Risk of Anemia and Vitamin B12 Deficiency in Patients with Type 2 Diabetes Mellitus on Metformin Therapy: A Systematic Review and Meta-Analysis
Notice bibliographique
Résumé
Introduction Metformin is a commonly used medication for the treatment of Type 2 Diabetes Mellitus (T2DM). It has also been hypothesized to reduce the absorption of vitamin B12 in the GI tract. Development of B12 deficiency due to metformin-associated reduced absorption would take years to develop, because vitamin B12 has sufficient stores for 3-10 years. As such, the present systematic review and meta-analysis aims to evaluate the effect of metformin on anemia and vitamin B12 deficiency, with outcomes stratified by duration and dosage of metformin exposure. Methods Electronic searches were conducted on MEDLINE, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials from inception to June 2023, supplemented with manual citation search. Two reviewers independently and in duplicate assessed titles, abstracts, and full-text articles, with discrepancies resolved by a third member. Studies considered for inclusion were randomized controlled trials (RCTs) and non-randomized studies (NRS) in any language, evaluating anemia risk in T2DM patients using metformin compared to standard-of-care non-metformin treatments for T2DM . The primary outcome was frequency of anemia. Secondary outcomes included frequency of vitamin B12 deficiency, changes in serum hemoglobin and vitamin B12 levels, folate deficiency, changes in serum folic acid, and homocysteine levels. Results were stratified based on the Metformin Use Index (MUI), which categorizes daily metformin dose in mg x duration in years/1000 into three subgroups: MUI ≤ 5, MUI > 5, and MUI Unspecified (when the primary study did not report or stratify based on metformin dosage and duration). Mantel-Haenszel random effects model was used to synthesize binary and continuous endpoints, providing odds ratios (OR) and mean differences (MD) with 95% confidence intervals (CI). Results 7443 studies were retrieved from electronic databases and 26 studies comprising 6 RCTs, and 20 NRS were included. In total, 17343 patients were included in this systematic review. Overall, the risk of anemia did not significantly differ between the metformin and control group (OR 1.10 [95%CI 0.64, 1.91]). Subgroup analysis also revealed no significant differences between metformin and control in the MUI ≤ 5 group (OR 1.58 [95%CI 0.54, 4.58]) and the MUI > 5 group (OR 1.12 [95%CI 0.48, 2.65]). Metformin was associated with an increased risk of vitamin B12 deficiency compared to control (OR 2.32 [95%CI 1.51, 3.57]). Subgroup analysis demonstrated that the difference was only significant in the MUI > 5 (OR 3.57 [95%CI 2.98, 4.27]) and the MUI Unspecified groups (OR 2.24 [95%CI 1.48, 3.38]), but not in the MUI ≤ 5 group (OR 1.01 [95%CI 0.83, 1.23]). The subgroup differences were significant (p<0.01). Metformin was associated with a decrease in serum vitamin B12 level (MD -71.55 pmol/L [95%CI -89.27, -53.82]), and change in serum hemoglobin could not be pooled given only one primary study. Serum homocysteine was higher in the metformin group (MD 2.45 µmol/L [95%CI 1.48, 3.41]), and there were no significant differences between metformin and control in both incidence of folate deficiency and change in serum folic acid. Conclusion Metformin use does not appear to increase the risk of anemia compared to placebo or other standard-of-care treatments in T2DM. Vitamin B12 deficiency is associated with metformin use, however likely only in those with longer/greater-dose (metformin use index > 5). Monitoring and supplementation of vitamin B12 level are likely beneficial in this population. Our study is limited by heterogenous criteria for anemia and vitamin B12 deficiency across jurisdictions. Further studies on the safety profile of metformin are recommended to include anemia as an outcome and result-stratification based on metformin dose and duration.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,010 | 0,027 |
| Méta-épidémiologie (sens strict) | 0,002 | 0,001 |
| Méta-épidémiologie (sens large) | 0,018 | 0,036 |
| Bibliométrie | 0,007 | 0,009 |
| Études des sciences et des technologies | 0,001 | 0,001 |
| Communication savante | 0,003 | 0,001 |
| Science ouverte | 0,002 | 0,001 |
| Intégrité de la recherche | 0,002 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».