OBJECTIVE To explore the complementary effects of a combination of dipeptidyl peptidase 4 and sodium–glucose cotransporter 2 inhibitors added to metformin on hormonal and metabolic responses to meal ingestion. RESEARCH DESIGN AND METHODS Forty-five patients (age 58 ± 8 years; HbA1c 58 ± 6 mmol/mol; BMI 30.7 ± 3.2 kg/m2) with type 2 diabetes uncontrolled with metformin were evaluated at baseline and 3 and 28 days after 5 mg saxagliptin (SAXA), 10 mg dapagliflozin (DAPA), or 5 mg saxagliptin plus 10 mg dapagliflozin (SAXA+DAPA) using a mixed-meal tolerance test (MMTT) spiked with dual-tracer glucose to assess glucose metabolism, insulin secretion, and sensitivity. RESULTS At day 3, fasting and mean MMTT glucose levels were lower with SAXA+DAPA (−31.1 ± 1.6 and −91.5 ± 12.4 mg/dL) than with SAXA (−7.1 ± 2.1 and −53 ± 10.5 mg/dL) or DAPA (−17.0 ± 1.1 and −42.6 ± 10.0 mg/dL, respectively; P < 0.001). Insulin secretion rate (SAXA+DAPA +75%; SAXA +11%; DAPA 3%) and insulin sensitivity (+2.2 ± 1.7, +0.4 ± 0.7, and +0.4 ± 0.4 mg ⋅ kg−1⋅ min−1, respectively) improved with SAXA+DAPA (P < 0.007). Mean glucagon-like peptide 1 (GLP-1) was higher with SAXA+DAPA than with SAXA or DAPA. Fasting glucagon increased with DAPA and SAXA+DAPA but not with SAXA. Fasting endogenous glucose production (EGP) increased with SAXA+DAPA and DAPA. During MMTT, EGP suppression was greater (48%) with SAXA+DAPA (vs. SAXA 44%; P = 0.02 or DAPA 34%; P = 0.2). Metabolic clearance rate of glucose (MCRglu) increased more with SAXA+DAPA. At week 4, insulin secretion rate, β-cell glucose sensitivity, and insulin sensitivity had further increased in the SAXA+DAPA group (P = 0.02), with no additional changes in GLP-1, glucagon, fasting or MMTT EGP, or MCRglu. CONCLUSIONS SAXA+DAPA provided superior glycemic control compared with DAPA or SAXA, with improved β-cell function, insulin sensitivity, GLP-1 availability, and glucose clearance.

中文翻译：

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接受达格列净加沙格列汀治疗的 2 型糖尿病患者对混合膳食的 β 细胞功能、肠促胰岛素作用和血糖动力学

目的 探讨二肽基肽酶 4 和钠-葡萄糖协同转运蛋白 2 抑制剂联合添加到二甲双胍中对膳食摄入的激素和代谢反应的互补作用。研究设计和方法 45 名二甲双胍未控制的 2 型糖尿病患者（年龄 58 ± 8 岁；HbA1c 58 ± 6 mmol/mol；BMI 30.7 ± 3.2 kg/m2）在基线以及服用 5 mg 后 3 天和 28 天进行评估沙格列汀 (SAXA)、10 mg 达格列净 (DAPA) 或 5 mg 沙格列汀加 10 mg 达格列净 (SAXA+DAPA)，使用掺有双示踪剂葡萄糖的混合膳食耐受试验 (MMTT) 来评估葡萄糖代谢、胰岛素分泌和灵敏度。结果 在第 3 天，SAXA+DAPA 组的空腹和平均 MMTT 血糖水平（−31.1 ± 1.6 和 −91.5 ± 12.4 mg/dL）低于 SAXA（−7.1 ± 2.1 和 −53 ± 10.5 mg/dL）或 DAPA 组（分别为-17.0 ± 1.1 和-42.6 ± 10.0 mg/dL；P < 0.001）。胰岛素分泌率（SAXA+DAPA +75%；SAXA +11%；DAPA 3%）和胰岛素敏感度（分别为+2.2 ± 1.7、+0.4 ± 0.7 和 +0.4 ± 0.4 mg·kg−1·min−1） ）通过 SAXA+DAPA 得到改善（P < 0.007）。 SAXA+DAPA 组的平均胰高血糖素样肽 1 (GLP-1) 高于 SAXA 或 DAPA 组。 DAPA 和 SAXA+DAPA 使空腹胰高血糖素增加，但 SAXA 则没有增加。 SAXA+DAPA 和 DAPA 增加了空腹内源性葡萄糖产生 (EGP)。在 MMTT 期间，SAXA+DAPA 的 EGP 抑制更大（48%）（相对于 SAXA 44%；P = 0.02 或 DAPA 34%；P = 0.2）。 SAXA+DAPA 组葡萄糖代谢清除率 (MCRglu) 增加更多。第 4 周时，SAXA+DAPA 组的胰岛素分泌率、β 细胞葡萄糖敏感性和胰岛素敏感性进一步增加 (P = 0.02)，而 GLP-1、胰高血糖素、禁食或 MMTT EGP 或 MCRglu 没有额外变化。结论 与 DAPA 或 SAXA 相比，SAXA+DAPA 提供了更好的血糖控制，并改善了 β 细胞功能、胰岛素敏感性、GLP-1 可用性和葡萄糖清除率。