Pharmacokinetics and Pharmacodynamics of the Long-Acting Insulin Analog Glargine After 1 Week of Use Compared With Its First Administration in Subjects With Type 1 Diabetes

RESEARCH DESIGN AND METHODS

After institutional review board approval, 20 type 1 diabetic subjects (12 male subjects, age 31 ± 2 years, type 1 diabetes duration 11 ± 1 years, BMI 23.3 ± 0.4 kg/m², fasting plasma C-peptide <0.02 nmol/l, and A1C 7.1 ± 0.2%) using NPH as basal insulin and human regular insulin (n = 7) or lispro insulin (n = 13), in combination with NPH at each meal as previously described (14), were studied.

During a 2-week run-in period, subjects continued their previous model of insulin therapy, i.e., human regular insulin or the rapid-acting insulin analog lispro at breakfast, lunch, and dinner and NPH insulin at bedtime, or even at each meal in those patients (n = 13) who used lispro (14). Thereafter, subjects were studied with the glucose clamp technique after subcutaneous injection of 0.3 units/kg insulin glargine as previously described (6). Subjects were studied for 32 h in order to capture the expected longer duration of action of insulin glargine after 1 week of use versus first injection. Subjects were studied on two occasions according to a randomized, crossover, open, 3-week period study (Fig. 1). On one occasion, the clamp was performed on the day the subject received the first injection of glargine (day-1 study), at the end of 1 week of NPH treatment (sequence: NPH_day-1/NPH_day-2/NPH_day-3/NPH_day-4/NPH_day-5/NPH_day-6/clamp-G_day-1). The clamp was then followed by a washout period of 1 week during which patients resumed the treatment they were on in the run-in period and after which each patient was crossed over to the other sequence when the clamp was performed on the day they received the seventh injection of glargine at the end of a 1-week treatment with once-daily glargine injection at 1700 h (day-7 study) (sequence: G_day-1/G_day-2/G_day-3/G_day-4/G_day-5/G_day-6/clamp-G_day-7) (Fig. 1). A randomization list was constructed from random numbers generated by a computer.

Plasma glucose, C-peptide and insulin concentrations, and A1C were measured as previously described (6). Onset of action was the time after subcutaneous injection of insulin, at which the rate of intravenous insulin consistently decreased by 50% compared with the 20-min preinjection time period. End of action was the time at which plasma glucose consistently increased to >150 mg/dl (or 32 h in case plasma glucose did not increase >150 mg/dl by the end of study), and duration of action was the time period between the onset and end of action (6).

Statistical analysis

The linear trapezoidal rule was used to calculate the area under the time concentration curve. C_max and T_max were read directly from the plasma concentration time data for each subject. Data analysis was carried out by using ANOVA for crossover design (15). Data are means ± SD unless stated otherwise.

RESULTS

Mean daily blood glucose during the 2-week run-in, 3-week sequence day-1→day-7 study and 3-week sequence day-7→day-1 study were no different (P > 0.2).

The amount of insulin infused intravenously during the time period −2 to 0 h (preinjection period), to maintain target plasma glucose, was higher in the day-1 (3 ± 1.2 IU) than the day-7 (1.8 ± 1 IU, P < 0.02) study.

After time 0 h (Fig. 2), the amount of insulin infused intravenously was greater in the day-1 (0.9 ± 0.5 IU) than the day-7 (0.4 ± 0.25 IU, P = 0.01) study. The median time of end of intravenous insulin infusion was 80 min (95% CI 0–100) in the day-1 study and 40 min (0–70) in the day-7 study (P = 0.01). Plasma insulin concentrations were no different in day-7 versus day-1 studies either at baseline or over 0–32 h (P > 0.2), but insulin levels from 24 h to the end of study (32 h) were lower in day-1 versus day-7 studies (83 ± 11 vs. 111 ± 24 μU/ml per 8 h, respectively, P = 0.01).

Plasma glucose concentration was greater on day-1 versus day-7 studies [PG_(0–24h) 135 ± 5 vs. 132 ± 2 mg/dl, P = 0.023; PG_(0–32h) 139 ± 9 vs. 133 ± 3 mg/dl, P = 0.01].

Baseline glucose infusion rate (GIR) was zero in the day-1 study but 0.19 ± 0.05 mg · kg⁻¹ · min⁻¹ in the day-7 study and subsequently increased slowly to similar plateau values on both occasions until 16 h, when GIR in day-7 studies was greater than in day-1 studies until the end of the study (P < 0.046).

The mean values of GIR (area under the curve: AUC_{0-end of GIR}) were lower in day-1 than in day-7 studies (1,122 ± 449 vs. 1,353 ± 327 mg/kg, P = 0.046). GIR excursions (SD) were greater in day-1 than in day-7 studies (0.5 ± 0.2 vs. 0.3 ± 0.13 mg · kg⁻¹ · min⁻¹, P = 0.01). Onset of insulin action initiated earlier on day 7 compared with day 1, with a median estimated difference of 25 min (P = 0.002). End of action (median 25.6 h [95% CI 22.0–28.5] vs. 22 h [19.0–27.0]) and duration of action (24 h [22.0–28.5] vs. 20.2 h [17.0–25.0]) were longer on day 7 compared with day 1.

CONCLUSIONS

The results of this study indicate that pharmacokinetics and pharmacodynamics of insulin glargine are different after several days of subcutaneous injections compared with the first injection. Insulin glargine has an earlier onset and longer duration of action (median 24 h) after 1 week compared with the first day of its use. However, the duration of action is underestimated because in some subjects end of action was beyond 32 h (time at which studies were truncated). In addition, the intrasubject variability of insulin glargine is lower after 1 week of use.

Considering that the long-acting insulin analog glargine has a duration of action of 24 h or longer after repeated administration, in the clinical setting insulin glargine should be injected every 24 h in type 1 diabetic patients and dose adjustments should be made at intervals >24 h, possibly every few days.

For those patients who exhibit elevation of afternoon blood glucose (“afternoon phenomenon”) (16), it is likely that factors other than the duration of action of glargine <24 h are involved. However, specific studies directed at understanding the mechanisms are needed.