Davidson Jaime A, Sloan Lance
Department of Medicine, Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Texas Institute for Kidney and Endocrine Disorders, Lufkin, TX, USA.
Adv Ther. 2017 Jan;34(1):41-59. doi: 10.1007/s12325-016-0434-2. Epub 2016 Nov 16.
Metformin is recommended as a first-line therapy for patients with type 2 diabetes mellitus (T2DM). However, many patients do not achieve glycemic goals with metformin monotherapy and require subsequent combination therapy with other antihyperglycemic agents (AHAs). For newly diagnosed patients with high blood glucose, initial combination therapy may be required to achieve glycemic control. The American Association for Clinical Endocrinologists algorithm for the treatment of T2DM recommends metformin plus a sodium glucose co-transporter 2 (SGLT2) inhibitor as the first oral combination in patients who present with HbA1c ≥7.5%. Canagliflozin, an SGLT2 inhibitor, lowers the renal threshold for glucose and increases urinary glucose excretion leading to a mild osmotic diuresis and a net caloric loss. The effect of canagliflozin is insulin-independent and complementary to other AHAs, including metformin. A fixed-dose combination (FDC) of canagliflozin and metformin is also available with variable dosing, which may be attractive to some patients owing to the potential for reduced pill burden and costs. This article reviews the efficacy and safety of canagliflozin in combination with metformin based on data from the canagliflozin phase 3 clinical program. As initial combination therapy in drug-naïve patients or as dual therapy with metformin or triple therapy in combination with metformin and other AHAs, canagliflozin 100 and 300 mg improved glycemic control and provided reductions in body weight and systolic blood pressure that were sustained for up to 104 weeks. Canagliflozin was generally well tolerated across studies in combination with metformin. An increased incidence of adverse events (AEs) related to the mechanism of SGLT2 inhibition (i.e., genital mycotic infections, urinary tract infections, osmotic diuresis-related AEs) was observed with canagliflozin. Canagliflozin was associated with a low incidence of hypoglycemia when not used in conjunction with AHAs associated with hypoglycemia (i.e., insulin or sulfonylurea). Together, these results support the use of a canagliflozin and metformin FDC as a treatment approach for a broad range of patients with T2DM.
Janssen Scientific Affairs, LLC.
二甲双胍被推荐作为2型糖尿病（T2DM）患者的一线治疗药物。然而，许多患者使用二甲双胍单药治疗无法达到血糖目标，需要随后与其他降糖药物（AHA）联合治疗。对于新诊断的高血糖患者，可能需要初始联合治疗以实现血糖控制。美国临床内分泌医师协会的T2DM治疗算法推荐，对于糖化血红蛋白（HbA1c）≥7.5%的患者，二甲双胍加钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂作为首个口服联合治疗方案。SGLT2抑制剂卡格列净可降低肾脏葡萄糖阈值并增加尿糖排泄，导致轻度渗透性利尿和净热量损失。卡格列净的作用不依赖胰岛素，且与包括二甲双胍在内的其他AHA具有互补性。卡格列净和二甲双胍的固定剂量复方制剂（FDC）也有不同剂量可供选择，由于可能减轻 pill 负担和降低成本，对一些患者可能具有吸引力。本文基于卡格列净3期临床项目的数据，综述了卡格列净与二甲双胍联合应用的疗效和安全性。作为初治患者的初始联合治疗，或与二甲双胍的双联治疗，或与二甲双胍及其他AHA的三联治疗，100 mg和300 mg卡格列净均改善了血糖控制，并使体重和收缩压降低，且持续长达104周。在与二甲双胍联合应用的各项研究中，卡格列净总体耐受性良好。观察到与SGLT2抑制机制相关的不良事件（AE）发生率增加（即生殖器真菌感染、尿路感染、渗透性利尿相关AE）。当不与可导致低血糖的AHA（即胰岛素或磺脲类药物）联合使用时，卡格列净导致低血糖的发生率较低。总之，这些结果支持将卡格列净和二甲双胍FDC作为广泛T2DM患者的一种治疗方法。
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