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      Clinical study of repaglinide efficacy and safety in type 2 diabetes mellitus patients with blood glucose levels inadequately controlled by sitagliptin

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          Abstract

          Aims/Introduction

          The aim of the present study was to evaluate the long‐term efficacy and safety of adding repaglinide in patients with type 2 diabetes mellitus whose blood glucose levels were not sufficiently controlled by treatment with a dipeptidyl peptidase‐4 inhibitor, sitagliptin, in addition to diet and exercise therapies.

          Materials and Methods

          This was a multicenter, uncontrolled, dose‐titration study with a treatment period of 52 weeks. The primary end‐point was the change in glycated hemoglobin levels from baseline.

          Results

          The glycated hemoglobin level was 7.43 ± 0.57% (mean ± standard deviation) at baseline, and decreased to 6.93 ± 0.91% at the end of the study. The mean changes in glycated hemoglobin levels at 4 weeks and at the end of the study were −0.44 ± 0.28% and −0.50 ± 0.82%, respectively. The glycated hemoglobin‐lowering effect was maintained for 52 weeks. The rate of adverse events was 86.0% (86/100), and there were 352 adverse events. The rate of adverse drug reactions was 21.0% (21/100). Hypoglycemia was reported in 5.0% (5/100) of patients, but there was no incidence of ‘major hypoglycemia’.

          Conclusions

          Combination therapy with repaglinide and sitagliptin was considered effective for a long term without clinical safety problems in patients with type 2 diabetes mellitus.

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          Most cited references 11

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          The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group.

          Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications. A total of 1441 patients with IDDM--726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly. In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of > or = 40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of > or = 300 mg per 24 hours) by 54 percent (95 percent confidence interval 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia. Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.
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            Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.

             R Turner,  C Fox,  DR Matthews (1998)
            Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial. 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group, the aim was the best achievable FPG with diet alone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy. Over 10 years, haemoglobin A1c (HbA1c) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group--an 11% reduction. There was no difference in HbA1c among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg). Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes.(ABSTRACT TRUNCATED)
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              Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.

              To determine the relation between exposure to glycaemia over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes. Prospective observational study. 23 hospital based clinics in England, Scotland, and Northern Ireland. 4585 white, Asian Indian, and Afro-Caribbean UKPDS patients, whether randomised or not to treatment, were included in analyses of incidence; of these, 3642 were included in analyses of relative risk. Primary predefined aggregate clinical outcomes: any end point or deaths related to diabetes and all cause mortality. Secondary aggregate outcomes: myocardial infarction, stroke, amputation (including death from peripheral vascular disease), and microvascular disease (predominantly retinal photo-coagulation). Single end points: non-fatal heart failure and cataract extraction. Risk reduction associated with a 1% reduction in updated mean HbA(1c) adjusted for possible confounders at diagnosis of diabetes. The incidence of clinical complications was significantly associated with glycaemia. Each 1% reduction in updated mean HbA(1c) was associated with reductions in risk of 21% for any end point related to diabetes (95% confidence interval 17% to 24%, P<0.0001), 21% for deaths related to diabetes (15% to 27%, P<0.0001), 14% for myocardial infarction (8% to 21%, P<0.0001), and 37% for microvascular complications (33% to 41%, P<0.0001). No threshold of risk was observed for any end point. In patients with type 2 diabetes the risk of diabetic complications was strongly associated with previous hyperglycaemia. Any reduction in HbA(1c) is likely to reduce the risk of complications, with the lowest risk being in those with HbA(1c) values in the normal range (<6.0%).
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                Author and article information

                Affiliations
                [ 1 ] Sportology CenterJuntendo University Graduate School of Medicine TokyoJapan
                [ 2 ] Department of General Internal Medicine 1Kawasaki Medical School KurashikiJapan
                [ 3 ] Department of Internal Medicine (I)Osaka Medical College TakatsukiJapan
                [ 4 ]Sumitomo Dainippon Pharma Co., Ltd. TokyoJapan
                [ 5 ]Clinical Research Support Center The Jikei University School of Medicine TokyoJapan
                [ 6 ]Labor, Health and Welfare Organization Chubu‐Rosai Hospital NagoyaJapan
                Author notes
                [* ] Correspondence

                Katsuhisa Ioriya

                Tel.: +81‐3‐5159‐2539

                Fax: +81‐3‐5159‐3231

                E‐mail address: katsuhisa-ioriya@ 123456ds-pharma.co.jp

                Journal
                J Diabetes Investig
                J Diabetes Investig
                10.1111/(ISSN)2040-1124
                JDI
                Journal of Diabetes Investigation
                John Wiley and Sons Inc. (Hoboken )
                2040-1116
                2040-1124
                19 July 2015
                March 2016
                : 7
                : 2 ( doiID: 10.1111/jdi.2016.7.issue-2 )
                : 253-259
                JDI12384
                10.1111/jdi.12384
                4773675
                27042279
                © 2015 Sumitomo Dainippon Pharma Co., Ltd. Journal of Diabetes Investigation published by Asian Association of the Study of Diabetes (AASD) and Wiley Publishing Asia Pty Ltd

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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                Pages: 7
                Product
                Funding
                Funded by: Sumitomo Dainippon Pharma Co., Ltd.
                Categories
                Clinical Trial
                Articles
                Clinical Science and Care
                Custom metadata
                2.0
                jdi12384
                March 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.7.6 mode:remove_FC converted:02.03.2016

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