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The Combination of Canagliflozin with a Half-Dose of Glimepiride Harada et al. Int J Diabetes Clin Res 2016, 3:065 Volume 3 | Issue 3 International Journal of ISSN: 2377-3634 Diabetes and Clinical Research Original Article: Open Access The Combination of Canagliflozin with a Half-Dose of Glimepiride Improves Glycemic Control and Blood Glucose Perturbation without Increasing the Risk of Hypoglycemia and Ketosis Mayuko Harada, Yasuhisa Abe, Yuki Maeda, Michiko Kajikawa, and Mitsuru Hashiramoto* Division of Diabetes and Endocrinology, Yodogawa Christian Hospital, Japan *Corresponding author: Mitsuru Hashiramoto, MD, PhD, Division of Diabetes and Endocrinology, Yodogawa Christian Hospital, 1-7-50 Kuni-Jima, Higashi-Yodogawa-Ku, Osaka 533-0024, Japan, Tel: +81-6-6322-2259, Fax: +81-6-6-6320-6308, E-mail: [email protected] Abstract Introduction Aim: To evaluate the efficacy and safety of administering The application of sulfonylurea (SU) remains one of the most canagliflozin to Japanese type 2 diabetes mellitus (T2DM) patients popular approaches in pharmacological therapy for type 2 diabetes and reducing the dosage of their existing regimen of sulfonylurea mellitus (T2DM) patients because SU exerts potent stimulatory (SU) by half. effects on insulin secretion from pancreatic β cells and is relatively Methods: Seventeen Japanese T2DM patients on antidiabetes inexpensive and well tolerated. Hypoglycemia, however, is a major medication (SU) completed this 12-week prospective single-arm safety concern that is associated with the use of SUs, because it open-label study. First, the dose of SU was reduced by half and impairs a patient's quality of life and can become life threatening a concomitant administration of canagliflozin (100 mg/day) was initiated. Glycemic control and other metabolic parameters were when protracted. measured at weeks 0, 4, 8 and 12. The cardiovascular (CV) toxicity of hypoglycemia has drawn Results: At 12 weeks, average HbA1c levels had declined from renewed attention because of recent large-scale clinical trials [1]. 7.3 ± 0.3% (56 mmol/mol) to 7.1 ± 0.4% (53 mmol/mol) (p < 0.05). Hypoglycemia, particularly when severe, is a powerful stimulant of Continuous glucose monitoring showed average blood glucose the sympathetic nervous system, which may potentially trigger CV (BG) levels (mg/dl) reduced from 156.8 ± 23.5 to 129.4 ± 10.4 (p < events such as sudden cardiac arrest, acute myocardial infarction, and 0.05) with a standard deviation (SD) of from 45.7 ± 12.6 to 32.4 ± 9.0 (NS). Neither severe hypoglycemia nor other serious adverse cardiac arrhythmias including prolongation of the QT interval and events developed during the study period. Serum ketone bodies ventricular arrhythmias [2,3]. Hypoglycemia is also proinflammatory were transiently elevated from 61 ± 47 to 162 ± 140 (p < 0.05) at 4 and can increase the risk of plaque inflammation, rupture, and CV weeks but were decreased afterward. events [4,5]. Thus, it is suggested that patients with long-standing Conclusion: This study showed that a combination of canagliflozin T2DM, who presumably bear higher CV risks such as progressed preceded by a reduced dose of SU resulted in an acceptable short- atherosclerosis and/or existing CV diseases, may be more susceptible term tolerability and a significant improvement in glycemic control to the cardio toxicity that can be induced by hypoglycemia. without increasing the risk of hypoglycemia and severe ketosis. Intensive therapeutic regimens like multiple daily insulin Keywords injections combined with frequent self-monitoring of capillary SGLT2 inhibitor, Sulfonylurea, Canagliflozin, Continuous glucose blood glucose levels (SMBG) are believed to be one of the most monitoring, Hypoglycemia, Ketosis, Ketoacidosis useful methods of achieving good metabolic control. Such Abbreviations intensive regimens, however, can usually increase the incidence of T2DM: type 2 diabetes mellitus; SU: sulfonylurea; SD: standard hypoglycemia over time. Thus, it often becomes difficult to achieve deviation; CV: cardiovascular; SMBG: self-monitoring of capillary blood optimal control [6], despite the use of multiple insulin injections and glucose levels; CGMs: continuous glucose monitoring system; SGLT: frequent SMBG, partly because of the limitations of the glycemic Sodium glucose transporter; BG: blood glucose; eGFR: estimated profile obtained from intermittent finger-sticks [7]. Furthermore, a glomerular filtration rate; FPG: fasting plasma glucose; SBP: systolic high incidence of unrecognized hypoglycemia has been detected in blood pressure; DBP: diastolic blood pressure; HOMA: homeostasis model assessment; LDL-C: low density lipoprotein cholesterol; diabetes patients treated with insulin [8]. Since the potential danger HDL-C: high density lipoprotein cholesterol; TG: triglyceride; FFA: free of these unrecognized bouts of hypoglycemia is well understood, one fatty acid; Ht: hematocrit; Alb: albumin; Cr: creatinine; AEs: adverse of the main objectives for glycemic control in patients with diabetes events; BMI: body mass index; DKA: diabetic ketoacidosis; MAGE: is to detect and prevent these events. mean amplitude of glycemic excursions; T1DM: type 1 diabetes mellitus; MODD: mean of the daily difference To overcome these limitations, a new sensor system for continuously measuring glucose concentrations in subcutaneous Citation: Harada M, Abe Y, Maeda Y, Kajikawa M, Hashiramoto M (2016) The Combination of Canagliflozin with a Half-Dose of Glimepiride Improves Glycemic Control and Blood Glucose Perturbation without Increasing the Risk of Hypoglycemia and Ketosis. Int J ClinMed Diabetes Clin Res 3:065 International Library Received: September 09, 2016: Accepted: September 30, 2016: Published: October 04, 2016 Copyright: © 2016 Harada M, et al. 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. Sulfonylurea Canagliflozin 100mg/day CGMs CGMs -12 0 4 8 12 Blood & urine exam. Blood & urine exam. Blood & urine exam. Blood & urine exam. Time of visits (weeks) Figure 1: Study design. tissue, the continuous glucose monitoring system (CGMs), has and < 9.0% (75 mmol/mol) at the time of screening. Key exclusion come on the market and has revolutionized the monitoring of short- criteria included an estimated glomerular filtration rate (eGFR) < term glucose variability. This system has been quickly validated by a 45 ml/min/1.73 m2 (using the MDRD equation); acute coronary variety of clinical settings in many countries and has provided data syndrome, stroke, or transient ischemic attack within 3 months prior showing a correlation between blood and interstitial glucose levels to consent; severe liver dysfunction. [9-11]. The CGMs has become a powerful system for the detection of unrecognized hypoglycemia, particularly at night and even between Treatment and interventions meals during the day. At the beginning of the study, the dose of previously prescribed Sodium glucose transporter (SGLT) 2 inhibitors is a new class SU, irrespective of the type and dose, was reduced by half and a of oral hypoglycemic agents that increase urinary glucose excretion concomitant administration of canagliflozin, 100 mg/day, was by inhibiting SGLT2 in the renal proximal tubules, which reduces initiated. Canagliflozin was taken once daily after breakfast. Study renal glucose reabsorption and decreases plasma glucose levels in visits were at the baseline and at weeks 4, 8, and 12 of treatment. an insulin-independent manner [12]. The glucose-lowering effect of Glycemic control (HbA1c, glycoalbumin) and other metabolic SGLT2 inhibition seems to be self-limiting such that when the blood parameters were measured at the baseline and at weeks 4, 8, and glucose (BG) concentration decreases to concentrations at which 12 of treatment. Daily profiles of BG and glycemic variability hypoglycemic symptoms are experienced, the remaining SGLT2 were evaluated via a CGMs (iPro2, Medtronix, Dublin, Ireland) activity and the SGLT1 activity can reabsorb much of the filtered at the baseline and at week 12 of treatment with canagliflozin glucose, preventing a further loss of glucose. The mechanism of action administration (Figure 1). CGMs measurement was based relies on SGLT2 inhibitors that save either endogenous or exogenous on enzymatic electrode method and was calibrated by SMBG insulin in patients who are treated with insulin secretagogue(s) and/ conducted four times per day before each meal and the bedtime. or insulin injection [13]. Thus, we could expect the co-administration Statistical analysis of the data was performed using a Wilcoxon of SGLT2 inhibitor with an existing SU regimen would result in a and Dunn test. reduction in the dose of SU without serious deterioration of glycemic control. Endpoints and assessments The aim of this study was to use CGMs to evaluate the efficacy The primary endpoints were the week-12 changes from the and safety of administering canagliflozin to Japanese T2DM patients baseline values for HbA1c, glycoalbumin, fasting plasma glucose who are already receiving an existing regimen of SU, which could (FPG), and in the daily profiles of BG and glycemic variability, as then be reduced by one-half. We assumed that the addition of evaluated via CGMs. The exploratory secondary endpoints were the SGLT2 inhibitors could be useful not only to reduce the dose of the week-12 values: changes from the baseline in weight, systolic blood preceding
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