Metformin Intake Research Articles

Effect of metformin therapy on the development of vitamin B12 deficiency in patients with type 2 diabetes mellitus

Introduction. For the past decades, metformin has been the drug of choice for the treatment of patients with type 2 diabetes mellitus (T2DM). However, its long-term use leads to a number of side effects, such as the development of vitamin B12 deficiency (VB12).Aim. Assess the safety of metformin use in real clinical practice in the treatment of patients with type 2 diabetes based on the analysis of the incidence of VB12 deficiency.Materials and methods. Sixty patients with T2DM aged 27 to 65 years were examined in a city polyclinic. The average anamnestic duration of T2DM was 68 [4; 291] months. All patients were on selected hypoglycemic therapy: 19 patients (31.7%) received metformin monotherapy, and 41 patients (68.3%) received metformin as part of combination therapy. The average duration of metformin therapy was 62 [3; 291] months. All patients underwent analysis of the VB12 content in the blood serum depending on the duration of metformin intake. Results. The average VB12 level in the examined patients was 345 [99; 770] pg/ml. Normal VB12 levels were observed in 51 (85%) patients (386 [221; 770] pg/ml), VB12 deficiency (<200 pg/ml) was detected in 9 (15%) patients (146 [99; 195] pg/ml), the differences between VB12 levels were significant (p < 0.05). At the same time, in 37 (61.7%) patients with normal VB12 levels, its values were assessed as borderline (in the range of 200–450 pg/ml), and amounted to 335 [221; 470] pg/ml. VB12 deficiency developed more often in patients taking metformin for more than 1 year (16.7%), borderline VB12 levels were more often found in patients taking metformin for less than a year (58.3%) and more than 5 years (71%). However, the dependence of VB12 levels on the duration of metformin intake was not significant (p > 0.05).Conclusion. Metformin use results in the development of VB12 deficiency in every sixth patient with T2DM, primarily after one year of treatment.

Combination Therapy with Vitamin D and Metformin: A Potential Approach to Mitigate Testicular Dysfunction in Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is a multifactorial disease that cannot be linked to a single pathway, causing the observed heterogeneity among T2DM patients. Despite this level of heterogeneity, T2DM is majorly managed by metformin (MET) monotherapy. However, recent findings have associated long-term metformin intake with progressive oxidative pancreatic β cell damage as the disease progresses. Hence, a significant number of patients treated with MET need an alternate therapy. Hence, identifying drug combinations that can effectively alleviate different diabetes complications would serve as a more promising therapy that can translate into active use. Hence, this study was designed to explore the possible synergistic effect of vitamin D and metformin on T2DM-induced testicular dysfunction. Thirty healthy male Wistar rats (weight: 120-150 g and age: 10 ± 2 weeks) were randomly divided into control, diabetes untreated (HFD+STZ), diabetes + vitamin D (1000 IU/kg), diabetes + metformin (180 mg/kg), and diabetes + vitamin D + metformin. All treatments lasted for 28 days and animals were sacrificed using IP injection of ketamine and xylaxine (40 and 4 mg/kg respectively). Vitamin D improved the ameliorative effect of metformin on T2DM-induced hyperglycemia and lipid dysmetabolism, accompanied by a significant decrease in testicular lactate dehydrogenase and lactate. Also, vitamin D + metformin significantly increased serum luteinizing hormone, follicle-stimulating hormone, testosterone, and testicular 5α reductase activities. Furthermore, vitamin D improved the anti-inflammatory and antioxidant effects of metformin by significantly decreasing T2DM-induced increase in testicular interleukin 1beta, interleukin 6, TNF-α, nitric oxide, and NF-κB and increasing T2DM-induced decrease in interleukin 10, glutathione, superoxide dismutase, catalase, GPx, and Nrf2. Vitamin D enhanced the ameliorative effect of metformin on T2DM-induced testicular dysfunction.

Metformin Treatment Is Not Associated with Altered PD-L1 Expression in Diabetic Patients with Oral Squamous Cell Carcinoma.

Background: The anti-neoplastic activity of metformin is a subject of current debate. Preclinical data have suggested that metformin enhances PD-L1 anti-tumor effects in various cancer entities by decreasing insulin levels and inducing energetic stress. However, its impact on PD-L1 expression remains unclear in a clinical setting. Therefore, we aim to investigate the impact of metformin treatment in type 2 diabetes mellitus (DM) patients on PD-L1 expression in patients with oral squamous cell carcinoma (OSCC). Methods: We performed a retrospective analysis of patients with DM and OSCC treated at our tertiary referral center over a period of 12 years. The tumor proportion score (TPS), immune cell score (IC), and combined positive score (CPS) were used to quantify PD-L1 expression. PD-L1 expression of patients receiving metformin was compared to a control group without metformin prescription. Results: A total of 68 patients diagnosed with OSCC and DM were analyzed, with 24 receiving and 44 not receiving metformin therapy. No statistically significant differences were identified between the metformin and non-metformin groups for any of the scores (TPS: p = 0.818; IC: p = 0.748; CPS: p = 0.387). Conclusions: In contrast to previous studies, we could not find significant differences in PD-L1 expression between patients with and without metformin intake. Further research needs to shed light on the exact mechanism of metformin in different tumor entities. A comprehensive understanding of metformin's role in cancer therapy could provide valuable insights for potential use of metformin as an adjuvant treatment to immune checkpoint therapy.

Factors that Influence Growth Rates of Abdominal Aortic Aneurysms. Analysis of a Mexican Cohort.

Abdominal Aortic Aneurysms (AAA) growth remains a process not fully understood. The objective of this study was to analyze risk factors associated with changes in AAA diameter in a Mexican cohort. An observational study in which we analyzed the entirely of patients in which an AAA was reported in a Computed Tomography (CT) study from 2014 to 2021 who had a follow-up CT. We divided them by groups depending on the diagnosis of type 2 diabetic mellitus and pharmacological history (diabetic vs non-diabetic, metformin vs non-metformin intake and statin vs non-statin intake). We compared pre and post follow-up AAA diameters using paired t-tests. A multivariate analysis was performed in order to identify independent variables associated with an increased growth rate. Statistical analysis was performed on Stata 17. During the studied period 72 (39.77%) patients had a follow-up CT. Mean age was 75years (±9.05) and 52 (72.22%) were men. When comparing infra-renal largest diameter through time based on metformin intake, a significant difference was found only in the metformin non-intake group (42.05 ± 12.54 vs45.34 ± 12.06 [P = 0.02]), in contrast the metformin intake group measures were non-significantly different (36.13 ± 7.04 vs 37.00 ± 4.51; P = 0.57) through follow-up. In the multivariate analysis AAA largest diameter at diagnosis correlated with significantly increased growth rate (coeff = 0.06, P < 0.05). AAA diameters appear to change through time in a non-linear pattern influenced by different epidemiological and clinical factors. Metformin intake appears to promote a stability in AAA diameter growth in our studied population.

Metformin-induced changes in the gut microbiome and plasma metabolome are associated with cognition in men

BackgroundAn altered gut microbiome characterized by reduced abundance of butyrate producing bacteria and reduced gene richness is associated with type 2 diabetes (T2D). An important complication of T2D is increased risk of cognitive impairment and dementia. The biguanide metformin is a commonly prescribed medication for the control of T2D and metformin treatment has been associated with a significant reduction in the risk of dementia and improved cognition, particularly in people with T2D. AimTo investigate the associations of metformin use with cognition exploring potential mechanisms by analyzing the gut microbiome and plasma metabolome using shotgun metagenomics and HPLC-ESI-MS/MS, respectively. MethodsWe explored two independent cohorts: an observational study (Aging Imageomics) and a phase IV, randomized, double-blind, parallel-group, randomized pilot study (MEIFLO). From the two studies, we analyzed four study groups: (1) individuals with no documented medical history or medical treatment (n = 172); (2) people with long-term T2D on metformin monotherapy (n = 134); (3) people with long-term T2D treated with oral hypoglycemic agents other than metformin (n = 45); (4) a newly diagnosed T2D subjects on metformin monotherapy (n = 22). Analyses were also performed stratifying by sex. ResultsSeveral bacterial species belonging to the Proteobacteria (Escherichia coli) and Verrucomicrobia (Akkermansia muciniphila) phyla were positively associated with metformin treatment, while bacterial species belonging to the Firmicutes phylum (Romboutsia timonensis, Romboutsia ilealis) were negatively associated. Due to the consistent increase in A. muciniphila and decrease in R.ilealis in people with T2D subjects treated with metformin, we investigated the association between this ratio and cognition. In the entire cohort of metformin-treated T2D subjects, the A.muciniphila/R.ilealis ratio was not significantly associated with cognitive test scores. However, after stratifying by sex, the A.muciniphila/R. ilealis ratio was significantly and positively associated with higher memory scores and improved memory in men.Metformin treatment was associated with an enrichment of microbial pathways involved in the TCA cycle, and butanoate, arginine, and proline metabolism in both cohorts. The bacterial genes involved in arginine metabolism, especially in production of glutamate (astA, astB, astC, astD, astE, putA), were enriched following metformin intake. In agreement, in the metabolomics analysis, metformin treatment was strongly associated with the amino acid proline, a metabolite involved in the metabolism of glutamate. ConclusionsThe beneficial effects of metformin may be mediated by changes in the composition of the gut microbiota and microbial-host-derived co-metabolites.

Safety of Contrast Agents Administration in Patients with Type 2 Diabetes Mellitus During Metformin Intake

Metformin is a sugar-lowering drug that is actively used in long-term therapy of type 2 diabetes mellitus (DM2). The safety of metformin for different groups of DM2 patients is currently well studied. However, the drug is contraindicated for patients with severe renal impairment and should be used with caution in cases of moderate renal impairment. Since contrast agents as well as metformin are excreted by kidneys, patients with reduced renal function taking metformin require special attention due to the risk of lactic acidosis, a life-threatening condition resulting from functional renal failure and accumulation of metformin in tissues. Numerous studies have shown that the risk of lactic acidosis is relatively low and in most cases is not associated with metformin therapy per se, but rather with comorbidities. Initial versions of clinical recommendations related to the use of contrast agents strictly limited the use of metformin before and after examination, but as data on lactate acidosis and possible causes of this condition expanded, the recommendations gradually became less strict. For emergency contrast studies, they are currently unchanged, but data are gradually accumulating on the safety of continuing metformin in these clinical situations. There is no consensus among contrast manufacturers on whether and in what regimen metformin should be interrupted during contrast studies as well as on a number of other related issues. The best strategy for clinicians is to check the instructions for each specific drug before use.

Abstract PO2-08-06: Metformin may improve the outcome of patients with breast cancer and type 2 diabetes mellitus through the effect of tumor immune microenvironment

Abstract Metformin, an anti-diabetic drug, is known to have anti-tumor effects. We examined the outcome of 177 patients with type 2 diabetes mellitus (T2DM) who received surgery for breast cancer. Among them, 49 patients were treated with drugs including metformin. In those patients, recurrence in distant organs was less frequent and postoperative disease-free survival (DFS) tended to be better than those without metformin intake. In patients who received preoperative systemic therapy (PST), rate of pathological complete response (pCR) was significantly more frequent in patients with metformin treatment (p &amp;lt; 0.05). Multiplex immunohistochemical staining of resected tumors revealed that the density of tumor associated macrophages (TAM), especially of CD68(+)CD163(+) M2-type TAM, was significantly lower in tumors with metformin treatment. In contrast, the rate of CD8(+) phenotype in CD3(+) tumor infiltrating lymphocytes (TILs) was significantly higher in metformin group. The results suggest that metformin can change the immune microenvironment from pro-tumorigenic to anti-tumorigenic status, which leads to the favorable outcome of the patients with breast cancer and T2DM. Citation Format: Satomi Shiba, Michiko Harao, Kasumi Ogihara, Takayo Fukuda, Masako Sakuragi, Kitayama Joji, Naohiro Sata. Metformin may improve the outcome of patients with breast cancer and type 2 diabetes mellitus through the effect of tumor immune microenvironment [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-08-06.

Morning exercise and pre-breakfast metformin interact to reduce glycaemia in people with type 2 diabetes: a randomized crossover trial.

Exercise is recommended in the treatment of type 2 diabetes and can improve insulin sensitivity. However, previous evidence suggests that exercise at different times of the day in people with type 2 diabetes may have opposing outcomes on glycaemia. Metformin is the most commonly prescribed initial pharmacological intervention in type 2 diabetes, and may alter adaptions to exercise. It is unknown if there is an interaction between metformin and diurnal exercise outcomes. We aimed to investigate glycaemic outcomes of moderate intensity morning vs. evening exercise in people with type 2 diabetes being prescribed metformin monotherapy. In this study, nine males and nine females with type 2 diabetes undergoing metformin monotherapy (age 61±8.2years, mean±SD) completed a 16-week crossover trial including 2-week baseline recording, 6weeks randomly assigned to a morning exercise (07.00-10.00h) or evening exercise (16.00-19.00h) and a 2-week wash-out period. Exercise arms consisted of 30min of walking at 70% of estimated max heart rate every other day. Glucose levels were measured with continuous glucose monitors and activity measured by wrist-worn monitors. Food-intake was recorded by 4-day food diaries during baseline, first and last 2weeks of each exercise arm. There was no difference in exercise intensity, total caloric intake or total physical activity between morning and evening arms. As primary outcomes, acute (24h) glucose area under the curve (AUC), was lower (P=0.02) after acute morning exercise (180.6±68.4mmol/l) compared to baseline (210.3±76.7mmol/l); and there were no differences identified for glucose (mmol/l) between baseline, morning and evening exercise at any specific time point when data were analysed with two-way ANOVA. As secondary outcomes, acute glucose AUC was significantly lower (P=0.01) in participants taking metformin before breakfast (152.5±29.95mmol/l) compared with participants taking metformin after breakfast (227.2±61.51mmol/l) only during the morning exercise arm; and during weeks 5-6 of the exercise protocol, glucose AUC was significantly lower (P=0.04) for participants taking metformin before breakfast (168.8±15.8mmol/l), rather than after breakfast (224.5±52.0mmol/l), only during morning exercise. Our data reveal morning moderate exercise acutely lowers glucose levels in people with type 2 diabetes being prescribed metformin. This difference appears to be driven by individuals that consumed metformin prior to breakfast rather than after breakfast. This beneficial effect upon glucose levels of combined morning exercise and pre-breakfast metformin persisted through the final 2weeks of the trial. Our findings suggest that morning moderate intensity exercise combined with pre-breakfast metformin intake may benefit the management of glycaemia in people with type 2 diabetes. KEY POINTS: Morning moderate exercise acutely lowers glucose levels in people with type 2 diabetes being prescribed metformin. This difference appears to be driven by individuals that consumed metformin prior to breakfast rather than after breakfast. Morning exercise combined with pre-breakfast metformin persistently reduced glucose compared to morning exercise combined with post-breakfast metformin through the final week (week 6) of the intervention. Our study suggests it may be possible to make simple changes to the time that people with type 2 diabetes take metformin and perform exercise to improve their blood glucose.

Metformin intake among geriatric patients may predispose to vitamin B12 deficiency: Polish population-based study

IntroductionVitamin B&lt;sub&gt;12&lt;/sub&gt; deficiency is becoming a major problem among geriatric population worldwide. It may contribute to higher prevalence of cognitive impairment and depression, and may occur as a side effect of commonly prescribed anti-diabetic and anti-acid treatments. However, the scale of this phenomenon in Poland remains unknown.AimWe investigated the scale of vitamin B&lt;sub&gt;12&lt;/sub&gt; deficiency across population of geriatric patients over 70 years old. Additionally, we examined the association between vitamin B&lt;sub&gt;12&lt;/sub&gt; deficiency, cognitive impairment or depression prevalence, and metformin or proton pump inhibitors intake.Material and methodsBased on the measured vitamin B&lt;sub&gt;12&lt;/sub&gt; serum level, we divided patients into 3 groups: (1) normal (≥300 pg/mL); (2) borderline (191–300 pg/mL), and (3) low (≤191 pg/mL). The assessment of cognitive impairment or depression was performed by using 5 distinct tests (mini-mental state examination, abbreviated mental test score, clock drawing test, and 4-item or 15-item geriatric depression scale). For statistical analysis, we used χ&lt;sup&gt;2&lt;/sup&gt; and ANOVA tests.Results and discussionWe showed no differences in the frequency of cognitive impairment, depression, and vitamin among characterized groups. Importantly, we found that metformin intake was associated with vitamin B&lt;sub&gt;12&lt;/sub&gt; deficiency (&lt;i&gt;P&lt;/i&gt; = 0.009), contrary to proton pump inhibitor (&lt;i&gt;P&lt;/i&gt; = 0.53) and combined these drugs (&lt;i&gt;P&lt;/i&gt; = 0.24).ConclusionsWe showed a relatively high prevalence of vitamin B&lt;sub&gt;12&lt;/sub&gt; deficiency across a population of geriatric patients. A preventive vitamin B&lt;sub&gt;12&lt;/sub&gt; supplementation should be considered when treating, especially geriatric diabetic patients. Due to conflicting results of retrospective studies, prospective clinical trial should be undertaken to describe the association between vitamin B&lt;sub&gt;12&lt;/sub&gt; deficiency and prevalence of cognitive impairment or depression.

Metformin may improve the outcome of patients with colorectal cancer and type 2 diabetes mellitus partly through effects on neutrophil extracellular traps

BackgroundAlthough metformin reduces the risk of cancer-related mortality in patents with type 2 diabetes, the mechanism of its anti-cancer effects has not been fully understood.MethodImpact of metformin on survival was examined in patients who underwent curative colectomy for colorectal cancer (CRC). The effects of metformin in neutrophil extracellular traps (NETs) were examined with in-vitro experiments and multiplex immunohistochemistry of surgically resected CRC specimens.ResultsPrior intake of metformin prolonged relapse-free (P = 0.036) and overall survival (P = 0.041) in 289 patients with T2DM to the comparable levels to those of 1576 non-diabetic patients. Metformin reduced the production of NETs stimulated with lipopolysaccharide or HT-29 colon cancer cells to 60% of control. Neutrophils markedly suppressed the chemotactic migration of activated T cells in an NET-dependent manner, which was reversed by metformin treatment up to approximately half of the migration without neutrophils. Immunohistochemical analysis revealed a significant association between metformin intake and a reduction in the numbers of tumor-associated neutrophils (TANs) and NETs. Simultaneously, metformin intake was found to increase the presence of CD3(+) and CD8(+) tumor-infiltrating T cells (TILs), particularly at the tumor-invasion front, especially in areas with fewer TANs and NETs.ConclusionMetformin suppresses the diabetes-associated enhancement of NET formation, which can augment the infiltration of TILs in CRC tissues. The anti-tumor effect of metformin in patients with T2DM may be, at least partly, attributable to the inhibition of NETs.

Metformin Regulates the miR-205/VEGFA Axis in Renal Cell Carcinoma Cells: Exploring a Clinical Synergism with Tyrosine Kinase Inhibitors

Introduction: Metformin (MF) intake could be associated with a favorable outcome in sunitinib (SUT)- and axitinib (AX)-treated clear cell renal cell carcinoma (ccRCC) patients. Functionally, MF induces miR-205, a microRNA serving as a tumor suppressor in several cancers. Methods: Real-time quantitative PCR, viability assays, and Western blotting analyzed MF and SUT/AX effects in RCC4 and 786-O cells. A tetracycline-inducible overexpression model was used to study the role of miR-205 and its known target gene, VEGFA. We analyzed miR-205 and VEGFA within a public and an in-house ccRCC cohort. Human umbilical vein endothelial cell (HUVEC) sprouting assays examined miR-205 effects on angiogenesis initiation. To determine the influence of the von Hippel-Lindau tumor suppressor (VHL), we examined VHL^wt reexpressing RCC4 and 786-O cells. Results: Viability assays confirmed a sensitizing effect of MF toward SUT/AX in RCC4 and 786-O cells. Overexpression of miR-205 diminished VEGFA expression – as did treatment with MF. Tumor tissue displayed a downregulation of miR-205 and an upregulation of VEGFA. Accordingly, miR-205 caused less and shorter vessel sprouts in HUVEC assays. Finally, VHL^wt-expressing RCC4 and 786-O cells displayed higher miR-205 and lower VEGFA levels. Conclusion: Our results support the protective role of MF in ccRCC and offer functional insights into the clinical synergism with tyrosine kinase inhibitors.

Oxidative Stress-regulating Enzymes and Endometrial Cancer Survival in Relation to Metformin Intake in Diabetic Patients.

Metformin inhibits tumorigenesis in endometrial carcinoma and interferes with the expression of oxidative stress-regulating proteins, such as nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1). Although manganese superoxide dismutase (MnSOD) is vital for withstanding mitochondrial oxidative stress, it has also been linked with chemoresistance and poorer outcomes in several cancer types. However, data on endometrial cancers are limited. This study aimed to highlight the relationship between mitochondrial redox regulation and endometrial cancer survival in relation to metformin consumption in women with type 2 diabetes mellitus (T2DM). Our retrospective hospital-based cohort study included 121 patients diagnosed with endometrial carcinoma and T2DM between 2007 and 2014. Fifty-eight patients were using metformin at the time of diagnosis. Nrf2 and Keap1 expression levels in the tumor samples were assessed immunohistochemically, and MnSOD levels were measured both immunohistochemically and from the serum samples. High MnSOD tissue expression was associated with better overall survival among metformin users in the univariate analysis (p=0.03). When adjusted for histology and stage, high serum MnSOD was associated with better overall survival (HR=0.22, 95%CI=0.07-0.71, p=0.01). No association was found between MnSOD, Nrf2, or Keap1 and overall survival among metformin non-users. Higher expression of MnSOD in patients with endometrial cancer and T2DM is associated with better overall survival if the patient is consuming metformin.

Reversible acute blindness in suspected metformin-associated lactic acidosis: a case report

BackgroundMetformin is commonly used for the treatment of type 2 diabetes mellitus. Its multiple advantages include low risk of hypoglycemia, weight neutrality, low cost, and cardioprotective and anti-inflammatory effects. Renal insufficiency is one of the contraindications for its use. Inadvertent prescription in patients with renal insufficiency may lead to metformin-associated lactic acidosis, which brings a high risk of mortality. The early recognition and management of metformin-associated lactic acidosis are essential.Case reportWe present the case of a 58-year-old Hui woman with a history of type 2 diabetes mellitus with nephropathy and heart disease for which she was treated with metformin, insulin, and heart medications. She developed nausea, vomiting, anion gap metabolic acidosis due to hyperlactatemia, and acute kidney injury. She was hospitalized to receive intravenous hydration and correction of metabolic acidosis after she suddenly developed blindness. The diagnostic workup ruled out central causes and her symptoms resolved briefly after continuous venovenous hemodialysis was initiated, confirming the diagnosis of metformin-associated lactic acidosis.ConclusionsMetabolic disruption can cause acute blindness. Metabolic acidosis in a patient with a history of metformin intake should suggest the possibility of metformin-associated lactic acidosis, which must be treated immediately, without waiting for the results of other examinations, especially in patients with sudden blindness. Further study of reversible blindness-associated severe metabolic acidosis is needed.

Metformin Does not Affect Outcomes in Patients With Locally Advanced Rectal Cancer Treated With Neoadjuvant Therapy and Resection.

There is emerging evidence that metformin may have a protective effect in patients with cancer. However, its current evidence in locally advanced rectal cancer (LARC) is inconclusive. We aim to assess the effect of metformin on long-term outcomes in patients with LARC who received neoadjuvant therapy and surgical resection. A retrospective review of 324 patients with nonmetastatic LARC who received neoadjuvant therapy and major surgical resection from 2004 to 2018. There were 27 patients who received metformin before surgery and 297 patients who did not receive metformin. Metformin users were associated with a significantly higher age, BMI, ASA score, and 30-day readmissions (P < .05). There was no difference in overall survival (OS, P = .18) or disease-free survival (DFS, P = .33) between the two groups. On Cox regression, metformin intake did not predict OS (HR 0.85, 95% CI 0.4-1.77) when controlled for age (HR 1.04, 1.02-1.06), sex (HR 1.13, 0.69-1.85), BMI (HR 0.97, 0.92-1.02), ASA score (HR: 1.7, 1.06-2.73), TNT (HR 0.31, 0.1-0.92), pathological Stage III disease (HR 2.55, 1.51-4.32), extramural vascular invasion (EMVI) (HR 3.06, 1.7-5.5), and adjuvant therapy (HR 0.1, 0.04-0.27 for <25months OS and HR 0.3, 0.15-0.59 for ≥25months). Disease-free survival showed a similar trend with no significant effect of metformin (HR 0.77, 0.39-1.52) when controlled for age, sex, BMI, ASA, TNT, Stage III disease, EMVI, and adjuvant therapy. Metformin does not affect long-term survival in LARC treated with neoadjuvant therapy followed by surgical resection. Studies with larger sample sizes are needed to validate the findings further.

Incidence and risk factors of prostate cancer among the Northern and Eastern parts of the United Arab Emirates population.

Prostate cancer (PCa) is a prevalent disease worldwide. However, the incidence and patient-specific risk factors of PCa in the Middle East, specifically in the United Arab Emirates,have not been previously reported. We conducted a retrospective cohort study on 2377 men diagnosed with either benign prostatic hyperplasia (BPH) or PCa in the Northern and Eastern regions of the United Arab Emirates, excluding the Western part, which includes Abu Dhabi. The study spanned from January 2012 and December 2021. To calculate the PCa incidence rate, we utilized the world age-standardized incidence rates (W-ASIR) categorized by age groups. Patient-specific risk factors of PCa were identified through a multivariate logistic regression analysis of clinical data. A total of 247 cases of PCa and 2130 cases of BPH were included in the study. In our cohort, the W-ASIR for PCa was 21.3 per 100,000 men. The incidence of PCa showed an increasing trend with age, with the highest incidence observed among men aged 70 years and older. Accordingly, multivariate analysis revealed that age over 70 was associated with an increased risk of PCa (OR: 2.546, 95% confidence interval [CI]: 1.892-3.425, p < 0.01). On the other hand, preexisting conditions such as hypertensionand diabetes mellituswere found to lower the risk of PCa (OR: 0.222, 95% CI: 0.163-0.302, p < 0.001) and (OR: 0.364, 95% CI: 0.205-0.648, p < 0.001), respectively. Additionally, metformin intake was associated with a reduced risk of PCa (OR: 0.385, 95% CI: 0.190-0.782, p = 0.008); while insulin usage increased the risk of PCa (OR: 2.586, 95% CI: 1.539-4.344, p < 0.001). Anti-BPH medications such as phosphodiesteraseinhibitors (OR: 0.223, 95% CI: 0.069-0.723, p = 0.012) or 5-α reductase (OR: 0.206, 95% CI: 0.110-0.389, p < 0.000), were found to lower the risk of PCa. The findings underscore the high incidence of PCa in the United Arab Emirates, with age being a significant factor. Furthermore, the study highlights the influence of certain comorbidities and medications on the risk of developing PCa within the United Arab Emiratespopulation.

Effects of metformin on vitamin B12 levels, including dose and duration of therapy: a narrative review

Background: Metformin, a biguanide derivative medication, is administered worldwide as the first-line treatment for patients with type 2 diabetes mellitus. Despite its many advantages, it is not devoid of side effects. As many studies have evidenced thus far, metformin treatment may increase the risk of vitamin B12 deficiency, with the prevalence of this deficiency varying from 1.8% to 53.2%. We performed a review of studies to summarize their results and present dose and duration associations between metformin therapy and serum cobalamin levels. Aim of the study: The purpose of this study was to evaluate the relationship between metformin and vitamin B12 deficiency from a historical perspective.Material and Methods: Thirty articles focused on vitamin B12 deficiency during metformin therapy, collected from the PubMed database from 1971 to July 2021, were analyzed.Results: Based on the literature reviewed, we observed a prevalence of vitamin B12 deficiency with metformin use ranging from 1.8% to 53.2%, with a median of 11.2%. In studies with follow-up longer than six months, the incidence of vitamin B12 deficiency during metformin treatment was approximately 6–10%. The vast majority of studies showed an inverse correlation between dose and length of metformin intake and serum vitamin B12 levels. The findings of three out of 16 analyzed studies proved dose-only associations, and the other three showed time-only effects. Two studies found no relationship with these variables.Conclusions: Patients undergoing long-term metformin therapy, especially at high doses, should have their vitamin B12 levels measured regularly to protect them from complications resulting from cobalamin deficiency.

Correlation between metformin intake and prostate cancer

Background: The relationship between metformin intake and prostate cancer incidence remains unclear. Therefore, we examined the correlation between prostate cancer and metformin use.Methods: The subjects were diabetes patients aged ≥50 years who had been diagnosed with prostate cancer and had undergone surgery at Seoul St. Mary's Hospital. Groups taking metformin (MET(+) group) and not taking metformin (MET(–) group) were divided and compared.Results: The mean preoperative prostate-specific antigen (PSA) levels in the MET(–) and MET(+) groups were 10.7±11.9 and 8.0±5.6 ng/mL, respectively, with no statistically significant difference between the two groups (P=0.387). The average prostate volume of the MET(–) group was 82.4±98.0 mL, and the average prostate volume of the MET(+) group was 55.4±20.1 mL, but there was no statistically significant difference between the two groups (P=0.226). The mean PSA velocity also did not show a significant difference between the two groups (0.025±0.102 ng/mL vs. 0.005±0.012 ng/mL, P=0.221).Conclusions: We did not identify a significant positive correlation between metformin and prostate cancer. However, preoperational PSA and PSA velocity tended to be lower in the MET(+) group. A sophisticated prospective study with a large sample size should be planned.

Is metformin the only culprit for cognitive impairment in diabetes?

Background: As patients with diabetes are conventionally on a long-term prescription for metformin, it is important to identify any increase in their risk for developing cognitive disorders due to metformin. Hence, an attempt was made to study the cognitive impairment by using Montreal Cognitive Assessment test (MoCA) as a possible predictor of development of cognitive impairment in type 2 diabetes patients on metformin therapy. Methods: Four hundred type 2 diabetes patients on metformin were enrolled for this cross-sectional study, and data recorded. Cognitive test MoCA was administered and a score less than 26 was considered abnormal. Results: In this study, the participants on metformin had a statistically significant correlation with age &gt; 65 years, duration of diabetes (&gt;5 years), metformin dose (1 gm and more) and presence of diabetes complications. Ordinal regressions showed significant correlation between abnormal MoCA scores and older age, longer duration of DM, and presence of one of the DM complications. Conclusions: Amongst patients receiving medical therapy for control of type 2 diabetes, participants using metformin showed a very high prevalence rate of abnormal MoCA scores (85%). Increased duration of metformin intake leads to a decline in MoCA performance.

Metformin Effects on Blood Levels of Myonectin in Polycystic Ovarian Women

Background: Polycystic ovary syndrome (PCOS) is a most prevalent endocrine diseases for females of childbearing age, and lead to an ovulatory infertility. It was shown that myonectin may be positively associated with insulin resistance parameters. Objectives: To evaluate serum myonectin levels and to determine the effects of metformin treatment on myonectin levels in patients with polycystic ovary syndrome. Patients and Methods: The Cross-Sectional Study carried out in the Department of Obstetrics and Gynecology Salahdeen general hospital in Tikrit city from 1st November 2022-30th January 2023. Patients diagnosed with PCOs depending based on the Rotterdam criteria. Participants were enrolled after all eligibility criteria were confirmed and informed consent completed. Sixty PCOS patients were selected as the PCOS group, while 30 healthy women matched for age with the PCOS patients were selected as the control group. Only 30 patients of them complete the follow up study and they agree to continue on metformin treatment during three months, the duration of the follow up. They take metformin 850 mg twice daily for three months and provide fasting blood samples on the second day of menstruation before and after treatment. The data collection done through: a designed closed and open-ended questionnaire, by using direct interviewing and Ultrasound examination, Laboratory examination. Myonectin, Luteinizing hormone (LH), Follicular Stimulating Hormone (FSH), and insulin were analysed by enzyme-linked immunosorbent assay (ELIZA) technique from Biomeriuex. Data were analyzed using SPSS for Windows 7. Results: The level of myonectin decreased significantly in PCOS patients compare to control group. The level of blood glucose, Insulin, and HOMA-IR, were increased significantly compared to the control. Serum LH levels were significantly higher, while the level of FSH were lowerin in women with PCOS than in controls. After metformin intake, all patients showed significant in decrease in gremlin concentration at p-values 0.05, but no significant difference (P&gt;0.05) in myonectin level when compared to pre-treatment. Treatment resulted a significant decrease in in body mass index, Blood glucose, Insulin, HOMA-IR, testosterone and LH at p-values 0.05. However, the study found no significant difference (p &gt; 0.05) in myonectin level between both groups in treated group with metformin compared with pre-treatment. Conclusion: Metformin testosterone and insulin resistance but can’t induce changes of myonectin level in patients with polycystic ovary syndrome.

Should we follow the guidelines on vitamin B12 deficiency and diabetes? A retrospective analysis of data from middle eastern population

ABSTRACT Background Vitamin B12 is a micronutrient required for hematopoietic, neuro-cognitive and cardiovascular function. Biochemical and clinical vitamin B12 deficiency has been recognized in patients with type 2 diabetes mellitus. One of the adverse effects of long-term metformin use is vitamin B12 malabsorption. Aim of the study was to assess the state of vitamin B12 deficiency in people with type 2 diabetes and to ascertain the relationship between vitamin B12 status, metformin use and peripheral neuropathy. It is a retrospective study that was conducted on 8040 subjects included 2126 type 2 diabetic patients, and 5914 nondiabetic individuals. Personal information, medical history, including metformin and multivitamin therapy use as well as the existence of clinical peripheral neuropathy, were all included data. For the purpose of measuring the amount of vitamin B12, blood samples were taken. Serum B12 levels <200 pg/ml was defined as B12 deficiency. Results Vitamin B12 deficiency was detected in 12.9% of diabetic group and 19.9% of control group. The mean value of vitamin B12 level between diabetic (563 ± 470.6 pg/ml) and non-diabetic (429.7 ± 310.9 pg/ml) showed a high significant difference, p value <0.001. The vitamin B12 levels were higher in people with diabetes. Vitamin B12 deficiency was not associated with metformin intake or diabetic neuropathy. Conclusions Vitamin B12 level was significantly higher in diabetic compared to nondiabetic individuals. Neither peripheral neuropathy, anemia nor metformin therapy was associated with vitamin B12 deficiency. Vitamin B12 supplementation is not recommended as a routine practice in people with diabetes. This is contrary to the common practice that is sometimes done. The cost of supplementation can be used to provide more beneficial services and drugs for these people.