A total of 821 subjects were enrolled in the study; 533 subjects were randomly assigned to liraglutide or placebo treatment after the metformin plus rosiglitazone run-in period (288 subjects were run-in failures due to FPG values out of range [135–230 mg/dl; 7.5–12.8 mmol/l] or other reasons). Three subjects were randomized but were withdrawn before receiving the study drug. Baseline characteristics were balanced across treatment groups (). The majority (83%) of the randomized subjects were treated with two or more OADs before the study.
Characteristics of randomized population and subject disposition
At the end of the study, the mean A1C values for the overall population decreased by (means ± SE) 1.5 ± 0.1% for both 1.2 and 1.8 mg/day liraglutide groups and 0.5 ± 0.1% for the placebo group. Liraglutide-treated subjects had superior glycemic control compared with those in the placebo group (liraglutide 1.2 mg/day vs. placebo: −0.9% [95% CI −1.1 to −0.8] and liraglutide 1.8 mg/day vs. placebo: −1.1% [−1.1 to −0.8]). Within the first 12 weeks of the study, mean A1C values decreased from baseline for the liraglutide-treated groups and thereafter remained steady throughout the trial (A).
Figure 1 A: A1C over time for the study population. B: Percentage of subjects achieving ADA and AACE/IDF A1C goals at the end of the study. C: FPG values over time. D: Change in body weight over time. E: SBP over time. F: Percentage of subjects with nausea by (more ...)
A logistic regression analysis demonstrated that a significantly greater percentage of subjects in both of the liraglutide groups achieved the ADA and AACE/IDF A1C goals compared with placebo (P < 0.0001 for all comparisons of liraglutide to placebo for both A1C goals) (B). At the end of the study, 57.5 and 53.7% of subjects in the 1.2 and 1.8 mg liraglutide/day groups, respectively, had an A1C <7%, compared with 28.1% in the placebo group, with 37.3 and 36.2%, respectively, reaching ≤6.5% compared with 14.4% with placebo.
FPG values decreased within 2 weeks of randomization with liraglutide, remaining relatively stable thereafter, while with placebo, smaller decreases occurred (C). End-of-study FPG values were 139 ± 49 mg/dl (7.7 ± 2.7 mmol/l), 137 ± 41 mg/dl (7.6 ± 2.3 mmol/l), and 171 ± 54 mg/dl (9.5 ± 3.0 mmol/l) in the 1.2 and 1.8 mg liraglutide/day and placebo groups, respectively. The decreases in FPG from baseline for the liraglutide groups (−40 mg/dl [−2.2 mmol/l] and −44 mg/dl [−2.4 mmol/l] for 1.2 and 1.8 mg liraglutide/day groups, respectively) were significantly greater than the decrease observed in the placebo group (−8 mg/dl [−0.4 mmol/l], P < 0.0001).
Mean 90-min PPG (mean of three meals), from self-monitored seven-point plasma glucose measurements at the end of the study, decreased from baseline in all treatment groups by −47 mg/dl (2.6 mmol/l) for 1.2 mg liraglutide/day, −49 mg/dl (2.7 mmol/l) for 1.8 mg liraglutide/day, and −14 mg/dl (0.8 mmol/l) for placebo (P < 0.001 comparisons of all liraglutide groups to placebo). The postprandial increment (postmeal value minus premeal) was significantly reduced over breakfast with liraglutide treatment (−16, −14, and −5 mg/dl [−0.9, −0.8, −0.3 mmol/l], respectively; P < 0.05 for both liraglutide treatment groups vs. placebo) but not for lunch and dinner.
Mean change in body weight over time is shown in D. Weight loss was observed in the liraglutide-treated groups ([means ± SE] 1.0 ± 0.3 and 2.0 ± 0.3 kg from baseline for 1.2 and 1.8 mg liraglutide/day groups, respectively) and was significantly different (P < 0.0001) from the weight gain in the placebo group (0.6 ± 0.3 kg). The weight loss in the 1.8 mg liraglutide/day group was significantly greater than the 1.2 mg liraglutide/day group (P = 0.011).
The 1.2 and 1.8 mg liraglutide/day groups had significant reductions in mean SBP compared with the placebo group () (E) (placebo-corrected difference: 1.2 mg liraglutide/day: −5.6 mmHg, P < 0.0001; 1.8 mg liraglutide/day: −4.5mmHg, P = 0.0009). There were no significant differences between treatment groups in diastolic blood pressure (DBP). Minor, but statistically significant, increases in pulse rate were observed in the liraglutide-treated groups versus placebo (2 and 3 bpm for 1.2 mg (P = 0.0071) and 1.8 mg liraglutide (P = 0.0001), respectively) with a decrease of 0.5 bpm for placebo. Changes in lipids from baseline are presented in showing that free fatty acid values decreased with liraglutide treatment as compared with an increase with placebo, and LDL cholesterol and triglycerides decreased significantly more in the 1.2 mg liraglutide group than in the placebo group.
Other end points of interest/metabolic intermediates change from baseline to end of study
The decreases in the proinsulin-to-insulin ratio from baseline (baseline of 0.4 across all groups) for the liraglutide groups were significant (P < 0.05) compared with the placebo group, which increased from baseline (). The increase in C-peptide was significantly greater in the liraglutide groups (131 and 144 pmol/l for 1.2 and 1.8 mg liraglutide, respectively) compared with an increase of 51 pmol/l for placebo (P < 0.05 for comparison of both liraglutide groups to placebo). Both liraglutide treatment groups had significant improvements (increase of 27 absolute percentage points) in HOMA-B for both groups from baseline values of 34 to 37%, respectively, compared with an improvement in the placebo group of 6 absolute percentage points from a baseline of 40% (P < 0.0001 for both groups vs. placebo). Insulin resistance (measured by HOMA-IR) was reduced in all three treatment groups but was not significantly different between groups. No significant differences in the change-from-baseline of HOMA-IR and fasting insulin and glucagon values were observed between either of the liraglutide groups versus the placebo group ().
Gastrointestinal disorders (including nausea, vomiting, and diarrhea) were the most frequently reported adverse events in the liraglutide groups and were reported by 45, 56, and 19% of the subjects in the 1.2 and 1.8 mg liraglutide and placebo groups, respectively. One episode or more of nausea was experienced by 29 and 40% in the 1.2 and 1.8 mg liraglutide groups, respectively, and vomiting was experienced by 7 and 17%, respectively. The majority of nausea was transient, as it occurred in the first 4 weeks of liraglutide treatment (216 events in weeks 1–4 vs. 65 events in weeks 4–26) (F). During the first 8 weeks of treatment, 71–84% of subjects in the liraglutide groups and 98% of subjects in the placebo group reported ≤7 days of nausea. Peripheral edema was reported by 5.1, 1.7, and 8.0% in the 1.2 mg liraglutide, 1.8 mg liraglutide, and placebo groups, respectively.
The percentages of subjects withdrawn because of adverse events were greater in the liraglutide groups than in the placebo group (). Nausea, vomiting, and/or diarrhea were the gastrointestinal events that lead to the withdrawal of five subjects treated with 1.2 mg liraglutide and 19 subjects treated with 1.8 mg liraglutide (). Most gastrointestinal adverse events resulting in withdrawal occurred during the first month of therapy. There were no episodes of pancreatitis, and no deaths occurred. Serious adverse events were infrequent (8 subjects [8 total events] for 1.2 mg liraglutide, 7 subjects [10 events] for 1.8 mg liraglutide, and 12 subjects [13 events] for placebo).
Minor hypoglycemia occurred at low incidence (9.0, 7.9, and 5.1% of subjects) resulting in a low rate of reported minor hypoglycemia (0.4. 0.6, and 0.2 events per year) for the 1.2 mg liraglutide, 1.8 mg liraglutide, and placebo groups, respectively. The rate of minor hypoglycemia for the 1.8 mg liraglutide group was significantly higher than placebo (P = 0.004). No major hypoglycemic event was reported.
No clinically relevant between-treatment differences were observed in physical examination findings, laboratory analyses (hematology and biochemistry analyses), electrocardiogram, or ophthalmoscopy. There was no significant treatment effect with 1.8 mg liraglutide versus placebo on calcitonin. Geometric mean– estimated repeated-measurement analysis showed calcitonin levels of 0.89, 0.83, and 0.75 ng/l for 1.2 mg liraglutide, 1.8 mg liraglutide, and placebo, respectively, at the end of the study (all values within the normal range). There was a significant increase for the 1.2 mg liraglutide group versus placebo group (P = 0.022) but no significant difference with the 1.8 mg liraglutide group. No difference in cardiovascular adverse events was reported between the liraglutide groups and placebo (five events [five subjects] with liraglutide 1.2, three events [three subjects] with liraglutide 1.8, and four events [four subjects] with placebo). There were 4.1 and 6.7% of subjects treated with 1.2 and 1.8 mg liraglutide and positive for liraglutide antibodies at the end of the study (versus none with placebo). Subjects with antibodies did not have an attenuated A1C response.