Lower Within-Subject Variability of Insulin Detemir in Comparison to NPH Insulin and Insulin Glargine in People With Type 1 Diabetes

Tim Heise; Leszek Nosek; Birgitte Biilmann Rønn; Lars Endahl; Lutz Heinemann; Christoph Kapitza; Eberhard Draeger


Diabetes. 2004;53(6) 

In This Article


There were no clinically relevant differences in demographic characteristics between subjects in the three treatment groups ( Table 1 ). A total of 51 subjects completed the trial (18 on insulin detemir, 17 on NPH insulin, and 16 on insulin glargine). One subject randomized to insulin glargine withdrew consent for private reasons, one subject randomized to insulin glargine was withdrawn due to technical difficulties with the glucose clamp procedure (bad vein condition), and one subject randomized to NPH insulin was withdrawn due to an adverse event (skin burn).

The within-subject variability for GIR-AUC(0-12 h) was significantly lower for insulin detemir (CV 27%) compared with NPH insulin (59%) and insulin glargine (46%) (P < 0.001 for both comparisons). Similarly, within-subject variability over 24 h [GIR-AUC(0-24 h)] was lower for insulin detemir compared with both NPH insulin and insulin glargine (P < 0.001 for both comparisons). The differences in variability were even more pronounced when the first 2 h of the glucose clamp procedure were excluded from the assessment [GIR-AUC(2-24 h)]. Although t GIRmax was ~500 min for all three insulin preparations, the within-subject variability of the level of GIRmax was significantly lower for insulin detemir than for NPH insulin and insulin glargine ( Table 2 ).

Mean values for GIR-AUC and for GIRmax were lower for insulin glargine than for either of the other two insulin preparations ( Table 2 ). However, due to the lower within-subject variability of insulin detemir, the highest expected GIRmax values for individual subjects are lower with insulin detemir. GIRmax for an individual subject will be >2 SDs above the mean in 2.5% of all dose administrations, and hence subjects receiving insulin detemir reach GIRmax >3.3 mg · kg-1 · min-1 in 2.5% of all dose administrations, subjects receiving NPH insulin reach GIRmax >5.8 mg · kg-1 · min-1, and subjects receiving insulin glargine reach GIRmax >3.4 mg · kg-1 · min-1.

Metabolic activity was ongoing after 24 h in 17 of 72 (24%) clamps performed with insulin detemir (7 different subjects), whereas NPH insulin showed ongoing activity in 10 of 69 (14%) clamps (5 different subjects) and insulin glargine in 25 of 64 (39%) clamps (14 different subjects).

The differences in within-subject variability between the insulin preparations are readily illustrated in the individual GIR profiles for the first nine subjects treated in each treatment group (Fig. 1). The GIR profiles for insulin detemir were generally more consistent over the four dosing days compared with those for NPH insulin and insulin glargine.

Individual time-action profiles (glucose infusion rates over time) of the first nine patients randomized to insulin detemir (A), NPH insulin (B), or insulin glargine (C). The four clamps in one subject are summarized in one plot. A low within-subject variability is indicated by the four lines in one plot being close to each other (e.g., subject no. 204), whereas major deviations between the time-action profiles in one subject (e.g., subject no. 224) shows a high within-subject variability.

Comparisons between serum insulin concentration levels are not meaningful since the three insulin preparations are different chemical entities with different modes of protraction administered in different molar doses. Moreover, within-subject variability of pharmacokinetic end points should be interpreted with caution as the precision of the assays used to assess serum insulin concentrations with each insulin preparation differs and will therefore contribute slightly to the within-subject variability estimated. Nevertheless, within-subject variability for the pharmacokinetic end points, INS-AUC(0-12 h), INS-AUC(0-), and C max were generally lower with insulin detemir than with NPH insulin and insulin glargine, which is consistent with the pharmacodynamic results ( Table 2 ).

Subcutaneous administration was generally well tolerated for all three basal insulin preparations. Only three adverse events were regarded as being possibly and/or probably related to trial drug: one subject reported two events of swelling at the injection site (insulin detemir), and one subject reported one event of vomiting (NPH insulin). There were no clinically relevant safety findings in other safety parameters, including laboratory variables of hematology and biochemistry.


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