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      Profile of saxagliptin in the treatment of type 2 diabetes: focus on Japanese patients

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          Saxagliptin is a selective and potent dipeptidyl peptidase (DPP)-4 inhibitor, approved as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus (T2DM) in the USA on July 2009, and had been launched globally in over 86 countries by September 2013. In patients with T2DM, once-daily administration of saxagliptin before breakfast achieves sustained inhibition of plasma DPP-4 activity and reduction of postprandial hyperglycemia, including after dinner, associated with an increase in plasma glucagon-like peptide-1 levels. This paper reviews the safety and efficacy of saxagliptin in Japanese patients with T2DM. The clinical development study in Japan supported its usefulness for the disease. Saxagliptin 1, 2.5, and 5 mg led to significant improvements in glycated hemoglobin (HbA 1c), and was generally well tolerated. Treatment with saxagliptin 5 mg induced a sustained reduction in HbA 1c over 52 weeks. Long-term combination therapy with saxagliptin and other oral hypoglycemic agents also provided sustained glycemic control and was well tolerated for up to 52 weeks. Saxagliptin as add-on to sulfonylureas or glinides has a tendency to increase hypoglycemia, but not with other oral antidiabetic agents, such as α-glucosidase inhibitors, metformin, or thiazolidinediones. The results of clinical trials have confirmed the long-term efficacy and safety of saxagliptin monotherapy as well as its use as add-on combination therapy, and support its usefulness as a therapeutic agent for T2DM. Saxagliptin has less concern for hypoglycemia and weight gain, which often becomes problematic in routine care of T2DM. Meta-analysis of clinical trials in the USA showed no evidence of increased risk of cardiovascular events associated with saxagliptin, suggesting the superior of saxagliptin in terms of safety. Recently, investigators in the SAVOR-TIMI (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction) 53 study suggested that DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events, although the rate of hospitalization for heart failure was increased. Although saxagliptin improves glycemic control, other approaches are necessary to reduce cardiovascular risk in patients with diabetes. Saxagliptin is applicable for various pathological conditions, and is considered to be clinically significant as a new therapeutic option for Japanese patients with T2DM.

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          The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes.

           S. J. Kahn (2002)
          The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes have been debated extensively. The concept that a feedback loop governs the interaction of the insulin-sensitive tissues and the beta cell as well as the elucidation of the hyperbolic relationship between insulin sensitivity and insulin secretion explains why insulin-resistant subjects exhibit markedly increased insulin responses while those who are insulin-sensitive have low responses. Consideration of this hyperbolic relationship has helped identify the critical role of beta-cell dysfunction in the development of Type 2 diabetes and the demonstration of reduced beta-cell function in high risk subjects. Furthermore, assessments in a number of ethnic groups emphasise that beta-cell function is a major determinant of oral glucose tolerance in subjects with normal and reduced glucose tolerance and that in all populations the progression from normal to impaired glucose tolerance and subsequently to Type 2 diabetes is associated with declining insulin sensitivity and beta-cell function. The genetic and molecular basis for these reductions in insulin sensitivity and beta-cell function are not fully understood but it does seem that body-fat distribution and especially intra-abdominal fat are major determinants of insulin resistance while reductions in beta-cell mass contribute to beta-cell dysfunction. Based on our greater understanding of the relative roles of insulin resistance and beta-cell dysfunction in Type 2 diabetes, we can anticipate advances in the identification of genes contributing to the development of the disease as well as approaches to the treatment and prevention of Type 2 diabetes.
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            Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and non-Asians: a systematic review and meta-analysis.

            The aim of this work was to compare the glucose-lowering efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors between Asian and non-Asian patients with type 2 diabetes. We searched MEDLINE, EMBASE, LILACS, CENTRAL, ClinicalTrials.gov and conference proceedings. Studies were eligible if they were randomised controlled trials with a treatment duration of at least 12 weeks, compared a DPP-4 inhibitor with a placebo as either monotherapy or oral combination therapy, had information on ethnicity and HbA1c values and were published or described in English. A systematic review and meta-analysis with a meta-regression analysis was conducted. Among 809 potentially relevant studies, 55 trials were included. A meta-analysis revealed that DPP-4 inhibitors lowered HbA1c to a greater extent in studies with ≥50% Asian participants (weighted mean difference [WMD] -0.92%; 95% CI -1.03, -0.82) than in studies with <50% Asian participants (WMD -0.65%; 95% CI -0.69, -0.60). The between-group difference was -0.26% (95% CI -0.36, -0.17, p < 0.001). The baseline BMI significantly correlated with the HbA1c-lowering efficacy of DPP-4 inhibitors. The RR of achieving the goal of HbA1c <7.0% (53.0 mmol/mol) was higher in studies with ≥50% Asian participants (3.4 [95% CI 2.6, 4.7] vs 1.9 [95% CI 1.8, 2.0]). The fasting plasma glucose-lowering efficacy was higher with monotherapy in the Asian-dominant studies, but the postprandial glucose-lowering efficacy and changes in body weight were comparable between the two groups. DPP-4 inhibitors exhibit a better glucose-lowering efficacy in Asians than in other ethnic groups; this requires further investigation to understand the underlying mechanism, particularly in relation to BMI.
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              Insulin secretion capacity in the development from normal glucose tolerance to type 2 diabetes.

              We have examined the contribution of insulin secretion and insulin resistance to glucose intolerance in Japanese. Some indices of insulin secretion and insulin sensitivity based on the results of OGTT were used. The decline of insulin secretion capacity was significant throughout the development of glucose intolerance from NGT via IGT to DM. Decreased insulinogenic indices were conspicuous when it is compared with other types of diabetes. Slight impairment of insulin secretion has begun in subjects with NGT. The progression from NGT via isolated IGT to isolated post-challenge hyperglycemia was considered mostly due to the deterioration of early-phase insulin secretion. It is summarized that decreased insulin secretion capacity takes a definite role in the development from NGT to type 2 diabetes in Japan.

                Author and article information

                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                11 July 2014
                : 10
                : 547-558
                [1 ]Department of Internal Medicine, Ashiya Municipal Hospital, Ashiya, Japan
                [2 ]Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
                [3 ]Division of Innovative Diabetes Treatment, Hyogo College of Medicine, Nishinomiya, Japan
                [4 ]Division of Diabetes, Department of Internal Medicine, Itami City Hospital, Itami, Hyogo, Japan
                Author notes
                Correspondence: Hiroyuki Konya, Department of Internal Medicine, Ashiya Municipal Hospital, 39-1 Asahigaoka-cho, Ashiya, Hyogo 659-8502, Japan, Tel +817 9731 2156, Fax +817 9722 8822, Email h-dyer@ 123456mvi.biglobe.ne.jp
                © 2014 Konya et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.



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