This is the first report that directly compares the effect of 4 weeks of liraglutide treatment on insulin dose and glycemic control in type 1 diabetic patients with and without residual β-cell function. The major finding was a reduction in insulin dose, which was significant in both groups of patients treated with liraglutide and also compared with patients treated with insulin alone. The reduction was accompanied by unchanged time spent with blood glucose >10 mmol/L, whereas HbA1c
and time spent with blood glucose <3.9 mmol/L tended to be reduced. Fast-acting insulin accounted for 63 and 85% of the reduction in insulin dose in C-peptide–positive and –negative patients, respectively. This is in accordance with a previous study (13
) in which 6 months’ treatment with exenatide in C-peptide–positive patients with longstanding disease decreased total insulin by 13% but prandial insulin by 30% and also with a short-term study in C-peptide–negative adolescents in which exenatide reduced glucose excursions despite a 20% reduction in insulin dose (14
). The current study also was inspired by previous short-term trials using intravenous or subcutaneous infusion of native GLP-1 in type 1 diabetic patients. In patients with low or undetectable C-peptide levels, pharmacological concentrations of GLP-1 were shown to reduce fasting plasma glucose from 13.4 to 10 mmol/L, glucagon concentration by 50% (8
), and isoglycemic meal–related insulin requirement by 50% (12
). Furthermore, subcutaneous exenatide or human GLP-1 administered together with the usual dose of insulin safely improved glucose control in patients without (7
) as well as with (10
) residual β-cell function.
In most cases, the antidiabetes effects were accompanied by a reduction of glucagon levels and/or by delayed gastric emptying. Therefore, inhibition of gastric emptying as well as reduced glucagon levels seem to explain the glucose-regulating effects of GLP-1 during a meal, whereas the importance of residual β-cell function is less well defined. In the current study using liraglutide, inhibition of gastric emptying may be less important because of the development of tachyphylaxis during continuous exposure (19
In our study, the reduction in insulin dose was larger in C-peptide–positive patients, and two patients completely discontinued insulin treatment without loss of glycemic control. Despite reduced insulin doses, neither fasting nor peak postprandial blood glucose measurements differed significantly between weeks 0 and 4 in any group. This is in accordance with our goal of preserving the same (good) glycemic control during the two periods. However, there were weak trends of higher mean postprandial levels in C-peptide–positive patients and of higher fasting levels in C-peptide–negative patients treated with liraglutide. This could theoretically result from worsening of glycemic control but also, and more likely, from reduced occurrence of hypoglycemia. It may be argued that part of the reduction in insulin dose was attributed to the initial reduction in the liraglutide-treated patients. However, this is highly unlikely because all patients were optimized in insulin dose before entering the study and because insulin dose afterward was titrated up or down to meet the same target blood glucose according to careful examination of at least 7-point blood glucose measurements for 3 consecutive days immediately after start of treatment and in week 2. In C-peptide–positive patients, HbA1c decreased from 6.6 to 6.4% and from 7.5 to 7.0% in C-peptide–negative patients treated with liraglutide, in both instances, with a tendency for decreased hypoglycemia, but this did not change in patients treated with insulin alone. The reduction in HbA1c may partly result from a carry-over effect from the optimization in insulin therapy before entry. However, all patients were dose adjusted if necessary, and random assignment took place after the initial correction, and HbA1c did not change in patients treated with insulin alone.
A limitation of the current study is the lack of blinding because of unavailable placebo pen devices. However, proper blinding would have been difficult because of the necessary reduction in insulin dose (for safety reasons) in liraglutide-treated patients and because of the gastrointestinal adverse effects. The reduction in insulin dose could theoretically also result from reduction in appetite, leading to an unintended (and unreported) decrease in carbohydrate intake in week 4 or from improved insulin sensitivity. However, change in insulin dose was not correlated with weight loss.
The lack of increments in glucose-stimulated as well as glucagon-stimulated C-peptide secretion during liraglutide treatment is puzzling but is in agreement with Rother et al. (13
), in which 6 months’ treatment with exenatide did not change the β-cell response to arginine.
The weight loss in the liraglutide-treated patients occurred (in 18 of 19 treated patients) despite encouragements to maintain body weight, but weight loss did not correlate with BMI. Nausea and vomiting occurred only in the first 2–3 treatment days and resolved spontaneously or subsequent to dose reduction, but patients also reported loss of appetite unrelated to nausea. Because almost all liraglutide-treated patients experienced transient gastrointestinal adverse effects, start dose should perhaps have been reduced.
We could not demonstrate a change in risk of hypoglycemia during cycling. However, in week 4, postprandial glucagon was significantly reduced but increased appropriately during exercise, when glucose levels fell; therefore, it appears that liraglutide, like GLP-1 (20
), does not inhibit the glucagon response to decreasing glucose levels.
Four weeks’ treatment with liraglutide reduces insulin dose in type 1 diabetic patients along with improved or unaltered glycemic control. Treatment effect is larger in patients with residual β-cell function, and some patients may discontinue insulin treatment. Almost all patients treated with liraglutide lost weight.