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Diabetic peripheral neuropathy (DPN) affects ∼50% of the 500 million people with type 2 diabetes worldwide and is considered disabling and irreversible. The current study was undertaken to assess the effect of metformin on peripheral neuropathy outcomes in type 2 diabetes. Participants with type 2 diabetes (n = 69) receiving metformin were recruited and underwent clinical assessment, peripheral nerve ultrasonography, nerve conduction studies, and axonal excitability studies. Also concurrently screened were 318 participants who were not on metformin, and 69 were selected as disease control subjects and matched to the metformin participants for age, sex, diabetes duration, BMI, HbA1c, and use of other diabetes therapies. Medical record data over the previous 20 years were analyzed for previous metformin use. Mean tibial nerve cross-sectional area was lower in the metformin group (metformin 14.1 ± 0.7 mm2, nonmetformin 16.2 ± 0.9 mm2, P = 0.038), accompanied by reduction in neuropathy symptom severity (P = 0.021). Axonal excitability studies demonstrated superior axonal function in the metformin group, and mathematical modeling demonstrated that these improvements were mediated by changes in nodal Na+and K+conductances. Metformin treatment is associated with superior nerve structure and clinical and neurophysiological measures. Treatment with metformin may be neuroprotective in DPN. Article Highlights: We aimed to assess whether peripheral neuropathy outcomes for patients with type 2 diabetes were better on metformin treatment. Metformin and nonmetformin groups with type 2 diabetes were matched for demographic and metabolic factors. Clinical neuropathy scores, peripheral nerve ultrasonography, nerve conduction studies, axonal excitability, and mathematical modeling findings were all superior in the metformin group. Mathematical modeling suggested this was due to superior nodal Na+and K+conductances. Treatment with metformin may be neuroprotective in diabetic peripheral neuropathy. [ABSTRACT FROM AUTHOR]

Background: Atherosclerosis (AS) is a progressive disease that interferes with blood flow, leading to cardiovascular complications such as hypertension, ischemic heart disease, ischemic stroke, and vascular ischemia. The progression of AS is correlated with inflammation, oxidative stress, and endothelial dysfunction. Various signaling pathways, like nuclear erythroid‐related factor 2 (Nrf2) and Kruppel‐like factor 2 (KLF2), are involved in the pathogenesis of AS. Nrf2 and KLF2 have anti‐inflammatory and antioxidant properties. Thus, activation of these pathways may reduce the development of AS. Metformin, an insulin‐sensitizing drug used in the management of type 2 diabetes mellitus (T2DM), increases the expression of Nrf2 and KLF2. AS is a common long‐term macrovascular complication of T2DM. Thus, metformin, through its pleiotropic anti‐inflammatory effect, may attenuate the development and progression of AS. Aims: Therefore, this review aims to investigate the possible role of metformin in AS concerning its effect on Nrf2 and KLF2 and inhibition of reactive oxygen species (ROS) formation. In addition to its antidiabetic effect, metformin can reduce cardiovascular morbidities and mortalities compared to other antidiabetic agents, even with similar blood glucose control by the Nrf2/KLF2 pathway activation. Conclusion: In conclusion, metformin is an effective therapeutic strategy against the development and progression of AS, mainly through activation of the KLF2/Nrf2 axis. [ABSTRACT FROM AUTHOR]

Metformin is an orally effective anti-hyperglycemic drug that despite being introduced over 60 years ago is still utilized by an estimated 120 to 150 million people worldwide for the treatment of type 2 diabetes (T2D). Metformin is used off-label for the treatment of polycystic ovary syndrome (PCOS) and for pre-diabetes and weight loss. Metformin is a safe, inexpensive drug with side effects mostly limited to gastrointestinal issues. Prospective clinical data from the United Kingdom Prospective Diabetes Study (UKPDS), completed in 1998, demonstrated that metformin not only has excellent therapeutic efficacy as an anti-diabetes drug but also that good glycemic control reduced the risk of micro- and macro-vascular complications, especially in obese patients and thereby reduced the risk of diabetes-associated cardiovascular disease (CVD). Based on a long history of clinical use and an excellent safety record metformin has been investigated to be repurposed for numerous other diseases including as an anti-aging agent, Alzheimer's disease and other dementias, cancer, COVID-19 and also atrial fibrillation (AF). AF is the most frequently diagnosed cardiac arrhythmia and its prevalence is increasing globally as the population ages. The argument for repurposing metformin for AF is based on a combination of retrospective clinical data and in vivo and in vitro pre-clinical laboratory studies. In this review, we critically evaluate the evidence that metformin has cardioprotective actions and assess whether the clinical and pre-clinical evidence support the use of metformin to reduce the risk and treat AF. [ABSTRACT FROM AUTHOR]

The association of type 2 diabetes with certain cancer risk has been of great interest for years. However, the effect of diabetic medications on cancer development is not fully understood. Prospective clinical trials have not elucidated the long‐term influence of hypoglycemic drugs on cancer incidence and the safety for cancer‐bearing patients with diabetes, whereas numerous preclinical studies have shown that antidiabetic drugs could have an impact on carcinogenesis processes beyond the glycemic control effect. Because there is no evidence of the safety profile of antidiabetic agents on cancer biology, careful consideration would be required when prescribing any medicines to patients with diabetes and existing tumor. In this review, we discuss the potential influence of each diabetes therapy in cancer 'initiation', 'promotion' and 'progression'. [ABSTRACT FROM AUTHOR]

Metformin is a widely prescribed oral antihyperglycemic agent and currently a first-line medication in the treatment of human type 2 diabetes, with a total of 92 million US prescriptions in 2022. The daily dose per human can be as much as 2.5 grams/day which is excreted largely unchanged into the environment. Metformin is chemically stable and a widely distributed environmental substance. Metformin therefore has the potential to be identified at trace levels in equine blood and urine samples as a result of random exposure to environmental metformin. Given these circumstances we have reviewed the scientific literature and calculated an irrelevant blood/plasma/serum concentration of metformin of 5 nanograms/ml. We now therefore propose this plasma concentration of metformin as an interim Screening Limit of Detection (SLOD) for metformin, below which concentration a blood/plasma/serum identification of metformin should not be considered appropriate for regulatory action. [ABSTRACT FROM AUTHOR]

The potential interaction between metformin and exercise on glucose-lowering effects remains controversial. We studied the separated and combined effects of metformin and/or exercise on fasting and postprandial insulin sensitivity in individuals with pre-diabetes and type 2 diabetes (T2D). Eight T2D adults (60 ± 4 yr) with overweight/obesity (32 ± 4 kg·m-2) under chronic metformin treatment (9 ± 6 yr; 1281 ± 524 mg·day-1) underwent four trials; 1) taking their habitual metformin treatment (MET), 2) substituting during 96 h their metformin medication by placebo (PLAC), 3) placebo combined with 50 min bout of high-intensity interval exercise (PLAC þ EX), and 4) metformin combined with exercise (MET þ EX). Plasma glucose kinetics using stable isotopes (6,6-2H2 and [U-13C] glucose), and glucose oxidation by indirect calorimetry, were assessed at rest, during exercise, and in a subsequent oral glucose tolerance test (OGTT). Postprandial glucose and insulin concentrations were analyzed as mean and incremental area under the curve (iAUC), and insulin sensitivity was calculated (i.e., MATSUDAindex and OGISindex). During OGTT, metformin reduced glucose iAUC (i.e., MET and MET þ EX lower than PLAC and PLAC þ EX, respectively; P = 0.023). MET þ EX increased MATSUDAindex above PLAC (4.8 ± 1.4 vs. 3.3 ± 1.0, respectively; P = 0.018) and OGISindex above PLAC (358 ± 52 vs. 306 ± 46 mL·min-1·m-2, respectively; P = 0.006). Metformin decreased the plasma appearance of the ingested glucose (Ra OGTT; MET vs. PLAC, -3.5; 95% CI -0.1 to -6.8 lmol·kg-1·min-1; P = 0.043). Metformin combined with exercise potentiates insulin sensitivity during an OGTT in individuals with pre-diabetes and type 2 diabetes. Metformin's blood glucose-lowering effect seems mediated by decreased oral glucose entering the circulation (gut-liver effect) an effect partially blunted after exercise. [ABSTRACT FROM AUTHOR]

Metformin (1,1‐dimethylbiguanidine hydrochloride) (MF) is a drug that has long been in use for the treatment of type 2 diabetes mellitus and recently is coming into use in the radiation therapy of cancer and other conditions. Exposure to ionizing radiation disturbs the redox homeostasis of cells and causes damage to proteins, membranes, and mitochondria, destroying a number of biological processes. After irradiation, MF activates cellular antioxidant and repair systems by signaling to eliminate the harmful consequences of disruption of redox homeostasis. The use of MF in the treatment of the negative effects of irradiation has great potential in medical patients after radiotherapy and in victims of nuclear accidents or radiologic terrorism. [ABSTRACT FROM AUTHOR]

Aims: This study investigated the safe use of metformin in patients with (1) type 2 diabetes mellitus (T2DM) and heart failure on metformin, and (2) heart failure without T2DM and metformin naïve. Methods: Two prospective studies on heart failure patients were undertaken. The first was a cross‐sectional study with two patient cohorts, one with T2DM on metformin (n = 44) and one without T2DM metformin naive (n = 47). The second was a 12‐week interventional study of patients without T2DM (n = 27) where metformin (500 mg immediate release, twice daily) was prescribed. Plasma metformin and lactate concentrations were monitored. Individual pharmacokinetics were compared between cohorts. Univariable and multivariable analysis analysed the effects of variables on plasma lactate concentrations. Results: Plasma metformin and lactate concentrations mostly (99.9%) remained below safety thresholds (5 mg/L and 5 mmol/L, respectively). Metformin concentration had no significant relationship with lactic acidosis safety markers. In the interventional study, New York Heart Association (NYHA) II (P <.03) and III (P <.001) grading was associated with higher plasma lactate concentrations, whereas male sex was associated with 47% higher plasma lactate concentrations (P <.05). The pharmacokinetics of heart failure patients with and without T2DM were similar. Conclusions: We observed no unsafe plasma lactate concentrations in patients with heart failure treated with metformin. Metformin exposure did not influence plasma lactate concentrations, but NYHA class and sex did. The pharmacokinetics of metformin in heart failure patients are similar irrespective of T2DM. These findings may support the safe use of metformin in heart failure patients with and without T2DM. [ABSTRACT FROM AUTHOR]

Metformin is used worldwide in the treatment of type 2 diabetes and has been used in the treatment of diabetes in pregnancy since the 1970s. It is highly acceptable to patients due to its ease of administration, cost and adverse effect profile. It is effective in reducing macrosomia, large-for-gestational-age infants and reduces maternal weight gain. Despite its many advantages, metformin has been associated with reductions in foetal size and has been associated with an increase in infants born small-for-gestational-age in certain cohorts. In this article, we review its efficacy, adverse effects and long-term follow-up before, during and after pregnancy for both mother and infant. We also evaluate the other forms of treatment for gestational diabetes, including oral therapies, insulin therapy and emerging treatments. [ABSTRACT FROM AUTHOR]

We review pharmacological/prescribing principles relating to metformin according to our mnemonic framework: 'BRAINS & AIMS' (Benefits, Risks, Adverse Effects, Interactions, Necessary prophylaxis, Susceptibilities, Administering, Informing, Monitoring and Stopping): Benefits: Metformin's licensed uses: Type 2 diabetes mellitus (T2DM) treatment, reduction in risk or delay of onset. No clear evidence metformin influences patient‐important outcomes [Cochrane Review (2020) of 18 RCTs (n = 10 680)]. Risks: Inexpensive, essential WHO list drug; use contraindicated/not tolerated in 15%: for example, contraindication: lactic acidosis in renal impairment (eGFR <30 mL/min/1.73 m2). Adverse effects: Common gastrointestinal (GI) side effects are dose‐related and include abdominal pain, decreased appetite, diarrhoea (usually transient), nausea and vomiting, altered taste; vitamin B12 deficiency. Rare: acute metabolic acidosis (lactic acidosis/diabetic ketoacidosis). Interactions (pharmacokinetic) occur with drugs impairing renal function and hence metformin excretion, and drugs inhibiting organic cation transporter 1 or 2 (OCT1, OCT2), and/or multidrug and toxin extrusion protein 1 (MATE1/2‐K), such as cimetidine, ranolazine, trimethoprim and verapamil, and inducers such as rifampicin. The risk of hypoglycaemia may increase when metformin is used in combination with other medications for diabetes (pharmacodynamic interaction). Necessary prophylaxis: Detect/treat vitamin B12 deficiency. Susceptible groups: Elderly/renal/liver impairment (lactic acidosis); safe in pregnancy/breastfeeding. Administering: Initially 500 mg once daily (morning) with breakfast; titrate only after 1 week. Informing (relevant BRAINS & A(I)MS principles). Monitoring: Renal function beforehand, and 6–12 monthly, HbA1c 3–6 monthly until controlled. Serum vitamin B12 levels if deficiency is suspected/risk factors for. Stopping: Encourage patients to continue medication, unless deteriorating renal/liver function. Reasons for deprescribing: no harms from stopping suddenly. [ABSTRACT FROM AUTHOR]

Aim: Metformin is used for the management of type 2 diabetes mellitus (T2DM) and is being tested clinically as an anticancer agent. Metformin concentrations safely achievable in human solid tissues including tumours are unknown. This study was designed to determine metformin concentration in tissue compartments as a function of dose to inform rational dosing in preclinical models and interpretation of clinical results." Methods: Subjects with solid tumours to be treated by resection and either (A) willingness to take metformin for 7‐10 days before surgery or (B) taking metformin for T2DM were eligible. Whole blood, plasma, tumour, tumour‐adjacent uninvolved tissue and subcutaneous adipose tissue were obtained for liquid chromatography with tandem mass spectrometry to measure metformin concentrations. Results: All subjects had primary lung tumours. Metformin dose was significantly correlated with drug concentrations in all tissues analysed. Intersubject metformin concentrations varied by over two orders of magnitude. Metformin concentrations were significantly higher in tumour tissues and lower in adipose tissues compared to other tissues. Concentrations in blood and plasma were significantly correlated with concentrations in solid tissues. Conclusion: Metformin accumulates in cellular compartments. Concentrations observed in plasma, blood, lung and tumour tissues in subjects treated with US Food and Drug Administration‐approved doses for T2DM are lower than those typically used in tissue culture studies. However, such tissue concentrations are in line with those found within cultured cells treated with supra‐pharmacological doses of metformin. Given the large intersubject variability in metformin concentrations, it is imperative to determine whether there is an association between tissue metformin concentration and anticancer activity in humans. [ABSTRACT FROM AUTHOR]

Background: Medication adherence, one of the most important aspects in the process of optimal medicines use, is unfortunately still a major challenge in modern healthcare, and further research is required into how adherence can be assessed and optimised. The aim of this study was to use a combined method approach of self-report and dried blood spot (DBS) sampling coupled with population pharmacokinetic (PopPK) modelling, to assess adherence to metformin in adult patients with type 2 diabetes. Further aims were to assess metformin exposure levels in patients, determine factors associated with non-adherence with prescribed metformin, and to explore the relationship between adherence and therapeutic outcomes. Methods: A combined method approach was used to evaluate metformin adherence in patients with type 2 diabetes who had been prescribed metformin for a minimum period of 6 months. Patients were recruited from consultant-led diabetic outpatient clinics at three hospitals in Northern Ireland, UK. Data collection involved self-reported questionnaires [Medication Adherence Report Scale (MARS), Beliefs about Medicines Questionnaire and Centre for Epidemiologic Studies Depression Scale], direct measurement of metformin concentration in DBS samples, and researcher-led patient interviews. The DBS sampling approach was coupled with population pharmacokinetic (PopPK) modelling, which took account of patient characteristics, metformin dosage and type of formulation prescribed (immediate or sustained release). Results: The proportion of patients considered to be adherent to their prescribed metformin, derived from self-reported MARS scores and metformin concentration in DBS samples, was 61.2% (74 out of 121 patients). The majority (n = 103, 85.1%) of recruited patients had metformin exposure levels that fell within the therapeutic range. However, 17 patients (14.1%) had low exposure to metformin and one patient (0.8%) had undetectable metformin level in their blood sample (non-exposure). Metformin self-administration and use of a purchased adherence pill box significantly increased the probability of a patient being classified as adherent based on logistic regression analysis. Both HbA1c and random glucose levels (representing poor glycaemic control) in the present research were, however, not statistically linked to non-adherence to metformin (P > 0.05). Conclusions: A significant proportion of participating patients were not fully adherent with their therapy. DBS sampling together with the use of a published PopPK model was a useful, novel, direct, objective approach to estimate levels of adherence in adult patients with type 2 diabetes (61.2%). [ABSTRACT FROM AUTHOR]

The epidemic of type 2 diabetes (T2D) is a significant global public health challenge and a major cause of morbidity and mortality. Despite the recent proliferation of pharmacological agents for the treatment of T2D, current therapies simply treat the symptom, i.e. hyperglycemia, and do not directly address the underlying disease process or modify the disease course. This article summarizes how genomic discovery has contributed to unraveling the heterogeneity in T2D, reviews relevant discoveries in the pharmacogenetics of five commonly prescribed glucose-lowering agents, presents evidence supporting how pharmacogenetics can be leveraged to advance precision medicine, and calls attention to important research gaps to its implementation to guide treatment choices. [ABSTRACT FROM AUTHOR]

Metformin has been recognized as the first-choice drug for type 2 diabetes mellitus (T2DM). The potency of metformin in the treatment of type 2 diabetes has always been in the spotlight and shown significant individual differences. Based on previous studies, the efficacy of metformin is related to the single-nucleotide polymorphisms of transporter genes carried by patients, amongst which a variety of gene polymorphisms of transporter and target protein genes affect the effectiveness and adverse repercussion of metformin. Here, we reviewed the current knowledge about gene polymorphisms impacting metformin efficacy based on transporter and drug target proteins. The reason for the difference in clinical drug potency of metformin can be attributed to the gene polymorphism of drug transporters and drug target proteins in the human body. Substantial evidence shows that genetic polymorphisms in transporters such as organic cation transporter 1 (OCT1) and organic cation transporter 2 (OCT2) affect the glucose-lowering effectiveness of metformin. However, optimization of individualized dosing regimens of metformin is necessary to clarify the role of several polymorphisms. [ABSTRACT FROM AUTHOR]

Context: Although metformin is the first-line treatment for type 2 diabetes, the blood sugar–lowering effect of metformin varies among populations. SLC47A1 plays an important role in metformin pharmacokinetics and pharmacodynamics. Objective: We performed a systematic review and meta-analysis to investigate the association between SLC47A1 rs2289669 (G > A) and the metformin response in drug-naive patients with type 2 diabetes. Methods: Studies published until January 27, 2022, were retrieved from Cochrane CENTRAL, Embase, PubMed, and Web of Science. Two reviewers independently screened titles, abstracts, and full-text articles. Studies conducted in newly diagnosed or drug-naive patients with type 2 diabetes who received metformin monotherapy were included. A total of 6 studies involving 953 patients were included in this meta-analysis. We extracted the study characteristics and changes in glycated hemoglobin (HbA1c) levels before and after treatment according to the SLC47A1 rs2289669 genotype. Changes in HbA1c levels were analyzed using mean differences (MDs) and 95% CIs. SLC47A1 rs2289669 was associated with changes in HbA1c levels (A carrier vs GG; MD = −0.55; 95% CI, −0.91 to − 0.20; I² = 63%). The sensitivity analysis yielded similar results to the main analysis (MD range, −0.64 to −0.37). When comparing all 3 genotypes, there were significant differences in HbA1c level changes between AA vs GG and GA vs GG, but not in GA vs AA. Conclusion: This meta-analysis showed that SLC47A1 rs2289669 is associated with the glycemic response to metformin in drug-naive patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Introduction: The combination tablets of dipeptidyl peptidase-4 (DPP-4) inhibitors and metformin are used for both once-daily and twice-daily agents in Japan. If there is no difference in effectiveness between the once-daily and twice-daily DPP-4 inhibitor/metformin combination tablets, the once-daily agent is advantageous in terms of frequency of administration. The aim of this study was to compare the effectiveness of once-daily alogliptin/metformin combination tablet (alogliptin 25 mg/metformin 500 mg) and twice-daily anagliptin/metformin combination tablet low dose (LD) (anagliptin 100 mg/metformin 250 mg). Methods: Forty-eight Japanese patients with type 2 diabetes whose metformin administration of 250 mg twice daily had remained unchanged for at least 8 weeks, except when using DPP-4 inhibitors, glucagon-like peptide-1 receptor agonists, or insulin, were randomized to either the once-daily alogliptin/metformin combination tablet group or the twice-daily anagliptin/metformin combination tablet LD group. The primary endpoint was the difference in glycosylated hemoglobin (HbA1c) levels from baseline to week 12 of administration, whereas the secondary endpoints were fasting blood glucose, body mass index (BMI), and adherence. Results: Forty-four patients completed the study, and intention-to-treat analyses were performed. The adjusted mean value (standard error) for the change in HbA1c from week 0 to 12, was − 0.75 (0.109)% for the once-daily alogliptin/metformin combination tablet group and − 0.65 (0.109)% for the twice-daily anagliptin/metformin combination tablet LD group, with an intergroup difference of − 0.10% (95% confidence interval, CI − 0.407, 0.215). The upper limit of the bilateral 95% CI was 0.215%, below the 0.40% pre-defined as the non-inferiority margin. Fasting blood glucose, BMI, and adherence were not significantly different between the groups. Conclusions: The once-daily alogliptin/metformin combination tablet was non-inferior to the twice-daily anagliptin/metformin combination tablet LD in Japanese patients with type 2 diabetes. Trial Registration: University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR) (registration number: UMIN000034951). [ABSTRACT FROM AUTHOR]

Interindividual variation is important in the response to metformin as the first-line therapy for type-2 diabetes mellitus (T2DM). Considering that OCT1 and MATE1 transporters determine the metformin pharmacokinetics, this study aimed to investigate the influence of SLC22A1 and SLC47A1 variants on the steady-state pharmacokinetics of metformin and the glycemic response. This research used the prospective-cohort study design for 81 patients with T2DM who received 500 mg metformin twice a day from six primary healthcare centers. SLC22A1 rs628031 A>G (Met408Val) and Met420del genetic variants in OCT1 as well as SLC47A1 rs2289669 G>A genetic variant in MATE1 were examined through the PCR-RFLP method. The bioanalysis of plasma metformin was performed in the validated reversed-phase HPLC-UV detector. The metformin steady-state concentration was measured for the trough concentration (Cssmin) and peak concentration (Cssmax). The pharmacodynamic parameters of metformin use were the fasting blood glucose (FBG) and glycated albumin (GA). Only SLC22A1 Met420del alongside estimated-glomerular filtration rate (eGFR) affected both Cssmax and Cssmin with an extremely weak correlation. Meanwhile, SLC47A1 rs2289669 and FBG were correlated. This study also found that there was no correlation between the three SNPs studied and GA, so only eGFR and Cssmax influenced GA. The average Cssmax in patients with the G allele of SLC22A1 Met408Val, reaching 1.35-fold higher than those with the A allele, requires further studies with regard to metformin safe dose in order to avoid exceeding the recommended therapeutic range. [ABSTRACT FROM AUTHOR]

Background: Metformin has been used for the treatment of type 2 diabetes for over 60 years; however, its mechanism of pharmacological action is not fully clear. Different hypotheses exist regarding metformin distribution and redistribution mechanisms between plasma and erythrocytes/red blood cells (RBCs). Objective: We aimed to test the hypothesis that the metformin distribution between plasma and RBC occurs via concentration difference-driven passive transport and estimated transport rate coefficient values based on metformin concentration time series in plasma and RBCs from in vivo studies. Methods: An ordinary differential equation (ODE) system with two compartments was used to describe diffusion-based passive transport between plasma and RBCs. Metformin concentration time series in plasma and RBCs of 35 individuals were used for metformin transport parametrization. Plasma concentration has been approximated by biexponential decline. Results: A single passive transport coefficient, k = 0.044 ± 0.014 (h–1), can be applied, describing the uptake and release transport rate versus the linear equation v = k × (Mpl − MRBC), where Mpl is the metformin concentration in plasma and MRBC is the metformin concentration in RBCs. Conclusions: Our research suggests that passive transport can explain metformin distribution dynamics between plasma and RBCs because transport speed is proportional to the metformin concentration difference and independent of the transport direction. Concentration difference-driven passive transport can explain the mechanism of faster metformin distribution to RBCs the first few hours after administration, and faster release and domination of the redistribution transport rate after metformin concentration in plasma becomes smaller than in RBCs. [ABSTRACT FROM AUTHOR]

The article presents the discussion on Metformin being a biguanide derived from the plant Galega officinalis. Topics include Metformin influencing AMP-activated protein kinase and the fructose-1,6-bisphosphatase pathway leading to a decrease in the AMP/ATP ratio and reducing the energy available for neoglycogenesis; and an increment in intestinal glucose expenditure and an increase in the secretion of GI incretins.

This research aims to develop and validate a bioanalytical method for simultaneous estimation of an antidiabetic combination using LC-MS/MS in rat plasma. Nateglinide and metformin hydrochloride are commonly used combination for clinical management of Type 2 diabetes. Hence, simultaneous determination in plasma is essential for the rapid analysis of samples from the pharmacokinetic studies. Statistical optimization was carried out for liquid chromatography (LC) parameters and mass spectroscopic (MS) parameters by design of experiment (DoE) (Design Expert Version 11, Stat Ease Inc., USA) approach. A 33 full factorial design was used for optimization of LC parameters; %methanol, %formic acid, and flow rate were selected as independent variables, whereas peak area and tailing factor were considered as dependent variables for both drugs. Box-Behnken design was used to optimize MS parameters including drying gas flow rate, nebulizing gas flow rate, DL temperature, heat block temperature, and positive voltage as independent factors, and responses selected were [M + H]+ intensity of nateglinide and metformin hydrochloride. The [M + H]+ intensity of the optimized method for nateglinide and metformin hydrochloride were 2,462,838 and 11,873,826, respectively. The model was found significant for optimizing LC and MS parameters with p < 0.05 for both nateglinide and metformin hydrochloride. The optimized method was validated as per the ICH-M10 guideline, which was accurate, precise, and selective. The method was cost-effective and capable of quantitating concentrations in picogram levels for nateglinide and metformin hydrochloride simultaneously. [ABSTRACT FROM AUTHOR]

Metformin is a biguanide drug widely used as the initial treatment of type 2 diabetes. Despite its widespread use, its precise mechanisms of action remain incompletely characterised. Its effect in lowering blood glucose is largely related to the suppression of gluconeogenesis in the liver, which is probably accomplished by partial inhibition of the mitochondrial respiratory chain complex 1 with a subsequent increase in intracellular AMP levels and activation of AMP kinase. Several local and systemic anti-inflammatory effects of metformin have been described. Many of these effects seem to be mediated by AMP kinase activation and downstream effects inhibiting mTOR and NF-κB pro-inflammatory signalling cascades. However, there are also studies describing actions independent of AMP kinase action. In this review, we summarise the currently known mechanisms of metformin on inflammatory pathways and the clinical evidence underpinning the use of metformin as a potential anti-inflammatory drug. [ABSTRACT FROM AUTHOR]

The complexes of metformin (MET) and the copolymer of N-vinylpyrrolidone with triethylene glycol dimethacrylate with absolute molecular weight ca. 26 kDa and hydrodynamic radius of macromolecules about 4 nm have been prepared and studied in water buffer solution. Their sizes in neutral phosphate buffer solution depended on MET (10–40 wt%) per the copolymer content, temperature and the copolymer concentrations. Quantum chemical simulation has shown the most energetically favorable and stable structure is one with the coordination of neighboring NH2 groups of MET via oxygen carbonyl of the VP fragment. The effective binding constant of MET with the copolymer estimated from the absorption spectroscopy was found to be ~ 1.8 × 103 M−1. The MET-copolymer compositions were analyzed by IR spectroscopy, thermogravimetry, differential scanning calorimetry, and X-ray diffraction. The copolymer complex with 20 wt% of MET affected blood glucose level in streptozotocin-induced diabetic mice like MET and decreased aldose reductase activity in contrast with the drug and MET-PVP complex. [ABSTRACT FROM AUTHOR]

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Excess nutrient intake and lack of exercise characterize the problem of obesity and are common factors in insulin resistance (IR). With an increasing number of prediabetic, and type 2 diabetic populations, metformin is still the most prescribed glucose-lowering drug and is often accompanied by recommendations for regular physical exercise. Metformin, by the inhibition of complex 1 of the electron transport chain, and exercise, by increasing energy expenditure, both elicit a low cellular energy state that leads to improvements in glucose control via activation of adenosine 5ʹ monophosphate-activated protein kinase (AMPK). An augmented stimulation of the energy-sensing enzyme AMPK by either of the two modalities leads to an increase in glycogenolysis, glucose uptake, fat oxidation, a decrease in glycogen and protein synthesis, and gluconeogenesis in muscle and the liver, which are remarked as having positive effects on metabolic pathophysiology observed in IR and type 2 diabetes mellitus (T2DM). While both modalities exploit the energy-sensing enzyme AMPK to attain glucose homeostasis, the synergistic effect of these two treatments is not distinctly supported by the literature. Further, an antagonistic dynamic has been observed in cases where metformin and exercise were combined. Reduction of insulin-sensitizing effects of exercise and an overall hindrance of exercise performance and adaptations have been reported and could suggest the possible incongruity of these two modalities. The aim of this review is to elucidate the effect that metformin and exercise have on the management of the metabolic abnormalities observed in T2DM and to provide an insight into the interaction of these two modalities. [ABSTRACT FROM AUTHOR]

The numerous beneficial health outcomes associated with the use of metformin to treat patients with type 2 diabetes (T2DM), together with data from pre-clinical studies in animals including the nematode, C. elegans, and mice have prompted investigations into whether metformin has therapeutic utility as an anti-aging drug that may also extend lifespan. Indeed, clinical trials, including the MILES (Metformin In Longevity Study) and TAME (Targeting Aging with Metformin), have been designed to assess the potential benefits of metformin as an anti-aging drug. Preliminary analysis of results from MILES indicate that metformin may induce anti-aging transcriptional changes; however it remains controversial as to whether metformin is protective in those subjects free of disease. Furthermore, despite clinical use for over 60 years as an anti-diabetic drug, the cellular mechanisms by which metformin exerts either its actions remain unclear. In this review, we have critically evaluated the literature that has investigated the effects of metformin on aging, healthspan and lifespan in humans as well as other species. In preparing this review, particular attention has been placed on the strength and reproducibility of data and quality of the study protocols with respect to the pharmacokinetic and pharmacodynamic properties of metformin. We conclude that despite data in support of anti-aging benefits, the evidence that metformin increases lifespan remains controversial. However, via its ability to reduce early mortality associated with various diseases, including diabetes, cardiovascular disease, cognitive decline and cancer, metformin can improve healthspan thereby extending the period of life spent in good health. Based on the available evidence we conclude that the beneficial effects of metformin on aging and healthspan are primarily indirect via its effects on cellular metabolism and result from its anti-hyperglycemic action, enhancing insulin sensitivity, reduction of oxidative stress and protective effects on the endothelium and vascular function. [ABSTRACT FROM AUTHOR]

Metformin is the first-line medication for type 2 diabetes, but it also has a long history of improved outcomes in infectious diseases, such as influenza, hepatitis C, and in-vitro assays of zika. In the current Covid-19 pandemic, which has rapidly spread throughout the world, 4 observational studies have been published showing reduced mortality among individuals with home metformin use. There are several potential overlapping mechanisms by which metformin may reduce mortality from Covid-19. Metformin's past anti-infectious benefits have been both against the infectious agent directly, as well as by improving the underlying health of the human host. It is unknown if the lower mortality suggested by observational studies in patients infected with Covid-19 who are on home metformin is due to direct activity against the virus itself, improved host substrate, or both. [ABSTRACT FROM AUTHOR]

Metformin is widely used as a firstline therapy to improve insulin sensitivity in type 2 diabetes mellitus (T2DM) patients. This is achieved primarily through regulating AMP-activated protein kinase (AMPK)-dependent pathways leading to reduced hepatic gluconeogenesis and improved muscular uptake of glucose. Epidemiological studies first recognized a relationship with metformin use in T2DM patients and reduced colorectal cancer (CRC) risk. Thereafter, metformin has gained wide attention as a candidate CRC chemopreventative agent; however, the molecular mechanisms underlying its gastrointestinal anti-cancer properties appear multi-faceted and are not well understood. An intriguing area of research is the growing evidence of metformin's metabolic juncture with gut microbiota at the intestinal mucosal interface. This review examines the mechanistic evidence which may account for metformin's protection against CRC through interactions between the drug, gut microbiota and the colonic epithelial mucosa. [ABSTRACT FROM AUTHOR]

Effects of metformin, the first-line drug for type 2 diabetes therapy, on gut microbiome composition in type 2 diabetes have been described in various studies both in human subjects and animals. However, the details of the molecular mechanisms of metformin action have not been fully understood. Moreover, there is a significant lack of information on how metformin affects gut microbiome composition in female mouse models, depending on sex and metabolic status in well controlled experimental setting. Our study aimed to examine metformin-induced alterations in gut microbiome diversity, composition, and functional implications of high-fat diet-induced type 2 diabetes mouse model, using, for the first time in mice study, the shotgun metagenomic sequencing that allows estimation of microorganisms at species level. We also employed a randomized block, factorial study design, and including 24 experimental units allocated to 8 treatment groups to systematically evaluate the effect of sex and metabolic status on metformin interaction with microbiome. We used DNA obtained from fecal samples representing gut microbiome before and after ten weeks-long metformin treatment. We identified 100 metformin-related differentially abundant species in high-fat diet-fed mice before and after the treatment, with most of the species relative abundances increased. In contrast, no significant changes were observed in control diet-fed mice. Functional analysis targeted to carbohydrate, lipid, and amino acid metabolism pathways revealed 14 significantly altered hierarchies. We also observed sex-specific differences in response to metformin treatment. Males experienced more pronounced changes in metabolic markers, while in females the extent of changes in gut microbiome representatives was more marked, indicated by 53 differentially abundant species with more remarkable Log fold changes compared to the combined-sex analysis. The same pattern manifested regarding the functional analysis, where we discovered 5 significantly affected hierarchies in female groups but not in males. Our results suggest that both sexes of animals should be included in future studies focusing on metformin effects on the gut microbiome. [ABSTRACT FROM AUTHOR]

Fixed‐dose combination (FDC) drugs with various dose combinations for the treatment of type 2 diabetes mellitus and dyslipidemia are currently in demand. We compared the pharmacokinetic (PK) profiles of the rosuvastatin/metformin sustained‐release (10/1000 mg) FDC and separate tablets and evaluated the effect of food by randomized, open‐label, 3‐period, 6‐sequence crossover studies conducted in healthy male subjects. Subjects were randomly assigned to one of the following treatments: separate tablets of 10 mg rosuvastatin and 1000 mg metformin sustained release in the fed state and the FDC in the fasted and fed states. PK samples were collected up to 72 hours postdose for rosuvastatin, N‐desmethyl rosuvastatin, and metformin. The PK parameters were determined using a noncompartmental method, and the geometric mean ratio (GMR) and the 90% confidence interval (CI) of the treatments were calculated. A total of 35 subjects completed the study. The GMR and 90%CI of the peak concentration (Cmax) and area under the plasma concentration‐time curve from time zero to the last measurable concentration (AUClast) of the FDC and the separate tablets were within the bioequivalence criteria (0.8–1.25) for both rosuvastatin and metformin. The effect of food was statistically significant for both rosuvastatin and metformin but not expected to be of clinical significance. [ABSTRACT FROM AUTHOR]

Metformin is a first-line therapy for the treatment of type 2 diabetes, due to its robust glucose-lowering effects, well-established safety profile, and relatively low cost. While metformin has been shown to have pleotropic effects on glucose metabolism, there is a general consensus that the major glucose-lowering effect in patients with type 2 diabetes is mostly mediated through inhibition of hepatic gluconeogenesis. However, despite decades of research, the mechanism by which metformin inhibits this process is still highly debated. A key reason for these discrepant effects is likely due to the inconsistency in dosage of metformin across studies. Widely studied mechanisms of action, such as complex I inhibition leading to AMPK activation, have only been observed in the context of supra-pharmacological (>1 mM) metformin concentrations, which do not occur in the clinical setting. Thus, these mechanisms have been challenged in recent years and new mechanisms have been proposed. Based on the observation that metformin alters cellular redox balance, a redox-dependent mechanism of action has been described by several groups. Recent studies have shown that clinically relevant (50-100 μM) concentrations of metformin inhibit hepatic gluconeogenesis in a substrate-selective manner both in vitro and in vivo, supporting a redox-dependent mechanism of metformin action. Here, we review the current literature regarding metformin's cellular and molecular mechanisms of action. [ABSTRACT FROM AUTHOR]

Even though metformin is widely used to treat type2 diabetes, reducing glycaemia and body weight, the mechanisms of action are still elusive. Recent studies have identified the gastrointestinal tract as an important site of action. Here we used intestinal organoids to explore the effects of metformin on intestinal cell physiology. Bulk RNA-sequencing analysis identified changes in hexose metabolism pathways, particularly glycolytic genes. Metformin increased expression of Slc2a1 (GLUT1), decreased expression of Slc2a2 (GLUT2) and Slc5a1 (SGLT1) whilst increasing GLUT-dependent glucose uptake and glycolytic rate as observed by live cell imaging of genetically encoded metabolite sensors and measurement of oxygen consumption and extracellular acidification rates. Metformin caused mitochondrial dysfunction and metformin's effects on 2D-cultures were phenocopied by treatment with rotenone and antimycin-A, including upregulation of GDF15 expression, previously linked to metformin dependent weight loss. Gene expression changes elicited by metformin were replicated in 3D apical-out organoids and distal small intestines of metformin treated mice. We conclude that metformin affects glucose uptake, glycolysis and GDF-15 secretion, likely downstream of the observed mitochondrial dysfunction. This may explain the effects of metformin on intestinal glucose utilisation and food balance. [ABSTRACT FROM AUTHOR]

Background: Metformin-associated lactic acidosis (MALA) is a widely documented adverse event of metformin. Despite being considered one of the main causes of metabolic acidosis, the association between an anion gap and MALA diagnosis is still uncertain.Case Presentation: Cases involving six Caucasian patients with suspected MALA who were admitted to the emergency department were analysed. All these patients presented with pH values < 7.35, lactate levels > 2 mmol/L, and estimated glomerular filtration < 30 mL/min. Metformin plasma concentrations were > 2.5 mg/L in all the patients. The highest metformin concentrations were not found in the patients with the highest lactate levels. The anion gap values ranged from 12.3 to 39.3, with only two patients exhibiting values > 14.Conclusions: In patients with MALA, there is a significant variability in the anion gap values, which is not related to the level of metformin accumulation, and therefore, it is doubtful whether measuring anion gaps is useful as an approach for MALA diagnosis. [ABSTRACT FROM AUTHOR]

Objective: Although hemodialysis is recommended for patients with severe metformin-associated lactic acidosis (MALA), the amount of metformin removed by hemodialysis is poorly documented. We analyzed endogenous clearance and hemodialysis clearance in a patient with MALA. Methods: A 62-year-old man with a history of type II diabetes mellitus presented after several days of vomiting and diarrhea and was found to have acute kidney injury (AKI) and severe acidemia. Initial serum metformin concentration was 315.34 μmol/L (40.73 μg/mL) (typical therapeutic concentrations 1–2 μg/mL). He underwent 6 h of hemodialysis. We collected hourly whole blood, serum, urine, and dialysate metformin concentrations. Blood, urine, and dialysate samples were analyzed, and clearances were determined using standard pharmacokinetic calculations. Results: The total amount of metformin removed by 6 h of hemodialysis was 888 mg, approximately equivalent to one therapeutic dose. Approximately 142 mg of metformin was cleared in the urine during this time. His acid-base status and creatinine improved over the following days. No further hemodialysis was required. Conclusion: We report a case of MALA likely secondary to AKI and severe volume depletion. The patient improved with supportive care, sodium bicarbonate, and hemodialysis. Analysis of whole blood, serum, urine, and dialysate concentrations showed limited efficacy of hemodialysis in the removal of metformin from blood, contrary to previously published data. Despite evidence of acute kidney injury, a relatively large amount of metformin was eliminated in the urine while the patient was undergoing hemodialysis. These data suggest that clinical improvement is likely due to factors besides removal of metformin. [ABSTRACT FROM AUTHOR]

Background: Metformin is the first-line therapy for newly diagnosed type 2 diabetes mellitus. It accomplished glycemic control by gluconeogenesis inhibition in the liver and enhance glucose uptake in the peripheral tissues. Adverse effects commonly include gastrointestinal symptoms, such as nausea, vomiting, and diarrhea. A rare but life-threatening lactic acidosis could develop in the setting of metformin use. Objective: This study aims to understand the mechanism and the reality behind metformin-associated lactic acidosis, particularly in patients with chronic kidney disease. Method: We searched in the PubMed database for relative articles using two Mesh terms, "metformin" and "lactic acidosis." Conclusion: Metformin-associated lactic acidosis is a rare but serious consequence, especially in patients with chronic kidney disease, congestive heart failure, and chronic liver disease. Most of the cases have at least one predisposing factor other than metformin use. The link between metformin and lactic acidosis was previously overestimated, and there are growing data showing that metformin can be used in patients with mild to moderate renal impairment. [ABSTRACT FROM AUTHOR]

Metformin has undisputed glucose-lowering effects in diabetes and an impressive safety record. It has also shown promising effects beyond diabetes, and several hundred clinical trials involving metformin are currently planned or active. Metformin targets intracellular effectors, but exactly which remain to be established, and in an era of precision medicine, an incomplete understanding of mechanisms of action may limit the use of metformin. Distribution of metformin depends on specific organic cation transporter proteins that are organ- and species-specific. Therefore, target tissues of metformin can be identified by cellular uptake of the drug, and exploring the biodistribution of the drug in humans becomes an attractive strategy to assist the many investigations into the mechanisms of action of metformin performed in animals. In this review, we combine the emerging evidence from the use of 11C-labeled metformin in humans to discuss metformin action in liver, intestines, and kidney, which are the organs with the most avid uptake of the drug. [ABSTRACT FROM AUTHOR]

Introduction: Vitamin B12 (cobalamin) deficiency is a frequent cause of megaloblastic anemia, manifested through various symptoms. Screening for this deficiency can be justified in case of patients with one or more risk factors present from the following: gastric resections, inflammatory bowel disease, use of metformin over a prolonged period of time, administration of proton pump inhibitors or H2 histamine receptor blockers for more than 12 months and in case of adults over 75 years of age. One method of determining vitamin B12 deficiency is measuring its serum levels, as well as performing measurements of serum levels of methylmalonic acid and homocysteine levels, which experience an increase in the early stages of vitamin B12 deficiency. Clinical Case: We bring to your attention, the case of a 62 years old patient diagnosed with Type 2 Diabetes Mellitus in 2015 that presented in the emergency room in October 2019 with an altered general condition, nausea, vomiting, abdominal pain, palpitation, and dyspnea. Treatment with metformin was initiated from the diagnosis of Type 2 Diabetes Mellitus, four years before. Investigations established the diagnosis of megaloblastic anemia by vitamin B12 deficiency. The symptoms disappeared after the injection of vitamin B12. Conclusion: Periodical dosing of vitamin B12 should be performed in the case of patients with Type 2 Diabetes Mellitus treated with metformin, especially if they associate anemia and/or peripheral diabetic polyneuropathy. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Metformin is the only approved oral agent for youth with type 2 diabetes but its mechanism of action remains controversial. Recent data in adults suggest a primary role for the enteroinsular pathway, but there are no data in youth, in whom metformin efficacy is only ~50%. Our objectives were to compare incretin concentrations and rates of glucose production and gluconeogenesis in youth with type 2 diabetes before and after short-term metformin therapy compared with peers with normal glucose tolerance (NGT). Methods: This is a case–control observational study in youth with type 2 diabetes who were not on metformin (n = 18) compared with youth with NGT (n = 10) who were evaluated with a 2 day protocol. A 75 g OGTT was administered to measure intact glucagon-like 1 peptide (iGLP-1), gastric inhibitory polypeptide (GIP) and peptide YY (PYY). Insulinogenic index (IGI) and whole-body insulin sensitivity were calculated using glucose and insulin levels from the OGTT. Basal rates of gluconeogenesis (2H2O), glucose production ([6,6-2H2]glucose) and whole-body lipolysis ([2H5]glycerol) were measured after an overnight fast on study day 2. Youth with type 2 diabetes (n = 9) were subsequently evaluated with an identical 2 day protocol after 3 months on the metformin study. Results: Compared with individuals with NGT, those with type 2 diabetes had higher fasting (7.8 ± 2.5 vs 5.1 ± 0.3 mmol/l, mean ± SD p = 0.002) and 2 h glucose concentrations (13.8 ± 4.5 vs 5.9 ± 0.9 mmol/l, p = 0.001), higher rates of absolute gluconeogenesis (10.0 ± 1.7 vs 7.2 ± 1.1 μmol [kg fat-free mass (FFM)]−1 min−1, p < 0.001) and whole-body lipolysis (5.2 ± 0.9 vs 4.0 ± 1.4 μmol kgFFM−1 min−1, p < 0.01), but lower fasting iGLP-1 concentrations (0.5 ± 0.5 vs 1.3 ± 0.7 pmol/l, p < 0.01). Metformin decreased 2 h glucose (pre metformin 11.4 ± 2.8 vs post metformin 9.9 ± 1.9 mmol/l, p = 0.04) and was associated with ~20–50% increase in IGI (median [25th–75th percentile] pre 1.39 [0.89–1.47] vs post 1.43 [0.88–2.70], p = 0.04), fasting iGLP-1 (pre 0.3 ± 0.2 vs post 1.0 ± 0.7 pmol/l, p = 0.02), 2 h iGLP (pre 0.4 ± 0.2 vs post 1.2 ± 0.9 pmol/l, p = 0.06), fasting PYY (pre 6.3 ± 2.2 vs post 10.5 ± 4.3 pmol/l, p < 0.01) and 2 h PYY (pre 6.6 ± 2.9 vs post 9.0 ± 4.0 pmol/l, p < 0.01). There was no change in BMI, insulin sensitivity or GIP concentrations pre vs post metformin. There were no differences pre vs post metformin in rates of glucose production (15.0 ± 3.9 vs 14.9 ± 2.2 μmol kgFFM−1 min−1, p = 0.84), absolute gluconeogenesis (9.9 ± 1.8 vs 9.7 ± 1.7 μmol kgFFM−1 min−1, p = 0.76) or whole-body lipolysis (5.0 ± 0.7 vs 5.3 ± 1.3 μmol kgFFM−1 min−1, p = 0.20). Post metformin iGLP-1 and PYY concentrations in youth with type 2 diabetes were comparable to levels in youth with NGT. Conclusions/interpretation: Overall, the improved postprandial blood glucose levels and increase in incretins observed in the absence of changes in insulin sensitivity and gluconeogenesis, support an enteroinsular mechanistic pathway in youth with type 2 diabetes treated with short-term metformin. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is the leading cause of chronic kidney disease (CKD). The prevalence of CKD is growing in parallel with the rising number of patients with type 2 diabetes globally. At present, the optimal approach to glycaemic control in patients with type 2 diabetes and advanced CKD (categories 4 and 5) remains uncertain, as these patients were largely excluded from clinical trials of glucose‐lowering therapies. Nonetheless, clinical trial data are available for the use of incretin therapies, dipeptidyl peptidase‐4 inhibitors and glucagon‐like peptide‐1 receptor agonists, for patients with type 2 diabetes and advanced CKD. This review discusses the role of incretin therapies in the management of these patients. Because the presence of advanced CKD in patients with type 2 diabetes is associated with a markedly elevated risk of cardiovascular disease (CVD), treatment strategies must include the reduction of both CKD and CVD risks because death, particularly from cardiovascular causes, is more probable than progression to end‐stage kidney disease. The management of hyperglycaemia is essential for good diabetes care even in advanced CKD. Current evidence supports an individualized approach to glycaemic management in patients with type 2 diabetes and advanced CKD, taking account of the needs of each patient, including the presence of co‐morbidities and concomitant therapies. Although additional studies are needed to establish optimal strategies for glycaemic control in patients with type 2 diabetes and advanced CKD, treatment regimens with currently available pharmacotherapy can be individually tailored to meet the needs of this growing patient population. [ABSTRACT FROM AUTHOR]

Aim: This work shows the development of pulsatile capsular pellets of metformin hydrochloride and its characterisation. Material and Methods: The novel drug delivery system consisted of hydroxy propyl cellulose Type H. It has a lag time modifier and Eudragit L-100 and Eudragit S-100 in different concentrations as pH-dependent release modifier in the gastrointestinal tract. The pellets were subjected to in vitro release studies using USP dissolution apparatus type-II in distilled water, phosphate buffer of pH 6.8, and 0.1 N HCl and methanol. Ultraviolet (UV), infrared (IR), high-performance liquid chromatography (HPLC), and mass spectroscopy were performed for active pharmaceutical ingredients and formulations. Result: The study was characterized by the complete release of the drug in pulses after a well-defined lag time of 6 h (±0.20) (period of no drug release) for the treatment of type II diabetes mellitus. Conclusion: The stability studies on the selected formulation of Metformin were found to be stable, with shelf life of 1.94 years. Hence it may be concluded that the newly formulated pulsatile drug delivery systems of Metformin Hydrochloride, when ingested at the bed time in the night, produce effective control of the increased blood glucose level after intake of meals by allowing the drug to release after a lag time of 6 h (after meals). [ABSTRACT FROM AUTHOR]

Metformin is the first-choice drug in uncomplicated type 2 diabetes (T2DM) and is effective in improving glycaemic control. It is the most widely prescribed oral antidiabetic medicine and has a good safety profile. However, there is an abundance of evidence that metformin use is associated with decreased Vitamin B12 status, though the clinical implications of this in terms of increased risk of diabetic peripheral neuropathy are debated. There is growing evidence that other B vitamins, vitamin D and magnesium may also be impacted by metformin use in addition to alterations to the composition of the microbiome, depending on the dose and duration of therapy. Patients using metformin for prolonged periods may, therefore, need initial screening with intermittent follow-up, particularly since vitamin B12 deficiency has similar symptoms to diabetic neuropathy which itself affects 40– 50% of patients with T2DM at some stage. Among patients with T2DM, 40% are reported to experience symptomatic gastroesophageal reflux disease (GORD), of whom 70% use oral antidiabetic medications. The most common medications used to treat GORD are proton pump inhibitors (PPIs) and antagonists of histamine selective H2 receptors (H2RAs), both of which independently affect vitamin B12 and magnesium status. Research indicates that co-prescribing metformin with either PPIs or H2RAs can have further deleterious effects on vitamin B12 status. Vitamin B12 deficiency related to metformin and polypharmacy is likely to contribute to the symptoms of diabetic neuropathy which may frequently be under-recognised. This review explores current knowledge surrounding these issues and suggests treatment strategies such as supplementation. [ABSTRACT FROM AUTHOR]

Exercise is widely accepted as having therapeutic effects; thus, it is important to know whether it interacts with medications. The aim of the present pilot study was to examine the effect of high‐intensity interval exercise (known to have antidiabetic action) on key pharmacokinetic parameters related to absorption of metformin (the first‐line medication against type 2 diabetes). Ten healthy men participated in two sessions, spaced one to two weeks apart in random, counterbalanced order. In both sessions, participants received 1000 mg of metformin orally, 1‐1.5 hours after breakfast. Then, they either ran for 60 minutes at alternating intensity, starting at 40 minutes after metformin administration, and rested without food consumption over the next 3 hours or they rested without food consumption during the entire testing period. Venous blood samples were collected before and at 0.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after metformin administration for metformin determination by liquid chromatography‐mass spectrometry. Capillary blood samples were also collected for lactate and glucose measurements. Data from the two sessions were compared through Wilcoxon or Student's t test, as appropriate. Maximum plasma concentration of metformin (Cmax) was higher at exercise compared to rest (P =.059). Time to reach Cmax (Tmax) decreased with exercise (P =.009), and the area under the metformin concentration vs time curve was higher at exercise (P =.047). The addition of exercise to metformin administration did not cause hypoglycemia or lactic acidosis. In conclusion, our results provide the first evidence that pharmacokinetic values related to metformin absorption are affected by exercise. [ABSTRACT FROM AUTHOR]

Summary: Background: The FDA approved 'label' for metformin lists hepatic insufficiency as a risk for lactic acidosis. Little evidence supports this warning. Aims: To investigate the safety and pharmacokinetics of metformin in patients with chronic liver disease (CLD). Methods: Chronic liver disease patients with and without type 2 diabetes mellitus (T2DM) were studied by a cross‐sectional survey of patients already prescribed metformin (n = 34), and by a prospective study where metformin (500 mg, immediate release, twice daily) for up to 6 weeks was prescribed (n = 24). Plasma metformin and lactate concentrations were monitored. Individual pharmacokinetics were obtained and compared to previously published values from healthy and T2DM populations without CLD. Results: All plasma metformin and lactate concentrations remained below the putative safety thresholds (metformin, 5 mg/L; lactate, 5 mmol/L). Lactate concentrations were unrelated to average steady‐state metformin concentrations. In patients with CLD, T2DM was associated with higher plasma lactate concentrations (48% higher than those without T2DM, P < 0.0001). CLD patients with cirrhosis had 23% higher lactate concentrations than those without cirrhosis (P = 0.01). The pharmacokinetics of metformin in CLD patients were similar to patients with T2DM and no liver disease. The ratio of apparent metformin clearance (CLMet/F) to creatinine clearance was marginally lower in CLD patients compared to healthy subjects (median, interquartile range; 12.6, 9.5‐15.9 vs 14.9, 13.4‐16.4; P = 0.03). Conclusions: The pharmacokinetics of metformin are not altered sufficiently in CLD patients to raise concerns regarding unsafe concentrations of metformin. There were no unsafe plasma lactate concentrations observed in CLD patients receiving metformin (ACTRN12619001292167; ACTRN12619001348145). [ABSTRACT FROM AUTHOR]

Background: The 5-year overall survival (OS) rate remains at 50% for patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC), thereby underscoring the need for improved treatments. An antidiabetic agent, metformin, was found in retrospective studies to improve survival in patients with HNSCC. Therefore, the authors conducted a phase 1 dose escalation study combining metformin with chemoradiotherapy in patients with LAHNSCC.Methods: Nondiabetic patients with LAHNSCC were enrolled in the current study to receive escalating doses of metformin and CRT based on the modified toxicity probability interval design. Metformin cohort doses included 2000 mg, 2550 mg, and 3000 mg daily in divided doses in addition to cisplatin (at a dose of 100 mg/m2 on days 1, 22, and 43) and standard radiotherapy (70 grays). Adverse events were categorized as per the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03).Results: Twenty patients were enrolled, 2 of whom withdrew consent. The median age of the patients was 56 years and the majority were male (83%), were white (88%), had p16-positive disease (72%), and were tobacco users (61%). The median length of metformin exposure was 28.5 days. The most common grade ≥3 toxicities were nausea (11%), vomiting (11%), mucositis (6%), acute kidney injury (17%), anemia (6%), and leukopenia (11%). Dose-limiting toxicities included diarrhea and acute kidney injury. After a median follow-up of 19 months, the 2-year overall survival and progression-free survival rates were 90% and 84%, respectively. No hypoglycemia events or lactic acidosis were observed. Cisplatin administration did not appear to affect metformin pharmacokinetics. The maximum tolerated dose for metformin could not be determined given the limited number of patients who tolerated metformin during chemoradiotherapy.Conclusions: To the authors' knowledge, the current study is the first phase 1 trial combining metformin with chemoradiotherapy. Rates of overall survival and progression-free survival were encouraging in this limited patient population, and warrant further investigation in a phase 2 trial. [ABSTRACT FROM AUTHOR]

Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type‐1 (HIV‐1) infection. In vitro and clinical data suggest that doravirine is unlikely to cause significant drug–drug interactions via major drug‐metabolizing enzymes or transporters. As a common HIV‐1 infection comorbidity, type 2 diabetes mellitus is often treated with metformin. Perturbations of metformin absorption or elimination may affect its safety and efficacy profile; therefore, understanding potential drug–drug interactions between doravirine and metformin is important. An open‐label, fixed‐sequence, 2‐period trial in healthy adults was conducted. Single‐dose metformin 1000 mg was administered in period 1; in period 2, doravirine 100 mg was administered once daily on days 1 to 7, and single‐dose metformin 1000 mg was administered on day 5. Plasma pharmacokinetics for metformin alone and coadministered with doravirine were assessed. Fourteen participants enrolled and completed the trial. Least‐squares geometric mean ratios and 90% confidence intervals of metformin AUC0‐∞, and Cmax following coadministration of metformin and doravirine compared with metformin alone were 0.94 (0.88‐1.00) and 0.94 (0.86‐1.03), respectively; metformin Tmax and half‐life were also minimally impacted. These data indicate that doravirine did not have a clinically relevant effect on the pharmacokinetics of metformin. Metformin alone and coadministered with doravirine was generally well tolerated. These data support coadministration of doravirine 100 mg and metformin 1000 mg without dose adjustment. [ABSTRACT FROM AUTHOR]

Background: Metformin has been widely used as a first-line agent to treat type 2 diabetes mellitus. Lactic acidosis is a rare but serious adverse effect in patients treated with metformin. Recent studies noted a correlation between metformin accumulation and lactic acidosis. Continuous renal replacement therapy for the treatment of metformin-associated lactic acidosis has been documented in some case reports; however, there is currently no specific treatment for metformin-associated lactic acidosis.Case Presentation: A 70-year-old Japanese woman with type 2 diabetes mellitus presented to an emergency room with metformin-associated lactic acidosis. She was found to be hypotensive and laboratory examinations revealed severe lactic acidosis: pH 6.618, partial pressure of carbon dioxide in arterial blood 17.3 mmHg, bicarbonate 1.7 mmol/L, and lactate 18 mmol/L. Severe acidemia persisted despite supportive care including intravenously administered fluids, sodium bicarbonate, antibiotics, and vasopressors. Continuous renal replacement therapy was initiated in our intensive care unit. After dialysis for 3 days, her lactate level and pH value completely normalized. The concentration of metformin detected was 77.5 mg/L, which is one of the highest in metformin-associated lactic acidosis successfully treated without overdose.Conclusions: The present case had one of the highest metformin concentrations in metformin-associated lactic acidosis successfully treated with continuous renal replacement therapy, and serum metformin concentrations may be useful for the diagnosis of metformin-associated lactic acidosis. Metformin-associated lactic acidosis is a rare but important etiology of lactic acidosis. Continuous renal replacement therapy is advantageous for the treatment of hemodynamically unstable patients with metformin-associated lactic acidosis. [ABSTRACT FROM AUTHOR]

Diabetes is a major health problem worldwide. Glycemic control is the main goal in the management of type 2 diabetes. While many anti-diabetic drugs and guidelines are available, almost half of diabetic patients do not reach their treatment goal and develop complications. The glucose-lowering response to anti-diabetic drug differs significantly between individuals. Relatively little is known about the factors that might underlie this response. The identification of predictors of response to anti-diabetic drugs is essential for treatment personalization. Unfortunately, the evidence on predictors of drugs response in type 2 diabetes is scarce. Only a few trials were designed for specific groups of patients (e.g. patients with renal impairment or older patients), while subgroup analyses of larger trials are frequently unreported. Physicians need help in picking the drug which provides the maximal benefit, with minimal side effects, in the right dose, for a specific patient, using an omics-based approach besides the phenotypic characteristics. [ABSTRACT FROM AUTHOR]

Metformin is the most widely prescribed treatment of hyperglycemia and type II diabetes since 1970s. During the last 15 years, its popularity increased due to epidemiological evidence, that metformin administration reduces incidence of cancer. However, despite the ongoing effort of many researchers, the molecular mechanisms underlying antihyperglycemic or antineoplastic action of metformin remain elusive. Most frequently, metformin is associated with modulation of mitochondrial metabolism leading to lowering of blood glucose or activation of antitumorigenic pathways. Here we review the reported effects of metformin on mitochondrial metabolism and their potential relevance as effective molecular targets with beneficial therapeutic outcome. [ABSTRACT FROM AUTHOR]

Epidemiological studies indicate that insulin resistance (IR), a hallmark of type 2 diabetes, is associated with an increased risk of major depression. Here, we demonstrated that male mice fed a high-fat diet (HFD) exhibited peripheral metabolic impairments reminiscent of IR accompanied by elevated circulating levels of branched-chain amino acids (BCAAs), whereas both parameters were normalized by chronic treatment with metformin (Met). Given the role of BCAAs in the regulation of tryptophan influx into the brain, we then explored the activity of the serotonin (5-HT) system. Our results indicated that HFD-fed mice displayed impairment in the electrical activity of dorsal raphe 5-HT neurons, attenuated hippocampal extracellular 5-HT concentrations and anxiety, one of the most visible and early symptoms of depression. On the contrary, Met stimulated 5-HT neurons excitability and 5-HT neurotransmission while hindering HFD-induced anxiety. Met also promoted antidepressant-like activities as observed with fluoxetine. In light of these data, we designed a modified HFD in which BCAA dietary supply was reduced by half. Deficiency in BCAAs failed to reverse HFD-induced metabolic impairments while producing antidepressant-like activity and enhancing the behavioral response to fluoxetine. Our results suggest that Met may act by decreasing circulating BCAAs levels to favor serotonergic neurotransmission in the hippocampus and promote antidepressant-like effects in mice fed an HFD. These findings also lead us to envision that a diet poor in BCAAs, provided either alone or as add-on therapy to conventional antidepressant drugs, could help to relieve depressive symptoms in patients with metabolic comorbidities. [ABSTRACT FROM AUTHOR]

■Metformin is recommended as first-line therapy for type 2 diabetes because of its safety, low cost and potential cardiovascular benefits. ■The use of metformin was previously restricted in people with chronic kidney disease (CKD) - a condition that commonly coexists with diabetes - due to concerns over drug accumulation and metformin-associated lactic acidosis. ■There are limited data from observational studies and small randomised controlled trials to suggest that metformin, independent of its antihyperglycaemic effects, may be associated with lower risk of myocardial infarction, stroke and all-cause mortality in people with type 2 diabetes and CKD. ■Research into the risk of metformin-associated lactic acidosis in CKD has previously been limited and conflicting, resulting in significant variation across international guidelines on the safe prescribing and dosing of metformin at different stages of renal impairment. ■Present-day large scale cohort studies now provide supporting evidence for the safe use of metformin in mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] 30-60 mL/min/1.73m2 ). However, prescribing metformin in people with severe renal impairment (eGFR < 30 mL/min/1.73m2 ) remains a controversial issue. Due to observed increased risk of lactic acidosis and all-cause mortality in people with type 2 diabetes and severe renal impairment, it is generally recommended that metformin is discontinued if renal function falls below this level or during acute renal deterioration. [ABSTRACT FROM AUTHOR]

Metformin is a drug from the biguanide family that is used for decades as the first-line therapeutic choice for the treatment of type 2 diabetes. Despite its worldwide democratization, owing to its clinical efficacy, high safety profile and cheap cost, the exact mechanism(s) of action of this anti-hyperglycemic molecule with pleiotropic properties still remains to be fully elucidated. The concept that metformin would exert some of its actions though modulation of the mitochondrial bioenergetics was initially forged in the 50s but undeniably revived at the beginning of the twenty-first century when it was shown to induce a weak but specific inhibition of the mitochondrial respiratory-chain complex 1. Furthermore, metformin has been reported to reduce generation of reactive oxygen species at the complex 1 and to prevent mitochondrial-mediated apoptosis, suggesting that it can protect against oxidative stress-induced cell death. Nevertheless, despite some recent progress and the demonstration of its key role in the inhibition of hepatic gluconeogenesis, the exact nature of the mitochondrial interaction between the drug and the complex 1 is still poorly characterized. Recent studies reported that metformin may also have anti-neoplastic properties by inhibiting cancer cell growth and proliferation, at least partly through its mitochondrial action. As such, many trials are currently conducted for exploring the repositioning of metformin as a potential drug for cancer therapy. In this mini-review, we discuss both historical and more recent findings on the central role played by the interaction between metformin and the mitochondria in its cellular mechanism of action. [ABSTRACT FROM AUTHOR]