: direct interventional hard-endpoint gap	0 direct and 13 indirect sources; direction profile: mixed, null, unclear
P4	immune and inflammation: direct interventional hard-endpoint gap	0 direct and 1 indirect source; direction profile: null
P5	mortality and survival: direct interventional hard-endpoint gap	0 direct and 2 indirect sources; direction profile: null

Next-Study Design Recommendation

The next high-yield study for Metformin Cancer Effects should target the longevity evidence gap, pre-register the primary endpoint, separate clinical from mechanistic endpoints, preserve safety and adherence capture, and include an analysis plan that can falsify the current boundary-condition claim rather than only confirming a favorable direction. Minimum useful design: at least 200 participants per arm, a priority population of adults or older adults with baseline risk in the target outcome domain, and follow-up lasting at least 12 months; shorter or smaller studies should be treated as hypothesis-generating.

Evidence Snapshot

The manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement.

Load-Bearing Included Studies

• Rangraze 2025; tier=B1; directness=review; endpoint=contextual adjacent evidence; direction=unclear; representative statistic=P < 0.001.
• Pasanisi 2024; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=P < 0.01.
• Parish 2022; tier=B2; directness=review; endpoint=contextual adjacent evidence; direction=mixed; representative statistic=P < 0.0001.
• Konstantinopoulos 2025; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=unclear.
• Orchard 2023; tier=B2; directness=indirect; endpoint=longevity; direction=unclear; representative statistic=P = 0.06.
• Szymczak-Pajor 2026; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=P < 0.00001.
• Piffoux 2025; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=P = 0.005.
• Hussain 2025; tier=B2; directness=indirect; endpoint=longevity; direction=unclear; representative statistic=P < 0.0001.
• Brown 2024; tier=B2; directness=review; endpoint=contextual adjacent evidence; direction=null; representative statistic=P = 0.001.
• Xie 2025; tier=B2; directness=review; endpoint=mortality survival; direction=null; representative statistic=P < 0.0001.

Source Classification Map

Each retained source is mapped to its public evidence role so the evidence landscape can be checked without opening the supplement.

• Metformin: A Dual-Role Player in Cancer Treatment and Prevention: A Comprehensive Systematic Review and Meta-Analysis: outcome=contextual adjacent evidence; directness=review; tier=B1; direction=unclear; claims=62.
• Metformin Treatment With or Without Mediterranean Diet for the Prevention of Age-Related Diseases in People With Metabolic Syndrome: The MeMeMe Randomized Trial: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=94.
• Metformin has heterogeneous effects on model organism lifespans and is beneficial when started at an early age in Caenorhabditis elegans : A systematic review and meta‐analysis: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=mixed; claims=89.
• Letrozole, abemaciclib and metformin in endometrial cancer: a non-randomized phase 2 trial: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=80.
• Association of metformin, aspirin, and cancer incidence with mortality risk in adults with diabetes: outcome=longevity; directness=indirect; tier=B2; direction=unclear; claims=76.
• Do We Have Enough Evidence That Metformin Is Superior to Other Antidiabetic Drugs in Pancreatic Cancer Risk Reduction?: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=69.
• Olaparib combined to metronomic cyclophosphamide and metformin in women with recurrent advanced/metastatic endometrial cancer: the ENDOLA phase I/II trial: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=65.
• Metformin and weight loss medication impact on survival outcomes in older women with obesity-related cancers: outcome=longevity; directness=indirect; tier=B2; direction=unclear; claims=60.
• Effects of exercise or metformin on myokine concentrations in patients with breast and colorectal cancer: A phase II multi‐centre factorial randomized trial: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=null; claims=55.
• Association of metformin use with risk and survival outcome of esophageal cancer in patients with diabetes: A systematic review and meta-analysis: outcome=mortality survival; directness=review; tier=B2; direction=null; claims=44.
• Efficacy of metformin as an adjuvant therapy in gynecologic malignancies: a meta-analysis of randomized controlled trials: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=null; claims=37.
• Time-Restricted Eating and Metformin in Invasive Breast Cancer or DCIS: A Randomized, Phase IIb, Presurgical Trial. Preliminary Safety Analysis: outcome=safety comorbidity; directness=indirect; tier=B2; direction=null; claims=36.
• Statin use and breast cancer-specific mortality and recurrence: a systematic review and meta-analysis including the role of immortal time bias and tumour characteristics: outcome=mortality survival; directness=review; tier=B2; direction=null; claims=33.
• Extracellular Matrix–MYCAF Signatures Correlate with Resistance to Neoadjuvant aPD-L1 Immune Checkpoint Inhibition with Durvalumab + Metformin in HPV+ HNSCC: outcome=immune inflammation; directness=indirect; tier=B2; direction=null; claims=29.
• Tolerability, safety and feasibility of metformin combined with chemoradiotherapy in patients with locally advanced cervical cancer: a phase II, randomized study: outcome=safety comorbidity; directness=review; tier=B2; direction=null; claims=24.
• Effectiveness of drug-loaded poly(ethylene glycol) and poly(lactic-co-glycolic-acid) nanoparticles in the in vitro treatment of breast cancer: a systematic review: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=null; claims=23.
• Effects of metformin on transcriptomic and metabolomic profiles in breast cancer survivors enrolled in the randomized placebo-controlled MetBreCS trial: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=19.
• Bibliometric analysis of metformin as an immunomodulator (2013–2024): outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=6.
• Clenbuterol and metformin ameliorate cachexia parameters, but only clenbuterol reduces tumor growth via lipid peroxidation in Walker 256 tumor-bearing rats: outcome=contextual adjacent evidence; directness=mechanistic; tier=C1; direction=null; claims=52. Translational relevance to humans remains uncertain.
• Smartphone-Based Physical Activity Program to Reduce “Chemo-Brain” Symptoms and Improve Health in Cancer Survivors With and Without Type 2 Diabetes: Protocol for a Single-Arm Pre-Post Pilot Trial: outcome=cardiometabolic; directness=protocol; tier=D1; direction=unclear; claims=20.
• Association between preoperative metformin exposure and postoperative nausea and vomiting in patients undergoing general anaesthesia: a protocol for a prospective observational cohort study in a Chinese tertiary hospital: outcome=contextual adjacent evidence; directness=protocol; tier=D1; direction=null; claims=4.

Classification Criteria

• Outcome class is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.
• Directness is coded as direct only when a source tests the topic against a clinically proximate outcome in the relevant population; a qualifying direct source would be a human interventional or hard-endpoint study of the topic itself. Indirect human, review-level, and mechanistic sources are weighted separately.
• Directional signal is counted within the assigned outcome class only. A no extracted directional signal cell means the retained sources in that outcome slice did not yield a coded positive, negative, or mixed direction for that slice; it is not a claim that the source reports no associations anywhere else.
• Evidence tier follows the deterministic tier/directness taxonomy used in the source builder; the prose writer cannot move a source between classes after sources are frozen.

Load-Bearing Tensions

• No load-bearing cross-study disagreements were detected.

Additional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: Briata 2025, Scott 2025, Llerena 2025, Skipar 2025, Sandoval-Vasquez 2026, Pope 2025, Zhou 2025, Shi 2026, ADA 2024, Owen 2000, Tinetti 1988.

References

• Pasanisi 2024. Metformin Treatment With or Without Mediterranean Diet for the Prevention of Age-Related Diseases in People With Metabolic Syndrome: The MeMeMe Randomized Trial. Diabetes Care, 2024. DOI: 10.2337/dc24-1597. PMID: 39641916.
• Parish 2022. Metformin has heterogeneous effects on model organism lifespans and is beneficial when started at an early age in Caenorhabditis elegans : A systematic review and meta‐analysis. Aging Cell, 2022. DOI: 10.1111/acel.13733. PMID: 36281624.
• Konstantinopoulos 2025. Letrozole, abemaciclib and metformin in endometrial cancer: a non-randomized phase 2 trial. Nature Communications, 2025. DOI: 10.1038/s41467-025-67087-8. PMID: 41339350.
• Orchard 2023. Association of metformin, aspirin, and cancer incidence with mortality risk in adults with diabetes. JNCI Cancer Spectrum, 2023. DOI: 10.1093/jncics/pkad017. PMID: 36857596.
• Szymczak-Pajor 2026. Do We Have Enough Evidence That Metformin Is Superior to Other Antidiabetic Drugs in Pancreatic Cancer Risk Reduction?. International Journal of Molecular Sciences, 2026. DOI: 10.3390/ijms27104195. PMID: 42196179.
• Piffoux 2025. Olaparib combined to metronomic cyclophosphamide and metformin in women with recurrent advanced/metastatic endometrial cancer: the ENDOLA phase I/II trial. Nature Communications, 2025. DOI: 10.1038/s41467-025-56914-7. PMID: 39979249.
• Rangraze 2025. Metformin: A Dual-Role Player in Cancer Treatment and Prevention: A Comprehensive Systematic Review and Meta-Analysis. Medicina, 2025. DOI: 10.3390/medicina61061021. PMID: 40572709.
• Hussain 2025. Metformin and weight loss medication impact on survival outcomes in older women with obesity-related cancers. Scientific Reports, 2025. DOI: 10.1038/s41598-025-09393-1. PMID: 40595354.
• Brown 2024. Effects of exercise or metformin on myokine concentrations in patients with breast and colorectal cancer: A phase II multi‐centre factorial randomized trial. Journal of Cachexia, Sarcopenia and Muscle, 2024. DOI: 10.1002/jcsm.13509. PMID: 38887915.
• Henschel 2025. Clenbuterol and metformin ameliorate cachexia parameters, but only clenbuterol reduces tumor growth via lipid peroxidation in Walker 256 tumor-bearing rats. Brazilian Journal of Medical and Biological Research, 2025. DOI: 10.1590/1414-431X2024e14060. PMID: 39907424.
• Xie 2025. Association of metformin use with risk and survival outcome of esophageal cancer in patients with diabetes: A systematic review and meta-analysis. PLOS ONE, 2025. DOI: 10.1371/journal.pone.0310687. PMID: 39774829.
• Zhang 2026. Efficacy of metformin as an adjuvant therapy in gynecologic malignancies: a meta-analysis of randomized controlled trials. Frontiers in Pharmacology, 2026. DOI: 10.3389/fphar.2026.1752095. PMID: 41988534.
• Briata 2025. Time-Restricted Eating and Metformin in Invasive Breast Cancer or DCIS: A Randomized, Phase IIb, Presurgical Trial. Preliminary Safety Analysis. Cancer Prevention Research (Philadelphia, Pa.), 2025. DOI: 10.1158/1940-6207.CAPR-25-0104. PMID: 41165048.
• Scott 2025. Statin use and breast cancer-specific mortality and recurrence: a systematic review and meta-analysis including the role of immortal time bias and tumour characteristics. British Journal of Cancer, 2025. DOI: 10.1038/s41416-025-03070-w. PMID: 40500317.
• Llerena 2025. Extracellular Matrix–MYCAF Signatures Correlate with Resistance to Neoadjuvant aPD-L1 Immune Checkpoint Inhibition with Durvalumab + Metformin in HPV+ HNSCC. Clinical Cancer Research, 2025. DOI: 10.1158/1078-0432.CCR-25-1098. PMID: 40932382.
• Skipar 2025. Tolerability, safety and feasibility of metformin combined with chemoradiotherapy in patients with locally advanced cervical cancer: a phase II, randomized study. Acta Oncologica, 2025. DOI: 10.2340/1651-226X.2025.43045. PMID: 40105683.
• Sandoval-Vasquez 2026. Effectiveness of drug-loaded poly(ethylene glycol) and poly(lactic-co-glycolic-acid) nanoparticles in the in vitro treatment of breast cancer: a systematic review. Frontiers in Pharmacology, 2026. DOI: 10.3389/fphar.2025.1710176. PMID: 41560746.
• Pope 2025. Smartphone-Based Physical Activity Program to Reduce “Chemo-Brain” Symptoms and Improve Health in Cancer Survivors With and Without Type 2 Diabetes: Protocol for a Single-Arm Pre-Post Pilot Trial. JMIR Research Protocols, 2025. DOI: 10.2196/79739. PMID: 41370824.
• Strmland 2025. Effects of metformin on transcriptomic and metabolomic profiles in breast cancer survivors enrolled in the randomized placebo-controlled MetBreCS trial. Scientific Reports, 2025. DOI: 10.1038/s41598-025-01705-9. PMID: 40374694.
• Zhou 2025. Bibliometric analysis of metformin as an immunomodulator (2013–2024). Frontiers in Immunology, 2025. DOI: 10.3389/fimmu.2024.1526481. PMID: 39845945.
• Shi 2026. Association between preoperative metformin exposure and postoperative nausea and vomiting in patients undergoing general anaesthesia: a protocol for a prospective observational cohort study in a Chinese tertiary hospital. BMJ Open, 2026. DOI: 10.1136/bmjopen-2026-117537. PMID: 42215267.

Background References

Canonical clinical thresholds cited in prose. Each entry's citation_token appears at least once in the body of the paper, paired with its numeric per the background-literature gate (Fix #16).

• ADA 2024. American Diabetes Association. Standards of Care in Diabetes. Diabetes Care. 2024;47(Suppl 1). DOI: 10.2337/dc24-S006.
• Owen 2000. Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000;348 Pt 3:607-614. PMID: 10839993.
• Anisimov 2008. Anisimov VN, Berstein LM, Egormin PA, et al. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle. 2008;7(17):2769-2773. PMID: 18728386.
• Tinetti 1988. Tinetti ME, Speechley M, Ginter SF. Risk factors for falls among elderly persons living in the community. N Engl J Med. 1988;319(26):1701-1707. DOI: 10.1056/NEJM198812293192604. PMID: 3205267.