Study Design and Population
The design of the ReFLeCT study has already been described in detail elsewhere . Briefly, ReFLeCT was a 12-month, multicenter, prospective, non-interventional study (ClinicalTrials.gov ID: NCT02392117) conducted across seven European countries (Italy, Denmark, the Netherlands, Spain, Sweden, Switzerland, and the UK) between March 2015 and March 2018. The aim of the study was to assess the safety and effectiveness of switching the treatment of adults with T1DM or T2DM from another basal insulin to insulin degludec once daily. The decision to initiate insulin degludec treatment with the patient occurred independently of patient enrollment in the study. Patients were followed for 4 weeks before (baseline period) and up to 12 months after being switched to insulin degludec (Fig. 1). At the end of the 4-week baseline period, the treating physicians re-evaluated each patient and confirmed or refuted the decision to switch to insulin degludec. Other than their basal insulin, patients could continue to use their other background glucose-lowering therapies. Change in dose, dose interval, and add-on or removal of bolus insulin and other antidiabetic drugs were at the discretion of the treating physician.
Clinical, laboratory, and patient-reported outcome data were collected as part of routine clinical practice in the following timeframes during the 12-month follow-up period: 0 months (+ 14 days), 3 months (± 45 days), 6 months (± 45 days), 9 months (± 45 days), and 12 months (± 45 days). Patients only attended visits that were part of routine clinical practice; therefore, not all patients were expected to attend all visits. The most recent values of hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), and body weight were recorded at each visit. The Diabetes Treatment Satisfaction Questionnaire status version (DTSQ-s)  and the Short Form-36 (SF-36® v2)  health status survey were completed by patients at each visit.
Patients were provided with up to five study-specific diaries. The first diary covered the 4-week baseline, pre-switch period and the remaining diaries covered the 4-week period prior to each subsequent visit. The diaries were used to record information on basal insulin dose and time of administration. The following information on every hypoglycemic event was also recorded: date/time of event; if it was self-treated or required assistance; which symptoms were experienced; blood glucose (BG) value (if recorded); resource use (e.g., additional visits or access to emergency department).
In accordance with the requirements of the Declaration of Helsinki, informed consent was obtained from all patients . All procedures followed were 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. The master ethics committee of the main center was Comitato Etico Palermo 1, Azienda Ospedaliera Universitaria Policlinico Giaccone. The complete list of Ethics Committees are given in the Electronic Supplementary Material (ESM).
In this subanalysis of the ReFLeCT study we considered only the Italian cohort, which represented 27 and 52% of the patients with T1DM and T2DM, respectively, in the ReFLeCT study.
The primary endpoint was the change from baseline in the overall rates of hypoglycemic events (number of events per patient-year). Overall hypoglycemia was defined as any hypoglycemic event recorded in the diary, irrespective of symptoms, BG measurement, and time of day .
Secondary endpoints included change from the baseline period in the number of severe, non-severe, nocturnal, severe or BG-confirmed, and severe or BG-confirmed symptomatic hypoglycemic events. Severe hypoglycemia was defined as an event requiring the assistance of another person to actively administer carbohydrate, glucagon, or other corrective actions . Non-severe hypoglycemia was defined as either an event with or without symptoms accompanied by a BG measurement ≤ 3.9 mmol/L (70 mg/dL), or an event with symptoms not accompanied by a BG measurement but assumed to be caused by a BG value ≤ 3.9 mmol/L (70 mg/dL). Nocturnal hypoglycemia was defined as an event (either severe or non-severe) occurring between 0001 and 0559 (inclusive) hours, regardless of whether the patient was awake or woken up. Other secondary endpoints included the changes from baseline in HbA1c, FPG, daily insulin dose (total, basal and bolus), body weight, health-related quality of life questionnaire scores (assessed using DTSQ-s and SF-36® v2), and flexibility in timing of doses after 12 months of treatment with insulin degludec.
The DTSQ-s consists of eight questions and investigates how satisfied patients are with their treatment . A total score is produced (range 0–36), with higher values indicating higher treatment satisfaction. The questionnaire also contains a separate question assessing perceived frequency of hypoglycemia, with a lower score indicating a lower perception of hypoglycemia (0 = never; 6 = most of the time).
The SF-36® v2 is a widely used questionnaire assessing the patient’s general health status. It includes 36 questions that cover eight different domains; two summary scores can also be computed (Physical Component Score and Mental Component Score) . Higher scores indicate better health status, with a score of 50 and a standard deviation (SD) of 10 representing the values for the general population.
All the analyses were done by diabetes type and were based on the full analysis set, including all patients who received at least one dose of insulin degludec. Baseline characteristics were summarized as the mean and SD or percentage, as appropriate. Hypoglycemia endpoints were analyzed using negative binomial regression specifying a log-transformed follow-up time offset term. Baseline covariates included period (pre/post-switch to insulin degludec), age, gender, HbA1c, diabetes duration, and body mass index (BMI). For patients with T2DM, additional covariates included use of bolus insulin (yes/no) and sulfonylurea or glinides (yes/no), as these medications could impact on the rates of hypoglycemia. The analyses compared the 12-month follow-up period with the 4-week baseline period. Results are expressed as incidence rate ratios (IRRs) with 95% confidence intervals (95% CI).
The changes in HbA1c, FPG, body weight, and insulin dose were estimated using analysis of covariance with a mixed model for repeated measures. Covariates included visit, baseline value, age, gender, BMI, and diabetes duration. For patients with T2DM, additional time-varying covariates included the use of bolus insulin (yes/no; omitted from the bolus insulin dose analysis), sulfonylurea or glinides (yes/no), glucagon-like peptide-1 receptor agonist (yes/no), and other antidiabetic drugs (yes/no). The results of the SF-36® v2  and DTSQ-s  were scored as per questionnaire instructions, and the mean change from baseline (95% CI) was summarized. A difference of more than half a standard deviation of the baseline score is considered to be a meaningful change . The number of patients who at 12 months had used the flexibility option for timing of doses was summarized using percentages. All statistical tests were two-tailed with a significance level of P < 0.05. All statistical analyses were performed using SAS version 9.3 or higher (SAS Institute, Cary, NC, USA).