Receiving Metformin Treatment Research Articles

Predicting Metformin Efficacy in Improving Insulin Sensitivity Among Women With Polycystic Ovary Syndrome and Insulin Resistance: A Machine Learning Study

ObjectiveMetformin is clinically effective in treating polycystic ovary syndrome (PCOS) with insulin resistance (IR), while its efficacy varies among individuals. This study aims to develop a machine learning model to predict the efficacy of metformin in improving insulin sensitivity among women with PCOS and IR. MethodsThis is a retrospective analysis of a multicenter, randomized controlled trial involving 114 women diagnosed with PCOS and IR. All women received metformin treatment for 4 months. We incorporated 27 baseline clinical variables of the women into the construction of our machine learning model. We firstly compared 4 commonly used feature selection methods to screen valuable clinical variables. Then we used the valuable variables as inputs to evaluate the performance of 5 machine learning models, including k-Nearest Neighbors, Support Vector Machine, Logistic Regression, Random Forest, and Extreme Gradient Boosting, in predicting the efficacy of metformin. ResultsAmong the 5 machine learning models, Support Vector Machine performed the best with an area under the receiver operating characteristic curve of 0.781 (95% confidence interval [CI]: 0.772-0.791). The key predictive variables identified were homeostasis model assessment of insulin resistance, body mass index, and low-density lipoprotein cholesterol. ConclusionThe developed machine learning model could be applied to predict the efficacy of metformin in improving insulin sensitivity among women with PCOS and IR. The result could help doctors evaluate the efficacy of metformin in advance, optimize treatment plans, and thereby enhance overall clinical outcomes.

Metformin-Induced Vitamin B12 Deficiency in Patients with Type 2 Diabetes: A Narrative Review with a Practical Approach for Screening, Diagnosing, and Managing Vitamin B12 Deficiency.

Metformin is the most widely used antihyperglycemic drug in patients with type 2 diabetes (T2D). Over the past 2 decades, several studies have highlighted a substantial increase in the risk of vitamin B12 deficiency in patients with T2D on metformin therapy. This can lead to several complications and induce or exacerbate peripheral neuropathy. Despite these data, there are no definite guidelines for screening, diagnosing, and treating vitamin B12 deficiency in patients with T2D on metformin therapy. Therefore, in this narrative review, we aimed to suggest a practical diagnostic and therapeutic strategy to address vitamin B12 deficiency in patients with T2D receiving metformin treatment. Clinical evidence supporting an increased risk of vitamin B12 deficiency in patients with T2D on metformin therapy and its risk factors and potential complications are also discussed.

Dexamethasone-Induced Insulin Resistance Attenuation by Oral Sulfur-Oxidovanadium(IV) Complex Treatment in Mice.

Vanadium compounds are known to exert insulin-enhancing activity, normalize elevated blood glucose levels in diabetic subjects, and show significant activity in models of insulin resistance (IR). Faced with insulin resistance, the present work investigates the antidiabetic performance of a known oxidovanadium(IV)-based coordination compound-[VIVO(octd)]-and effects associated with glucocorticoid-induced insulin resistance in mice. The effects of [VIVO(octd)] were evaluated in a female Swiss mice model of insulin resistance induced by seven days of dexamethasone treatment in comparison with groups receiving metformin treatment. Biological assays such as hematological, TyG index, hepatic lipids, glycogen, oxidative stress in the liver, and oral glucose tolerance tests were evaluated. [VIVO(octd)] was characterized with 51V NMR, infrared spectroscopy (FTIR), electron paramagnetic resonance (EPR), electronic absorption spectroscopy, and mass spectrometry (ESI-FT-MS). The [VIVO(octd)] oral treatment (50 mg/kg) had an antioxidant effect, reducing 50% of fast blood glucose (p < 0.05) and 25% of the TyG index, which is used to estimate insulin resistance (p < 0.05), compared with the non-treated group. The oxidovanadium-sulfur compound is a promising antihyperglycemic therapeutic, including in cases aggravated by insulin resistance induced by glucocorticoid treatment.

Effect of Metformin on Sertoli Cell Fatty Acid Metabolism and Blood-Testis Barrier Formation.

Sertoli cells (SCs) are essential to maintaining germ cell development. Metformin, the main pharmacologic treatment for pediatric type 2 diabetes, is administered to children during SC maturation. The present study aimed to analyze whether metformin affects SC energy metabolism and blood-testis barrier (BTB) integrity. Primary SC cultures were used for the in vitro studies. In vivo effects were studied in Sprague-Dawley rats treated with 200 mg/kg metformin from Pnd14 to Pnd30. Metformin decreased fatty acid oxidation and increased 3-hydroxybutyrate production in vitro. Moreover, it decreased the transepithelial electrical resistance across the monolayer and induced ZO-1 redistribution, suggesting an alteration of cell junctions. In vivo, a mild but significant increase in BTB permeability and ZO-1 expression was observed in the metformin group, without changes in testicular histology and meiosis progression. Additionally, adult rats that received metformin treatment during the juvenile period showed no alteration in BTB permeability or daily sperm production. In conclusion, metformin exposure may affect BTB permeability in juvenile rats, but this seems not to influence spermatogenesis progression. Considering the results obtained in adult animals, it is possible to speculate that metformin treatment during the juvenile period does not affect testicular function in adulthood.

The Effect of Metformin Treatment on Disease Control in Patients with Acromegaly.

The increase in portal insulin levels has been shown to upregulate growth hormone receptor expression in the liver, leading to increased insulin-like growth hormone- 1 levels. Metformin inhibits hepatic gluconeogenesis and reduces fasting insulin. We evaluated the effect of metformin treatment in patients with acromegaly on growth hormone, insulin-like growth hormone-1, and pituitary adenoma size. Patients who were followed up with the diagnosis of acromegaly in Istanbul University- Cerrahpaşa, Cerrahpaşa Medical Faculty were evaluated. The patients were divided into three groups after pituitary adenectomy as those who received somatostatin receptor ligand and metformin treatment (group A), somatostatin receptor ligand treatment only (group B), and those who received metformin treatment only (group C). Groups A and B were compared with each other, and patients in group C were compared among themselves. While the median insulin-like growth factor-1 level decreased to 170 ng/ml in Group A after the treatment, the median insulin-like growth factor-1 level decreased to 229 ng/ml in Group B, and a statistically significant difference was found between the two groups (p =0.020). There was no significant difference in post-treatment growth hormone levels and residual adenoma sizes between groups A and B (p >0.005). In group C, there was no significant difference in growth hormone values pre-and post-metformin treatment (p =0.078); however, the median insulin-like growth factor-1 level decreased from 205 ng/ml to 168 ng/ml during metformin treatment and was found to be statistically significant (p =0.027). Due to the effect of metformin treatment on insulin-like growth factor-1 values in patients with acromegaly, it can be used in disease control, as well as diabetes treatment.

Metformin treatment is associated with improved survival in diabetic patients hospitalized with acute heart failure: A prospective observational study using the Korean acute heart failure registry data

AimsAlthough the hypothesis that metformin is beneficial for patients with diabetes and heart failure (HF) has been steadily raised, there is limited data on metformin use in patients with acute HF. We analyzed the association of metformin on all-cause mortality in hospitalized patients with type 2 diabetes and acute HF. MethodsThe Korean Acute Heart Failure registry prospectively enrolled patients hospitalized for acute HF from 2011 to 2014. Among this cohort, we analyzed patients with diabetes with baseline estimated glomerular filtration rate (eGFR) of 30 ml/min/1.73 m2 or more. We analyzed the all-cause mortality and re-hospitalization for HF within 1 year after discharge. Inverse probability treatment weighting method was used to adjust baseline differences on metformin treatment. ResultsThe study analyzed data from 1,309 patients with HF and diabetes (mean age 69 years, 56 % male). Among them, 613 (47 %) patients were on metformin at admission. During the median follow-up period of 11 months, 132 (19 %) and 74 (12 %) patients not receiving and receiving metformin treatment died, respectively. The mortality rate was lower in metformin users than in non-users (hazard ratio 0.616 [0.464–0.819] P<0.001). After adjustment, metformin was significantly associated with a lower risk for the mortality (hazard ratio 0.677 [0.495–0.928] P=0.015). In subgroup analyses, this association remains significant irrespective of baseline kidney function (eGFR <60 or ≥60 ml/min/1.73 m2, P-for-interaction=0.176) or left ventricular ejection fraction (<40 %, 40–49 %, or ≥50 %, P-for-interaction=0.224). ConclusionsMetformin treatment at the time of admission was associated with a lower risk for 1-year mortality in patients with diabetes, hospitalized for acute HF.

Metformin treatment reduces inflammation, dysmyelination and disease severity in a mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammation, death or damage of oligodendrocytes, and axonal degeneration. Current MS treatments are non-curative, associated with undesired side-effects, and expensive, highlighting the need for expanded therapeutic options for patients. There is great interest in developing interventions using drugs or therapeutics to reduce symptom onset and protect pre-existing myelin. Metformin is a well-tolerated drug used to treat Type 2 diabetes that has pleiotropic effects in the central nervous system (CNS), including reducing inflammation, enhancing oligodendrogenesis, increasing the survival/proliferation of neural stem cells (NSCs), and increasing myelination. Here, we investigated whether metformin administration could improve functional outcomes, modulate oligodendrocyte precursor cells (OPCs), and reduce inflammation in a well-established mouse model of MS- experimental autoimmune encephalomyelitis (EAE). Male and female mice received metformin treatment at the time of EAE induction (“acute”) or upon presentation of disease symptoms (“delayed”). We found that acute metformin treatment improved functional outcomes, concomitant with reduced microglia numbers and decreased dysmyelination. Conversely, delayed metformin treatment did not improve functional outcomes. Our findings reveal that metformin administration can improve EAE outcomes when administered before symptom onset in both sexes.

Association of Metformin Treatment with Risk for Death in Diabetic Patients with Concomitant Gastric Cancer.

Despite the existing guideline's recommendation of metformin therapy as the initial approach for managing diabetes mellitus (DM), there remains a scarcity of comprehensive documentation regarding metformin's impact on outcomes that are important for patients. The objective of this study was to assess the potential impact of metformin treatment on the risk of death in individuals diagnosed with both gastric cancer and pre-existing diabetes mellitus (DM); Design, Setting, and Participants: The study made use of a dataset encompassing nationwide health insurance claims, allowing for a retrospective analysis of all patients with a history of gastric cancer diagnosis (classified under International Classification of Diseases 10th Revision code: C16.X) spanning from 1 January 2002 to 31 December 2012. The primary objective was to observe death within a 5-year follow-up period. The study population comprised 63,664 individuals who fell into two categories: those treated with metformin (n = 29,548) and those who did not receive metformin treatment (n = 34,116). This classification was based on the initial treatment allocation following the diagnosis of gastric cancer. Metformin treatment, comorbidities, concurrent medication, and procedural information. All-cause death, disease-specific death, cardiovascular death. During the 5-year follow-up period, the metformin treatment group exhibited a lower cumulative incidence of all-cause death (27.5%) in comparison to the group not receiving metformin treatment (32.8%). Furthermore, the relative hazards for all-cause death were significantly reduced in the metformin treatment group (HR: 0.80, 95% CI 0.78-0.82), indicating a lower risk of death when compared to the non-metformin group. In addition, metformin treatment was associated with lower occurrences of disease-specific death (related to gastric cancer) and cardiovascular death when compared to the group not undergoing metformin treatment. The findings demonstrated that the use of metformin was effective at improving prognosis among gastric cancer patients documented with prior DM. In this population-based cohort study, metformin treatment was associated with reduced risk of mortality.

Metformin regulates bone marrow stromal cells to accelerate bone healing in diabetic mice.

Diabetes mellitus is a group of chronic diseases characterized by high blood glucose levels. Diabetic patients have a higher risk of sustaining osteoporotic fractures than non-diabetic people. The fracture healing is usually impaired in diabetics, and our understanding of the detrimental effects of hyperglycemia on fracture healing is still inadequate. Metformin is the first-line medicine for type 2 diabetes (T2D). However, its effects on bone in T2D patients remain to be studied. To assess the impacts of metformin on fracture healing, we compared the healing process of closed-wound fixed fracture, non-fixed radial fracture, and femoral drill-hole injury models in the T2D mice with and without metformin treatment. Our results demonstrated that metformin rescued the delayed bone healing and remolding in the T2D mice in all injury models. In vitro analysis indicated that compromised proliferation, osteogenesis, chondrogenesis of the bone marrow stromal cells (BMSCs) derived from the T2D mice were rescued by metformin treatment when compared to WT controls. Furthermore, metformin could effectively rescue the impaired detrimental lineage commitment of BMSCs isolated from the T2D mice in vivo as assessed by subcutaneous ossicle formation of the BMSC implants in recipient T2D mice. Moreover, the Safranin O staining of cartilage formation in the endochondral ossification under hyperglycemic condition significantly increased at day 14 post-fracture in the T2D mice receiving metformin treatment. The chondrocyte transcript factors SOX9 and PGC1α, important to maintain chondrocyte homeostasis, were both significantly upregulated in callus tissue isolated at the fracture site of metformin-treated MKR mice on day 12 post-fracture. Metformin also rescued the chondrocyte disc formation of BMSCs isolated from the T2D mice. Taken together, our study demonstrated that metformin facilitated bone healing, more specifically bone formation and chondrogenesis in T2D mouse models.

Comparative Effects of Glucose-Lowering Medications on Kidney Outcomes in Type 2 Diabetes

Type 2 diabetes (T2D) is the leading cause of kidney disease in the US. It is not known whether glucose-lowering medications differentially affect kidney function. To evaluate kidney outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) trial comparing 4 classes of glucose-lowering medications added to metformin for glycemic management in individuals with T2D. A randomized clinical trial was conducted at 36 sites across the US. Participants included adults with T2D for less than 10 years, a hemoglobin A1c level between 6.8% and 8.5%, and estimated glomerular filtration rate (eGFR) greater than or equal to 60 mL/min/1.73 m2 who were receiving metformin treatment. A total of 5047 participants were enrolled between July 8, 2013, and August 11, 2017, and followed up for a mean of 5.0 years (range, 0-7.6 years). Data were analyzed from February 21, 2022, to March 27, 2023. Addition of insulin glargine, glimepiride, liraglutide, or sitagliptin to metformin, with the medication combination continued until the HbA1c was greater than 7.5%; thereafter, insulin was added to maintain glycemic control. Chronic eGFR slope (change in eGFR between year 1 and trial end) and a composite kidney disease progression outcome (albuminuria, dialysis, transplant, or death due to kidney disease). Secondary outcomes included incident eGFR less than 60 mL/min/1.73 m2, 40% decrease in eGFR to less than 60 mL/min/1.73 m2, doubling of urine albumin-to-creatinine ratio (UACR) to 30 mg/g or greater, and progression of Kidney Disease Improving Global Outcomes stage. Analyses were intention-to-treat. Of the 5047 participants, 3210 (63.6%) were men. Baseline characteristics were mean (SD) age 57.2 (10.0) years; HbA1c 7.5% (0.5%); diabetes duration, 4.2 (2.7) years; body mass index, 34.3 (6.8); blood pressure 128.3/77.3 (14.7/9.9) mm Hg; eGFR 94.9 (16.8) mL/min/1.73 m2; and median UACR, 6.4 (IQR 3.1-16.9) mg/g; 2933 (58.1%) were treated with renin-angiotensin-aldosterone inhibitors. Mean chronic eGFR slope was -2.03 (95% CI, -2.20 to -1.86) mL/min/1.73 m2 per year for patients receiving sitagliptin; glimepiride, -1.92 (95% CI, -2.08 to -1.75) mL/min/1.73 m2 per year; liraglutide, -2.08 (95% CI, -2.26 to -1.90) mL/min/1.73 m2 per year; and insulin glargine, -2.02 (95% CI, -2.19 to -1.84) mL/min/1.73 m2 per year (P = .61). Mean composite kidney disease progression occurred in 135 (10.6%) patients receiving sitagliptin; glimepiride, 155 (12.4%); liraglutide, 152 (12.0%); and insulin glargine, 150 (11.9%) (P = .56). Most of the composite outcome was attributable to albuminuria progression (98.4%). There were no significant differences by treatment assignment in secondary outcomes. There were no adverse kidney events attributable to medication assignment. In this randomized clinical trial, among people with T2D and predominantly free of kidney disease at baseline, no significant differences in kidney outcomes were observed during 5 years of follow-up when a dipeptidyl peptidase 4 inhibitor, sulfonylurea, glucagonlike peptide 1 receptor agonist, or basal insulin was added to metformin for glycemic control. ClinicalTrials.gov Identifier: NCT01794143.

Don't sugar coat it: The independent and synergistic impacts of obesity and gestational diabetes on placental parameters.

Don't sugar coat it: The independent and synergistic impacts of obesity and gestational diabetes on placental parameters.

The role of circulating miRNAs in mechanism of action and prediction of therapeutic responses of metformin in polycystic ovarian syndrome

To study the involvement of microribonucleic acids (miRNAs) in the pathogenesis of chronic anovulation and mechanism of metformin treatment in polycystic ovary syndrome (PCOS). Case-control and prospective validation cohort study. Tertiary university hospital. A total of 146 patients with PCOS and chronic anovulation and 20 non-PCOS controls were enrolled. Patients who resumed ovulation after metformin treatment (MET-OV) and remained anovulatory after metformin treatment (MET-AO) were assigned to MET-OV and MET-AO groups, respectively. All patients with PCOS received metformin treatment for 6 months. Baseline and chronological changes in the plasma levels of 14 miRNAs (miR-21, 93, 132, 193b, 221, 222, 223, 27a, 125b, 200b, 212, 320a, 429, and 483) selected by literature review, anthropometric data, and hormonal as well as metabolic profiles were measured. Predictive modeling based on baseline circulatory miRNA levels and clinical parameters was performed to predict ovulation recovery after metformin treatment. No significant differences were observed in the baseline hormonal and metabolic profiles between the MET-OV and MET-AO groups. However, the expression of miR-27a, miR-93, and miR-222 was significantly higher in the MET-OV group than that for the MET-AO and control groups. After 6 months of metformin treatment, the levels of insulin, luteinizing hormone, and 6 circulating miRNAs (miR-21, 27a, 93, 221, 222, and 223) and homeostatic model assessment for insulin resistance decreased significantly in the MET-OV group, but remained unchanged in the MET-AO group. The area under curve, sensitivity, and specificity of the adjusted prediction model, based on miRNA levels and clinical parameters using logistic regression analysis for predicting ovulatory response after metformin treatment, were 0.807, 0.892, and 0.632, respectively. The present study demonstrated a distinct pattern of baseline expression and chronological changes in the levels of several circulatory miRNAs between the MET-OV and MET-AO groups, suggesting that aberrantly overexpressed diabetogenic miRNAs are involved in the pathophysiology of chronic anovulation in PCOS, and their down-regulation might contribute toward the therapeutic effects of metformin. This could provide new insights into the mechanism of action and applicability of individualized metformin therapy in women with PCOS.

Correlation between long-term use of metformin and incidence of NAFLD among patients with type 2 diabetes mellitus: A real-world cohort study.

Studies have demonstrated that the short-term use of metformin benefits liver function among patients with type 2 diabetes mellitus (T2DM). However, few studies have reported on the effects of long-term metformin treatment on liver function or liver histology. This study investigated the correlation between metformin use and the incidence of nonalcoholic fatty liver disease (NAFLD) among patients with T2DM. This population-based study investigated the risk of NAFLD among patients with T2DM who received metformin treatment between 2001-2018. Metformin users and metformin nonusers were enrolled and matched to compare the risk of NAFLD. After 3 years, the patients who received <300 cDDD of metformin and those with metformin use intensity of <10 and 10-25 DDD/month had odds ratios (ORs) of 1.11 (95% confidence interval [CI] = 1.06-1.16), 1.08 (95% CI = 1.02-1.13), and 1.18 (95% CI = 1.11-1.26) for NAFLD, respectively. Moreover, metformin users who scored high on the Diabetes Complications and Severity Index (DCSI) were at high risk of NAFLD. Patients with comorbid hyperlipidemia, hyperuricemia, obesity, and hepatitis C were also at high risk of NAFLD. Patients with T2DM who received metformin of <300 cDDD or used metformin at an intensity of <10 and 10-25 DDD/month were at a high risk of developing NAFLD. The results of this study also indicated that patients with T2DM receiving metformin and with high scores on the DCSI were at a high risk of developing NAFLD.

Metabolic and clinical profiles of young people with mood or psychotic disorders who are prescribed metformin in an inpatient setting.

Youth with early-onset mood or psychotic disorders are occasionally prescribed metformin to manage cardiometabolic risk. This retrospective study explores the demographic, clinical and metabolic factors associated with metformin prescription youth with mood or psychotic disorders. Participants included 72 youth with mood or psychotic disorders from a young adult mental health inpatient unit, of which 18 (33%) were newly prescribed metformin, and 54 (66%) were not prescribed metformin. Demographic and clinical information were extracted from the patients' medical files along with body mass index (BMI), fasting serum bloods and calculated updated homeostatic model of insulin resistance assessment (HOMA2-IR) scores to compare profiles between groups. Of those prescribed metformin, 83% were overweight or obese and 72% had elevated HOMA2-IR scores. Of those not receiving metformin treatment, 41% were overweight or obese and 22% had elevated HOMA2-IR scores. Youth prescribed metformin had significantly higher BMI, and elevated markers of insulin resistance, but did not differ to those not prescribed metformin on other demographic, clinical or metabolic factors. While metformin is prescribed to some youth with mood or psychotic disorders displaying markers of cardiometabolic disturbance, there is a need to develop clearer treatment guidelines for metformin in these youth.

Insulin resistance attenuates the impact of levothyroxine on thyroid autoimmunity and hypothalamic-pituitary-thyroid axis activity in women with autoimmune subclinical hypothyroidism.

Subjects with both subclinical hypothyroidism and autoimmune thyroiditis are frequently diagnosed with metabolic syndrome. The purpose of the current study was to investigate whether insulin sensitivity determines levothyroxine action on thyroid antibody titres and hypothalamic-pituitary-thyroid axis activity in young women with autoimmune subclinical hypothyroidism. The study population consisted of three age-, thyroid antibody- and thyrotropin-matched groups of women with autoimmune subclinical hypothyroidism: metformin-naive women with insulin resistance (group A, n=31), women receiving metformin treatment because of insulin resistance (group B, n=32), as well as metformin-naive women with normal insulin sensitivity (group C, n=35). Throughout the study, all subjects were treated with levothyroxine. Titres of thyroid peroxidase and thyroglobulin antibodies, as well as circulating levels of glucose, insulin, lipids, thyrotropin, free thyroid hormones, prolactin, high-sensitivity C-reactive protein (hsCRP) and 25-hydroxyvitamin D were determined at the beginning of the study and 6months later. Except for two individuals, all patients completed the study. At baseline, group A differed from groups B and C in circulating levels of glucose, HDL-cholesterol, triglycerides, hsCRP, 25-hydroxyvitamin D and the homeostatic model assessment 1 of insulin resistance (HOMA1-IR). Although levothyroxine reduced thyroid antibody titres, decreased thyrotropin levels and increased free thyroid hormone levels in all studied groups, the effect on antibody titres and thyrotropin levels was more pronounced in groups B and C than in group A. The impact of levothyroxine on thyroid antibody titres correlated with baseline and treatment-induced changes in HOMA1-IR, thyrotropin, hsCRP and 25-hydroxyvitamin D. The results of the current study suggest that the impact of exogenous levothyroxine on thyroid autoimmunity and hypothalamic-pituitary-thyroid axis activity is determined by insulin sensitivity.

The effect of non-oncology drugs on clinical and genomic risk in early luminal breast cancer.

e12505 Background: In women with ER-positive, HER2-negative early stage breast cancer (BC), treatment decisions for adjuvant chemotherapy are based on genomic risk and clinical risk. Recently, an effect of non-oncology medications on cancer cell lines and cancer outcome have been suggested. In this study we aimed to systematically examine the impact of non- oncology drugs on clinical risk and genomic risk (based on OncotypeDx recurrence score [RS]) in early BC. Methods: We collected data from 1385 files of ER positive HER2 negative breast cancer patients regarding their clinical risk (stage and grade), genomic risk (OncotypeDx RS) as well as data regarding medications the patients received during the month before their surgery. Statistical analysis was applied to identify the influence of various medications on OncotypeDx RS. Results: Out of the various medications we examined, we found that Levothyroxine was significantly associated with high median OncotypeDx RS (RS median = 25 ;p &lt; 0.0001) and Metformin was associated with low median OncotypeDx RS (RS median = 12 p &lt; 0.0011) in comparison to patients not receiving these medications (RS median = 17). By contrast there were no differences in the clinical risk between patients who received Metformin or Levothyroxine. Notably, Levothyroxine and metformin did not impact proliferation marker (Ki67) levels but did impact progesterone-related features, suggesting they influence genomic risk through estrogen dependent modules. Indeed, scores of other genomic tests (PAM50, Mammaprint), which are determined largely by proliferative features, were not influenced by Levothyroxine or Metformin. Finally, by using contemporary guidelines to recommend adjuvant chemotherapy based on clinical risk and genomic risk (OncotypeDx ) we show that patients (Age &gt; 50) who received Metformin treatment had 14.5% chance to be recommended adjuvant chemotherapy while patients who received Levothyroxine had 49% (p = 0.0001). Conclusions: The results of this study indicate significant impact of Metformin and Levothyroxine on clinical decisions with potential impact on early BC patients.

Dose-dependent accumulation of glucose in the intestinal wall and lumen induced by metformin as revealed by 18 F-labelled fluorodeoxyglucose positron emission tomography-MRI.

To investigate the relationships between various clinical variables and the metformin-induced accumulation of fluorodeoxyglucose (FDG) in the intestine, with distinction between the intestinal wall and lumen, in individuals with type 2 diabetes who were receiving metformin treatment and underwent 18 F-labelled FDG ([18 F]FDG) positron emission tomography (PET)-MRI. We evaluated intestinal accumulation of [18 F]FDG with both subjective (a five-point visual scale determined by two experienced radiologists) and objective analyses (measurement of the maximum standardized uptake value [SUVmax ]) in 26 individuals with type 2 diabetes who were receiving metformin and underwent [18 F]FDG PET-MRI. [18 F]FDG accumulation within the intestinal wall was discriminated from that in the lumen on the basis of SUVmax . SUVmax for the large intestine was correlated with blood glucose level (BG) and metformin dose, but not with age, body mass index, HbA1c level or estimated glomerular filtration rate (eGFR). SUVmax for the small intestine was not correlated with any of these variables. Visual scale analysis yielded essentially similar results. Metformin dose and eGFR were correlated with SUVmax for the wall and lumen of the large intestine, whereas BG was correlated with that for the wall. Multivariable analysis identified metformin dose as an explanatory factor for SUVmax in the wall and lumen of the large intestine after adjustment for potential confounders including BG and eGFR. Metformin dose is an independent determinant of [18 F]FDG accumulation in the wall and lumen of the large intestine in individuals treated with this drug.

Metformin treatment vs a diabetes model of prenatal care in women with mild fasting hyperglycemia diagnosed in pregnancy: a feasibility study

Introduction Guidelines disagree on the diagnostic thresholds for gestational diabetes (GDM); treatment of women with mild fasting hyperglycemia may not be cost-effective and increase unnecessary intervention. Materials and methods Single-center, open-label randomized controlled feasibility trial (ISRCTN86503951). “Metformin” treatment (2 g/day) without home blood glucose monitoring (HBGM) compared to NICE “standard” diabetes prenatal care in women with fasting 5.1–5.4 mmol/L, 2H <8.5 mmol/L) at oral glucose tolerance test (OGTT). Results Process outcome: From the 173 women approached, 40/147 (27%) met the eligibility criteria and agreed to participate (non-completion n = 3). All women received dietary advice. Overall, compliance was good; with the majority of women in the treatment arm reporting missing metformin tablets less than 1–3 times/week. In the treatment arm (n = 18), median compliance (returned packets) was 65% [0–98%]; four women were unable to tolerate the full recommended dose of metformin. All women reported being satisfied with their treatment; with 9 out of 18 women (metformin arm) reporting they would choose the same treatment in a future pregnancy however 8 women reported they would want closer prenatal monitoring. Clinical outcome: Baseline characteristics and pregnancy outcomes were not different between participants and non-participants (n = 133). In women randomized to the standard care arm who performed HBGM, 15/19 were prescribed metformin based on values above target despite diet and lifestyle modifications; two women required additional insulin (10%). Data on glycemic control were available for 16/19 women; a reduction in fasting and post-prandial glucose was achieved in 15/16 from recruitment to 36 weeks. There was no change in A1C in women in the treatment arm vs the standard care arm. There was no difference in the rates of LGA between participants (n = 40) and non-participants (n = 133), although there was a reduction in the median birthweight centiles in the participants, the majority of whom received metformin treatment, compared with the non-participants (35 [IQR 12–54] vs 52 [25–78]; p = .045). Discussion Treatment with metformin in conjunction with routine care was acceptable to women with mild fasting hyperglycemia who participated in the trial, although overall recruitment to the study was low. Most women with mild fasting hyperglycemia (5.1–5.4 mmol/L) would meet the threshold for pharmacological treatment if identified as GDM based on current NICE guideline target blood glucose levels. However, given the low consent rate, it is unlikely that a future RCT comparing metformin treatment (in conjunction with routine prenatal care and without HBGM monitoring) to a diabetes prenatal clinic model of care would have the generalisability to inform the future management of this group.

Metformin use reduced the overall risk of cancer in diabetic patients: A study based on the Korean NHIS-HEALS cohort

Background and aimSeveral studies have reported the preventive effect of metformin on cancer development. This study aimed to investigate the relationship between use of metformin and risk of cancer in Koreans. Methods and ResultsThis study was designed retrospectively using the National Health Insurance Service-National Health Screening Cohort conducted between 2002 and 2015. 40 to 69-year-old subjects who received a health screening examination from 2002 to 2003 were enrolled. Hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer were estimated in a multivariate Cox proportional regression analysis.A total of 323,430 subjects was enrolled (301,905 individuals without diabetes [No DM], 8643 diabetic patients with metformin treatment [metformin users], and 12,882 diabetic patients without metformin treatment [metformin non-users]). The median follow-up period was 12.7 years. Cumulative incidence of overall cancer was 7.9% (7.7, 10.3, and 11.1% in No DM, metformin users and non-users, respectively). Compared to metformin non-users, the fully adjusted HRs (95% CIs) of metformin users and No DM for overall cancer incidence were 0.73 (0.66–0.81) and 0.75 (0.64–0.88), respectively, in men and 0.83 (0.78–0.89) and 0.81 (0.72–0.92) in women. ConclusionsDiabetic patients receiving metformin treatment, and individuals without diabetes were at lower risk for cancer incidence than diabetic patients without metformin treatment.

SUN-695 Should Vitamin B12 Status Monitoring Be Implemented for Patients Taking Metformin?

Introduction: Cobalamin (vitamin B12) is used in multiple metabolic processes, functioning primarily as a coenzyme with Methylmalonyl-CoA mutase and Methionine synthase in humans. Without functioning enzyme, substrate levels build up which are neurotoxic, leading to neurological debilitation. Lack of enzyme also halts cellular replication processes causing severe anemia. Since numerous studies have found decreased cobalamin levels in patients who regularly take metformin1, then could regular monitoring of cobalamin levels in such patients prevent these outcomes? Case Presentation: We present a 50-year-old female who reported to the ED with general weakness and shortness of breath after having a seizure. Her medical history included type 2 diabetes mellitus being treated with metformin and a history of seizures controlled by carbamazepine since childhood.Neurological exam abnormalities consisted of DTRs that were 1/4 on all proximal and distal upper and lower extremities and absent fine sensory and vibratory sensation on ankles and feet bilaterally. Patient was also ataxic. Hgb A1c was 14%. Head CT, chest x-ray, EKG, and cardiac markers found no abnormalities. CBC found a profound pancytopenia with WBC 1.6, RBC 1.27, Hgb 5.2, MCV 119, MCH 40.9, MCHC 34.3, RDW 18.2, and platelets 113. Blood smear was normal. Bone marrow sample showed normochromic macrocytic cells with no other abnormalities. Folate level was normal and cobalamin was found to be low (61.5 pmol/L). Intrinsic factor antibodies were negative. Extensive autoimmune workup was also negative. Discussion: Our patient’s neurological symptoms and pancytopenia were found to be due to multiple factors. R. Pawlak, found that metformin use had a 2.45 (p < 0.0001) times higher odds of developing B12 deficiency in comparison to non-metformin users1. This was also supported by a systemic review of the impact of metforminCarbamazepine is known for its effects on decreasing the absorption of folate and has statistically been found to decrease cobalamin significantly as well.There are several B12 assessment methods available to providers, including serum/plasma B12, Mean Corpuscular Volume (MCV), Homocysteine (Hcy), Holotranscobalamin II (holoTCII), and serum and urinary Methylmalonic Acid (MMA). Urinary MMA has been found to be the most specific and sensitive of these markers when adjusted by kidney function (through serum creatinine levels) and while fasting Conclusion: Currently, there are no screening guidelines by the U.S.P.S.T.F or American Diabetes Association for cobalamin deficiency. However, neurologic deficits and macrocytic anemia could be prevented through monitoring cobalamin levels in diabetics receiving metformin treatment. This monitoring might be needed more in patients with seizure disorderon Carbamazebin.