Introduction
People with type 2 diabetes inadequately controlled by oral glucose-lowering drugs can achieve clinically relevant improvements in HbA
1c with the addition of insulin therapy [
1‐
3]. However, patients and healthcare providers are often reluctant to initiate insulin due to concerns over injections, fear of hypoglycaemia and additional weight gain, and also because insulin treatment is perceived as complex and an added burden to diabetes management [
4,
5]. Moreover, once insulin is initiated, recommended targets for glycaemic control (HbA
1c < 6.5–7.0%) are often not met [
5‐
7].
In recent years, the basal insulin analogues glargine and detemir have been introduced. These were developed to improve upon the limitations of NPH insulin (NPH) and other conventional basal insulins, which have an inadequate duration of action, a marked peak glucose-lowering effect and variability in response from one injection to another [
8]. These analogues might help to overcome some of the barriers to insulin initiation and optimisation, including concerns over hypoglycaemia and weight gain.
Several recent studies have assessed basal insulin as an add-on therapy to oral glucose-lowering drugs, comparing either insulin glargine or insulin detemir with NPH, and using titration algorithms based on glucose monitoring [
1,
9‐
13]. These studies have demonstrated that simple regimens involving a once or twice daily injection of a basal insulin analogue can achieve clinically important improvements in glycaemic control similar to those achievable with NPH, but with less risk of hypoglycaemia. Insulin detemir has consistently shown less body weight gain than NPH when used in this way, as well as when used in basal plus mealtime insulin therapy [
14,
15], whereas a weight advantage has been reported in only a few of the comparative trials of glargine vs NPH, as for example in the recent LANMET study [
11].
Insulin glargine is licensed only for once daily use as a basal insulin for people with diabetes. Insulin detemir, in contrast, is available for once or twice daily use. Glucose clamp comparisons between these insulins have given contradictory information on whether their duration of effect is comparable [
16,
17]. The only direct comparison in patients with type 2 diabetes suggests very similar pharmacodynamic profiles at clinically relevant doses [
16], but methodological issues remain controversial. The objective of the current study was to compare treatment with insulin detemir and insulin glargine in line with their licensed indications as add-on therapy to oral glucose-lowering agents in insulin-naive patients with type 2 diabetes.
Discussion
The results of this first head-to-head comparison of insulin detemir and insulin glargine as add-on for treatment with oral glucose-lowering agents in people with type 2 diabetes using forced insulin titration suggest that clinically significant and similar improvements in glycaemic control can be achieved with both analogues, together with a similarly low risk of hypoglycaemia. Insulin doses were higher with insulin detemir overall, partly as a result of the doses used by those taking it twice daily. The withdrawal rate appeared to be higher with insulin detemir (21 vs 13%), which was partly accounted for by adverse events (8 vs 4%), this excess being primarily due to injection site reactions. Insulin detemir was associated with a modest relative reduction in weight gain, consistent with observations in previous comparisons of this analogue with NPH in type 2 diabetes [
12,
13,
19,
20]. In the present study, the between-treatment difference in weight was primarily accounted for by those patients completing the study on once-daily insulin detemir. It is, however, possible that differences in eating pattern were contributory factors in both the insulin detemir dosing schedule and the different levels of weight gain observed between the two insulin detemir dosing schedules. The mechanism(s) responsible for relatively lower weight gain observed here and previously with insulin detemir remain the object of speculation [
14,
15,
21,
22].
The present study was designed to compare the two basal insulin analogues as they had been used in previous studies and according to label. Thus, insulin glargine was given once daily at bedtime regardless of glycaemic profile, while for insulin detemir an option was provided for adding a second dose, primarily based on pre-dinner blood glucose level following a structured insulin titration protocol. The decision to use twice-daily insulin detemir could not be attributed to hypoglycaemia, as patients who were switched to a twice-daily regimen had on average 3.7 hypoglycaemic episodes per patient-year prior to transfer, compared with 4.7 episodes per patient-year in patients completing treatment on once-daily insulin detemir. The frequency of nocturnal hypoglycaemia was also lower in relevant patients before transfer (0.7 vs 0.9 episodes per patient-year).
Interestingly, the initiation of insulin with once-daily insulin detemir has recently been tested by Philis-Tsimikas et al. in type 2 diabetes patients on oral glucose-lowering agents, resulting in HbA
1c reductions of 1.5% (morning injection) and 1.6% (evening injection) from baseline values of 9.1 and 8.9%, respectively [
13]. These improvements in glycaemic control approach the magnitude of HbA
1c reduction shown in the current study and in previous studies of once-daily insulin glargine [
9‐
11], although the insulin detemir doses were higher at trial-end and the absolute HbA
1c values achieved at trial-end were relatively high.
The design of the current study does not allow definitive conclusions for comparison of once and twice daily dosing with insulin detemir, although these post hoc observations do suggest that once daily administration can be an appropriate starting regimen for people using insulin detemir as add-on to oral glucose-lowering drug therapy. However, with dose optimisation, a significant proportion of patients may eventually need a twice-daily regimen, guided by structured glucose monitoring. Further studies are required to better define the differences between these two basal insulin analogues on the basis of a similar insulin administration regimen, once daily only, for both insulins. Alternatively, if the option of adding a second insulin dose is available for both insulins, then a properly designed study protocol should allow addition of this second insulin injection only when a normal or much lower FPG target is achieved. Indeed, the use of lower FPG targets (e.g. ≤5.5 mmol/l, as has been used previously) should also enable a higher proportion of patients to reach guideline HbA1c targets.
In conclusion, the use of insulin detemir or insulin glargine as add-on to oral glucose-lowering therapy resulted in comparable HbA1c improvements and a similarly low risk of hypoglycaemia. Further comparisons of detemir and glargine are required to fully understand how each may relatively benefit defined groups of patients starting on insulin.
Acknowledgements
The investigators and participants are thanked for their participation. A full list of investigators can be seen in the ESM
1. The study was funded and monitored by Novo Nordisk. The authors and/or their institutions received support from Novo Nordisk (J. Larsen and C. Koenen are employees) and Aventis (now sanofi aventis) for consultation/research/teaching activities. The authors thank T. Rambrand, M. Edmunds and C. Jones for assistance with manuscript preparation. An abstract based on feasibility of titration data was presented at American Diabetes Association (ADA) meeting in 2004 (Rosenstock et al. Diabetes 53 (Suppl. 2): A145) and another abstract reporting the findings was presented at the ADA meeting in 2006 (Rosenstock et al. Diabetes 55(1): A132).
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