Insulin Detemir Results in Less Weight Gain than NPH Insulin When Used in Basal-Bolus Therapy for Type 2 Diabetes Mellitus, and this Advantage Increases with Baseline Body Mass Index

Abstract and Introduction

Objective: Weight gain during insulin therapy can be a challenging problem in already overweight type 2 diabetes mellitus patients, affecting treatment compliance and long-term prognosis. The analogue insulin detemir has been reported to have a weight-sparing effect compared with other basal insulins. This pooled analysis investigated whether this potential advantage is related to body mass index (BMI) when insulin detemir is used as the basal component of basal-bolus therapy.
Methods: Data were pooled from two randomised, parallel group trials of 22 and 24 weeks' duration, in which 900 insulin-treated patients with type 2 diabetes mellitus had their treatment intensified to basal-bolus therapy. Patients received once- or twice-daily insulin detemir or neutral protamine Hagedorn (NPH) insulin in conjunction with insulin aspart or human soluble insulin at mealtimes.
Results: Patients treated with insulin detemir had minimal weight gain (mean <1kg), regardless of their BMI at entry (estimated slope -0.032), whereas, in patients treated with NPH insulin, weight gain increased as baseline BMI increased (estimated slope 0.075, p = 0.025). Indeed, NPH insulin-treated patients with the largest BMI (>35 kg/m²) gained the most weight (mean of ≈2.4kg). In contrast, insulin detemir-treated patients with a BMI >35 kg/m² lost weight (mean of ≈-0.5kg). Glycaemic control was similar with the two treatments.
Conclusion: Insulin detemir may provide a clinical advantage in terms of reduced weight gain in the treatment of overweight patients with type 2 diabetes.

Intensified insulin therapy is often necessary to maintain glycaemic control in type 2 diabetes mellitus, which in turn minimises and delays the presentation and progression of long-term complications.^[1,2] However, weight gain can be an undesirable side effect of intensified insulin treatment, as illustrated by landmark trials such as the DCCT (Diabetes Control and Complications Trial)^[3] and the UKPDS (United Kingdom Prospective Diabetes Study).^[4]

Insulin-related weight gain can be detrimental to the patient with diabetes for a number of reasons. The prospect of weight gain, coupled with concerns about hypoglycaemia, can lead to reluctance or delay by healthcare professionals and patients in initiating insulin therapy. In patients with type 1 diabetes, weight gain associated with insulin therapy has been shown to have potentially undesirable physiological effects, including increased blood pressure, low-density lipoprotein and total cholesterol levels, decreased high-density lipoprotein (HDL) cholesterol level and increased waist-to-hip ratio.^[5] A recent report from the Swedish National Diabetes Register^[6] detailed similar findings in patients with type 2 diabetes. Here, data from a cross-sectional study of more than 44,000 patients showed that obesity was associated with high prevalences of hypertension (88%) and hyperlipidaemia (81%) as well as an elevated triglyceride:HDL cholesterol ratio, while data from a 6-year prospective study of nearly 4500 patients showed that gains in body mass index (BMI) were associated with increases in blood pressure. As these changes are known to increase cardiovascular risk, it is possible that they will to some extent limit the prognostic benefits gained from improved glycaemic control. There is therefore a need to minimise weight gain associated with insulin therapy.

Insulin detemir has been shown in phase III clinical trials to be associated with significantly less weight gain than neutral protamine Hagedorn (NPH) insulin in type 1^{[7,8,9,10,11,12,13]} and type 2 diabetes.^[14,15,16] For example, in a trial comparing basal-bolus therapy in type 2 diabetes with insulin detemir plus insulin aspart or NPH insulin plus regular human insulin, insulin detemir resulted in significantly less mean weight gain (0.51kg) than NPH insulin (1.13kg, p = 0.038) at equivalent glycaemic control.^[16] Patients treated with insulin detemir plus insulin aspart also experienced lower within-patient variability in self-measured fasting blood glucose and reduced episodes of nocturnal hypoglycaemia than those treated with NPH insulin plus regular human insulin. Reduced weight gain was also observed in a comparative trial of basal-bolus treatment with insulin detemir or NPH insulin combined with insulin aspart.^[15] Insulin detemir-treated patients experienced less mean weight gain (1.0 vs 1.8kg, respectively; p = 0.017) and there was lower within-patient variability in fasting blood glucose compared with NPH insulin plus insulin aspart. Glycaemic control was similar in the two treatment groups.

The relationship between baseline BMI and weight change following the addition of insulin detemir and NPH insulin to oral antihyperglycaemic therapy in 476 poorly controlled diabetic patients was recently examined in a parallel-group, treat-to-target trial.^[14] Insulin doses were intensively titrated towards pre-breakfast and pre-dinner plasma glucose targets of =6.0 mmol/L over a 24-week period. Again, insulin detemir was associated with a significantly lower relative gain in weight compared with NPH insulin (1.2 vs 2.8kg, respectively; p < 0.001) and a clear trend for increasing BMI at entry to be associated with reducing weight gain was observed with insulin detemir, whereas no such relationship was found for NPH insulin.

It has not yet been established how the weight advantage observed with insulin detemir could be related to a patient's initial BMI in the context of basal-bolus therapy. Therefore, the aim of the present analysis, which pooled data from two randomised trials, was to identify if a relationship between weight advantage and BMI exists when insulin detemir is used as the basal component of basal-bolus therapy and, if so, whether this relationship is similar to that observed in a previous study^[14] in which insulin detemir was compared with NPH insulin as an additional treatment in patients taking oral antihyperglycaemic therapy.

Clin Drug Invest. 2007;27(4):279-285. © 2007  Adis Data Information BV

Cite this: Insulin Detemir Results in Less Weight Gain than NPH Insulin When Used in Basal-Bolus Therapy for Type 2 Diabetes Mellitus, and this Advantage Increases with Baseline Body Mass Index - Medscape - Apr 01, 2007.