Efficacy Of Metformin Research Articles

Abstract 4118959: Pulmonary Artery-Targeted Metformin-Loaded Nanocapsules Enhance Treatment of Pulmonary Arterial Hypertension

Background: Pulmonary arterial hypertension (PAH) remains a therapeutic challenge despite the availability of various medications. Metformin can be able to treat PAH but is associated with significant side effects. This study aims to enhance the efficacy and safety of metformin through a novel drug delivery system using low-dose metformin encapsulated in pulmonary artery-targeted nanocapsules. Methods: Metformin-loaded lung-targeted nanocapsules (MET nanocapsules) were synthesized using a specific lipid composition, including cationic lipids. The uptake and effects on cell viability were assessed in human pulmonary arterial smooth muscle cells (hPASMCs) from both healthy individuals and PAH patients. The therapeutic efficacy of MET nanocapsules was evaluated in a rat model of PAH. Safety was confirmed via serum biochemical tests in rats. Results: MET nanocapsules were successfully synthesized and demonstrated significant inhibition of PASMC proliferation. In the PAH rat model, MET nanocapsule treatment led to improved hemodynamic parameters, reduced right ventricular hypertrophy, and decreased pulmonary arterial medial thickening. Importantly, MET nanocapsules showed effective accumulation in the lungs of PAH rats. Conclusions: Intravenous administration of MET nanocapsules represents a safe and innovative therapeutic approach for PAH. This targeted delivery system has the potential to improve treatment outcomes while minimizing side effects and may have broader applications for other forms of pulmonary hypertension.

Metformin in gestational diabetes: physiological actions and clinical applications.

Metformin is an effective oral hypoglycaemic agent used in the treatment of type 2 diabetes mellitus; however, its use in pregnancy for the treatment of gestational diabetes mellitus (GDM) remains controversial owing to concerns around safety and efficacy. This comprehensive review outlines the physiological metabolic functions of metformin and synthesizes existing literature and key knowledge gaps pertaining to the use of metformin in pregnancy across various end points in women with GDM. On the basis of current evidence, metformin reduces gestational weight gain, neonatal hypoglycaemia and macrosomia and increases insulin sensitivity. However, considerable heterogeneity between existing studies and the grouping of aggregate and often inharmonious data within meta-analyses has led to disparate findings regarding the efficacy of metformin in treating hyperglycaemia in GDM. Innovative analytical approaches with stratification by individual-level characteristics (for example, obesity, ethnicity, GDM severity and so on) and treatment regimens (diagnostic criteria, treatment timing and follow-up duration) are needed to establish efficacy across a range of end points and to identify which, if any, subgroups might benefit from metformin treatment during pregnancy.

Metformin Attenuates Vocal Fold Fibrosis via AMPK Signaling.

Vocal fold fibrosis is a challenging condition with no clear consensus on effective treatment methods. Given the demonstrated efficacy of metformin in treating various fibrotic diseases, we hypothesized that metformin could reduce vocal fold fibrosis via the AMPK signaling pathway. In our study, we induced vocal fold injury in rabbits and administered metformin intraperitoneally at a dose of 250mg/kg two weeks post-injury. Four weeks after the injury, vocal folds were excised and analyzed for fibrosis using Masson's trichrome staining, immunohistochemistry, quantitative real-time polymerase chain reaction (qPCR), and Western blotting. In vitro, vocal fold fibroblasts treated with metformin (10μM) ± TGF-β1 (10ng/mL) were utilized to assess metformin's antifibrotic effects, with Compound C (10μM) employed to inhibit AMPK signaling. Our results demonstrate that metformin significantly improved the structural integrity of the vocal fold lamina, reduced collagen deposition, and decreased the expression levels of COL1A1 and α-SMA. Furthermore, metformin activated the AMPK signaling pathway in vocal fold fibroblasts, resulting in decreased expression of COL1A1, α-SMA, TGF-β, Smad2, and Smad3. These findings suggest that metformin attenuates vocal fold fibrosis by modulating the AMPK signaling pathway, providing a foundation for developing new therapeutic options for vocal fold fibrosis.

The population-specific Thr44Met OCT3 coding variant affects metformin pharmacokinetics with subsequent effects on insulin sensitivity in C57Bl/6J mice.

Metformin is an important first-line treatment for type 2 diabetes and acts by increasing the body's ability to dispose of glucose. Metformin's efficacy can be affected by genetic variants in the transporters that regulate its uptake into cells. The SLC22A3 gene (also known as EMT; EMTH; OCT3) codes for organic cation transporter 3 (OCT3), which is a broad-specificity cation transporter that also transports metformin. Most SLC22A3 variants reduce the rate of metformin transport but the rs8187715 variant (p.Thr44Met) is reported to increase uptake of metformin in vitro. However, the impact of this on in vivo metformin transport and efficacy is unknown. Very few carriers of this variant have been reported globally, but, notably, all were of Pacific Island descent. Therefore, this study aims to understand the prevalence of this variant in Polynesian peoples (Māori and Pacific peoples) and to understand its impact on metformin transport and efficacy in vivo. rs8187715 was genotyped in 310 individuals with Māori and Pacific ancestry recruited in Aotearoa New Zealand. To study this variant in a physiological context, an orthologous knockin mouse model with C57BL/6J background was used. Pharmacokinetic analysis compared uptake rate of metformin into tissues. Plasma growth/differentiation factor 15 (GDF-15) was also measured as a marker of metformin efficacy. Glucose and insulin tolerance was assessed after acute or sustained metformin treatment in knockin and wild-type control mice to examine the impact of the variant on metformin's glycaemic control. The minor allele frequency of this variant in the Māori and Pacific participants was 15.4%. There was no association of the variant with common metabolic parameters including diabetes status, BMI, blood pressure, lipids, or blood glucose and HbA1c. However, in the orthologous knockin mouse model, the rate of metformin uptake into the blood and tissues was increased. Acute metformin dosing increased insulin sensitivity in variant knockin mice but this effect was lost after longer-term metformin treatment. Metformin's effects on GDF-15 levels were also lost in variant knockin mice with longer-term metformin treatment. These data provide evidence that the SLC22A3 rs8187715 variant accelerates metformin uptake rate in vivo. While this acutely improves insulin sensitivity, there was no increased effect of metformin with longer-term dosing. Thus, our finding of a high prevalence of this variant specifically in Māori and Pacific peoples identifies it as a potential population-specific pharmacogenetic marker with potential to guide metformin therapy in these peoples.

Metformin modulates the TXNIP-NLRP3-GSDMD pathway to improve diabetic bladder dysfunction

To validate the therapeutic efficacy of metformin on diabetic bladder dysfunction (DBD) and further elucidate whether the TXNIP-NLRP3-GSDMD axis serves as a target for metformin in ameliorating DBD. C57BL/6J mice were induced with diet-induced obesity by being fed a high-fat diet (HFD) for 16 weeks. After establishing the model, the mice were treated with metformin for 4 weeks, and their glucose metabolism-related parameters were assessed. Urine spot assays and urodynamic measurements were conducted to reflect the bladder function and urinary behavior in mice, while histological examination was performed to observe morphological changes. Western blot analysis was employed to measure the expression levels of pyroptotic factors such as TXNIP, NLRP3, GSDMD, and tight junction proteins. Metformin treatment significantly improved glucose tolerance and insulin sensitivity in mice. Moreover, it showed promise in decreasing urinary spot occurrence, reducing urination frequency, alleviating non-voiding contractions, and stabilizing peak urinary pressure. Following metformin therapy, mice displayed restored epithelial fold structure, increased thickness of the muscular layer, substantial decrease in muscle fiber content, notably reduced levels of TXNIP and GSDMD proteins in the metformin-treated group compared to the DBD group, and restored expression of tight junction proteins Zo-1, Claudin-1, and Occludin. Metformin ameliorates urothelial cells damage in DBD mice by inhibiting TXNIP generation and reducing NLRP3 and GSDMD production.

Unveiling the impacts of metformin on hepatocellular carcinoma: A bioinformatic exploration in cell lines

The most common type of liver cancer is hepatocellular carcinoma (HCC), accounting for 75–85% of cases. Despite its associated side effects, sorafenib remains the standard treatment for HCC. Given the critical need to improve therapeutic efficacy while minimizing adverse effects, alternative drugs must be thoroughly investigated. Numerous studies indicate that combining sorafenib with metformin results in a more favorable treatment profile. The aim of this study was to employ bioinformatics methodologies to elucidate the molecular pathways and genetic underpinnings of metformin's efficacy in HCC treatment. Genes associated with metformin and its action against HCC (Huh-7 and HepG2 cells) were acquired from the NCBI-GEO data collection by utilizing pre-determined keywords. Subsequently, pathways implicated in metformin-mediated HCC treatment were analyzed through the Kyoto Encyclopedia of Genes and Genomes (KEGG). Our analysis revealed the involvement of multiple pathways, with metabolic pathways implicated in 80% of the total cases. Neurodegenerative pathways were involved in only around 60% of the total cases. These findings align with the multifaceted mechanisms of metformin’s action, encompassing adenosine monophosphate-activated protein kinase activation, apoptosis induction, insulin regulation, anti-inflammatory responses, and modulation of cell proliferation. This comprehensive investigation sheds light on the intricate molecular landscape underpinning metformin's therapeutic efficacy in HCC, thereby informing potential avenues for optimizing treatment strategies.

Safety and Efficacy of Metformin for Idiopathic Intracranial Hypertension. A U.S-Based Real-World Data Retrospective Multicenter Cohort Study.

Idiopathic intracranial hypertension (IIH) remains a challenging condition to manage, with limited therapeutic options. This study investigated the potential of metformin as a novel treatment for IIH, exploring its effects on disease outcomes and safety profile. We conducted a retrospective cohort study using the TriNetX database, analyzing data from 2009 to August 2024. Patients diagnosed with IIH were included, with exclusions for other causes of elevated intracranial pressure and pre-existing diabetes. Propensity score matching was employed to balance cohorts according to age, sex, race, ethnicity, Hemoglobin A1C, and baseline body mass index (BMI) at the time of metformin initiation. Outcomes were assessed at various follow-up points up to 24 months. Our study initially comprised 1,268 patients in the metformin group and 49,262 in the control group, with notable disparities in several parameters. Post-matching, both cohorts were refined to 1,267 patients each after matching with metformin group. Metformin-treated patients showed significantly lower risks of papilledema, headache, and refractory IIH status at all follow-up points (p<0.0001). The metformin group also had reduced rates of therapeutic spinal punctures and acetazolamide continuation. BMI reductions were more pronounced in the metformin group, with significant differences observed from 6 months onward (p<0.0001). Notably, metformin's beneficial effects persisted independently of BMI changes. The safety profile of metformin was favorable, with no significant differences in adverse events compared to the control group which did not receive metformin during the study timeframe. Our study provides evidence for metformin's potential as a disease-modifying therapeutic approach in IIH, demonstrating improvements across multiple outcomes. The benefits appear to extend beyond weight loss, suggesting complex mechanisms of action. These findings warrant further investigation through prospective clinical trials to establish metformin's role in IIH management and explore its underlying therapeutic mechanisms.

Association of metformin use with asthma development and adverse outcomes: A systematic review and meta-analysis.

Asthma and diabetes are prevalent chronic diseases affecting a significant population globally. Research has suggested that metformin, a commonly used medication for diabetes management, may also have beneficial effects in enhancing asthma outcomes. Considering the comorbidity of asthma and diabetes, a comprehensive analysis was performed to investigate the efficacy of metformin in reducing adverse outcomes of asthma patients with diabetes. To gather relevant data, we conducted a systematic search of the PubMed, Embase, and CENTRAL databases for observational studies published prior to September 2023. We specifically looked for studies involving individuals diagnosed with both asthma and diabetes, comparing the incidence and severity of asthma exacerbations in metformin users versus nonusers. The inclusion criteria encompassed studies that recruited participants aged 18 years and older. The primary outcome of interest was the risk of newly developing asthma, while secondary outcomes included the adjusted risk of asthma-induced exacerbations, emergency room visits, and hospitalizations. All data analyses and visualizations were performed using the R programming language. We identified and included 7 studies involving a total of 1,176,398 patients in our analysis. The pooled effect size indicated a potential reduction in the incidence of newly developed asthma among patients with type 2 diabetes who used metformin, although this finding did not reach statistical significance. Similar conclusions have also been observed in other outcomes, such as exacerbation, asthma-related emergency department visits, risk of systemic corticosteroid prescription. The only positive outcome is that the use of metformin can reduce the chance of patients being hospitalized due to asthma. In most outcome indicators, it cannot be assumed that the use of metformin can reduce asthma-related adverse events. However, the conclusion is not so certain, and longer observation and more evidence are still required. Metformin still shows some potential in the intervention of respiratory diseases.

Efficacy of WeChat-Based Digital Intervention Versus Metformin in Women With Polycystic Ovary Syndrome: Randomized Controlled Trial.

The first-line treatment for polycystic ovary syndrome (PCOS) is lifestyle modification. However, it is currently unknown whether digital medicine can assist patients with PCOS in maintaining a healthy lifestyle while alleviating PCOS symptoms. This study aims to evaluate the efficacy of WeChat-based digital intervention versus metformin treatment in women with PCOS and insulin resistance. A total of 80 women with PCOS and insulin resistance were recruited from an endocrinology clinic and randomly assigned to receive either a WeChat-based digital intervention (n=40, 50%) or metformin (n=40, 50%) for 12 weeks. The WeChat-based digital intervention consisted of 3 modules; a coach assisted the patients in using the intervention. The primary outcome was the change in a homeostatic model assessment for insulin resistance. At baseline and after the 12-week intervention, anthropometric parameters, menstruation frequency, sex hormone levels, metabolic factors, and body fat distribution were measured in the clinic. Furthermore, self-assessed web-based questionnaires on diet, exercise, sleep, anxiety, and depression were obtained. A total of 72 participants completed the follow-up (for a 90% follow-up rate), including 35 of 40 (88%) participants from the digital intervention group and 37 of 40 (93%) participants from the metformin group. The homeostatic model assessment for insulin resistance in the digital intervention group was significantly improved after 12 weeks of treatment with a mean change of -0.93 (95% CI -1.64 to -0.23), but no statistical difference was observed between the groups (least squares mean difference -0.20; 95% CI -0.98 to 0.58; P=.62). Both digital intervention and metformin treatment significantly improved menstruation frequency (digital intervention: P<.001; metformin: P<.001) and reduced body weight (digital intervention: P<.001; metformin: P<.001) and total fat mass (digital intervention: P<.001; metformin: P<.001). Furthermore, the digital intervention had a significant advantage over metformin in improving waist circumference (least squares mean difference -1.84; 95% CI -3.44 to -0.24; P=.03), waist-to-hip ratio (least squares mean difference -0.02; 95% CI -0.03 to 0.00; P=.03), total fat mass (least squares mean difference -1.59; 95% CI -2.88 to -0.30; P=.02), and dehydroepiandrosterone sulfate (least squares mean difference -69.73; 95% CI -129.70 to -9.75; P=.02). In terms of safety, the main adverse events were sensations of hunger in the digital intervention group (2/40, 5%) and gastrointestinal adverse events in the metformin group (12/40, 30%). Our data suggest that digital intervention is an effective treatment option for patients with PCOS, with an efficacy comparable to that of metformin, and that it can also alleviate the negative effects of medications and make it easier and more efficient to adhere to lifestyle treatments. WeChat-based digital interventions have the potential to provide a new path for the improvement and health of women with PCOS in China. ClinicalTrials.gov NCT05386706; https://clinicaltrials.gov/study/NCT05386706.

9353 The Impact Of Artificially Sweetened Drinks On Metformin Efficacy

9353 The Impact Of Artificially Sweetened Drinks On Metformin Efficacy

Metformin Preconditioning Augments Cardiac Perfusion and Performance in a Large Animal Model of Chronic Coronary Artery Disease.

To test the efficacy of metformin (MET) during the induction of coronary ischemia on myocardial performance in a large animal model of coronary artery disease (CAD) and metabolic syndrome (MS), with or without concomitant extracellular vesicular (EV) therapy. Although surgical and endovascular revascularization are durably efficacious for many patients with CAD, up to one-third are poor candidates for standard therapies. For these patients, many of whom have comorbid MS, adjunctive strategies are needed. EV therapy has shown promise in this context, but its efficacy is attenuated by MS. We investigated whether MET pretreatment could ameliorate therapeutic decrements associated with MS. Yorkshire swine (n = 29) were provided a high-fat diet to induce MS, whereupon an ameroid constrictor was placed to induce CAD. Animals were initiated on 1000 mg oral MET or placebo; all then underwent repeat thoracotomy for intramyocardial injection of EVs or saline. Swine were maintained for 5 weeks before the acquisition of functional and perfusion data immediately before terminal myocardial harvest. Immunoblotting and immunofluorescence were performed on the most ischemic tissue from all groups. Regardless of EV administration, animals that received MET exhibited significantly improved ejection fraction, cardiac index, and contractility at rest and during rapid myocardial pacing, improved perfusion to the most ischemic myocardial region at rest and during pacing, and markedly reduced apoptosis. MET administration reduced apoptotic cell death, improved perfusion, and augmented both intrinsic and load-dependent myocardial performance in a highly translatable large animal model of chronic myocardial ischemia and MS.

Testosterone and the prevention of type 2 diabetes mellitus: therapeutic implications from recent trials.

Type 2 diabetes (T2D) is increasing to epidemic proportions and frequently associated with obesity and a low serum testosterone concentration in men. This review valuates recent randomized controlled trials (RCTs) investigating the effect of testosterone treatment on glycemic control and T2D prevention. The 2-year Testosterone for the Prevention of Type 2 diabetes Trial (T4DM) study showed that in men aged 50 years and over with visceral obesity and impaired glucose tolerance, testosterone treatment on the background of a lifestyle intervention reduced T2D risk by 40%. The Testosterone Effects on Atherosclerosis Progression in Aging Men and Testosterone Trials demonstrated modest improvements in insulin sensitivity and body composition. However, the Testosterone Replacement Therapy for Assessment of Long-Term Vascular Events and Efficacy Response in Hypogonadal Men trial found no significant glycemic benefits over 2 years. Recent data from the Diabetes Prevention Program Outcome Study support the cost efficacy and durability of metformin. In men at high risk of T2D, treatment with testosterone prevents the disease; however, there are caveats to its use and other approaches may be more applicable. Differences in trial designs, age groups, and outcome measures contribute to varying results. HbA1C is a suboptimal outcome measure. Future research should explore potential synergies between testosterone and GLP-1 receptor agonists in T2D management, while considering cost-effectiveness.

Efficacy of Metformin plus Sodium Glucose Transporter-2 inhibitors (SGLT-2i) in Obese Type 2

Efficacy of Metformin plus Sodium Glucose Transporter-2 inhibitors (SGLT-2i) in Obese Type 2

Metformin dampens the progression of cholangiofibrosis induced by thioacetamide using deep learning

PurposeThe consistent use of metformin has been linked to a reduced incidence of neoplastic diseases among diabetic populations. As a preventive intervention, metformin may offer a more favorable risk-benefit profile. Here, we explored the efficacy of metformin in the primary prevention of cholangiofibrosis, which can precede the carcinogen-induced development of cholangiocarcinoma (CCA). Our objective was to assess the potential of metformin to act as an intervention prior to the onset of these conditions. MethodsA rat model of thioacetamide (TAA)-induced cholangiofibrosis was utilized to assess the impact of metformin on the induction process of cholangiocarcinoma (CCA). Liver tissues were harvested and analyzed histologically using light microscopy, complemented by a deep-learning convolutional neural network for enhanced evaluation. Additionally, RNA sequencing (RNA-seq) was performed to investigate the genetic alterations associated with metformin treatment in this TAA-induced cholangiofibrosis model. ResultsIn the rat model, the TAA control group exhibited an increased incidence and average count of cholangiofibrosis cases in the liver, with rates of 100 % and an average of 12.0, compared to the metformin-treated group, which showed an incidence of 70 % and an average of 3.3. Notably, the progression from normal cholangioles to cholangiofibrosis was associated with the upregulation of several proteins critical for metabolic processes and the tumor microenvironment. These alterations were significantly mitigated by metformin treatment. ConclusionsLong-term metformin use may offer protective benefits against cholangiofibrosis, partially by regulating metabolic processes and improving the tumor microenvironment.

Evaluating the Efficacy of Metformin and Camel Milk on Streptozotocin-nicotinamide Induced Diabetic Albino Rats

Background: This study was intended to evaluate the anti-diabetic activity of metformin and camel milk solely or in combination in streptozotocin- nicotinamide induced type II diabetic albino Wistar rats. Methods: Thirty albino Wistar rats were induced with type II diabetes through streptozotocin (60 mg/kg), followed by the administration of nicotinamide (120 mg/kg) after 15 min. The rats were randomly divided into control, diabetic control, metformin-treated (100 mg/kg), camel milk-treated (50 ml/rat/day) and metformin + camel milk-treated groups for 30 days. For this study, rats with blood glucose levels higher than 250 mg/dL were included. Blood glucose levels and body weight were measured at the beginning of the study and at regular intervals throughout the experiment.Furthermore, histopathological examination of liver, kidney and pancreatic tissue was conducted to determine the effects of metformin and camel milk on these organs. Result: The results showed that treatment with metformin, camel milk, or a combination of both significantly reduced fasting blood glucose levels and improved body weight compared to the diabetic control group. Morphological improvements were also observed in the histopathological examination of liver, kidney and pancreatic tissue. The results of this study are consistent with previous research showing the anti-diabetic effects of metformin and support the emerging role of alternative therapies such as camel milk. However, further research is needed to explore the potential mechanisms underlying the observed effects.

Drug therapy of type-2-diabetes-is metformin dispensable now?

Metformin has been recommended as first-line pharmacological therapy in type‑2 diabetes (T2D) since 1998. It was the first medication that demonstrated cardiovascular benefits in obese subjects with T2D. Efficacy and safety of metformin have since been demonstrated in further studies and in real-world data on its use in practice. The recommendation of metformin as baseline therapy has reached wide acceptance internationally. During the period 2015-2021, large cardiovascular safety trials showed superiority for cardiovascular morbidity and partly also mortality outcomes for most substances of the novel antidiabetic substance classes of GLP‑1 receptor agonists and SGLT‑2 inhibitors in people with T2D and very high cardiovascular risk or preexisting cardiovascular disease. The evidence for these two substance classes is now broader than for metformin. Therefore, the question arises as to whether it is still justified to recommend metformin generally as first-line therapy in T2D. This article provides an overview of the study data as well as an overview of the evidence-based guidelines. The status and position of metformin in the treatment of T2D are discussed.

Interplay between gut microbiota and tryptophan metabolism in type 2 diabetic mice treated with metformin.

This study provides valuable insights into the interrelationship between metformin administration, changes in the tryptophan (TRP) metabolome, and gut microbiota in type 2 diabetes mellitus (T2DM) mice. Indole-3-lactic acid (ILA)/indole-3-propionic acid (IPA) emerges as a potential biomarker for the development of T2DM and prediction of therapeutic response. While the indole metabolic pathway has long been associated exclusively with the gut microbiome, recent research has demonstrated the ability of host interleukin-4-induced-1 to metabolize TRP. The detection of indole derivatives in the serum of germ-free mice suggests the existence of inherent endogenous indole metabolic pathways. These findings deepen our understanding of metformin's efficacy in correcting TRP metabolic disorders and provide valuable directions for further investigation. Moreover, this knowledge may pave the way for the development of targeted treatment strategies for T2DM, focusing on the gut microbiome and restoration of associated TRP metabolism.

Association of Single Nucleotide Polymorphism in OCT1 and OCT3 Genes with the Efficacy of Metformin Response in North Indian Type 2 Diabetes Mellitus Patients

Introduction: Variability in the effectiveness of metformin treatment among individuals with type 2 diabetes mellitus (T2DM) has been linked to various genetic factors. Understanding the genetic mechanisms underlying the action of metformin can greatly aid the personalized management of T2DM. Our investigation aimed to explore the impact of genetic variations in the organic cation transporters (OCT1 and OCT3) genes on the efficacy of metformin therapy in T2DM individuals from North India. Methods: This observational cross-sectional study assessed the influence of OCT1 (rs628031) and OCT3 (rs2292334) polymorphisms on metformin response in T2DM patients. Metformin response was determined based on HbA1c levels, dividing patients (n = 177) into two categories: responders (HbA1C&lt;7%; n = 127) and non-responders (HbA1C≥7%; n = 50). Responders were further classified as T2DM patients receiving either monotherapy (n = 55) or combination therapy (n = 72). Genotyping was conducted using the PCR-RFLP method. Results: No significant association was observed between OCT1 (rs628031) polymorphism and metformin response in T2DM patients. However, a notable association was found between OCT3 (rs2292334) polymorphism and metformin response. Carriers of the AA genotype exhibited enhanced efficacy of metformin in both monotherapy (OR (CI)= 0.29(0.11-0.72), p=0.007) and combination therapy (OR (CI)= 0.41(0.16-1.0), p=0.047). Additionally, the A allele was more prevalent in responders (OR (CI)= 0.48(0.28-0.84), p=0.010), while the G allele was associated with reduced efficacy of metformin in T2DM patients (OR (CI)= 2.07(1.19-3.61), p=0.010). Conclusion: Genotyping of OCT3 (rs2292334) may serve as a valuable tool in predicting the response to metformin in T2DM patients.

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.

Efficacy and Safety of Metformin and Atorvastatin Combination Therapy vs. Monotherapy with Either Drug in Type 2 Diabetes Mellitus and Dyslipidemia Patients (ATOMIC): Double-Blinded Randomized Controlled Trial.

It is well known that a large number of patients with diabetes also have dyslipidemia, which significantly increases the risk of cardiovascular disease (CVD). This study aimed to evaluate the efficacy and safety of combination drugs consisting of metformin and atorvastatin, widely used as therapeutic agents for diabetes and dyslipidemia. This randomized, double-blind, placebo-controlled, parallel-group and phase III multicenter study included adults with glycosylated hemoglobin (HbA1c) levels >7.0% and <10.0%, low-density lipoprotein cholesterol (LDL-C) >100 and <250 mg/dL. One hundred eighty-five eligible subjects were randomized to the combination group (metformin+atorvastatin), metformin group (metformin+atorvastatin placebo), and atorvastatin group (atorvastatin+metformin placebo). The primary efficacy endpoints were the percent changes in HbA1c and LDL-C levels from baseline at the end of the treatment. After 16 weeks of treatment compared to baseline, HbA1c showed a significant difference of 0.94% compared to the atorvastatin group in the combination group (0.35% vs. -0.58%, respectively; P<0.0001), whereas the proportion of patients with increased HbA1c was also 62% and 15%, respectively, showing a significant difference (P<0.001). The combination group also showed a significant decrease in LDL-C levels compared to the metformin group (-55.20% vs. -7.69%, P<0.001) without previously unknown adverse drug events. The addition of atorvastatin to metformin improved HbA1c and LDL-C levels to a significant extent compared to metformin or atorvastatin alone in diabetes and dyslipidemia patients. This study also suggested metformin's preventive effect on the glucose-elevating potential of atorvastatin in patients with type 2 diabetes mellitus and dyslipidemia, insufficiently controlled with exercise and diet. Metformin and atorvastatin combination might be an effective treatment in reducing the CVD risk in patients with both diabetes and dyslipidemia because of its lowering effect on LDL-C and glucose.