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Background: The Diabetes Health Plan (DHP), a value-based insurance plan that reduces cost sharing, was previously shown to modestly increase employer-level medication adherence. However, it is unclear whether the DHP has a larger impact on individual-level medication adherence among lower- or higher-income beneficiaries. Methods: An employer-level propensity score match was done to identify suitable control employers, followed by individual-level propensity score weighting. These weights were applied to difference-in-difference (DID) models examining 1) the effect of the DHP and 2) the effect of income on changes in adherence to metformin, statins, and ACE/ARBs. The weights were then applied to a differences-in-differences-in-differences (DDD) model to estimate the differential impact of DHP status on changes in adherence by income group. This is a retrospective, quasi-experimental study.Results: There were no significant differences in changes to adherence for any medications between beneficiaries enrolled in the DHP versus standard plans. However, changes in adherence were higher for all medications among those in the highest income strata (>$75,000) versus those in the lowest income strata (Conclusion: We did not find significant associations between the DHP and changes in individual-level medication adherence, even for low-income beneficiaries. New strategies to improve consumer engagement may be needed in order to translate value-based insurance designs into changes in patient behavior.

Background: According to available research, there have been no head-to-head studies comparing the effect of glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose cotransporter 2 (SGLT-2) inhibitors on cardiovascular outcomes among patients with type 2 diabetes not reaching glycemic goal with metformin. Methods: Relevant studies were identified through electronic searches of PubMed and EMBASE published up to January 15, 2020. Efficacy outcomes of interest included the composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, its individual components, all-cause death, and hospitalization for heart failure (HF). Safety outcomes included all suggested side effects of both agents previously reported. Results: Eleven studies, including 94,727 patients were used for the analysis. The risk of composite end point was significantly lower in both groups compared to the control group (hazard ratio [HR], 0.88, 95% confidence interval [CI] 0.85–0.92, p < 0.001). The risk of hospitalization for HF was significantly lower in both groups but the magnitude of the effect was more pronounced in the SGLT-2 inhibitors group (HR 0.68, 95% CI 0.60–0.76, p < 0.001) than the GLP-1 agonists group (HR 0.92, 95% CI 0.84–0.99, p = 0.03). Patients treated with GLP-1 agonists discontinued trial medications more frequently compared to conventionally treated patients because of serious side effects. Conclusions: Both GLP-1 agonists and SGLT-2 inhibitors showed comparable cardiovascular outcomes in patients with type 2 diabetes. However, the SGLT-2 inhibitors were associated with more pronounced reduction of hospitalization for HF and lower risk of treatment discontinuation than GLP-1 agonists.

BACKGROUND Since the turn of the century, the prevalence of diabetes mellitus in Australia has increased, primarily due to rising rates of type 2 diabetes. Simultaneously, the landscape of diabetes medications has evolved significantly. The change in prescribing trends and public spending on diabetes medications within Australia during this period are not well defined. AIMS We sought to establish the frequency and cost of dispensed diabetes medications in the Australian public healthcare system between 2003 and 2019. METHODS We performed a longitudinal nationwide observational study using data obtained from the Pharmaceutical Benefits Scheme (PBS) and Medicare Benefits Schedule websites, which contain information on frequency and spending of diabetes medications dispensed in Australia. RESULTS The total number of PBS-subsidised prescriptions dispensed for diabetes increased from 5,218,690 in 2003 to 12,188,568 in 2019, and spending increased from $117,241,031 to $598,904,983. Of the non-insulin agents, metformin was consistently the most frequently dispensed agent, with a rapid growth in metformin combination tablets. Dispensation of sulphonylureas and thiazolidinediones have declined, with a simultaneous increase in DPP-4 inhibitors, SGLT2 inhibitors, and GLP-1 receptor agonists. CONCLUSIONS Our data show a large growth in the use of diabetes medications between 2003 and 2019. The rapid growth in dispensing of drugs with proven cardiovascular and renal benefits reflect the evolving approach of diabetes treatment, from a historical approach targeting glycaemic control alone, to a modern individualised approach targeting specific co-morbidities. This article is protected by copyright. All rights reserved.

Background and aim The present study evaluates the antidiabetic effects of aqueous (CPAQ) and methanolic (CPME) extract of Costus pictus D. Don singly and/or in combination with metformin in alloxan-induced diabetic rats. Experimental procedure CPAQ and CPME (400 mg/kg dose), metformin (120 mg/kg) and two different combinations of plant extracts and metformin (200 + 60 mg/kg and 400 mg/kg + 60 mg/kg) were orally given to alloxan-induced diabetic rats for 21 days. At 0, 7, 14, and 21 days, body weight and blood glucose levels were measured. Results and conclusion After 21 days of treatment, biochemical profiling and histopathology analysis were carried out. CPAQ and CPME, when administrated separately, could decrease blood glucose levels (P ≤ 0.05). CPME showed more promising results (P ≤ 0.05) compared to the diabetic control group. Extracts co-administrated with metformin showed dose-dependent significant recovery of hypoglycemic activity of metformin. Fasting blood glucose levels, body weight, protein, and lipid profile of the treatment group were compared to the diabetic and normal control groups. Animal groups co-administered with CPME and metformin showed more significant effects on the recovery of tissue damages. The synergistic effect of plant extracts with metformin has positive effects on all the parameters and enhanced the efficiency and reduction of blood glucose levels.

Background. The safety and efficacy of combination tablets of metformin plus sulfonylurea or plus dipeptidyl peptidase-4 inhibitors have not been studied previously. This study aimed to compare the efficacy and safety of Gliconorm versus Sitavia plus among patients with type 2 diabetes mellitus who fast Ramadan. Methods. This was an open-label study conducted from 1 May 2018 till 1 July 2018. People with type 2 diabetes mellitus who were drug-naive or on metformin only, with HbA1c < 10 % were included. The participants were divided into two groups. The first group was given Gliconorm (glibenclamide 5 mg + metformin 1000 mg), while the second group was given Sitavia plus (sitagliptin 50 mg + metformin 1000 mg) imme-diately after Iftar. Glycated hemoglobin (HbA1c) was measured before and after Ramadan. Several home recordings of blood glucose were collected. In addition, patients were asked to report any hypoglycemic or severe hyperglycemic episodes. Results. A total of 34 participants (18 women) (19 in the first group and 15 in the second group) were involved the study. The mean age was 49.6 ± 9.3 years. HbA1c reduced from 8.7 % (72 mmol/mol) to 7.6 % (60 mmol/mol) and from 8.7% (72 mmol/mol) to 7.7 % (61 mmol/mol) in the first and second group, respectively (p < 0.0001). Only one patient in the first group experienced one episode of hypoglycemia and hyperglycemia. Conclusion. Both medications seem to be safe and effective during Ramadan fasting.

Background: Observational studies suggest an anti-neoplastic effect associated with statins, metformin, dipeptidyl peptidase-4 inhibitors (DPP4i), while sulfonylureas may have a neutral or detrimental effect. The aim of this study was to determine the impact of these medications in patients with myelodysplastic syndromes (MDS). Methods: A prospective Canadian national registry containing disease and patient-related characteristics enrolled patients with MDS between January 1, 2006 and December 31, 2019. The Ontario subset of the registry was linked to population-based health system administrative databases. The primary outcome was the impact of statin/oral hypoglycemic medication exposure on overall survival (OS). Cumulative medication exposure (in months) was evaluated from 1-year prior to registry enrollment to date of death or end of follow-up (March 31, 2020) as a time-varying covariate. Cox regression analysis controlling for comorbid disease burden (Aggregated Diagnosis Groups; ADG) and sociodemographic factors (age, sex, rurality, income quintile) examined the relationship between medication exposure and OS. Our secondary outcome was leukemia-free survival (LFS), in which cause-specific hazard model was used to evaluate the association between medication exposure and LFS, taking death as the competing event. Results: In total, 533 patients aged >66 years were included (395 lower-risk IPSS, 130 higher-risk IPSS). The median age was 76.0 years (IQR 72.0-81.0), 65.1% were male and 9% had secondary MDS. The mean follow-up was 2.6 years (SD+ 2.4). Starting one year prior to registry enrollment and until the end of follow-up, 49.3% used a statin, 18.9% used metformin, 9.0% used a sulfonylurea and 6.4% used a DPP4i. On univariate analysis, we identified an improved OS in the lower-risk IPSS group using DPP4i (HR 0.98, 95% CI 0.95-1.00, p=0.05), while there was no significant difference in the higher-risk IPSS group for users of DPP4i (HR 1.03, 95% CI 0.99-1.07, p=0.21). In both lower and higher-risk IPSS groups, there was no difference in mortality for statins (HR 1.00, CI 1.00-1.01, p=0.93), metformin (HR 1.00, CI 0.99-1.01, p=0.81) and sulfonylureas (HR 1.00, CI 0.99-1.02, p=0.43). Increased age (p There was no association between exposure to the studied medications and LFS in the lower-risk group: metformin (HR 0.99, 95% CI 0.96-1.02, p=0.32), sulfonylureas (HR 0.99, 95% CI 0.94-1.04, p=0.57) and statins (HR 0.99, 95% CI 0.98-1.01, p=0.41). The impact of DPP4i exposure on LFS could not be assessed in lower risk disease due to infrequent events. There was also no association in the higher-risk IPSS group: DPP4i (HR 1.06, 95% CI 1.00-1.12, p=0.05), metformin (HR 1.02, CI 0.98-1.05, p=0.34), sulfonylureas (HR 1.04, 1.00-1.08, p=0.07) and statins (HR 1.02, 1.00-1.04, p=0.12). On multivariable analysis in the lower-risk IPSS group, no associations were identified between the use of medications of interest and all-cause mortality: DPP4i (HR 0.98, 95% CI 0.95-1.00, p=0.06), metformin (HR 1.00, 95% CI 0.99-1.01, p=0.99), sulfonylurea (HR 1.00, 95% CI 0.99-1.02, p=0.65) and statins (HR 1.00, 95% CI 0.99-1.00, p=0.56). In those with known cause of death, the main cause of death amongst DPP4i users was infection (35.7%) followed by acute myeloid leukemia (AML) (21.4%) and cardiac disease (14.3%), while the main cause of death in patients not on DPP4i was progressive MDS (23.2%) followed by AML (22.5%) and infections (22.1%). Conclusions: DPP4i may confer a survival benefit in lower-risk but not higher-risk MDS that cannot be explained by a reduction in cardiovascular deaths. Metformin, sulfonylureas and statins showed no impact on OS and LFS in lower and higher-risk groups. Improved bone marrow function through exosome inhibition and increased granulocyte-macrophage colony stimulating activity is the suggested mechanism for the potential survival benefit with DPP4i in lower-risk IPSS patients. This represents the first study evaluating the impact of oral hypoglycemic mediations and statins in a large cohort of patients with MDS. Further prospective studies are required to further evaluate the effects of DPP4i in MDS. Disclosures Leber: AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TaiHo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Khalaf: Pfizer: Honoraria; Novartis: Honoraria; Paladin: Honoraria. Sabloff: TaiHo: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Jaxx: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; ROCHE: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Yee: Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Research Funding; Janssen: Research Funding; Jazz: Research Funding; MedImmune: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Research Funding; Tolero: Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Paladin: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forma Therapeutics: Research Funding. Buckstein: Celgene: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; TAIHO: Research Funding; Otsuka: Research Funding.

Background Consensus lacks regarding the association between diabetes mellitus (DM) and the prognosis of patients with non-Hodgkin lymphoma (NHL). We aimed to systematically evaluate the above association, as well as the potential influence of metformin use in a meta-analysis of cohort studies. Materials and Methods Cohort studies investigating the association between DM and survival outcomes of patients with NHL were included by search of electronic databases that included PubMed, Embase, and Web of Science. A random-effects model was adopted to combine the results. Results Eight cohort studies including 8652 patients with NHL were analyzed. Compared to non-DM patients with NHL, DM was associated with poor overall survival (OS, hazard ratio [HR] = 1.49, 95% confidence interval [CI]: 1.18-1.89, P .10). Conclusions DM is associated with poor survival outcomes in patients with B-cell NHL, which is consistent in patients with DLBCL. Concurrent metformin use in DM patients with NHL may be associated with improved survival outcomes.

Background:Oxandrolone is a synthetic testosterone analogue that is widely used among bodybuilders and athletes. However, oxandrolone causes male infertility. Recently, it was found that metformin reduces the risk of infertility associated with diabetes mellitus.Aim:This study aimed to investigate the protective effects of metformin against oxandrolone-induced infertility in male rats.Methods:Rats continuously received one of four treatments (n=7) over 14 days: control DMSO administration, oxandrolone administration, metformin administration, or co-administration of oxandrolone and metformin. Doses were equivalent to those used for human treatment. Subsequently, testicular and blood samples were collected for morphological, biochemical, and histological examination. In addition, gene expression of the testosterone synthesizing enzyme CYP11A1 was analyzed in the testes using RT-PCR.Results:Oxandrolone administration induced male infertility by significantly reducing relative weights of testes by 48%, sperm count by 82%, and serum testosterone levels by 96% (ANOVA, P value < 0.05). In addition, histological examination determined that oxandrolone caused spermatogenic arrest which was associated with 2-fold downregulation of testicular CYP11A1 gene expression. However, co-administration of metformin with oxandrolone significantly ameliorated toxicological alterations induced by oxandrolone exposure (ANOVA, P value < 0.05).Conclusion:Metformin administration protected against oxandrolone-induced infertility in male rats. Further clinical studies are needed to confirm the protective effect of metformin against oxandrolone-induced infertility among athletes.

Background Skeletal muscle atrophy is a severe condition that involves loss of muscle mass and quality. Drug intake can also cause muscle atrophy. Biguanide metformin is the first‐line and most widely prescribed anti‐diabetic drug for patients with type 2 diabetes. The molecular mechanism of metformin in muscle is unclear. Methods Myostatin expression was investigated at the protein and transcript levels after metformin administration. To investigate the pathways associated with myostatin signalling, we used real‐time polymerase chain reaction, immunoblotting, luciferase assay, chromatin immunoprecipitation assay, co‐immunoprecipitation, immunofluorescence, primary culture, and confocal microscopy. Serum analysis, physical performance, and immunohistochemistry were performed using our in vivo model. Results Metformin induced the expression of myostatin, a key molecule that regulates muscle volume and triggers the phosphorylation of AMPK. AMPK alpha2 knockdown in the background of metformin treatment reduced the myostatin expression of C2C12 myotubes (−49.86 ± 12.03%, P 3.12‐fold ± 0.13, P 3.3‐fold, P

Formation of reactive oxygen species has been linked to the development of diabetes complications. Treatment with metformin has been associated with a lower risk of developing diabetes complications, including when used in combination with insulin. Metformin inhibits Complex 1 in isolated mitochondria and thereby decreases the formation of reactive oxygen species. Thus, we post-hoc investigated the effect of metformin in combination with different insulin regimens on RNA and DNA oxidation in individuals with type 2 diabetes. Four hundred and fifteen individuals with type 2 diabetes were randomized (1:1) to blinded treatment with metformin (1,000 mg twice daily) versus placebo and to (1:1:1) open-label biphasic insulin, basal-bolus insulin, or basal insulin therapy in a 2 × 3 factorial design. RNA and DNA oxidation were determined at baseline and after 18 months measured as urinary excretions of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), respectively. Urinary excretion of 8-oxoGuo changed by +7.1% (95% CI: 0.5% to 14.0%, P = 0.03) following metformin versus placebo, whereas changes in 8-oxodG were comparable between intervention groups. Biphasic insulin decreased urinary excretion of 8-oxoGuo (within-group: −9.6% (95% CI: −14.4% to −4.4%)) more than basal-bolus insulin (within-group: 5.2% (95% CI: −0.5% to 11.2%)), P = 0.0002 between groups, and basal insulin (within-group: 3.7% (95% CI: −2.0% to 9.7%)), P = 0.0007 between groups. Urinary excretion of 8-oxodG decreased more in the biphasic insulin group (within-group: −9.9% (95% CI: −14.4% to −5.2%)) than basal-bolus insulin (within group effect: −1.2% (95% CI: −6.1% to 3.9%)), P = 0.01 between groups, whereas no difference was observed compared with basal insulin. In conclusion, eighteen months of metformin treatment in addition to different insulin regimens increased RNA oxidation, but not DNA oxidation. Biphasic insulin decreased both RNA and DNA oxidation compared with other insulin regimens.

Colorectal cancer (CRC) is one of the main causes of cancer-related mortality in the developed world despite recent developments in detection and treatment. Several epidemiological studies indicate that metformin, a widely prescribed antidiabetic drug, exerts a protective effect on different cancers including CRC. Furthermore, a recent double-blind placebo-controlled, randomized trial showed that metformin significantly decreased colorectal adenoma recurrence. Studies exploring the mechanism of action of metformin in cells derived from different types of cancers reported many effects including respiratory chain complex 1 inhibition, Akt phosphorylation inhibition, ATP depletion, PKA activation and Wnt signaling inhibition. However, many of these results were obtained employing metformin at concentrations several fold higher than those achieved in target tissues in diabetic patients receiving therapeutic recommended doses of metformin. In contrast, recent studies obtained with metformin at concentrations compatible with those detected in human intestines revealed that metformin elicit responses that target β-catenin, PI3K/Akt, E-cadherin, p120-catenin and focal adhesion kinase which are key molecules and signaling pathways associated to colorectal cancer development. This brief review revisit several know aspects as well as novel ones on the effects of metformin on cancer cells. Fil: Amable, Gastón Federico. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina Fil: Martínez León, Eduardo Antonio. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina Fil: Picco, María Elisa. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina Fil: Rey, Osvaldo. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina

Background and Objectives : Non-alcoholic fatty liver disease (NAFLD) is associated with inflammation and subsequent increase in cardiovascular risk. Because of its widespread presence and distribution, invasive diagnostic procedures (i.e., liver biopsy) are reserved for a limited number of subjects. With liver ultrasound, Fatty liver index (FLI) and fibrosis-4 (FIB-4) scores non-invasively assess liver steatosis and fibrosis. We aimed to evaluate the changes in inflammatory markers and FLI/FIB-4 scores in non-obese metformin-treated type 2 diabetes patients (T2DM) with NAFLD. Methods: All subjects underwent abdominal ultrasound aiming for NAFLD stratification (grade 1 to 3 according to its severity). Metabolic parameters (morning glycaemia, HbA1C, lipids, liver function tests) and serum inflammatory markers (C-reactive protein, ferritin, and nitric oxide), and FLI/FIB-4 are calculated. Results: FLI score and ultrasound NAFLD grades correlated (p Conclusion: This pilot study suggests that the serum inflammatory markers at the average normal values point to the sufficiency of metformin-single therapy in inflammation control in non-obese T2DM patients with NAFLD.

Metformin is the first-line oral antidiabetic drug that shows multiple pleiotropic effects of anti-inflamation, anti-cancer, anti-aging, anti-microbia, anti-atherosclerosis, and immune modulation. Metformin's effects on men's related health are reviewed here, focusing on reproductive health under subtitles of erectile dysfunction (ED), steroidogenesis and spermatogenesis; and on prostate-related health under subtitles of prostate specific antigen (PSA), prostatitis, benign prostate hyperplasia (BPH), and prostate cancer (PCa). Updated literature suggests a potential role of metformin on arteriogenic ED but controversial and contradictory effects (either protective or harmful) on testicular functions of testosterone synthesis and spermatogenesis. With regards to prostate-related health, metformin use may be associated with lower levels of PSA in humans, but its clinical implications require more research. Although there is a lack of research on metform's effect on prostatitis, it may have potential benefits through its anti-microbial and anti-inflammatory properties. Metformin may reduce the risk of BPH by inhibiting the insulin-like growth factor 1 pathway and some but not all studies suggest a protective role of metformin on the risk of PCa. Many clinical trials are being conducted to investigate the use of metformin as an adjuvant therapy for PCa but results currently available are not conclusive. While some trials suggest a benefit in reducing the metastasis and recurrence of PCa, others do not show any benefit. More research works are warranted to illuminate the potential usefulness of metformin in the promotion of men's health.

Metformin treatment improved ADPKD disease severity in a relevant, slowly progressive ADPKD mouse model that recapitulates a PKD-associated PKD1 mutation. Relative to controls, metformin reduced kidney weight/body weight, cystic index and BUN levels, while improving GFR, blood pressure and anemia. Metformin also reduced key inflammatory and injury markers, along with cell proliferation markers. These findings suggest several beneficial effects of metformin in this ADPKD mouse model, which may help inform new ADPKD therapies in patients.

Sodium-glucose cotransporter 2 inhibitors have been shown to reduce cardiovascular events but are currently not used as the first-line therapy. This study was conducted to evaluate the cost-effectiveness of first-line empagliflozin plus metformin versus metformin monotherapy among Australians with type 2 diabetes mellitus (T2DM) and existing cardiovascular disease (CVD).A Markov model with 1-year cycles and a 5-year time horizon was constructed to simulate the occurrence of recurrent cardiovascular events among Australians aged 50 to 84 years with T2DM and CVD. Efficacy results were derived from the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose trial. Costs and utilities were drawn from published sources. The evaluation adopted both health care and societal perspectives, with the latter ascribing the Australian government's "value of statistical life year" (A$213 000) to each year lived by a person. Future outcomes were discounted at 5% annually. Sensitivity analyses were conducted to enhance the robustness of conclusions.Compared with metformin monotherapy, first-line empagliflozin plus metformin reduced overall cardiovascular events by 0.82% and overall deaths by 7.72% over 5 years. There were 0.2 years of life saved per person and 0.16 quality-adjusted life years gained, at a net health care cost of A$4408. These equated to incremental cost-effectiveness ratios of A$22 076 per year of life saved and A$28 244 per quality-adjusted life year gained. The gains in the value of statistical life year equated to A$42 530 per person, meaning that from a societal perspective, the intervention was cost-saving.First-line empagliflozin plus metformin may represent a cost-effective strategy for the management of T2DM and CVD in Australia.

BACKGROUND AND AIMS: This study assesses the influence of demographic, lifestyle, and medication in the association between CRP and mortality in a national sample of adults with diabetes. METHODS AND RESULTS: Cross-sectional study of data from 1999-2010 National Health and Nutrition Examination Survey (unweighted n= 3,952; Weighted n= 19,064,710). Individuals were categorized as having diabetes if told by a provider they had diabetes, were taking insulin or other diabetes medications, or had a glycosylated hemoglobin A1c (HbA1c) ≥ 6.5%. CRP was classified into four categories: normal (1.0 mg/dL). Higher risk for mortality was associated with a very high-risk of CRP (HR=1.88 (95% CI: 1.27 - 2.78), being a current (HR=1.49 (95% CI: 1.10 - 2.01) or former (HR=1.34 (95% CI: 1.03 – 1.73) smoker, and taking insulin (HR=1.60 (95% CI: 1.25 – 2.05), taking anti-hypertensives (HR=1.50 (95% CI: 1.22 – 1.85), and having comorbidities such as cancer (HR=1.32 (95% CI: 1.05 – 1.66) and hepatitis infection (HR=1.76 (95% CI: 1.07 – 2.91), while taking Metformin (HR=0.62 (95% CI: 0.50 – 0.76) had a lower risk of mortality. CONCLUSION: In this sample of adults with diabetes, demographic, lifestyle, and medication factors influenced the association between CRP and mortality. Interventions should focus on these factors to reduce mortality in adults with diabetes.

Background: Obesity-induced inflammation facilitates depression and premenstrual tension syndrome. Hypoxia is a common feature of inflammation. Hypoxia inducible factors adapt cells to low oxygen tension and inflammation. Objectives: We aimed to see how obesity, along with Amiloride, Hydrochlorothiazide, Metformin, calorie restriction, and walking exercise, affected psychosomatic characteristics of premenstrual tension syndrome, during a six-month period.Patients and methods: A prior ethical committee approval and informed patients’ consent were taken. This study was performed in Tanta University, Egypt from May 2019 to December 2019. This study aims at evaluating the effects of obesity-induced inflammatory mediators on psychosomatic effects in women having premenstrual tension syndrome. Effects of combined therapy using (Metformin, Amiloride. Hydrochloride/ Hydrochlorthiazide, caloric restriction, half an hour of walking exercise per day, and Vitazinc capsules) treatment was compared to the same combined therapy including Royal vitamin G treatment (instead of Vitazinc) on alleviating psychosomatic manifestations of premenstrual tension syndrome. Sixty obese women having premenstrual tension syndrome were categorized into younger age group (18-39 years) and older age (40-48 years) versus a non-obese age-matched control group. Body mass index in addition to serum tumour necrosis factor-α (TNF- α), hypoxia-inducible factor-1α (HIF-1α) and receptor activator of nuclear factor- kappa-Β ligand (RANKL) were assessed. Related psychosomatic manifestations of premenstrual tension syndrome (edema, anxiety, and fatigue) were also assessed. Results: Obesity significantly increased serum TNF-α (p < 0.01), HIF-1 α (p < 0.01) and RANKL (p < 0.01). Obesity-induced biochemical effects were higher in older obese women than younger ones. Obesity significantly exaggerated the severity of investigated psychosomatic manifestations (p < 0.001). Both combined therapies (including either Vitazinc or Royal vitamin G) significantly and dramatically decreased the percentage of cases having psychosomatic manifestations (p < 0.001) that was closely related to the decreased serum biochemical parameters. Conclusion: Combined therapy containing Royal vitamin G significantly improved serum biochemical parameters and psychosomatic manifestations better than combined therapy containing Vitazinc.

Aim: Study aims to assess amylase, lipase of patients with Type 2 diabetes under different types of treatments. Materials & methods: Patients’ treatment modalities including insulin, metformin, pioglitazone, sodium-glucose co-transporter-2 inhibitors, insulin secretagogues, dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists were compared. Results: There was no difference in amylase and lipase levels between dipeptidyl peptidase-4 inhibitor users and non-users (p = 0.2, p = 0.3, respectively) and glucagon like peptide-1 analog users and non-users (p = 0.1, p = 0.7, respectively). Patients who use insulin secretagogues had significantly higher amylase, lipase (77.2 ± 39.8 vs 69.5 ± 33.0, p = 0.038 and 47.2 ± 33.2 vs 39.6 ± 26.8, p = 0.01, respectively) and patients on basal insulin had lower amylase levels (69.9 ± 37.7 vs 77.2 ± 33.7, p = 0.014). Conclusion: Incretin-based therapies showed no difference in amylase and lipase levels whereas there was increase with secretagogues and decrease with basal insulin.

Background Metformin has recently been shown not to increase the risk of lactic acidosis in patients with chronic kidney disease (CKD). Thus, the criteria for metformin use in this population has expanded. However, the relationship between metformin use and clinical outcomes in CKD remains controversial. Methods This study considered data from 97,713 diabetes patients with an estimated glomerular filtration rate of

BACKGROUND AND AIMS In patients with nonalcoholic fatty liver disease (NAFLD), those with type 2 diabetes (DM) have a high risk of progression to hepatocellular carcinoma (HCC). However, the determinants of HCC risk in these patients remain unclear. APPROACH AND RESULTS We assembled a retrospective cohort of patients with NAFLD and DM diagnosed at 130 facilities in the Veterans Administration between 1/1/2004 and 12/31/2008. We followed patients from the date of NAFLD diagnosis to HCC, death or 12/31/2018. We used landmark Cox proportional hazards models to determine the effects of anti-DM medications (metformin, insulin, sulfonylureas) and glycemic control (% of follow up time with HbA1c < 7%) on the risk of HCC, while adjusting for demographics and other metabolic traits (hypertension, obesity, dyslipidemia). We identified 85,963 patients with NAFLD and DM. In total, 524 patients developed HCC during a mean of 10.3 years of follow up. Most common treatments were metformin monotherapy (19.7%), metformin-sulfonylureas (19.6%), insulin (9.3%), and sulfonylureas monotherapy (13.6%). Compared to no medication, metformin was associated with 20% lower risk of HCC (HR 0.80, 95% CI 0.93-0.98). Insulin had no effect on HCC risk (HR 1.02, 95% CI 0.85-1.22, p=0.85). Insulin in combination with other oral medications was associated with a 1.6-1.7-fold higher risk of HCC. Adequate glycemic control was associated with a 31% lower risk of HCC (HR 0.69, 95% CI 0.62-0.78). CONCLUSIONS In this large cohort of patients with NAFLD and DM, use of metformin was associated with a reduced risk of HCC while use of combination therapy was associated with increased risk. Glycemic control can serve as a biomarker for HCC risk stratification in patients with NAFLD and diabetes.

Introduction. Recently, many studies have been devoted to the study of type 2 diabetes mellitus (DM2) worldwide. In most countries of the world, the increase in the prevalence of DM2 among children and adolescents is accompanied by an increase in childhood obesity. The presence of obesity or overweight in children can complicate the diagnosis of various types of DM. Detection and treatment of DM2 is extremely important for the society due to the wide range of severe diabetes complications.The aim of this work was to analyze the frequency of DM2 according to the Register of patients with DM, and to determine the state of glycemic control in children with DM2. Materials and methods. An analysis of glycemic control in children with DM2 who received various treatment regimens: with diet and lifestyle modifications, or with additional oral hypoglycemic agents (metformin monotherapy, or combination with insulin therapy). The glycemic control was assessed by measurement of glycated hemoglobin (HbA1c) level. Results. According to the data Register in Ukraine, the prevalence of DM among children has a tendency to rise — from 8.6 per 10 thousand children in 2005, to 13.14 — in 2019 year. The prevalence of DM2 in 2019 was 0.47 % of all cases of DM, and its prevalence contained 0.062 per 10 thousand children under 19 years of age with significant differences in the frequency of its diagnosis in different regions of Ukraine. We analyzed the state of glycemic control in children with DM2 aged from 9 up to 19 years old (Me 16.2 [15.5; 18.0]), with a disease duration 0.5—12 years (Me 4.5 [1.0] ; 7.5]). The age of diagnosis of DM2 was 2-17 years old (Me 11.7 [8.5; 15.0]), and 91.3 % of patients had obesity. Diet and lifestyle modifications were used in 34.8 % of patients, metformin monotherapy in 52.2 %, and metformin and insulin combination therapy in 13 % of patients. HbA1c values ​​ranged from 5.0 to 11.4 % (Me 7.2 % [5,8; 8,0]). The proportion of children who had ideal or optimal glycemic control (HbA1c 7.0—7.5 %) was 52.2 %, suboptimal (HbA1c 7.6—9.0 %) — 39.1 %, high-risk glycemic control (HbA1c> 9.1 %) — 8.7 % of children. The most unsatisfactory HbA1c levels ​​were registered in children who received metformin in combination with insulin (Me 10.6 % [10,15; 11,4]). Chronic complications of DM2 have not been reported.Conclusions. We found a low prevalence of DM2 among the pediatric population in Ukraine, more likely due to the low quality of its detection among children diagnosed with DM, as well as among children among high risk groups. Most children with DM 2 were obese. The majority of patients with DM2 (52.2 %) received metformin monotherapy, more than a third did not receive oral hypoglycemic agents. In most children with DM2 (52,2 %), the state of glycemic control corresponded to the optimal (

Метою дослідження було вивчення впливу препарату метформін на рівень деяких гормонів жирової тканини та медіаторів генералізованого неспецифічного запалення при цукровому діабеті 2-го типу. Обстежено 38 пацієнтів з уперше виявленим цукровим діабетом 2-го типу перед початком і після 12 місяців цукрознижувальної монотерапії Глюкофажем. Отримані результати свідчать, що нормалізація показників вуглеводного обміну, зниження маси тіла пацієнтів на тлі проведеного лікування спричинено не лише прямим впливом метформіну на поліпшення поглинання глюкози периферичними тканинами, а і його здатністю модулювати секрецію адипоцитокінів.

З метою вивчення впливу цукрознижувальної терапії за допомогою комбінації глімепіриду й метформіну SR упродовж 12 тижнів на показники вуглеводного й ліпідного обміну, динаміку рівня адипокінів у плазмі крові та показники жорсткості артеріальної стінки великих артерій (аорти та її гілок) спостерігали 30 пацієнтів (з них 18 — жінки) з цукровим діабетом 2-го типу віком 60,10 ± 1,08 року із серед-ньою тривалістю основного захворювання 5,7 ± 0,9 року. Результати. Порівняно з початковими значеннями відзначено покращення показників вуглеводного обміну. Так, рівень HbA1c знизився на 1,7 % (р < 0,001), глікемії натще — на 22 % (р < 0,001), постпрандіальної глікемії — на 44 % (р < 0,001). Крім того, на тлі терапії спостерігалося покращення ліпідного обміну: зниження загального холестерину на 13,2 % (р < 0,01), холестерину ліпопротеїнів низької щільності — на 19,3 % (р < 0,01), тригліцеридів — на 30,6 % (р < 0,05). Спостерігалися зміни рівня адипокінів у плазмі крові: зниження рівня адипонектину з 5,98 ± 0,52 мг/мл до 4,45 ± 0,29 мг/мл (р < 0,01), а також тенденція до збільшення рівня лептину в плазмі крові з 14,6 ± 2,3 нг/мл до 18,12 ± 2,90 нг/мл (р > 0,05). Зміни швидкості пульсової хвилі в аорті та аортального індексу аугментації були статистично незначущими (р > 0,05). Зміни антропометричних показників (ваги, індексу маси тіла, окружності талії і стегон), а також загальної кількості жирової тканини, визначеної методом імпедансометрії, були статистично незначущими (р > 0,05).Висновки. Комбінована цукрознижувальна терапія глімепіридом і метформіном SR упродовж 12 тижнів призвела до статистично значущого покращення вуглеводного та ліпідного обміну, не впливала на антропометричні показники й загальну кількість жирової тканини, запобігала прогресуванню артеріосклерозу великих судин за даними показників жорсткості артеріальної стінки.

Комбинация метформина (МФ) (2 г в сутки) и пиоглитазона (ПГ) (30 мг в сутки) у 57 больных ишемической болезнью сердца (ИБС) и сахарным диабетом 2-го типа (СД-2) снижает показатели хронического воспаления (ХВ) низкой интенсивности: уровень фактора некроза опухоли альфа в крови — в 5 раз через 6 месяцев, интерлейкина-6 — в четыре раза соответственно по сравнению с исходным уровнем. Эта комбинация является безопасной, оказывает позитивный клинический эффект в отношении ИБС и более эффективно нормализует уровень гликированного гемоглобина у больных по сравнению с комбинацией МФ и препарата сульфонилмочевины. Поскольку ХВ является фактором, инициирующим развитие атеросклероза, ИБС, артериальной гипертензии и СД-2, комбинацию МФ и ПГ следует считать эффективным и безопасным средством профилактики и лечения этих заболеваний, что подтверждается анализом современной научной литературы.

Метформін — препарат першої лінії для лікування цукрового діабету (ЦД) 2-го типу, застосування якого зменшує прогресування порушень вуглеводного обміну і сприяє зниженню показників летальності. Прогресуючий перебіг ЦД 2-го типу призводить до того, що пацієнтам, початкова терапія яких включала лише метформін, зрештою потрібне покрокове додавання інших цукрознижувальних препаратів для досягнення і підтримання глікемічного контролю. В огляді літератури аналізуються різні підходи до покрокової індивідуальної інтенсифікації терапії ЦД 2-го типу. Найбільш популярною і вивченою комбінацією, спрямованою на обидва дефекти, що визначають розвиток метаболічних порушень при ЦД 2-го типу (відносний дефіцит інсуліну та інсулінорезистентність), залишається комбінація метформіну з препаратами сульфонілсечовини. Глімепірид має унікальне поєднання інсуліносекретогенних («ощадлива» стимуляція) та інсуліносенситайзерних властивостей при нейтральному ефекті на масу тіла і низькому ризику гіпоглікемій. Тому глімепірид на сьогодні є кращим вибором у хворих на ЦД 2-го типу за наявності кардіоваскулярного ризику порівняно з іншими сульфонілсечовинними препаратами.

Background: DPP-4 inhibitors (DPP-4i) and sulphonylureas remain the most widely prescribed add-on treatments after metformin. However, there is limited evidence from clinical practice comparing major adverse cardiovascular events (MACE) in patients prescribed these treatments, particularly among those without prior history of MACE and from vulnerable population.Methods: Using electronic health records from the UK primary care, we undertook a retrospective cohort study with people diagnosed type-2 diabetes mellitus, comparing incidence of MACE (myocardial infarction, stroke, major cardiovascular surgery, unstable angina) and all-cause mortality among those prescribed DPP-4i versus sulphonylureas as add-on to metformin. We stratified analysis by history of MACE, age, social deprivation and comorbidities and adjusted for HbA1c, weight, smoking-status, comorbidities and medications.Results: We identified 17,570 patients prescribed sulphonylureas and 6,267 prescribed DPP-4i between 2008-2017. Of these, 16.3% had pre-existing MACE. Primary incidence of MACE was similar in patients prescribed DPP-4i and sulphonylureas (10.3 vs 8.5 events per 1000 person-years; adjusted Hazard Ratio (adjHR): 0.94; 95%CI 0.80–1.14). For those with pre-existing MACE, rates for recurrence were higher, but similar between the two groups (21.8 vs 17.2 events per 1000 person-years; adjHR: 0.93; 95%CI 0.69–1.24). For those aged over 75 and with BMI less than 25kg/m2 there was a protective effect for DPP-I, warranting further investigation.Conclusions: Patients initiating a DPP-4i had similar risk of cardiovascular outcomes to those initiating a sulphonylurea. This indicates the choice should be based on safety and cost, not cardiovascular prognosis, when deciding between a DPP-4i or sulphonylurea as add-on to metformin.

Efforts to determine whether metformin can increase the effectiveness of neoadjuvant chemoradiotherapy in rectal cancer have increased in recent years. However, retrospective studies have yielded inconclusive results. Objectives The aim of this study was to compare oncological outcomes and survival after neoadjuvant chemoradiotherapy in patients with rectal cancer taking metformin versus in those not taking metformin. Methods This study analyzed 423 consecutive patients with locally advanced rectal cancer who underwent neoadjuvant chemoradiotherapy and curative surgery between January 2010 and May 2020; of these, 59 were taking metformin and 364 were not taking metformin. Results Patients taking metformin had a lower proportion of tumor regression (6.8% versus 22.0%, P = 0.012) as well as a lower proportion of patients achieving a pathological complete response (6.8% versus 20.6%, P = 0.011). In the multivariate analysis, independent predictors of pathologic complete response were not taking metformin (OR: 5.26, 95% CI: 1.12-24.85, P= 0.035) and cT2 stage (OR: 3.49, 95% CI: 1.10-11.07, P= 0.034); the interval was also an independent predictor of tumor regression (OR: 1.78, 95% CI: 1.06-2.96, P= 0.028). No differences were observed in survival between groups. Conclusion Metformin was not associated with better tumor responses or survival after neoadjuvant treatment.

The prevalence of non-obese nonalcoholic fatty liver disease (NAFLD) is increasing worldwide with unclear etiology and pathogenesis. Here, we show GP73, a Golgi protein upregulated in livers from patients with a variety of liver diseases, exhibits Rab GTPase-activating protein (GAP) activity regulating ApoB export. Upon regular-diet feeding, liver-GP73-high mice display non-obese NAFLD phenotype, characterized by reduced body weight, intrahepatic lipid accumulation, and gradual insulin resistance development, none of which can be recapitulated in liver-GAP inactive GP73-high mice. Common and specific gene expression signatures associated with GP73-induced non-obese NAFLD and high-fat diet (HFD)-induced obese NAFLD are revealed. Notably, metformin inactivates the GAP activity of GP73 and alleviates GP73-induced non-obese NAFLD. GP73 is pathologically elevated in NAFLD individuals without obesity, and GP73 blockade improves whole-body metabolism in non-obese NAFLD mouse model. These findings reveal a pathophysiological role of GP73 in triggering non-obese NAFLD and may offer an opportunity for clinical intervention., Dysregulation of lipid metabolism and transport contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here the authors identify GP73 as a TBC-domain Rab GTPase-activating protein that regulates very low-density lipoprotein export and promotes NAFLD development in mice.

Background: Two distinct subtypes of treatment-resistant schizophrenia (TRS) have been recently reported, including early-treatment resistance (E-TR) as the dominant subtype and late-treatment resistance (L-TR). However, the response rate to clozapine, incidence of clozapine-induced prediabetes/diabetes, and effects of metformin at preventing clozapine-induced prediabetes/diabetes in patients with schizophrenia E-TR subtype need investigating. To assess clozapine-induced metformin-resistant prediabetes/diabetes and its correlation with clinical efficacy in schizophrenia E-TR subtype. Methods: This prospective cohort study enrolled 230 patients with schizophrenia E-TR subtype from Tianjin Kangtai Hospital between January 2015 and December 2020.The patients were treated with adequate doses of clozapine for 16 weeks, during which patients with prediabetes/diabetes were assigned to receive add-on metformin. Incidence of clozapine-induced prediabetes/diabetes and metformin-resistant prediabetes/diabetes and the efficacy of clozapine as assessed by the Positive and Negative Syndrome Scale (PANSS) score. Findings: Clozapine-induced prediabetes/diabetes occurred in 176 patients (170 prediabetes and 6 diabetes), with 76.52% incidence. The blood sugar of 43 (24.43%) patients was controlled with metformin. Despite add-on metformin, 47.06% (74/170) of patients with clozapine-induced prediabetes progressed to diabetes. In total, the incidence of clozapine-induced metformin-resistant prediabetes/diabetes was 75.57% (133/176). On completion of 16-week clozapine treatment, 16.52% (38/230) patients showed clinical improvement with PANSS scores of ≥50% declining. Furthermore, clozapine-induced prediabetes/diabetes was significantly correlated with the poor clinical efficacy of clozapine for schizophrenia E-TR subtype. In comparison with patients that did not have clozapine-induced prediabetes/diabetes, clinical efficacy was significantly lower in patients with clozapine-induced prediabetes/diabetes. Of note, the lowest clinical efficacy detected in patients with clozapine-induced diabetes [odds ratio (OR) of 0.18; 95% confidence interval (CI), 0.07–0.44]. Interpretation: The incidence of clozapine-induced metformin-resistant prediabetes/diabetes was considerably high in the schizophrenia E-TR subtype. Clozapine-induced metformin-resistant prediabetes/diabetes represents an independent risk factor that adversely affects the clinical efficacy of clozapine for the schizophrenia E-TR subtype. This study provided new evidence for re-evaluating the use of clozapine for TRS, especially E-TR subtype, and the use of metformin for the glycemic control of clozapine-induced prediabetes/diabetes. Funding: This study was supported by the National Natural Science Foundation of China (81871052 and 81571319). Declaration of Interests: All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and there is no conflict of interest to disclose. Ethics Approval Statement: The study protocol was reviewed and approved by the Ethic Committee of Tianjin Kangtai Hospital (Tianjin, China).

Background: Is insulin initiation linked to increasing body mass index (BMI) in all patients with type-2-diabetes (T2D)? To determine distinct longitudinal patterns of BMI change over time. Materials and Methods: 5057 patients with T2D (55% males, median BMI [IQR]: 30.0 [26.9-33.3] kg/m2) aged ≥40 years at diabetes diagnosis and with ≥2 years of follow-up after insulin initiation irrespective of previous or concurrent use of metformin/dipeptidyl peptidase-4-inhibitor from the multicenter prospective diabetes registry DPV were studied. To identify subgroups following a similar pattern of BMI change after insulin initiation, longitudinal group-based trajectory modeling was applied. Multinomial logistic regression was then used to analyze covariates associated with group membership. Results: Three heterogeneous groups with either relevant BMI increase (delta-BMI: +4.0 kg/m2 after 2 years; 12% of patients); slight BMI increase (+0.4 kg/m2; 80%); or BMI decrease (-3.2 kg/m2; 8%) were identified. Patients with older age [OR (95% CI): 1.37 (1.11-1.69)] and obesity [2.05 (1.65-2.55)] before insulin start were more often in the BMI decreasing group, and less often in the BMI increasing class [0.80 (0.67-0.95); 0.82 (0.69-0.98)]. A worse HbA1c both at insulin start and during follow-up [1.90 (1.60-2.26); 1.17 (1.07-1.27)], a higher insulin dose [1.67 (1.33-2.10)], and severe hypoglycemic events [2.38 (1.60-3.53)] after insulin initiation were all linked with higher odds of belonging to the BMI increasing trajectory. Conclusions: Patient heterogeneity with respect to weight gain after initiation of insulin therapy in adult T2D was detected by an objective computer algorithm. Older people with obesity should not defer from insulin use due to fear of weight gain.

Objectives To assess the cost-effectiveness and cost utility of sitagliptin/metformin for the treatment of type 2 diabetes mellitus compared to those of glibenclamide/metformin in a semiprivate hospital and to compare the cost-effectiveness and cost utility of sitagliptin/metformin in a semiprivate hospital to those in the public health system (PHS) of Ecuador in 2019. Methods A cost-effectiveness study considering the probability of cardiovascular death as the outcome and quality-adjusted life-year as a measure of utility, estimating direct medical costs in US dollars by a model case from the perspective of the third payer. The results will be presented as an incremental cost-effectiveness ratio. One-way and 2-way sensitivity analyses with tornado diagrams were performed. Results Direct medical costs were lower at the hospital than from the PHS in Ecuador. Considering the drugs metformin/sitagliptin, the total cost was $35.69 less in the hospital ($880.38) than from the comparator ($916.07). The highest percentage of direct medical costs corresponded to drugs (between 63.94% and 84.65%). An ICER of –$19 131.61 was obtained at the Hospital Un Canto a la Vida and –$1621.85 at PHS. In addition, the cost per quality-adjusted life-year earned was $611.11. Sensitivity analysis showed that the probability of drug use and the relative risk of cardiovascular death associated with such prescription were parameters that most affected the model. Conclusions The combination therapy metformin/sitagliptin compared to metformin/glibenclamide was shown not to be cost-effective in the Hospital Un Canto a la Vida, and highly cost-effective in the PHS.

Metformin, a commonly used, well-tolerated treatment for type 2 diabetes, is being deployed in clinical trials to ameliorate aging in older non-diabetic humans. Concerningly, some experiments in model organisms have suggested that metformin use at old ages shortens lifespan and is toxic to mitochondria. The demonstrated safety of metformin therapy in humans and the conflicting data from model organisms compelled us to test the hypothesis that metformin treatment would be toxic to older rats. To define an effective dose in 30-month-old hybrid rats, we evaluated two doses of metformin (0.1%, 0.75% of the diet) and treated the rats for four months. Body mass decreased at the 0.75% dose. Neither dose affected mortality between 30- and 34-months of age. We assessed mitochondrial integrity by measuring mitochondrial DNA copy number and deletion mutation frequency, and mitochondrial respiration in skeletal muscle and the heart. In skeletal muscle, we observed no effect of metformin on quadriceps mass, mtDNA copy number, or deletion frequency. In the heart, metformin-treated rats had higher mtDNA copy number, lower cardiac mass, with no change in mtDNA deletion frequency. Metformin treatment resulted in lower mitochondrial Complex I-dependent respiration in the heart. We found that, in old rats, metformin did not compromise mitochondrial DNA integrity, did not affect mortality, and may have cardiac benefits. These data provide some reassurance that a metformin intervention in aged mammals is not toxic at appropriate doses.

We assessed the glycaemic durability with early combination (EC; vildagliptin+metformin [MET], n=22) versus MET monotherapy (n=17), among newly-diagnosed type 2 diabetes mellitus (T2DM) enrolled (between 2012 and 2014) in the VERIFY study from Korea (n=39). Primary endpoint was time to initial treatment failure (TF) (glycosylated hemoglobin [HbA1c] ≥7.0% at two consecutive scheduled visits after randomization [end of period 1]). Time to second TF was assessed when both groups were receiving and failing on the combination (end of period 2). With EC the risk of initial TF significantly reduced by 78% compared to MET (n=3 [15%] vs. n=10 [58.7%], P=0.0228). No secondary TF occurred in EC group versus five patients (29.4%) in MET. Patients receiving EC treatment achieved consistently lower HbA1c levels. Both treatment approaches were well tolerated with no hypoglycaemic events. In Korean patients with newly diagnosed T2DM, EC treatment significantly and consistently improved the long-term glycaemic durability as compared with MET.

Introduction Although metformin is recommended as a first-line treatment for patients with type 2 diabetes (T2D) in Western countries, no specific treatment is recommended in Japan, and various agents are used. Metformin has long been used at low doses in Japan, and information regarding its effect at the maximum maintenance dose is lacking. Here, we compared the efficacy and safety of metformin at 1500 mg/day with those of the other oral anti-diabetic drugs (OADs) approved in Japan. Methods Randomized controlled trials comparing a change in hemoglobin A1c (HbA1c) from baseline at 12 weeks or later (ΔHbA1c) among OADs (including placebo) as a first-line treatment in adult patients with T2D were selected by systematic review with comprehensive searching of CENTRAL, MEDLINE, Ichushi Web, and EMBASE and manual searching of clinical trial registries. The ΔHbA1c and incidence of hypoglycemia were compared among OAD treatments using Bayesian network meta-analysis (NMA). The relative risk (RR) of the incidence of hypoglycemia was determined relative to that of placebo. Results Forty-six randomized controlled trials were identified in the systematic review, and 37 studies, comprising 38 different types of treatments, including placebos, were selected for the NMA of ΔHbA1c. Compared with metformin 1500 mg/day, 20 OAD treatments were significantly less effective in reducing HbA1c from baseline (differences from metformin 1500 mg/day: 0.40–0.96%). Two treatments (glimepiride 2 mg/day and pioglitazone 45 mg/day) showed greater mean reductions in HbA1c from baseline than metformin 1500 mg/day (− 0.38% and − 0.03%), although these differences were not significant. Regarding the incidence of hypoglycemia, only pioglitazone 30 mg/day among 31 treatments showed a lower RR (

The safety windows and toxicity of clinically available known drugs allow drug repurposing to be a popular treatment strategy for several diseases, including cancers. Several common drugs, e.g., metformin, statin, and aspirin are on clinical trials for repurposing in oncology treatment. Most of repurposed drugs, however, cannot be used as single agents and some do not exert any clinically significant effects. The limitations and possible biases from observational studies and preclinical models to repurpose these drugs are debatable. In this article, the limitations and probability of using metformin, one of the most repurposed drugs for cancer treatment and in oncological practice, are discussed.

Individuals with diabetes have an increased risk of breast, colorectal, pancreatic and prostate cancer. Metformin, an oral biguanide used to treat diabetes, has anti-hyperglycaemic, anti-hyperinsulinemic and antioxidant activities. The effects of metformin on testicular tissue damage in cancer and diabetic + cancer rat models were evaluated histologically, immunohistochemically and biochemically. The diabetic model was produced in Copenhagen rats using a single dose of streptozotocin (65 mg/kg), while prostate cancer was induced through subcutaneous inoculation of 2 x 10(4) Mat-LyLu cells into the animals. At the end of the experimental period, testicular tissues with a close functional relationship to the prostate were collected. Histological evaluation found moderate to severe damage to testes following the diabetes and cancer process. Histopathological and biochemical impairments were observed in the early stage of prostate cancer, which were increased in the diabetic animals. Metformin administration reversed these injuries and provided substantial protection of the testes. In particular, metformin had protective effects on tissue damage, apoptosis, oxidative stress and antioxidant capacity. This suggests that metformin should be further investigated as a targeted protective drug against prostate cancer-related damage to the testes. Istanbul University

The aim of the present study was the evaluation and comparison between four different Metformin and Vildagliptin tablets which are commercially available in Indian market. These tablets were assessed for various pharmacopoeial quality control tests. Parameters including weight variation, hardness, friability, drug content, and disintegration time were evaluated. Results were within acceptable limits for all selected products (three generic and an innovator). These results show that the tested generic products were biopharmaceutically similar to the innovator formulation. Therefore, the consumer can select any one of these equivalent products as a substitute for innovator product in case of cost concern or unavailability.

Background Metformin, by reducing intracellular Mycobacterium tuberculosis growth, can be considered an adjunctive therapy to anti-tuberculosis treatment (ATT). We determined whether metformin with standard ATT reduces time to sputum culture conversion and tissue inflammation in adults with pulmonary tuberculosis (PTB). Methods In a randomized, 8-week, clinical trial, newly diagnosed, culture-positive PTB patients were randomized to standard ATT (HREZ = control arm) or standard ATT plus daily 1000 mg metformin (MET-HREZ = Metformin with Rifampicin [METRIF] arm) for 8 weeks during 2018–2020 at 5 sites in India. The primary end point was time to sputum culture conversion by liquid culture during 8 weeks of ATT. Plasma inflammatory markers were estimated in a subset. A Cox proportional hazard model was used to estimate time and predictors of culture conversion. Results Of the 322 patients randomized, 239 (74%) were male, and 212 (66%) had bilateral disease on chest radiograph with 54 (18%) showing cavitation. The median time to sputum culture conversion by liquid culture was 42 days in the METRIF arm and 41 days in the control arm (hazard ratio, 0.8; 95% confidence interval [CI], .624–1.019). After 8 weeks of ATT, cavitary lesions on X-ray (7, 5.3% vs 18, 12.9%; relative risk, 0.42; 95% CI, .18–.96; P = .041) and inflammatory markers were significantly lower in the METRIF arm. Higher body mass index and lower sputum smear grading were associated with faster sputum culture conversion. Conclusions The addition of metformin to standard ATT did not hasten sputum culture conversion but diminished excess inflammation, thus reducing lung tissue damage as seen by faster clearance on X-ray and reduced inflammatory markers. Clinical Trials Registration Clinical Trial Registry of India (CTRI/2018/01/011176)

BACKGROUND Neuropathy is a common chronic complication in type 2 diabetes mellitus (T2DM). Statin and metformin are commonly used medications in T2DM patients, and some studies showed statin- or metformin-induced neuropathy. AIM To evaluate the incidence of neuropathy among patients with T2DM associated with statin and metformin therapies. METHODS Korean Health Insurance Review and Assessment national patient sample data from 2016 and 2017 were used. Patients with T2DM and no complications were divided into statin/metformin/statin + metformin users and non-users. Neuropathy incidence was defined by International Statistical Classification of Diseases and Related Health Problems, 10th revision codes and concomitant prescriptions for anticonvulsants or antidepressants. Logistic regression analyses were conducted to examine the associations between statin/metformin/statin + metformin therapies and the incidence of neuropathy. Propensity score (PS) matching was performed on the basis of age, sex and comorbidities. RESULTS Overall, 34964 and 35887 patients with T2DM and no complications were included in the Korean Health Insurance Review and Assessment national patient sample datasets from 2016 and 2017, respectively. Statin therapy was associated with increased risks of neuropathy in 2016 and 2017 [PS-matched odds ratio (OR) = 1.22, 95% confidence interval (CI): 1.08-1.38; PS-matched OR = 1.17, 95%CI: 1.03-1.33, respectively]. Metformin therapy was associated with reduced risks of neuropathy in 2016 and 2017 (PS-matched OR = 0.30, 95%CI: 0.21-0.42; PS-matched OR = 0.44, 95%CI: 0.32-0.60, respectively). Combined statin + metformin therapy was not significantly associated with neuropathy in 2016 or 2017 (PS-matched OR = 0.85, 95%CI: 0.61-1.19; PS-matched OR = 0.95, 95%CI: 0.66-1.38, respectively). CONCLUSION Statin therapy was associated with enhanced risk of new-onset neuropathy in patients with T2DM, but metformin therapy showed the opposite association.

Substantial inconsistencies exist in current guidelines regarding recommendations of metformin usage with the administration of a contrast medium. We aimed to perform a meta-analysis to determine whether the risks of contrast-induced acute kidney injury (CI-AKI) and lactic acidosis increase with metformin use in diabetic patients receiving a contrast medium. Studies were retrieved from databases from inception to May 15, 2021. Studies that compared the outcomes of using metformin with not using metformin during contrast medium administration were included. The primary outcomes were incidence of CI-AKI and lactic acidosis. The secondary outcomes were renal function changes from baseline. Data analysis was using risk ratio (RR) for dichotomous outcomes and mean differences (MD) with 95% confidence intervals (CI) for continuous outcomes. Analyses of two randomized controlled trials and four retrospective cohorts examining a total of 1459 patients revealed no significant differences in the incidence of CI-AKI (RR = 1.08; 95% CI, 0.72 to 1.63) and in changes in renal function measurements (serum creatinine: MD = 0.00 mg/dL, 95% CI, − 0.05 to 0.05; estimated glomerular filtration rate: MD = 0.22, 95% CI, − 2.47 to 2.91) after contrast medium administration between patients using and not using metformin. There is no evidence that continuing metformin during contrast medium administration is associated with a higher risk of CI-AKI, lactic acidosis, or renal function deterioration compared to patients who discontinued metformin or who were not metformin users. The limited quality of the included studies may compromise the strength of evidence provided in this meta-analysis.

Objectives This study aimed to determine the safety and efficacy of canagliflozin in comparison to metformin in polycystic ovary syndrome (PCOS) patients with insulin resistance (IR). Methods A single center, prospective, randomized open-label (ratio 1:1) non-inferiority trial was conducted at the Department of Endocrinology, Shanghai Tenth People's Hospital, between July 2019 and April 2021. Women aged 18-45 years with PCOS and IR were enrolled and randomly assigned to either 100 mg (n = 33) canagliflozin daily or 1500-2000 mg metformin daily (n = 35) for 12 weeks. The primary outcome was changes in homeostatic model assessment (HOMA)-IR after 12 weeks of treatment. The secondary outcomes included changes in anthropometric measurements, menstrual frequency, sex hormone levels, metabolic parameters, and body fat distribution. Results For lowering of HOMA-IR after 12 weeks of treatment, canagliflozin was found to be non-inferior to metformin (least-squares mean difference -0.81% [95% CI: -2.13 to 0.51]). Both canagliflozin and metformin could significantly improve menstrual pattern, reduce body weight and total fat mass, and decrease triglyceride levels. Compared with metformin, canagliflozin had significant advantages in reducing uric acid and dehydroepiandrosterone sulfate levels. Pruritus vulvae (9.09%) and gastrointestinal reaction (55.55%) were the main adverse events in the metformin group and canagliflozin group, respectively. Conclusion Our study demonstrates that canagliflozin was not inferior to metformin in PCOS patients with IR, which suggests that sodium-glucose co-transporter 2 inhibitors should be considered as effective drugs in the treatment of PCOS patients with IR. This article is protected by copyright. All rights reserved.

Insulin resistance and hyperinsulinemia play a key role in type 1 endometrial cancer pathogenesis. Most of these cancers develop on a background of overweight or type 2 diabetes mellitus (T2DM). One of the medications widely used in the treatment of T2DM is biguanide derivative, metformin, which exerts promising anticancer properties principally through activation of adenosine monophosphate kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) pathways. Many epidemiological studies on diabetic patients show potential preventative role of metformin in endometrial cancer patients, but data regarding its therapeutic role is still limited. So far, most of attention has been paid to the concept of metformin use in fertility sparing treatment of early-stage cancer. Another investigated alternative is its application in patients with primary advanced or recurrent disease. In this review we present the latest data on clinical use of metformin in endometrial cancer patients and potential underlying mechanisms of its activity. Finally, we present some most important clinical information regarding metformin efficacy in other gynaecological malignancies, mainly breast and ovarian cancer.

Introduction While the main mode of transmission of coronavirus disease 2019 (COVID-19) is close contact with other individuals, the presence of chronic underlying diseases such as Diabetes Mellitus (DM) increases the chance of hospitalization and mortality rate due to infection. Areas covered To investigate the effects of COVID-19 infection in DM patients, we reviewed literature from Google Scholar search engine and PubMed database from '2013 to 2020' using the terms "COVID-19; SARS-CoV-2; Diabetes mellitus; obesity; Angiotensin-converting enzyme 2; ACE2; Insulin and Metformin. Evidence suggests that COVID-19 exacerbates the course of diabetes. Presence of pro-inflammatory conditions, increased expression of receptors, and more difficult control of glucose levels in diabetics COVID-19 patients are some of the problems that diabetic patients may face. Also, psychological problems caused by the COVID-19 epidemic in diabetic patients is one of the most important problems in these patients, which is less covered. Expert opinion DM is a strong and independent risk factor with a poor prognosis, which increases the risk of COVID-19 infection, the need for emergency services, the rate of hospitalization in the intensive care unit and also increases the mortality rate of COVID-19 patients.

AIMS/INTRODUCTION Metformin is associated with the risk of gastrointestinal complications, and probiotic Bifidobacterium bifidum G9-1 (BBG9-1) can improve the symptoms of diarrhea. This study aimed to clarify the effects of probiotic BBG9-1 on the gastrointestinal symptoms of type 2 diabetes mellitus patients using metformin. MATERIALS AND METHODS In this open-label single-arm exploratory study, 40 patients (mean age 64.0 ± 9.4 years) were given probiotic BBG9-1 for 10 weeks. Changes in the gastrointestinal symptom rating scale total score, which was the primary end-point, gastrointestinal symptom rating scale subscale scores, glycated hemoglobin levels and gut microbiota after the administration of probiotic BBG9-1 were evaluated by the Student's t-test. RESULTS The gastrointestinal symptom rating scale total score significantly improved (from 2.02 ± 0.51 to 1.59 ± 0.43, change, -0.43 ± 0.49, P

BACKGROUND Irisin is an adipo-myokine with potential implications in metabolic disorders such as polycystic ovary syndrome (PCOS). Despite of a strong evidence showing increased irisin level in PCOS, there is no conclusive evidence on the effect of metformin intervention on circulatory irisin in PCOS. AIM The aim of this meta-analysis was to compare the circulatory (serum/plasma) irisin levels before and after metformin intervention in subjects with PCOS. METHODS Relevant studies were retrieved by online database and manual searching. The standardized mean differences (SMDs) with 95% confidence intervals (CIs) were obtained by a random-effects meta-analysis. A one-study leave-out sensitivity analysis was conducted to validate the overall obtained results. RESULTS A total of five observations were included in this meta-analysis. The results based on random effects meta-analysis indicated that irisin levels were significantly decreased after metformin intervention as compared to the baseline pretreatment levels in PCOS (SMD: -1.00, 95% CI: -1.60 to -0.41, Z: 3.29, p = .001). The sensitivity analysis leaving-out a particular observation at a time and repeating the meta-analysis validated the robustness of the overall finding suggesting the significant effect of metformin treatment on irisin levels in PCOS. CONCLUSION Circulating irisin levels were significantly decreased upon metformin intervention in PCOS patients. The higher pretreatment irisin levels in PCOS may recede once the altered metabolic state is restored upon metformin intervention. Well-designed randomized trials with large sample sizes are warranted to further substantiate the reported evidence reported and to establish the possible mechanisms.

Background Metformin, an oral drug used to treat patients with diabetes, has been associated with prolonged survival in patients with various visceral carcinomas. Although the exact mechanisms are unknown, preclinical translational studies demonstrate that metformin may impair tumor cellular metabolism, alter matrix turnover, and suppress oncogenic signaling pathways. Currently used chemotherapeutic agents have not been very successful in the adjuvant setting or for treating patients with metastatic sarcomas. We wanted to know whether metformin might be associated with improved survival in patients with a soft tissue sarcoma. Questions/purposes In patients treated for a soft tissue sarcoma, we asked: (1) Is there an association between metformin use and longer survival? (2) How does this association differ, if at all, among patients with and without the diagnosis of diabetes? Methods The Surveillance, Epidemiology, and End Results-Medicare (SEER-Medicare) database was used to identify patients with a diagnosis of soft tissue sarcoma from 2007 to 2016. Concomitant medication use was identified using National Drug Codes using the Medicare Part D event files. This database was chosen because of the large number of captured sarcoma patients, availability of tumor characteristics, and longitudinal linkage of Medicare data. A total of 14,650 patients were screened for inclusion. Patients with multiple malignancies, diagnosis at autopsy, or discrepant linkage to the Medicare database were excluded. Overall, 4606 patients were eligible for the study: 598 patients taking metformin and 4008 patients not taking metformin. A hazard of mortality (hazard ratio) was analyzed comparing patients taking metformin with those patient groups not taking metformin and expressed in terms of a 95% confidence interval. Cox regression analysis was used to control for patient-specific, disease-specific, and treatment-specific covariates. Results Having adjusted for disease-, treatment-, and patient-specific characteristics, patients taking metformin experienced prolonged survival compared with all patients not taking metformin (HR 0.76 [95% CI 0.66 to 0.87]). Associated prolonged survival was also seen when patients taking metformin were compared with those patients not on metformin irrespective of a diabetes diagnosis (HR 0.79 [95% CI 0.66 to 0.94] compared with patients with a diagnosis of diabetes and HR 0.77 [95% CI 0.67 to 0.89] compared with patients who did not have a diagnosis of diabetes). Conclusion Without suggesting causation, we found that even after controlling for confounding variables such as Charlson comorbidity index, tumor grade, size, stage, and surgical/radiation treatment modalities, there was an association between metformin use and increased survival in patients with soft tissue sarcoma. When considered separately, this association persisted in patients not on metformin with and without a diabetes diagnosis. Although metformin is not normally prescribed to patients who do not have a diabetes diagnosis, these data support further study, and if these findings are substantiated, it might lead to the performance of multicenter, prospective clinical trials about the use of metformin as an adjuvant therapy for the treatment of soft tissue sarcoma in patients with and without a preexisting diabetes diagnosis. Level of evidence Level III, therapeutic study.

Introduction Type 2 diabetes (T2D) is increasingly prevalent and associated with increased risk for cardiovascular and renal disease. After lifestyle modification, metformin is usually the first-line pharmacotherapy and sulfonylureas are traditionally added after metformin failure. However, with newer glucose lowering drugs that may have less risk of hypoglycemia or that may reduce cardiovascular and renal events, the position of sulfonylureas is being reevaluated. Areas covered In this article, the authors review relevant publications related to the use of sulfonylureas. Expert opinion Sulfonylureas are potent glucose lowering drugs. The risk of hypoglycemia varies with different drugs within the class and can be minimized by using the safer drugs, possibly in lower doses. Cardiovascular events do not appear to be increased with some of the newer generation drugs. The durability of glycemic control also appears comparable to other newer agents. Sulfonylureas are the preferred treatment for some types of monogenic diabetes and selection of T2D patients who may have greater benefit from sulfonylureas based on certain phenotypes and genotypes is likely to be refined further by precision medicine. Sulfonylureas are inexpensive and readily available everywhere and they are still the most frequently used second-line treatment for T2D in many parts of the world.

OBJECTIVE The aim of this study was to investigate prenatal factors associated with insulin prescription as a first-line pharmacotherapy for gestational diabetes mellitus (GDM; compared with oral antidiabetic medication) after failed medical nutrition therapy. METHODS This is a retrospective cohort study of 437 women with a singleton pregnancy and diagnosis of A2GDM (GDM requiring pharmacotherapy), delivering in a university hospital between 2015 and 2019. Maternal sociodemographic and clinical characteristics, as well as GDM-related factors, including provider type that manages GDM, were compared between women who received insulin versus oral antidiabetic medication (metformin or glyburide) as the first-line pharmacotherapy using univariable and multivariable analyses. RESULTS In univariable analysis, maternal age, race and ethnicity, insurance, chronic hypertension, gestational age at GDM diagnosis, glucose level after 50-g glucose loading test, and provider type were associated with insulin prescription. In multivariable analysis, after adjusting for sociodemographic and clinical maternal factors, GDM characteristics and provider type, Hispanic ethnicity (0.26, 95% confidence interval [CI]: 0.09-0.73), and lack of insurance (0.34, 95% CI: 0.13-0.89) remained associated with lower odds of insulin prescription, whereas endocrinology management of GDM (compared with obstetrics and gynecology [OBGYN]) (8.07, 95% CI: 3.27-19.90) remained associated with higher odds of insulin prescription. CONCLUSION Women of Hispanic ethnicity and women with no insurance were less likely to receive insulin and more likely to receive oral antidiabetic medication for GDM pharmacotherapy, while management by endocrinology was associated with higher odds of insulin prescription.This finding deserves more investigation to understand if differences are due to patient choice or a health disparity in the choice of pharmacologic agent for A2GDM. KEY POINTS · Insulin is recommended as a first-line pharmacotherapy for gestational diabetes.. · Women of Hispanic ethnicity were less likely to receive insulin as first line.. · Lack of insurance was also associated with lower odds of insulin prescription..

What is known and objective Although several clinical trials have compared the clinical efficacy of clomiphene citrate (CC) combined with metformin (MET) in the treatment of women with polycystic ovary syndrome (PCOS), the results are controversial. Therefore, this study was designed to conduct a pooled analysis to evaluate the efficacy of CC combined with MET versus CC in these patients. Methods Computerized searches of the PubMed, Web of Science, Embase and Cochrane Library databases were conducted to identify eligible randomized controlled trials (RCTs) from the data obtained up to June 2021. The Cochrane Collaboration risk of bias tool was used to assess the risk of bias in individual RCTs, and RevMan 5.4 was used for data statistical analysis. Results and discussion A total of 13 RCTs were included in the meta-analysis. These studies involved 1,353 patients, 707 of these were in the combination group and 646 in the monotherapy group. The results indicated a higher clinical pregnancy rate (risk ratio [RR] 1.28, 95% confidence interval [CI] 1.06-1.54, p = 0.01) in the combined group compared to the monotherapy group. However, no significant differences were observed in the ovulation rate (RR 1.13, 95% CI 0.98-1.30, p = 0.10), live birth rate (RR 1.13, 95% CI 0.89-1.42, p = 0.32), multiple pregnancy rate (RR 0.58, 95% CI 0.19-1.73, p = 0.33) and abortion rate (RR 1.26, 95% CI 0.86-1.84, p = 0.23) between the two groups. What is new and conclusion CC combined with MET has an advantage in improving the clinical pregnancy rate compared to CC alone; however, there is no significant difference in the rate of ovulation. For better management of PCOS, a high-quality RCT is needed to demonstrate the safety of the combination.