Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU)

Abstract

Aim: To compare the effects of combining liraglutide (0.6, 1.2 or 1.8 mg/day) or rosiglitazone 4 mg/day (all n >or= 228) or placebo (n = 114) with glimepiride (2-4 mg/day) on glycaemic control, body weight and safety in Type 2 diabetes.

Methods: In total, 1041 adults (mean +/- sd), age 56 +/- 10 years, weight 82 +/- 17 kg and glycated haemoglobin (HbA(1c)) 8.4 +/- 1.0% at 116 sites in 21 countries were stratified based on previous oral glucose-lowering mono : combination therapies (30 : 70%) to participate in a five-arm, 26-week, double-dummy, randomized study.

Results: Liraglutide (1.2 or 1.8 mg) produced greater reductions in HbA(1c) from baseline, (-1.1%, baseline 8.5%) compared with placebo (+0.2%, P < 0.0001, baseline 8.4%) or rosiglitazone (-0.4%, P < 0.0001, baseline 8.4%) when added to glimepiride. Liraglutide 0.6 mg was less effective (-0.6%, baseline 8.4%). Fasting plasma glucose decreased by week 2, with a 1.6 mmol/l decrease from baseline at week 26 with liraglutide 1.2 mg (baseline 9.8 mmol/l) or 1.8 mg (baseline 9.7 mmol/l) compared with a 0.9 mmol/l increase (placebo, P < 0.0001, baseline 9.5 mmol/l) or 1.0 mmol/l decrease (rosiglitazone, P < 0.006, baseline 9.9 mmol/l). Decreases in postprandial plasma glucose from baseline were greater with liraglutide 1.2 or 1.8 mg [-2.5 to -2.7 mmol/l (baseline 12.9 mmol/l for both)] compared with placebo (-0.4 mmol/l, P < 0.0001, baseline 12.7 mmol/l) or rosiglitazone (-1.8 mmol/l, P < 0.05, baseline 13.0 mmol/l). Changes in body weight with liraglutide 1.8 mg (-0.2 kg, baseline 83.0 kg), 1.2 mg (+0.3 kg, baseline 80.0 kg) or placebo (-0.1 kg, baseline 81.9 kg) were less than with rosiglitazone (+2.1 kg, P < 0.0001, baseline 80.6 kg). Main adverse events for all treatments were minor hypoglycaemia (< 10%), nausea (< 11%), vomiting (< 5%) and diarrhoea (< 8%).

Conclusions: Liraglutide added to glimepiride was well tolerated and provided improved glycaemic control and favourable weight profile.

FIGURE 1

Overview of trial design and treatment arms.

FIGURE 2

Flow of patients through the study.

FIGURE 3

Mean glycated haemoglobin (HbA_1c) by treatment and week (intent-to-treat population with last observation carried forward): (a) overall population; (b) previously on monotherapy; or (c) previously on combination therapy; (d) mean changes in HbA_1c from baseline after 26 weeks of treatment. Keys: (a–c) liraglutide 0.6 mg: grey dotted line with squares; liraglutide 1.2 mg: black solid line with triangles; liraglutide 1.8 mg: black dotted line with squares; rosiglitazone: grey solid line with circles; placebo: black solid line with circles. (d) liraglutide 0.6 mg: black stripes on white; liraglutide 1.2 mg: white stripes on black, liraglutide 1.8 mg: grey tint; rosiglitazone: white; placebo: black. ****P < 0.0001 compared with placebo; ††††P < 0.0001 compared with rosiglitazone.

FIGURE 4

Subjects achieving specified glycated haemoglobin (HbA_1c) levels: (a) percentage reaching HbA_1c < 7.0% (American Diabetes Association/European Association for the Study of Diabetes target); (b) percentage reaching HbA_1c < 6.5% (International Diabetes Federation/American Association of Clinical Endocrinologists targets); (c) cumulative distribution of HbA_1c at 26 weeks for the intent-to-treat (ITT) population; and (d) for the ITT last observation carried forward (LOCF) population. Keys: (a, b) liraglutide 0.6 mg: black stripes on white; liraglutide 1.2 mg: white stripes on black, liraglutide 1.8 mg: grey tint; rosiglitazone: white; placebo: black. (c, d) liraglutide 0.6 mg: pale grey solid line; liraglutide 1.2 mg: grey solid line, liraglutide 1.8 mg: black solid line; rosiglitazone: dotted black line; placebo: dotted grey line; baseline visit: long dashed black line. ****P < 0.0001 or **P < 0.01 compared with placebo; ††††P < 0.0001 or †††P = 0.0005 compared with rosiglitazone.

FIGURE 5

Mean changes from baseline in fasting plasma glucose after 26 weeks of treatment. ****P < 0.0001 compared with placebo; ††P < 0.01 compared with rosiglitazone.

FIGURE 6

Mean changes in body weight from baseline after 26 weeks of treatment. *P < 0.05 compared with placebo; ††††P < 0.0001 compared with rosiglitazone.

FIGURE 7

Percentage of subjects experiencing nausea over the course of the study. Key: liraglutide 0.6 mg with glimepiride: black line with filled circles; liraglutide 1.2 mg with glimepiride: black line with filled triangles; liraglutide 1.8 mg with glimepiride: grey line with hollow circles; glimepiride grey lines with filled squares; rosiglitazone and glimepiride: grey line with hollow triangles.