Metformin Group Research Articles

Effects of Metformin on COVID-19 Patients with Type 2 Diabetes: A Retrospective Study.

The pandemic of coronavirus disease 2019 (COVID-19) has highlighted the intricate relationship between underlying conditions and death. We designed this study to determine whether metformin therapy for type 2 diabetes mellitus (T2D) is associated with low in-hospital mortality in patients hospitalized for COVID-19. This was a retrospective study including patients with COVID-19 and T2D in Wuhan, from February 4th to April 11th, 2020. Patients were divided into two groups according to metformin exposure. The hazard ratio (HR) of COVID-19-related mortality and invasive mechanical ventilation was estimated using Cox regression. There were 571 T2D patients among the 4330 confirmed COVID-19 patients. Of those patients, 241 received metformin therapy. The in-hospital mortality and invasive mechanical ventilation of metformin group was lower than non-metformin group. In the multivariate model, metformin use was linked to a decreased in-hospital mortality and invasive mechanical ventilation when compared with that of the control group (HR: 0.376 [95% CI 0.154-0.922]; P = 0.033). Our study indicated that metformin therapy was associated with decreased death risk in COVID-19 patients with T2D.

Correlation between metformin intake and prostate cancer

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

EFEK PEMBERIAN KAPSUL EKSTRAK JAMU HIPERGLIKEMI TERHADAP KUALITAS HIDUP

Quality of Life (QoL) in diabetes mellitus (DM) has become highly emphasized in recent years as health care outcome. Hyperglicemic herbs potio, one of scientific herbs, has been proven to be safe and efficacious. The use of extract capsules as an innovative form of herbal medicine continues to be developed. The study aimed to examine the effect of giving hyperglicemic herbal extract capsules on the QoL of hyperglycemic patients at Rumah Riset Jamu (RRJ) Hortus Medicus. The method used was pre and post-test design with quasi-experimental. A total of 60 patients followed the study during September-November 2019. The hyperglycemic herbs formula consisting of 5 grams daun Salam, 5 grams sambiloto, 7 grams kayu manis and 10 grams temulawak which converted to the one extract capsule. For the daily doses are two capsules twice a day. The Metformin 500 mg single dose as a control of the study. Before this study and on day 28th, the patients had been examined the QoL using the short form-36 (SF-36). The data were analyzed using the Wilcoxon and Mann Whitney test. The results showed that there was a significant increase in total score of SF-36 (p=0,000) between before and after taking extract capsules, especially for the general health domain (p=0,002). The total score of SF-36 between extract capsules and Metformin groups was not significantly difference (p=0,323). Hyperglycemic herbal extract capsules improved the QoL of the hyperglycemic patients.

Real-world risk of cardiovascular diseases in patients with type 2 diabetes associated with sodium-glucose cotransporter 2 inhibitors in comparison with metformin: A propensity score-matched model analysis in Japan.

We aimed to compare the effects of cardiovascular disease risk in Japanese patients with type 2 diabetes on sodium-glucose cotransporter 2 inhibitors (SGLT2Is) or metformin. This retrospective, real-world cohort study was carried out using a claims database and propensity score matching; 58,402 eligible patients (29,201 per group) were included. The outcomes included nonfatal myocardial infarction, angina pectoris, nonfatal stroke, hospitalization for heart failure and composite end-points. The hazard ratio (HR) for the composite end-point was 0.79, which was lower for SGLT2Is than for metformin. For male patients (HR 0.76), patients aged <65 years (HR 0.94), patients aged ≥75 years (HR 0.78) and patients with body mass index ≥25 kg/m2 (HR 0.76), the HRs for the composite end-point were significantly lower in the SGLT2I group than in the metformin group. SGLT2Is might be superior to metformin in reducing the composite risk of cardiovascular disease in patients with type 2 diabetes.

Effects of metformin and intensive lifestyle interventions on the incidence of kidney disease in adults in the DPP/DPPOS

AimsWe analyzed the incidence of kidney disease in the Diabetes Prevention Program Outcomes Study (DPPOS) by originally randomized treatment group assignment: Intensive Lifestyle (ILS), Metformin (MET) or Placebo (PLB). MethodsThe current analyses used a time-to-event approach in which the primary outcome was kidney disease, ascertained as urine albumin-to-creatinine ratio (ACR) ≥ 3.39 mg/mmol (30 mg/g) or eGFR <45 mL/min/1.73m2, with confirmation required at the next visit, or adjudicated end-stage kidney disease (ESKD). ResultsAt a median of 21 years following randomization in DPP, diabetes development was reduced in both the ILS (HR 0.73 [95%CI = 0.62, 0.85]) and MET groups (HR 0.85 [0.73, 0.99]) compared to the PLB group. Although risk for developing the primary kidney disease outcome was higher among those with incident diabetes compared to those without (HR 1.81 [1.43, 2.30]), it did not differ by intervention groups (ILS vs. PLB 1.02 (0.81, 1.29); MET vs. PLB 1.08 (0.86, 1.35). There was a non-significant metformin by age interaction (p = 0.057), with metformin being beneficial for kidney disease in the younger but potentially harmful in the older participants. ConclusionsDevelopment of kidney disease was increased in participants who developed diabetes but did not differ by original treatment group assignment. Clinical trial registrationsDiabetes Prevention Program (DPP) Clinical trial reg. no. NCT00004992DPP Outcomes Study (DPPOS) Clinical trial reg. no. NCT0038727

Anthropometrics of neonates born to mothers with PCOS with metformin or placebo exposure in utero.

Fetal growth may be affected by both maternal polycystic ovary syndrome (PCOS) and metformin therapy. Here, we explore the effect of intrauterine metformin exposure on birth anthropometrics of infants born to women with PCOS. We also investigated whether the effect of metformin on birth anthropometrics is modified by maternal pre-pregnancy body mass index, PCOS hyperandrogenic phenotype, serum androgen levels, preconception use of metformin and offspring sex. Additionally, we assessed newborn anthropometrics in relation to a national reference population. Individual data from three randomized controlled triasl were pooled. The randomized controlled trials investigated the effects of metformin in pregnant women with PCOS. In all, 397 and 403 were randomized to the metformin and placebo groups, respectively. A Scandinavian growth reference was used to calculate sex and gestational age adjusted z-scores. Linear regression models were used to estimate the effect of metformin on offspring z-scores of head circumference, birth length, birthweight, placental weight, body mass index, ponderal index and birthweight:placental weight ratio. S-testosterone, s-androstenedione, and s-sex-hormone binding globulin from four timepoints in pregnancy were analyzed. Compared with the PCOS-placebo group, newborns in the PCOS-metformin group had larger head circumference (head circumference z-score: mean difference = 0.25, 95% CI = 0.11- 0.40). This effect of metformin on head circumference z-score was particularly observed among offspring of overweight/obese mothers and mothers with hyperandrogenic PCOS-phenotype. We observed no difference in other anthropometric measures between the metformin and placebo groups or any clear interaction between maternal androgen levels and metformin. Newborns in the PCOS-placebo group were shorter than in the reference population (birth length z-score: mean = -0.04, 95% CI = -0.05 to -0.03), but head circumference and birthweight were similar. Larger head circumference was observed at birth in metformin-exposed offspring of mothers with PCOS. PCOS-offspring were also shorter, with a similar birthweight to the reference population, indirectly indicating higher weight-to-height ratio at birth.

Comparison of SGLT2 inhibitors with DPP-4 inhibitors combined with metformin in patients with acute myocardial infarction and diabetes mellitus

BackgroundAlthough sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated cardiovascular benefits in patients with type 2 diabetes mellitus, real-world evidence regarding their benefits to diabetic patients with acute myocardial infarction (AMI) is insufficient. This study evaluated cardiovascular outcomes by comparing SGLT2i with dipeptidyl peptidase-4 inhibitors (DPP-4i) in combination with metformin in diabetic patients with AMI.MethodsThis study involved 779 diabetic participants with AMI from a Korean nationwide multicenter observational cohort, who were divided into two groups: (1) metformin plus SGLT2i group (SGLT2i group, n = 186) and (2) metformin plus DPP-4i (DPP-4i group, n = 593). The primary endpoint was one year of major adverse composite events (MACEs), a composite outcome of all-cause mortality, non-fatal myocardial infarction, any revascularization, cerebrovascular accident, and stent thrombosis. To balance the baseline differences, inverse probability of treatment weighting (IPTW) was performed.ResultsAfter IPTW, the rate of MACEs in the SGLT2i group was not significantly lower than that in the DPP-4i group (hazard ratio [HR], 0.99; 95% confidence interval [Cl], 0.46 to 2.14, p = 0.983). In the unadjusted and adjusted analyses, all items for clinical outcomes were comparable between the two groups. In our exploratory analysis, the left ventricular ejection fraction showed a significant improvement in the SGLT2i group than in the DPP-4i group before achieving statistical balancing (6.10 ± 8.30 versus 2.95 ± 10.34, p = 0.007) and after IPTW adjustment (6.91 ± 8.91 versus 3.13 ± 10.41, p = 0.027).ConclusionsOur findings demonstrated that SGLT2i did not influence the rate of MACEs compared with DPP-4i in combination with metformin in diabetic patients with AMI but did improve left ventricular ejection fraction.Trial registrationNot applicable (retrospectively registered).

Metformin for the prevention of diabetes among people with HIV and either impaired fasting glucose or impaired glucose tolerance (prediabetes) in Tanzania: a Phase II randomised placebo-controlled trial

Aims/hypothesisIn sub-Saharan Africa (SSA), 5% of adults are living with type 2 diabetes and this is rising sharply, with a greater increase among people with HIV. Evidence on the efficacy of prevention strategies in this cohort is scarce. We conducted a Phase II double-blind placebo-controlled trial that aimed to determine the impact of metformin on blood glucose levels among people with prediabetes (defined as impaired fasting glucose [IFG] and/or impaired glucose tolerance [IGT]) and HIV in SSA.MethodsAdults (≥18 years old) who were stable in HIV care and found to have prediabetes (IFG and/or IGT) and who were attending hospitals in Dar es Salaam, Tanzania, were randomised to receive sustained-release metformin, 2000 mg daily, or matching placebo between 4 November 2019 and 21 July 2020. Randomisation used permuted blocks. Allocation was concealed in the trial database and made visible only to the Chief Pharmacist after consent was taken. All participants, research and clinical staff remained blinded to the allocation. Participants were provided with information on diet and lifestyle and had access to various health information following the start of the coronavirus disease 2019 (COVID-19) pandemic. Participants were followed up for 12 months. The primary outcome measure was capillary blood glucose measured 2 h following a 75 g glucose load. Analyses were by intention-to-treat.ResultsIn total, 364 participants (182 in each arm) were randomised to the metformin or placebo group. At enrolment, in the metformin and placebo arms, mean fasting glucose was 6.37 mmol/l (95% CI 6.23, 6.50) and 6.26 mmol/l (95% CI 6.15, 6.36), respectively, and mean 2 h glucose levels following a 75 g oral glucose load were 8.39 mmol/l (95% CI 8.22, 8.56) and 8.24 mmol/l (95% CI 8.07, 8.41), respectively. At the final assessment at 12 months, 145/182 (79.7%) individuals randomised to metformin compared with 158/182 (86.8%) randomised to placebo indicated that they had taken >95% of their medicines in the previous 28 days (p=0.068). At this visit, in the metformin and placebo arms, mean fasting glucose levels were 6.17 mmol/l (95% CI 6.03, 6.30) and 6.30 mmol/l (95% CI 6.18, 6.42), respectively, and mean 2 h glucose levels following a 75 g oral glucose load were 7.88 mmol/l (95% CI 7.65, 8.12) and 7.71 mmol/l (95% CI 7.49, 7.94), respectively. Using a linear mixed model controlling for respective baseline values, the mean difference between the metformin and placebo group (metformin–placebo) was −0.08 mmol/l (95% CI −0.37, 0.20) for fasting glucose and 0.20 mmol/l (95% CI −0.17, 0.58) for glucose levels 2 h post a 75 g glucose load. Weight was significantly lower in the metformin arm than in the placebo arm: using the linear mixed model adjusting for baseline values, the mean difference in weight was −1.47 kg (95% CI −2.58, −0.35). In total, 16/182 (8.8%) individuals had a serious adverse event (Grade 3 or Grade 4 in the Division of Acquired Immunodeficiency Syndrome [DAIDS] adverse event grading table) or died in the metformin arm compared with 18/182 (9.9%) in the placebo arm; these events were either unrelated to or unlikely to be related to the study drugs.Conclusions/interpretationBlood glucose decreased over time in both the metformin and placebo arms during the trial but did not differ significantly between the arms at 12 months of follow up. Metformin therapy was found to be safe for use in individuals with HIV and prediabetes. A larger trial with longer follow up is needed to establish if metformin can be safely used for the prevention of diabetes in people who have HIV.Trial registrationThe trial is registered on the International Standard Randomised Controlled Trial Number (ISRCTN) registry (www.isrctn.com/), registration number: ISCRTN76157257.FundingThis research was funded by the National Institute for Health Research using UK aid from the UK Government to support global health research.Graphical

Rubus chingii Hu relieved the polycystic ovary syndrome with enhanced insulin sensitivity through inhibiting TXNIP/NLRP3 inflammasome signaling

Background Polycystic ovary syndrome (PCOS) is one of the most prevalent endocrine disorders in gynecology with severe metabolic abnormalities. Therefore, identifying effective treatments and drugs for PCOS is important. We aimed to investigate effect of the traditional Chinese medicine (TCM) Rubus chingii Hu (R. chingii) on ovarian function and insulin resistance (IR) of PCOS rat models, and to explore the underlying mechanisms Methods A PCOS rat model was established by subcutaneous injection of dehydroepiandrosterone (DHEA) solution for 20 days. PCOS rats were randomly divided into a control group (CON), model group (MOD), metformin group (MET), TCM R. chingii group (RCG), and RCG + Ad-TXNIP groups. After 28 days of treatment, the samples were collected for subsequent experiments. Results R. chingii treatment alleviated hormone imbalance and IR while improving ovarian pathology in the PCOS model. R. chingi inhibited the activation of the thioredoxin-interacting protein (TXNIP)/NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in the ovarian tissue of PCOS rats. Furthermore, TXNIP overexpression hindered the protective effect of R. chingii intervention in PCOS rats, as evidenced by the increase of homeostasis model assessment of insulin resistance (HOMA-IR), luteinizing hormone (LH), testosterone (T), C-reactive protein (CRP) levels, and atretic follicles. Conclusion R. chingii intervention improved ovarian polycystic development by suppressing the TXNIP/NLRP3 inflammasome, which may be an effective treatment for PCOS.

Neuroprotective effects of terpenoids against streptozotocin-nicotinamide-induced diabetic rats: An in silico, in vitro and in vivo study

The present study focused to determine the neuroprotective effects of terpenoids in streptozotocin & nicotinamide-induced type-2 diabetes in rats. The in silico studies were carried out for 68 terpenoids using AutoDock 4.2. The in vitro cholinestrerase, α-amylase enzyme inhibitory assays were perfomed using standard procedures. For in vivo neuroprotective studies, male wistar rats were separated into five groups and each group comprised of six animals. Treatment groups were received low dose and high dose α-Bisabolol 100 and 200 mg/kg respectively, and the standard groups received rivastigmine 2 mg/kg, p.o. and metformin group 100 mg/kg, p.o. for 30 consecutive days. Administration of streptozotocin (45 mg/kg, i.p.) and nicotinamide (110 mg/kg, i.p.)-induced the type 2 diabetes in all groups except the control. The behavioural assessments such as Morris water maze, and open field test were performed and biochemical parameters such as acetylcholinesterase levels and enzymatic antioxidants and reduced glutathione level were estimated from brain homogenates. Treatment of diabetic rats with α-Bisabolol was lowered blood glucose level, improved spatial recognition memory in behavioural assessments in a concentration dependent manner. It can be concluded that α-Bisabolol could act as a potential drug candidate in the management of diabetic Alzheimer's disease.

Association of Metformin Use with Iron Deficiency Anemia in Urban Chinese Patients with Type 2 Diabetes.

Previous evidence yielded contradictory findings on the relationship between metformin and anemia. This study aims to assess whether metformin use is associated with iron-deficiency anemia (IDA) risk in patients with type 2 diabetes (T2D) in Beijing, China. Overall, 60,327 newly diagnosed T2D patients were included based on a historical cohort study design. The information pertaining to these patients was gathered from the Beijing Medical Claim Data for Employees Database. These patients were then categorized into the metformin and non-metformin groups and matched on a 1:1 propensity score based on their initial antidiabetic prescription. The Cox proportional hazards models were utilized to calculate the incidences and the hazard ratios (HRs). The study enrolled 27,960 patients with type 2 diabetes, with 13,980 patients in each of the initial glucose-lowering prescription groups: metformin and non-metformin. During a median follow-up period of 4.84 years, 4832 patients developed IDA. The incidence of IDA was significantly lower in the metformin group (26.08/1000 person-years) than in the non-metformin group (43.20/1000 person-years). Among the three groups divided by the proportion of days covered by metformin, we found a negative correlation between the proportion of days covered by metformin and the risk of IDA. The risk of IDA in patients with a proportion of days covered by metformin of <20%, 20-79%, and ≥80% was 0.43 (0.38, 0.48), 0.37 (0.34, 0.42), and 0.91 (0.85, 0.98), respectively, compared to the non-metformin group. We also performed subgroup analyses and sensitivity analyses: the incidence of IDA in the metformin group was lower than that in the non-metformin group in all subgroups, and the protective effect was more significant in subgroups of patients aged ≥65, with Charlson comorbidity index (CCI) ≥2, and with gastric acid inhibitor use. In Chinese patients with T2DM, metformin treatment was associated with a decreased risk of IDA admission, and this risk responded positively to the proportion of days covered by metformin. These findings suggest that metformin may have a pleiotropic effect on IDA in patients with type 2 diabetes. Our study has important clinical implications for the management of patients with diabetes and other conditions that increase the risk of IDA.

A Placebo-Controlled, Double-Blind Clinical Investigation to Evaluate the Efficacy of a Patented Trigonella foenum-graecum Seed Extract “Fenfuro®” in Type 2 Diabetics

Background Trigonella foenum-graecum (Fenugreek) is an extensively researched phytotherapeutic for the management of Type 2 diabetes without any associated side effects. The major anti-diabetic bioactive constituents present in the plant are furostanolic saponins, which are more abundantly available in the seed of the plant. However, the bioavailability of these components depends on the method of extraction and hence formulation of the phytotherapeutic constitutes a critical step for its success. Objective The present study reports the efficacy of a novel, patented fenugreek seed extract, Fenfuro®, containing significant amount of furostanolic saponins, in an open-labelled, two-armed, single centric study on a group of 204 patients with Type 2 diabetes mellitus over a period of twelve consecutive weeks. Results Administration of Fenfuro® in the dosage of 500 mg twice daily along with metformin and/or sulfonylurea-based prescribed antidiabetic drug resulted in a reduction of post-prandial glucose by more than 33% along with significant reduction in fasting glucose, both of which were greater than what resulted for the patient group receiving only Metformin and/or Sulfonylurea therapy. Fenfuro® also resulted in reduction in mean baseline HOMA index from 4.27 to 3.765, indicating restoration of insulin sensitivity which was also supported by a significant decrease in serum insulin levels by >10% as well as slight reduction in the levels of C-peptide. However, in the case of the Metformin and/or Sulfonylurea group, insulin levels were found to increase by more than 14%, which clearly indicated that drug-induced suppression of glucose levels instead of restoration of glucose homeostasis. Administration of the formulation was also found to be free from any adverse side effects as there were no changes in hematological profile, liver function and renal function. Conclusion The study demonstrated the promising potential of this novel phytotherapeutic, Fenfuro®, in long-term holistic management of type-2 diabetes.

Safety and effectiveness of metformin plus lifestyle intervention compared with lifestyle intervention alone in preventing progression to diabetes in a Chinese population with impaired glucose regulation: a multicentre, open-label, randomised controlled trial

Impaired glucose regulation (defined as either impaired glucose tolerance or impaired fasting glucose) is an important risk factor for the development of diabetes. We aimed to evaluate the safety and effectiveness of metformin plus lifestyle intervention compared with lifestyle intervention alone in preventing diabetes in Chinese participants with impaired glucose regulation. We did a multicentre, open-label, randomised controlled trial at 43 endocrinology departments in general hospitals across China. Eligible participants were individuals with impaired glucose regulation (ie, impaired glucose tolerance or impaired fasting glucose, or both), men or women aged 18-70 years with a BMI of 21-32 kg/m2. Eligible participants were randomly assigned (1:1) via a computer-generated randomisation to receive either standard lifestyle intervention alone or metformin (850 mg orally once per day for the first 2 weeks and titrated to 1700 mg orally per day [850 mg twice per day]) plus lifestyle intervention. Block randomisation was used with a block size of four, stratified by glucose status (impaired fasting glucose or impaired glucose tolerance), hypertension, and use of any anti-hypertensive medication. Lifestyle intervention advice was given by investigators at all participating sites. The primary endpoint was the incidence of newly diagnosed diabetes at the end of the 2-year follow-up. Analysis was done using the full analysis set and per-protocol set. This study is registered with ClinicalTrials.gov, number NCT03441750, and is completed. Between April, 2017, and June, 2019, 3881 individuals were assessed for eligibility, of which 1678 (43·2%) participants were randomly assigned to either the metformin plus lifestyle intervention group (n=831) or the lifestyle intervention alone group (n=847) and received the allocated intervention at least once. During a median follow-up of 2·03 years, the incidence rate of diabetes was 17·27 (95% CI 15·19-19·56) per 100 person-years in the metformin plus lifestyle intervention group and 19·83 (17·67-22·18) per 100 person-years in the lifestyle intervention alone group. The metformin plus lifestyle intervention group showed a 17% lower risk of developing diabetes than the lifestyle intervention alone group (HR 0·83 [95% CI 0·70-0·99]; log-rank p=0·043). A higher proportion of participants in the metformin plus lifestyle intervention group reported adverse events than in the lifestyle intervention alone group, primarily due to more gastrointestinal adverse events. The percentage of participants reporting a serious adverse event was similar in both groups. Metformin plus lifestyle intervention further reduced the risk of developing diabetes than lifestyle intervention alone in Chinese people with impaired glucose regulation, showing additional benefits of combined intervention in preventing progression to diabetes without new safety concerns. Merck Serono China, an affiliate of Merck KGaA, Darmstadt, Germany. For the Chinese translation of the abstract see Supplementary Materials section.

Metformin restores cognitive dysfunction and histopathological deficits in an animal model of sporadic Alzheimer's disease

BackgroundMetformin has been introduced as a neuroprotective agent in recent years. Here we evaluate the therapeutic effects of metformin in sporadic mouse model of Alzheimer's disease (SAD). MethodsAD was induced by streptozotocin (STZ, 0.5 mg/kg) on days 1 and 3. Metformin (MET, 200 mg/kg per day) was used for two weeks. Novel objective recognition (NOR) and Barnes Maze test were used to test the learning and memory. Nissl staining was used as s histological method for counting the dying neurons in different regions of hippocampus. Immunofluorescence staining against glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule 1 (Iba1) and NeuN were used to visualize reactive astrocytes, microglia and neurons, respectively. ResultsIn NOR test, the discrimination indices in the STZ group were significantly lower than the control and treatment groups. Goal sector/non-goal sector (GS/NGS) ratio index in Barnes maze was increased in metformin group compared to other groups. The number of dying neurons was increased by SAD and metformin reduced it. GFAP level was increased in CA1, CA3 and cortex of STZ group and reversed following the treatment. Iba1 level was significantly higher in STZ group in CA3 and cortex regions compared to Control and decreased by metformin in CA3 and cortex. Counting NeuN+ cells demonstrated significant reduction of neurons in DG+CA1 and CA3 after SAD induction. SignificanceMetformin decreased inflammatory cells and reactive astrocytes as well as the dying neurons in the hippocampus region and the cortex in SAD, and improved the cognitive performance.

P-665 Timing of metformin treatment in women with polycystic ovarian syndrome and associated pregnancy outcomes: a systematic review and meta-analysis

Abstract Study question Does giving women with polycystic ovarian syndrome (PCOS) preconception metformin and continuing it through at least the first trimester improve pregnancy outcomes? Summary answer Giving women with PCOS preconception metformin and continuing throughout the first trimester significantly reduces the risk of early miscarriage, and can improve pregnancy outcomes. What is known already Metformin, either alone or in combination with other ovulation induction agents, can improve ovulation and clinical pregnancy rates in women with PCOS. Its impact on miscarriage and live birth rate are less well understood. Furthermore the impact of both the timing and duration of metformin treatment on subsequent pregnancy outcomes, in women with PCOS, is unknown. We sought to evaluate the role that preconception metformin, continued until at least the point of positive pregnancy test, may have on pregnancy outcomes in women with PCOS and the effect that stopping metformin once pregnant might have. Study design, size, duration We conducted a systematic review and meta-analysis. A search within MEDLINE, Embase and the Cochrane Central Register of Controlled Trials for studies listed from database inception to 13th October 2022 was conducted. Potentially eligible studies identified through other sources (such as the reference lists of the selected primary studies and review articles) were also screened for inclusion. We adopted Grading of Recommendations, Assessment, Development and Evaluation (GRADE) for determining the quality of the evidence. Participants/materials, setting, methods The full-text of studies identified as being potentially suitable for inclusion were obtained. Those meeting the study selection criteria, outlined, were included in the systematic review and meta-analysis. Studies were included if they were prospective randomised controlled trials, comparing the use of metformin in women with PCOS, which had been started pre-conceptually and continued at least until pregnant (confirmed urinary pregnancy test), to either placebo or no treatment. Main results and the role of chance A total of 12 studies (1517 women) were included in the systematic review and meta-analysis. Women who were given preconception metformin which was continued until at least the end of the first trimester showed a significantly reduced risk of early miscarriage [OR 0.51 95% CI (0.27-0.96), 6 studies, n = 294, I2=0%], compared to either placebo or no treatment. Continuing preconception metformin until at least the end of first trimester also significantly increased clinical pregnancy rates [OR 1.92 95% CI (1.43-2.59), 5 studies, n = 793, I2=67%]. Only 3 studies, looked at live birth outcome which showed an increased odds of live birth in the metformin group, but this was not statistically significant [OR 1.38 95% CI (0.65-2.92), 3 studies, n = 212, I2=0%]. In women who stopped taking metformin following a positive pregnancy test, there was a suggestion of improvement in clinical pregnancy [OR 1.36 95% CI (0.99-1.87), 6 studies, n = 663, I2=45%] and live birth rates [OR 1.15 95% CI (0.57-2.35), 5 studies, n = 244, I2=0%]; but these were not statistically significant. Conversely, there was an increased odds of early miscarriage [OR 1.22 95% CI (0.59-2.52), 6 studies, n = 244, I2=0%], but this was also not statistically significant. Limitations, reasons for caution Whilst a role for commencing metformin pre-conceptually and continuing until at least the end of the first trimester has been demonstrated to be effective in improving clinical pregnancy rates and reducing miscarriage risk, the effectiveness and safety of continuing it throughout the remainder of the pregnancy remains unclear. Wider implications of the findings Continuing metformin treatment until at least the end of first trimester can increase the clinical pregnancy rate and reduce the risk of miscarriage. Stopping metformin once pregnant could be harmful and increase the risk of miscarriage. These findings should be considered when managing women with PCOS wishing to conceive. Trial registration number CRD42017073976

Pyridylnidulin exerts anti-diabetic properties and improves non-alcoholic fatty liver disease in diet-induced obesity mice.

Introduction: Non-alcoholic fatty liver disease (NAFLD) is one of the metabolic disorders related to the pathophysiology of type 2 diabetes mellitus (T2DM). Therapeutic strategies are focused on the improvement of energy balance and lifestyle modification. Additionally, the derivative of the bioactive fungal metabolite is of interest to provide health benefits, especially in obese and pre-diabetic conditions. In our screening of anti-diabetic compounds from fungal metabolites and semisynthetic derivatives, a depsidone derivative, namely pyridylnidulin (PN), showed potent glucose uptake-inducing activity. The present study aimed to investigate the liver lipid metabolism and anti-diabetic properties of PN in diet-induced obesity mice. Methods: Male C57BL/6 mice were induced obesity and pre-diabetic conditions by dietary intervention with a high-fat diet (HFD) for 6 weeks. These obese mice were orally administered with PN (40 or 120 mg/kg), metformin (150 mg/kg), or vehicle for 4 weeks. Glucose tolerance, plasma adipocytokines, hepatic gene and protein expressions were assessed after treatment. Results: Improved glucose tolerance and reduced fasting blood glucose levels were found in the PN and metformin-treated mice. Additionally, hepatic triglyceride levels were consistent with the histopathological steatosis score regarding hepatocellular hypertrophy in the PN and metformin groups. The levels of plasma adipocytokines such as tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) were reduced in the PN (120 mg/kg) and metformin-treated mice. In addition, hepatic gene expression involved in lipid metabolism, including lipogenic enzymes was significantly reduced in the PN (120 mg/kg) and metformin-treated mice. The increased protein expression levels of phosphorylated AMP-activated protein kinase (p-AMPK) was also found in PN and metformin-treated mice. Discussion: Considering the increased p-AMPK protein expression levels in PN and metformin-treated mice were revealed as the underlying mechanisms to improve metabolic parameters. These results suggested that PN provided the health benefit to slow the progression of NAFLD and T2DM in obese and pre-diabetic conditions.

P-395 Protective effect of metformin on the ovarian reserve of prepubertal mice under cyclophosphamide chemotherapy

Abstract Study question Can metformin reduce the side effects of cyclophosphamide on the ovaries of prepubertal mice treated with cyclophosphamide? Summary answer Yes, metformin, as an inhibitor of mTOR and, by affecting the HIPPO pathway, can exert its protective effect in the chemotherapy mice model. What is known already PI3K/AKT and HIPPO pathways are influential pathways in the process of activation of primordial follicles and proliferation of cell growth, which are affected by various agents and drugs such as cyclophosphamide. One of the side effects of cyclophosphamide is the reduction of the ovarian reserve through abnormal changes in the PI3K/AKT and HIPPO pathways. Metformin is a drug that is used to treat type 2 diabetes and at the same time regulates PI3K/AKT and HIPPO pathways and prohibits the proliferation of cancer cells. Study design, size, duration Controlled experimental study. After metformin and cyclophosphamide dose adjustment, 12 female NMRI 14-day-old mice were randomly divided into four groups: the control group (CONT), metformin group (MET), cyclophosphamide group (CYC) and metformin with cyclophosphamide group (MET-CYC). Participants/materials, setting, methods Mice were treated by intraperitoneal injection of a dose of 150mg/kg of metformin for 11 consecutive days, and/or a dose of 65mg/kg of cyclophosphamide every three days (The third, sixth and ninth days). The mice were sacrificed 24 hours after the last metformin injection or 3 days after the last cyclophosphamide injection. The ovaries were collected for stereological evaluation, and expression of Pten, Mtor, Yap-1, p53, Bcl-2, and Bax genes by qRT-PCR method. Main results and the role of chance The stereological evaluation showed that the ovarian volume and primordial follicle number in the CYC group were decreased compared to the other groups (P &amp;lt; 0.05), and also in the MET-CYC group reduced compared to the CONT and MET groups, but increased significantly compared to the CYC group (P &amp;lt; 0.05). A significantly increased number of growing follicles was observed in the CYC group compared to the other groups (P &amp;lt; 0.05). The molecular analysis showed that the Pten expression in the CYC group was lower than CONT and MET groups (P &amp;lt; 0.05). Mtor expression in the CYC group was significantly increased compared to other groups (P &amp;lt; 0.05). The expression of Yap-1 was significantly decreased in the MET group compared to other groups (P &amp;lt; 0.05), and was lower in the MET-CYC than in the CYC group (P &amp;lt; 0.05). The of P53 expression in the MET-CYC group was higher than CONT and MET groups (P &amp;lt; 0.05), and was increased in the CYC compared to the CONT group (P &amp;lt; 0.05). Bcl-2 expression was higher in CONT and MET groups than in MET-CYC and CYC groups (P &amp;lt; 0.05). The expression of Bax in the CYC group was significantly increased compared to CONT and MET groups (P &amp;lt; 0.05). Limitations, reasons for caution Due to ethical issues in less use of mice, dose of metformin was obtained according to the articles used in adult mice and also by using the human to animal dose conversion formula. Wider implications of the findings It can be concluded that metformin during cyclophosphamide treatment can maintains ovarian volume, reserve, and activity in prepubertal mice by regulating PI3K/AKT and HIPPO pathways. Considering the relatively acceptable cost and long-term safety of metformin, it is a promising factor to be used to preserve fertility during chemotherapy. Trial registration number not applicable

1516-P: Free Fatty Acid and Amino Acid Predictors of Response to Metformin in Polycystic Ovary Syndrome

Metformin is one of the most widely used antidiabetic drugs and is also effectively used in treating women with polycystic ovary syndrome (PCOS). Our global objective is to separate women with PCOS into subtypes by their response to metformin. This pilot study aims to determine which free fatty acids and amino acids metabolites predict response to metformin as categorized by changes in insulin sensitivity and testosterone concentrations after three months of metformin therapy. We recruited 42 participants with PCOS aged between 18-50 years. Participants were randomly categorized into metformin (n= 29; 32.41 ± 7.4 years) and placebo groups (n=13; 32.15 ± 5.65 years). The Metformin group was challenged with three months of metformin titrated to at least 1500 mg daily. Body weights decreased significantly in the metformin treatment group from 98.55 ± 22.76 to 97.27 ± 23.14 (p-value=0.01) but did not change in the placebo group. Fasting plasma glucose decreased only in the metformin group from 89.25 ± 9.12 to 86.37 ± 9.53. Testosterone levels decreased in the metformin-treated group after 12 weeks from 29.0 (18.5 - 35.5) to 23.0 (15.5 - 32.5), but no significant change was observed in the placebo group from 28.0 (20.0 - 43.0) to 27.0 (21.5 -49.0). However, we did not observe a statistically significant change in insulin sensitivity values in PCOS and placebo groups. Linear regression analysis was performed to check the predictive power of those associated metabolites with delta values of testosterone and insulin sensitivity. Our results showed that changes in insulin sensitivity and testosterone levels after metformin treatment could be significantly predicted by using concentrations of metabolites (Fig.1). Disclosure A.Y. Chang: None. A.K. Asokan: None. D. Sakrikar: Employee; The Binding Site. A. Lalia: None. I.R. Lanza: None. M. Petterson: None. K. Nair: None. Funding National Institutes of Health (UL1TR000135)

896-P: Effectiveness of Newly Prescribed SGLT2 Inhibitors as Second-Line Therapy following DPP-4 Inhibitors or Metformin as First-Line Therapy in Type 2 Diabetes Patients

Prescriptions of SGLT2 inhibitors (SGLT2i) for patients with type 2 diabetes (T2DM) are increasing. In this study real-world data were used to evaluate the long-term benefits of SGLT2i as a second-line drug for glycemic control in people with T2DM being treated with DPP-4 inhibitor (DPP4i) or metformin (MET) monotherapy. People with T2DM patients on DPP4i or MET monotherapy were followed for at least 12 months after receiving a new SGLT2i prescription. Patients were divided into DPP4i and MET groups, and patient background factors were controlled for using propensity score matching (PM). Changes in HbA1c and other indexes during the 12 months after the new prescription were compared using t-tests, and the factors affecting changes in HbA1c were examined using multiple regression analysis. After PM, there were 192 patients in the DPP4i (n=96) and MET (n=96) groups, with no significant differences in patient backgrounds. HbA1c levels 12 months after a new SGLT2i prescription were significantly lower in both groups compared to base line (8.1% to 7.0%, p&amp;lt;0.001; 8.1% to 7.1%, p&amp;lt;0.001), but there were no significant differences between the two groups in the change in HbA1c level (p=0.271), body weight (p=0.371), systolic blood pressure (p=0.828), eGFR (p=0.642), and Fib-4 index (p=0.674). The change in HbA1c was greater for those with initially higher HbA1c levels (-0.629 [-0.722-0.536], p&amp;lt;0.001) and those with shorter diabetes histories (0.024 [0.001-0.048], p=0.044), but it was not significantly different between the two groups (p=0.236). After controlling for patient background, there was no significant difference in the long-term effects of a new SGLT2i prescription between those previously receiving either DPP4i or MET monotherapy, but higher previous HbA1c levels and a shorter diabetes history may be prediction of better HbA1c 12 months after a new SGLT2i prescription, regardless of prior medication. Disclosure H.Takahashi: Speaker's Bureau; Eli Lilly Japan K.K., Boehringer Ingelheim Japan, Inc., Medtronic, Novo Nordisk. Y.Suganuma: None. T.Ohno: None. R.Nishimura: Speaker's Bureau; Sanofi K.K., Medicure Inc., Boehringer Ingelheim Inc., Takeda Pharmaceutical Company Limited, Kissei Pharmaceutical Co., Ltd., Novartis Pharma K.K., Eli Lilly Japan K.K., Novo Nordisk, Merck &amp; Co., Inc., Abbott Japan Co., Ltd., Astellas Pharma Inc., Teijin Pharma Limited, Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., AstraZeneca.

866-P: Quantitative Analysis of Metformin-Induced Glucose Excretion in the Intestine

The enhancement of the uptake of 18F-labeled fluorodeoxyglucose (FDG) during [18F]FDG PET is a recently found metformin action in the gut. Taking advantage of PET-MRI, which provides better tissue registration and soft-tissue contrast than conventional PET-CT, we revealed that metformin enhanced FDG accumulation in the intestinal lumen. We now quantitatively analyzed the phenomenon with a newly developed protocol of PET-MRI. We also analyzed the intestinal glucose dynamics using 13C-labeled glucose and mass spectrometry in mice. We adopted imaging sequences of MR enterography to create 3D images of the intestinal tract, then superimposed the [18F]FDG PET images to obtain the 3D distribution of radioactivity. We conducted this test on type 2 diabetes subjects treated (N=5) or not (control, N=5) with metformin. Radioactivity was detected in the wall and lumen at similar extents in the control. However, in the metformin group, the radioactivity in the lumen, but not the wall, was three to four-fold greater than that in the control. We mathematically analyzed the data using a compartment model and calculated the glucose excretion rate (GER). GER of the control and metformin groups were 6.8 ± 1.2 mg/min and 26.1 ± 2.9 mg/min, respectively, the latter being comparable to glucose excretion into the urine induced by SGLT2 inhibitors. For mouse experiments, we intravenously injected 13C-glucose into C57/B6 mice and analyzed the feces 1 hour after injection with a gas chromatography-quadrupole mass spectrometry. We could not detect 13C-glucose in the feces, possibly because gut microbiota metabolizes glucose in the intestine. However, the content of 13C in short-chain fatty acids (SCFAs) was increased by the injection of 13C-glucose, and metformin augmented the incorporation of 13C into SCFAs. These results suggest that glucose in the circulation transfers to the intestinal lumen at a considerable rate and is metabolized by microbiota, at least partly, into SCFAs and that metformin augments the processes. Disclosure Y.Hosokawa: None. K.Sakaguchi: Research Support; Sumitomo Dainippon Pharma Co., Ltd. J.Ito: None. K.Sugawara: None. Y.Morita: None. W.Ogawa: Advisory Panel; Abbott Japan Co., Ltd., Research Support; Boehringer Ingelheim Japan, Inc., Eli Lilly Japan K.K., Novo Nordisk, Teijin Pharma Limited, Kowa Company, Ltd., Sumitomo Dainippon Pharma Co., Ltd., Abbott Japan Co., Ltd., Speaker's Bureau; Sumitomo Dainippon Pharma Co., Ltd. Funding Japan Society for the Promotion of Science (21K08578, 22K18393)