Fixed-dose Combination Of Metformin Research Articles

Pharmacokinetic Profile and Comparative Bioavailability of an Oral Fixed-Dose Combination of Metformin and Acetylsalicylic Acid (Aspirin).

Patients with diabetes face a 2-4-fold greater cardiovascular risk compared to those without diabetes. Both metformin and acetylsalicylic acid (aspirin) treatment have demonstrated a significant reduction in this risk. This single-center, open-label, sequence randomized, 2×2 crossover, single-dose clinical trial evaluated the pharmacokinetics profile and comparative bioavailability of a novel oral fixed-dose combination (FDC) of metformin/acetylsalicylic acid (500/100mg tablet) versus the reference mono-drugs administered concomitantly, metformin 500mg tablet and acetylsalicylic acid 100mg tablet, in 22 healthy Mexican adult volunteers under fasting conditions. Blood samples were collected predose and at specified intervals across a 24-hour period following administration and were analyzed for metformin and salicylic acid using high-performance liquid chromatography coupled with tandem mass spectrometry. Test products were considered to have comparative bioavailability if confidence intervals of natural log-transformed (maximum plasma drug concentration (Cmax), (area under the plasma drug concentration-time curve form 0 up to last sampling time (AUC0 -t), and (area under the plasma drug concentration-time cruve from 0 up to infinity (AUC0 ∞) data were within the range of 80%-125%. The results obtained from the present clinical study demonstrate the comparative bioavailability of the FDC when compared with the coadministration of reference mono-drugs. There were no adverse events or adverse reactions reported throughout the study.

Fixed-Dose Combination of Canagliflozin and Metformin as an Adjunct to Diet and Exercise in Indian Adults with Type 2 Diabetes Mellitus: Results from a Multicentric, Open-Label, Single-Arm, Phase IV Study.

Canagliflozin and metformin fixed-dose combination (CANA/MET FDC), an approved treatment for type 2 diabetes mellitus (T2DM) in India, effectively lowers glycated hemoglobin (HbA1c), promotes weight loss, and improves patient adherence. As a regulatory requirement, we aimed to evaluate the safety and efficacy of CANA/MET FDC in Indian patients with T2DM. This prospective, multicenter, open-label, single-arm, phase IV study included Indian patients with T2DM (aged 18-65 years) inadequately controlled on diet and exercise. Patients received CANA/MET (50/500 and 50/1000 mg) immediate-release (IR) FDC twice daily for 24 weeks. The primary endpoint was safety assessment, including adverse events (AEs) and serious AEs (SAEs). The secondary endpoint included a change in HbA1c from baseline to weeks 12 and 24. Descriptive statistics were used for all continuous safety variables and efficacy parameters. Of the 310 patients screened, 276 were enrolled. 114/274 (41.6%) patients had ≥1 treatment-emergent AE [treatment-emergent AEs (TEAEs), among which 29 (10.6%) were related to study intervention]. The most common TEAEs were dyslipidemia (4.7%), pyrexia (4.7%), genital infections (3.3%), hypoglycemia (3.3%), and urinary tract infections (2.6%). Three (1.1%) patients had serious TEAEs, and all cases were resolved. No deaths were reported. The mean change in HbA1c from baseline was -0.92 and -0.93% at weeks 12 and 24, respectively. The study demonstrates the safety and efficacy of CANA/MET FDC in Indian patients with T2DM, presenting a safe therapeutic option for diabetes management in India.

Physicians Perspectives on the Preference of Antihyperglycemics for the Management of Diabetes Mellitus in India

As they were commonly prescribed together for blood glucose control, metformin and more recent sulfonylureas, such as glimepiride, have been shown in numerous clinical studies to effectively reverse insulin resistance and promote insulin secretion. In India, primary care physicians and specialists used the fixed-dose combination of metformin and glimepiride in various doses. The results of clinical trials needed to be applied to regular clinical practice in the real world in order to close the knowledge gap. Regarding this, professional opinions will provide insightful information about the use of antihyperglycemics and their combinations, including their safety, effectiveness, and usefulness for a particular subgroup of patients with diabetes. So, a cross-sectional study was conducted on the prescription pattern of oral anti-diabetic drugs for patients with diabetes mellitus. The choice of oral anti-diabetic agents for diabetic patients with comorbidities was analysed by using 26 questions. About 845 physicians participated in the survey by sharing their opinions/views on the questionnaire. Also, 400 physicians out of 845 prefers glimepiride and metformin as the preferred combination to achieve the targeted glycated haemoglobin level. Moreover, 723 physicians out of 845 experienced glycated haemoglobin reduction with glimepiride and metformin for more than 3 years. Maximum glycated haemoglobin reduction with glimepiride and metformin was 1.5%-2% by 383 physicians as per the survey. They also experienced good glycaemic control and good cardiovascular safety with glimepiride and metformin. Thus, the experts recommended glimepiride and metformin very often in elderly individuals. Glycated haemoglobin reduction was more than 3 years with glimepiride and metformin, as per the clinical experience of the experts participated in the survey. They also witnessed good glycaemic control and cardiovascular safety profile with glimepiride and metformin combination.

Expert opinion on glimepiride, pioglitazone, and metformin fixed-dose combination in Type 2 Diabetes Mellitus patients: The results of One Pride study

Expert opinion on glimepiride, pioglitazone, and metformin fixed-dose combination in Type 2 Diabetes Mellitus patients: The results of One Pride study

ADMIRE Study: Dapagliflozin and Metformin Fixed-dose Combination as Initial Choice of Therapy in Type 2 Diabetes Mellitus: A Real-world Study

Abstract Introduction: The use of sodium-glucose cotransporter 2 inhibitors with metformin has become one of the preferred therapies for the management of Type 2 diabetes mellitus (T2DM). In this study, we assessed prescribing patterns in T2DM patients who were initiated dapagliflozin and metformin (Dapa-Met) as initial choice fixed dose combination (FDC). We assessed the indications for choosing Dapa-Met FDC and changes in cardiometabolic parameters. Methods: In this retrospective analysis, we included T2DM patients with hemoglobin A1C (HbA1C) >7% who were initiated with Dapa-Met FDC as initial treatment. Data HbA1C, fasting plasma glucose (FPG), postprandial plasma glucose (PPG), weight, systolic blood pressure (BP), and diastolic BP were recorded after 6 months of Dapa-Met FDC. Results: In total, data from 485 T2DM patients (mean age: 59.7 ± 9.8 years) were included. The mean duration of diabetes was 6.9 ± 4.7 years. For Dapa-Met FDC, 10 mg and 500 mg were the most preferred strengths. Nearly, 78% of patients required additional antidiabetic drug. Sulphonylureas (50.7%) and dipeptidyl peptidase 4-inhibitors (36.7%) were the most common co-prescribed drugs. Besides glycemia control, Dapa-Met FDC was preferred for weight loss (77.1%) and reducing cardiovascular events and related hospitalizations (46.8%). After 6 months, changes in HbA1C (D - 2.19%, P < 0.0001), FPG (D - 21.4 mg/dL, P < 0.0001), and PPG (D - 37.1 mg/dL, P < 0.0001) were significant. Hypoglycemic events (16.7%) and genitourinary infections (8.9%) were the common adverse events. Conclusion: Dapa-Met (10/500 mg) as FDC is effective and safe in Indian patients with T2DM when used as an initial choice treatment for T2DM. Additional antidiabetic therapies may be necessary to achieve glycemic targets.

FRI649 ADMIRE: Assessing Dapagliflozin And Metformin As An Initial Regimen In Diabetes Mellitus For Enhanced Glucose Control

Abstract Disclosure: D. Phadke: None. D. Gopal: None. D. Biswas: None. D. Birla: None. A. Prasad: None. P. Joshi: None. Introduction: Early aggressive glucose lowering in type 2 diabetes mellitus (T2DM) has shown improved outcomes, and combination oral antidiabetic agents (OAAs) on top of lifestyle therapy are necessary. In India, most T2DM patients receive combination therapy with two or more OAAs to achieve glycemic targets more rapidly. The fixed dose combination (FDC) of dapagliflozin and metformin is widely used in India, as it improves glycemia, reduces weight and blood pressure (BP), and has good tolerability. This study aimed to evaluate physician practices, efficacy, and tolerability of dapagliflozin and metformin FDC as initial therapy for T2DM patients in a real-world setting. Methods: This multicenter, retrospective, observational study enrolled 481 T2DM patients across 49 clinical units for a period of 6 months. The study aimed to evaluate physician practices, efficacy, and tolerability of dapagliflozin and metformin FDC as the initial choice FDC in T2DM. The study was conducted in compliance with the principles of the Declaration of Helsinki, good clinical practice, and regulatory guidelines. Ethical approval for the study was obtained on August 6, 2022, and the study was conducted from August 15, 2022, to January 20, 2023. Results: The study demonstrated that dapagliflozin and metformin FDC significantly reduced weight by 4.2 kg (p < 0.0001), fasting plasma glucose by 21.4 mg/dL (p < 0.0001), and improved estimated glomerular filtration rate (eGFR) by 1.9 m²/1.73 ml/min (p < 0.0001). Additionally, systolic BP was reduced by 10.7 mmHg (p < 0.0001), and diastolic BP was reduced by 6.6 mmHg (p < 0.0001), which is in combination with the concomitant medications. Incidence of genito-urinary tract infection was 8.9%. Conclusion: In a real-world setting, dapagliflozin and metformin FDC can be used as initial therapy for T2DM with good efficacy, tolerability, and safety. Physicians preferred this combination due to its ability to promote weight loss, reduce cardiovascular events, and decline in renal function. The excellent safety and efficacy reported by physicians for this FDC of dapagliflozin and metformin has contributed to improved compliance with the treatment. Thus, in the Indian population, dapagliflozin and metformin FDC is effective, safe, and has good tolerability as an initial therapy for T2DM. Presentation: Friday, June 16, 2023

Low-Dose Glimepiride and Metformin Fixed-Dose Combination in treating Maturity-Onset Diabetes of the Young Type (MODY): A Cross Sectional Survey

Low-Dose Glimepiride and Metformin Fixed-Dose Combination in treating Maturity-Onset Diabetes of the Young Type (MODY): A Cross Sectional Survey

Pharmacokinetic Variables of Dapagliflozin/Metformin Extended-release Fixed-dose Combination in Healthy Chinese Volunteers and Regional Comparison

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. 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. 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. 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. gov identifier: NCT04856007.

Bioequivalence Evaluation in Healthy Volunteers: New Generic Formulations of Sitagliptin and Sitagliptin-Metformin Fixed-Dose Combination Compared with the Originator Products.

Three studies compared the bioequivalence (BE) of new generic tablet formulations of sitagliptin (100mg; fasting) and the fixed-dose combination (FDC) of sitagliptin/metformin (50/850mg, 50/1000mg; both fed) in healthy volunteers with the same tablet strengths of the reference products Januvia and Janumet. The study design was open-label, single-dose, randomized with two-way crossover periods. Blood sampling was performed for 72/48h in the sitagliptin/FDC studies, respectively. Primary pharmacokinetic (PK) parameters for sitagliptin and metformin were area under the plasma concentration-time curve from time 0 to last timepoint of measurable concentration (AUC0-t) and maximum plasma concentration (Cmax). Test (T) and reference (R) formulations proved bioequivalent if 90% confidence interval (CI) of geometric least-squares mean ratio for AUC0-t and Cmax were within BE acceptance range of 80.00-125.00%. Safety evaluations included vital signs, clinical laboratory tests, and adverse events (AEs). Treated/evaluable volunteers for BE per study were: 30/28 (sitagliptin 100mg), 26/25 (FDC 50/850mg), and 26/24 (FDC 50/1000mg). The 90% CI of the geometric means of T/R ratios for primary PK parameters were within predefined BE limits: CI for AUC0-t and Cmax were 95.83-100.37% and 91.85-109.56% (sitagliptin 100mg); 100.84-103.69% and 93.44-105.10% (FDC 50/850mg), and 101.26-105.20% and 98.71-112.89% (FDC 50/1000mg); respective values for metformin were 94.23-101.89% and 91.66-99.38% (FDC 50/850mg) and 98.45-104.89% and 96.79-105.62% (FDC 50/1000mg). All AEs were nonserious, transient, and mostly mild. Safety evaluations did not reveal any relevant difference between T and R formulations. The new generic tablet formulations of sitagliptin 100mg and the FDCs sitagliptin/metformin 50/850mg and 50/1000mg demonstrated bioequivalence to originator reference products. Therefore, the new products are expected to provide efficacy and tolerability similar to those of the reference products in the treatment of patients with type 2 diabetes (T2D). EudraCT EU Clinical Trials Registry (2014-005437-31); ClinicalTrials.gov Registry (NCT05549570 and NCT05549583, both retrospectively registered on 20 September 2022).

EVALUATION OF WEIGHT REDUCTION EFFICACY AND SAFETY OF SIBUTRAMIN-CONTAINING DRUGS IN PATIENTS WITH ALIMENTARY OBESITY

The article presents clinical study results of the efficacy and safety of combination therapy with sibutramine and metformin (fixed combination) in comparison with sibutramine therapy with microcrystalline cellulose in patients with alimentary obesity.The aim is to evaluate the efficacy and safety of using the sibutramine+metformin fixed dose combination (Reduxin® Forte) and compare it with the sibutramine + microcrystalline cellulose combination (Reduxin®) in patients with alimentary obesity in the course of the obesity therapy.Materials and methods. Male and female patients (240 people) aged 18 to 65 years inclusive with alimentary obesity, meeting the inclusion criteria and not meeting the non-inclusion criteria, were randomized into 2 groups in a 1:1 ratio. One group (n=120) received sibutramine+ metformin p. o., 1 tablet (850 mg + 10 mg) once per day, the second group (n=120) received sibutramine+ microcrystalline cellulose (MCC) p. o., 1 capsule (10 mg + 158.5 mg) once per day in the morning. On day 30 ± 1, in the absence of a 2 kg weight loss compared to the first visit, the dose was increased in accordance with the medical instruction. The therapy period was 180 days. The randomization list was generated by the factory method of random numbers. The efficacy and safety were assessed by anthropometric, clinical and laboratory parameters and the SF-36 questionnaire. The proportion of patients who achieved a decrease in body weight by more than 5% in 6 months, the magnitude and dynamics of changes in body weight and body mass index, waist and hip measurements, their ratios, changes in lipid profile, blood pressure, as well as the total number of adverse events, their frequency and nature of occurrence were analyzed.Results. The both drugs have demonstrated efficacy in all parameters of the obesity therapy. At the same time, in a comparative analysis, a statistically significant advantage of therapy with sibutramine + metformin was demonstrated in relation to the proportion of patients who had achieved more than 5% weight loss (body weight dynamics). Significant benefits were shown in terms of the magnitude of the change in body mass index (BMI); there was a statistically significant increase in the proportion of the patients who had switched from one category of BMI to another. By the end of the study, the vast majority of patients had no longer met the criteria for the diagnosis of “Obesity”. There was also a statistically significant benefit of sibutramine + metformin in terms of lowering triglycerides and low-density lipoprotein levels. The analysis of the safety parameters of sibutramine + metformin confirms a high safety profile of the drug, a comparative statistical analysis of adverse events in terms of their presence, severity, causal relationship with therapy and outcome have not revealed intergroup differences. Adverse events were transient and did not require discontinuation of therapy.Conclusion. The results of the study showed that therapy with Reduxin® and Reduxin® Forte provides a pronounced decrease in body weight. However, the use of a fixed combination has a more effective positive effect on the lipid profile and patients’ quality of life, which, combined with a high safety profile, proves the possibility and expediency of using Reduxin® Forte for the treatment of obesity and restoring metabolic health, even in patients without additional carbohydrate metabolism disorders.

Principal Component Analysis and DoE-Based AQbD Approach to Multipurpose HPTLC Method for Synchronous Estimation of Multiple FDCs of Metformin HCl, Repaglinide, Glibenclamide and Pioglitazone HCl.

Metformin HCl (MET) is a mostly used antidiabetic drug and several fixed-dose combinations are available in the market with other antidiabetic drugs for the treatment of insulin-independent diabetes. Numerous chromatographic methods have been reported for the estimation of multiple fixed dose combination (FDC) of MET but each FDC needs a separate and dedicated chromatographic method for analysis. No chromatographic method has been reported yet in the literature which promotes synchronous estimation of multiple FDCs of MET to minimize organic solvent consumption, time and cost of analysis. Hence, the multipurpose-high performance thin layer chromatography (HPTLC) method was developed for the synchronous estimation of FDCs of MET by the implementation of an enhanced analytical quality by design approach. Principal component analysis was applied for the identification of critical method risk parameters. Box-Behnken design was applied for response surface analysis. The method operable design ranges was navigated and the control strategy was framed. The developed method was applied for the analysis of multiple FDCs of metformin. The developed method can synchronously analyze multiple FDCs of MET which required several chromatographic methods. Hence, the present method is multipurpose-HPTLC for the synchronous estimation of multiple FDCs of MET which required minimum organic solvent, time and cost of analysis.

Clinical Utility of Glimepiride and Metformin Fixed-Dose Combination in Obese/Overweight Patients with Type 2 Diabetes Mellitus in Indian Settings

Clinical Utility of Glimepiride and Metformin Fixed-Dose Combination in Obese/Overweight Patients with Type 2 Diabetes Mellitus in Indian Settings

Design of Experiments for Critical Material Attributes Assessment of Linagliptin and Metformin Fixed-dose Combination Tablets

Abstract: Aim of work: This study aimed to determine the amount of excipients in the critical material attributes of linagliptin and metformin sustained release (SR) fixed-dose combination (FDC) tablets using design of experiments (DoE). Methods: A 23 full factorial design with three center points was performed. For the screening of excipients, 3-factor responses (mannitol, sodium starch glycolate and pregelatinized starch for linagliptin; hydroxypropyl methylcellulose, sodium carboxymethyl cellulose (CMC) and hydroxypropyl cellulose for metformin), 2-levels and 1-center (n=3) point with three responses (friability, assay and dissolution) were applied to the DoE batch using Design-Expert. Results: Most excipients were an important factor in the friability, assay and dissolution results (P<0.05). In the screening of excipients, mannitol (40-60 mg) and pregelatinized starch (40-60 mg) with sodium starch glycolate (5 mg) for linagliptin and hydroxypropyl cellulose (15-23 mg) and CMC (40-55 mg) with hydroxypropyl methylcellulose (260 mg) for metformin were optimal. Conclusion: In summary, selection for the amount of excipients can be defined through levels of risk based on three responses. It can be concluded that the ranges of excipients leading to high quality (low friability and optimal ranges of assay and dissolution) for the screening of excipients were successfully observed by the DoE approach. Key words: Critical material attributes, Design of experiments, Linagliptin, Metformin, Quality by design.

Fixed Drug Eruption: A Rare Case of Polysensitivity between Two Unrelated Fixed Dose Combination Preparations - A Case Report

Background: A fixed drug eruption is a type IV hypersensitivity reaction to a medication that characteristically re-emerges on the same site each time the specific drug is taken. Antimicrobials (including fixed dose combinations) are frequently implicated in fixed drug eruption while gliptins (as separate drugs or as combined preparations) on the other hand are infrequent triggers. Drugs belonging to similar classification and having similar chemical structures can show cross reactivity, but here we describe a case of cross reactivity between unrelated drug classes, also known as polysensitivity.&#x0D; The Case: A 58-year-old man presented with painful, burning, and pruritic blisters with ulcerations on the oral mucosa of lips, hard palate, and tip of the tongue. The patient had been on vildagliptin - metformin fixed dose combination tablets for one year. He was asked to stop the drug and lesions started improving thereafter. A week later he suffered from gastroenteritis for which he took a combined preparation of ofloxacin and ornidazole and lesions re-appeared at the same site as before with severe itching and burning.&#x0D; Conclusion: This case highlights polysensitivity amongst chemically unrelated drugs, especially available in fixed-dose combination. It is an extremely rare occurrence (less than 0.2%). Moreover, there have only been a few cases of such delayed reactions occurring to gliptins, especially vildagliptin. A clinician must keep a high index of suspicion to identify this phenomenon.

Effect of Gliclazide or Gliclazide plus Metformin Combination on Glycemic Control in Patients with T2DM in India: A Real-World, Retrospective, Longitudinal, Observational Study from Electronic Medical Records.

BackgroundThe efficacy of gliclazide has been reported in clinical trials in India. However, real-world data on the effectiveness of gliclazide in India is unavailable.ObjectiveTo provide real-world evidence regarding the effectiveness of gliclazide or gliclazide + metformin fixed-dose combination or separate medications, used either as monotherapy or as the latest add-on to other antihyperglycemic agents in reducing glycated hemoglobin (HbA1c) levels in Indian patients with type 2 diabetes mellitus (T2DM).MethodsElectronic medical record data of adult patients who were diagnosed with T2DM who were newly initiated on or had been prescribed gliclazide or gliclazide + metformin combination for < 30 days as monotherapy or as add-on therapy to other antihyperglycemic agents, and had HbA1c ≥ 6.5% were retrospectively analyzed. Mean change in HbA1c from baseline was the primary endpoint. Secondary endpoints were assessment of dosages and formulations of gliclazide or gliclazide + metformin prescribed in the HbA1c spectrum and antihyperglycemic agents to which gliclazide or gliclazide + metformin was added as an adjunct. Readings were obtained before initiating gliclazide or gliclazide + metformin and after at least 90 days of treatment with gliclazide or gliclazide + metformin.ResultsIncluded patients (n = 498) were categorized into gliclazide only (n = 66), gliclazide + metformin only (n = 179), gliclazide add-on (n = 169), and gliclazide + metformin add-on (n = 84) groups. Mean (95% confidence interval [CI]) change in HbA1c among patients with baseline HbA1c > 7% was − 0.8% (− 1.26, − 0.34) in gliclazide only group; − 1.6% (− 1.89, − 1.31; p < 0.001) in gliclazide + metformin group; − 1.2% (− 1.50, − 0.90; p < 0.001) in add-on gliclazide group; and − 1.4% (− 1.75, − 1.05; p < 0.001) in add-on gliclazide + metformin group. Gliclazide once daily was the most prescribed regimen in the gliclazide only group (72.7%), with 60 mg being the most prescribed modified-release dose (62.5%). Gliclazide + metformin twice daily was the most prescribed regimen in the gliclazide + metformin group (69.3%) with 80 mg + 500 mg being the most prescribed immediate-release dose (62.9%). Gliclazide and gliclazide + metformin were most added as an adjunct to existing prescriptions of biguanides (83.4%) or insulin (64.3%), respectively.ConclusionGliclazide or gliclazide + metformin prescribed as mono- or add-on therapy during routine clinical practice effectively reduced HbA1c in Indian patients with T2DM, thus validating the use of gliclazide and gliclazide + metformin for managing T2DM in India.

Formulation and Optimization of Monolithic Fixed-Dose Combination of Metformin HCl and Glibenclamide Orodispersible Tablets.

The treatment of type II DM involves the use of combination of drugs, especially at the chronic stage. However, the pill burden of this combination therapy combined with swallowing difficulties, occurring at a later stage of DM, has been the major challenge for successful treatment outcomes. This study was aimed at formulating and optimizing a monolithic fixed-dose combination (FDC) of metformin (MET) and glibenclamide (GLB) orodispersible tablets (ODTs) to overcome both the pill burden and swallowing problems. The FDC ODTs were prepared by the melt granulation technique using polyethylene glycol (PEG) 6000 as a binding agent and crospovidone as a superdisintegrant. In the preliminary study, the effects of sodium lauryl sulphate (SLS), PEG 6000, crospovidone, and compression force on friability, disintegration time, and drug release of tablets were investigated. The FT-IR studies showed that there were no incompatibilities between MET and GLB as well as within excipients. The preliminary studies revealed that PEG 6000 and compression force significantly affect both the friability and the disintegration time, while SLS and crospovidone only affect the disintegration time. Therefore, the effects of PEG 6000, crospovidone, and compression force were further studied and optimized using the central composite design. Accordingly, the most desirable optimal values were obtained at 3.82% of PEG 6000, 9.83% of crospovidone, and 10.6 kN compression force having a friability of 0.302% and a disintegration time of 18.7 seconds. From these results, it can be concluded that a monolithic FDC of MET and GLB ODTs having adequate mechanical strength and faster disintegration time was successfully formulated.

Safety and Efficacy of Fixed Dose Combination of Glimepiride and Metformin in Type 2 Diabetic Patients in Egypt: A Real-Life Study

AbstractBackground: Previous reports showed a significant im-provement in the glycemic control of patients with Type 2 Diabetes Mellitus (T2DM) following the use of Glimepiride/ Metformin Fixed-Dose Combination (G/M FDC), with a reasonable safety profile. In this real-life study on Egyptian population, we aim to investigate the safety and effectiveness of G/M FDC among patients with T2DM.Subjects and Methods: The present observational, multi-center study included 1211 T2DM patients from Egypt, for whom the investigator decided to prescribe G/M FDC. Patients started G/M FDC at the beginning of the study or one month earlier, and the combination dose was decided by the investi-gators to reflect the in-practice approach. Data were recorded at the initial assessment visit and six months later. Safety outcomes were measured throughout the course of treatment.Results: At the end of six months follow-up duration, 45.2% of the patients achieved the targeted HbA1c £7% and 79.5% achieved the targeted reduction in HbA1c by ³0.7%. The total percentage of patients who achieved either the targeted HbA1c £7% or reduction in HbA1c ³0.7% were 86.5%, while those who achieved both target HbA1c £7% and reduction in HbA1c ³0.7% constituted 38.3% of the patients. The mean HbA1c level reduced throughout the study period from 8.8±1.3% to 7.3±0.9% at the end sixth month (p<0.001). Hyperglycemia was the most commonly reported adverse events (3.5%), followed by hypoglycemia (1.2%).Conclusion: The prescription of G/M FDC in treating patients with T2DM in Egypt is effective in achieving the targeted glycemic control with tolerable safety profile.

ADIPONEKTIN HIGH MOLECULAR WEIGHT DAN KEKAKUAN VASKULAR DI PENYAKIT DIABETES MELITUS TIPE 2 TERKAIT GABUNGAN GLIMEPIRIDE METFORMIN DOSIS TETAP

Diabetic patients have the tendency to develop micro vascular and macro vascular complications due to the hyperglycaemic state. Thereare various types of oral hypoglycaemic agents available in Indonesia, nevertheless, these agents fail to decrease mortality and morbiditydue to the endothelial dysfunction in diabetic patients. It is not yet known whether glimepiride metformin fixed dose combination isable to improve the serum High Molecular Weight (HMW) adiponectin and vascular stiffness which are important parameters of thecardiovascular risk factors. This study was to know the effect of glimepiride metformin fixed dose combination by investigation after 12weeks of treatment towards HMW adiponectin level and vascular stiffness using ba-PWV in type 2 diabetes. This research was carried outby a Quasi experimental study with pre and post test design. The subjects were type 2 diabetes patients who came to the EndocrinologyOutpatient Clinic at the Dr. Soetomo Hospital and 6 health centres in Surabaya during December 2010 to December 2011. In this study,measuring the HMW adiponectin level in plasma was by using ELISA method and the ba-PWV by using the V Serra-1000 before and aftertreatment with glimepiride metformin fixed dose for 12 weeks. Based on the thirty five type 2 diabetic patients who met the inclusion andexclusion criteria and who were enrolled in this study, after 12 weeks of treatment, the median HMW Adiponectin level was increasedfrom 1736 ng/mL to 1770 ng/mL, which was statistically not significant (p=0.317). After 12 weeks treatment, the median of ba-PWVwas decreased from 1580 cm/sec to 1450 cm/sec, which was statistically significant (p=0.028). The level of HMW adiponectin was notsignifantly different between before and after treatment. The level of brachial ankle Pulse Wave Velocety (ba-PWV) was significantlydifferent between before and after treatment. Glimepiride metformin fixed dose combination decreases the vascular stiffness, which isone of the parameters of the endothelial dysfunction.

Population pharmacokinetic analysis of metformin administered as fixed-dose combination in Korean healthy adults.

Metformin, an oral antihyperglycemic agent, is widely used as the first-line pharmacotherapy for type 2 diabetes mellitus (T2DM). It has been in use for several decades as numerous different formulations. However, despite its use, population pharmacokinetic (PK) modeling of metformin is not well developed. The aim of the present study was to evaluate the effect of formulation on PK parameters by developing a population PK model of metformin in Koreans and using this model to assess bioequivalence. We used a comparative PK study of a single agent and a fixed-dose combination of metformin in 36 healthy volunteers. The population PK model of metformin was developed using NONMEM (version 7.3). Visual predictive checks and bootstrap methods were performed to determine the adequacy of the model. The plasma concentration-time profile was best described by a two-compartment, first-order elimination model with first-order absorption followed by zeroorder absorption with lag time. From the covariate analysis, formulation had significant effect (p < 0.01) on relative bioavailability (F = 0.94) and first-order absorption constant (Ka = 0.83), but the difference was within the range of bioequivalence criteria. No other covariate was shown to have significant effect on PK parameters. The PK profile of the disposition phase was consistent with the published literature. However, in the present study, the multiple peaks found during the absorption phase implied the possible diversity of absorption PK profile depending on formulation or population. Unlike traditional bioequivalence analysis, the population PK model reflects formulation differences on specific parameters and reflected simulation can be performed.

A study on drug utilization pattern of metformin and its different formulations used in patients with type-2 diabetes mellitus in tertiary care teaching hospital

Background: Drug utilization evaluation is conducted to determine the rational use of drug by describing the drug usage pattern. This study aimed to describe the drug utilization pattern of metformin and its oral formulations. Objectives: The objectives of the study were to identify the prescribing pattern of metformin in fixed-dose combination (FDC), along with adjuvant antidiabetic therapy and it is prescribing in different formulations. Methodology: This is an observational study in which a total of 100 type 2 diabetic patients visited to or admitted in General Medicine Department, Dhiraj General Hospital , Piparia, Vadodara, were included as per our inclusion criteria. Result: Among 100 type 2 diabetic patients, 15 patients received monotherapy and 85 patients received combinational therapy of metformin. Out of 120 FDCs of metformin prescribed in 100 patients, plain (conventional release) formulations were most commonly prescribed (39.17%). Among FDC therapy of metformin, glimepiride + metformin, and glimepiride + pioglitazone + metformin combinations were most commonly found. As an adjuvant therapy with metformin, human analog insulin was most commonly prescribed. The sulfonylureas (SUs) were found to be the most commonly prescribed oral antidiabetic drug class along with metformin (SUs). In this study, we found 49% of the patients receiving metformin with low medication adherence. Conclusion: The practice of metformin monotherapy is limited and it is frequently prescribed in combinations with other antidiabetic agents. We observed an almost equal utilization of different oral formulations of metformin. A low medication adherence with metformin emphasizes the need for appropriate patient counseling and therapeutic interventions.