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在早前的一项研究中，糖尿病持续时间短的患者能通过早期联合治疗（维格列汀和二甲双胍）使血糖水平正常化 [54] 。因此，建议降低目标HbA1c水平是必要的，并应当强调其对于糖尿病缓解的重要性。如前所述，代谢手术是一种很好的治疗选择，但它的局限性在于接受治疗的患者必须在限制性体重或BMI范围内（体重指数BMI≥40.0kg/m 2 ；亚洲人BMI≥37.5kg/m 2 ）。此外，单纯的强化生活方式改变会使患者难以保持体重和糖尿病缓解。因此，通过改变生活方式联合药物治疗达到血糖正常，可以促进糖尿病的持续缓解。血糖正常后，如果在保持体重的同时对药物减量，则可持续缓解。然而，糖尿病缓解的药物治疗策略有两个基本前提。一是低血糖风险低：如果低血糖频繁发生，则不能通过足量使用疗效高的药物来达到血糖正常。二是药物疗法需要对减肥有益。通常，钠-葡萄糖共转运蛋白2抑制剂（SGLT2i）和GLP-1受体激动剂（GLP-1 RA）都会导致体重减轻。然而，SGLT2i的减肥效果低于GLP-1 RA。同时满足以上两点的药物类型是GLP-1 RA，特别是利拉鲁肽和司美格鲁肽，这两者最初用于治疗2型糖尿病，可有效降低血糖并减轻体重。由于GLP-1对食欲和能量平衡的调节作用，GLP-1 RA是治疗肥胖症的药物。GLP-1从L细胞中释放，并能够刺激2型糖尿病患者的胰岛素分泌。GLP-1的另一个重要作用是延迟胃排空。此外，在中枢神经系统中GLP-1受体位于下丘脑，这是调节食物摄入的部分。因此，GLP-1 RA能通过多种机制减轻体重 [55] （如图3-6所示）。同时，《ADA/EASD共识》中指出GLP-1 RA因其高效性和安全性而优于胰岛素 [56] 。
图3-6 GLP-1的作用机制与2型糖尿病缓解
利拉鲁肽和司美格鲁肽被批准为抗糖尿病药物，前者每天皮下给药一次，后者每周皮下给药一次。而更高剂量的这两种药物被开发用于2型糖尿病患者或非2型糖尿病的肥胖患者治疗肥胖以及控制血糖。早在2014年，美国食品和药物管理局（FDA）批准了利拉鲁肽用于成人肥胖症的治疗。2022年12月4日美国FDA批准了利拉鲁肽注射液的说明书标签更新，准许其用于治疗体重在60kg以上、身体质量指数（BMI）在30kg/m 2 或以上的12～17岁青少年肥胖症，作为低热量饮食和增加运动的辅助疗法。在非糖尿病和糖尿病患者肥胖和糖尿病前期试验（SCALE）中，与安慰剂相比，3.0mg利拉鲁肽减轻了体重（差异为-5.6kg；95%可信区间为-6.0～-5.1kg；P＜0.001）。此外，在3年的随访中，利拉鲁肽组2型糖尿病延缓发生，其发生时间是安慰剂组的2.7倍（95%CI，1.9～3.9；P＜0.0001），相应的风险比（HR）为0.21（95%CI，0.13～0.34） [9] 。2021年6月美国FDA批准使用2.4mg的司美格鲁肽，用于肥胖或超重的、伴随至少一种体重相关疾病（如高血压、2型糖尿病或高胆固醇）的成年患者减肥。其在国内截至2023年2月尚没有获批治疗肥胖症。在司美格鲁肽治疗肥胖患者的效果（STEP）2期试验中，从基线到第68周，患者平均体重的估计变化为-9.6%（标准误差，0.4）。给予2.4mg司美格鲁肽的患者的HbA1c浓度从基线到第68周降低了1.6%（标准误差，0.1）。给予2.4mg司美格鲁肽的患者第68周基线体重减少≥10%的比例为45.6%，给予2.4mg的司美格鲁肽并达到HbA1c≤6.5%水平的患者比例为67.5%。结果表明，其降糖效果和减肥效果与代谢手术一样有意义 [57] 。
最近，一种GLP-1/GIP双受体激动剂替尔泊肽在肥胖糖尿病患者的治疗中显示出令人鼓舞的结果 [58] 。在健康个体中，与单独使用每种激素相比，GIP和GLP-1 RA的联合使用在增加胰岛素应答方面具有相加效应。然而，在2型糖尿病患者中，短时间内联合使用GIP和GLP-1 RA不会产生比单独使用GLP-1 RA更强的促胰岛素分泌作用。替尔泊肽作为一种GLP-1/GIP双受体激动剂，是根据天然GIP序列配制的含有39个氨基酸的合成线性肽。它与天然GIP具有相似的GIP受体亲和力，对GLP-1受体亲和力是天然GLP-1的1/6。在SURPASS-1中，替尔泊肽显著改善了血糖和体重。替尔泊肽15mg组患者HbA1c降低2.07%，体重平均减轻9.5kg。HbA1c水平达到≤6.5%的患者比例为86% [58] 。体重减少≥10%的患者比例达47%。此外，替尔泊肽通过了全球Ⅲ期临床研究（SURPASS-2），是第一个完成Ⅲ期临床试验的GLP-1/GIP双受体激动剂。在SURPASS-2试验中，将替尔泊肽与司美格鲁肽1mg进行比较，替尔泊肽优于司美格鲁肽。另一方面，两项试验均未报告临床显著低血糖（血糖＜3.0mmol/L）。这些特征可以满足糖尿病缓解的所有要求 [59] 。除了尚未在临床上联合替尔泊肽，肠促胰岛素已通过联合代谢手术和强化生活方式的改变来维持体重减轻和糖尿病缓解 [60] 。在2型糖尿病病程相对较短的情况下，GLP-1 RA单独使用导致的体重减轻可能足以实现糖尿病缓解。即使在停止肠促胰岛素刺激后，显著的体重减轻和血糖正常化也有助于维持糖尿病的缓解 [61] 。
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