Comparison of Pharmacokinetics and Dynamics of the Long-Acting Insulin Analogs Glargine and Detemir at Steady State in Type 1 Diabetes

Abstract

OBJECTIVE -To compare pharmacokinetics and pharmacodynamics of insulin analogs glargine and detemir, 24 subjects with type 1 diabetes (aged 38 Ϯ 10 years, BMI 22.4 Ϯ 1.6 kg/m 2 , and A1C 7.2 Ϯ 0.7%) were studied after a 2-week treatment with either glargine or detemir once daily (randomized, double-blind, crossover study).RESEARCH DESIGN AND METHODS -Plasma glucose was clamped at 100 mg/dl for 24 h after subcutaneous injection of 0.35 unit/kg. The primary end point was end of action (time at which plasma glucose was Ͼ150 mg/dl).RESULTS -With glargine, plasma glucose remained at 103 Ϯ 3.6 mg/dl up to 24 h, and all subjects completed the study. Plasma glucose increased progressively after 16 h with detemir, and only eight subjects (33%) completed the study with plasma glucose Ͻ180 mg/dl. Glucose infusion rate (GIR) was similar with detemir and glargine for 12 h, after which it decreased more rapidly with detemir (P Ͻ 0.001). Estimated total insulin activity (GIR area under the curve [AUC] 0 -end of GIR ) was 1,412 Ϯ 662 and 915 Ϯ 225 mg/kg (glargine vs. detemir, P Ͻ 0.05), with median time of end of action at 24 and 17.5 h (glargine vs. detemir, P Ͻ 0.001). The antilipolytic action of detemir was lower than that of glargine (AUC free fatty acids 0 -24 h 11 Ϯ 1.7 vs. 8 Ϯ 2.8 mmol/l, respectively, P Ͻ 0.001).CONCLUSIONS -Detemir has effects similar to those of glargine during the initial 12 h after administration, but effects are lower during 12-24 h.

Pharmacokinetics and Pharmacodynamics of Insulin Glargine Given in the Evening as Compared With in the Morning in Type 2 Diabetes

“…In brief, two venous lines were inserted, an antecubital vein on one arm (for infusions) and a dorsal vein (cannulated retrogradely with a 20-gauge butterfly needle) on the contralateral hand (kept at 658C in a hot box) for intermittent sampling of arterialized venous blood. An intravenous feedback insulin infusion was initiated to achieve and maintain PG at 100 6 5 mg/dL until time 0 (i.e., 1000 or 2200 h), as previously described (21). At 2120 min, a primed sterile, pyrogen-free constant infusion (0.222 mmol/kg/min) of [6,6-2 H 2 ]-glucose (Cambridge Isotope Laboratories, Cambridge, MA) was started and maintained throughout the experiment to determine glucose kinetics.…”

The interpretation of glucose clamp studies of long-acting insulin analogues: from physiology to marketing and back

“…Also, in one head-to-head study in type 2 diabetic patients the two long-acting insulin analogues were found to be comparable [10], whereas another comparison in individuals with type 1 diabetes showed lower total activity and a shorter duration of action for insulin detemir [12]. Some have attributed these conflicting findings to differences in study design, such as the study insulin dose [12], or to inherent differences in the PD profiles in type 1 vs type 2 diabetic patients [10]. Others have simply labelled inconsistent results as 'outlier findings' [6].…”

“…However, during manual clamps, (un)conscious investigator-related bias cannot be ruled out, despite attempted blinding of the study insulin. This may explain why manual clamp studies have reported different time-action profiles for the same longacting insulin analogue [12,15].…”

“…For example, insulin glargine's time-action profile has been characterised as being flat [7,8] and as waxing and waning with a maximum effect approximately 10 h after injection [9][10][11]. Also, in one head-to-head study in type 2 diabetic patients the two long-acting insulin analogues were found to be comparable [10], whereas another comparison in individuals with type 1 diabetes showed lower total activity and a shorter duration of action for insulin detemir [12]. Some have attributed these conflicting findings to differences in study design, such as the study insulin dose [12], or to inherent differences in the PD profiles in type 1 vs type 2 diabetic patients [10].…”

A practical guide to the interpretation of PK/PD profiles of longer-acting analogue insulins. Part one: The principles of glucose clamp studies

“…Results from glucose clamp studies performed in healthy volunteers, 9,30 patients diagnosed with Type 1 diabetes mellitus 7,8,21 and Type 2 diabetes mellitus 22,23 have been published. However, for each population a number of potentially confounding factors must be considered when interpreting the results.…”