Orforglipron compared with dapagliflozin in adults with type 2 diabetes and inadequate glycaemic control with metformin (ACHIEVE-2): a multicentre, randomised, non-inferiority, open-label, phase 3 trial.

This study assessed the efficacy and safety of orforglipron, an oral, non-peptide GLP-1 receptor agonist, versus dapagliflozin, an oral SGLT2 inhibitor, in participants with type 2 diabetes and inadequate glycaemic control with metformin.

本研究评估了口服非肽类GLP-1受体激动剂orforglipron与口服SGLT2抑制剂dapagliflozin在2型糖尿病患者中的疗效和安全性，这些患者在使用二甲双胍治疗后血糖控制不佳。

Methods

This 40-week, phase 3, multicentre, open-label (orforglipron dose-blinded), randomised study was conducted in 73 sites across six countries.

这是一项为期40周的3期、多中心、开放标签（orforglipron剂量盲法）、随机研究，在六个国家的73个地点进行。

The study included adults with type 2 diabetes using metformin (≥1500 mg/day) with glycated haemoglobin (HbA1c) concentrations between 7·0% and 10·5% (53-91 mmol/mol), stable bodyweight (±5%), and a BMI of 23·0 kg/m2 or more.

该研究包括使用二甲双胍（≥1500 mg/天）的2型糖尿病成人患者，其糖化血红蛋白（HbA1c）浓度在7.0%至10.5%（53-91 mmol/mol）之间，体重稳定（±5%），且BMI为23.0 kg/m2或更高。

Participants were randomly assigned in a 1:1:1:1 ratio to receive once-daily oral orforglipron (3 mg, 12 mg, or 36 mg) or dapagliflozin 10 mg.

参与者以1:1:1:1的比例随机分配，每天一次口服或forglipron（3毫克、12毫克或36毫克）或达格列净10毫克。

The primary endpoint was change from baseline in HbA1c at week 40, using a non-inferiority margin of 0·3% for orforglipron versus dapagliflozin; analysis was based on the treatment-regimen estimand (data obtained regardless of study intervention discontinuation or initiation of additional glucose-lowering agents).

主要终点是第40周从基线开始的HbA1c变化，使用0·3%的非劣效性边界比较orforglipron与达格列净；分析基于治疗方案估计值（无论研究干预的中断或额外降糖药物的开始，均获得数据）。

The treatment regimen estimand was the primary estimand, with the efficacy estimand considered supportive.

治疗方案的估计值是主要估计值，疗效估计值被视为支持性估计值。

Safety was assessed in all randomised participants who received at least one dose of study drug.

在所有随机参与者中评估了安全性，这些参与者至少接受了研究药物的一剂。

This trial is registered at ClinicalTrials.gov (NCT06192108, completed).

该试验已在ClinicalTrials.gov注册（NCT06192108，已完成）。

Results

From Jan 10, 2024, to Sept 26, 2025, 1404 adults were assessed and 962 participants were randomly assigned to orforglipron 3 mg (n=240), 12 mg (n=241), or 36 mg (n=241), or dapagliflozin 10 mg (n=240).

从2024年1月10日至2025年9月26日，共有1404名成年人接受了评估，其中962名参与者被随机分配到orforglipron 3毫克组（n=240）、12毫克组（n=241）或36毫克组（n=241），或 dapagliflozin 10毫克组（n=240）。

The baseline population included 474 (49%) females and had a mean age of 56·1 years (SD 11·5), HbA1c of 8·14% (1·04), type 2 diabetes duration of 8·0 years (6·7), and BMI of 32·6 kg/m2 (6·6).

基线人群包括474名（49%）女性，平均年龄为56.1岁（标准差11.5），HbA1c为8.14%（1.04），2型糖尿病病程为8.0年（6.7），BMI为32.6 kg/m2（6.6）。

At week 40, for the treatment regimen estimand, all orforglipron doses were non-inferior to dapagliflozin in reducing HbA1c.

在第40周，对于治疗方案的估计值，所有或forglipron剂量在降低HbA1c方面不劣于dapagliflozin。

Change from baseline in mean HbA1c was -1·23% (SE 0·08), -1·50% (0·08), and -1·56% (0·09) with orforglipron 3 mg, 12 mg, and 36 mg, respectively, versus -0·81% (0·07) with dapagliflozin 10 mg; estimated treatment difference versus dapagliflozin was -0·42% (95% CI -0·62 to -0·23), -0·70% (-0·90 to -0·49), and -0·75% (-0·96 to -0·55) with orforglipron 3 mg, 12 mg, and 36 mg, respectively (all p<0·0001).

基线时平均糖化血红蛋白(HbA1c)的变化分别为-1.23% (标准误SE 0.08), -1.50% (0.08), 和-1.56% (0.09) 与orforglipron 3 mg, 12 mg, 和36 mg治疗相关, 相对于dapagliflozin 10 mg的-0.81% (0.07); 与dapagliflozin相比, orforglipron 3 mg, 12 mg, 和36 mg的估计治疗差异分别为-0.42% (95% 置信区间CI -0.62至-0.23), -0.70% (-0.90至-0.49), 和-0.75% (-0.96至-0.55) (所有p<0.0001)。

The most frequent adverse events associated with orforglipron were mild-to-moderate gastrointestinal events, observed in 112 (47%) of 240 participants receiving orforglipron 3 mg, 112 (46%) of 241 receiving 12 mg, and 130 (54%) of 241 receiving 36 mg, versus 29 (12%) of 240 receiving dapagliflozin.

与orforglipron相关的最常见不良事件是轻度至中度的胃肠道事件, 在接受orforglipron 3 mg治疗的240名参与者中有112例(47%), 接受12 mg治疗的241名中有112例(46%), 接受36 mg治疗的241名中有130例(54%), 相对于接受dapagliflozin治疗的240名中有29例(12%)。

More study intervention discontinuations were observed with orforglipron 3 mg (35 [15%] of 240), 12 mg (44 [18%] of 241), and 36 mg (47 [20%] of 241) than with dapagliflozin (14 [6%] of 240).

与 dapagliflozin 相比，观察到更多的研究干预中止情况，其中 orforglipron 3 mg (240 例中有 35 例 [15%])，12 mg (241 例中有 44 例 [18%]) 和 36 mg (241 例中有 47 例 [20%])。

No severe episode of hypoglycaemia was reported.

未报告有严重低血糖发作。

interpretation

Orforglipron demonstrated superior glycaemic control compared with dapagliflozin, with a tolerability profile consistent with the GLP-1 receptor agonist class, including increased rates of discontinuation due to adverse events, positioning it as a potential effective oral treatment option for type 2 diabetes.

Orforglipron 与 dapagliflozin 相比显示出更优越的血糖控制效果，其耐受性特征与 GLP-1 受体激动剂类药物一致，包括因不良事件导致的停药率增加，这使其成为2型糖尿病潜在有效的口服治疗选择。

funding

Eli Lilly and Company.

礼来公司