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Empagliflozin and metformin are oral antidiabetic drugs commonly used to treat type 2 diabetes mellitus as a combination therapy. This study aimed to compare the pharmacokinetics and safety of a newly developed fixed-dose combination of 5-mg empagliflozin L-proline and 1000-mg metformin with the reference drug. A randomized, open-label, single-dose, 2-period, 2-treatment, crossover study was conducted in healthy Korean subjects. The subjects received a single oral dose of reference drug or test drug at each period. The pharmacokinetic (PK) parameters were calculated using a noncompartmental method. The geometric mean ratios and 90% confidence intervals of the plasma maximum concentration (C max ) and area under the concentration-time curve from time zero to the last quantifiable concentration (AUC last ) were calculated. A total of 27 healthy subjects were included in the PK analysis. For empagliflozin, the geometric mean ratios (90% confidence intervals) of the test to reference drug for C max and AUC last were 1.03 (0.99-1.08) and 1.03 (1.00-1.06), respectively. For metformin, the corresponding values for C max  and AUC last were 0.99 (0.92-1.06) and 1.00 (0.94-1.06), respectively. In conclusion, a fixed-dose combination of empagliflozin L-proline and metformin showed similar PK characteristics to the reference drug, and both drugs were safe in healthy subjects., (© 2023, The American College of Clinical Pharmacology.)

Metformin, a hypoglycemic drug for Type 2 diabetes mellitus, shows variability in pharmacokinetics and response due to membrane transporters. This study followed 34 Type 2 diabetes mellitus patients on metformin treatment. Genetic variants in 11 metformin transport-related genes were analyzed, revealing associations. Specifically, SLC47A1 rs2289669 A/A and SLC22A4 rs1050152 T/T genotypes correlated with glycated hemoglobin values at 6 months. SLC47A1 rs2289669 G/A genotype influenced glucose levels at 6 months, while SLC29A4 rs3889348 A/A, SLC47A1 rs2289669 A/A, SLC22A4 rs1050152 C/T and SLC47A2 rs12943590 A/A genotypes were linked to glucose levels at 12 months. Additionally, ABCB1 rs2032582 C/A and ABCG2 rs2231137 C/T genotypes impacted cholesterol levels at 12 months. These findings shed light on metformin response determinants, offering insights for further research.

Purpose: A fixed-dose combination (FDC) product combining dapagliflozin and metformin may increase medication adherence in patients with type 2 diabetes mellitus (T2DM) by minimizing pill burden associated with co-administration of individual component (IC) formulations and, consequently, improve cost-efficiency and compliance. This study evaluated the bioequivalence of the dapagliflozin/metformin FDC product versus IC administration in healthy volunteers from a Chinese population and assessed the safety profile of the FDC product. In addition, pharmacokinetic (PK) and safety comparisons of dapagliflozin and metformin across different regions were conducted to evaluate regional differences., Methods: This single-center, open-label, parallel-cohort, randomized, 2-period, crossover study enrolled Chinese adults (aged 18-55 years). Volunteers in cohort 1 received either a single FDC tablet of dapagliflozin/metformin extended release (XR) (5/500 mg) or IC tablets (dapagliflozin [5 mg] and metformin XR [500 mg]). Volunteers in cohort 2 received a higher dosage in a similar manner (dapagliflozin [10 mg] and metformin XR [1000 mg]). Volunteers in each cohort were subsequently crossed over to receive the alternate cohort treatment. Plasma concentrations of dapagliflozin and metformin were determined, and bioequivalence analyses were performed under standard fed conditions., Findings: Eighty healthy Chinese volunteers (89.9% male; mean age, 28.7 years) were randomized into cohort 1 (n = 40) and cohort 2 (n = 39; 1 volunteer withdrew before receiving study treatment). The mean plasma concentration-time profiles of the dapagliflozin and metformin FDC and IC formulations for both doses were found to be nearly superimposable. Dapagliflozin and metformin XR FDC were bioequivalent to the IC tablets, with 90% CIs for each pairwise comparison contained within the 80% to 125% bioequivalence limits. Both the FDC and IC formulations were well tolerated, with no serious adverse events/death. PK parameters for dapagliflozin in the Chinese volunteers were slightly to moderately higher than those from studies conducted in Brazil, Russia, and the United States, and the safety profile of the dapagliflozin/metformin FDC product was consistent with that of other studies. The difference in PK parameters among the 4 regions was not clinically meaningful., Implications: The bioequivalence of the dapagliflozin/metformin FDC and IC formulations in healthy Chinese adults was established without any new safety concerns. Notably, the observed bioequivalence may be extrapolated to patients with T2DM as the PK parameters of dapagliflozin and metformin in healthy adults are similar to those reported in patients with T2DM., Clinicaltrials: gov identifier: NCT04856007., Competing Interests: Declaration of Competing Interest Ms. Zhao, Dr Ning, Mr. Hui, Dr Boulton and Dr Tang are employees of AstraZeneca. Dr Bouton and Dr Tang own AstraZeneca stock and/or stock options. Mr. Hui was a summer intern at AstraZeneca when conducting this research., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Metformin has been used for the treatment of type II diabetes mellitus for decades due to its safety, low cost, and outstanding hypoglycemic effect clinically. The mechanisms underlying these benefits are complex and still not fully understood. Inhibition of mitochondrial respiratory-chain complex I is the most described downstream mechanism of metformin, leading to reduced ATP production and activation of AMP-activated protein kinase (AMPK). Meanwhile, many novel targets of metformin have been gradually discovered. In recent years, multiple pre-clinical and clinical studies are committed to extend the indications of metformin in addition to diabetes. Herein, we summarized the benefits of metformin in four types of diseases, including metabolic associated diseases, cancer, aging and age-related diseases, neurological disorders. We comprehensively discussed the pharmacokinetic properties and the mechanisms of action, treatment strategies, the clinical application, the potential risk of metformin in various diseases. This review provides a brief summary of the benefits and concerns of metformin, aiming to interest scientists to consider and explore the common and specific mechanisms and guiding for the further research. Although there have been countless studies of metformin, longitudinal research in each field is still much warranted., (© 2023. Higher Education Press.)

Aims/hypothesis: The objective was to investigate if metformin pharmacokinetics is modulated by time-of-day in humans using empirical and mechanistic pharmacokinetic modelling techniques on a large clinical dataset. This study also aimed to generate and test hypotheses on the underlying mechanisms, including evidence for chronotype-dependent interindividual differences in metformin plasma and efficacy-related tissue concentrations., Methods: A large clinical dataset consisting of individual metformin plasma and urine measurements was analysed using a newly developed empirical pharmacokinetic model. Causes of daily variation of metformin pharmacokinetics and interindividual variability were further investigated by a literature-informed mechanistic modelling analysis., Results: A significant effect of time-of-day on metformin pharmacokinetics was found. Daily rhythms of gastrointestinal, hepatic and renal processes are described in the literature, possibly affecting drug pharmacokinetics. Observed metformin plasma levels were best described by a combination of a rhythm in GFR, renal plasma flow (RPF) and organic cation transporter (OCT) 2 activity. Furthermore, the large interindividual differences in measured metformin concentrations were best explained by individual chronotypes affecting metformin clearance, with impact on plasma and tissue concentrations that may have implications for metformin efficacy., Conclusions/interpretation: Metformin's pharmacology significantly depends on time-of-day in humans, determined with the help of empirical and mechanistic pharmacokinetic modelling, and rhythmic GFR, RPF and OCT2 were found to govern intraday variation. Interindividual variation was found to be partly dependent on individual chronotype, suggesting diurnal preference as an interesting, but so-far underappreciated, topic with regard to future personalised chronomodulated therapy in people with type 2 diabetes., (© 2023. The Author(s).)

The rational combination of oral antidiabetic agents is more likely to provide better glycemic control than monotherapy. Metformin glibenclamide tablets can be used as second-line therapy for patients with type 2 diabetes mellitus who cannot successfully control their blood glucose levels by diet and exercise plus metformin or sulfonylureas. The aim of this study was to evaluate the bioequivalence and safety of metformin hydrochloride and glibenclamide tablets (500 mg/5 mg) prepared by 2 different vendors in healthy Chinese subjects under fasting and fed conditions. This is an open-label, single-center, randomized, 2-formulation, 2-period crossover study. After screening, 40 subjects were enrolled in the fasting trial, while 40 subjects were enrolled in the fed trial. Qualified subjects were randomly assigned to receive a monotherapy dose of 500 mg/5 mg of the test or reference formulation, and after a 1-week washout period, they took the alternative formulation. Blood samples were collected from 24 blood collection sites per cycle for pharmacokinetic analysis until 36 hours after oral administration. In total, 78 subjects completed the study. Under fasting and fed conditions, the geometric mean ratios of maximum plasma concentration, area under the plasma concentration-time curve (AUC) from time 0 to time of last quantifiable drug level , and AUC from time 0 to infinity between the 2 products, as well as the corresponding 90%CIs, were all within the range of 80%-125%. It was found that exposure (AUC from time 0 to infinity) to metformin is decreased by about 25% in the fed state compared to fasting, whereas glibenclamide exposure is increased by about 30% in the fed state. No severe adverse events were observed in the study., (© 2023, The American College of Clinical Pharmacology.)

Henagliflozin proline and metformin hydrochloride sustained-release tablets (HR20033) are a fixed-dose combination of the novel, highly selective, and effective sodium-glucose cotransporter-2 inhibitor henagliflozin, with a metformin sustained-release layer for the treatment of type 2 diabetes mellitus in conjunction with dietary control and exercise. The aims of this study were to investigate the effect of a high-fat diet on the pharmacokinetics of henagliflozin and metformin after a single administration of HR20033 and the effect of repeated oral administration of HR20033 on their pharmacokinetics in healthy volunteers. The food-effect clinical study involved 18 healthy subjects randomized to receive either HR20033 in the fasted condition followed by HR20033 in the fed condition or the reverse schedule, with the two doses separated by a washout period of at least 7 days. The multiple-dose clinical study was conducted on 10 healthy subjects. In the food-effect study, compared with those in the fasted condition, the area under the blood concentration curve (AUC) and peak concentration (C max ) of henagliflozin decreased by 12.64% and 40.89%, respectively, while the AUC of metformin increased by 31.13% and C max decreased by 7.09% in the fed state. There was no significant accumulation of HR20033 in the body after multiple oral doses. No serious adverse event was observed in either of the two clinical studies. Food did not have a clinically meaningful effect on the absorption of HR20033., (© 2022, The American College of Clinical Pharmacology.)

Two-thirds of patients with type 2 diabetes mellitus have hypertension, and thus the combination of two or more drugs to treat these diseases is common. It has been shown that the combination of metformin and enalapril has beneficial effects, but few studies have evaluated the interactions between these two drugs. This study investigated the effects of enalapril on the pharmacokinetics and urinary excretion of metformin in rats, with a focus on transporter-mediated drug interactions. Rats were dosed orally with metformin alone (100 mg/kg) or in combination with enalapril (4 mg/kg). The concentration of metformin was measured by high performance liquid chromatography and the level of organic cation transporters (rOCTs) and multidrug and toxin excretion protein 1 (rMATE1), which mediate the uptake and efflux of metformin, respectively, were evaluated by immunoblotting. After single and 7-day dosing, the plasma concentration of metformin in the co-administration group was significantly lower than that in the metformin-only group, and the CL/F and urinary excretion were increased in the co-administration group. Enalapril did not affect the K p of metformin but reduced renal slice-uptake of metformin. The expression of rMATE1 was increased, whereas rOCT2 expression was decreased in rat kidney. Importantly, long-term co-administration of metformin and enalapril markedly decreased the level of lactic acid and uric acid in the blood. Enalapril increases the urinary excretion of metformin through the up-regulation of rMATE1. This reveals a new mechanism of drug interactions and provides a basis for drug dosage adjustment when these drugs are co-administered., (© 2022 John Wiley & Sons Ltd.)

Background: Early-onset androgenic alopecia is considered the phenotypic equivalent of polycystic ovary syndrome in men. The purpose of the current study was to investigate whether the presence of early-onset male-pattern baldness modulates metabolic effects of metformin., Methods: This prospective case-control study included 2 groups of men at high risk for type 2 diabetes: 72 individuals with androgenic alopecia (group A) and 75 subjects with normal hair growth (group B). Both groups were matched for age, blood pressure, body mass index, insulin sensitivity and plasma lipids. Glycated hemoglobin, glucose, plasma lipids, indices of insulin sensitivity/resistance, sex hormones, high-sensitivity C-reactive protein (hsCRP) and 25-hydroxyvitamin D were determined before and after metformin treatment (1.7 g daily)., Results: Twelve-month metformin treatment reduced fat content, waist circumference, glycated hemoglobin, glucose and triglycerides, as well as improved insulin sensitivity. Although observed in both study populations, these effects were more pronounced in group B. Moreover, metformin decreased hsCRP and bioavailable testosterone levels in group B, as well as reduced 25-hydroxyvitamin D concentration in group A. Treatment-induced changes in glucose homeostasis markers correlated with the impact of metformin on hsCRP and 25-hydroxyvitamin D levels., Conclusions: Metabolic effects of metformin in males are attenuated if they have coexisting early-onset androgenic alopecia. This finding may be partially explained by differences in severity of low-grade systemic inflammation and vitamin D status. The obtained results, requiring confirmation in large prospective studies, suggest that men with early-onset male-pattern baldness benefit to a lesser degree from metformin treatment than other men at high risk for type 2 diabetes., (© 2021. The Author(s).)

Acarbose and metformin have been recommended both as monotherapy and add-on therapy in type 2 diabetes mellitus. A novel fixed-dose combination (FDC) of acarbose and metformin has been developed to improve compliance and patient adherence to therapy. The current study investigated the bioequivalence (BE) between acarbose/metformin FDC (50 mg/500 mg) with corresponding loose combination of individual components under fasting conditions in healthy Chinese male and female subjects, using a randomized, 2-period, 2-way crossover study design. Pharmacodynamic parameters of serum glucose ratio between treatment day and baseline (ratio of maximum concentration [C max ], day 1/C max , day -1 and ratio of area under the concentration-time curve [AUC] from time 0 to 4 hours, day 1/AUC from time 0 to 4 hours, day -1) were used as the primary variables to evaluate BE of acarbose. Pharmacokinetic parameters C max , AUC from time 0 to the last data point greater than the lower limit of quantification, and AUC were used to evaluate BE of metformin. The results showed that the 90% confidence intervals of the ratios of all primary target variables including ratio of C max , day 1/C max , day -1 and ratio of AUC from time 0 to 4 hours, day 1/AUC from time 0 to 4 hours, day -1 for acarbose, and C max , AUC from time 0 to the last data point greater than the lower limit of quantification, and AUC for metformin all fell within the acceptance limits of 0.8 to 1.25. Thus, BE between 50-mg acarbose and 500-mg metformin as an FDC and loose combination was established. Furthermore, different kinds of exploratory pharmacodynamic parameters (based on either serum glucose or insulin) including several newly proposed parameters were also investigated for acarbose BE evaluation in this study, and inconsistent results were observed., (© 2021 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Purpose: Metformin is the first-line antidiabetic drug and shown to reduce cardiovascular risk independent from its glucose lowering action. Particularly in poorly controlled diabetes, tissue factor (TF) is expressed in the vasculature and accounts for thromboembolic complications. Here, we aimed to assess the effect of metformin on TF activity and markers of vascular inflammation in poorly controlled type 2 diabetes., Methods: In a cohort of patients with uncontrolled type 2 diabetes (glycosylated hemoglobin 8.39 ± 0.24%, 68.1 ± 2.6 mmol/mol, n = 46) of whom half of the individuals were treated with metformin and the other half did not receive metformin as part of an anti-diabetic combination therapy, we assessed TF activity and markers of vascular inflammation. In vitro, human monocytic cells (THP-1) were exposed to metformin and TF expression measured in the presence and absence of the AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide riboside (AICAR) or the AMPK inhibitor compound C., Results: In the patients, metformin treatment was associated with lower levels of TF protein (241.5 ± 19 vs. 315.4 ± 25 pg/mL, p = 0.03) and reduced TF activity (408.9 ± 49 vs. 643.8 ± 47 U/mL, p = 0.001) compared with controls. Moreover, the patients on metformin showed lower levels of vascular cell adhesion molecule (VCAM)1 (26.6 ± 1.4 vs. 35.03 ± 3.1 ng/mL, p = 0.014) and higher expression of miR-126-3p/U6sno (11.39 ± 2.8 vs. 4.26 ± 0.9, p = 0.006), a known post-transcriptional down regulator of TF and VCAM1. In vitro, metformin dose-dependently reduced lipopolysaccharide (LPS)-induced TF expression in THP-1 cells. The AMPK activator AICAR alone lowered TF expression in THP-1, while the AMPK inhibitor compound C abrogated the metformin-dependent reduction in TF expression., Conclusions: Our data are the first to report that metformin is associated with reduced plasma TF procoagulant activity possibly explaining-at least in part-the vasculoprotective properties of metformin.

Background: Patients with type 2 diabetes mellitus (T2DM) are characterized by an elevated glycemic index and are at a higher risk for complications such as cardiovascular disease, nephropathy, retinopathy and peripheral neuropathy. Normalization of glycemic index can be achieved by dosing combinations of metformin with other anti-diabetic drugs. The present study (Clintrials number NCT00519480) was conducted to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of remogliflozinetabonate, an SGLT2 inhibitor, withdoses (500 mg and 750 mg BID) greater than the commercial dose (100 mg BID)in combination with metformin with minimum daily dose of 2000 mg given in two divided doses., Methods: This was a randomized, double-blinded, repeat dose study in 50 subjects with T2DM. The study was conducted in three phases; run-in, randomization, and treatment. All subjects were on a stable metformin dosing regimen. Cohort 1 subjects were randomly allocated to receive either remogliflozin etabonate 500 mg BID or placebo BID (2:1) in addition to metformin. Cohort 2 subjects were administered with either remogliflozin etabonate 750 mg BID or placebo BID (2:1) in addition to metformin for 13 days. All the subjects were assessed for safety (adverse events, lactic acid levels, vital signs, electrocardiogram [ECG]), pharmacokinetic evaluation, and pharmacodynamics (Oral Glucose Tolerance Testing) parameters., Results: Co-administration of remogliflozin etabonate and metformin was well tolerated in all subjects during the observation period. There were no severe or serious adverse events (SAEs) and no increase in lactic acid concentration was reported during the study. The statistical results showed that concomitant administration of remogliflozin etabonate, either 500 mg or 750 mg BID, with metformin had no effect on the pharmacokinetics of metformin. The accumulation ratios, Day 13 vs. Day 1, for AUC values of remogliflozin etabonate and its metabolites were all very close to 1, indicating no accumulation in plasma concentrations of remogliflozin etabonate and its metabolites. Mean glucose values from baseline and glucose and insulin values following oral glucose tolerance test (OGTT) were decreased in all treatment groups., Conclusion: Co-administration of doses of remogliflozin etabonate (500 mg BID or 750 mg BID) greater than the commercial dose (100 mg BID) with metformin (2000 mg BID) was shown to be safe and effective during the observation period., Trial Registration: ClinicalTrials.gov , NCT00519480 . Registered:22 August 2007.

Metformin is the primary drug for type 2 diabetes treatment and a promising candidate for other disease treatment. It has significant deviations between individuals in therapy efficiency and pharmacokinetics, leading to the administration of an unnecessary overdose or an insufficient dose. There is a lack of data regarding the concentration-time profiles in various human tissues that limits the understanding of pharmacokinetics and hinders the development of precision therapies for individual patients. The physiologically based pharmacokinetic (PBPK) model developed in this study is based on humans' known physiological parameters (blood flow, tissue volume, and others). The missing tissue-specific pharmacokinetics parameters are estimated by developing a PBPK model of metformin in mice where the concentration time series in various tissues have been measured. Some parameters are adapted from human intestine cell culture experiments. The resulting PBPK model for metformin in humans includes 21 tissues and body fluids compartments and can simulate metformin concentration in the stomach, small intestine, liver, kidney, heart, skeletal muscle adipose, and brain depending on the body weight, dose, and administration regimen. Simulations for humans with a bodyweight of 70kg have been analyzed for doses in the range of 500-1500mg. Most tissues have a half-life (T1/2) similar to plasma (3.7h) except for the liver and intestine with shorter T1/2 and muscle, kidney, and red blood cells that have longer T1/2. The highest maximal concentrations (Cmax) turned out to be in the intestine (absorption process) and kidney (excretion process), followed by the liver. The developed metformin PBPK model for mice does not have a compartment for red blood cells and consists of 20 compartments. The developed human model can be personalized by adapting measurable values (tissue volumes, blood flow) and measuring metformin concentration time-course in blood and urine after a single dose of metformin. The personalized model can be used as a decision support tool for precision therapy development for individuals., Competing Interests: The authors have declared that no competing interests exist.

Metformin was found to reduce elevated, but not normal, thyrotropin and prolactin levels. This non-randomized, uncontrolled pilot study investigated hypothalamic-pituitary-testicular axis activity in men with primary hypogonadism receiving metformin. The study population included 29 men with prediabetes, 10 of whom had been diagnosed with primary hypogonadism. Throughout the study, the participants were treated with metformin (2.55-3 g daily). Glucose homeostasis markers (fasting glucose, glycated hemoglobin, and HOMA1-IR), as well as circulating levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, thyrotropin, prolactin, estradiol, and creatinine, were assessed at the beginning of the study and 16 weeks later. Both groups differed in baseline gonadotropin and testosterone levels. Fasting glucose, glycated hemoglobin, and HOMA1-IR were lower after than before metformin treatment. The changes in fasting glucose and HOMA1-IR were more pronounced in hypogonadal men than in subjects with testosterone levels within the reference range. Only in hypogonadal men, plasma concentrations of FSH and LH were lower at the end than at the beginning of the study. Levels of the remaining hormones remained unchanged throughout the study period. The reduction in FSH and LH levels correlated with their baseline levels and with the changes in HOMA1-IR. The results of our study suggest that metformin may decrease FSH and LH levels in men with hypergonadotropic hypogonadism., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

We aimed to develop a metformin dosing strategy to optimise efficacy and safety in patients with reduced kidney function. Metformin data from two studies stratified by kidney function were analysed. The relationship between metformin clearance and kidney function estimates was explored using a regression analysis. The maintenance dose range was predicted at different bands of kidney function to achieve an efficacy target of 1 mg/L for steady-state plasma concentrations. The dosing strategy was evaluated using simulations from a published metformin pharmacokinetic model to determine the probability of concentrations exceeding those associated with lactic acidosis risk, i.e. a steady-state average concentration of 3 mg/L and a maximum (peak) concentration of 5 mg/L. A strong relationship between metformin clearance and estimated kidney function using the Cockcroft and Gault (r2 = 0.699), MDRD (r2 = 0.717) and CKD-Epi (r2 = 0.735) equations was found. The probability of exceeding the safety targets for plasma metformin concentration was <5% for most doses and kidney function levels. The lower dose of 500 mg daily was required to maintain concentrations below the safety limits for patients with an eGFR of 15-29 mL/min. Our analysis suggests that a maximum daily dose of 2250, 1700, 1250, 1000, and 500 in patients with normal kidney function, CKD stage 2, 3a, 3b and 4, respectively, will provide a reasonable probability of achieving efficacy and safety. Our results support the cautious of use metformin at appropriate doses in patients with impaired kidney function., Competing Interests: The authors have no relevant conflicts to declare.

Introduction: Conversion in the metabolism of drugs occurs in diabetes mellitus. Considering the importance of metabolic enzymes' activities on the efficacy and safety of medicines, the changes in liver enzymatic activity of CYP2D1 and its related hepatic clearance, by using Dextromethorphan as probe in the animal model of type I and type II diabetes, before and after treatment, was assessed in this study., Methods: Male Wistar rats were randomly divided into 6 groups. Seven days after induction of diabetes type I and type II, treatment groups were received insulin and metformin daily for 14 days, respectively. In day 21, rats were subjected to liver perfusion by Krebs-Henseleit buffer containing Dextromethorphan as CYP2D1 probe. Perfusate samples were analyzed by HPLC fluorescence method in order to evaluate any changes in CYP2D1 activity., Results: The average metabolic ratio of dextromethorphan and hepatic clearance were changed from 0.012 ± 0.004 and 6.3 ± 0.1 in the control group to 0.006 ± 0.0008 and 5.2 ± 0.2 in the untreated type I diabetic group, and 0.008 ± 0.003 and 5.0 ± 0.6 in the untreated type II diabetic rats. Finally, the mean metabolic ratio and hepatic clearance were changed to 0.008 ± 0.001 and 5.4 ± 0.1, and 0.013 ± 0.003 and 6.1 ± 0.4 in the treated groups with insulin and metformin, respectively., Conclusion: In type I diabetic rats, corresponding treatment could slightly improve enzyme activity, whereas the hepatic clearance and enzyme activity reached to the normal level in type II group. Graphical abstract .

Approximately 35% of patients fail to attain ideal initial blood glucose control under metformin monotherapy. The objective of this observational study is to simulate the optimal protocol of metformin according to the different renal function.The population pharmacokinetics of metformin was performed in 125 subjects with type 2 diabetes mellitus. Plasma concentrations of metformin were quantified by high-performance liquid chromatography. A population pharmacokinetic model of metformin was developed using NONMEN (version 7.2, Icon Development Solutions, USA). Monte Carlo simulation was used to simulate the concentration-time profiles for doses of metformin for 1000 times at different stages of renal function.The mean population pharmacokinetic parameters were apparent clearance 53.0 L/h, apparent volume of distribution 438 L, absorption rate constant 1.4 hour and lag-time 0.91 hour. Covariate analyses revealed that estimated glomerular filtration rate (eGFR) and bodyweight as individual factors influencing the apparent oral clearance: CL/F = 53.0 × ( bodyweight/75) × (eGFR/102.5)EXP(0.1797). The results of the simulation showed that patients should be prescribed metformin 2550 mg/d (t.i.d.) vs 3000 mg/d (b.i.d.) as the minimum doses for patients with augmented renal clearance.eGFR had a significant impact on metformin pharmacokinetics. Patients administered metformin twice a day require higher total daily doses than those with a regimen of 3 times a day at each stage of kidney function.

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.

Background: Metformin is the most widely used oral antihyperglycemic agent for patients with type 2 diabetes mellitus (T2DM). Despite the possible benefits of metformin on diabetes mellitus (DM) and heart failure (HF), acute or unstable HF remains a precaution for its use., Objective: The aim of the present prospective randomized controlled trial was to assess whether metformin treatment has beneficial effects on patients with T2DM with hypertension without overt HF., Methods: A total of 164 patients (92 males, 72 females; median age 66 years) were included in this study. Patients with T2DM with a history of hypertension were randomized 1:1 to treatment for 1 year with either metformin (metformin-treated group) or other hypoglycemic agents (control group). The primary endpoints were changes in brain natriuretic peptide (BNP) levels, left ventricular (LV) mass index, and indicators of LV diastolic function. We also evaluated changes in both clinical findings and blood laboratory examination data., Results: We observed no significant changes between baseline and 1-year post-treatment in LV mass index, BNP levels, or E/e' (early diastolic transmitral flow velocity/early diastolic mitral annular velocity; an indicator of LV diastolic function) in either the metformin-treated (n = 83) or the control (n = 81) groups. The metformin-treated group had a significant reduction of body mass index (BMI) and low-density lipoprotein cholesterol (LDL-C), but the control group did not. We determined that renal function, including serum creatinine and estimated glomerular filtration rate, deteriorated significantly in the control group but not in the metformin-treated group., Conclusion: LV mass and diastolic function were not affected after 1 year of metformin treatment in patients with T2DM. However, we observed benefits in terms of reductions in both BMI and LDL-C levels and preservation of renal function., Trial Registration: UMIN000006504. Registered 7 October 2011.

This study's primary objective was to fully characterize the pharmacokinetics of metformin in pregnant women with gestational diabetes mellitus (GDM) versus nonpregnant controls. Steady-state oral metformin pharmacokinetics in pregnant women with GDM receiving either metformin monotherapy ( n = 24) or a combination with glyburide ( n = 30) as well as in nonpregnant women with type 2 diabetes mellitus (T2DM) ( n = 24) were determined utilizing noncompartmental techniques. Maternal and umbilical cord blood samples were collected at delivery from 38 women. With both 500- and 1000-mg doses, metformin bioavailability, volume of distribution beta (V β ), clearance, and renal clearance were significantly increased during pregnancy. In addition, in the women receiving metformin 500 mg, significantly higher metformin apparent oral clearance (CL/F) (27%), weight-adjusted renal secretion clearance (64%), and apparent oral volume of distribution beta (V β /F) (33%) were seen during pregnancy. Creatinine clearance was significantly higher during pregnancy. Increasing metformin dose from 500 to 1000 mg orally twice daily significantly increased V β /F by 28%, weight-adjusted V β /F by 32% and CL/F by 25%, and weight-adjusted CL/F by 28% during pregnancy. Mean metformin umbilical cord arterial-to-venous plasma concentration ratio was 1.0 ± 0.1, venous umbilical cord-to-maternal concentration ratio was 1.4 ± 0.5, and arterial umbilical cord-to-maternal concentration ratio was 1.5 ± 0.5. Systemic exposure after a 500-mg dose of metformin was lower during pregnancy compared with the nonpregnant women with T2DM. However, in patients receiving metformin 1000 mg, changes in estimated bioavailability during pregnancy offset the changes in clearance leading to no significant change in CL/F with the higher dose. SIGNIFICANCE STATEMENT: Gestational diabetes mellitus complicates 5%-13% of pregnancies and is often treated with metformin. Pregnant women undergo physiological changes that alter drug disposition. Preliminary data suggest that pregnancy lowers metformin concentrations, potentially affecting efficacy and safety. This study definitively describes pregnancy's effects on metformin pharmacokinetics and expands the mechanistic understanding of pharmacokinetic changes across the dosage range. Here we report the nonlinearity of metformin pharmacokinetics and the increase in bioavailability, clearance, renal clearance, and volume of distribution during pregnancy., (U.S. Government work not protected by U.S. copyright.)

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 (CL Met /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)., (© 2020 John Wiley & Sons Ltd.)

Polymorphisms in SLC22A1 lead to variability in metformin clinical efficacy. Sixty-three Lebanese patients with type 2 diabetes who administered metformin, were followed up for six months and genotyped for rs622342A>C. The area under the plasma concentration-time curve and the maximum concentration of metformin was highest in CC patients (P ≤ 0.03). There was a significant difference between groups in the percentage decrease in fasting blood sugar (FBS) and glycated hemoglobin (HbA 1 c). Going into the same direction, rs622342C was associated with decrease in FBS levels after three and six months of treatment (P ≤ 0.02), whereas with HbA 1 c, the decrease was noticed after six months (β = -2.78; P = 0.03). In contrast, the serum levels of lactate and creatinine did not vary significantly according to rs622342A>C genotypes. The rs622342A>C in SLC22A1 may be associated with metformin pharmacokinetics and variability in therapeutic efficacy., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2019 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Aims: Metformin may have clinical benefits in dialysis patients; however, its safety in this population is unknown. This systematic review evaluated the safety of metformin in dialysis patients., Methods: MEDLINE, Embase, CENTRAL, PsycINFO and the Cochrane Library were searched for randomised controlled trials and observational studies evaluating metformin use in dialysis patients. Three authors reviewed the studies and extracted data. The primary outcomes were mortality, occurrence of lactic acidosis and myocardial infarction (MI) in patients taking metformin during dialysis treatment for ≥12 months (long term). Risk of bias was assessed using Risk Of Bias In Nonrandomised Studies of Interventions (ROBINS-1). Overall quality of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE)., Results: Fifteen observational studies were eligible; 7 were prospective observational studies and 8 were case reports/case series. No randomised controlled trials were identified. The 7 prospective observational studies (n = 194) reported on cautious metformin use in patients undergoing maintenance dialysis. Only 3 provided long-term follow-up data. In 2 long-term studies of metformin therapy (≤1000 mg/d) in patients undergoing peritoneal dialysis (PD), 1 reported 6 deaths (6/83; 7%) due to major cardiovascular events (3 MI) and the other reported no deaths (0/35). One long-term study of metformin therapy (250 mg to 500 mg thrice weekly) in patients undergoing haemodialysis reported 4 deaths (4/61; 7%) due to major cardiovascular events (2 MI). These findings provide very low-quality evidence as they come from small observational studies., Conclusion: The evidence regarding the safety of metformin in people undergoing dialysis is inconclusive. Appropriately designed randomised controlled trials are needed to resolve this uncertainty., (© 2019 The British Pharmacological Society.)

The current study aimed to formulate gelatin/sodium alginate nanoparticles utilizing BÜCHI nano spray dryer B-90. Nanoparticles possess many of the advantages including new routes of drug administrations and sustained release properties. Utilizing B-90 technology, metformin hydrochloride (MET) nanoparticles were successfully developed. Preformulation studies such as atomization head mesh size, flow rate, head temperature, polymer viscosity, and surface tension, were adjusted. Additionally, post-formulation characters such as particle size, flowability, surface scan, and dissolution profiles, were evaluated. Spray head (7 µm hole), flow rate (3.5 ml/min) and head temperature (120 °C) were optimized. Polymer viscosity was less than 11.2 cP with a surface tension less than 70.1 dyne/cm. Moreover, anti-diabetic effects of MET formulations were evaluated in streptozotocin-induced diabetic rats. Here, discrete, non-aggregated free-flowing nanoparticle powders with a particle size less than 850 nm were generated. Gelatin/sodium-alginate (1:3) produced nanoparticles were successfully sustained by the in vitro release profile of the drug. In vivo evaluations of the previous formula showed a significant reduction of blood glucose level over 24 h. In conclusion, Nano Spray Dryer B-90 (Büchi Labortechnik AG, Flawil, Switzerland) offers a promising technology for nanoparticles formulation as controlled drug delivery systems enhancing compliance of type-II diabetic patients.

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.

Introduction: Fasting has no adverse effects on healthy Muslims during Ramadan. However, it can induce serious complications for patients with type 2 diabetes (T2D). We aimed to follow the variation of some biochemical and clinical parameters in T2D patients before and after Ramadan; and to determine the incidence of fasting on hypoglycaemia and lactic acidosis associated with antidiabetic agents such as metformin., Materials and Methods: This work is a prospective study conducted during Ramadan on 150 patients, recruited 2 to 3 weeks prior to the start. These patients were sensitized about the Ramadan lifestyle and diet as well as the medications to take., Results: This study results indicated a significant decrease of glycated haemoglobin (from 8.06% to 7.42%) and a similar trend in the fasting plasma glucose (from 1.81 to 1.36g/L) before and after Ramadan respectively. The serum lipid profile showed significant variations during the study period, and antidiabetic medications was associated with low serum lactate. The plasma creatinine and uric acid were reduced but remained insignificant., Discussion and Conclusion: Based on data from our study, we concluded that a safe fasting with a lower risk hypoglycaemia, can be achieved in a well-controlled patients, under antidiabetic drugs. However, the diabetes medication was associated with a small increase in serum lactate levels that seemed to be dose-independent and not affected by treatment duration., (Copyright © 2019 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Aims: Metformin is first-line treatment of type 2 diabetes mellitus and reduces cardiovascular events in patients with insulin resistance and type 2 diabetes. Target tissue for metformin action is thought to be the liver, where metformin distribution depends on facilitated transport by polyspecific transmembrane organic cation transporters (OCTs). Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the western world with strong associations to insulin resistance and the metabolic syndrome, but whether NAFLD affects metformin biodistribution to the liver is not known. In this study, the primary aim was to investigate in vivo hepatic uptake of metformin dynamically in humans with variable degrees of liver affection. As a secondary aim, we wished to correlate hepatic metformin distribution with OCT gene transcription determined in diagnostic liver biopsies., Methods: Eighteen patients with biopsy-proven NAFLD were investigated using 11C-metformin PET/CT technique. Gene transcripts of OCTs were determined by real-time polymerase chain reaction (PCR)., Results: We observed similar hepatic volume of distribution of metformin between patients with simple steatosis and non-alcoholic steatohepatitis (NASH) (Vd 2.38 ± 0.56 vs. 2.10 ± 0.39, P = 0.3). There was no association between hepatic exposure to metformin and the degree of inflammation or fibrosis, and no clear correlation between metformin distribution and OCT gene transcription., Conclusion: Metformin is distributed to the liver in patients with NAFLD and the distribution is not impaired by inflammation or fibrosis. The findings imply that metformin action in liver in patients with NAFLD may be preserved., (© 2019 The British Pharmacological Society.)

Purpose: Dried blot spot (DBS) analysis of drugs or clinical parameters offers many advantages. We investigated the feasibility of using DBS for analysis of anti-diabetic drugs concomitantly with the estimated creatinine clearance (Cl crea )., Methods: The cross-sectional study involved physicians in an enabling analysis with 70 diabetic patients and community pharmacists in a field investigation with 84 participants. All 154 DBS samples were analyzed for creatinine, metformin, and sitagliptin., Results: The diabetic patients revealed of a wide range of age (32-88 years), BMI values (19.8-54.7 kg/m 2 ), and extent of polypharmacotherapy (1-21 drugs). A correlation factor to convert capillary blood creatinine from DBS into plasma concentrations was determined. Patients' Cl crea ranged from 21.6-155.9 mL/min. The results indicated statistically significant correlations (p < 0.05) between the use of two or three particular drug classes (diuretics, NSAIDs, renin-angiotensin system blockers) and a decreased renal function. DBS concentrations of metformin ranged between 0.23-4.99 μg/mL. The estimated elimination half-life (t ½) of metformin was 11.9 h in patients with a Cl Crea higher than 60 mL/min and 18.5 h for diabetics with lower Cl Crea . Sitagliptin capillary blood concentrations ranged between 11.12-995.6 ng/mL. Calculated t ½ of sitagliptin were 8.4 h and 13.0 h in patients with a Cl Crea above and below 60 mL/min, respectively., Conclusions: DBS allow for the analysis of concentrations of predominantly renally eliminated drugs and community pharmacists can provide a valuable contribution to DBS sampling.

Background: The choice of the specific modality and treatment duration of renal replacement therapy (RRT) to adopt in metformin-associated lactic acidosis (MALA) is still debated. We aimed to verify if sustained low-efficiency dialysis (SLED) is a rational choice in patients with MALA and acute kidney injury (AKI)., Methods: We collected serial serum metformin measurements, clinical parameters, and outcome data in ten consecutive patients (mean age 77 years [range 58-88], 5 males) admitted to our renal intensive care unit for suspected MALA associated with AKI and hemodynamic instability. Patients underwent a 16-h SLED session performed with either conventional dialysis machines or machines for continuous RRT (CRRT). A 2-compartment open-infusion pharmacokinetic model with first-order elimination was fitted to each subject's serum concentration-time data to model post-SLED rebound and predict the need for further treatments., Results: Two patients died within 24 h after SLED start. Three patients needed one further dialysis session. Surviving patients (n = 8) were dialysis-free at discharge. Metformin levels were in the toxic range at baseline (median [range] 32.5 mg/l [13.6-75.6]) and decreased rapidly by the end of SLED (8.1 mg/l [4.5-15.8], p < 0.001 vs. baseline), without differences according to the dialysis machine used (p = 0.84). We observed a slight 4-h post-SLED rebound (9.7 mg/l [3.5-22.0]), which could be predicted by our pharmacokinetic model. Accordingly, we predicted that the majority of patients would need one additional dialysis session performed the following day to restore safe metformin levels., Conclusions: A 16-h SLED session, performed with either conventional dialysis machines or CRRT machines, allows effective metformin removal in patients with MALA and AKI. However, due to possible post-SLED rebound in serum metformin levels, one additional dialysis treatment is required the following day in the majority of patients.

The objective of the present study was to develop a population pharmacodynamic (PPD) model to describe the glycated hemoglobin (HbA1c)-lowering effects of metformin in type 2 diabetes mellitus patients with and without secondary failure and to characterize changes in HbA1c levels in the two subpopulations using a mixture model. Information on patients was collected retrospectively from electronic medical records. In this study, the mixture model was used to characterize the bimodal effects of metformin. A PPD analysis was performed using NONMEM 7.3.0. A physiological indirect response model, based on 829 HbA1c levels of 69 patients, described the time course for the HbA1c-lowering effects of metformin. Evidence for the different effectiveness of metformin subpopulations was provided using the mixture model. In the final PPD model, the inhibition effect was constant over a study duration in a patient subpopulation without secondary failure. In contrast, the inhibition effect decreased as a function of time after start of metformin treatment in a subpopulation with secondary failure. These results indicated that HbA1c improvements appeared to deteriorate over time in patients with secondary failure. In a PPD analysis of metformin, it was possible to assign patients with secondary failure using the mixture model., (Copyright © 2018 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Introduction: Metformin is recommended as first-line treatment for type 2 diabetes (T2D) by all major diabetes guidelines. With appropriate usage it is safe and effective overall, but its efficacy and tolerability show considerable variation between individuals. It is a substrate for several drug transporters and polymorphisms in these transporter genes have shown effects on metformin pharmacokinetics and pharmacodynamics. Areas covered: This article provides a review of the current status of the influence of transporter pharmacogenomics on metformin efficacy and tolerability. The transporter variants identified to have an important influence on the absorption, distribution, and elimination of metformin, particularly those in organic cation transporter 1 (OCT1, gene SLC22A1), are reviewed. Expert opinion: Candidate gene studies have shown that genetic variations in SLC22A1 and other drug transporters influence the pharmacokinetics, glycemic responses, and gastrointestinal intolerance to metformin, although results are somewhat discordant. Conversely, genome-wide association studies of metformin response have identified signals in the pharmacodynamic pathways rather than the transporters involved in metformin disposition. Currently, pharmacogenomic testing to predict metformin response and tolerability may not have a clinical role, but with additional data from larger studies and availability of safe and effective alternative antidiabetic agents, this is likely to change.

Type 2 diabetes (T2D) is the most common type of diabetes mellitus and is mainly characterized by insulin resistance, β-cell dysfunction, and elevated hepatic glucose output. Metformin is a first-line antihyperglycemic agent that works mainly by regulating hepatic glucose production and peripheral insulin sensitivity. Metformin has been clinically applied for more than half a century, although the underlying pharmacological mechanisms remain elusive. This current review mainly focused on the development history of metformin and related preclinical studies on structural modification, pharmacological mechanisms for treatment of T2D, toxicology, pharmacokinetics, and pharmaceutics. The pharmacological function of metformin in lowering hyperglycemia suggests that multi-targeting could be an effective strategy for the discovery of new anti-diabetic drugs. A number of discoveries have revealed the pharmacologic mechanisms of metformin; however, precise mechanisms remain unclear. Deeper investigations on the biological features of metformin are expected to provide more rational applications and indications of this evergreen anti-T2D agent, which will in turn help to better understand the complicated pathogenesis of T2D., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

The pharmacokinetics of metformin therapy in patients with chronic kidney disease stage 4 (CKD-4) were studied using data from the largest Phase I consecutive cohort trial yet performed in this population. Eighteen metformin-naïve men and women with Type 2 Diabetes and creatinine clearance (CrCl) in the range 18-49 mL/min (eGFR 15-29 mL/min/1.73 m 2 ) were allocated to daily immediate-release metformin of 250 mg, 500 mg, or 1000 mg. A first-dose profile and trough concentrations for 4 weeks were taken on all patients. Pharmacokinetic (PK) parameters were estimated by fitting a first-order compartment model with absorption in a peripheral compartment to concentrations measured 24 hours post-first dose. Single-dose PK parameters time to maximum concentration ( t max ) and maximum concentration ( C max ) were consistent with previous observations in patients with normal renal function (healthy and diabetic), as was the association between CrCl and apparent total oral clearance ( Cl/F ). However, patients with a CrCl below 32 mL/min had trough concentrations that were consistently above the steady-state minimum implied by the population PK model. This suggests the model may not apply to patients with CrCl below 32 mL/min. Metformin in doses of 500-1000 mg/day could be taken by CKD-4 patients. However, the single-compartment model breaks down as CrCl declines below 32 mL/min suggesting that metformin levels should be monitored regularly in progressive stage 4 CKD.

Continuous glucose monitoring (CGM) systems allow patients with diabetes mellitus to closely track glucose concentrations over several days, identify trends in glucose levels, and avoid glucose excursions. This technology has not only advanced diabetes mellitus management but has increased patient safety through greater glycemic awareness. Due to these attributes, CGM is now being applied in therapeutic research as a pharmacodynamic tool to support early clinical drug development programs. However, to date only a handful of studies have utilized CGM in type 2 diabetes mellitus (T2DM) drug development. A potential barrier from fostering greater use of CGM in clinical development may be related to concerns over subject variability. Therefore, we investigated a key consideration when implementing CGM into early clinical research studies: daily variation within patients with T2DM from multiple clinical research units. From 24 patients with T2DM, we observed strong daily reproducibility (Pearson R = 0.86, P < .0001) in CGM results and found that this technique is practical for multisite studies. Altogether, with low daily variability, CGM is a powerful pharmacodynamic tool for drug efficacy and safety monitoring., (© 2018, The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.)

Introduction: Metformin is the first-line glucose-lowering medication in type 2 diabetes mellitus (T2DM), but it generally requires soon or later the addition of a second-line therapy, among which a sodium-glucose cotransporter type 2 (SGLT-2) inhibitor, to reach and maintain adequate glucose control. Areas covered: This narrative review provides an analysis of both efficacy and safety of a dual therapy combining metformin and empagliflozin, a SGLT-2 inhibitor that has proven its' potential to reduce major cardiovascular (CV) events, mortality, and renal outcomes in patients with T2DM and established CV disease. Pharmacokinetic studies showed the absence of drug-drug interactions and demonstrate bioequivalence between fixed-dose combination (FDC) and individual tablets of empagliflozin and metformin. Focus will be put on the use of this dual therapy in special populations. Expert opinion: The addition of empagliflozin to metformin therapy improves glucose control, with a minimal risk of hypoglycemia, while reducing body weight and arterial blood pressure. EMPA-REG OUTCOME showed that this combined therapy may be used in patients with established CV disease or heart failure. However, caution may be required in fragile elderly patients and in patients with severe impaired renal function. Further post-marketing surveillance is recommended to demonstrate long-term safety. FDC may improve adherence.

Aims: To assess potential causes of metformin intolerance, including altered metformin uptake from the intestine, increased anaerobic glucose utilization and subsequent lactate production, altered serotonin uptake, and altered bile acid pool., Methods: For this pharmacokinetic study, we recruited 10 severely intolerant and 10 tolerant individuals, matched for age, sex and body mass index. A single 500-mg dose of metformin was administered, with blood sampling at 12 time points over 24 hours. Blood samples were analysed for metformin, lactate, serotonin and bile acid concentrations, and compared across the phenotypes., Results: The intolerant individuals were severely intolerant to 500 mg metformin. No significant difference was identified between tolerant and intolerant cohorts in metformin pharmacokinetics: median (interquartile range [IQR]) peak concentration 2.1 (1.7-2.3) mg/L and 2.0 (1.8-2.2) mg/L, respectively (P = .76); time to peak concentration 2.5 hours; median (IQR) area under the curve (AUC) 0-24 16.9 (13.9-18.6) and 13.9 (12.9-16.8) mg/L*h, respectively (P = .72). Lactate concentration peaked at 3.5 hours, with mean peak concentration of 2.4 mmol/L in both cohorts (95% CI 2.0-2.8 and 1.8-3.0 mmol/L, respectively), and similar incremental AUC 0-24 in each cohort: tolerant cohort 6.98 (95% CI 3.03-10.93) and intolerant cohort 4.47 (95% CI -3.12-12.06) mmol/L*h (P = .55). Neither serotonin nor bile acid concentrations were significantly different., Conclusions: Despite evidence of severe intolerance in our cohort, there was no significant difference in metformin pharmacokinetics or systemic measures of lactate, serotonin or bile acids. This suggests that metformin intolerance may be attributable to local factors within the lumen or enterocyte., (© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: Metformin, an oral hypoglycemic drug is the first line of treatment for Type 2 diabetes individuals. We studied the effect of critical gene single nucleotide polymorphisms  on the glucose lowering effect of metformin., Method: We performed a prospective study on 221 newly diagnosed, treatment-naive Type 2 diabetes subjects. Individuals were started with metformin monotherapy and followed up for 12 weeks., Results: Our association analysis revealed that SLC22A2 rs316019 and SLC47A2 rs12943590 were significantly associated with metformin drug response across co-dominant and dominant models, respectively. SLC22A2 rs316019 GG and SLC47A2 rs12943590 GA combined genotypes showed maximum average change in HbA1c level., Conclusion: The present study proposes a role of SLC22A2 rs316019 and SLC47A2 rs12943590 in the pharmacokinetic action of metformin.

Patients with diabetes type 2 have an increased risk for cardiovascular disease and commonly use combination therapy consisting of the anti-diabetic drug metformin and a cholesterol-lowering statin. However, both drugs act on glucose and lipid metabolism which could lead to adverse effects when used in combination as compared to monotherapy. In this review, the proposed molecular mechanisms of action of statin and metformin therapy in patients with diabetes and dyslipidemia are critically assessed, and a hypothesis for mechanisms underlying interactions between these drugs in combination therapy is developed.

Objective: This study was conducted to define a safe, effective dose regimen for metformin in moderate and severe chronic kidney disease (CKD; stages 3A/3B and 4, respectively), after the lifting of restrictions on metformin use in patients with diabetes with moderate-to-severe CKD in the absence of prospective safety and efficacy studies., Research Design and Methods: Three complementary studies were performed: 1 ) a dose-finding study in CKD stages 1-5, in which blood metformin concentrations were evaluated during a 1-week period after each dose increase; 2 ) a 4-month metformin treatment study for validating the optimal metformin dose as a function of the CKD stage (3A, 3B, and 4), with blood metformin, lactate, and HbA 1c concentrations monitored monthly; and 3 ) an assessment of pharmacokinetic parameters after the administration of a single dose of metformin in steady-state CKD stages 3A, 3B, and 4., Results: First, in the dose-finding study, the appropriate daily dosing schedules were 1,500 mg (0.5 g in the morning [qam] +1 g in the evening [qpm]) in CKD stage 3A, 1,000 mg (0.5 g qam + 0.5 g qpm) in CKD stage 3B, and 500 mg (qam) in CKD stage 4. Second, after 4 months on these regimens, patients displayed stable metformin concentrations that never exceeded the generally accepted safe upper limit of 5.0 mg/L. Hyperlactatemia (>5 mmol/L) was absent (except in a patient with myocardial infarction), and HbA 1c levels did not change. Third, there were no significant differences in pharmacokinetic parameters among the CKD stage groups., Conclusions: Provided that the dose is adjusted for renal function, metformin treatment appears to be safe and still pharmacologically efficacious in moderate-to-severe CKD., (© 2018 by the American Diabetes Association.)

Background: Metformin is an oral hypoglycemic agent frequently used in patients with type 2 diabetes. In this study, we have investigated the influence of the dietary fiber Plantago ovata husk on the pharmacokinetics of this drug when included in the diet, as well as when administered at the same time as metformin., Methods: Six groups of 6 rabbits were used. Groups 1 to 3 were fed with standard chow and groups 4 to 6 with chow supplemented with fiber (3.5 mg/kg/day). Groups 1 and 4 received metformin intravenously (30 mg/kg). Groups 2 and 5 received metfomin orally (30 mg/kg), and number 3 and 6 were treated orally with metformin (30 mg/kg) and fiber (300 mg/kg)., Results: The changes caused by the inclusion of fiber in the feeding were more important in groups that received oral metformin. In this way, metformin oral bioavailability showed an increase of 34.42% when rabbits were fed with supplemented chow., Conclusions: Plantago ovata husk increased the amount of absorbed metformin when included in the diet (significant increase in AUC), and delayed its absorption when administered at the same time (significant increase in t max ).

Background: Metformin hydrochloride (MtHCL) is an oral antidiabetic drug and has many other therapeutic benefits. It has poor bioavailability, narrow absorption window and extensive liver metabolism. Moreover, children and elders face difficulty to swallow the commercial oral tablets., Objectives: Preparation, in vitro/in vivo evaluation of MtHCL suppositories for rectal administration to solve some of these problems., Methods: Suppository fatty bases (Witepsol ® , Suppocire ® and Massa ® ; different grades) and PEG bases 1000, 4000 and 6000 (different ratios), were used to prepare rectal suppository formulations each containing 500 mg drug. These were characterized for manufacturing defects, and pharmacotechnical performance and formulations showing superior results were subjected to bioavailability testing in human volunteers compared with the commercial oral tablet (Ref) applying LC-MS/MS developed analytical technique., Results: The preparation method produced suppositories with satisfactory characteristics and free of manufacturing defects. The fatty bases were superior compared with PEG bases regarding the physical characteristics. Three formulations were chosen for bioavailability testing and the results showed comparable bioavailability compared to the Ref., Conclusions: The fatty bases showed superior characteristics compared with the PEG bases. MtHCL formulated in selected fatty bases could be a potential alternative to the commercial oral tablets particularly for pediatric and geriatric patients.

Metformin is widely used for the treatment of type II diabetes mellitus. It was reported to be substrate of OCT3/Oct3, which is expressed in the brush boarder membrane of the enterocytes. However, the role of OCT3/Oct3 in the intestinal absorption process of metformin remains obscure. In the present study, we aimed to clarify the impact of Oct3 on the oral bioavailability and pharmacokinetics of metformin in mice, by means of in vivo pharmacokinetic study using wild-type (Oct3 +/+ ) and Oct3-knockout (Oct3 -/- ) mice. When metformin (8.0 mg/kg) was intravenously administered to male Oct3 +/+ and Oct3 -/- mice, AUC 0-∞ of metformin was evaluated to be 659 ± 133 μg h/mL and 734 ± 213 μg h/mL, respectively. In the case of orally administered metformin (15 mg/kg), AUC 0-∞ was 578 ± 158 μg h/mL and 449 ± 101 μg h/mL in Oct3 +/+ and Oct3 -/- mice, respectively. Based on these pharmacokinetic parameters, absolute bioavailability (F) of metformin in Oct3 +/+ mice was evaluated as 46.8%, and it was significantly decreased to 32.6% in Oct3 -/- mice. Taking into account the fact that metformin undergoes negligible metabolism, these results imply that intestinal absorption of metformin is mediated at least in part by Oct3 in mice., (Copyright © 2016 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Metformin is the basic drug of antihyperglycemic therapy in type 2 diabetes: according to actual therapeutic guidelines, it should be given in the absence of contraindications or intolerance during the whole course of the disease even after the initiation of insulin therapy. Recently more and more details have been explored regarding the molecular background of its effects, however, in parallel with the enormous growing knowledge, the number of questions still waiting to be answered has also grown. This review article deals with data already crystallized as well as with details not definitely cleared up. Genetic polymorphisms as well as potential drug interactions influencing the effects of metformin are also briefly summarized.

Aim: To report the results of two phase III trials assessing the efficacy of ranolazine for glycaemic control in patients with type 2 diabetes on metformin or glimepiride background therapy., Methods: In two double-blind trials we randomized 431 and 442 patients with type 2 diabetes to ranolazine 1000 mg twice daily versus placebo added to either glimepiride (glimepiride add-on study) or metformin background therapy (metformin add-on study). Patients receiving ranolazine added to metformin had their metformin dose halved (with the addition of a metformin-matched placebo) relative to the placebo group to correct for a metformin-ranolazine pharmacokinetic interaction. The primary endpoint of the trials was the change from baseline in glycated haemoglobin (HbA1c) at week 24., Results: When added to glimepiride, ranolazine caused a 0.51% least squares mean [95% confidence interval (CI) 0.71, 0.32] decrease from baseline in HbA1c at 24 weeks relative to placebo and roughly doubled the proportion of patients achieving an HbA1c of <7% (27.1 vs 14.1%; p = 0.001). When added to metformin background therapy, there was no significant difference in the 24-week HbA1c change from baseline [placebo-corrected LS mean difference -0.11% (95% CI -0.31, 0.1)]., Conclusions: Compared with placebo, addition of ranolazine in patients with type 2 diabetes treated with glimepiride, but not metformin, significantly reduced HbA1c over 24 weeks. The decreased dose of metformin used in the metformin add-on study complicates the interpretation of this trial. Whether an effective regimen of ranolazine added to metformin for glycaemic control can be identified remains unclear., (© 2016 John Wiley & Sons Ltd.)

Metformin is the first choice among drugs used for the treatment of type II diabetes mellitus mainly because of several advantages: proven hypoglycemic effect, good safety profile, virtually no risk of hypoglycemia, body weight reduction, lipid-lowering effect, efficacy in preventing micro- and macrovascular complications as well as adverse cardiac and cerebrovascular events and reduced cost. Previous reports had shown an increased risk of lactic acidosis in patients receiving metformin. However, the current Guidelines have greatly limited this risk to certain categories of patients, such as those with severe chronic renal failure, particularly when predisposing risk factors such as administration of iodinated contrast are present. In this review, we reported the main data of the literature on the use of metformin in patients with chronic renal failure and both highly expected benefits and high potential risks.