glucose, and mean blood glucose (MBG)] were measured. MannâWhitney U ... glucose, CV of glucose, and MBG between groups. ... and abnormal glucagon secretion.6 Glycated hemoglobin. A1c ... A1C fails to estimate glycemic variability.7.
DIABETES TECHNOLOGY & THERAPEUTICS Volume 19, Number 8, 2017 ª Mary Ann Liebert, Inc. DOI: 10.1089/dia.2017.0020
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ORIGINAL ARTICLE
Effect of Linagliptin Versus Metformin on Glycemic Variability in Patients with Impaired Glucose Tolerance Tonatiuh Gonza´lez-Heredia, MD, MSc, PhD, Diana M. Herna´ndez-Corona, RD, MSc, PhD, Manuel Gonza´lez-Ortiz, MD, MSc, PhD, FACP, and Esperanza Martı´nez-Abundis, MD, MSc, PhD, FACP
Abstract
Background: Impaired glucose tolerance (IGT) and glycemic variability may be associated with increased risk of micro- and macrovascular complications. The aim of this study was to assess the effect of linagliptin versus metformin on glycemic variability in patients with IGT. Material and Methods: A randomized, double-blind clinical trial with parallel groups was carried out in 16 adult patients with IGT, overweight or obesity. All patients signed an informed consent. The therapies were randomly assigned: (a) metformin 500 mg bid (n = 8) or (b) linagliptin 5 mg a.m. and placebo p.m. (n = 8), both for 90 days. At the beginning of the trial and 3 months later, fasting glucose, glycated hemoglobin A1c, oral glucose tolerance test (OGTT), and glycemic variability [area under the curve (AUC) of glucose, mean amplitude of glycemic excursion (MAGE), standard deviation (SD) of glucose, coefficient of variation (CV) of glucose, and mean blood glucose (MBG)] were measured. Mann–Whitney U, Wilcoxon, and Fisher exact tests were used for statistical analyses. Results: Both groups were similar in basal characteristics. After linagliptin administration, a significant decrease in glucose levels at 120 min of OGTT (9.0 – 0.9 vs. 6.9 – 2.2 mmol/L, P = 0.012) was observed. Glycemic variability showed a similar behavior and there were no significant differences in the AUC, MAGE, SD of glucose, CV of glucose, and MBG between groups. Conclusion: Linagliptin administration resulted in better glycemic control according to the decrease of glucose levels by the OGTT at 120 min in patients with IGT. Meanwhile, glycemic variability was not modified in any of the study groups. Keywords: Linagliptin, Metformin, Glycemic variability, Continuous glucose monitoring, Glucose intolerance.
oral agents and/or basal insulin because of factors such as insulin resistance, insufficient insulin production or action, and abnormal glucagon secretion.6 Glycated hemoglobin A1c (A1C) measures glucose from the previous 3 months, but A1C fails to estimate glycemic variability.7 Metformin therapy for prevention of type 2 diabetes may be considered in those patients with prediabetes (IGT, impaired fasting glucose, or A1C 5.7%–6.4%). In addition, it has been demonstrated that metformin has the strongest evidence base for long-term safety as a pharmacological therapy for diabetes prevention8,9 Linagliptin, a dipeptidyl peptidase-4 inhibitor, increases glucose-induced insulin secretion, decreases glucagon secretion, and reduces postprandial glycemic excursions,
Introduction
I
mpaired glucose tolerance (IGT) represents a state that often progresses to overt diabetes within a few years. In addition, IGT and glycemic variability may be associated with increased risk of micro- and macrovascular complications.1 In recent years, studies suggest that not only chronic hyperglycemia but also daily glycemic fluctuation or glycemic variability leads to accelerated glycation in the short term and to the development of long-term micro- and macrovascular complications. Glycemic fluctuation occurs not only in patients with type 2 diabetes but also in IGT subjects.2–5 Glycemic control has been difficult with traditional
Department of Physiology, Institute of Experimental and Clinical Therapeutics, Health Sciences University Center, University of Guadalajara, Guadalajara, Mexico.
1
´ LEZ-HEREDIA ET AL. GONZA
2
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making it a good candidate to enhance glycemic control and variability.10 The aim of this study was to evaluate the effect of linagliptin versus metformin on glycemic variability in patients with IGT. Materials and Methods
A randomized, double-blind clinical trial with parallel groups was performed in 16 adults (30 to 60 years of age) who were overweight or obese [body mass index (BMI), 25– 34.9 kg/m2] and IGT [glucose 7.7–11 mmol/L after a 2-h oral glucose tolerance test (OGTT) with a 75-g oral dextrose load]. Weight of the participants was stable for at least 3 months before the study. Exclusion criteria were pregnant patients, those who were breastfeeding, patients with diabetes mellitus, hypertension, and thyroid, renal or liver disease, or any other chronic disease. In addition, patients were excluded from the study if they exhibited any contraindication for the use of metformin or linagliptin or if they were using any medications with known effects on glucose metabolism. Sixteen patients with IGT participated in this trial. Eight patients were randomly allocated to receive an oral dose of metformin (500 mg bid) (Predial, Laboratorios Silanes, S.A. de C.V., Me´xico) before breakfast and dinner. The second group with eight subjects received 5 mg of linagliptin (Trayenta, Boehringer Ingelheim–Lilly, Mexico) before breakfast and 500 mg of placebo before dinner. Both groups followed the treatments for 3 months. All patients received general recommendations about their medical nutritional therapy and were instructed to not modify their usual exercise habits. At the beginning of the study and 3 months later, clinical and laboratory measurements were evaluated. At days 30, 60, and 90, tolerability and compliance of medications were assessed in all subjects. Tests were performed at 8:00 a.m. after a 10–12 h overnight fast. Weight and height were recorded with the subjects wearing light clothing and without shoes and assessed by bioelectrical impedance analysis using a contact electrode foot-foot body fat analyzer system (TBF-300- A; Tanita Corporation of America, Inc., Arlington Heights, IL). Height was measured and rounded off to the nearest centimeter with the subjects standing. Waist circumference was taken at the midline between the highest point of the iliac crest and the lowest rib in the mid-axillary line. BMI was calculated as weight (kg) divided by height squared (m). Blood pressure was measured three times at the left arm with a digital sphygmomanometer (Omron Hem-907 XL) with the subject seated on a chair after a 5 min rest. The mean of the three measurements was considered as the value of systolic blood pressure and diastolic blood pressure expressed in mmHg. Venous blood was obtained with the subject lying supine in a quiet room. Blood was allowed to clot for 30 min at room temperature and then centrifuged. The resulting serum was placed into an aliquot, which was immediately used for measurement of serum glucose, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Immediately afterward, a glucose load containing the equivalent to 75 g of anhydrous glucose dissolved in water was given to all patients and 2 h later a new blood sample was obtained to measure glucose concentration. Serum glucose was determined by the glucose–oxidase technique with an intra- and interassay coefficient of varia-
tion (CV) of
