Efficacy and safety of using insulin glargine 300 U/mL in patients with type 2 diabetes on basal insulin and oral antidiabetic drugs failing to achieve their blood sugar targets

Fasting blood glucose (FBG) response rate during month 1-6 and month 1-12 after start of insulin glargine 300 U/mL treatment, respectively; response being defined as achieving at least two FBG values ≤ 110 mg/dL (≤ 6.1 mmol/L) within the respective observational period. Response rates were summarized with frequency distribution and, in addition, adjusted frequency distribution considering only patients with nonmissing data. Exact 95% confidence intervals (CI) according to Clopper-Pearson were calculated.

Unless stated otherwise, measured at baseline, and after 6 and 12 months:
1. Absolute change in HbA1c [%]
2. Absolute change in fasting blood glucose (FBG) [mg/dL]
3. Response rate 6 and 12 months after start of insulin glargine 300 U/mL treatment defined by:
3.1. Either reaching two FBG values ≤110 mg/dL (≤6.1 mmol/L) or at least once the predefined individual HbA1c target value
3.2. Reaching at least one HbA1c value [%] equal or less to the predefined individual HbA1c target value
3.3. Reaching two FBG values ≤110 mg/dL (≤6.1 mmol/L) and at least once the predefined individual HbA1c target value
4. Time from start of insulin glargine 300 U/mL treatment to response for each of the response endpoints (see definitions above, including primary efficacy parameter) was analyzed using Kaplan-Meier methods. Reaching a response criterion for the first time was considered as event in these analyses. Response in FBG required at least two values ≤110 mg/dL (≤6.1mmol/L) whereas start of response was defined at the first occurrence. Patients without response were censored at the date of last measurement of FBG or HbA1c, respectively. Median time to response and corresponding 95% CI were estimated using the Kaplan-Meier method. In addition, cumulative incidence curves were produced.
5. Duration (persistence) of response for each of the response endpoints (see definitions above, including primary efficacy parameter) was analyzed using Kaplan-Meier methods. Only patients with documented response and valid duration time (not missing, not negative) were included in these analyses. End of response was defined as one of the following (depending on endpoint definition):
5.1. The second FBG value >110 mg/dL (>6.1 mmol/L) after start of FBG response
5.2. The first HbA1c value [%] above the predefined individual target
5.3. Change to another form of insulin therapy or change of basal insulin
Patients without documented end of response were censored at the date of last measurement of FBG or HbA1c, respectively. Median duration of response and corresponding 95% CI were estimated using the Kaplan-Meier method. In addition, Kaplan-Meier curves were produced.
6. Incidences and event rates per patient year were calculated for symptomatic, confirmed symptomatic, nocturnal, severe, and severe nocturnal hypoglycemia as reported in the electronic Case Report Form (eCRF). Confirmation of symptomatic hypoglycemia was defined as self-measured blood glucose (SMBG) measurement ≤70 mg/dL (≤3.9 mmol/L). Severe hypoglycemia was defined as necessity of the assistance of another person or a SMBG measurement of ≤56 mg/dL (≤3.1 mmol/L). Nocturnal hypoglycemia was defined as hypoglycemia occurring during the night (approximately 10pm-6am), while the patient was asleep (symptomatic or confirmed by SMBG measurement ≤70 mg/dL [≤3.9 mmol/L]). Severe nocturnal hypoglycemia was defined as those nocturnal hypoglycemia fulfilling the definition of a severe hypoglycemia. 95% CIs for incidence rates were calculated according to Clopper-Pearson. Rates per patient year were calculated as cumulative number of hypoglycemic events for all patients divided by the cumulative duration of insulin glargine 300 U/mL therapy in years, whereas patients with missing treatment duration or missing number of hypoglycemic events were excluded. Details for calculation are provided in the Statistical Analysis Plan (SAP).
7. Absolute change in the 4-point blood glucose profile [mg/dL]
8. Absolute change in body weight [kg]
9. Absolute change in daily insulin doses (number of units per day and number of units per kg body weight [BW] per day) and number of dose modifications per visits; baseline and monthly documentation until month 12.
10. Values and absolute changes for blood lipids [mg/dL] (triglycerides, high-density Lipoprotein [HDL], low-density Lipoprotein [LDL] and total cholesterol)
11. Type of LLT overall and by LDL subgroups (<70 mg/dL, <100 mg/dL, 100-190 mg/dL, >190 mg/dL at respective visit). An intensification of LLT was defined as administration of an additional LLT drug compared to baseline, or a higher dosing of statin, i.e. change from moderate at one visit to intensive at a following visit