Insulin Glargine

An overview of policies on biosimilars used in European countries was obtained via a questionnaire, administered to different country experts, and supplemented with relevant articles. Topics for the questionnaire were derived from previous work on generic medicines [16 (link)] and The Belgian Health Care Knowledge Centre (KCE) report 199 on biosimilars [17 ]. Topics were organized in five themes: the availability of biosimilars, pricing policies, reimbursement policies, demand-side policies (broken down by the 4Es–Education, Engineering, Economics and Enforcement [18 (link)]), and recommendations to enhance uptake of biosimilars. Open as well as closed questions were included. The questionnaire was written in English. The questionnaire as updated in August 2016 can be consulted as supporting information (S1 Questionnaire). All molecules for which a biosimilar was marketed in Europe at that time (filgrastim, somatropin, erythropoietin alfa, insulin glargine, follitropin, infliximab and etanercept) were included. This article presents several highlights from this extensive questionnaire. Results were rearranged in three themes: i) availability of biosimilars, ii) national policies, and iii) recommendations from the country experts.
A pilot survey was carried out in two countries (Slovenia, Lithuania) to validate the questions in terms of clarity, after which the refined questionnaire was sent out to experts of different European countries with knowledge of the biosimilar market. These experts were initially contacts within the Piperska Group [19 ], which is a network of professionals doing research on the rational use of medicines. These contacts were then further supplemented with other contacts in the network of the KU Leuven / Erasmus MC team. Country experts represented regulatory authorities in different European countries, pricing and reimbursement authorities, health insurance companies, health technology assessment (HTA) bodies, procurement agencies, and academia, and were contacted via e-mail or telephone to participate in this study. Initially, one expert per country was contacted. This expert acted as the national contact, responsible for collecting data for the survey, and contacting additional national stakeholders. When responses were not clear, clarification was requested via e-mail or phone calls. This approach was used before when assessing different policies and their impact, as well as debating key issues such as managed entry agreements, personalized medicine and new models to enhance the managed entry of new medicines [20 (link)–26 (link)]. The data obtained via the questionnaire were supplemented with relevant articles, and, if possible, responses were validated by contacting other experts in the individual countries. Descriptive statistics were used to analyze the data, with frequencies being reported where appropriate, and open questions being examined via qualitative analysis. During critical review of the manuscript, the experts were asked to include data collected until the end of April 2017. Data was collected between November 2015 and May 2017.

The BG target range during the study period was 90 to 120 mg/dl for all patients admitted to the ICU, a modest upward revision of the target range shown to improve mortality and morbidity of populations of critically ill patients in previously published interventional trials [5 (link),6 (link)] (Additional file 1). This target was chosen explicitly to maximize the percentage of values within a broader 70 to 140 mg/dl range, a range that the ICU nurses felt that they could achieve. We chose this range because (1) <70 mg/dl is a widely used definition of hypoglycemia and (2) ≥140 mg/dl is a widely accepted threshold for hyperglycemia. Nurses performed BG monitoring using ACCU-CHEK Inform II glucose meters (Roche Diagnostics, Indianapolis, IN, USA) to test capillary, venous or arterial blood. Monitoring guidelines precluded use of capillary blood in the setting of shock or marked peripheral edema. The measurement frequency was every 3 hours at a minimum for all patients. Sustained hyperglycemia—two consecutive BG readings ≥180 mg/dl—triggered the institution of continuous intravenous regular insulin infusion and hourly BG measurement. The nurses treated lesser degrees of hyperglycemia with subcutaneous insulin aspart at an interval of every 3 hours. It is the standard of care in the ICU to initiate nutritional support in the first 24 to 48 hours of admission. Patients requiring more than 10 U/day of insulin who were receiving a continuous source of calories were typically administered insulin glargine to supply a portion of their daily insulin requirement. The typical starting dose of insulin glargine was one-third to one-half of the previous 24-hour insulin requirement.

PREVAIL was a 20-week, open-label, parallel-arm trial wherein patients aged 30–80 years with T2DM of ≤ 7 years duration were randomized (1:1:1) to 8-weeks treatment with insulin glargine, glargine + thrice-daily lispro, or glargine + twice-daily exenatide, followed by 12-weeks washout. The study protocol and primary outcome have been described in detail previously [9 (link)]. The study was approved by the Mount Sinai Hospital Research Ethics Board and registered at ClinicalTrials.Gov (NCT02194595). All participants provided written informed consent. While the primary and metabolic outcomes have been reported recently [9 (link)], the current report presents the pre-specified ancillary outcome of endothelial function and associated vascular measures.

The subjects were enrolled form the outpatient department of Tri-Service General Hospital between January 2018 and October 2019. All study subjects were anonymous, and informed consent was obtained prior to participation. The study proposal was reviewed and approved by the institutional review board of Tri-Service General Hospital
It is a single-arm, open, observational study. The subjects with documented T2D diagnosis longer than 3 months with aged from 40 to 80 with HbA1C levels between 7.0% to 11.0% under treatment of premixed insulin, NovoMix® 30 (30% insulin aspart and 70% insulin aspart protamine) with or without combination with metformin were enrolled into the study. The patients with Alanine transaminase (ALT) and Aspartate transaminase (AST) > 3 times normal, and estimated GFR < 30mL/minute/1.73m², or major systemic disease were excluded from the study.
After enrollment, patients were scheduled for laboratory tests and insertion of CGMS after an 8 to 10 hours NPO. Patients were kept treating with premixed insulin for another week during CGMS insertion by experienced staff. After 1 week, antidiabetic regimen was changed to insulin glargine with an initial dose 40% to 50% of the previous total daily dose of premixed insulin. At the same time liraglutide was also started with an initial dose of 0.6 mg/day with subsequent up-titration to 1.2 mg/day after 1 week, if well tolerated. Repaglinide 1 to 2 mg 3 times per day were prescribed to reach the goal of postprandial glucose level < 180 mg/dL. Insulin glargine dose was regularly up-titrated at weekly interval according to fasting plasma glucose to reach goal of 90 to 130 mg/dL or reaching insulin dose of 50% of patient’s weight. After a total treatment duration of 12 weeks, another CGMS procedure were performed again The glycemic index, clinical cardiovascular risk profiles, safety issues (body weight and hypoglycemia), and GV indices from CGMS before and after 3 months treatment modification was evaluated.
Body mass index (BMI) was calculated as body weight (kg)/height (m2). Systolic blood pressure and diastolic blood pressure were measured in the right arm of seated individuals by using a standard mercury sphygmomanometer.

This study followed the guidelines set forth by the Animal Welfare Act and the National Institutes of Health Guide for the Care and Use of Laboratory Animals and was under approval from the Sanford Research Institutional Animal Care and Use Committee (Protocol #170-06-23B). All animals were housed in a temperature-controlled, light–dark cycled facility with free access to water and chow. Female Sprague–Dawley rats (Envigo, Indianapolis, IN) received control (TD2018 Teklad, Envigo; 18% fat, 24% protein, 58% carbohydrates) or HFD (TD95217 custom diet Teklad, Envigo; 40% fat, 19% protein, 41% carbohydrates) for at least 28 days prior to breeding to simulate a dietary “lifestyle.” Diets were selected to equate commonly attainable low-fat diets (18% of calories as fat) or HFD (40% of calories as fat) with more saturated and monounsaturated fat content. Omega 6:3 ratios were similar between diets. Female rats were bred with healthy male rats and fed a control diet and monitored by daily vaginal swab for spermatozoa. When spermatozoa were first present, timed pregnancy started as embryonic day 0 (E0). After confirming the pregnancy with an ultrasound, dams received an intraperitoneal injection of either citrate-buffered saline (Thomas Scientific, Swedesboro, NJ) diluent or 65 mg/kg streptozotocin (Sigma-Aldrich, Inc., St. Louis, MO, USA) to induce late gestation diabetes on E14. With a goal to keep blood glucose levels at 200–400 mg/dL, dams were partially treated with sliding scale insulin (regular and glargine, Eli Lilly and Co., Indianapolis, IN) two times per day. Whole blood sampling from a tail nick was done to measure glucose at least twice daily and ketones (βHOB) daily (Precision Xtra glucometer and ketone meter, Abbott Laboratories, Abbott Park, IL, USA). Dams with blood glucose < 200 mg/dL within 48 h after streptozotocin were excluded from the study. Although this model induces maternal diabetes by streptozotocin-mediated pancreatic damage, we have consistently shown that the developing offspring, our experimental subjects, are exposed to maternal hyperglycemia, hyperlipidemia, and fetal hyperinsulinemia in the last 1/3 of pregnancy [9 (link),11 (link),12 (link),13 (link),56 (link)]. Dams were allowed to deliver spontaneously in order to yield offspring of both sexes from two distinct groups: controls and combination exposed (diabetes + HFD). On postnatal day 1 (P1), offspring hearts (n = 10–12 litter per group and each group comprised 5–6 male and female hearts) were collected under 5% isoflurane anesthesia and immediately used for the isolation of NRCM or snap frozen in liquid nitrogen and stored at −80 °C until analysis. Maternal and offspring characteristics are given in Supplementary Tables S1 and S2.