Dahl D et al.JAMA. 2022 Feb 8;327(6):534-545.  

泰瑞帕肽是一种双糖依赖的促胰岛素性多肽和胰高血糖素样肽-1受体激动剂，作为甘精胰岛素补充治疗，其作用尚未被描述。本文章主要评价泰瑞帕肽与甘精胰岛素治疗血糖控制不足的2型糖尿病患者的疗效和安全性。

该项研究纳入475例患者，随机接受皮下注射5mg (n = 116)、10mg (n = 119)或15mg (n = 120)替泽肽或按体积匹配安慰剂(n = 120)。替泽肽起始剂量为2.5 mg/周，每4周递增2.5 mg，直到达到指定剂量。与安慰剂相比，15mg、10mg组HbA1c均显著降低降低 （p＜0.001）

研究结果表明，接受甘精胰岛素治疗但血糖控制不充分的2型糖尿病患者中，与安慰剂相比，皮下注射泰瑞帕肽滴定甘精胰岛素，40周后血糖控制均显著改善。

IMPORTANCE The effects of tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, as an addition to insulin glargine for treatmentof type 2 diabetes have not been described.

OBJECTIVE To assess the efficacy and safety of tirzepatide added to insulin glargine in patients with type 2 diabetes with inadequate glycemic control.

DESIGN, SETTING, AND PARTICIPANTS Randomized phase 3 clinical trial conducted at 45medical research centers and hospitals in 8 countries (enrollment from August 30, 2019, to March 20, 2020; follow-up completed January 13, 2021) in 475 adults with type 2 diabetes and inadequate glycemic control while treated with once-daily insulin glargine with or without metformin.

INTERVENTIONS Patients were randomized in a 1:1:1:1 ratio to receive once-weekly subcutaneous injections of 5-mg (n = 116), 10-mg (n = 119), or 15-mg (n = 120) tirzepatide or volume-matched placebo (n = 120) over 40 weeks. Tirzepatide was initiated at 2.5 mg/week and escalated by 2.5 mg every 4 weeks until the assigned dose was achieved.

MAIN OUTCOMES AND MEASURES The primary end point was mean change from baseline in glycated hemoglobin A1c (HbA1c) at week 40. The 5 key secondary end points included mean change in body weight and percentage of patients achieving prespecified HbA1c levels.

RESULTS Among 475 randomized participants (211 [44%] women; mean [SD] age, 60.6 [9.9]years; mean [SD] HbA1c, 8.31% [0.85%]), 451 (94.9%) completed the trial. Treatment wasprematurely discontinued by 10% of participants in the 5-mg tirzepatide group, 12% in the10-mg tirzepatide group, 18% in the 15-mg tirzepatide group, and 3% in the placebo group. Atweek 40, mean HbA1c change from baseline was −2.40% with 10-mg tirzepatide and −2.34%with 15-mg tirzepatide vs −0.86% with placebo (10 mg: difference vs placebo, −1.53% [97.5%CI, −1.80% to −1.27%]; 15 mg: difference vs placebo, −1.47% [97.5% CI, −1.75% to −1.20%];P < .001 for both). Mean HbA1c change from baseline was −2.11% with 5-mg tirzepatide(difference vs placebo, −1.24% [95% CI, −1.48% to −1.01%]; P < .001]). Mean body weight change from baseline was −5.4 kg with 5-mg tirzepatide, −7.5 kg with 10-mg tirzepatide, −8.8kg with 15-mg tirzepatide and 1.6 kg with placebo (5 mg: difference, −7.1 kg [95% CI, −8.7 to−5.4]; 10 mg: difference, −9.1 kg [95% CI, −10.7 to −7.5]; 15 mg: difference, −10.5 kg [95% CI,−12.1 to −8.8]; P < .001 for all). Higher percentages of patients treated with tirzepatide vs those treated with placebo had HbA1c less than 7% (85%-90% vs 34%; P < .001 for all). 

Themost common treatment-emergent adverse events in the tirzepatide groups vs placebo group were diarrhea (12%-21% vs 10%) and nausea (13%-18% vs 3%).CONCLUSIONS AND RELEVANCE Among patients with type 2 diabetes and inadequate glycemic control despite treatment with insulin glargine, the addition of subcutaneous tirzepatide,compared with placebo, to titrated insulin glargine resulted in statistically significant improvements in glycemic control after 40 weeks

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