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继日本中央社会保险医疗委员会批准了Victoza®（利拉鲁肽）的定价之后，诺和诺德制药公司计划将尽快在当地市场推出这种产品。诺和诺德表示，Victoza®是首个在日本获准上市的GLP-1类药物，既可以单独用药，也可以作为辅助药物与磺脲类降糖药(SU)联用。
Liraglutide(利拉鲁肽)安全性、有效性3期临床研究LEAD的6个随机对照研究介绍
LEAD study
The efficacy and safety of liraglutide were examined in the phase 3 Liraglutide Effect and Action in Diabetes (LEAD) trial program, a series of 6 randomized controlled studies involving > 4400 patients with type 2 diabetes who were unable to maintain glycemic control with diet and exercise alone or with oral treatment, ~2700 of whom received liraglutide.21,22,24–28 In these trials, liraglutide was examined as monotherapy and in combination with various oral agents. Five phase 3a trials (LEAD 1–5) were submitted to regulatory authorities while 1 phase 3b, head-to-head trial against exenatide (LEAD-6) has since been completed.
Overview ： The LEAD Trial Program
The LEAD studies were designed to evaluate the effects of liraglutide on glycemic control, body weight, and β-cell function, and to establish safety and tolerability in patients with type 2 diabetes. Additional endpoints included effects on BP and lipid profiles. Glucose control was assessed with HbA1c, fasting plasma glucose, and postprandial glucose measurements. β-cell function was measured by fasting C-peptide levels, proinsulin-to-insulin ratio, and homeostasis model assessments of β-cell function (HOMA-β). Taken together, the 6 LEAD liraglutide phase 3 trials covered a wide scope in the continuity of care as currently practiced in the treatment of type 2 diabetes, although liraglutide has not been studied in combination with thiazolidinediones or insulin alone.
The LEAD-3 monotherapy trial demonstrated that liraglutide can maintain glycemic control in most patients for 52 weeks, with greater efficacy in the drug-naïve cohort who were unable to achieve glycemic control with diet and exercise. In LEAD-1 and LEAD-2, liraglutide was effectively combined with 1 oral agent. In LEAD-4 and LEAD-5, liraglutide was successfully combined with 2 oral agents. In LEAD-6, liraglutide or exenatide was effectively combined with 1 or 2 oral agents. The key findings from each trial are described below, with data for the primary endpoint and major secondary endpoints presented in Table 2. Studies examining the effects of liraglutide in combination with insulin detemirand comparing liraglutide versus the DPP-4 inhibitor sitagliptin are ongoing.
LEAD系列研究的其他5个研究结果：
Liraglutide Added to Metformin and Glimepiride (LEAD-5)
The LEAD-5 study showed the efficacy of liraglutide in combination with both metformin and a sulfonylurea when compared with insulin glargine added to metformin and a sulfonylurea in 581 patients in a 26-week randomized study. Adding liraglutide 1.8 mg to metformin + glimepiride resulted in superior glycemic control compared with metformin + glimepiride therapy alone (P < 0.0001) and insulin glargine + metformin + glimepiride (P = 0.0015). The percentage of patients reaching the ADA target HbA1c < 7% was also significantly higher among liraglutide treated patients compared with metformin + glimepiride therapy alone (P < 0.05) and insulin glargine + metformin + glimepiride therapy (P = 0.05). Patients in the liraglutide group lost more weight than those in the metformin + glimepiride therapy alone group (P = 0.0001), while a weight gain was observed in the insulin glargine group (P < 0.0001). The largest reduction in mean SBP was seen in liraglutide-treated patients, while an increase was seen among those receiving insulin glargine. Nausea was the most common adverse event among liraglutide-treated patients. Major hypoglycemic events occurred in 5 patients in the liraglutide group; only 1 patient required medical assistance.
Liraglutide Added to Metformin and Rosiglitazone (LEAD-4)
Adding liraglutide to the combination of metformin and a thiazolidinedione provided superior glycemic control to that of metformin and a thiazolidinedione alone in the LEAD-4 study. In addition, SBP was significantly reduced in both liraglutide groups compared with the metformin + rosiglitazone group; mean SBP reduction with liraglutide was ~6 mm Hg, and in the metformin + thiazolidinedione cohort, SBP decreased by ~1 mm Hg.
In LEAD-4, 533 patients with type 2 diabetes were randomized to liraglutide in combination with metformin and rosiglitazone versus metformin and rosiglitazone alone for 26 weeks. Treatment with liraglutide 1.2 mg and 1.8 mg combined with metformin and rosiglitazone reduced HbA1c by 1.5% versus 0.5% for metformin + rosiglitazone (P < 0.0001). The liraglutide 1.2- and 1.8-mg groups also had a higher percentage of patients reaching the ADA target HbA1c < 7% (P < 0.0001). Reductions in mean fasting plasma glucose were significantly greater with liraglutide treatment compared with metformin + rosiglitazone treatment (P < 0.0001). A mean decrease in body weight was observed in both liraglutide groups, while a mean increase was seen in the metformin + rosiglitazone group (P < 0.0001). In the liraglutide groups, β-cell function significantly improved versus the metformin + rosiglitazone group, as assessed by HOMA-β (P < 0.0001) and proinsulin-to-insulin ratio (P < 0.05). Gastrointestinal adverse events occurred more often with liraglutide, but were transient in nature. No major hypoglycemia was observed during the study.
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