Incretin-based Therapies for Type 2 Diabetes
16 weeks in the 21 % of patients receiving a thiazolidinedione alone and in the 79 % of patients receiving a thiazolidinedione with metformin (all p<0.001 versus placebo). Mean disease duration was 7.3–8.2 years.52
Liraglutide
The extensive Liraglutide effect and action in diabetes (LEAD) program of six clinical trials, with a total randomized population of 4,456 patients with type 2 diabetes, has established the efficacy, tolerability, and safety of liraglutide as part of various combination regimens with sulfonylureas, metformin, or thiazolidinedione or as a monotherapy (see Table 2 and Figure 1).53–60
Liraglutide monotherapy significantly reduced HbA1c compared with glimepiride in 746 patients with inadequate type 2 diabetes control and
mean disease duration between 5.2 and 5.6 years (LEAD-3 trial, p≤0.0014 for liraglutide 1.2 mg and 1.8 mg versus glimepiride 8 mg).55,61 The superiority of liraglutide monotherapy over glimepiride was sustained until the end of a 52-week open-label extension (two year follow-up).56
The monotherapy trial yielded comparable FPG and PPG reductions with liraglutide or glimepiride (both superior to placebo) at 52 weeks, but FPG was lower after two years of liraglutide therapy compared with glimepiride (p=0.0001 and p=0.0015 for 1.8 mg and 1.2 mg doses, respectively).55,56
Liraglutide 1.8 mg was also associated with significantly lower PPG than glimepiride after two years (p=0.0105).56
In the LEAD-2 trial, combining liraglutide with metformin yielded significant HbA1c reductions versus placebo over 24 weeks: -0.8 % (95 % confidence interval [CI] -1.0 to -0.6), -1.1 % (95 % CI -1.3 to -0.9), and
-1.1 (95 % CI -1.3 to -0.9) with 0.6 mg, 1.2 mg, and 1.8 mg doses, respectively. Liraglutide was non-inferior to glimepiride as an add-on therapy to metformin. Mean daily PPG values fell by 30.6 mg/dl, 41.4 mg/dl, 46.8 mg/dl, and 45.0 mg/dl with liraglutide 0.6 mg, 1.2 mg, 1.8 mg, and glimepiride, respectively, compared with -10.8 mg/dl in the placebo group (p<0.001). This study included 1,091 patients with poorly controlled type 2 diabetes; mean disease duration was seven to eight years.58
The 26-week LEAD-1 study linked liraglutide (0.6 mg, 1.2 mg, or 1.8 mg
per day) with significant HbA1c and FPG reductions versus placebo (p<0.0001). Liraglutide 1.2 mg and 1.8 mg also showed significantly
greater efficacy than rosiglitazone (p<0.0001 and p≤0.006 for HbA1c and FPG, respectively, versus placebo). Mean daily PPG values fell by 45.0 mg/dl and 48.6 mg/dl with liraglutide 1.2 mg and 1.8 mg, respectively (p=0.043 and p=0.0022) and by 32.4 mg/dl with liraglutide 0.6 mg (p<0.0001), versus rosiglitazone.57
Liraglutide has also shown efficacy in patients with prolonged disease duration (mean duration nine or more years) whose glycemic control is poor despite combination therapy.59,60
The LEAD-4 trial compared liraglutide combined with metformin and rosiglitazone with placebo in
533 patients. HbA1c, FPG, and PPG values all fell significantly from baseline in liraglutide-treated patients over 26 weeks (p<0.0001, p<0.0001, and p<0.001, respectively, versus placebo).60
Mean PPG values
decreased by 46.8 mg/dl and 48.6 mg/dl with liraglutide 1.2 mg and 1.8 mg, respectively, compared with -14.4 mg/dl in the placebo group.60
Adding liraglutide to combined metformin plus a sulfonylurea significantly improved HbA1c, FPG, and PPG versus placebo (p<0.0001) in
US ENDOCRINOLOGY B
10 20 30 40 50 60 70
0
Liraglutide 1.2 mg
Liraglutide 1.8 mg
Glimepiride 8 mg
HbA1c = glycosylated hemoglobin; LEAD = Liraglutide effect and action in diabetes.
Figure 1: Percentage of Participants Treated to HbA1c Targets Lower than 7 % in the LEAD-3 Trial56
A
10 20 30 40 50 60 70
0
Liraglutide 1.2 mg
Liraglutide 1.8 mg
HbA1c≤6.5 % (≤48 mmol/mol) p=0.0436
Glimepiride 8 mg
HbA1c<7 % (<53 mmol/mol) p=0.0269
p=0.0054 58 % 53 % 37 %
44 %
42 % 29 %
the LEAD-5 study of 581 patients with poorly controlled type 2 diabetes. Both FPG and PPG fell even more significantly with liraglutide versus placebo (treatment differences -37.44 mg/dl and -33.12 mg/dl, respectively, both p<0.0001). This study also linked liraglutide with
significantly better HbA1c control than the active comparator, insulin glargine (p=0.0015).59
These results should be interpreted with caution
because an intensive treat-to-target approach might have produced more effective insulin glargine dosing. The patient-driven titration in this study was, however, consistent with real-life clinical experience (mean daily insulin glargine dose 24 International Units [IU] at end of study).59
Head-to-head Trials of Incretin-based Therapies Data from some head-to-head trials of incretin-based therapies in type 2 diabetes are summarized in Table 3. A few trials have directly compared individual incretin-based agents.53,54,62,63
A preliminary
two-week comparison in 95 patients showed that exenatide twice daily produced greater reductions in post-prandial glucose and triglycerides than sitagliptin (p<0.0001, p=0.0118, respectively).64
An eight-week
cross-over RCT also reported significantly greater reductions in mean 24-hour and post-prandial glucose values with exenatide twice daily than with sitagliptin.65
87
Participants (%)
Participants (%)
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