The Efficacy of Metformin and Exenatide in Polycystic Ovary Syndrome (PCOS) Patients / La eficacia de metformina y exenatida en pacientes con síndrome de ovario poliquístico (SOP)

Introducción: El Síndrome del Ovario Poliquístico (SOP) es un trastorno hormonal que afecta al 5-10% de las mujeres que se encuentran en edad reproductiva. este metanálisis tiene como objetivo evaluar la eficacia de la metformina y la exenatida, respectivamente, y comparar la eficacia de ambos fármacos utilizando el Índice de Masa Corporal (IMC), el colesterol de lipoproteínas de baja densidad (LDL-C), el colesterol de lipoproteínas de alta densidad (HDL-C) y los niveles de testosterona. Método: En este estudio se consultaron Scopus, Science Direct, Oxford Journal, Wiley Online Library y Medline a través del motor de búsqueda PubMed. El análisis estadístico de los estudios incluidos se realizó mediante el software RevMan 5.4. Resultados: Hubo 6 estudios incluidos en el análisis del estudio. Hubo una reducción significativa en el IMC de las pacientes con SOP con exenatida frente a metformina (diferencia de medias = 0,51; intervalo de confianza (IC) del 95 % = 0,07; 0,96; I 2 = 52 %; p = 0,02). También hubo una reducción significativa en el nivel de testosterona de los pacientes con SOP con exenatida frente a metformina (diferencia de medias = 0,15; intervalo de confianza (IC) del 95 % = 0,07; 0,22;I 2 = 0 %; p = 0,0002). No hubo efecto sobre la media de LDL-C y de HDL-C cuando se comparó entre metformina y exenatida. Este muestra que la exenatida es eficaz para reducir el IMC y los niveles de testosterona en pacientes con SOP. Conclusiones: Hubo una reducción significativa en el IMC y los niveles de testosterona de los pacientes con SOP cuando se usó exenatida en comparación con metformina. Sin embargo, no hubo efecto sobre la media de los niveles de LDL-C y HDL-C de las pacientes con SOP. (AU)

Introduction: Polycystic Ovary Syndrome (PCOS) is a hormonal disorder that affects 5-10% of women who are their reproductive age. This meta-analysis aims to evaluate the efficacy of metformin and exenatide, respectively, and to compare the efficacy of both drugs using Body Mass Index (BMI), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and testosterone level. Method: Scopus, Science Direct, Oxford Journal, Wiley Online Library, and Medline (through the PubMed search engine) were used in this study. Statistical analysis of the included studies was done using the RevMan 5.4 software. Results: There were 6 studies included in the analysis of the study. There was a significant reduction in BMI of PCOS patients with exenatide versus metformin (mean difference = 0.51; 95% confidence interval (CI)= 0.07, 0.96, I 2= 52%; p=0.02). There was also a significant reduction in the testosterone level of PCOS patients with exenatide versus met-formin (mean difference = 0.15; 95% confidence interval (CI)= 0.07, 0.22, I 2= 0%; p=0.0002). There was no effect on the mean of LDL-C and of HDL-C when compared between metformin and exenatide This meta-analysis shows that exenatide is effective in reducing BMI and testosterone levels in PCOS patients. Conclusions: There were a significant reduction in BMI and testosterone levels of PCOS patients when exenatide was used as compared to metformin. However, there was no effect on the mean of the LDL-C and HDL-C levels of the PCOS patients. (AU)

Dual A1 and A2A adenosine receptor antagonists, methoxy substituted 2-benzylidene-1-indanone, suppresses intestinal postprandial glucose and attenuates hyperglycaemia in fructose-streptozotocin diabetic rats.

BACKGROUND/AIM: Recent research suggests that adenosine receptors (ARs) influence many of the metabolic abnormalities associated with diabetes. A non-xanthine benzylidene indanone derivative 2-(3,4-dihydroxybenzylidene)-4-methoxy-2,3-dihydro-1 H-inden-1-one (2-BI), has shown to exhibit higher affinity at A1/A2A ARs compared to caffeine. Due to its structural similarity to caffeine, and the established antidiabetic effects of caffeine, the current study was initiated to explore the possible antidiabetic effect of 2-BI. METHODS: The study was designed to assess the antidiabetic effects of several A1 and/or A2A AR antagonists, via intestinal glucose absorption and glucose-lowering effects in fructose-streptozotocin (STZ) induced diabetic rats. Six-week-old male Sprague-Dawley rats were induced with diabetes via fructose and streptozotocin. Rats were treated for 4 weeks with AR antagonists, metformin and pioglitazone, respectively. Non-fasting blood glucose (NFBG) was determined weekly and the oral glucose tolerance test (OGTT) was conducted at the end of the intervention period. RESULTS: Dual A1/A2A AR antagonists (caffeine and 2-BI) decreased glucose absorption in the intestinal membrane significantly (p < 0.01), while the selective A2A AR antagonist (Istradefylline), showed the highest significant (p < 0.001) reduction in intestinal glucose absorption. The selective A1 antagonist (DPCPX) had the least significant (p < 0.05) reduction in glucose absorption. Similarly, dual A1/A2A AR antagonists and selective A2A AR antagonists significantly reduced non-fast blood glucose and improved glucose tolerance in diabetic rats from the first week of the treatment. Conversely, the selective A1 AR antagonist did not reduce non-fast blood glucose significantly until the 4th week of treatment. 2-BI, caffeine and istradefylline compared well with standard antidiabetic treatments, metformin and pioglitazone, and in some cases performed even better. CONCLUSION: 2-BI exhibited good antidiabetic activity by reducing intestinal postprandial glucose absorption and improving glucose tolerance in a diabetic animal model. The dual antagonism of A1/A2A ARs presents a positive synergism that could provide a new possibility for the treatment of diabetes.

Influence of prior internist encounter on glycaemic control among patients with type 2 diabetes mellitus at a family practice setting in Nigeria.

Background: The huge global diabetes burden and the paucity of diabetes specialists make primary care physicians important stakeholders in controlling diabetes. Hence, we examined the predictors of glycaemic control among primary care patients with type 2 diabetes mellitus (T2DM), highlighting the influence of prior internist encounters during the preceding year on glycaemic control. Methods: This questionnaire-based cross-sectional study involved 276 T2DM patients systematically recruited from attendees of a general outpatient clinic (GOPC) in Kano, Nigeria. Data regarding their sociodemographic, clinical and internist encounter and GOPC visit characteristics were collected. Data were subjected to descriptive and inferential statistical analysis. Results: Most participants (56.5%) were females; their mean age was 57.7 ± 9.6 years, mean glycated haemoglobin level was 7.3 ± 1.9%. Age, educational level, ethnicity, insurance status, current blood pressure (BP), treatment type, medication adherence, awareness of the importance of diet in DM control, specialist diabetic clinic visited, number of GOPC visits and prior encounter with an internist in the preceding year were associated with glycaemic control after bivariate analysis (P < 0.05). On multivariate regression, low education, retirees, being self-employed, uninsured, overweight, having optimal BP, using metformin alone, sulphonylurea-metformin and insulin-based treatments and prior encounter with the internist in the preceding year were predictors of optimal glycaemic control. Conclusion: There are multiple predictors of glycaemic control in this setting. These predictors should be considered in glycaemic control risk stratification towards quality individualised care, which includes establishing referral protocols to available specialists. Regular training of primary care physicians on diabetes care is also required.

Expanding the evidence for managing metformin poisoning to support decision-making.

INTRODUCTION: Metformin-associated lactic acidosis is a well-described and commonly encountered condition associated with significant morbidity and mortality. Patients with metformin-associated lactic acidosis are frequently managed in the intensive care unit with supportive care, including volume resuscitation and consideration of an extracorporeal treatment to correct metabolic acidemia and remove metformin and lactate. EXTRACORPOREAL TREATMENTS IN POISONING WORKGROUP: The Extracorporeal Treatments in Poisoning Workgroup published evidence-based consensus recommendations in 2015 regarding the use of extracorporeal treatment in metformin toxicity. These recommendations list both clinical and biochemical indications, and they outline the rationale and evidence supporting each recommendation. NEW RESEARCH SINCE RECOMMENDATIONS WERE PUBLISHED: Subsequent publications have provided new information regarding metformin-associated lactic acidosis and its treatment. A retrospective study showed that patients who did not meet the Extracorporeal Treatments in Poisoning Workgroup criteria for initiation of an extracorporeal treatment had a 100% survival. In patients who met the criteria, survival was approximately 75%; only 66% of these patients received an extracorporeal treatment, and this treatment did not appear to impact survival. Two other retrospective studies in patients diagnosed with metformin-associated lactic acidosis noted that extracorporeal treatments did not improve survival. However, those who received an extracorporeal treatment were more severely ill, potentially supporting a benefit from this intervention. A systematic review of patients receiving continuous kidney replacement therapy identified an overall survival that was higher than the overall survival in patients included in the Workgroup publication. This led the authors to suggest that intermittent hemodialysis may not be the preferred treatment for metformin toxicity. However, a closer look at the Workgroup data identified improved survival with each decade since the initial reports in the 1970s. Furthermore, there are multiple reports of persistent metformin-associated lactic acidosis that did not improve with standard continuous kidney replacement therapy, prompting an increase in the dosage of the extracorporeal treatment. The data supporting these observations are largely derived from retrospective studies, which have inherent biases, so prospective studies are required. PRESCRIBING EXTRACORPOREAL TREATMENTS FOR PATIENTS WITH METFORMIN POISONING: Case-based decision-making is always necessary, but in general, we continue to follow the Extracorporeal Treatments in Poisoning Workgroup criteria because a convincing reason for changing these has not yet been presented. This includes the use of intermittent hemodialysis where possible, particularly in cases of severe poisoning. For patients with less severe poisoning or when intermittent hemodialysis is not readily available, it is reasonable to trial continuous modalities with careful observation for deterioration.

The Influence of Gut Microbial Species on Diabetes Mellitus.

Diabetes mellitus (DM) is a metabolic disorder with an alarming incidence rate and a considerable burden on the patient's life and health care providers. An increase in blood glucose level and insulin resistance characterizes it. Internal and external factors such as urbanization, obesity, and genetic mutations could increase the risk of DM. Microbes in the gut influence overall health through immunity and nutrition. Recently, more studies have been conducted to evaluate and estimate the role of the gut microbiome in diabetes development, progression, and management. This review summarizes the current knowledge addressing three main bacterial species: Bifidobacterium adolescentis, Bifidobacterium bifidum, and Lactobacillus rhamnosus and their influence on diabetes and its underlying molecular mechanisms. Most studies illustrate that using those bacterial species positively reduces blood glucose levels and activates inflammatory markers. Additionally, we reported the relationship between those bacterial species and metformin, one of the commonly used antidiabetic drugs. Overall, more research is needed to understand the influence of the gut microbiome on the development of diabetes. Furthermore, more efforts are required to standardize the model used, concentration ranges, and interpretation tools to advance the field further.

Clinical characteristics and management of patients with nonalcoholic steatohepatitis in a real-world setting: analysis of the Ipsos NASH therapy monitor database.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is the more severe, inflammatory type of nonalcoholic fatty liver disease (NAFLD). NASH, a leading indication for liver transplantation, is growing in prevalence. The extent of liver fibrosis, ranging from fibrosis stage (FS) of none (F0) to cirrhosis (F4), is a strong predictor of health outcomes. There is little information on patient demographics and clinical characteristics by fibrosis stage and NASH treatment outside of academic medical centers. METHODS: We conducted a cross-sectional observational study using Ipsos' syndicated NASH Therapy Monitor database, consisting of medical chart audits provided by sampled NASH-treating physicians in the United States in 2016 (n = 174) and 2017 (n = 164). Data was collected online. RESULTS: Of 2,366 patients reported on by participating physicians and included in the analysis, 68% had FS F0-F2, 21% had bridging fibrosis (F3), and 9% had cirrhosis (F4). Common comorbidities were type 2 diabetes (56%), hyperlipidemia (44%), hypertension (46%), and obesity (42%). Patients with more advanced fibrosis scores (F3-F4) had higher comorbidity rates than patients with F0-F2. Commonly used diagnostic tests included ultrasound (80%), liver biopsy (78%), AST/ALT ratio (43%), NAFLD fibrosis score (25%), transient elastography (23%), NAFLD liver fat score (22%), and Fatty Liver Index (19%). Most commonly prescribed medications were vitamin E (53%), statins (51%), metformin (47%), angiotensin converting enzyme inhibitors (28%), and beta blockers (22%). Medications were commonly prescribed for reasons other than their known effects. CONCLUSION: Physicians in this study, drawn from a spectrum of practice settings, relied on ultrasound and liver biopsy for diagnosis and vitamin E, statins, and metformin for pharmacological treatment of NASH. These findings imply poor adherence to guidelines in the diagnosis and management of NAFLD and NASH. Nonalcoholic steatohepatitis (NASH) is a liver disease caused by excess fat in the liver which can lead to liver inflammation and scarring (fibrosis), ranging from stage F0 (no scarring) to F4 (advanced scarring). The stage of liver scarring can predict the likelihood of future health problems, including liver failure and liver cancer. However, we do not fully understand how patient characteristics may vary at different stages of liver scarring. We looked at medical information from physicians treating patients diagnosed with NASH to understand how patient characteristics might differ based on the severity of their liver scarring. The majority (68%) of patients were stage F0-F2, with 30% having advanced scarring (F3-F4). In addition to NASH, many patients also had type 2 diabetes, high cholesterol, high blood pressure, and obesity. Patients with more advanced scarring (F3-F4) were more likely to have these diseases than patients with less severe disease (F0-F2). Diagnosis of NASH by participating physicians was based on tests including imaging (ultrasound, CT scan, MRI), liver biopsy, blood tests, and whether patients had other conditions that would put them at risk for NASH. The medications that the doctors prescribed most often to their patients included vitamin E and drugs to treat high cholesterol, high blood pressure, or diabetes. Medications were frequently prescribed for reasons other than their known effects. By understanding how patient characteristics vary by stages of liver scarring and how NASH is currently managed may help guide the evaluation and treatment of NASH when NASH-specific therapies become available.

[Cost-effectiveness of treatment of type 2 diabetes mellitus in México]. / Costo-efectividad del tratamiento de la diabetes mellitus tipo 2 en México.

Background: Type 2 Diabetes Mellitus (DM2) is a public health and socioeconomic problem, generating direct medical costs for its treatment. Objective: To analyze the cost-effectiveness of monotherapy and bitherapy treatments in patients with DM2. Methods: Cost-effectiveness, observational, ambispective, cross-sectional and analytical analysis of files in a first level medical unit. The data in the cost matrix was executed with the Office Excel 2010 program; the most prescribed drug was identified and compared with monotherapy and bitherapy. Results: The annual direct medical costs of the total population were drug cost $118,561.70MN, hospitalization cost $243,756.00MN, consultation cost $327,414.00MN and clinical trial cost $2416.79MN, obtaining an annual total of $692,148.58MN. metformin was the most indicated in monotherapy (88.4%) and as standard therapy it has higher cost-effectiveness compared to glibenclamide. In bitherapy it was metformin/glibenclamide (35.7%) versus the therapeutics of metformin/NPH insulin, metformin/insulin glargine and metformin/dapagliflozin, which had a better cost-effective result, with an incremental cost effectiveness of -$1,128,428.50MN, -$34,365.00 MN, -$119,848.97MN respectively. Conclusions: Metformin presented a better cost-effectiveness ratio in monotherapy, while in bitherapy it was the metformin/NPH insulin association.

Introducción: La Diabetes Mellitus tipo 2 (DM2) es un problema de salud pública y socioeconómico, tanto por su alta incidencia como por la generación de los costos médicos directos para su tratamiento. Objetivo: Analizar el costo-efectividad de los tratamientos en monoterapia y biterapia en pacientes con DM2. Métodos: Análisis costo-efectividad, observacional, ambispectivo, transversal y analítico. Análisis de expedientes en una unidad médica de primer nivel. Se ejecutaron los datos en la matriz de costos con el programa Office Excel 2010; se identificó el fármaco más prescrito, se comparó con monoterapia y biterapia. Resultados: Los costos médicos directos anuales del total de la población fueron: costo del medicamento $118,561.70MN, costo por hospitalización $243,756.00MN, costo por consultas $ 327,414.00MN y costo por estudios clínicos $2416.79MN, obteniendo un total anual de $692,148.58MN. La metformina fue la más indicada en monoterapia (88.4%) y como terapéutica estándar tiene mayor costo-efectividad comparada con la glibenclamida. En biterapia fue metformina/glibenclamida (35.7%) versus las terapéuticas de metformina/insulina NPH, metformina/insulina glargina y metformina/dapagliflozina, las cuales tuvieron un resultando más costo-efectivo, con un costo efectividad incremental de -$1,128,428.50MN, -$34,365.00MN, -$119,848.97MN respectivamente. Conclusiones: La metformina presento mejor relación costo efectividad en monoterapia, mientras que en biterapia fue la asociación metformina/Insulina NPH.

Description of a French Population of Diabetics Treated Followed up by General Practitioners.

In France, the prevalence of treated diabetes has been estimated at 4.6%, or more than 3 million people and 5.2% in Northern France. The reuse of primary care data allows to study outpatient clinical data such as laboratory results and drug prescriptions, which are not documented in claims and hospital databases. In this study, we selected the population of treated diabetics from the Wattrelos primary care data warehouse, in North of France. Firstly, we studied the laboratory results of diabetics by identifying whether the recommendations of the French National Authority for Health (HAS) were respected. In a second step, we studied the prescriptions of diabetics by identifying the oral hypoglycemic agents treatments and insulins treatments. The diabetic population represents 690 patients of the health care center. The recommendations on labortatory are respected for 84% of diabetics. The majority of diabetics are treated with oral hypoglycemic agents 68.6%. As recommended by the HAS, metformin is the first-line treatment in the diabetic population.

[Effect of Liraglutide on platelet distribution width and carotid intima-media thickness in type 2 diabetic mellitus patients with obesity].

Objective: To investigate the effect of Liraglutide on platelet distribution width(PDW) and carotid intima-media thickness(cIMT) in type 2 diabetic mellitus patients with obesity. Methods: Randomized controlled trial. A total of 80 type 2 diabetes mellitus (T2DM) obese patients with unsatisfactory glucose control were prospectively enrolled in this study from the Department of Endocrinology of Yuhuangding Hospital Affiliated to Qingdao University from January to December 2021. All the participants were treated with metformin or sulfonylureas. They were randomly divided into two groups: Liraglutide treatment group (Li group, n=40) and Control group (Con group, n=40).The Li group started the treatment with Liraglutide on the basis of the original hypoglycemic agents and the Con group was treated with metformin and sulfonylurea. After 16 weeks of treatment, the changes of PDW, cIMT and body mass index (BMI) in the two groups were observed, multiple linear regression was uesd to analyze the influencing factors of cIMT variation, and the effect of liraglutide on PDW and cIMT in obese patients with type 2 diabetes was analyzed. Results: Finally, 38 patients completed the study in Li group, including 23 males and 15 females, aged 30-69(56±11) years. All 40 patients in Con group completed the study, including 18 males and 22 females, aged 39-67(59±7) years. After 16 weeks of treatment, the levels of PDW and cIMT in Li group were (12.8±1.6) fl and (0.85±0.08) mm, respectively, lower than those before treatment (15.0±1.6) fl and (1.14±0.10) mm (t=18.61 and 20.37, respectively, both P<0.001); The PDW and cIMT in Con group were (13.6±1.5) fl and (1.05±0.10) mm, respectively, lower than those before treatment (15.0±1.5) fl and (1.13±0.13) mm (t=17.42 and 9.65, respectively, both P<0.001). The levels of fasting plasma glucose (FPG) and total cholesterol (TC) in both groups were lower than those before treatment(all P<0.001). After the treatment, the levels of PDW, cIMT, FPG and TC in Li group were lower than those in Con group (all P<0.05). The changes of PDW and cIMT before and after the treatment in Li group were (2.2±0.7) fl and (0.30±0.09) mm, respectively, higher than those in the Con group [(1.4±0.5) fl and (0.09±0.06) mm], with a statistically significant difference (both P<0.001). The changes of FPG and TC in Li group were significantly higher than those in Con group (all P<0.05). Multiple linear regression analysis showed that liraglutide, the changes of TC and systolic blood pressure (SBP) were the influencing factors for the changes of cIMT [ß (95%CI) were 0.20 (0.17-0.23), 0.03 (0.01-0.06), 0.01 (0.00-0.01), respectively, all P<0.05] Conclusion: Liraglutide treatment could reduce PDW and cIMT, thus contributing to cardiovascular benefits.

[Research progresses on interventions of obesity in children and adolescents].

Childhood and adolescent obesity has become a global epidemic. The interventions mainly include lifestyle intervention, medication treatment and bariatric surgery. Among them, lifestyle intervention, especially intensive lifestyle intervention with participation of family members, is the first-line treatment for obesity in children and adolescents. Both medication and bariatric surgery are adjuvant treatments for severely obese children and adolescents. Currently, metformin is the most widely used drug for the treatment of obesity in children and adolescents in both China and other countries; orlistat and liraglutide are also the drugs that are safe and often used in other countries; other drugs are not recommended. As a tertiary prevention and treatment strategy for obesity, bariatric surgery should be carried out on the basis of good compliance from both the children and their family members, with the cooperation of multiple disciplines. Sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) are the most common types of procedure performed. Meanwhile, as a new treatment method, intra-gastric balloon procedure needs to be paid more attention to its efficacy and safety.

The Association between Metformin and the Cancer-Specific Mortality Rate in Nasopharyngeal Cancer Patients: Real-World Evidence.

OBJECTIVES: Nasopharyngeal cancer is a common cancer in East and South Asia. The radiotherapy and chemotherapy regimen has advanced in recent years. However, many patients still suffer from local recurrence and distant metastasis; thus, identifying medication that can be combined with standard treatment to improve the treatment outcomes in nasopharyngeal cancer patients is an unmet need. METHODS: We included nasopharyngeal cancer patients from the Taiwan National Health Insurance Database (NHIRD). The primary endpoint was set as the cancer-specific mortality rate. Metformin cohorts and non-Metformin cohorts were matched by sex, age, and the year of the index date. Propensity score matching with a ratio of 1:1 was applied. RESULTS: A total of 6078 subjects were included in the study, with 3039 patients in each group. Male participants outnumbered female participants. Most of the patients were aged 50 to 64; the mean age was 60.4 ± 10.4 years in Metformin non-users, and that of Metformin users was 59.9 ± 10.5 years. Metformin users had a lower risk of death due to nasopharyngeal cancer (adjusted HR = 0.80; 95% CI = 0.71, 0.90) than controls. CONCLUSIONS: We concluded that Metformin might be effective at reducing the cancer-specific mortality rate in nasopharyngeal cancer patients. Further randomized control trials should be completed.

Metformin sensitises osteosarcoma to chemotherapy via the IGF-1R/miR-610/FEN1 pathway.

Metformin can enhance cancer cell chemosensitivity to anticancer drugs. IGF-1R is involved in cancer chemoresistance. The current study aimed to elucidate the role of metformin in osteosarcoma (OS) cell chemosensitivity modulation and identify its underlying mechanism in IGF-1R/miR-610/FEN1 signalling. IGF-1R, miR-610, and FEN1 were aberrantly expressed in OS and participated in apoptosis modulation; this effect was abated by metformin treatment. Luciferase reporter assays confirmed that FEN1 is a direct target of miR-610. Moreover, metformin treatment decreased IGF-1R and FEN1 but elevated miR-610 expression. Metformin sensitised OS cells to cytotoxic agents, while FEN1 overexpression partly compromised metformin's sensitising effects. Furthermore, metformin was observed to enhance adriamycin's effects in a murine xenograft model. Metformin enhanced OS cell sensitivity to cytotoxic agents via the IGF-1R/miR-610/FEN1 signalling axis, highlighting its potential as an adjuvant during chemotherapy.

Metformin and Cancer: Solutions to a Real-World Evidence Failure.

The quest to repurpose metformin, an antidiabetes drug, as an agent for cancer prevention and treatment, which began in 2005 with an observational study that reported a reduction in cancer incidence among metformin users, generated extensive experimental, observational, and clinical research. Experimental studies revealed that metformin has anticancer effects via various pathways, potentially inhibiting cancer cell proliferation. Concurrently, multiple nonrandomized observational studies reported remarkable reductions in cancer incidence and outcomes with metformin use. However, these studies were shown, in 2012, to be affected by time-related biases, such as immortal time bias, which tend to greatly exaggerate the benefit of a drug. The observational studies that avoided these biases did not find an association. Subsequently, the randomized trials of metformin for the treatment of type 2 diabetes and as adjuvant therapy for the treatment of various cancers, advanced or metastatic, did not find reductions in cancer incidence or outcomes. Most recently, the largest phase 3 randomized trial of metformin as adjuvant therapy for breast cancer, which enrolled 3,649 women with a 5-year follow-up, found no benefit for disease-free survival or overall survival with metformin. This major failure of observational real-world evidence studies in correctly assessing the effects of metformin on cancer incidence and outcomes was caused by preventable biases which, surprisingly, are still prominent in 2022. Rigorous approaches for observational studies that emulate randomized trials, such as the incident and prevalent new-user designs along with propensity scores, avoid these biases and can provide more accurate real-world evidence for the repurposing of drugs such as metformin.

Synergistic Effect of Metformin and Lansoprazole Against Gastric Cancer through Growth Inhibition.

Cancer has been linked to metabolic disorders and diverse gene mutations. Metformin, which is widely used to treat type 2 diabetes, inhibits the growth of cancer cells in animal models. Here we investigated the effects of metformin on human gastric cancer cell lines. We also investigated the synergistic anticancer effect of metformin and proton pump inhibitors. Lansoprazole, a proton pump inhibitor, is effective for treating gastroesophageal reflux disease. Our results revealed that metformin and lansoprazole can significantly inhibit cancer cell growth in a dose-dependent manner by suppressing cell cycle progression and inducing apoptosis. Low concentrations of metformin and lansoprazole have a synergistic effect on AGS cell growth inhibition. In summary, our findings suggest a new and safe treatment protocol for treating stomach cancers.

A Microstirring Oral Pill for Improving the Glucose-Lowering Effect of Metformin.

Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia due to persistent insulin resistance, resulting in elevated blood glucose levels. Metformin is the most prescribed oral drug for lowering high blood glucose levels in T2DM patients. However, it is poorly absorbed and has low bioavailability. Here, we introduce magnesium-based microstirrers to a metformin-containing pill matrix to enhance the glucose-lowering effect of metformin. The resulting microstirring pill possesses a built-in mixing capability by creating local fluid transport upon interacting with biological fluid to enable fast pill disintegration and drug release along with accelerated metformin delivery. In vivo glucose tolerance testing using a murine model demonstrates that the metformin microstirring pill significantly improves therapeutic efficacy, lowering blood glucose levels after a meal more rapidly compared to a regular metformin pill without active stirring. As a result, the microstirrers allow for dose sparing, providing effective therapeutic efficacy at a lower drug dosage than passive metformin pills. These encouraging results highlight the versatility of this simple yet elegant microstirring pill technology, which enhances drug absorption after gastrointestinal delivery to improve therapeutic efficacy.

Effects of metformin on human gingival fibroblasts: an in vitro study.

OBJECTIVE: To investigate the effects of metformin (MF) treatment on the matrix metalloproteinases (MMPs) and proinflammatory cytokines production from lipopolysaccharide (LPS) - stimulated human gingival fibroblasts (HGFs). METHODS: HGFs were obtained from subcultures of biopsies from clinically healthy gingival tissues of patients undergoing oral surgeries. Cell cytotoxicity assay was used to determine the effect of different concentrations of MF on viability of HGFs. HGFs were then incubated and treated with different concentrations of MF and Porphyromonas gingivais (Pg) LPS. MMP-1, MMP-2, MMP-8, MMP-9, IL-1ß, and IL-8 expression analysis was performed using xMAP technology (Luminex 200, Luminex, Austin, TX, USA). Student's t-test for a single sample was used to compare the mean values of the study groups with the control value. A p-value of <0.05 and 95% confidence intervals were used to report the statistical significance and precision of mean values. RESULTS: Concentrations of 0.5, 1- and 2-mM MF had a minimal non-significant cytotoxic effect on the HGFs and caused statistically significant reduction of MMP-1, MMP-2, MMP-8 and IL-8 expressed by the LPS-stimulated HGFs. CONCLUSION: The results of the present study confirm that MF suppresses MMP-1, MMP-2, MMP-8 and IL-8 in LPS-stimulated HGFs suggesting an anti-inflammatory effect of MF and potential adjunct therapeutic role in the treatment of periodontal diseases.

Analysis of Antidiabetic Activity of Squalene via In Silico and In Vivo Assay.

Squalene has been tested widely in pharmacological activity including anticancer, antiinflammatory, antioxidant, and antidiabetic properties. This study aims to examine antidiabetic activity of squalene in silico and in vivo models. In the in silico model, the PASS server was used to evaluate squalene antidiabetic properties. Meanwhile, the in vivo model was conducted on a Type 2 Diabetes Mellitus (T2DM) with the rats separated into three groups. These include squalene (160 mg/kgbw), metformin (45 mg/kgbw), and diabetic control (DC) (aquades 10 mL/kgbw) administered once daily for 14 days. Fasting Blood Glucose Level (FBGL), Dipeptidyl Peptidase IV (DPPIV), leptin, and Superoxide Dismutase (SOD) activity were measured to analysis antidiabetic and antioxidant activity. Additionally, the pancreas was analysed through histopathology to examine the islet cell. The results showed that in silico analysis supported squalene antidiabetic potential. In vivo experiment demonstrated that squalene decreased FBGL levels to 134.40 ± 16.95 mg/dL. The highest DPPIV level was in diabetic control- (61.26 ± 15.06 ng/mL), while squalene group showed the lowest level (44.09 ± 5.29 ng/mL). Both metformin and squalene groups showed minor pancreatic rupture on histopathology. Leptin levels were significantly higher (p < 0.05) in diabetic control group (15.39 ± 1.77 ng/mL) than both squalene- (13.86 ± 0.47 ng/mL) and metformin-treated groups (9.22 ± 0.84 ng/mL). SOD activity were higher in both squalene- and metformin-treated group, particularly 22.42 ± 0.27 U/mL and 22.81 ± 0.08 U/mL than in diabetic control (21.88 ± 0.97 U/mL). In conclusion, in silico and in vivo experiments provide evidence of squalene antidiabetic and antioxidant properties.