2f:I[703058,["/_next/static/immutable/chunks/3bhq_5eh1d760.js","/_next/static/immutable/chunks/1855-ogyi8eh4.js","/_next/static/immutable/chunks/2pfsjpn6k6zlg.js","/_next/static/immutable/chunks/26c7v3_3uwnwu.js","/_next/static/immutable/chunks/25a3ozcrvi1ff.js","/_next/static/immutable/chunks/2r4wx50nvjh_4.js","/_next/static/immutable/chunks/23fsw06hsi5b1.js","/_next/static/immutable/chunks/06_yt270h41rg.js","/_next/static/immutable/chunks/3ezsiz-7shkna.js","/_next/static/immutable/chunks/20x2y96ldu5wx.js","/_next/static/immutable/chunks/2lxntcm3pd1_h.js","/_next/static/immutable/chunks/00dgco8irq3jw.js","/_next/static/immutable/chunks/00nwe-kq0rboc.js","/_next/static/immutable/chunks/2051ffx3xzio9.js"],"PaperListPageClient"] 30:T4a4,Metformin is a versatile biguanide drug primarily prescribed for type II diabetes. Despite its extensive use, the mechanisms underlying its clinical effects, including attenuated postprandial glucose excursions and elevated intestinal glucose uptake, remain unclear. Here we map these and other effects of metformin to intestine-specific mitochondrial complex I inhibition. Using human metabolomic data and an orthogonal genetics approach in male mice, we demonstrate that metformin suppresses citrulline synthesis, a metabolite generated exclusively by small intestine mitochondria, and increases GDF15 by inhibiting the mitochondrial respiratory chain at complex I. This inhibition co-opts the intestines to function as a glucose sink, driving the uptake of excess glucose and its conversion to lactate and lactoyl-phenylalanine. We also find that glucose lowering by metformin is due to repeated bolus exposure rather than a cumulative chronic response. Notably, the efficacy of phenformin, another biguanide, and berberine, a structurally unrelated nutraceutical, similarly depends on intestine-specific mitochondrial complex I inhibition, underscoring a shared therapeutic mechanism.31:T4e9,Abstract Metformin is a versatile biguanide drug primarily prescribed for type II diabetes. Despite its extensive use, the mechanisms underlying its clinical effects, including attenuated postprandial glucose excursions and elevated intestinal glucose uptake, remain unclear. Here we map these and other effects of metformin to intestine-specific mitochondrial complex I inhibition. Using human metabolomic data and an orthogonal genetics approach in male mice, we demonstrate that metformin suppresses citrulline synthesis, a metabolite generated exclusively by small intestine mitochondria, and increases GDF15 by inhibiting the mitochondrial respiratory chain at complex I. This inhibition co-opts the intestines to function as a glucose sink, driving the uptake of excess glucose and its conversion to lactate and lactoyl-phenylalanine. We also find that glucose lowering by metformin is due to repeated bolus exposure rather than a cumulative chronic response. Notably, the efficacy of phenformin, another biguanide, and berberine, a structurally unrelated nutraceutical, similarly depends on intestine-specific mitochondrial complex I inhibition, underscoring a shared therapeutic mechanism.32:T621,In a co-twin control design, we aimed to examine whether individuals who initiate metformin treatment have an altered risk of incident diagnosis of osteoarthritis (OA), for up to 11 years after starting the treatment, compared with their non-treated co-twin. In all twin pairs different for metformin treatment (N=1 261 pairs) and all eligible twins/singletons (N=52 341) aged 35-75 years living in Sweden on December 31st 2005, without prior diagnosis of OA and no prior treatment with metformin, we studied the outcome OA in any joint as diagnosed in specialist care. We used a stratified Cox model in discordant pairs to estimate hazard ratio (HR) and a within-between Weibull shared frailty model to estimate incidence proportions and differences. Models were adjusted for age, sex, education level, body mass index (BMI) and smoking. Among treated twins, 68 (5.4%) developed OA over the 11-year follow-up, compared to 79 (6.3%) among the non-treated twins (crude HR [95% confidence interval -CI] = 0.86 [0.62-1.19]). Treated twins had higher BMI. Adjusted HR comparing treated with non-treated was 0.60 (95% CI =0.44-0.82). After 10 years, 6.7% (95% CI=4.8-8.6) of treated twins, compared to 9.7% (95% CI=9.3-10.1) of non-treated twins had incident OA, with difference of -3.1% (95% CI=-5.1- (-1.1)). Starting metformin treatment may be associated with a decreased risk of incident diagnosis of OA in specialist care over an 11-year follow-up period. The 10-year cumulative incidence was ∼3 percentage points lower among metformin initiators than non-initiators.33:T4e5,A total of 5414 participants reported their daily medication and substance use in the month before pregnancy and the level of nausea and vomiting during pregnancy. Using metformin before the first pregnancy was associated with a >70% reduction in the risk for hyperemesis gravidarum (adjusted relative risk, 0.29; 95% confidence interval, 0.12-0.71; P=.007). Tobacco use was also associated with a significant reduction in the risk (adjusted relative risk, 0.51; 95% confidence interval, 0.30-0.86; P=.011). Conversely, selective serotonin reuptake inhibitors were associated with an increased risk for hyperemesis gravidarum (adjusted relative risk, 2.41; 95% confidence interval, 1.33-4.38; P=.004). The use of metformin was also associated with an 82% reduction in the risk for severe nausea and vomiting of pregnancy and hyperemesis gravidarum (adjusted odds ratio, 0.18; 0.06-0.59; P=.005) in the second pregnancy, even after adjustment for the 86% reoccurrence risk identified in this study. Conversely, the use of cannabis or selective serotonin reuptake inhibitors before the second pregnancy were each associated with increased risk (adjusted odds ratio, 3.48; 1.80-6.75; P<.001; and adjusted odds ratio, 1.84; 1.12-3.04; P=.016, respectively).34:Te24,Severe nausea and vomiting of pregnancy and hyperemesis gravidarum are associated with adverse maternal, fetal, and child outcomes. The recurrence risk is reported to be as high as 89%. Identifying an effective, safe, and affordable method to prevent hyperemesis gravidarum is critical to reducing the risk for reoccurrence and improving maternal, fetal, and child health. We recently demonstrated that a genetic predisposition to hyperemesis gravidarum is mediated by low prepregnancy levels of the emetogenic hormone, growth and differentiation factor 15, which leads to hypersensitivity to its rapid rise during pregnancy. Because metformin increases circulating levels of growth and differentiation factor 15, we hypothesized that the use of metformin before pregnancy will desensitize patients to the hormone and lower the risk for severe nausea and vomiting in pregnancy and hyperemesis gravidarum. The objective of the study was to determine whether daily use of metformin is associated with a lower risk for severe nausea and vomiting of pregnancy and hyperemesis gravidarum. Through means of a structured questionnaire, visitors to the Hyperemesis Gravidarum Education and Research Foundation social media sites from January 2023 to September 2024 reported daily use of 32 common substances in the month before each pregnancy and the level of nausea and vomiting of pregnancy. Crude and multivariate associations between the use of each substance and severe nausea and vomiting of pregnancy and hyperemesis gravidarum in the subsequent pregnancy were estimated using a logistic regression. The final multivariate models included tobacco use and maternal age; the number and type of additional drugs used and race and ethnicity had little influence and were not retained. A total of 5414 participants reported their daily medication and substance use in the month before pregnancy and the level of nausea and vomiting during pregnancy. Using metformin before the first pregnancy was associated with a >70% reduction in the risk for hyperemesis gravidarum (adjusted relative risk, 0.29; 95% confidence interval, 0.12-0.71; P=.007). Tobacco use was also associated with a significant reduction in the risk (adjusted relative risk, 0.51; 95% confidence interval, 0.30-0.86; P=.011). Conversely, selective serotonin reuptake inhibitors were associated with an increased risk for hyperemesis gravidarum (adjusted relative risk, 2.41; 95% confidence interval, 1.33-4.38; P=.004). The use of metformin was also associated with an 82% reduction in the risk for severe nausea and vomiting of pregnancy and hyperemesis gravidarum (adjusted odds ratio, 0.18; 0.06-0.59; P=.005) in the second pregnancy, even after adjustment for the 86% reoccurrence risk identified in this study. Conversely, the use of cannabis or selective serotonin reuptake inhibitors before the second pregnancy were each associated with increased risk (adjusted odds ratio, 3.48; 1.80-6.75; P<.001; and adjusted odds ratio, 1.84; 1.12-3.04; P=.016, respectively). Prepregnancy metformin treatment may decrease the risk for severe nausea and vomiting, whereas prepregnancy cannabis use and selective serotonin reuptake inhibitors may increase the risk. Metformin, which is routinely used before and after conception, may be a safe and affordable treatment to offer patients with a history of hyperemesis gravidarum to decrease the chance of reoccurrence. Clinical trials are warranted to investigate metformin use before pregnancy to lower the risk for hyperemesis gravidarum, thereby mitigating the associated adverse maternal and offspring outcomes.25:[[["$","script","0",{"type":"application/ld+json","dangerouslySetInnerHTML":{"__html":"{\"@context\":\"https://schema.org\",\"@type\":\"CollectionPage\",\"name\":\"Biguanide: modality Research & Clinical Takeaways\",\"description\":\"Explore peer-reviewed papers on Biguanide (modality). Clinician-written summaries and actionable practice insights. 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results should be interpreted with caution.","value_numeric":null},{"paper_doi":"10.1007/s00125-026-06830-2","tag_type":"warning","value":"Stroke was self-reported and not subtyped (haemorrhagic vs ischaemic), limiting mechanistic interpretation of the elevated stroke prevalence in lean participants.","value_numeric":null},{"paper_doi":"10.1007/s00125-026-06830-2","tag_type":"warning","value":"The cross-sectional design is a major constraint — observed complication differences could reflect survivorship bias, differential diabetes duration, or late diagnosis in lean individuals rather than true phenotypic divergence.","value_numeric":null},{"paper_doi":"10.1007/s00125-026-06830-2","tag_type":"warning","value":"The RODAM cohort included European Ghanaian migrants (65% of RODAM), whose environment and BMI differ substantially from those in Africa; sensitivity analysis showed attenuation of the stroke association after site adjustment, suggesting geographical heterogeneity may partially influence results.","value_numeric":null}],"summaries":{"what_studied":"This multi-cohort cross-sectional analysis compared complication profiles in African adults with type 2 diabetes who were lean (BMI <25 kg/m²) vs overweight/obese (BMI ≥25 kg/m²), using harmonised individual-level data from the AADM (n=2,790) and RODAM (n=541) cohorts across Ghana, Nigeria, and Kenya.","key_result":"Lean adults had significantly higher prevalence of diabetic retinopathy (pPR 1.36 [95% CI 1.13–1.63]) and stroke (pPR 1.41 [95% CI 1.01–1.99]), but lower hypertension (pPR 0.77 [95% CI 0.71–0.85]) and 10-year CVD risk (pPR 0.85 [95% CI 0.74–0.97]) compared with overweight/obese peers; CKD prevalence did not differ. Body fat percentage mediated up to 92% of these differences.","limitations":"- Cross-sectional design prevents causal inference or assessment of temporal sequence between phenotype and complications.\n- Stroke ascertainment relied on self-reported history without subtyping; CKD was defined by eGFR alone without albuminuria, potentially missing early microvascular kidney disease.\n- Residual confounding from unmeasured variables (medication adherence, healthcare access, true diabetes duration) cannot be excluded.","practice_takeaway":"Nearly 40% of African adults with type 2 diabetes are lean and show a distinct complication pattern—more microvascular disease (retinopathy, stroke) but less hypertension and macrovascular risk—likely driven by insulin secretory failure rather than insulin resistance. Clinicians managing lean African patients with type 2 diabetes should be alert to this divergent risk profile and the potential inadequacy of insulin-sensitising agents alone."}},{"doi":"10.3389/fpsyt.2026.1930167","pmid":null,"title":"Metabolic dysfunction and insulin resistance in depression: mechanisms, evidence, and therapeutic implications","journal_title":"Frontiers in Psychiatry","journal_issn":"1664-0640","published_at":"2026-08-20T00:00:00.000Z","url":"https://doi.org/10.3389/fpsyt.2026.1930167","source_score":12,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":false,"crossref":true,"unpaywall":true},"created_at":"2026-08-26T06:20:08.620Z","updated_at":"2026-08-26T06:20:08.620Z","tags":[{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"category","value":"Psychiatry","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"condition","value":"Insulin Resistance","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"condition","value":"Major Depressive Disorder","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"condition","value":"Metabolic Dysfunction","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"condition","value":"Obesity","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"condition","value":"Treatment-Resistant Depression","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"generic","value":"metformin","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"level_of_evidence","value":"5","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"modality","value":"Biguanide","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"modality","value":"GLP-1 Receptor Agonist","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"modality","value":"Insulin Sensitizer","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"study_design","value":"Narrative Review","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"warning","value":"Age group tagged as 'adult' by inference from the clinical context; the review does not explicitly restrict to any age group.","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"warning","value":"Full text body pages (1–7) contain minimal extractable content beyond the abstract and metadata; summary is based primarily on the abstract. Specific studies cited, effect sizes, and detailed mechanistic findings could not be verified from the provided text.","value_numeric":null},{"paper_doi":"10.3389/fpsyt.2026.1930167","tag_type":"warning","value":"No specific GLP-1 agonist brand or generic names beyond metformin are individually named in the extractable text; 'GLP-1 Receptor Agonist' is listed as a keyword.","value_numeric":null}],"summaries":{"what_studied":"This narrative review examines the bidirectional relationship between major depressive disorder (MDD) and metabolic dysfunction — including obesity, insulin resistance, and HPA axis dysregulation — and evaluates the potential antidepressant effects of insulin-sensitizing agents (e.g., metformin, GLP-1 receptor agonists).","key_result":"Evidence for insulin-sensitizing therapies improving depressive symptoms is mixed and mechanisms remain poorly elucidated; up to 30% of MDD patients are treatment-resistant, with higher rates in those with comorbid metabolic dysfunction.","limitations":"- Narrative review design limits causal inference and is subject to selection bias.\n- Mechanisms by which insulin-targeting agents may improve depression are not clearly established in current studies.\n- No original data; conclusions depend entirely on the quality of cited primary literature.","practice_takeaway":"Consider routine metabolic screening (glucose, insulin resistance markers) in patients with MDD, especially those who are treatment-resistant, as metabolic dysfunction may identify candidates for precision therapies targeting insulin pathways.\nInsulin-sensitizing agents show promise but lack sufficient evidence to recommend routine use for depression at this time."}},{"doi":"10.1186/s12933-026-03316-8","pmid":"42625219","title":"A cardiometabolic perspective on post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID","journal_title":"Cardiovascular Diabetology","journal_issn":"1475-2840","published_at":"2026-08-20T00:00:00.000Z","url":"https://doi.org/10.1186/s12933-026-03316-8","source_score":109,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-08-26T06:20:07.611Z","updated_at":"2026-08-26T06:20:07.611Z","tags":[{"paper_doi":"10.1186/s12933-026-03316-8","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1186/s12933-026-03316-8","tag_type":"category","value":"Cardiac & Cardiovascular Systems","value_numeric":null},{"paper_doi":"10.1186/s12933-026-03316-8","tag_type":"category","value":"Endocrinology & Metabolism","value_numeric":null},{"paper_doi":"10.1186/s12933-026-03316-8","tag_type":"condition","value":"Long COVID","value_numeric":null},{"paper_doi":"10.1186/s12933-026-03316-8","tag_type":"condition","value":"Metabolic Syndrome","value_numeric":null},{"paper_doi":"10.1186/s12933-026-03316-8","tag_type":"condition","value":"Myalgic Encephalomyelitis / Chronic Fatigue Syndrome","value_numeric":null},{"paper_doi":"10.1186/s12933-026-03316-8","tag_type":"condition","value":"Obesity","value_numeric":null},{"paper_doi":"10.1186/s12933-026-03316-8","tag_type":"condition","value":"Type 2 Diabetes","value_numeric":null},{"paper_doi":"10.1186/s12933-026-03316-8","tag_type":"generic","value":"metformin","value_numeric":null},{"paper_doi":"10.1186/s12933-026-03316-8","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1186/s12933-026-03316-8","tag_type":"level_of_evidence","value":"7","value_numeric":null},{"paper_doi":"10.1186/s12933-026-03316-8","tag_type":"modality","value":"Biguanide","value_numeric":null},{"paper_doi":"10.1186/s12933-026-03316-8","tag_type":"modality","value":"GLP-1 Receptor Agonist","value_numeric":null},{"paper_doi":"10.1186/s12933-026-03316-8","tag_type":"study_design","value":"Perspective / Opinion","value_numeric":null},{"paper_doi":"10.1186/s12933-026-03316-8","tag_type":"warning","value":"Age and sex distribution of the target population are not specified in the paper.","value_numeric":null},{"paper_doi":"10.1186/s12933-026-03316-8","tag_type":"warning","value":"No sample size is applicable; the paper presents a framework, not a study cohort.","value_numeric":null},{"paper_doi":"10.1186/s12933-026-03316-8","tag_type":"warning","value":"Several authors are editors or board members of the publishing journal (Cardiovascular Diabetology), which is a declared conflict of interest.","value_numeric":null},{"paper_doi":"10.1186/s12933-026-03316-8","tag_type":"warning","value":"This is a perspective/opinion piece with no original data; all findings are conceptual or drawn from cited literature.","value_numeric":null}],"summaries":{"what_studied":"This perspective paper proposes a conceptual framework for investigating post-exertional malaise (PEM) in ME/CFS and Long COVID through longitudinal assessment of post-exertional physiological trajectories, with explicit attention to disease severity and underlying cardiometabolic health (including obesity and type 2 diabetes).","key_result":"The authors argue that PEM may reflect disrupted temporal coordination across interconnected physiological systems (cardiovascular, autonomic, endothelial, metabolic, immune) rather than simple symptom exacerbation, and that recurrent PEM episodes could contribute to cumulative cardiometabolic burden over time.","limitations":"This is a conceptual perspective with no original data, experimental cohort, or statistical findings. Causality between PEM and cardiometabolic dysfunction remains unestablished. The proposed framework has not yet been empirically tested.","practice_takeaway":"Clinicians should assess timing of PEM when interpreting physiological test results in ME/CFS and Long COVID patients, as disease state at the moment of evaluation can significantly alter observed phenotype. Cardiometabolic comorbidities (obesity, T2D) may shape post-exertional trajectories and should be documented and considered in patient stratification."}},{"doi":"10.1001/jamapsychiatry.2026.1814","pmid":"42418179","title":"Pharmacological Interventions for Weight Reduction in Patients With Schizophrenia Treated With Antipsychotics","journal_title":"JAMA Psychiatry","journal_issn":"2168-622X","published_at":"2026-07-08T00:00:00.000Z","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13347271/","source_score":16,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-07-14T13:24:02.454Z","updated_at":"2026-07-14T13:24:02.454Z","tags":[{"paper_doi":"10.1001/jamapsychiatry.2026.1814","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1814","tag_type":"brand","value":"Byetta","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1814","tag_type":"brand","value":"Glucophage","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1814","tag_type":"brand","value":"Ozempic","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1814","tag_type":"brand","value":"Topamax","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1814","tag_type":"brand","value":"Victoza","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1814","tag_type":"category","value":"Psychiatry","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1814","tag_type":"condition","value":"Antipsychotic-Induced Weight Gain","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1814","tag_type":"condition","value":"Schizophrenia Spectrum Disorder","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1814","tag_type":"generic","value":"exenatide","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1814","tag_type":"generic","value":"liraglutide","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1814","tag_type":"generic","value":"metformin","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1814","tag_type":"generic","value":"semaglutide","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1814","tag_type":"generic","value":"topiramate","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1814","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1814","tag_type":"level_of_evidence","value":"1","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1814","tag_type":"modality","value":"Antiepileptic","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1814","tag_type":"modality","value":"Biguanide","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1814","tag_type":"modality","value":"GLP-1 Receptor Agonist","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1814","tag_type":"sample_size","value":"n=5898","value_numeric":5898},{"paper_doi":"10.1001/jamapsychiatry.2026.1814","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1814","tag_type":"study_design","value":"Systematic Review and Network Meta-Analysis","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1814","tag_type":"warning","value":"Brand name tags for generic drugs are provided for common formulations but may not reflect the specific products used across the 95 included trials.","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1814","tag_type":"warning","value":"Full text is under PMC embargo until July 2027; all extracted data are based solely on the published abstract. Methodological details such as individual study durations, risk of bias assessments, and subgroup analyses could not be verified.","value_numeric":null},{"paper_doi":"10.1001/jamapsychiatry.2026.1814","tag_type":"warning","value":"The 'mixed sex' tag is inferred from the population type and study scope; sex breakdown is not explicitly reported in the abstract.","value_numeric":null}],"summaries":{"what_studied":"This systematic review and frequentist random-effects network meta-analysis evaluated 39 pharmacological interventions for antipsychotic-induced weight gain in adults with schizophrenia spectrum disorders (SSDs), drawing from 95 RCTs (pooled N = 5,898) identified through searches up to December 2025.","key_result":"Semaglutide produced the largest weight reduction vs. placebo (MD −10.98 kg; 95% CI −13.33 to −8.62; moderate certainty), followed by liraglutide (−5.43 kg), topiramate (−3.95 kg), metformin (−3.86 kg), and exenatide (−2.97 kg). Clinically meaningful weight loss (≥5%) was observed only with semaglutide and metformin. No major safety signals for GI adverse effects or dropout rates were identified across interventions.","limitations":"- Full text was under embargo; results are drawn from the abstract only, limiting appraisal of methodological detail.\n- Individual trial durations varied, and no restriction on study length was applied, which may introduce heterogeneity.\n- Several interventions (e.g., ramelteon, nizatidine, aripiprazole) had very low certainty evidence, limiting confidence in their effect estimates.","practice_takeaway":"For patients with schizophrenia on antipsychotics who have gained significant weight, semaglutide or metformin offer the strongest evidence for clinically meaningful weight loss (≥5%) and should be considered first-line pharmacological options. Liraglutide, topiramate, and exenatide are reasonable alternatives with moderate-certainty evidence."}},{"doi":"10.1001/jamapediatrics.2026.2248","pmid":"42329656","title":"Obesity Management Pharmacotherapies and Lifestyle Treatment for Pediatric Obesity Management","journal_title":"JAMA Pediatrics","journal_issn":"2168-6203","published_at":"2026-06-22T00:00:00.000Z","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13288192/","source_score":28,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-07-01T13:27:05.864Z","updated_at":"2026-07-01T13:27:05.864Z","tags":[{"paper_doi":"10.1001/jamapediatrics.2026.2248","tag_type":"age_group","value":"adolescent","value_numeric":null},{"paper_doi":"10.1001/jamapediatrics.2026.2248","tag_type":"age_group","value":"child","value_numeric":null},{"paper_doi":"10.1001/jamapediatrics.2026.2248","tag_type":"brand","value":"Ozempic","value_numeric":null},{"paper_doi":"10.1001/jamapediatrics.2026.2248","tag_type":"category","value":"Pediatrics","value_numeric":null},{"paper_doi":"10.1001/jamapediatrics.2026.2248","tag_type":"condition","value":"Pediatric Obesity","value_numeric":null},{"paper_doi":"10.1001/jamapediatrics.2026.2248","tag_type":"generic","value":"metformin","value_numeric":null},{"paper_doi":"10.1001/jamapediatrics.2026.2248","tag_type":"generic","value":"orlistat","value_numeric":null},{"paper_doi":"10.1001/jamapediatrics.2026.2248","tag_type":"generic","value":"phentermine-topiramate","value_numeric":null},{"paper_doi":"10.1001/jamapediatrics.2026.2248","tag_type":"generic","value":"semaglutide","value_numeric":null},{"paper_doi":"10.1001/jamapediatrics.2026.2248","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1001/jamapediatrics.2026.2248","tag_type":"level_of_evidence","value":"1","value_numeric":null},{"paper_doi":"10.1001/jamapediatrics.2026.2248","tag_type":"modality","value":"Biguanide","value_numeric":null},{"paper_doi":"10.1001/jamapediatrics.2026.2248","tag_type":"modality","value":"GLP-1 Receptor Agonist","value_numeric":null},{"paper_doi":"10.1001/jamapediatrics.2026.2248","tag_type":"modality","value":"Lifestyle Intervention","value_numeric":null},{"paper_doi":"10.1001/jamapediatrics.2026.2248","tag_type":"modality","value":"Lipase Inhibitor","value_numeric":null},{"paper_doi":"10.1001/jamapediatrics.2026.2248","tag_type":"modality","value":"Sympathomimetic-Anticonvulsant Combination","value_numeric":null},{"paper_doi":"10.1001/jamapediatrics.2026.2248","tag_type":"sample_size","value":"n=3835","value_numeric":3835},{"paper_doi":"10.1001/jamapediatrics.2026.2248","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1001/jamapediatrics.2026.2248","tag_type":"study_design","value":"Systematic Review and Network Meta-Analysis","value_numeric":null},{"paper_doi":"10.1001/jamapediatrics.2026.2248","tag_type":"warning","value":"Age range (10–19 years) spans both child and adolescent categories; median age of 14.5 years suggests predominantly adolescent population.","value_numeric":null},{"paper_doi":"10.1001/jamapediatrics.2026.2248","tag_type":"warning","value":"Brand tag 'Ozempic' applied as a representative semaglutide brand; the specific formulation or brand studied may differ across included RCTs.","value_numeric":null},{"paper_doi":"10.1001/jamapediatrics.2026.2248","tag_type":"warning","value":"Full text is under PMC embargo until June 22, 2027; all extracted data are based solely on the published abstract.","value_numeric":null},{"paper_doi":"10.1001/jamapediatrics.2026.2248","tag_type":"warning","value":"Semaglutide combination results are derived from a limited number of studies — confidence intervals are wide and estimates should be interpreted cautiously.","value_numeric":null}],"summaries":{"what_studied":"This systematic review and network meta-analysis compared the effectiveness of health behavior and lifestyle treatment (HBLT), obesity management pharmacotherapies (GLP-1 receptor agonists, metformin, orlistat, phentermine-topiramate), and their combinations on BMI, BMI z score, waist circumference, fat mass, and lean mass in children and adolescents aged 10–19 years with obesity across 42 RCTs (n=3,835) over typically 6–12 months.","key_result":"Semaglutide plus counseling produced the largest BMI reduction (MD −8.31; 95% CI −12.33 to −4.28) and BMI z score reduction (MD −1.80; 95% CI −2.39 to −1.21). All pharmacotherapies were more effective when paired with lifestyle treatment. HBLT alone also showed meaningful reductions vs. control (BMI MD −3.85; BMI z score MD −0.89).","limitations":"- Semaglutide combination estimates were based on a limited number of studies, reducing precision.\n- Outcomes reflect short-term follow-up (typically 6–12 months); long-term safety and sustainability data are limited.\n- Full text was under embargo; findings are based on the published abstract only.","practice_takeaway":"Combine pharmacotherapy (especially semaglutide) with structured lifestyle treatment for the greatest short-term weight reduction in adolescents with obesity. HBLT alone still delivers clinically meaningful BMI reduction and should remain the foundation of any treatment plan."}},{"doi":"10.1016/j.cmet.2026.05.012","pmid":"42309059","title":"Hepatocyte-to-intestinal stem cell remote communication regulates blood glucose homeostasis","journal_title":"Cell Metabolism","journal_issn":"1550-4131","published_at":"2026-06-17T00:00:00.000Z","url":"https://doi.org/10.1016/j.cmet.2026.05.012","source_score":9,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-06-21T13:29:48.671Z","updated_at":"2026-06-21T13:29:48.671Z","tags":[{"paper_doi":"10.1016/j.cmet.2026.05.012","tag_type":"category","value":"Endocrinology & Metabolism","value_numeric":null},{"paper_doi":"10.1016/j.cmet.2026.05.012","tag_type":"condition","value":"Fatty Liver Disease","value_numeric":null},{"paper_doi":"10.1016/j.cmet.2026.05.012","tag_type":"condition","value":"Hyperglycemia","value_numeric":null},{"paper_doi":"10.1016/j.cmet.2026.05.012","tag_type":"condition","value":"Type 2 Diabetes","value_numeric":null},{"paper_doi":"10.1016/j.cmet.2026.05.012","tag_type":"generic","value":"metformin","value_numeric":null},{"paper_doi":"10.1016/j.cmet.2026.05.012","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1016/j.cmet.2026.05.012","tag_type":"level_of_evidence","value":"6","value_numeric":null},{"paper_doi":"10.1016/j.cmet.2026.05.012","tag_type":"modality","value":"Alkaline Phosphatase Inhibitor","value_numeric":null},{"paper_doi":"10.1016/j.cmet.2026.05.012","tag_type":"modality","value":"Biguanide","value_numeric":null},{"paper_doi":"10.1016/j.cmet.2026.05.012","tag_type":"study_design","value":"Preclinical Mechanistic Study","value_numeric":null},{"paper_doi":"10.1016/j.cmet.2026.05.012","tag_type":"warning","value":"No sample size is reported in the abstract; this appears to be an animal/cell-based study. Human applicability is speculative at this stage.","value_numeric":null},{"paper_doi":"10.1016/j.cmet.2026.05.012","tag_type":"warning","value":"Study design label 'Preclinical Mechanistic Study' is inferred from abstract content; the paper does not explicitly state the model organisms or experimental systems used.","value_numeric":null},{"paper_doi":"10.1016/j.cmet.2026.05.012","tag_type":"warning","value":"The impact_flag 'practice_changing' reflects the novelty of the liver-gut-ISC mechanism and the therapeutic implication for ALP inhibition + metformin, but the study is entirely preclinical — no human validation data are presented. Clinicians should interpret with caution until clinical studies are available.","value_numeric":null}],"summaries":{"what_studied":"This study investigated how fatty liver worsens hyperglycemia via a liver-to-gut signaling axis — specifically, how hepatocyte-derived alkaline phosphatase (ALP) communicates remotely with intestinal stem cells (ISCs) to impair L-cell differentiation and reduce hypoglycemic hormone secretion, independent of intrahepatic gluconeogenesis.","key_result":"Hepatocyte-derived ALP activates α2δ-1 on ISCs → promotes Cav1.2 membrane translocation → raises intracellular calcium → activates calcineurin/NFATC2 → suppresses SOX21 → reduces BMP7 → fewer L-cells and lower GLP-1/PYY secretion → hyperglycemia. Inhibiting ALP in fatty liver independently lowered blood glucose and synergistically enhanced metformin's hypoglycemic effect.","limitations":"Preclinical mechanistic study — translational relevance to humans is not yet established. No clinical or human-tissue validation cohort is described. Long-term safety and specificity of ALP inhibition as a therapeutic target are not assessed.","practice_takeaway":"This is a mechanistic study and not yet ready for clinical application, but it identifies hepatic ALP as a potential drug target in fatty liver–associated hyperglycemia. Clinicians should watch for future trials exploring ALP inhibition as an adjunct to metformin in metabolic dysfunction–associated steatotic liver disease (MASLD) with type 2 diabetes."}},{"doi":"10.1001/jama.2026.8492","pmid":"42295772","title":"Lifestyle and Metformin Interventions and Risk of Multimorbidity in Adults With Prediabetes","journal_title":"JAMA","journal_issn":"0098-7484","published_at":"2026-06-15T00:00:00.000Z","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13270327/","source_score":274,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-06-23T13:25:08.937Z","updated_at":"2026-06-23T13:25:08.937Z","tags":[{"paper_doi":"10.1001/jama.2026.8492","tag_type":"age_group","value":"older_adult","value_numeric":null},{"paper_doi":"10.1001/jama.2026.8492","tag_type":"category","value":"Medicine, General & Internal","value_numeric":null},{"paper_doi":"10.1001/jama.2026.8492","tag_type":"condition","value":"Multimorbidity","value_numeric":null},{"paper_doi":"10.1001/jama.2026.8492","tag_type":"condition","value":"Prediabetes","value_numeric":null},{"paper_doi":"10.1001/jama.2026.8492","tag_type":"generic","value":"metformin","value_numeric":null},{"paper_doi":"10.1001/jama.2026.8492","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1001/jama.2026.8492","tag_type":"level_of_evidence","value":"2","value_numeric":null},{"paper_doi":"10.1001/jama.2026.8492","tag_type":"modality","value":"Biguanide","value_numeric":null},{"paper_doi":"10.1001/jama.2026.8492","tag_type":"modality","value":"Lifestyle Intervention","value_numeric":null},{"paper_doi":"10.1001/jama.2026.8492","tag_type":"sample_size","value":"n=1173","value_numeric":1173},{"paper_doi":"10.1001/jama.2026.8492","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1001/jama.2026.8492","tag_type":"study_design","value":"Observational Follow-up of Randomized Controlled Trial","value_numeric":null},{"paper_doi":"10.1001/jama.2026.8492","tag_type":"warning","value":"Full text is under PMC embargo until December 15, 2026; summary is based on the abstract and results section only — detailed methodology, subgroup analyses, and covariate adjustments could not be verified.","value_numeric":null},{"paper_doi":"10.1001/jama.2026.8492","tag_type":"warning","value":"Median follow-up age of 74 years suggests the cohort was elderly at analysis; findings may not generalize to younger adults with prediabetes.","value_numeric":null},{"paper_doi":"10.1001/jama.2026.8492","tag_type":"warning","value":"The study design is observational post-RCT, so treatment effects after DPPOS enrollment (unmasking, lifestyle classes offered to all groups) may dilute or confound original randomization effects.","value_numeric":null}],"summaries":{"what_studied":"This observational follow-up of the Diabetes Prevention Program (DPP) and DPP Outcomes Study (DPPOS) examined whether intensive lifestyle intervention or metformin (vs. placebo) reduced long-term multimorbidity (≥2 of 15 chronic conditions) in 1,173 adults with prediabetes, followed from 1996 to 2021 using CMS claims data.","key_result":"Lifestyle intervention was associated with a 21% lower risk of multimorbidity vs. placebo (HR 0.79; 95% CI 0.68–0.93); for the costliest condition dyads, the reduction was 43% (HR 0.57; 95% CI 0.38–0.85). Metformin showed no significant benefit vs. placebo (HR 0.91; 95% CI 0.78–1.07). Overall, 85% of participants developed ≥2 conditions (82% lifestyle, 85% metformin, 87% placebo).","limitations":"- Only 1,173 of 3,234 original DPP participants had CMS data available (consent-based subset), raising selection bias concerns.\n- Observational follow-up design after the RCT phase limits causal inference, especially given unmasking and protocol changes in DPPOS.\n- Multimorbidity defined using administrative claims (CMS Chronic Condition Data Warehouse), which may miss or misclassify conditions.","practice_takeaway":"Intensive lifestyle intervention in adults with prediabetes is associated with meaningful, long-term reductions in multimorbidity burden — effects that persist decades later. Clinicians should prioritize structured lifestyle programs for prediabetic patients as a strategy to delay not just diabetes, but multiple chronic diseases."}},{"doi":"10.1093/cid/ciag335","pmid":"42240559","title":"Metformin on the Presence of COVID-19 Symptoms 6 Months after Infection: The ACTIV-6 Randomized Clinical Trial","journal_title":"Clinical Infectious Diseases","journal_issn":"1058-4838","published_at":"2026-06-04T00:00:00.000Z","url":"https://doi.org/10.1093/cid/ciag335","source_score":14,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-06-11T13:43:04.693Z","updated_at":"2026-06-11T13:43:04.693Z","tags":[{"paper_doi":"10.1093/cid/ciag335","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1093/cid/ciag335","tag_type":"category","value":"Immunology","value_numeric":null},{"paper_doi":"10.1093/cid/ciag335","tag_type":"category","value":"Infectious Diseases","value_numeric":null},{"paper_doi":"10.1093/cid/ciag335","tag_type":"condition","value":"COVID-19","value_numeric":null},{"paper_doi":"10.1093/cid/ciag335","tag_type":"condition","value":"Long COVID","value_numeric":null},{"paper_doi":"10.1093/cid/ciag335","tag_type":"condition","value":"Post-Acute Sequelae of SARS-CoV-2","value_numeric":null},{"paper_doi":"10.1093/cid/ciag335","tag_type":"generic","value":"metformin","value_numeric":null},{"paper_doi":"10.1093/cid/ciag335","tag_type":"impact_flag","value":"confirms_prior","value_numeric":null},{"paper_doi":"10.1093/cid/ciag335","tag_type":"level_of_evidence","value":"1","value_numeric":null},{"paper_doi":"10.1093/cid/ciag335","tag_type":"modality","value":"Biguanide","value_numeric":null},{"paper_doi":"10.1093/cid/ciag335","tag_type":"sample_size","value":"n=2983","value_numeric":2983},{"paper_doi":"10.1093/cid/ciag335","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1093/cid/ciag335","tag_type":"study_design","value":"Randomized Controlled Trial","value_numeric":null},{"paper_doi":"10.1093/cid/ciag335","tag_type":"warning","value":"DOI suffix 'ciag335' appears atypical for Clinical Infectious Diseases; publication date of 2026-06-04 is noted as future relative to most training data but consistent with today's stated date.","value_numeric":null},{"paper_doi":"10.1093/cid/ciag335","tag_type":"warning","value":"The enrolled population had a very low PASC rate (2.6%), likely reflecting high prior immunity (83%), which may have substantially reduced the trial's ability to detect a treatment effect.","value_numeric":null},{"paper_doi":"10.1093/cid/ciag335","tag_type":"warning","value":"The primary PASC outcome (self-reported symptoms on day 180) did not meet the pre-specified PPE threshold of 0.975, but the secondary clinician-diagnosed long COVID outcome did (PPE 0.96) — clinical significance of this distinction should be interpreted cautiously given multiple outcomes.","value_numeric":null},{"paper_doi":"10.1093/cid/ciag335","tag_type":"warning","value":"The study used a Bayesian adaptive platform design; the PPE framework and thresholds differ from traditional frequentist p-value interpretation — clinicians should note this when comparing results to other RCTs.","value_numeric":null}],"summaries":{"what_studied":"A quadruple-blinded, placebo-controlled RCT (ACTIV-6) evaluated 14 days of metformin vs. placebo in 2,983 outpatient adults ≥30 years with confirmed mild-to-moderate SARS-CoV-2 infection (≥2 symptoms, within 7 days of onset) across 90 sites, to assess prevention of post-acute sequelae (PASC) or death at day 180.","key_result":"Metformin did not meet the pre-specified efficacy threshold (PPE ≥0.975) for preventing self-reported COVID-19 symptoms at day 180 (2.6% overall; absolute risk reduction 0.8 pp, 95% CrI −2.2 to 0.6; PPE 0.83; RR 0.79). However, clinician-diagnosed long COVID was reduced by 0.7 pp (RR 0.495, 95% CrI 0.155–0.995; PPE 0.96), meeting the efficacy threshold for that secondary outcome.","limitations":"- Low overall PASC rate (2.6% at day 180) in a largely immune population (83% with prior infection or ≥2 vaccines), limiting statistical power to detect a difference.\n- Primary outcome relied on self-report of COVID-attributed symptoms, which may be imprecise.\n- Results may not generalize to higher-risk or immunologically naïve populations.","practice_takeaway":"For low-risk, largely immune outpatients with mild-to-moderate COVID-19, a 14-day course of metformin does not clearly prevent long COVID symptoms by self-report, but does appear to reduce clinician-diagnosed long COVID. Clinicians treating higher-risk patients may consider this signal, while awaiting further evidence."}},{"doi":"10.1001/jamaophthalmol.2026.1799","pmid":"42240995","title":"Reported Metformin Use and Age-Related Macular Degeneration in Patients With Diabetes","journal_title":"JAMA Ophthalmology","journal_issn":"2168-6165","published_at":"2026-06-04T00:00:00.000Z","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13237703/","source_score":11,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-06-10T14:23:45.789Z","updated_at":"2026-06-10T14:23:45.789Z","tags":[{"paper_doi":"10.1001/jamaophthalmol.2026.1799","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1001/jamaophthalmol.2026.1799","tag_type":"category","value":"Ophthalmology","value_numeric":null},{"paper_doi":"10.1001/jamaophthalmol.2026.1799","tag_type":"condition","value":"Age-Related Macular Degeneration","value_numeric":null},{"paper_doi":"10.1001/jamaophthalmol.2026.1799","tag_type":"condition","value":"Diabetes Mellitus","value_numeric":null},{"paper_doi":"10.1001/jamaophthalmol.2026.1799","tag_type":"generic","value":"metformin","value_numeric":null},{"paper_doi":"10.1001/jamaophthalmol.2026.1799","tag_type":"level_of_evidence","value":"3","value_numeric":null},{"paper_doi":"10.1001/jamaophthalmol.2026.1799","tag_type":"modality","value":"Biguanide","value_numeric":null},{"paper_doi":"10.1001/jamaophthalmol.2026.1799","tag_type":"study_design","value":"Cohort Study","value_numeric":null},{"paper_doi":"10.1001/jamaophthalmol.2026.1799","tag_type":"warning","value":"Full text was not retrievable — only the abstract was available. Key results, sample size, effect sizes, follow-up duration, and confounders are unknown and could not be extracted.","value_numeric":null},{"paper_doi":"10.1001/jamaophthalmol.2026.1799","tag_type":"warning","value":"Study design (cohort) limits causal inference; confounding by indication (metformin users may differ systematically from nonusers) is a likely concern but cannot be assessed without the full text.","value_numeric":null},{"paper_doi":"10.1001/jamaophthalmol.2026.1799","tag_type":"warning","value":"The study population is described as multiethnic Asian; findings may not generalize to other ethnic groups.","value_numeric":null}],"summaries":{"what_studied":"This cohort study evaluated whether metformin use is associated with a lower incidence of age-related macular degeneration (AMD) in multiethnic Asian patients with diabetes, comparing users vs. nonusers of metformin.","limitations":"Full text was inaccessible; only the abstract was available, so specific outcomes, effect sizes, sample size, and methodological details cannot be confirmed."}},{"doi":"10.2147/copd.s609302","pmid":"42261400","title":"Type 2 Diabetes Mellitus and Chronic Obstructive Pulmonary Disease – from Pathophysiology to Effective Management Overview","journal_title":"International Journal of Chronic Obstructive Pulmonary Disease","journal_issn":"1178-2005","published_at":"2026-06-01T00:00:00.000Z","url":"https://doi.org/10.2147/copd.s609302","source_score":4,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-06-10T14:24:39.954Z","updated_at":"2026-06-10T14:24:39.954Z","tags":[{"paper_doi":"10.2147/copd.s609302","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.2147/copd.s609302","tag_type":"brand","value":"Dupixent","value_numeric":null},{"paper_doi":"10.2147/copd.s609302","tag_type":"category","value":"Respiratory System","value_numeric":null},{"paper_doi":"10.2147/copd.s609302","tag_type":"condition","value":"Chronic Obstructive Pulmonary Disease","value_numeric":null},{"paper_doi":"10.2147/copd.s609302","tag_type":"condition","value":"Heart Failure","value_numeric":null},{"paper_doi":"10.2147/copd.s609302","tag_type":"condition","value":"Type 2 Diabetes Mellitus","value_numeric":null},{"paper_doi":"10.2147/copd.s609302","tag_type":"generic","value":"dupilumab","value_numeric":null},{"paper_doi":"10.2147/copd.s609302","tag_type":"generic","value":"empagliflozin","value_numeric":null},{"paper_doi":"10.2147/copd.s609302","tag_type":"generic","value":"ensifentrine","value_numeric":null},{"paper_doi":"10.2147/copd.s609302","tag_type":"generic","value":"metformin","value_numeric":null},{"paper_doi":"10.2147/copd.s609302","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.2147/copd.s609302","tag_type":"level_of_evidence","value":"5","value_numeric":null},{"paper_doi":"10.2147/copd.s609302","tag_type":"modality","value":"Biguanide","value_numeric":null},{"paper_doi":"10.2147/copd.s609302","tag_type":"modality","value":"GLP-1 Receptor Agonist","value_numeric":null},{"paper_doi":"10.2147/copd.s609302","tag_type":"modality","value":"Inhaled Corticosteroid","value_numeric":null},{"paper_doi":"10.2147/copd.s609302","tag_type":"modality","value":"Long-Acting Beta-2 Agonist","value_numeric":null},{"paper_doi":"10.2147/copd.s609302","tag_type":"modality","value":"Long-Acting Muscarinic Antagonist","value_numeric":null},{"paper_doi":"10.2147/copd.s609302","tag_type":"modality","value":"SGLT2 Inhibitor","value_numeric":null},{"paper_doi":"10.2147/copd.s609302","tag_type":"modality","value":"Statin","value_numeric":null},{"paper_doi":"10.2147/copd.s609302","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.2147/copd.s609302","tag_type":"study_design","value":"Narrative Review","value_numeric":null},{"paper_doi":"10.2147/copd.s609302","tag_type":"warning","value":"No sample size tag was applied because this is a narrative review aggregating multiple external studies, not a single primary dataset.","value_numeric":null},{"paper_doi":"10.2147/copd.s609302","tag_type":"warning","value":"The EMPA-REG OUTCOME trial cited for empagliflozin cardiovascular benefits predates this review; the paper frames it as relevant to COPD comorbidity, but this is an extrapolation rather than a pre-specified COPD subgroup analysis.","value_numeric":null},{"paper_doi":"10.2147/copd.s609302","tag_type":"warning","value":"The impact_flag 'practice_changing' reflects the review's strong clinical guidance on SGLT2i/GLP-1 RA use in comorbid patients, but underlying evidence comes from trials not specifically designed for this comorbidity—clinicians should interpret with caution.","value_numeric":null},{"paper_doi":"10.2147/copd.s609302","tag_type":"warning","value":"The 'practice_changing' flag was used because the review integrates two major 2026 guideline updates (GOLD and ADA) with novel genetic biomarker data, representing a meaningful synthesis for clinical workflow—but the underlying evidence base varies in quality.","value_numeric":null}],"summaries":{"what_studied":"This narrative review synthesizes pathophysiological, genetic, epigenetic, and therapeutic interactions between T2DM and COPD in comorbid patients, evaluated against GOLD 2026 and ADA 2026 guidelines, drawing on PubMed/MEDLINE, Scopus, and Web of Science literature from the past 10 years.","key_result":"~30% of COPD patients also have T2DM; comorbid patients have a fourfold higher risk of heart failure (Swedish registry data) and significantly higher cardiovascular and respiratory mortality (cohort of 120,000 T2DM patients, ~12% with COPD). SGLT2i reduced severe COPD-related outcomes (hospitalizations, need for non-invasive ventilation); HbA1c <7% was associated with fewer COPD exacerbations. A bioinformatics study identified 186 shared genes (including CADPS, EDNRB, THBS4, TMEM27) as potential biomarkers.","limitations":"- Narrative (not systematic) review design limits reproducibility and introduces selection bias.\n- No validated epigenetic markers definitively shared between COPD and T2DM exist; current epigenetic overlap is associative, not causal.\n- Key cited trials (e.g., EMPA-REG OUTCOME) were not specifically designed for COPD–T2DM comorbidity; pulmonary subgroup data are indirect.","practice_takeaway":"Screen COPD patients regularly for T2DM (and vice versa), prioritizing agents with pleiotropic benefits—SGLT2i and GLP-1 RAs—given their cardiovascular risk reduction and potential to lower severe COPD events. Avoid sulfonylureas when possible in comorbid patients, and closely monitor glucose when systemic corticosteroids are used for COPD exacerbations."}},{"doi":"10.1111/jdi.70343","pmid":"42170888","title":"Risk of urinary tract infection with\n SGLT2\n inhibitor initiation in patients with immune‐mediated inflammatory diseases and type 2 diabetes: A target trial emulation using a Japanese hospital‐based claims database","journal_title":"Journal of Diabetes Investigation","journal_issn":"2040-1116","published_at":"2026-05-22T00:00:00.000Z","url":"https://doi.org/10.1111/jdi.70343","source_score":8,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-06-01T13:39:37.287Z","updated_at":"2026-06-01T13:39:37.287Z","tags":[{"paper_doi":"10.1111/jdi.70343","tag_type":"age_group","value":"older_adult","value_numeric":null},{"paper_doi":"10.1111/jdi.70343","tag_type":"category","value":"Endocrinology & Metabolism","value_numeric":null},{"paper_doi":"10.1111/jdi.70343","tag_type":"condition","value":"Genital Infection","value_numeric":null},{"paper_doi":"10.1111/jdi.70343","tag_type":"condition","value":"Immune-Mediated Inflammatory Diseases","value_numeric":null},{"paper_doi":"10.1111/jdi.70343","tag_type":"condition","value":"Type 2 Diabetes","value_numeric":null},{"paper_doi":"10.1111/jdi.70343","tag_type":"condition","value":"Urinary Tract Infection","value_numeric":null},{"paper_doi":"10.1111/jdi.70343","tag_type":"generic","value":"metformin","value_numeric":null},{"paper_doi":"10.1111/jdi.70343","tag_type":"impact_flag","value":"confirms_prior","value_numeric":null},{"paper_doi":"10.1111/jdi.70343","tag_type":"level_of_evidence","value":"3","value_numeric":null},{"paper_doi":"10.1111/jdi.70343","tag_type":"modality","value":"Biguanide","value_numeric":null},{"paper_doi":"10.1111/jdi.70343","tag_type":"modality","value":"SGLT2 Inhibitor","value_numeric":null},{"paper_doi":"10.1111/jdi.70343","tag_type":"sample_size","value":"n=3344","value_numeric":3344},{"paper_doi":"10.1111/jdi.70343","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1111/jdi.70343","tag_type":"study_design","value":"Target Trial Emulation (Active-Comparator New-User Design)","value_numeric":null},{"paper_doi":"10.1111/jdi.70343","tag_type":"warning","value":"Level of evidence assigned as 3 (observational/emulation design); not a randomized trial.","value_numeric":null},{"paper_doi":"10.1111/jdi.70343","tag_type":"warning","value":"Mean age of 71.8 years skews older than typical IMID populations — caution extrapolating to younger patients.","value_numeric":null},{"paper_doi":"10.1111/jdi.70343","tag_type":"warning","value":"No specific SGLT2 inhibitor agents are named; findings may not apply equally to all drugs in the class.","value_numeric":null}],"summaries":{"what_studied":"Target trial emulation comparing SGLT2 inhibitor initiation vs. metformin initiation on risk of UTI, upper UTI, and genital infection in adults with immune-mediated inflammatory diseases (IMIDs) and type 2 diabetes, using a Japanese hospital-based claims database (2014–2024).","key_result":"Among 1,845 SGLT2i and 1,499 metformin initiators (mean age 71.8 years; 55.4% female), SGLT2i initiation was **not** associated with increased UTI risk (HR 1.14, 95% CI 0.84–1.55) or upper UTI risk (HR 1.28, 95% CI 0.71–2.31). However, genital infection risk was significantly higher with SGLT2i (HR 2.31, 95% CI 1.16–4.63). No effect modification was seen across immunosuppressive therapy strata, including glucocorticoid dose.","limitations":"- Single-country (Japanese) hospital-based claims data may limit generalizability to other populations.\n- Residual confounding cannot be excluded in an observational emulation design.\n- Relatively small sample size may have limited power to detect modest UTI risk differences.","practice_takeaway":"Clinicians can likely use SGLT2 inhibitors in patients with IMIDs and type 2 diabetes without excess UTI concern, even in those on immunosuppressants — but should counsel patients about a roughly 2-fold higher genital infection risk compared with metformin."}},{"doi":"10.1152/ajpendo.00012.2026","pmid":"42139118","title":"Influence of metformin on exercise metabolism and capacity: a systematic review and meta-analysis","journal_title":"American Journal of Physiology-Endocrinology and Metabolism","journal_issn":"0193-1849","published_at":"2026-05-15T00:00:00.000Z","url":"https://doi.org/10.1152/ajpendo.00012.2026","source_score":9,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-06-22T13:24:13.713Z","updated_at":"2026-06-22T13:24:13.713Z","tags":[{"paper_doi":"10.1152/ajpendo.00012.2026","tag_type":"age_group","value":"mixed","value_numeric":null},{"paper_doi":"10.1152/ajpendo.00012.2026","tag_type":"category","value":"Endocrinology & Metabolism","value_numeric":null},{"paper_doi":"10.1152/ajpendo.00012.2026","tag_type":"condition","value":"Prediabetes","value_numeric":null},{"paper_doi":"10.1152/ajpendo.00012.2026","tag_type":"condition","value":"Type 2 Diabetes Mellitus","value_numeric":null},{"paper_doi":"10.1152/ajpendo.00012.2026","tag_type":"generic","value":"metformin","value_numeric":null},{"paper_doi":"10.1152/ajpendo.00012.2026","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1152/ajpendo.00012.2026","tag_type":"level_of_evidence","value":"1","value_numeric":null},{"paper_doi":"10.1152/ajpendo.00012.2026","tag_type":"modality","value":"Biguanide","value_numeric":null},{"paper_doi":"10.1152/ajpendo.00012.2026","tag_type":"sample_size","value":"n=325","value_numeric":325},{"paper_doi":"10.1152/ajpendo.00012.2026","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1152/ajpendo.00012.2026","tag_type":"study_design","value":"Systematic Review and Meta-Analysis","value_numeric":null},{"paper_doi":"10.1152/ajpendo.00012.2026","tag_type":"warning","value":"Sex imbalance across study types (acute studies mostly young males; habitual studies mostly older females) may confound subgroup interpretations.","value_numeric":null},{"paper_doi":"10.1152/ajpendo.00012.2026","tag_type":"warning","value":"The meta-analysis pooled acute (single-dose) and nonacute (multi-dose) studies separately, but the overall sample is small and heterogeneous; SMD for lactate should be interpreted with caution.","value_numeric":null},{"paper_doi":"10.1152/ajpendo.00012.2026","tag_type":"warning","value":"The 'practice_changing' flag reflects a first-of-its-kind synthesis with direct clinical relevance, but the evidence base is limited by small, varied studies — further large RCTs are needed.","value_numeric":null}],"summaries":{"what_studied":"This systematic review and meta-analysis evaluated the effect of metformin (doses 500–3,000 mg/day, single dose to 12 weeks) on exercise metabolism (lactate, glucose, insulin, free fatty acids) and exercise capacity across 21 studies involving 325 adults with prediabetes or type 2 diabetes.","key_result":"Metformin was associated with significantly higher lactate concentrations during exercise (SMD = 0.98, 95% CI: 0.36–1.60, P = 0.002); effects on glucose, insulin, and exercise capacity were also evaluated, with the direction of interactions varying by dose, duration, and participant characteristics.","limitations":"- Small total sample (n = 325), with acute studies skewed toward young healthy males and habitual studies toward older females, limiting generalizability.\n- Heterogeneity in metformin dose, duration, and study design makes pooled estimates difficult to interpret cleanly.\n- Risk of bias was assessed but study quality varied across the 21 included trials.","practice_takeaway":"Clinicians coprescribing metformin and exercise should be aware that metformin may increase lactate accumulation during exercise, which could affect perceived exertion and exercise tolerance. Dose, duration, and patient demographics likely modulate this effect and should be considered when designing combined treatment plans."}},{"doi":"10.1001/jamanetworkopen.2026.12133","pmid":"42113513","title":"Survival and Recurrence With GLP-1 Receptor Agonists in Breast Cancer","journal_title":"JAMA Network Open","journal_issn":"2574-3805","published_at":"2026-05-11T00:00:00.000Z","url":"https://doi.org/10.1001/jamanetworkopen.2026.12133","source_score":175,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-05-16T13:22:23.962Z","updated_at":"2026-05-16T13:22:23.962Z","tags":[{"paper_doi":"10.1001/jamanetworkopen.2026.12133","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1001/jamanetworkopen.2026.12133","tag_type":"age_group","value":"older_adult","value_numeric":null},{"paper_doi":"10.1001/jamanetworkopen.2026.12133","tag_type":"category","value":"Medicine, General & Internal","value_numeric":null},{"paper_doi":"10.1001/jamanetworkopen.2026.12133","tag_type":"condition","value":"Breast Cancer","value_numeric":null},{"paper_doi":"10.1001/jamanetworkopen.2026.12133","tag_type":"condition","value":"Obesity","value_numeric":null},{"paper_doi":"10.1001/jamanetworkopen.2026.12133","tag_type":"condition","value":"Type 2 Diabetes","value_numeric":null},{"paper_doi":"10.1001/jamanetworkopen.2026.12133","tag_type":"generic","value":"metformin","value_numeric":null},{"paper_doi":"10.1001/jamanetworkopen.2026.12133","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1001/jamanetworkopen.2026.12133","tag_type":"level_of_evidence","value":"3","value_numeric":null},{"paper_doi":"10.1001/jamanetworkopen.2026.12133","tag_type":"modality","value":"Biguanide","value_numeric":null},{"paper_doi":"10.1001/jamanetworkopen.2026.12133","tag_type":"modality","value":"GLP-1 Receptor Agonist","value_numeric":null},{"paper_doi":"10.1001/jamanetworkopen.2026.12133","tag_type":"modality","value":"Insulin","value_numeric":null},{"paper_doi":"10.1001/jamanetworkopen.2026.12133","tag_type":"modality","value":"SGLT-2 Inhibitor","value_numeric":null},{"paper_doi":"10.1001/jamanetworkopen.2026.12133","tag_type":"sample_size","value":"n=841831","value_numeric":841831},{"paper_doi":"10.1001/jamanetworkopen.2026.12133","tag_type":"sex","value":"female","value_numeric":null},{"paper_doi":"10.1001/jamanetworkopen.2026.12133","tag_type":"study_design","value":"Retrospective Cohort Study","value_numeric":null},{"paper_doi":"10.1001/jamanetworkopen.2026.12133","tag_type":"warning","value":"GLP-1 RA exposure was defined by ≥2 prescriptions — actual drug use, adherence, and specific agents (e.g., semaglutide vs liraglutide) are not differentiated.","value_numeric":null},{"paper_doi":"10.1001/jamanetworkopen.2026.12133","tag_type":"warning","value":"Propensity-matched cohort sizes (1,610–4,052) are small relative to the full eligible population of 841,831, suggesting a highly selected subgroup.","value_numeric":null},{"paper_doi":"10.1001/jamanetworkopen.2026.12133","tag_type":"warning","value":"Study design is retrospective and observational; causal inference is not supported. Authors themselves call for RCTs.","value_numeric":null},{"paper_doi":"10.1001/jamanetworkopen.2026.12133","tag_type":"warning","value":"The HR of 0.09 for all-cause mortality (GLP-1 RA vs insulin/metformin in T2D) is unusually large and may reflect residual channeling bias or unmeasured confounders rather than a true treatment effect — interpret with caution.","value_numeric":null}],"summaries":{"what_studied":"This retrospective cohort study evaluated the association between GLP-1 receptor agonist (GLP-1 RA) use and 10-year all-cause mortality and recurrence-free survival (RFS) in women ≥18 years with breast cancer (BC) and comorbid obesity or type 2 diabetes (T2D), using propensity score–matched data from 68 US health care organizations (diagnoses April 2006–April 2023).","key_result":"Among patients with obesity, GLP-1 RAs were associated with significantly lower all-cause mortality (HR 0.35; 95% CI 0.21–0.58) and better RFS (HR 0.44; 95% CI 0.30–0.64) vs nonuse. Among patients with T2D, GLP-1 RAs vs insulin or metformin showed even larger reductions in mortality (HR 0.09; 95% CI 0.06–0.15) and improved RFS (HR 0.33; 95% CI 0.21–0.50); no significant difference was found vs SGLT-2 inhibitors.","limitations":"- Retrospective design with residual confounding despite propensity score matching (e.g., unmeasured lifestyle factors, cancer stage details, treatment adherence).\n- GLP-1 RA exposure defined by ≥2 prescriptions, without verification of actual medication use or dose.\n- The extraordinarily low HR of 0.09 for mortality (GLP-1 RA vs insulin/metformin) warrants caution, as it may reflect channeling bias or unmeasured confounders.","practice_takeaway":"GLP-1 RAs may offer survival and recurrence benefits for breast cancer patients with obesity or T2D beyond glycemic and weight control alone — but these are observational findings; clinicians should await RCT data before changing oncologic management based on this evidence."}},{"doi":"10.1210/clinem/dgag198","pmid":"42105324","title":"Approach to the diagnosis and treatment of polycystic ovarian syndrome in adolescent patients","journal_title":"The Journal of Clinical Endocrinology & Metabolism","journal_issn":"0021-972X","published_at":"2026-05-09T00:00:00.000Z","url":"https://doi.org/10.1210/clinem/dgag198","source_score":40,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-05-18T13:25:42.648Z","updated_at":"2026-05-18T13:25:42.648Z","tags":[{"paper_doi":"10.1210/clinem/dgag198","tag_type":"age_group","value":"adolescent","value_numeric":null},{"paper_doi":"10.1210/clinem/dgag198","tag_type":"category","value":"Endocrinology & Metabolism","value_numeric":null},{"paper_doi":"10.1210/clinem/dgag198","tag_type":"condition","value":"Polycystic Ovary Syndrome","value_numeric":null},{"paper_doi":"10.1210/clinem/dgag198","tag_type":"generic","value":"metformin","value_numeric":null},{"paper_doi":"10.1210/clinem/dgag198","tag_type":"impact_flag","value":"confirms_prior","value_numeric":null},{"paper_doi":"10.1210/clinem/dgag198","tag_type":"level_of_evidence","value":"5","value_numeric":null},{"paper_doi":"10.1210/clinem/dgag198","tag_type":"modality","value":"Biguanide","value_numeric":null},{"paper_doi":"10.1210/clinem/dgag198","tag_type":"modality","value":"Combined Oral Contraceptive","value_numeric":null},{"paper_doi":"10.1210/clinem/dgag198","tag_type":"sex","value":"female","value_numeric":null},{"paper_doi":"10.1210/clinem/dgag198","tag_type":"study_design","value":"Narrative Review","value_numeric":null},{"paper_doi":"10.1210/clinem/dgag198","tag_type":"warning","value":"No primary trial data or systematic search reported — this is expert opinion/narrative review; level of evidence is limited.","value_numeric":null},{"paper_doi":"10.1210/clinem/dgag198","tag_type":"warning","value":"No sample size applies as this is a review article, not an original study.","value_numeric":null},{"paper_doi":"10.1210/clinem/dgag198","tag_type":"warning","value":"Treatment recommendations for adolescents are largely extrapolated from adult PCOS data; adolescent-specific RCT evidence is sparse.","value_numeric":null}],"summaries":{"what_studied":"This review examines the diagnosis and management of polycystic ovary syndrome (PCOS) specifically in adolescents, addressing the challenges of distinguishing PCOS from normal pubertal development and outlining evidence-based treatment strategies.","key_result":"A definitive PCOS diagnosis in adolescents requires both persistent hyperandrogenism and menstrual irregularity; those with only one feature should be followed longitudinally. Combined oral contraceptives (COCs) are first-line for menstrual irregularity and hyperandrogenism; metformin is first-line for metabolic comorbidities.","limitations":"This is a narrative review without systematic search methodology or pooled data, so recommendations reflect expert synthesis rather than primary trial evidence. Adolescent-specific randomized controlled trial data are limited, and much guidance is extrapolated from adult populations.","practice_takeaway":"Do not diagnose PCOS in adolescents on a single feature alone — require both persistent hyperandrogenism and menstrual irregularity, and follow borderline cases longitudinally. Pair COCs for reproductive symptoms with metformin for metabolic risk, and address mental health as part of routine care."}},{"doi":"10.1038/s42255-026-01532-w","pmid":"42103930","title":"Metformin lowers blood glucose by targeting intestinal mitochondrial complex I","journal_title":"Nature Metabolism","journal_issn":"2522-5812","published_at":"2026-05-09T00:00:00.000Z","url":"https://doi.org/10.1038/s42255-026-01532-w","source_score":18,"is_retracted":false,"is_open_access":false,"raw_metadata":{"ooir":{"day":"2026-05-11","doi":"10.1038/s42255-026-01532-w","days":"7","issn":"2522-5812","rank":"6","field":"Clinical Medicine","score":"18","category":"Endocrinology & Metabolism","categories":["Endocrinology & Metabolism"],"_categories":["Endocrinology & Metabolism"]},"pubmed":{"doi":"10.1038/s42255-026-01532-w","title":"Metformin lowers blood glucose by targeting intestinal mitochondrial complex I.","journal":"Nature metabolism","methods":"","results":"","abstract":"","keywords":[],"pubmed_id":"42103930","conclusions":"","publication_date":"2026-05-09T00:00:00"},"crossref":{"DOI":"10.1038/s42255-026-01532-w","URL":"https://doi.org/10.1038/s42255-026-01532-w","ISSN":["2522-5812"],"link":[{"URL":"https://www.nature.com/articles/s42255-026-01532-w.pdf","content-type":"application/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https://www.nature.com/articles/s42255-026-01532-w","content-type":"text/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https://www.nature.com/articles/s42255-026-01532-w.pdf","content-type":"application/pdf","content-version":"vor","intended-application":"similarity-checking"}],"page":null,"type":"journal-article","issue":null,"score":1,"title":["Metformin lowers blood glucose by targeting intestinal mitochondrial complex I"],"author":null,"issued":{"date-parts":[[2026,5,8]]},"member":"297","prefix":"10.1038","source":"Crossref","volume":null,"created":{"date-time":"2026-05-08T10:02:21Z","timestamp":1778234541000,"date-parts":[[2026,5,8]]},"indexed":{"date-time":"2026-05-08T10:12:24Z","timestamp":1778235144457,"date-parts":[[2026,5,8]]},"license":[{"URL":"https://www.springernature.com/gp/researchers/text-and-data-mining","start":{"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000,"date-parts":[[2026,5,8]]},"delay-in-days":0,"content-version":"tdm"},{"URL":"https://www.springernature.com/gp/researchers/text-and-data-mining","start":{"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000,"date-parts":[[2026,5,8]]},"delay-in-days":0,"content-version":"vor"}],"subject":[],"abstract":null,"language":"en","relation":{},"resource":{"primary":{"URL":"https://www.nature.com/articles/s42255-026-01532-w"}},"subtitle":[],"assertion":[{"name":"first_online","group":{"name":"ArticleHistory","label":"Article History"},"label":"First Online","order":1,"value":"8 May 2026"}],"deposited":{"date-time":"2026-05-08T10:02:21Z","timestamp":1778234541000,"date-parts":[[2026,5,8]]},"issn-type":[{"type":"electronic","value":"2522-5812"}],"published":{"date-parts":[[2026,5,8]]},"publisher":"Springer Science and Business Media LLC","reference":[{"DOI":"10.2337/diabetes.49.12.2063","key":"1532_CR1","year":"2000","issue":null,"author":"RS Hundal","volume":"49","first-page":"2063","unstructured":"Hundal, R. 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The full article (Sebo et al., Nat. Metab. 2026, DOI: 10.1038/s42255-026-01530-y) should be consulted for complete evidence appraisal.","value_numeric":null}],"summaries":{"what_studied":"This research briefing summarizes a mechanistic study examining how metformin lowers blood glucose, using metabolomic analysis of plasma from metformin-treated humans combined with mouse model experiments to identify the drug's primary site of action.","key_result":"Metformin selectively inhibits mitochondrial complex I in intestinal epithelium — not the liver — driving enhanced intestinal glucose uptake, improved postprandial glycemic control, and increased production of GDF15 and N-lactoyl-phenylalanine.","limitations":"This is a research briefing (preview) of the full article; full methods, sample sizes, and statistical details are not available here. The mechanistic evidence relies partly on mouse models, so direct human translation requires further confirmation.","practice_takeaway":"This finding reframes metformin's primary glucose-lowering action as intestinal rather than hepatic, which may explain why oral dosing outperforms equivalent systemic exposure and could guide development of gut-targeted formulations."}},{"doi":"10.1038/s42255-026-01530-y","pmid":"42103929","title":"Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control","journal_title":"Nature Metabolism","journal_issn":"2522-5812","published_at":"2026-05-09T00:00:00.000Z","url":"https://doi.org/10.1038/s42255-026-01530-y","source_score":203,"is_retracted":false,"is_open_access":true,"raw_metadata":{"ooir":{"day":"2026-05-11","doi":"10.1038/s42255-026-01530-y","days":"7","issn":"2522-5812","rank":"2","field":"Clinical Medicine","score":"203","category":"Endocrinology & Metabolism","categories":["Endocrinology & Metabolism"],"_categories":["Endocrinology & Metabolism"]},"pubmed":{"doi":"10.1038/s42255-026-01530-y","title":"Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control.","journal":"Nature metabolism","methods":"","results":"","abstract":"$30","keywords":[],"pubmed_id":"42103929","conclusions":"","publication_date":"2026-05-09T00:00:00"},"crossref":{"DOI":"10.1038/s42255-026-01530-y","URL":"https://doi.org/10.1038/s42255-026-01530-y","ISSN":["2522-5812"],"link":[{"URL":"https://www.nature.com/articles/s42255-026-01530-y.pdf","content-type":"application/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https://www.nature.com/articles/s42255-026-01530-y","content-type":"text/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https://www.nature.com/articles/s42255-026-01530-y.pdf","content-type":"application/pdf","content-version":"vor","intended-application":"similarity-checking"}],"page":null,"type":"journal-article","issue":null,"score":1,"title":["Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control"],"author":[{"given":"Zachary L.","family":"Sebo","sequence":"first","affiliation":[]},{"given":"Ram P.","family":"Chakrabarty","sequence":"additional","affiliation":[]},{"given":"Rogan A.","family":"Grant","sequence":"additional","affiliation":[]},{"given":"Karis B.","family":"D’Alessandro","sequence":"additional","affiliation":[]},{"given":"Alec R.","family":"Koss","sequence":"additional","affiliation":[]},{"given":"Jenna L. 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Effect sizes, sample sizes, and statistical details could not be verified.","value_numeric":null},{"paper_doi":"10.1038/s42255-026-01530-y","tag_type":"warning","value":"Only male mice were used; sex-based differences in this mechanism are unknown.","value_numeric":null},{"paper_doi":"10.1038/s42255-026-01530-y","tag_type":"warning","value":"Study design label is non-standard — this is a hybrid mechanistic study combining human metabolomics with mouse genetics; level of evidence assigned accordingly.","value_numeric":null},{"paper_doi":"10.1038/s42255-026-01530-y","tag_type":"warning","value":"The 'practice_changing' impact flag is applied cautiously: the mechanistic novelty is high, but clinical translation awaits human interventional validation.","value_numeric":null}],"summaries":{"what_studied":"This study examined how metformin lowers postprandial glucose, focusing on whether intestine-specific mitochondrial complex I inhibition is the key mechanism — using human metabolomic data and a genetics-based mouse model (male mice).","key_result":"Metformin suppresses citrulline synthesis (a small intestine mitochondria-exclusive metabolite) and raises GDF15 by blocking mitochondrial complex I in the gut. This turns the intestine into a glucose sink, converting excess glucose to lactate and lactoyl-phenylalanine. Glucose lowering depends on repeated bolus exposure, not chronic accumulation. Phenformin and berberine share this same intestine-specific mechanism.","limitations":"Study used only male mice, limiting generalizability to females. Full-text data beyond the abstract was not available, restricting assessment of effect sizes and statistical details. Human data is metabolomic (observational), not interventional.","practice_takeaway":"Metformin's glucose-lowering effect is tied to intestinal — not systemic — complex I inhibition, suggesting dosing timing relative to meals matters more than steady-state drug levels. Berberine, a common nutraceutical, appears to work by the same gut-based mechanism, which clinicians should factor in when counseling patients using it alongside metformin or phenformin."}},{"doi":"10.7326/annals-25-03959","pmid":"41911553","title":"The Effect of Fluvoxamine and Metformin for Fatigue in Patients With Long COVID","journal_title":"Annals of Internal Medicine","journal_issn":"0003-4819","published_at":"2026-03-30T00:00:00.000Z","url":"https://doi.org/10.7326/annals-25-03959","source_score":467,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-05-24T13:23:18.573Z","updated_at":"2026-05-24T13:23:18.573Z","tags":[{"paper_doi":"10.7326/annals-25-03959","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.7326/annals-25-03959","tag_type":"category","value":"Medicine, General & Internal","value_numeric":null},{"paper_doi":"10.7326/annals-25-03959","tag_type":"condition","value":"Fatigue","value_numeric":null},{"paper_doi":"10.7326/annals-25-03959","tag_type":"condition","value":"Long COVID","value_numeric":null},{"paper_doi":"10.7326/annals-25-03959","tag_type":"condition","value":"Post-Acute Sequelae of SARS-CoV-2","value_numeric":null},{"paper_doi":"10.7326/annals-25-03959","tag_type":"generic","value":"fluvoxamine","value_numeric":null},{"paper_doi":"10.7326/annals-25-03959","tag_type":"generic","value":"metformin","value_numeric":null},{"paper_doi":"10.7326/annals-25-03959","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.7326/annals-25-03959","tag_type":"level_of_evidence","value":"2","value_numeric":null},{"paper_doi":"10.7326/annals-25-03959","tag_type":"modality","value":"Biguanide","value_numeric":null},{"paper_doi":"10.7326/annals-25-03959","tag_type":"modality","value":"Selective Serotonin Reuptake Enhancer","value_numeric":null},{"paper_doi":"10.7326/annals-25-03959","tag_type":"sample_size","value":"n=399","value_numeric":399},{"paper_doi":"10.7326/annals-25-03959","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.7326/annals-25-03959","tag_type":"study_design","value":"Randomized Controlled Trial","value_numeric":null},{"paper_doi":"10.7326/annals-25-03959","tag_type":"warning","value":"No proprietary brand name for fluvoxamine was specified in the paper; the 'brand' tag has been omitted.","value_numeric":null},{"paper_doi":"10.7326/annals-25-03959","tag_type":"warning","value":"'practice_changing' impact flag applied with caution — this is a single trial; independent replication is warranted before broad adoption.","value_numeric":null},{"paper_doi":"10.7326/annals-25-03959","tag_type":"warning","value":"The adaptive trial design uses Bayesian credible intervals rather than traditional frequentist p-values; clinicians should interpret results accordingly.","value_numeric":null},{"paper_doi":"10.7326/annals-25-03959","tag_type":"warning","value":"The FSS mean differences, while statistically credible, are modest in absolute terms — clinical meaningfulness of a ~0.4–0.6 point change on the FSS scale should be considered in context.","value_numeric":null},{"paper_doi":"10.7326/annals-25-03959","tag_type":"warning","value":"Trial was conducted exclusively in Brazil; generalizability to other populations and healthcare settings is uncertain.","value_numeric":null}],"summaries":{"what_studied":"Randomized, placebo-controlled, adaptive trial in 399 Brazilian adults with fatigue ≥90 days after confirmed SARS-CoV-2 infection, comparing fluvoxamine (100 mg twice daily) vs. metformin (750 mg twice daily) vs. placebo over 60 days of treatment with follow-up to 90 days.","key_result":"Fluvoxamine significantly reduced fatigue (FSS mean difference vs. placebo: −0.43 [95% CrI, −0.80 to −0.07] at day 60; −0.58 [CrI, −0.98 to −0.16] at day 90) and improved quality-of-life scores; metformin showed no significant benefit. Adverse events were least frequent with fluvoxamine (20.0%) vs. metformin (28.8%) vs. placebo (29.7%); grade ≥3 events were rare in all groups.","limitations":"- Follow-up capped at 90 days limits conclusions about long-term durability of effect.\n- Only fatigue was the primary outcome; other common long COVID symptoms (e.g., cognitive dysfunction, dyspnea) were not addressed.\n- Single-country outpatient setting (Brazil) may limit generalizability.","practice_takeaway":"Consider fluvoxamine (100 mg twice daily for 60 days) as a treatment option for long COVID fatigue in adults, given its significant reduction in FSS scores and favorable adverse-event profile compared with placebo. Metformin does not appear to offer benefit for this indication."}},{"doi":"10.1016/j.joca.2025.12.014","pmid":"41421423","title":"Metformin and incident osteoarthritis: Causal insights from a co-twin control study","journal_title":"Osteoarthritis and Cartilage","journal_issn":"1063-4584","published_at":"2025-12-21T00:00:00.000Z","url":"https://doi.org/10.1016/j.joca.2025.12.014","source_score":21,"is_retracted":false,"is_open_access":true,"raw_metadata":{"ooir":{"day":"2025-12-23","doi":"10.1016/j.joca.2025.12.014","days":"30","issn":"1063-4584","rank":"4","field":"Clinical Medicine","score":"21","category":"Rheumatology","categories":["Rheumatology"],"_categories":["Rheumatology"]},"pubmed":{"doi":"10.1016/j.joca.2025.12.014","title":"Metformin and incident osteoarthritis: Causal insights from a co-twin control study.","journal":"Osteoarthritis and cartilage","methods":"","results":"Among treated twins, 68 (5.4%) developed OA over the 11-year follow-up, compared to 79 (6.3%) among the non-treated twins (crude HR [95% confidence interval -CI] = 0.86 [0.62-1.19]). Treated twins had higher BMI. Adjusted HR comparing treated with non-treated was 0.60 (95% CI =0.44-0.82). After 10 years, 6.7% (95% CI=4.8-8.6) of treated twins, compared to 9.7% (95% CI=9.3-10.1) of non-treated twins had incident OA, with difference of -3.1% (95% CI=-5.1- (-1.1)).","abstract":"$32","keywords":["Diabetes","Genetics","Metformin","Osteoarthritis"],"pubmed_id":"41421423","conclusions":"Starting metformin treatment may be associated with a decreased risk of incident diagnosis of OA in specialist care over an 11-year follow-up period. 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At 10 years, cumulative incidence was 6.7% (95% CI 4.8–8.6) in treated vs 9.7% (95% CI 9.3–10.1) in non-treated, an absolute difference of −3.1% (95% CI −5.1 to −1.1).","limitations":"Outcome was restricted to OA diagnosed in specialist care. Treated twins had higher BMI than non-treated. Event counts were small (68 vs 79), which may limit precision.","practice_takeaway":"For adults starting metformin, this twin design found a lower adjusted hazard of specialist-diagnosed OA and a ~3% absolute reduction in 10-year incidence versus non-initiators; consider this observational signal when counseling but not as practice-changing evidence."}},{"doi":"10.1016/j.ajog.2025.06.055","pmid":"40588059","title":"Prepregnancy metformin use associated with lower risk of severe nausea and vomiting of pregnancy and hyperemesis gravidarum","journal_title":"American Journal of Obstetrics and Gynecology","journal_issn":"0002-9378","published_at":"2025-07-01T00:00:00.000Z","url":"https://doi.org/10.1016/j.ajog.2025.06.055","source_score":52,"is_retracted":false,"is_open_access":false,"raw_metadata":{"ooir":{"day":"2025-11-22","doi":"10.1016/j.ajog.2025.06.055","days":"14","issn":"0002-9378","rank":"1","field":"Clinical Medicine","score":"52","category":"Obstetrics & Gynecology","categories":["Obstetrics & Gynecology"],"_categories":["Obstetrics & Gynecology"]},"pubmed":{"doi":"10.1016/j.ajog.2025.06.055","title":"Prepregnancy metformin use associated with lower risk of severe nausea and vomiting of pregnancy and hyperemesis gravidarum.","journal":"American journal of obstetrics and gynecology","methods":"","results":"$33","abstract":"$34","keywords":["GDF15","cannabis","growth and differentiation factor 15","hyperemesis gravidarum","metformin","morning sickness","nausea","pregnancy","prevention","selective serotonin reuptake inhibitors","vomiting"],"pubmed_id":"40588059","conclusions":"Prepregnancy metformin treatment may decrease the risk for severe nausea and vomiting, whereas prepregnancy cannabis use and selective serotonin reuptake inhibitors may increase the risk. 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Pregnancy","value_numeric":null},{"paper_doi":"10.1016/j.ajog.2025.06.055","tag_type":"generic","value":"metformin","value_numeric":null},{"paper_doi":"10.1016/j.ajog.2025.06.055","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1016/j.ajog.2025.06.055","tag_type":"level_of_evidence","value":"5","value_numeric":null},{"paper_doi":"10.1016/j.ajog.2025.06.055","tag_type":"modality","value":"Biguanide","value_numeric":null},{"paper_doi":"10.1016/j.ajog.2025.06.055","tag_type":"modality","value":"Selective Serotonin Reuptake Inhibitor","value_numeric":null},{"paper_doi":"10.1016/j.ajog.2025.06.055","tag_type":"sample_size","value":"n=5414","value_numeric":5414},{"paper_doi":"10.1016/j.ajog.2025.06.055","tag_type":"study_design","value":"Cross-Sectional Study","value_numeric":null},{"paper_doi":"10.1016/j.ajog.2025.06.055","tag_type":"warning","value":"Design classification is ambiguous (self-reported online survey with retrospective recall); treated here as cross-sectional.","value_numeric":null},{"paper_doi":"10.1016/j.ajog.2025.06.055","tag_type":"warning","value":"Findings rely on self-reported prepregnancy exposures and pregnancy symptoms.","value_numeric":null},{"paper_doi":"10.1016/j.ajog.2025.06.055","tag_type":"warning","value":"Summary is based on the provided abstract; full-methods details may add nuances.","value_numeric":null}],"summaries":{"what_studied":"An online questionnaire of 5414 visitors to a hyperemesis gravidarum foundation’s social media (Jan 2023–Sep 2024) assessed daily use of 32 substances in the month before each pregnancy and the severity of nausea/vomiting in the subsequent pregnancy, analyzed with logistic regression.","key_result":"Prepregnancy metformin use was associated with lower risk of hyperemesis gravidarum in the first pregnancy (adjusted relative risk 0.29; 95% CI 0.12–0.71; P=.007) and lower risk of severe nausea/vomiting or hyperemesis in the second pregnancy (adjusted odds ratio 0.18; 0.06–0.59; P=.005) despite an 86% recurrence risk. Tobacco use was associated with lower risk (ARR 0.51; 0.30–0.86; P=.011), whereas selective serotonin reuptake inhibitors were associated with higher risk (first pregnancy ARR 2.41; 1.33–4.38; P=.004; second pregnancy AOR 1.84; 1.12–3.04; P=.016) and cannabis use before the second pregnancy increased risk (AOR 3.48; 1.80–6.75; P<.001).","limitations":"Data were self-reported by visitors to social media sites via an online questionnaire. Multivariable models adjusted for maternal age and tobacco use; race/ethnicity and other drug variables had little influence and were not retained.","practice_takeaway":"Prepregnancy metformin use was linked to a lower risk of severe nausea/vomiting and hyperemesis gravidarum; authors suggest it may be a safe, affordable option for patients with prior hyperemesis, and they call for randomized trials. Prepregnancy SSRIs and cannabis were associated with higher risk, while tobacco use was associated with lower risk."}}],"initialOffset":19,"fetchConfig":{"kind":"tags","tags":[{"tag_type":"modality","value":"Biguanide"}]},"breadcrumbItems":[{"name":"Home","href":"/"},{"name":"Research Hub","href":"/hub"},{"name":"Modalities","href":"/hub/tag/modality"},{"name":"Biguanide"}],"hrefConfig":{"basePath":"/hub/papers","webViewQueryParams":{"hub_ctx":"tag","hub_tag_type":"modality","hub_tag_value":"Biguanide"}}}]]

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