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      Efficacy and Safety of Lobeglitazone Monotherapy in Patients with Type 2 Diabetes Mellitus over 24-Weeks: A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo Controlled Trial

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          Abstract

          Objective

          The aim of this study was to assess the glucose-lowering and lipid-modifying effects, and safety profile of lobeglitazone, a novel peroxisome proliferator-activated receptor- γ agonist, compared to placebo as a monotherapy in patients with type 2 diabetes.

          Research Design and Methods

          In this 24-week, multicenter, randomized, double-blind, parallel-group, placebo controlled study, 173 patients were randomly assigned (a 2∶1 ratio) to lobeglitazone 0.5 mg (n = 115) or matching placebo (n = 58) orally once daily. The primary endpoint was the change in glycated hemoglobin (HbA1c) from baseline to the end of treatment. The secondary endpoints included various glycemic parameters, lipid parameters and safety profile (ClinicalTrials.gov number NCT01001611).

          Results

          At 24 weeks, a significant reduction in HbA1c was observed with lobeglitazone versus placebo (−0.44% vs 0.16%, mean difference −0.6%, p<0.0001). The goal of HbA1c <7% was achieved significantly more in the lobeglitazone group compared to the placebo group (44% vs 12%, p<0.0001). Markers of insulin resistance were also improved in the lobeglitazone group. In addition, lobeglitazone treatment significantly improved triglycerides, high density lipoprotein cholesterol, small dense low density lipoprotein cholesterol, free fatty acid, and apolipoprotein-B/CIII compared to placebo (p<0.01, respectively). More weight gain was observed in the lobeglitazone group than the placebo group (0.89 kg vs – 0.63 kg, mean difference 1.52 kg, p<0.0001). The safety profile was comparable between the two groups and lobeglitazone was well tolerated.

          Conclusions

          Lobeglitazone 0.5 mg showed a favorable balance in the efficacy and safety profile. The results support a potential role of lobeglitazone in treating type 2 diabetes.

          Trial Registration

          Clinicaltrials.gov NCT01001611

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          Most cited references 13

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          Thiazolidinediones

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            Rosiglitazone revisited: an updated meta-analysis of risk for myocardial infarction and cardiovascular mortality.

            Controversy regarding the effects of rosiglitazone therapy on myocardial infarction (MI) and cardiovascular (CV) mortality persists 3 years after a meta-analysis initially raised concerns about the use of this drug. To systematically review the effects of rosiglitazone therapy on MI and mortality (CV and all-cause). We searched MEDLINE, the Web site of the Food and Drug Administration, and the GlaxoSmithKline clinical trials registry for trials published through February 2010. The study included all randomized controlled trials of rosiglitazone at least 24 weeks in duration that reported CV adverse events. Odds ratios (ORs) for MI and mortality were estimated using a fixed-effects meta-analysis of 56 trials, which included 35 531 patients: 19 509 who received rosiglitazone and 16 022 who received control therapy. Rosiglitazone therapy significantly increased the risk of MI (OR, 1.28; 95% confidence interval [CI], 1.02-1.63; P = .04) but not CV mortality (OR, 1.03; 95% CI, 0.78-1.36; P = .86). Exclusion of the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes) trial yielded similar results but with more elevated estimates of the OR for MI (OR, 1.39; 95% CI, 1.02-1.89; P = .04) and CV mortality (OR, 1.46; 95% CI, 0.92-2.33; P = .11). An alternative analysis pooling trials according to allocation ratios allowed inclusion of studies with no events, yielding similar results for MI (OR, 1.28; 95% CI, 1.01-1.62; P = .04) and CV mortality (OR 0.99; 95% CI, 0.75-1.32; P = .96). Eleven years after the introduction of rosiglitazone, the totality of randomized clinical trials continue to demonstrate increased risk for MI although not for CV or all-cause mortality. The current findings suggest an unfavorable benefit to risk ratio for rosiglitazone.
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              Thiazolidinediones and PPARγ agonists: time for a reassessment.

              Thiazolidinediones (TZDs) are anti-diabetic drugs that act as insulin sensitizers and are used in the management of type 2 diabetes mellitus. TZDs, which are ligands for the transcription factor peroxisome proliferator-activated receptor PPARγ, have a wide spectrum of action, including modulation of glucose and lipid homeostasis, inflammation, atherosclerosis, bone remodeling and cell proliferation. Randomized clinical trials have demonstrated the efficacy and durability of the anti-hyperglycemic action of TZDs, and have suggested that the TZD pioglitazone also exerts cardioprotective action. However, the clinical use of TZDs is limited by the occurrence of several adverse events, including body-weight gain, congestive heart failure, bone fractures and possibly bladder cancer. Therefore, there is an unmet need for the development of new safer PPARγ-modulating drugs. Copyright © 2012 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                15 April 2014
                : 9
                : 4
                Affiliations
                [1 ]Department of Internal Medicine, Korea University Anam Hospital, Seoul, Korea
                [2 ]Department of Internal Medicine, Hallym University Kangdong Sacred Heart Hospital, Seoul, Korea
                [3 ]Department of Internal Medicine, Kyung Hee University Hospital, Seoul, Korea
                [4 ]Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
                [5 ]Department of Internal Medicine, Wonju Severance Christian Hospital, Wonju, Korea
                [6 ]Department of Internal Medicine, Inje University Sanggye Paik Hospital, Seoul, Korea
                [7 ]Department of Internal Medicine, Inje University Pusan Paik Hospital, Pusan, Korea
                [8 ]Department of Internal Medicine, Hanyang University Guri Hospital, Guri, Korea
                [9 ]Department of Internal Medicine, Soon Chun Hyang University Cheonan Hospital, Cheonan, Korea
                Johns Hopkins Bloomberg School of Public Health, United States of America
                Author notes

                Competing Interests: This study is funded by Chong Kun Dang Pharmaceutical Corp, manufacture of lobeglitazone. There are no further patents, products in development or marketed products to declare. This does not alter our adherence to all the PLoS ONE policies on sharing data and materials. The investigators and representatives from Chong Kun Dang were responsible for the study design, protocol, statistical analysis plans, analysis, and reporting of the results. The decision to submit the manuscript for publication was made jointly by all authors.

                Conceived and designed the experiments: SGK DMK JW HCJ CHC KSK JHP YSP SJK DSC. Performed the experiments: SGK DMK JW HCJ CHC KSK JHP YSP SJK DSC. Analyzed the data: SGK DMK JW HCJ CHC KSK JHP YSP SJK DSC. Contributed reagents/materials/analysis tools: SGK DMK JW HCJ CHC KSK JHP YSP SJK DSC. Wrote the paper: SGK DSC.

                Article
                PONE-D-13-31775
                10.1371/journal.pone.0092843
                3988010
                24736628

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 7
                Funding
                The study was funded by Chong Kun Dang Pharmaceutical Corp, the manufacturer of lobeglitazone and was supported by the Medicine and Bio Project for ‘Development of New Medicine and Medical Material’ of the Chungcheong Leading Industry Office of the Korean Ministry of Knowledge Economy, which is a government organization (70007613, ‘Clinical development of lobeglitazone, a thiazolidinedione insulin sensitizing agent for diabetes mellitus’). SGK's contribution was supported by grant of the Korea Healthcare Technology Research & Development Project, Ministry for Health, Welfare & Family Affairs of the Republic of Korea (A070001). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Physiology
                Endocrine Physiology
                Medicine and Health Sciences
                Clinical Medicine
                Clinical Trials
                Endocrinology
                Diabetic Endocrinology
                Metabolic Disorders
                Diabetes Mellitus
                Type 2 Diabetes
                Pathology and Laboratory Medicine
                Clinical Pathology
                Pharmacology
                Clinical Pharmacology
                Drug Research and Development
                Pharmacodynamics
                Research and Analysis Methods
                Bioassays and Physiological Analysis
                Biochemical Analysis
                Clinical Chemistry
                Research Design
                Clinical Research Design

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