The data of the post hoc analysis were from our study on a phase IV, randomized, crossover, open-label, investigator-initiated clinical trial in Chinese patients with T2DM switching from premixed human insulin 70/30 (PHI70/30) to LM25 or LM50. This clinical trial was registered at http://www.chictr.org.cn (ChiCTR-TTRCC-12002516) .
The study consisted of a 2-week screening period and a 2-week lead-in period followed by two 16-week crossover treatment periods (Fig. 1). All subjects continued to receive PHI70/30 treatment during the 2-week lead-in period and then were randomly divided into two treatment arms based on a random number table: one arm received LM25 twice daily while the other arm received LM50 twice daily during the first 16-week treatment stage, and the two arms then switched regimens during the next 16-week treatment stage.
Male or non-pregnant, non-breastfeeding female Chinese T2DM patients at least 18 years of age who had received a stable dose of PHI70/30 twice daily (whether combined with oral hypoglycemic agents or not) for at least 90 days with an HbA1c of ≥ 6.0% were enrolled to participate in this comparative study on LM25 and LM50. The patients visited the Department of Endocrinology at Peking Union Medical College Hospital (PUMCH) from 1 November 2013 to 31 May 2015.
Key exclusion criteria included the following: patients with liver dysfunction (alanine transaminase or alkaline phosphatase > 2.5-fold the upper limit of the reference range) or renal insufficiency (serum creatinine ≥ 133 μmol/l for males or ≥ 110 μmol/l for females); patients with other diseases or receiving other drugs that may influence blood glucose (BG) and hemoglobin; patients with an inability to eat normally.
Study Procedures and Treatment
After recruitment, all subjects were randomly divided into group A and B according to a random number table. Group A (LM25/LM50 group) received LM25 twice daily during the first 16-week treatment stage and LM50 twice daily during the next 16-week treatment stage. Group B (LM50/LM25 group) was opposite to group A. The initial total daily dose of LM25 or LM50 was determined according to the total daily dose of the original PHI70/30 and distributed to breakfast and dinner in a 1:1 ratio. When the two arms switched therapy, the initial total daily dose of insulin was the same as the total daily dose of insulin in the previous stage and also distributed to breakfast and dinner in a 1:1 ratio. Insulin dose titration was performed in the first 4 weeks of each 16-week treatment stage. The subjects got a 4-point BG profile by SMBG (preprandial BG of three meals plus bedtime BG at least 1 day every week, adding a BG test while having hypoglycemia symptoms and recording severe hypoglycemia episodes that required others’ help). They were followed up every 2 weeks to adjust the insulin dose according to the BG profile (insulin sliding scale was presented in a previous article ). The targets of insulin titration were BG > 3.9 mmol/l and ≤ 6.1 mmol/l before breakfast and dinner. Insulin doses remained stable for the subsequent 12 weeks of this stage. The types and dosages of original oral hypoglycemic agents in combination were not adjusted throughout the trial.
During the trial, the subjects were advised to follow the Chinese guidelines for diet control and exercise; 45–60% of the total daily energy derived from carbohydrates, 25–35% from dietary fat and 15–25% from protein. The total daily energy intake was calculated according to the height and weight of each subject. The subjects were required to exercise regularly during the trial. CGM was performed for 3 days at the end of lead-in period and each treatment stage.
During the 3 days of CGM, the subjects received high-carbohydrate test meals (with 56.8–58.4% of the total energy deriving from carbohydrates, 15.7–17.2% from protein and 24.4–26.7% from fat) on day 1 and high-fat test meals (with 39.8–40.7% of the total energy deriving from carbohydrates, 23.0–24.4% from protein and 33.0–36.1% from fat) on day 2. They continued their habitual diets on day 3.
At the time of recruitment, the subjects’ medical history data (age, gender, duration of diabetes, insulin dose, combined oral hypoglycemic agents, etc.) and anthropometric data [blood pressure, height, weight, body mass index (BMI), waist circumference, etc.] were recorded. In addition, HbA1c and 72 h CGM were performed at enrollment and at the end of each treatment phase. CGM was conducted using the GOLD CGM system (Medtronic, USA). This system can measure the interstitial glucose (IG) levels every 10 s, record the average value every 5 min and record 288 measurements daily. The subjects recorded SMBG using an EZ-508 meter (Sinomedisite, China) to allow regular insulin dose titration.
Hypoglycemia data came from SMBG and CGM of the subjects. The same hypoglycemia episode recorded by SMBG and CGM was based on the value measured by the SMBG. Hypoglycemia was defined as BG or IG level ≤ 3.9 mmol/l. According to the time of hypoglycemia, it can be divided into total hypoglycemia, daytime hypoglycemia (06:00 a.m.–22:00 p.m.) and nocturnal hypoglycemia (00:00 a.m.–06:00 a.m. and 22:00 p.m.–24:00 p.m.). According to the severity of hypoglycemia, it can be divided into mild (BG or IG ≤ 3.9 mmol/l and > 3.0 mmol/l), moderate (BG or IG ≤ 3.0 mmol/l) and severe hypoglycemia (a severe event characterized by altered mental and/or physical status requiring assistance).
According to the 72-h CGM data, we can get mean blood glucose (MBG), mean amplitude of glucose excursion (MAGE, the mean value of the valid blood glucose excursion amplitudes that were greater than the standard deviation for all the glucose excursions during the given day), the percentage of hypoglycemic time (percentage of time with IG ≤ 3.9 or 3.0 mmol/l during a particular day), frequency of hypoglycemia (frequency of hypoglycemic episodes with IG ≤ 3.9 or 3.0 mmol/l excursions during a particular day, allowing up to two consecutive readings above the threshold within the same episode; if a following episode started within 1 h of the start of the previous episode, they were combined and recorded as one episode) and the proportion of subjects with hypoglycemia. According to the SMBG data, we can get the frequency of hypoglycemia (frequency of hypoglycemic episodes with BG ≤ 3.9 or 3.0 mmol/l during a particular day; if a following episode started within 1 h of the start of the previous episode, they were combined and recorded as one episode) and the proportion of subjects with hypoglycemia.
The present study was post hoc in nature. Measurement data were expressed as the mean ± SD, and count data were expressed as frequency. The rates between the two groups were compared using the chi-square test. The crossover analysis was based on a univariate general linear model, including the treatment regimen and phase and dietary pattern as fixed effects and patients as a random effect. p < 0.05 was considered statistically significant. For multiple tests, the Bonferroni method was used to correct the test level: α′ = α/m (α = 0.05, m = the number of tests). SPSS 22.0 software was used to complete statistical analysis.
Compliance with Ethical Guidelines
The study was conducted 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, and was approved by the PUMCH Ethics Committee. All patients signed informed consent before enrollment.