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A Randomized Controlled Trial of Liraglutide Versus Therapeutics The Journal of Clinical Pharmacology A Randomized Controlled Trial of Liraglutide 2015, XX(XX) 1–8 © 2015, The American College of Clinical Pharmacology Versus Insulin Detemir Plus Sitagliptin: Effective DOI: 10.1002/jcph.483 Switch From Intensive Insulin Therapy to the Once-Daily Injection in Patients With Well-Controlled Type 2 Diabetes Yuichiro Inoue, MD1, Akinobu Nakamura, MD, PhD1,2, Yoshinobu Kondo, MD1,3, Kumiko Hamano, MD4, Shinobu Satoh, MD, PhD3, and Yasuo Terauchi, MD, PhD1 Abstract This study aimed to compare the efficacy and safety of liraglutide versus insulin detemir plus sitagliptin in Japanese patients with type 2 diabetes treated with a basal-bolus insulin regimen. In this multicenter, open-label trial, 90 patients whose diabetes had been controlled well or moderately (glycated hemoglobin [HbA1c] 7.3%) with basal-bolus insulin regimen were randomly assigned to a liraglutide group or a detemir group and were followed up for 24 weeks. The primary end point was HbA1c change from baseline to 24 weeks. Of the 90 enrolled patients, 82 completed this trial. At 24 weeks, the mean changes in HbA1c from baseline were 0.1% Æ 0.9% versus 0.3% Æ 0.8% in the liraglutide versus detemir groups, respectively (P ¼ .46). The “overall” satisfaction score for the Diabetes Treatment Satisfaction Questionnaire changed from 25.2 Æ 7.4 to 29.9 Æ 5.3 (P < .001) and from 26.4 Æ 6.1 to 28.3 Æ 6.4 (P ¼ .12) in the liraglutide and detemir groups, respectively. Although the mean change difference in HbA1c between both groups was not significant, switching from a basal-bolus insulin regimen to liraglutide once daily improved patient satisfaction levels without loss of glycemic control. Keywords liraglutide, basal-bolus insulin regimen, patient’s satisfaction, type 2 diabetes In patients with type 2 diabetes and uncontrolled ing from frequent injections to once-daily injections may hyperglycemia, a basal-bolus insulin regimen is the be convenient for these patients and may improve their recommended treatment compared with biphasic, prandi- treatment satisfaction. al, or basal insulin regimens.1,2Tight glycemic control is A new class of incretin-based antidiabetic agents, associated with reduced risks of long-term microvascular glucagon-like peptide-1 (GLP-1) receptor agonists and complications for these patients.3–5 However, intensive glucose-lowering therapy can result in an increased frequency of hypoglycemia and weight gain.6,7 Further- more, the intensive treatment arm of the Action to Control 1Department of Endocrinology and Metabolism, Graduate School of Cardiovascular Risk in Diabetes study, targeting glycated Medicine, Yokohama City University, Yokohama, Japan 2Division of Immunology and Metabolism, Department of Internal hemoglobin (HbA1c) < 6.0% (42 mmol/mol), was discontinued because of higher mortality and cardiovas- Medicine II, Graduate School of Medicine, Hokkaido University, Sapporo, Japan cular events in this group compared with the standard 3Department of Endocrinology and Metabolism, Chigasaki Municipal therapy group targeting HbA1c from 7.0% (53 mmol/mol) Hospital, Chigasaki, Kanagawa, Japan 8 to 7.9% (63 mmol/mol). 4Department of Diabetes and Endocrinology, Kanto Rosai Hospital, The prevalence of type 2 diabetes mellitus in the Kawasaki, Kanagawa, Japan elderly population is increasing, and diabetes is associated Submitted for publication 24 November 2014; accepted 11 February with an increased incidence of functional disability. The 2015. causes are multifactorial, including microvascular and macrovascular complications, comorbidities, and aging.9 Corresponding Author: In addition, diabetes has been associated with a greater Yasuo Terauchi, MD, PhD, Professor, Department of Endocrinology 10,11 and Metabolism, Graduate School of Medicine, Yokohama City risk of cognitive decline and function. Therefore, it is University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan assumed that there will be increased difficulty among this Email: [email protected] population to continue frequent insulin therapy. Switch- HbA1c is expressed by NGSP values. 2 The Journal of Clinical Pharmacology / Vol XX No XX 2015 dipeptidyl peptidase–4 (DPP-4) inhibitors, is available for was continued during the first week, reduced by half the treatment of type 2 diabetes. The GLP-1 receptor during the second week, and discontinued at the end of the agonist, especially liraglutide, improves postprandial second week. At 4 and 8 weeks, if self-measured fasting glycemic control and reduces body weight without blood glucose (FBG) was >160 mg/dL, glimepiride increasing the risk of severe hypoglycemia in patients 0.5 mg/day was added, and the dose was increased to with type 2 diabetes.12,13 Adding a DPP-4 inhibitor to 1.0 mg/day, if necessary. insulin therapy is also useful in glycemic control without In the detemir group, the starting dose was used causing severe hypoglycemia, especially for long-acting throughout the study. At 0 weeks, sitagliptin (50 mg/day, and once-daily insulin regimens.14 after breakfast) was added to insulin detemir. During the However, there are no prospective studies assessing first 8 weeks, insulin detemir was titrated once every 2 the effectiveness of switching from a basal-bolus insulin weeks by patients, based on self-measured FBG, aiming regimen to once-daily injection. Therefore, in this study, for a target value of 90 FBG 130 mg/dL. we compared the efficacy, safety, and patient satisfaction Subsequently, the insulin detemir dose was fixed for 16 with liraglutide versus insulin detemir plus sitagliptin. weeks. Liraglutide (6.0 mg/mL) and insulin detemir (100 units/mL) were injected subcutaneously once daily with injection pens. Patients and Methods Trial Design Outcomes The study was a 24-week open-label, randomized, The primary outcome measure was the change in HbA1c controlled trial conducted in Japanese patients with type from randomization (week 0) to week 24 after the 2 diabetes at 3 institutions (Yokohama City University administration of liraglutide or insulin detemir. The School of Medicine, Yokohama, Japan; Chigasaki Munic- secondary outcome measures were the changes in FPG, ipal Hospital, Chigasaki, Japan; and Kanto Rosai Hospital, self-monitoring blood glucose (SMBG), and body weight Kawasaki, Japan). The trial was registered at the University at 0, 8, 16, and 24 weeks. Our patients measured blood Hospital Medical Information Network (UMIN) Center glucose 6 times per day (each before and 2 hours after the under the identifier UMIN 000007009. The study protocol start of meals), once weekly. We calculated the mean was compliant with the Declaration of Helsinki, and it was postprandial blood glucose based on the data measured at approved by the ethics committee of the participating sites. the latest 2 times. All patients provided their written informed consent. Eight Adverse effects, such as hypoglycemia and gastrointes- weeks before randomization, the long-acting insulin tinal symptoms, were monitored during this trial. Hypo- injection was switched to insulin detemir once daily glycemia was defined as an FPG of <70 mg/dL or the before breakfast, and the oral glucose-lowering agents presence of hypoglycemic symptoms. The occurrence of were discontinued. Patients were randomized in a 1:1 ratio other symptoms was diagnosed by the physicians in to liraglutide or insulin detemir group by the institution charge. using central computer-based randomization. Patient-reported outcomes were measured using the The 90 randomized patients with type 2 diabetes were Diabetes Treatment Satisfaction Questionnaire, status aged 20 years and were treated with a basal-bolus version (DTSQs). 15 The DTSQs includes 8 items, and insulin regimen for at least 3 months before screening. responses are scored on a 7-point scale, from þ6 to 0. The Inclusion criteria included a diagnosis of type 2 diabetes, scores of the 6 items of the DTSQs (current treatment, HbA1c level 7.3% (56 mmol/mol), and treatment with a convenience, flexibility, understanding, likelihood of basal-bolus insulin regimen and insulin dose of 30 units. recommending their present treatment [recommend], Patients with a history of diabetic ketoacidosis or diabetic and satisfaction to continue with their present treatment coma within 6 months prior to the study entry, who were [continue]) were summed as the “overall” treatment pregnant or lactating, with severe infection or trauma, satisfaction score, ranging from þ36 to 0, with higher undergoing surgical operation during the study, undergo- scores denoting greater treatment satisfaction. In addition, ing steroid therapy, with a history of cardiac failure, with we included “perceived frequency of hyperglycemia severe organ dysfunction, with type 1 diabetes, with (Hyperglycemia)” and “perceived frequency of hypogly- insulin secretion disorders (fasting serum C-peptide < cemia (Hypoglycemia)” in the DTSQs, which were rated 0.5 ng/mL), and with a history of hypersensitivity to on a scale of þ6 (“most of the time”) to 0 (“never”). liraglutide, detemir, or sitagliptin were excluded. Patients completed a Japanese version of the DTSQ at 0 In the liraglutide group, patients underwent a 2-week and 24 weeks.16 dose escalation, starting at 0.3 mg once daily with weekly increments of 0.3 mg, reaching a final daily dose of 0.9 mg Statistical Analysis by the end of the second week. Subsequently, the A total of 74 patients (37 per treatment) were required to liraglutide dose was fixed for 22 weeks. Insulin detemir
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