Adult subjects with type 2 diabetes were screened and enrolled if they were 18–80 years of age, had A1C between 7 and 11% (prestudy OAD monotherapy for ≥3 months) or between 7 and 10% (prestudy combination OAD therapy for ≥3 months), and had BMI ≤40 kg/m2
. Subjects were excluded if they had used insulin during the previous 3 months (except short-term treatment). The protocol was approved by local institutional review boards, and all subjects provided written informed consent before initiation of any trial-related activities. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines (14
In this 26-week, double-blind, double-dummy, active-control, parallel-group, multicenter (170 sites), multinational (21 countries) trial, subjects were randomly assigned (2:2:2:1:2) to receive one of three once-daily doses of liraglutide (0.6, 1.2, or 1.8 mg/day; Novo Nordisk, Bagsvaerd, Denmark) injected subcutaneously in combination with metformin, to receive liraglutide placebo with metformin monotherapy (placebo group), or to receive combination therapy with glimepiride and metformin (4 mg glimepiride once daily with the first meal of the day). The most relevant position for initiating treatment with GLP-1 may be after metformin failure, but to facilitate recruitment into the trial other monotherapy or combination treatments were allowed. Accordingly, the objective of this study was to compare the efficacy and safety of liraglutide with both placebo and another commonly used therapeutic option (glimepiride) after metformin failure. The double-dummy design required that subjects in the liraglutide and placebo groups received a glimepiride placebo, whereas subjects in the glimepiride and placebo groups received an injection of liraglutide placebo.
Randomization was performed using a telephone-based or web-based randomization system. Subjects were randomly assigned to the lowest available randomization number and stratified with respect to their previous use of OAD monotherapy or combination therapy. Subjects completing the study could enroll in an 18-month open-label extension period.
Randomization to treatment occurred after a 3-week forced metformin titration period (dose increased up to 2,000 mg/day: 1,000 mg in the morning and 1,000 mg in the evening) followed by a 3-week metformin maintenance period. Subjects taking metformin at enrollment could go through a modified titration period or advance directly to the metformin maintenance period. After randomization, subjects underwent a 2- and 3-week titration period for liraglutide (up to 0.6, 1.2, or 1.8 mg, as per randomization, at 0.6-mg increases per week) and glimepiride (up to 4 mg, with 1-, 2-, and 4-mg doses at weeks 1, 2, and 3). Glimepiride (active and placebo) was taken orally once daily in the morning. Liraglutide (active or placebo) was injected subcutaneously once daily at any time of the day in the upper arm, abdomen, or thigh using a pen injector device. Subjects were encouraged to inject liraglutide at the same time each day.
The titration period was followed by a 23- or 24-week maintenance period during which the doses of study drugs were to be maintained. However, metformin could be decreased to a minimum of 1,500 mg/day in the case of unacceptable hypoglycemia or other adverse events but had to be maintained between 1,500 and 2000 mg/day during the maintenance period.
The primary outcome measure was change in A1C at the end of the study. Secondary end points included changes in body weight, fasting plasma glucose (FPG), 7-point plasma glucose profiles (before each meal, 90 min after breakfast, lunch, and dinner, and at bedtime), and β-cell function based on fasting insulin, fasting C-peptide, fasting proinsulin-to-insulin ratio, and the homeostasis model assessment index of β-cell function (HOMA-B) (15
). Laboratory analyses were performed by a central laboratory (MDS Pharma Services in Canada, France, Germany, Singapore, and Switzerland and Laboratories Hildago in Argentina). A1C was assayed by a method certified by the National Glycohemoglobin Standardization Program. Subjects were provided with MediSense Precision Xtra/MediSense Optium glucose meters (Abbott, Maidenhead, U.K.) calibrated to plasma glucose to determine self-measured plasma glucose and recorded values in their diaries. Serum insulin and C-peptide values were determined using a chemiluminescence immunoassay, and proinsulin was measured in serum using an enzyme-linked immunosorbent assay.
Safety variables included adverse events, vital signs, electrocardiogram, biochemical and hematology measures, and subject-reported hypoglycemic episodes (based on symptoms and plasma glucose <3.1 mmol/l). Minor hypoglycemic episodes were self-treated; major episodes required third-party assistance.
The analyses of efficacy end points were based on the intent-to-treat population defined as subjects who were exposed to at least one dose of trial product and had one postbaseline measurement of the parameter. Each end point was analyzed using an ANCOVA model with treatment, country, and previous antidiabetic treatment as fixed effects and baseline as the covariate. Missing data were imputed as the last observation carried forward. Sample size calculations were based on showing A1C and body weight differences of 0.5 and 3%, respectively, after 6 months of treatment. The assumed standard deviation for A1C and the coefficient of variance for weight were 1.2 and 3%, respectively. The combined power (calculated as the product of the marginal powers for A1C and weight) was at least 85%.
Superiority or noninferiority of glycemic control with liraglutide versus comparators was concluded if the upper limit of the two-sided 95% CI for the treatment difference was <0%; noninferiority was concluded if it was <0.4%. The proportion of subjects achieving A1C targets (ADA target <7%; American Association of Clinical Endocrinologists [AACE] target ≤6.5%) was compared between treatments using a logistic regression model with treatment and baseline A1C as covariates. CIs for secondary end points were corrected using Dunnett's test. Hypoglycemic episodes were analyzed using a general linear model including treatment as a fixed effect. Values are expressed as means ± SD unless otherwise noted. The significance level was set at P < 0.05.