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©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
Blood glucose response after oral lactulose intake in type 2 diabetic individuals
Thomas R Pieber, Eva Svehlikova, Ines Mursic, Tamara Esterl, Manfred Wargenau, Tina Sartorius, Lioba Pauly, Susann Schwejda-Guettes, Annalena Neumann, Valentin Faerber, John Friedrich Stover, Barbara Gaigg, Angelika Kuchinka-Koch
Thomas R Pieber, Eva Svehlikova, Ines Mursic, Tamara Esterl, Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz 8036, Austria
Manfred Wargenau, Department of Statistic, M.A.R.C.O. GmbH & Co. KG, Institute for Clinical Research and Statistics, Düsseldorf 40211, Germany
Tina Sartorius, Department of Nutritional CRO, BioTeSys GmbH, Esslingen 73728, Germany
Lioba Pauly, Susann Schwejda-Guettes, Department of Medical & Clinical Affairs, Market Access & Education Business Unit Enteral Nutrition, Bad Homburg 61352, Germany
Annalena Neumann, Valentin Faerber, Department of Medical, Clinical & Regulatory Affairs, Business Unit Parenteral Nutrition, Keto-Analogues and Standard I.V. Fluids, Fresenius Kabi Deutschland GmbH, Bad Homburg 61352, Germany
John Friedrich Stover, Department of Consultancy, Stover-Solutions, Zurich 8006, Switzerland
Barbara Gaigg, Angelika Kuchinka-Koch, Market Unit Lactulose, Fresenius Kabi Austria GmbH, Linz 4020, Austria
Author contributions: Pieber TR, Svehlikova E, Mursic I, and Esterl T performed the study, data collection and interpretation; Stover JF, Pauly L, Schwejda-Guettes S, Kuchinka-Koch A, and Gaigg B designed and supervised the study; Wargenau M planned and performed the statistical analysis of the data and interpreted the results; Sartorius T, Neumann A, and Faerber V wrote the manuscript; all authors reviewed, edited, and approved the manuscript for submission.
Supported by Fresenius Kabi Deutschland GmbH, Germany.
Institutional review board statement: This study protocol was reviewed and approved by the Independent Ethics Committee of the Medical University of Graz, Austria.
Clinical trial registration statement: This study was registered in the European Union Drug Regulating Authorities Clinical Trials Database, No. 2018-002359-14.
Informed consent statement: All study participants provided written informed consent prior to enrollment.
Conflict-of-interest statement: The study was sponsored by Fresenius Kabi Deutschland GmbH, Germany. The sponsor’s representatives contributed to the study design and the selection of outcome measures before study start but had no role in study execution or data collection, or data analyses. All other authors declare no potential conflicts of interest related to this paper.
Data sharing statement: No additional data are available.
CONSORT 2010 statement: The authors read the CONSORT 2010 Statement, and the manuscript was prepared and revised according to that statement.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
http://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Valentin Faerber, PhD, Director, Department of Medical, Clinical & Regulatory Affairs, Business Unit Parenteral Nutrition, Keto-Analogues and Standard I. V. Fluids, Fresenius Kabi Deutschland GmbH, Else-Kroener-Straße 1, Bad Homburg 61352, Germany. valentin.faerber@fresenius-kabi.com
Received: December 3, 2020
Peer-review started: December 3, 2020
First decision: March 14, 2021
Revised: April 7, 2021
Accepted: April 22, 2021
Article in press: April 22, 2021
Published online: June 15, 2021
BACKGROUND
Lactulose is approved for the symptomatic treatment of constipation, a gastrointestinal (GI) complication common in individuals with diabetes. Lactulose products contain carbohydrate impurities (e.g., lactose, fructose, galactose), which occur during the lactulose manufacturing process. These impurities may affect the blood glucose levels of individuals with type 2 diabetes mellitus (T2DM) using lactulose for the treatment of mild constipation. A previous study in healthy subjects revealed no increase in blood glucose levels after oral lactulose intake. However, it is still unclear whether the intake of lactulose increases blood glucose levels in individuals with diabetes.
AIM
To evaluate the blood glucose profile after oral lactulose intake in mildly constipated, non-insulin-dependent subjects with T2DM in an outpatient setting.
METHODS
This prospective, double-blind, randomized, controlled, single-center trial was conducted at the Clinical Research Center at the Medical University of Graz, Austria, in 24 adult Caucasian mildly constipated, non-insulin-dependent subjects with T2DM. Eligible subjects were randomized and assigned to one of six treatment sequences, each consisting of four treatments stratified by sex using an incomplete block design. Subjects received a single dose of 20 g or 30 g lactulose (crystal and liquid formulation), water as negative control or 30 g glucose as positive control. Capillary blood glucose concentrations were measured over a period of 180 min post dose. The primary endpoint was the baseline-corrected area under the curve of blood glucose concentrations over the complete assessment period [AUCbaseline_c (0-180 min)]. Quantitative comparisons were performed for both lactulose doses and formulations vs water for the equal lactulose dose vs glucose, as well as for liquid lactulose vs crystal lactulose. Safety parameters included GI tolerability, which was assessed at 180 min and 24 h post dose, and adverse events occurring up to 24 h post dose.
RESULTS
In 24 randomized and analyzed subjects blood glucose concentration-time curves after intake of 20 g and 30 g lactulose were almost identical to those after water intake for both lactulose formulations despite the different amounts of carbohydrate impurities (≤ 3.0% for crystals and approx. 30% for liquid). The primary endpoint [AUCbaseline_c (0-180 min)] was not significantly different between lactulose and water regardless of lactulose dose and formulation. Also with regard to all secondary endpoints lactulose formulations showed comparable results to water with one exception concerning maximum glucose level. A minor increase in maximum blood glucose was observed after the 30 g dose, liquid lactulose, in comparison to water with a mean treatment difference of 0.63 mmol/L (95% confidence intervals: 0.19, 1.07). Intake of 30 g glucose significantly increased all blood glucose endpoints vs 30 g liquid and crystal lactulose, respectively (all P < 0.0001). No differences in blood glucose response were observed between the different lactulose formulations. As expected, lactulose increased the number of bowel movements and was generally well tolerated. Subjects experienced only mild to moderate GI symptoms due to the laxative action of lactulose.
CONCLUSION
Blood glucose AUCbaseline_c (0-180 min) levels in mildly constipated, non-insulin dependent subjects with T2DM are not affected by the carbohydrate impurities contained in 20 g and 30 g crystal or liquid lactulose formulations.
Core Tip: Individuals with diabetes are at risk of developing constipation, which can be symptomatically treated with lactulose. The question arose whether carbohydrate impurities in crystal and liquid lactulose formulations would increase blood glucose levels in individuals with diabetes. This study demonstrates that, at the recommended maintenance dosage of 20 g and at a higher dosage of 30 g lactulose, the blood glucose baseline-corrected area under the curve from 0 to 180 min levels in mildly constipated, non-insulin dependent subjects with type 2 diabetes mellitus are not affected.
