Effects of Insulin Lispro Mix 25 and Insulin Lispro Mix 50 on Postprandial Glucose Excursion in Patients with Type 2 Diabetes: A Prospective, Open-Label, Randomized Clinical Trial

Diabetes Ther (2018) 9:699–711 https://doi.org/10.1007/s13300-018-0398-0 ORIGINAL RESEARCH Effects of Insulin Lispro Mix 25 and Insulin Lispro Mix 50 on Postprandial Glucose Excursion in Patients with Type 2 Diabetes: A Prospective, Open-Label, Randomized Clinical Trial Wei Li . Fan Ping . Lingling Xu . Meicen Zhou . Hongmei Li . Yaxiu Dong . Yuxiu Li Received: January 20, 2018 / Published online: March 8, 2018 Ó The Author(s) 2018. This article is an open access publication ABSTRACT Introduction: We compared the effects of insulin lispro mix 25 (LM25) and insulin lispro mix 50 (LM50) on postprandial glucose excursion in patients with type 2 diabetes mellitus (T2DM). Methods: In this randomized, open-label, investigator-initiated trial, 81 T2DM patients treated with premixed human insulin 70/30 (PHI70/30) for more than 90 days were randomly divided into two groups and received a crossover protocol of either LM25 or LM50 twice daily for 16 weeks. Continuous glucose monitoring (CGM) was performed for 72 h at baseline and at the end of each treatment phase to evaluate glycemic excursions in the subjects. Results: The LM50 regimen resulted in significantly smaller postprandial glycemic excursions Enhanced content To view enhanced content for this article go to https://doi.org/10.6084/m9.figshare. 5924773. W. Li  F. Ping  L. Xu  M. Zhou  Y. Dong  Y. Li (&) Department of Endocrinology, Key Laboratory of Endocrinology of National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China e-mail: H. Li Department of Endocrinology, China Meitan General Hospital, Beijing, China than the LM25 regimen after breakfast (1.3 ± 2.5 vs. 2.4 ± 2.6 mmol/L, P = 0.046) and dinner (1.5 ± 2.8 vs. 2.8 ± 2.4 mmol/L, P = 0.036). Glycosylated hemoglobin levels were similar for the patients on the three regimens. The percentage of patients who achieved their glycosylated hemoglobin target was significantly higher for the LM25 and LM50 regimens than for the PHI70/30 regimen, regardless of whether the target was set at 7.0% or 6.5%. The proportion of the patients who were hypoglycemic for a high percentage ([ 10%) of the time was lower for the LM50 regimen than for the LM25 and PHI70/30 regimens. Conclusions: LM50 may provide better glycemic excursion control after breakfast and dinner than LM25 in T2DM patients. Trial Registration: http://www.chictr.org.cn # ChiCTR-TTRCC-12002516. Funding: Lilly Suzhou Pharmaceutical Co., Ltd. (Shanghai Branch, China) and National Key Program of Clinical Science of China (WBYZ 2011-873). Keywords: Postprandial glucose; insulin; Type 2 diabetes mellitus Premixed INTRODUCTION In recent years, the incidence of type 2 diabetes has been rapidly increasing in China; it had reached 11.6% in Chinese adults according to Diabetes Ther (2018) 9:699–711 700 an epidemiological survey in 2010. As a result, China has become the nation with the largest number of diabetic patients [1]. The purpose of treating diabetes is to prevent the occurrence of complications. Epidemiological and intervention studies have demonstrated that glycosylated hemoglobin (HbA1c) is an independent risk factor for diabetic chronic complications. In addition, some studies have suggested that glucose excursions are closely related to the occurrence of complications [2–4]. When islet b-cell failure occurs in patients with type 2 diabetes, insulin therapy becomes inevitable. While insulin treatment can effectively reduce HbA1c levels in patients, the pharmacokinetic characteristics of human insulin mean that it is sometimes difficult to avoid glycemic fluctuations and even hypoglycemia. Given the disadvantage of the slow onset of action of regular human insulin, a variety of fast-acting insulin analogues have been developed since the 1990s. Similarly, premixed insulin has developed from premixed human insulin to premixed insulin analogues. Several studies have demonstrated that postprandial glycemic control was improved and overall control was similar when T2DM patients were treated with a premixed insulin analogue rather than premixed human insulin [5–7]. Currently, there are two premixed insulin analogues available on the Chinese market, namely LM25 (HumalogÒ Mix25, which contains 25% insulin lispro and 75% insulin lispro protamine) and LM50 (HumalogÒ Mix50, which contains 50% insulin lispro and 50% insulin lispro protamine). However, there has been limited research into the effects of LM25 and LM50 on glucose control and glycemic excursions [8–10]. Compared to the self-monitoring of blood glucose (SMBG) using a fingerstick, continuous glucose monitoring (CGM) provides the opportunity to collect comprehensive information on both glycemic control and variability over the course of a day (24 h) and information on hypoglycemic episodes that the patient is unaware of (due to a lack of symptoms or because they are asleep at the time) [11]. Some studies have shown that glycemic excursion parameters evaluated by CGM were significantly related to plasma markers (glycosylated albumin and 1,5-anhydroglucitol) [12, 13]. Therefore, we conducted an open-label, randomized, crossover clinical trial to investigate the effects on glycemic control and excursions of switching from premixed human insulin 70/30 (PHI70/30) to LM25 or LM50 in T2DM patients with CGM. Among reported studies evaluating the effects of LM25 and LM50 on glycemic variability via CGM, our study included by far the largest number of subjects. The primary objective of this study was to evaluate the effects of LM25 and LM50 on postprandial glucose excursions, and the secondary objective was to compare the effects of the two premixed insulin analogues and PHI70/ 30 on postprandial glucose excursions, glycosylated hemoglobin, body weight, and hypoglycemia. METHODS Study Design This study was a randomized, open-label, crossover, controlled, investigator-initiated clinical trial, and is registered with http://www. chictr.org.cn (registration number: ChiCTRTTRCC-12002516). The study comprised a 2-week screening period, a 2-week lead-in period, and two 16-week crossover treatment periods. The study design is shown in Fig. 1. The subjects continued to receive the PHI70/ 30 regimen during a 2-week lead-in period, but were then randomly divided into two treatment arms: one arm received the LM25 regimen while the other arm received the LM50 regimen during the first 16-week treatment period, and the two arms then switched regimens for the subsequent 16-week treatment period. All procedures were designed and performed in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964, as revised in 2013. Informed consent was obtained from all patients included in the study. Diabetes Ther (2018) 9:699–711 701 Fig. 1 Subject flow diagram. PHI70/30 (...truncated)