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    Rosiglitazone/Metformin. Wellington Keri Drugs The thiazolidinedione rosiglitazone and the biguanide metformin are effective antihyperglycaemic agents with different modes of action; rosiglitazone primarily increases insulin sensitivity, whereas metformin primarily reduces hepatic glucose output. Antihyperglycaemic combination therapy is often required to achieve effective glycaemic control. A fixed-dose formulation of rosiglitazone/metformin was recently approved in the EU and the US for the treatment of type 2 diabetes mellitus in patients inadequately controlled on metformin monotherapy. Bioequivalence between the fixed-dose combination tablet and coadministration of rosiglitazone with metformin at the same dosage has been established in a pharmacokinetic study. Fixed-dose rosiglitazone/metformin 8 mg/2g per day reduced glycosylated haemoglobin (HbA1c) and fasting plasma glucose (FPG) levels to a significantly greater extent than metformin 3 g/day in patients with type 2 diabetes in a 24-week, randomised, double-blind study. Rosiglitazone plus metformin was significantly more effective than metformin alone at reducing HbA1c and FPG levels in patients with type 2 diabetes in three 26-week, randomised, double-blind, placebo-controlled studies. Rosiglitazone plus metformin was generally well tolerated in all studies and had a tolerability profile similar to that of metformin monotherapy. Mild or moderate symptomatic hypoglycaemia was reported in <or=4.4% of rosiglitazone plus metformin recipients. 10.2165/00003495-200565110-00013
    Linagliptin plus metformin: a pharmacokinetic and pharmacodynamic evaluation. Scheen André J Expert opinion on drug metabolism & toxicology INTRODUCTION:The first-choice drug therapy in the management of type 2 diabetes is metformin . However, most patients require a combined therapy to reach and/or maintain targets of glucose control. Dipeptidyl peptidase-4 (DPP-4) inhibitors, commonly referred to as gliptins, offer new options for combined therapy with metformin. Linagliptin is the most recently launched gliptin, with a unique pharmacokinetic (PK) profile characterized by negligible renal excretion and is now also available as a fixed-dose combination (FDC) with metformin. AREAS COVERED:An extensive literature search was performed to analyze the potential PK and pharmacodynamic interactions between linagliptin and metformin. Linagliptin and metformin may be administered together, either separately or as FDC supported by bioequivalence studies. Linagliptin and metformin are not prone to PK drug-drug interactions. Their coadministration improves blood glucose control more potently than either compound separately, without hypoglycemia and without increasing metformin-related gastrointestinal side effects. EXPERT OPINION:The combination linaglitpin plus metformin, if not contraindicated (renal failure), may be used as first-line or second-line therapy in the management of type 2 diabetes. That being said, the durability of the glucose-lowering effect of this combination needs to be further explored in long-term controlled trials. 10.1517/17425255.2013.767892
    Long-term clinical outcomes of oral antidiabetic drugs as fixed-dose combinations: A nationwide retrospective cohort study. Diabetes, obesity & metabolism AIM:To compare treatment patterns and clinical outcomes of single-pill fixed-dose combination (FDC) and two-pill combination (TPC) therapies using real-world data. METHODS:We conducted a nationwide retrospective cohort study using South Korea's healthcare database (2002-2015). We identified two cohorts of incident patients with type 2 diabetes who initiated FDC or TPC therapy within 4 months of their first prescription for metformin or sulphonylurea. We examined persistence and adherence patterns and the clinical outcome of a composite endpoint of death or hospitalization for acute myocardial infarction, heart failure or stroke and compared the differences in treatment patterns and clinical outcomes using Cox models. RESULTS:Of 5143 and 10 973 patients who initiated FDC and TPC therapy, respectively, we identified 5143 patient pairs after propensity score matching. The FDC group exhibited greater median time to treatment discontinuation (163 vs. 146 days), and proportion of days covered at 12 months (mean 0.60 vs. 0.57, P < .0001) and at 24 months (0.53 vs. 0.51, P = .014) than the TPC group. The FDC group, compared with the TPC group, had reduced risks of the composite clinical outcome (hazard ratio 0.86, 95% confidence intervals 0.77-0.97) and hospitalization for stroke (0.80, 0.67-0.96). CONCLUSION:FDC therapy may provide favourable cardiovascular benefits, especially reducing the risk of hospitalization for stroke, and has better medication adherence among patients with type 2 diabetes. 10.1111/dom.14792
    Impact of fixed-dose combination drugs on adherence to prescription medications. Pan Feng,Chernew Michael E,Fendrick A Mark Journal of general internal medicine BACKGROUND:The inverse correlation between the complexity of a drug regimen and medication adherence is well established. Fixed-dose combination (FDC) therapies are hypothesized to enhance compliance by decreasing the number of required pills. OBJECTIVE:The objective of the study is to compare adherence of a FDC [Glucovance, a FDC of metformin and glyburide] to a 2-pill regimen. DESIGN:Longitudinal data from a large claims database were used to assess adherence from January 1, 2000, to December 31, 2001. Propensity scoring methods were used to mitigate concerns related to non-random assignment of patients to treatments. SUBJECTS:The subjects of the study were individuals prescribed metformin or sulfonylurea or both before July 2000, who were prescribed both metformin and sulfonylurea concurrently (either separately or FDC) after August 2000. MEASUREMENTS:Adherence was measured by medication possession ratio; the proportion of days on which a patient had medication available. RESULTS:The FDC enhanced adherence rates by approximately 13% when compared to a 2-pill regimen. CONCLUSIONS:Compared to 2-pill therapy, a FDC resulted in important increases in patient adherence. Economic analyses are warranted to determine whether the clinical benefits attributable to the adherence gains are worth the incremental cost of a FDC. 10.1007/s11606-008-0544-x
    New fixed dose chemical combinations: the way forward for better diabetes type II management? Abdulsalim Suhaj,Peringadi Vayalil Munawar,Miraj Sonal Sekhar Expert opinion on pharmacotherapy INTRODUCTION:Diabetes type II is a complex disease with unclear pathophysiology. Lack of adherence and high cost of medicines invariably make the management of diabetes type II highly challenging. Newer fixed drug combinations (FDC) are cost effective and can improve the medication adherence thereby prevent the complications of diabetes. Safety and efficacy of newer FDCs are not well established in all populations. Moreover, extrapolating the efficacy and safety data globally may not be pragmatic. Our review will discuss newer chemical combinations available for the treatment of diabetes type II. Areas covered: In the present review, the authors discussed the newer FDCs available as add on therapy to the existing pharmacological interventions of diabetes type II that have shown promising results in various randomised trials with regard to efficacy and safety. Expert opinion: Safety and efficacy data of newer FDCs available as an adjuvant therapy to conventional pharmacological interventions in diabetes type II revealed that fewer new FDCs are promising with their high efficacy and low adverse effect. However, there is a need to explore the place in therapy to establish the utility of FDC in diabetes type II management. 10.1080/14656566.2016.1241235
    Pattern of Disease and Therapy for Diabetes along with Impact of Generic Prescribing on Cost of Treatment among Outpatients at a Tertiary Care Facility. Journal of pharmacy & bioallied sciences BACKGROUND:India has become the diabetes capital of the world. Analyzing trends in drug prescribing helps in judging rationality of prescriptions in different settings. This study aimed to assess disease and prescribing trends with a special emphasis on evaluating use of metformin, insulin, fixed dose combinations (FDCs), concomitant medications, pill burden, and costs of drug therapy in diabetes. MATERIALS AND METHODS:This was a cross-sectional study in which patients of either sex who attended the diabetes clinic at a tertiary care center over 9 months were included consecutively. Basic demographic profile, clinical, and treatment details on the day of visit were collected from the prescription charts. Drug costs for prescriptions were calculated using generic and median brand prices of formulations using a recognized commercial drug directory and generic price list of the government, respectively. Data were analyzed by using Microsoft Excel and Open Epi online software to compare results with published studies. RESULTS:Average age of diabetics was 53.9 ± 11.8 years and disease duration was 8.13 ± 7.78 years in 336 prescriptions analyzed. Dual drug regimens were seen in 32.7% prescriptions, most commonly metformin and sulfonylureas, followed by triple drug regimens (25%) with inhibition of dipeptidyl peptidase IV (DPP IV) inhibitor. Metformin was prescribed in 95% prescriptions (mean dose 1511 ± 559.87 mg) and insulin in 22.6% prescriptions. Angiotensin receptor blocker (ARBs) and statins were the most commonly prescribed concomitant drugs. One FDC per prescription (median) each for diabetes and comorbidities were prescribed. Daily pill burden was 4.59 ± 2.65 pills. The median monthly cost of drug therapy with branded prescribing was INR 870.43 and INR 393.72 with the use of generics. Inferences drawn by comparison with published data showed variable results for different parameters analyzed. CONCLUSION:Disease pattern was as expected for the region and trends of therapy showed concurrence with rational prescribing. Pill burden and cost of therapy remain high with a significant contribution of comorbidities. 10.4103/jpbs.JPBS_405_20
    Combine and conquer: advantages and disadvantages of fixed-dose combination therapy. Bell D S H Diabetes, obesity & metabolism The majority of patients with type 2 diabetes mellitus (T2DM) do not achieve the glycaemic goals recommended by leading diabetes organizations using monotherapy alone, and often require multiple antihyperglycaemic agents to achieve glycaemic control. Fixed-dose combination (FDC) therapies offer a means to simplify complex treatment regimens, and have several advantages that help patients reach their glycaemic goals. In this review, four key benefits are identified and discussed in support of FDCs for treatment of patients with T2DM: (i) Greater efficacy compared with higher dose monotherapy, (ii) Reduced risk of adverse reactions relative to higher dose monotherapy, (iii) Lower overall costs and (iv) Improved medication concordance. Given these advantages, the place of fixed combination therapy in the course of treatment is discussed. Establishing a therapeutic strategy that incorporates fixed combination therapy (including combinations with insulin) will simplify the treatment of diabetes, ideally resulting in improved medication concordance, clinical outcomes and quality of life for patients with T2DM. 10.1111/dom.12015
    [Fixed-dose combination]. Nagai Yoshio Nihon rinsho. Japanese journal of clinical medicine Many patients with type 2 diabetes mellitus(T2DM) do not achieve satisfactory glycemic control by monotherapy alone, and often require multiple oral hypoglycemic agents (OHAs). Combining OHAs with complementary mechanisms of action is fundamental to the management of T2DM. Fixed-dose combination therapy(FDC) offers a method of simplifying complex regimens. Efficacy and tolerability appear to be similar between FDC and treatment with individual agents. In addition, FDC can enhance adherence and improved adherence may result in improved glycemic control. Four FDC agents are available in Japan: pioglitazone-glimepiride, pioglitazone-metformin, pioglitazone-alogliptin, and voglibose-mitiglinide. In this review, the advantages and disadvantages of these four combinations are identified and discussed.
    Bioequivalence, Food Effect, and Steady-State Assessment of Dapagliflozin/Metformin Extended-release Fixed-dose Combination Tablets Relative to Single-component Dapagliflozin and Metformin Extended-release Tablets in Healthy Subjects. Chang Ming,Liu Xiaoni,Cui Dapeng,Liang Dan,LaCreta Frank,Griffen Steven C,Lubin Susan,Quamina-Edghill Donette,Boulton David W Clinical therapeutics PURPOSE:Simplification of therapeutic regimens for patients with type 2 diabetes mellitus can provide convenience that leads to improved compliance. Dapagliflozin/metformin extended-release (XR) fixed-dose combination (FDC) tablets offer the convenience of once-daily dosing. Two pharmacokinetic (PK) studies were conducted to establish bioequivalence for 2 doses of dapagliflozin/metformin XR FDC versus the same dosage of the individual component (IC) tablets in healthy adults. METHODS:Two open-label, randomized, 4-period, 4-arm crossover studies were conducted to assess the bioequivalence and PK properties of dapagliflozin and metformin FDCs in healthy subjects under fed and fasting conditions. Participants received single oral doses or once-daily dosing of dapagliflozin/metformin XR (5 mg/500 mg [study 1] or 10 mg/1000 mg [study 2]) for 4 days in an FDC formulation or corresponding strengths of IC tablets. FINDINGS:For both of the studies, dapagliflozin and metformin 5 mg/500 mg or 10 mg/1000 mg FDC tablets were bioequivalent to the respective IC tablets. The 90% CIs of the ratio of the adjusted geometric means for all key PK parameters (Cmax, AUC0-T, and AUC0-∞) were contained within the predefined 0.80 to 1.25 range to conclude bioequivalence for both dapagliflozin and metformin. Once-daily dosing to steady state of each FDC tablet had no effect on the PK properties of dapagliflozin or metformin. When the FDCs were administered with a light-fat meal, there was no effect on metformin PK values and only a modest, nonclinically meaningful effect on dapagliflozin PK values. There were no safety or tolerability concerns. IMPLICATIONS:Bioequivalence of the FDCs of dapagliflozin/metformin XR and the ICs was established, and no safety issues of clinical concern were raised. 10.1016/j.clinthera.2015.05.004
    Efficacy and safety of pioglitazone/metformin fixed-dose combination therapy compared with pioglitazone and metformin monotherapy in treating patients with T2DM. Perez Alfonso,Zhao Zhen,Jacks Randal,Spanheimer Robert Current medical research and opinion BACKGROUND:Studies have shown that many patients with type 2 diabetes do not achieve optimal glycemic control, and progression of diabetes over time requires more than one pharmacotherapy to achieve glycemic goal. OBJECTIVE:To examine the efficacy and safety of the fixed-dose combination (FDC) of pioglitazone 15 mg and metformin 850 mg versus its individual components in a twice-daily regimen over 24 weeks of treatment in type 2 diabetes patients who were currently not receiving antidiabetes therapy. METHODS:This was a double-blind, randomized, parallel-group, controlled study. The primary endpoint was change from baseline in hemoglobin A1c (HbA1c) of pioglitazone/metformin FDC therapy compared with pioglitazone and metformin monotherapy. Secondary endpoints included change from baseline in fasting plasma glucose (FPG), fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR). Safety and tolerability of pioglitazone/metformin FDC therapy and its individual components were also evaluated. Study limitations to be noted include the early stage of diabetes in these patients, which may be more responsive to treatment, and the 6 month treatment period, which does not provide durability data. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov, NCT00727857. RESULTS:From a baseline HbA1c >8.6%, mean HbA1c decreased the most with pioglitazone/metformin FDC (-1.83%) (P < 0.0001), compared with pioglitazone (-0.96%) and metformin (-0.99%) monotherapy, with 63.8% of FDC patients achieving HbA1c < or = 7% versus 46.9% of pioglitazone- and 38.9% of metformin-treated patients. The decrease from baseline to final visit in FPG was significantly larger in the pioglitazone/metformin FDC group (-39.9 mg/dL) (P < 0.01) compared with either monotherapy; the decrease in mean HOMA-IR was greatest with pioglitazone/metformin FDC. The pioglitazone/metformin FDC was well tolerated with no unexpected findings in adverse events of special interest, including hypoglycemia, bone fractures, peripheral edema, and cardiac failure. CONCLUSIONS:Overall, treatment with pioglitazone/metformin FDC demonstrated greater efficacy than its individual components. The FDC therapy was well tolerated, with reduced or similar adverse event rates compared with each individual monotherapy. 10.1185/03007990903350011
    Fixed-dose combination antidiabetic therapy: real-world factors associated with prescribing choices and relationship with patient satisfaction and compliance. Benford Mike,Milligan Gary,Pike James,Anderson Peter,Piercy James,Fermer Steve Advances in therapy INTRODUCTION:Compliance with antidiabetic therapy has the potential to impact on the risk for complications by an effect on glycemic control. Fixed-dose combinations (FDCs) offer a simplified dosing regimen that may improve patient compliance. We undertook a retrospective database analysis to understand the real-world association between FDCs, treatment practices, glycated hemoglobin (HbA(1c)) levels, and patient perspectives in type 2 diabetes. METHODS:Data were drawn from the Adelphi Diabetes Disease Specific Programme (DSP), a multicenter, patient recordbased market research study of primary care physicians and diabetologists/endocrinologists in Europe. The study is based on physician interviews, completion of detailed patient record forms by physicians, and a self-completion questionnaire by patients. Regression analyses were used to identify factors associated with (1) physician-reported dipeptidyl peptidase-4 inhibitor (DPP-4)/metformin FDC prescribing in dual or triple therapy regimens; (2) HbA1c of patients prescribed a DPP-4 FDC alone versus free-form DPP-4 plus metformin dual therapy regimens; and (3) differences between patients prescribed any oral antidiabetic therapy (OAD) FDC therapy (alone or in combination with one other OAD) versus those prescribed dual or triple OAD free-form combination therapy. RESULTS:Physician-reported data were available for 5891 patients (mean age 61.5 years, 43% female, mean duration since diagnosis 5.7 years). Factors associated with DPP-4 FDC usage included physicians' reason for choice being "improves patient compliance." The relative mean % HbA(1c) level associated with being on a DPP-4 FDC rather than free-form independent of the physician perception of patient compliance was 0.25 lower (CI -0.40 to -0.09). When physician-perceived patient compliance was described as "fairly compliant" rather than "poorly compliant" or "not at all compliant," the relative mean % HbA1c level was 0.42 lower (CI -0.67 to -0.18). Similarly, being perceived as "fully compliant" rather than "fairly compliant" was associated with a relative mean % HbA(1c) level that was 0.17 lower (CI -0.31 to -0.02). A significant predictor for the current regimen being any FDC (alone or in combination with one other OAD) regimen was patients' satisfaction with treatment (odds ratio 1.32; 95% CI 1.10 to 1.58; P=0.003). CONCLUSIONS:These results suggest that DPP-4 FDC prescribing is considered to be a positive prescribing choice to improve compliance and that choice is associated with improved glycemic control. From the patient's perspective, the decision to prescribe an FDC is associated with improved satisfaction with treatment. 10.1007/s12325-011-0096-z
    Glycemic effectiveness and medication adherence with fixed-dose combination or coadministered dual therapy of antihyperglycemic regimens: a meta-analysis. Han Steven,Iglay Kristy,Davies Michael J,Zhang Qiaoyi,Radican Larry Current medical research and opinion OBJECTIVES:To compare effects of fixed-dosed combinations (FDCs) and coadministered dual therapy (CDT) of antihyperglycemic agents on glycemic control (i.e., HbA(1c)) and medication adherence. METHODS:A systematic literature review and meta-analysis were performed to compare the HbA(1c) response and medication adherence between the two drug regimens. Selected articles were limited to studies that compared equivalent drug components within FDC and CDT. Searches used PubMed, Embase, Web of Knowledge, and Cochrane databases. The search results were independently screened and reviewed by two authors (SH, KI). Of the 1246 identified abstracts, 152 articles were reviewed, and ten met the inclusion criteria. Results were extracted and pooled in a meta-analysis, using a random-effects model. Cohort comparisons were described as mean differences (MDs) with 95% confidence intervals (CIs). RESULTS:The ten articles that met the inclusion criteria had a total study size of 70,573 patients. Four articles reported HbA(1c) results, which had a total of five cohort comparisons of FDC and CDT use. The meta-analysis revealed a significantly greater HbA(1c) reduction with FDC (MD = -0.53% [95% CI: -0.78, -0.28]; p < 0.0001). Eight studies evaluated medication adherence (measured as medication possession ratio [MPR]). Of the eight studies reporting MPR results, a total of 12 cohort comparisons were made and were further divided into three subgroups based on comparison types. Five comparisons described MPR for FDC versus CDT cohorts, with significantly higher MPR with FDC (MD = 8.6% [95% CI: 1.6, 15.6]; p = 0.0162]). Four comparisons examined patients who switched from monotherapy to FDC or CDT, with higher MPR for patients who switched to FDC (MD = 7.7% [95% CI: 5.7, 9.6]; p < 0.0001). Three comparisons described results for patients who switched from CDT to FDC or stayed on CDT, with higher MPR for patients who switched to FDC (MD = 5.0% [95% CI: 3.1, 6.8]; p < 0.0001). LIMITATIONS:A limited number of published studies were available for this meta-analysis and all of those included were observational studies. There was heterogeneity between studies in the statistical methods used to control for confounding variables and differing population characteristics. CONCLUSIONS:In a meta-analysis, use of FDCs with antihyperglycemic agents was associated with lower HbA(1c) and higher MPR values compared to CDT use in patients with type 2 diabetes. 10.1185/03007995.2012.684045
    Investigation of bioequivalence of a new fixed-dose combination of acarbose and metformin with the corresponding loose combination as well as the drug-drug interaction potential between both drugs in healthy adult male subjects. Kim S,Jang I-J,Shin D,Shin D S,Yoon S,Lim K S,Yu K-S,Li J,Zhang H,Liu Y,Brendel E,Blode H,Wang Y Journal of clinical pharmacy and therapeutics WHAT IS KNOWN AND OBJECTIVE:Both metformin and acarbose are recommended monotherapy and add-on therapy in type 2 diabetes mellitus (T2DM). A fixed-dose combination (FDC) of acarbose and metformin has been developed to reduce pill burden and potentially improve compliance. The current study investigated the bioequivalence of the acarbose/metformin FDC compared with the individual agents administered simultaneously (loose combination). Secondary endpoints were the safety and tolerability of the FDC and the potential for drug-drug interactions between acarbose and metformin. METHODS:A single-centre, randomized, open-label, four-period crossover study was conducted in healthy male Korean subjects aged 18-45 years. Following one-period balanced Williams design, participants were randomized to receive four single oral treatments on different study days separated by ≥7 days' washout. Treatments were as follows: (i) acarbose/metformin 50/500 mg FDC (test); (ii) acarbose 50 mg and metformin 500 mg as loose combination (reference); (iii) acarbose 50 mg; and (iv) metformin 500 mg. Serial blood samples were taken for glucose and insulin levels for 4 h after a sucrose load on the day before and day of study drug administration. Additionally, serial blood samples were taken for analysis of metformin levels for 24 h after each drug containing metformin. The area under the curve for 4 h post-test (AUC0-4 h ) and the maximal serum concentration (Cmax ) of plasma glucose and serum insulin were primary pharmacodynamic (PD) parameters, and Cmax , AUC0-last and AUC for metformin levels were primary pharmacokinetic (PK) parameters. The bioequivalence of the FDC to the loose combination was considered established if the 90% confidence intervals (CIs) of the baseline-adjusted PD parameter ratios (test vs. reference) for plasma glucose and the PK parameter ratios for metformin fell completely within current acceptance limits (0·8-1·25). RESULTS AND DISCUSSION:Thirty-three of 40 randomized subjects completed the study; five withdrew consent and two discontinued because of adverse events (AEs). The 24-h plasma concentration-time curves of metformin and the 4-h plasma glucose-time curves after acarbose/metformin FDC (test) and acarbose + metformin loose combination (reference) were almost superimposable. The geometric least squares (LS) mean of the RatioAUC and RatioCmax for plasma glucose after the FDC vs. loose combination, and the LS mean of the ratios in metformin AUC, AUC0-last and Cmax were close to unity, and the 90% CI of all these parameters fell within the predefined equivalence range of 0·8-1·25, confirming bioequivalence. The metformin AUC was reduced by 26% and Cmax by 34% after acarbose + metformin compared with metformin alone. Eight subjects (20·0%) reported AEs, but all were mild, and most were gastrointestinal, as expected for these agents. The incidence of AEs was not higher with the combinations vs. monotherapy. WHAT IS NEW AND CONCLUSION:These data demonstrate that the acarbose/metformin FDC is bioequivalent to the loose combination of these agents. Although acarbose slightly reduced the bioavailability of metformin, the accumulated evidence of the efficacy of this combination implies that this is clinically irrelevant. The observed AE profile was consistent with the established knowledge on the safety of the two drugs. 10.1111/jcpt.12166
    Clinical Benefits of Fixed Dose Combinations Translated to Improved Patient Compliance. Arya D S,Chowdhury Subhankar,Chawla Rajeev,Das A K,Ganie Mohd Ashraf,Kumar K M Prasanna,Nadkar Milind Y,Rajput Rajesh The Journal of the Association of Physicians of India Pharmacotherapy with fixed dose combination (FDC) drugs is becoming popular as evidence-based clinical guidelines recommend using multiple therapeutic agents in complex regimens for many chronic diseases including type 2 diabetes mellitus (T2DM). FDC formulations have unique advantages such as complementary mechanism of action, synergistic effects, better tolerability, elongated product life-cycle management, and cost savings. Polypharmacy is a frequent problem in T2DM patients having hypertension, dyslipidemia, and other comorbidities. Use of FDCs is a rational approach for achieving optimal therapeutic benefits while minimizing pill-burden. Greater convenience with decreased pill-burden leads to improved adherence, resulting in superior clinical outcomes and greater cost-effectiveness. However, the general guidance for the clinical development and approval of FDC drugs in India is not much standardized. For rationale approval, the central and state regulators must harmonize their procedures for licensing FDCs. Because regulatory approval of FDCs is based on bioavailability data, similar to the way generic medications are approved, the lack of prospective, randomized controlled trials directly comparing FDCs with their component drugs administered as separate pills should not be considered a limitation to their use. Nevertheless, all new and existing FDC products should be subjected to submission of longterm safety surveillance through closely monitored national level postmarketing studies.
    Metformin + saxagliptin for type 2 diabetes. Scheen André J Expert opinion on pharmacotherapy INTRODUCTION:Metformin is considered as the first-line drug therapy for the management of type 2 diabetes. Dipeptidyl peptidase-4 (DPP-4) inhibitors, by promoting insulin secretion and reducing glucagon secretion in a glucose-dependent manner, offer new opportunities for oral therapy after failure of metformin. AREAS COVERED:An updated review of the literature demonstrates that saxagliptin, a DPP-4 inhibitor, and metformin may be administered together, separately or in fixed-dose combination (FDC), either as saxagliptin added to metformin or as initial combination in drug-naive patients. Both compounds exert complementary pharmacodynamic actions leading to better improvement in blood glucose control (fasting plasma glucose, postprandial glucose, HbA1c) than either compound separately. Adding saxagliptin to metformin monthotherapy results in a consistent, sustained and safe reduction in HbA1c levels. Tolerance is excellent without hypoglycemia or weight gain. EXPERT OPINION:The combination saxaglitpin plus metformin may be used as first-line or second-line therapy in the management of type 2 diabetes, especially as a valuable alternative to the classical metformin-sulfonylurea combination. 10.1517/14656566.2012.642867
    A treatment strategy implementing combination therapy with sitagliptin and metformin results in superior glycaemic control versus metformin monotherapy due to a low rate of addition of antihyperglycaemic agents. Olansky L,Reasner C,Seck T L,Williams-Herman D E,Chen M,Terranella L,Mehta A,Kaufman K D,Goldstein B J Diabetes, obesity & metabolism AIMS:Combination therapy with sitagliptin and metformin has shown superior efficacy compared with metformin monotherapy. In this study, we compare two strategies: initial combination therapy with sitagliptin/metformin as a fixed-dose combination (FDC) and initial metformin monotherapy, with the option to add additional antihyperglycaemic agents (AHAs) in either treatment arm during the second phase of the study in order to reach adequate glycaemic control. METHODS:We evaluated the sitagliptin and metformin FDC compared with metformin monotherapy over 44 weeks in 1250 patients with type 2 diabetes mellitus in a two-part, double-blind, randomized, controlled clinical trial. The initial 18-week portion (Phase A) of this study in which additional AHAs were only allowed based on prespecified glycaemic criteria, has been previously reported. Here, we present results from the 26-week Phase B portion of the study during which double-blind study medication continued; however, unlike Phase A, during Phase B investigators were unmasked to results for haemoglobin A1C (HbA1c) and fasting plasma glucose (FPG) and directed to manage glycaemic control by adding incremental AHA(s) as deemed clinically appropriate. RESULTS:There were 1250 patients randomized in the study with 965 completing Phase A and continuing in Phase B. Among patients receiving sitagliptin/metformin FDC or metformin monotherapy, 8.8% and 16.7% received additional AHA therapy, respectively. Although glycaemic therapy in both groups was to have been managed to optimize HbA1c reductions with the option for investigators to supplement with additional AHAs during Phase B, patients randomized to initial therapy with sitagliptin/metformin FDC had larger reductions of HbA1c from baseline compared with patients randomized to initial metformin monotherapy [least squares (LS) mean change: -2.3% and -1.8% (p < 0.001 for difference) for sitagliptin/metformin FDC and metformin monotherapy groups, respectively]. A significantly larger reduction in FPG from baseline was observed in the sitagliptin/metformin FDC group compared with the metformin monotherapy group (p = 0.001). Significantly more patients in the sitagliptin/metformin FDC group had an HbA1c of less than 7.0% or less than 6.5% compared with those on metformin monotherapy. Both treatment strategies were generally well tolerated, with a low and similar incidence of hypoglycaemia in both groups and lower incidences of abdominal pain and diarrhoea in the sitagliptin/metformin FDC group compared with the metformin monotherapy group. CONCLUSIONS:A strategy initially implementing combination therapy with sitagliptin/metformin FDC was superior to a strategy initially implementing metformin monotherapy, even when accounting for the later addition of supplemental AHAs. Sitagliptin/metformin FDC was generally well tolerated. 10.1111/j.1463-1326.2011.01416.x
    Evaluation of efficacy and safety of fixed dose combination of glimepiride 2 mg pluspioglitazone 15 mg plus metformin SR 500 mg in the management of patients with type-2 diabetes mellitus. Meshram D M,Langade D G,Kinagi Satish B,Naikwadi Akram A,Morye Vinita,Chopra Dimple Journal of the Indian Medical Association An estimated 25 million Indians currently have diabetes and the projections indicate Indians would be the largest group by the year 2025 AD. An open, phase III, multicentric study was conducted to determine the efficacy and tolerability of the triple drug combination glimepiride 2 mg plus pioglitazone hydrochloride 15 mg plus metformin SR 500 mg for 8 weeks in 101 Indian patients with type 2 diabetes mellitus. The study revealed that the triple drug combination could achieve the recommended goals, recommended by American Diabetic Association, for fasting blood glucose < or = 140 mg/dl and glycosylated haemoglobin (HbA1c) of < or = 8%. After 8 weeks, the mean fasting blood glucose (baseline 189.61) was reduced to 111.68 (41% reduction); the mean glycosylated haemoglobin (baseline 10.32) was significantly reduced to 7.54 (26% reduction). The triple drug combination significantly reduced the levels of triglyceride, low density lipoproteins and total cholesterol. These significant levels were achieved within 8 weeks and all patients tolerated the drug well with no reported case of serious adverse events including hypoglycaemia. There were also no reported drug interactions in the study. Since the decrease in HbA1c was continuous and throughout the study, a further decrease in the HbA1c levels would have been noted since the present trial was designed for a period of 8 weeks. Thus, the present study confirms the efficacy and safety of FDC of the triple drug combination in patients with type 2 diabetes.
    [Jentadueto, fixed combination of linagliptin plus metformin for the treatment of type 2 diabetes]. Scheen A J,Van Gaal L F Revue medicale de Liege In case of failure of metformin monotherapy, several pharmacological strategies may be considered for the treatment of type 2 diabetes. Among these, the addition of an inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme, a medication commonly named as gliptin, is increasingly used because of two main advantages over sulfonylureas, i.e. the absence of both hypoglycaemia and weight gain. The combination of a gliptin and metformin further improves glycaemic control compared to either monotherapy, due to complementary mechanisms of action. Most patients with type 2 diabetes are treated every day with numerous drugs because of the presence of comorbidities so that poor drug compliance is a major concern in such a population. The use of fixed-dose combinations (FDCs) may improve compliance and, therefore, several gliptin-metformin FDCs are now available. The most recent one is Jentadueto, which combines linagliptin, a selective DPP-4 inhibitor without renal excretion, and metformin, the first-line antidiabetic compound. This FDC is commercialized with two dosages of metformin, i.e. 2.5 mg linagliptin/850 mg metformin and 2.5 mg linagliptin/1.000 mg metformin, and should be administered twice daily with meal.While linagliptin may be prescribed whatever the renal function, the use of FDC should take into account classical restrictions imposed by the presence of metformin.
    Initial therapy with the fixed-dose combination of sitagliptin and metformin results in greater improvement in glycaemic control compared with pioglitazone monotherapy in patients with type 2 diabetes. Wainstein J,Katz L,Engel S S,Xu L,Golm G T,Hussain S,O'Neill E A,Kaufman K D,Goldstein B J Diabetes, obesity & metabolism AIMS:To evaluate the efficacy and safety of initial therapy with a fixed-dose combination (FDC) of sitagliptin and metformin compared with pioglitazone in drug-naÏve patients with type 2 diabetes. METHODS:After a 2-week single-blind placebo run-in period, patients with type 2 diabetes, HbA1c of 7.5-12% and not on antihyperglycaemic agent therapy were randomized in a double-blind manner to initial treatment with a FDC of sitagliptin/metformin 50/500 mg twice daily (N = 261) or pioglitazone 30 mg per day (N = 256). Sitagliptin/metformin and pioglitazone were up-titrated over 4 weeks to doses of 50/1000 mg twice daily and 45 mg per day, respectively. Both treatments were then continued for an additional 28 weeks. RESULTS:From a mean baseline HbA1c of 8.9% in both groups, least squares (LS) mean changes in HbA1c at week 32 were -1.9 and -1.4% for sitagliptin/metformin and pioglitazone, respectively (between-group difference = -0.5%; p < 0.001). A greater proportion of patients had an HbA1c of <7% at week 32 with sitagliptin/metformin vs. pioglitazone (57% vs. 43%, p < 0.001). Compared with pioglitazone, sitagliptin/metformin treatment resulted in greater LS mean reductions in fasting plasma glucose (FPG) [-56.0 mg/dl (-3.11 mmol/l) vs. -44.0 mg/dl (-2.45 mmol/l), p < 0.001] and in 2-h post-meal glucose [-102.2 mg/dl (-5.68 mmol/l) vs. -82.0 mg/dl (-4.56 mmol/l), p < 0.001] at week 32. A substantially greater reduction in FPG [-40.5 mg/dl (-2.25 mmol/l) vs. -13.0 mg/dl (-0.72 mmol/l), p < 0.001] was observed at week 1 with sitagliptin/metformin vs. pioglitazone. A greater reduction in the fasting proinsulin/insulin ratio and a greater increase in homeostasis model assessment of β-cell function (HOMA-β) were observed with sitagliptin/metformin than with pioglitazone, while greater decreases in fasting insulin and HOMA of insulin resistance (HOMA-IR), and a greater increase in quantitative insulin sensitivity check index (QUICKI) were observed with pioglitazone than with sitagliptin/metformin. Both sitagliptin/metformin and pioglitazone were generally well tolerated. Sitagliptin/metformin led to weight loss (-1.4 kg), while pioglitazone led to weight gain (3.0 kg) (p < 0.001 for the between-group difference). Higher incidences of diarrhoea (15.3% vs. 4.3%, p < 0.001), nausea (4.6% vs. 1.2%, p = 0.02) and vomiting (1.9% vs. 0.0%, p = 0.026), and a lower incidence of oedema (1.1% vs. 7.0%, p < 0.001), were observed with sitagliptin/metformin vs. pioglitazone. The between-group difference in the incidence of hypoglycaemia did not reach statistical significance (8.4 and 4.3% with sitagliptin/metformin and pioglitazone, respectively; p = 0.055). CONCLUSION:Compared with pioglitazone, initial therapy with a FDC of sitagliptin and metformin led to significantly greater improvement in glycaemic control as well as a higher incidence of prespecified gastrointestinal adverse events, a lower incidence of oedema and weight loss vs. weight gain. 10.1111/j.1463-1326.2011.01530.x
    Combination therapy of dipeptidyl peptidase-4 inhibitors and metformin in type 2 diabetes: rationale and evidence. Liu Y,Hong T Diabetes, obesity & metabolism The main pathogenesis of type 2 diabetes mellitus (T2DM) includes insulin resistance and pancreatic islet dysfunction. Metformin, which attenuates insulin resistance, has been recommended as the first-line antidiabetic medication. Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel oral hypoglycaemic agents that protect glucagon-like peptide-1 (GLP-1) from degradation, maintain the bioactivity of endogenous GLP-1, and thus improve islet dysfunction. Results from clinical trials have shown that the combination therapy of DPP-4 inhibitors and metformin [as an add-on, an initial combination or a fixed-dose combination (FDC)] provides excellent efficacy and safety in patients with T2DM. Moreover, recent studies have suggested that metformin enhances the biological effect of GLP-1 by increasing GLP-1 secretion, suppressing activity of DPP-4 and upregulating the expression of GLP-1 receptor in pancreatic β-cells. Conversely, DPP-4 inhibitors have a favourable effect on insulin sensitivity in patients with T2DM. Therefore, the combination of DPP-4 inhibitors and metformin provides an additive or even synergistic effect on metabolic control in patients with T2DM. This article provides an overview of clinical evidence and discusses the rationale for the combination therapy of DPP-4 inhibitors and metformin. 10.1111/dom.12128
    A multicenter, phase III evaluation of the efficacy and safety of a new fixed-dose pioglitazone/glimepiride combination tablet in Japanese patients with type 2 diabetes. Hiroi Shinzo,Sugiura Kenkichi,Matsuno Kumi,Hirayama Masashi,Kuriyama Kenji,Kaku Kohei,Kawakami Koji Diabetes technology & therapeutics BACKGROUND:This study aimed to determine the efficacy and safety of pioglitazone/glimepiride as a fixed-dose combination (FDC) in Japanese patients with type 2 diabetes. SUBJECTS AND METHODS:In this multicenter, phase III, open-label evaluation, eligible patients had to have a glycosylated hemoglobin (HbA(1c)) level of ≥7.4% and <10.4% halfway through a 4-week run-in period while being treated with glimepiride 1 or 3 mg once daily plus diet and exercise. At baseline, patients were assigned to 8 weeks of treatment with pioglitazone/glimepiride (15 mg/1 mg) FDC once daily (group A; n=31) or pioglitazone/glimepiride (30 mg/3 mg) FDC once daily (group B; n=31) according to their glimepiride dose during run-in. RESULTS:Pioglitazone/glimepiride significantly reduced the mean HbA(1c) level from baseline (primary end point) by 0.59±0.556% in group A (P<0.0001) and by 0.55±0.637% in group B (P<0.0001). Corresponding reductions in the mean fasting blood glucose level were 12.5±21.67 mg/dL (P=0.0032) and 29.1±35.38 mg/dL (P<0.0001). Significant alterations from baseline to week 8 in either one or both treatment groups were also noted for the following parameters: 1,5-anhydroglucitol, glycoalbumin, triglycerides, high-density lipoprotein cholesterol, and free fatty acid levels. Five patients in group A (16.1%) had five treatment-related adverse events, and 10 patients in group B (32.3%) had 13 such events; all events were mild. CONCLUSIONS:Pioglitazone/glimepiride as a FDC (30 mg/3 mg and 15 mg/1 mg once daily) significantly improved glycemic control and lipid profiles and was well tolerated in Japanese patients with type 2 diabetes. 10.1089/dia.2012.0246
    Epidemiologic Surveillance of Glycemic Response to a Scored, Breakable, Extended Release, Fixed Dose Combination of Gliclazide and Metformin in Persons with Type 2 Diabetes. Kalra Sanjay,Das Ashok Kumar The Journal of the Association of Physicians of India BACKGROUND:The combination of metformin and a sulphonylurea has been recommended for treatment of type 2 diabetes. A, scored, breakable, extended release, once daily fixed dose combination (FDC) of gliclazide and metformin is available in India. OBJECTIVE:To assess the initial blood glucose lowering efficacy, glycemic control and patient acceptability of the fixed dose combination of original gliclazide 60mg and metformin 500mg in an extended release, scored and breakable formulation (in a range of 1, 1½, and 2 tablets) among Indian patients in day to day practice. METHODS:In a multi-center epidemiologic surveillance protocol of 60 days, patients with type 2 diabetes were prospectively prescribed 1 to 2 tablet of gliclazide 60mg + metformin 500mg during the course of study. The possibility of breaking the tablet in two equal halves enabled administration of 1½ tablets wherever required. Primary data on fasting plasma glucose response and adverse events was extracted for analysis from the case records of patients kept with the investigators. The primary outcome was the proportion of patients achieving glycemic control, defined as fasting plasma glucose of 90-130 mg/dl at the end of the study. RESULTS:Of the 759 patients treated with an extended release FDC of gliclazide 60mg + metformin 500mg, the number (%, 95% CI) which achieved glycemic control was 474/759 (62.5%, 59.0% to 65.8%). The proportion controlled with 1 tablet was, 252/759 (33.2%, 29.9% to 36.6%); with 1½ tablets, 149/298, (50.0%, 44.3% to 55.6%); and with 2 tablets, 73/94, (77.5%, 68.2% to 85.0%). Mean (95% CI) FPG mg/dl decreased from baseline by 48.7 (45.0 to 51.4) with 1 tablet; by 71.3 (66.0 to 76.6) with 1½ tablets; and by 86.3 (75.7 to 96.9) with 2 tablets. Frequency of hypo-glycaemia was 0.7%. CONCLUSIONS:Extended release FDC of gliclazide 60mg + metformin 500mg, a scored, breakable, once daily, formulation was effective in controlling blood glucose in a large proportion of type 2 diabetes with a low risk of hypoglycaemia.
    Dapagliflozin and saxagliptin tablets for adults with type 2 diabetes. Scheen André J Expert review of clinical pharmacology INTRODUCTION:Saxagliptin (a dipeptidyl peptidase-4 inhibitor, DPP-4i) and dapagliflozin (a sodium-glucose cotransporter type 2 inhibitor, SGLT2i) improve glucose control in type 2 diabetes (T2D) through different potentially complementary mechanisms, thus offering the opportunity for a combined therapy. Area covered: The characteristics of the saxagliptin/dapagliflozin combination are analysed, focusing on: 1) pharmacokinetic and pharmacodynamic properties; 2) efficacy and safety in phase III trials with concurrent and sequential add-on therapy; and 3) potential use in clinical practice, including in special populations (cardiovascular disease, heart failure, chronic kidney disease, elderly). Expert commentary: Conclusions drawn from clinical trials investigating combination with the separate drugs are considered to apply to the fixed-dose combination (FDC) that demonstrates bioequivalence. Dual saxagliptin/dapagliflozin therapy is more potent than either monotherapy and can be used as an initial combination or a stepwise sequential approach. Dual therapy is generally well tolerated and may be used in special populations, with some limitations because of the presence of dapagliflozin. However, the latter may offer some advantages because of multiple effects attributed to SGLT2i. The best place of this dual combination for the management of T2D and the profile of patients who will make the most of this combined therapy remains to be defined. 10.1080/17512433.2017.1389645
    Pharmacokinetic drug evaluation of saxagliptin plus dapagliflozin for the treatment of type 2 diabetes. Scheen André J Expert opinion on drug metabolism & toxicology INTRODUCTION:Combining a dipeptidyl peptidase-4 inhibitor and a sodium-glucose cotransporter type 2 inhibitor is an attractive option to treat hyperglycaemia in type 2 diabetes. Areas covered: The saxagliptin plus dapagliflozin combination is carefully analysed, focusing on: 1) pharmacokinetic properties, 2) pharmacodynamics data, and 3) results of randomised controlled trials (dual combination versus either monotherapy, sequential therapy saxagliptin added to dapagliflozin or dapagliflozin added to saxagliptin). Expert opinion: Pharmacokinetic findings demonstrate the absence of drug-drug interaction and the bioequivalence of the FDC compared with separated tablets. Pharmacodynamic observations confirm a complementary mode of action of the two agents. Dual saxagliptin-dapagliflozin therapy is more potent than either monotherapy. It may be used as an initial combination, although this approach remains debatable and should probably be reserved in case of high glycated hemoglobin, or a stepwise strategy, according to a personalized approach. The developed saxagliptin-dapagliflozin FDC may simplify anti-hyperglycemic therapy and improve drug compliance. 10.1080/17425255.2017.1315102
    Dapagliflozin/Saxagliptin Fixed-Dose Tablets: A New Sodium-Glucose Cotransporter 2 and Dipeptidyl Peptidase 4 Combination for the Treatment of Type 2 Diabetes. Coppenrath Valerie Azzopardi,Hydery Tasmina The Annals of pharmacotherapy OBJECTIVE:To review the pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of the fixed-dose combination (FDC) product, QTERN (dapagliflozin/saxagliptin) tablets. DATA SOURCES:Searches of MEDLINE (1946 to July 1, 2017) were conducted using the keywords QTERN, saxagliptin, and dapagliflozin. Additional data were obtained from the prescribing information, the product dossier, and Clinicaltrials.gov . STUDY SELECTION AND DATA EXTRACTION:All English language articles related to pharmacology, pharmacokinetics, efficacy, or safety of the combination therapy in human subjects were reviewed. DATA SYNTHESIS:The pharmacokinetics of saxagliptin and dapagliflozin were not affected significantly when administered as an FDC product. Saxagliptin may suppress the increased secretion of glucagon associated with dapagliflozin. The combination dapagliflozin/saxagliptin has been studied as add-on therapy to metformin in patients with uncontrolled type 2 diabetes mellitus (T2DM). The difference in hemoglobin A (A1C) between saxagliptin + dapagliflozin + metformin (triple therapy) and saxagliptin + metformin was -0.59 (95% CI = -0.81 to -0.37, P < 0.0001), and the difference between triple therapy and dapagliflozin + metformin was -0.27 (95% CI = -0.48 to -0.05, P = 0.0166). The combination was well tolerated when added to metformin. CONCLUSION:QTERN (dapagliflozin/saxagliptin) tablets are a reasonable option for patients with T2DM not controlled on metformin, but cost, insurance coverage, and a lackluster reduction in A1C will likely limit its use until more data regarding its effects on complications of diabetes and cardiovascular outcomes become available. 10.1177/1060028017731111
    DPP-4 inhibitor plus SGLT-2 inhibitor as combination therapy for type 2 diabetes: from rationale to clinical aspects. Scheen André J Expert opinion on drug metabolism & toxicology INTRODUCTION:Type 2 diabetes (T2D) is a complex disease with multiple defects, which generally require a combination of several pharmacological approaches to control hyperglycemia. Combining a dipeptidyl peptidase-4 inhibitor (DPP-4i) and a sodium-glucose cotransporter type 2 inhibitor (SGT2i) appears to be an attractive approach. Area covered: An extensive literature search was performed to analyze the pharmacokinetics, pharmacodynamics and clinical experience of different gliptin-gliflozin combinations. Expert opinion: There is a strong rationale for combining a DPP-4i and a SGLT2i in patients with T2D because the two drugs exert different and complementary glucose-lowering effects. Dual therapy (initial combination or stepwise approach) is more potent than either monotherapy in patients treated with diet and exercise or already treated with metformin. Combining the two pharmacological options is safe and does not induce hypoglycemia. The additional glucose-lowering effect is more marked when a gliflozin is added to a gliptin than when a gliptin is added to a gliflozin. Two fixed-dose combinations (FDCs) are already available (saxagliptin-dapagliflozin and linagliptin-empagliflozin) and others are in current development. Bioequivalence of the two compounds given as FDC tablets was demonstrated when compared with coadministration of the individual tablets. FDCs could simplify the anti-hyperglycaemic therapy and improve drug compliance. 10.1080/17425255.2016.1215427
    Acarbose plus metformin fixed-dose combination outperforms acarbose monotherapy for type 2 diabetes. Wang Jun-Sing,Huang Chien-Ning,Hung Yi-Jen,Kwok Ching-Fai,Sun Jui-Hung,Pei Dee,Yang Chwen-Yi,Chen Ching-Chu,Lin Ching-Ling,Sheu Wayne Huey-Herng, Diabetes research and clinical practice AIM:To compare the efficacy and safety of acarbose plus metformin fixed-dose combination (FDC) versus acarbose monotherapy for type 2 diabetes (T2D). METHODS:Eligible T2D patients undergoing treatment with diet control only or oral antidiabetic medications were run-in on acarbose 50mg thrice-daily for 4 weeks, then randomised either to continue this monotherapy, or to acarbose 50mg plus metformin hydrochloride 500mg FDC (acarbose/metformin FDC), each thrice-daily for 16 weeks. RESULTS:Acarbose/metformin FDC therapy significantly reduced HbA1c, fasting plasma glucose (FPG), and postprandial plasma glucose (PPG) from baseline (all p<0.0001) with superior efficacy compared with acarbose monotherapy (between-group differences; HbA1c -1.35%; FPG -29.5mg/dl; PPG -41.6mg/dl; all p<0.0001). Proportionally more patients treated with acarbose/metformin FDC achieved HbA1c <7.0% (47.8% vs. 10.7%, p<0.0001). Both treatments reduced bodyweight (p<0.0001), with a significant between-group difference (-0.6kg, p<0.01) favouring acarbose/metformin FDC. Hypoglycaemia was not reported with either treatment, and the incidence of other adverse events did not differ significantly between the groups. CONCLUSIONS:Compared with acarbose monotherapy, acarbose/metformin FDC has superior antihyperglycaemic efficacy, brings proportionally more T2D patients to HbA1c goal, and further reduces bodyweight. Acarbose/metformin FDC is well-tolerated without significant risk of hypoglycaemia and is a potentially advantageous therapy for T2D. 10.1016/j.diabres.2013.08.001
    Comparison of persistence and adherence between fixed-dose combinations and two-pill combinations in Japanese patients with type 2 diabetes. Nishimura Rimei,Kato Haruka,Kisanuki Koichi,Oh Akinori,Onishi Yoshie,Guelfucci Florent,Shimasaki Yukio Current medical research and opinion OBJECTIVE:To compare treatment patterns, persistence and adherence between fixed-dose combinations (FDCs) and two-pill combinations (TPCs) of oral antidiabetic drug (OAD) classes in Japanese patients with type 2 diabetes mellitus (T2DM) using administrative claims databases (Japan Medical Data Center [JMDC] and Medical Data Vision [MDV]). METHODS:This was a retrospective, longitudinal cohort analysis conducted between 2011 and 2015, in patients with T2DM receiving OADs as FDC or TPC. Outcomes included prescribing patterns, treatment persistence and adherence. RESULTS:Data from 3474 and 3066 patients receiving FDCs, and 4325 and 5192 patients receiving TPCs from the JMDC and MDV databases, respectively, was extracted. The most common OAD combination received by over half of all patients was dipeptidyl peptidase-4 inhibitor (DPP-4i) + thiazolidinediones (TZDs) (64.1% [JMDC] and 70.5% [MDV]). Overall, 12-month persistence rates were higher in patients receiving FDCs compared with TPCs (70.4 vs. 66.2% [JMDC], 75.6 vs. 55.7% [MDV]). In the JMDC population receiving FDCs or TPCs, persistence rates were highest with DPP-4i schedules (67.5-83.5%). Median time to discontinuation was significantly longer with biguanide + TZD, and DPP-4i + TZD FDC schedules (p < .05) than TPC; adherence rates were ≥80% across all antidiabetic drug classes in both database populations. CONCLUSIONS:Persistence with and adherence to OADs in Japanese patients with T2DM were greater with FDCs than with TPCs, which may suggest increased patient satisfaction due to reduced treatment burden. Further studies are warranted to investigate the impact of adherence and persistence of FDCs of OADs on glycemic control. 10.1080/03007995.2018.1551192
    Hot Topics in Primary Care: Titratable Fixed-Ratio Combinations in Type 2 Diabetes Mellitus: Focus on GLP-1R Agonists Combined With Basal Insulin. LaSalle James,White John R The Journal of family practice The treatment of hyperglycemia in patients without glycemic control despite metformin monotherapy is the focus of this article, with particular focus on the use of fixed-dose (FDC) and fixed-ratio combination products.
    Glycemic Improvement with a Fixed-dose combination of DPP-4 inhibitor + metformin in patients with Type 2 diabetes (GIFT study). Bajaj Harpreet S,Ye Chenglin,Jain Esha,Venn Karri,Stein Eden,Aronson Ronnie Diabetes, obesity & metabolism This study investigates changes in A1C following a switch from dual therapy of metformin and DPP-4 inhibitor to a fixed-dose combination (FDC) of metformin + DPP-4 inhibitor following the introduction of the FDC in the provincial formulary. The LMC Diabetes Registry was queried retrospectively for patients with type 2 diabetes, aged between 18 and 80 years with at least one A1C recorded prior and ≥3 months post-switch. Five hundred and sixty-eight subjects with mean age 64 ± 12 years and mean A1C 7.7% ± 1.2% met study criteria. Overall, A1C was 0.3% lower post-switch to FDC (P < .01). In stratified analysis, subjects with baseline A1C between 7% and 10% had 0.4% lower A1C (P < .01), with 31% of these subjects reaching target A1C ≤7%, post-switch. A1C reduction was greater among patients with a higher baseline pill burden: 0.4% among those using ≥10 pills/day vs. 0.1% for those with <10 pills/day (P = .02). In this real-world study, switching to FDC of metformin + DPP-4 inhibitor was associated with a significant improvement in A1C. Switching to FDC, especially in patients with high pill burden, can improve A1C goal achievement in clinical practice. 10.1111/dom.13040
    A retrospective study of persistence, adherence, and health economic outcomes of fixed-dose combination vs. loose-dose combination of oral anti-diabetes drugs. Lokhandwala Tasneem,Smith Nancy,Sternhufvud Catarina,Sörstadius Elisabeth,Lee Won Chan,Mukherjee Jayanti Journal of medical economics OBJECTIVE:To compare outcomes between patients with type 2 diabetes mellitus (T2DM) using fixed-dose combination (FDC) and loose-dose combination (LDC) products. METHODS:This retrospective cohort study used MarketScan Commercial and Medicare Supplemental data from January 1, 2009-December 31, 2013. The identified population included patients with T2DM and ≥1 additional oral anti-diabetic prescription (of the same regimen [FDC/LDC] as the index prescription) within 12 months following the fill date. Persistence (no ≥30-day gap) and adherence (medication possession ratio [MPR] ≥0.8) were assessed as primary end-points; secondary end-points included hypoglycemia, healthcare resource utilization, and costs. RESULTS:Of 23,361 patients identified, 12,590 (53.9%) were on FDC therapy and 10,771 (46.1%) were on LDC therapy. FDC patients had a significantly lower rate of non-persistence (67.9% vs. 73.4%, p < 0.0001) and a significantly higher rate of adherence to therapy (57.0% vs. 50.7%, p < 0.0001) when compared to LDC patients. Average time to non-persistence was significantly longer among FDC vs. LDC patients (207.1 vs. 186.3 days, p < 0.0001). After adjusting for baseline characteristics, the odds of non-persistence were 21% lower with FDC vs. LDC therapy (OR = 0.79, 95% CI = 0.74-0.85, p < 0.0001), with a 28% higher odds of adherence (OR = 1.28, 95% CI = 1.20-1.36, p < 0.0001). Differences in most secondary outcomes significantly favored FDC therapy, including total predicted monthly all-cause costs ($1008 vs. $1053; p = 0.006) and T2DM-related costs ($142 vs. $155; p < 0.001). LIMITATIONS:Cohort classification was based on prescription claims data. The lack of clinical data limits assessment of potential influencers of FDC vs. LDC decisions, residual confounding was possible, and diabetes-related medical costs only captured claims with a primary diagnosis for diabetes. The results may not be generalizable to populations such as Medicaid. CONCLUSION:Management of T2DM using FDC therapies provides a compliance benefit relative to LDC therapies that may translate to reductions in healthcare utilization and costs. 10.3111/13696998.2015.1109518
    The effect of initial therapy with the fixed-dose combination of sitagliptin and metformin compared with metformin monotherapy in patients with type 2 diabetes mellitus. Reasner C,Olansky L,Seck T L,Williams-Herman D E,Chen M,Terranella L,Johnson-Levonas A O,Kaufman K D,Goldstein B J Diabetes, obesity & metabolism AIMS:This study was conducted to compare the glycaemic efficacy and safety of initial combination therapy with the fixed-dose combination of sitagliptin and metformin versus metformin monotherapy in drug-naive patients with type 2 diabetes. METHODS:This double-blind study (18-week Phase A and 26-week Phase B) randomized 1250 drug-naÏve patients with type 2 diabetes [mean baseline haemoglobin A1c (HbA1c) 9.9%] to sitagliptin/metformin 50/500 mg bid or metformin 500 mg bid (uptitrated over 4 weeks to achieve maximum doses of sitagliptin/metformin 50/1000 mg bid or metformin 1000 bid). Results of the primary efficacy endpoint (mean HbA1c reductions from baseline at the end of Phase A) are reported herein. RESULTS:At week 18, mean change from baseline HbA1c was -2.4% for sitagliptin/metformin FDC and -1.8% for metformin monotherapy (p < 0.001); more patients treated with sitagliptin/metformin FDC had an HbA1c value <7% (p < 0.001) versus metformin monotherapy. Changes in fasting plasma glucose were significantly greater with sitagliptin/metformin FDC (-3.8 mmol/l) versus metformin monotherapy (-3.0 mmol/l; p < 0.001). Homeostasis model assessment of β-cell function (HOMA-β) and fasting proinsulin/insulin ratio were significantly improved with sitagliptin/metformin FDC versus metformin monotherapy. Baseline body weight was reduced by 1.6 kg in each group. Both treatments were generally well tolerated with a low and similar incidence of hypoglycaemia. Abdominal pain (1.1 and 3.9%; p = 0.002) and diarrhoea (12.0 and 16.6%; p = 0.021) occurred significantly less with sitagliptin/metformin FDC versus metformin monotherapy; the incidence of nausea and vomiting was similar in both groups. CONCLUSION:Compared with metformin monotherapy, initial treatment with sitagliptin/metformin FDC provided superior glycaemic improvement with a similar degree of weight loss and lower incidences of abdominal pain and diarrhoea. 10.1111/j.1463-1326.2011.01390.x
    Triple fixed-dose combination empagliflozin, linagliptin, and metformin for patients with type 2 diabetes. Lingvay Ildiko,Beetz Nadine,Sennewald Regina,Schuler-Metz Annette,Bertulis Julia,Loley Christina,Lang Benjamin,Lippert Caroline,Lee Jisoo,Manning Linda Shapiro,Terada Derek Postgraduate medicine OBJECTIVES:Fixed-dose combination (FDC) therapy can improve outcomes in type 2 diabetes (T2D). We evaluated the bioequivalence of 2 doses of an FDC of extended-release metformin (metformin XR), empagliflozin, a sodium-glucose co-transporter 2 inhibitor, and linagliptin, a dipeptidyl peptidase-4 inhibitor, versus corresponding free tablet combinations. METHODS:Two randomized, open-label, two-way crossover studies in healthy adults compared: 2 FDC tablets of empagliflozin 5 mg/linagliptin 2.5 mg/metformin XR 1000 mg (Study 1; N = 30), 1 FDC tablet of empagliflozin 25 mg/linagliptin 5 mg/metformin XR 1000 mg (Study 2; N = 30) versus corresponding dose of free combinations. Subjects received study medication under fed conditions; washout was ≥35 days between treatments. Primary endpoints: area under the plasma concentration-time curve (AUC) from time 0 to last quantifiable data point for empagliflozin and metformin; AUC from time 0 to 72 hours for linagliptin, and peak plasma concentration (C) for empagliflozin, linagliptin, and metformin. Bioequivalence was defined as adjusted geometric mean ratios (FDC: free combination) and two-sided 90% confidence intervals (CIs) of AUC and C for each component within 80.00-125.00%. RESULTS:Study 1: 27/29 and 28/30 treated participants were included in the pharmacokinetic analysis for the FDC and free combination periods, respectively. Study 2: 29/29 treated participants were included in the pharmacokinetic analysis for both periods. The adjusted geometric mean ratios of FDCs to their respective free tablet combinations and two-sided 90% CIs were all within the predefined range. The shapes of the mean plasma concentration-time profile of empagliflozin, linagliptin, and metformin XR were similar for subjects in the FDC and free combination groups in both studies. No serious adverse events were reported. CONCLUSION:The evaluated doses of empagliflozin/linagliptin/metformin XR FDC tablets were bioequivalent to the corresponding free combinations. Based on these two bioequivalence studies and existing phase 3 data, the FDA has recently approved this triple FDC to improve glycemic control in adults with T2D. 10.1080/00325481.2020.1750228
    Clinical Evidence of Evogliptin plus Metformin in Management of Type 2 Diabetes mellitus. Bajaj Sarita,Aiwale Amol,Trailokya Abhijit,Sharma Akhilesh The Journal of the Association of Physicians of India Achieving adequate glycemic control in type 2 diabetes mellitus (T2DM) remains a difficult but achievable goal. Oral agents (OADs) are important option for management of T2DM. Most T2DM patients require more than one medication for adequate glycemic control. Metformin based combination therapy is recommended when monotherapy is insufficient. Evogliptin is a recently developed dipeptidyl peptidase-4 (DPP-4) inhibitor, which can to be combined with metformin for treating T2DM. Combination therapy of Evogliptin and Metformin lowers blood glucose via augmentation of insulin secretion, suppression of glucagon secretion, and insulin sensitization. Co-administration of Evogliptin and Metformin showed no clinically relevant pharmacokinetic differences compared to the administration of each drug alone. Combination therapy of Evogliptin and Metformin also provides significantly better glycemic control compared to the respective monotherapies. Efficacy and safety of Evogliptin and Metformin had been demonstrated in several multicentre randomized clinical trials conducted in various countries like South Korea, Russia and India. Consequently, fixed dose combination (FDC) of Evogliptin and Metformin is approved in South Korea and India. Complexity of the treatment regimen and polypharmacy are well-known factors of poor medication adherence and FDCs have the potential to improve adherence by reducing the pill burden. Adoption of this combination therapy in clinical practice for management of T2DMs will provide a greater degree of HbA1c reduction than that observed with the use of either drug as monotherapy, and is unlikely to cause significant hypoglycemia. Combination therapy of Evogliptin and Metformin is a promising strategy in the treatment of T2DM.
    Hemoglobin A1c outcomes and health care resource use in type 2 diabetes mellitus patients treated with combination oral antidiabetic drugs through step therapy and loose-dose and fixed-dose combinations. Williams Setareh A,Buysman Erin K,Hulbert Erin M,Bergeson Joette Gdovin,Zhang Bin,Graham John Managed care (Langhorne, Pa.) PURPOSE:To compare outcomes of type 2 diabetes mellitus (T2DM) patients initiating therapy with FDC vs. those with loose-dose combination (LDC) or step therapy (ST) in a managed care population. DESIGN:A retrospective claims database analysis. METHODOLOGY:Treatment-naive T2DM patients who were continuously enrolled in a health plan during 2006-2009 were studied. Eligible patients were assigned to FDC, LDC, or ST cohorts. Glycated hemoglobin goal attainment (HbA1c < 7%) was assessed using the American Diabetes Association (ADA) treatment guidelines. Health care resources use and costs, including inpatient, emergency room (ER), and ambulatoryvisits, were measured during the 12 months after therapy initiation. All-cause and diabetes-related use and costs were assessed. PRINCIPAL FINDINGS:21,048 patients met study criteria (FDC n = 8,416, ST n = 8,407, LDC n = 4,225), and 1,926 of these patients had HbA1c results. FDC patients had lower rates of post-index all-cause inpatient stays and ER visits compared with the other cohorts. FDC patients had lower average counts of diabetes-related ambulatory visits (2.7) compared with ST (3.7; p < 0.001) and LDC (3.2; p < 0.001) and significantly lower average post-index all-cause and diabetes-related costs compared with the other cohorts, with average all-cause costs for FDC, ST, and LDC of $8,445, $10,515, and $9,688, respectively, and diabe-tes-related costs of $1,641, $2,099, and $1,900, respectively. FDC patients had higher rates of achieving HbA1c goal (61%) compared to ST (48%; p < 0.001) or LDC (52%; p = 0.015). Differences in outcomes remained following multivariate analyses. CONCLUSION:Treatment with FDC was associated with lower health care resources use and costs and better likelihood of HbA1c goal attainment.