OBJECTIVE To examine the effects of insulin-adjunctive therapy with a sodium–glucose cotransporter 2 (SGLT2) inhibitor and a glucagon receptor antagonist (GRA) on glycemia, insulin use, and ketogenesis during insulinopenia in type 1 diabetes. RESEARCH DESIGN AND METHODS In a randomized, double-blind, placebo-controlled, crossover trial we assessed the effects of adjunctive SGLT2 inhibitor therapy (dapagliflozin 10 mg daily) alone and in combination with the GRA volagidemab (70 mg weekly) in 12 adults with type 1 diabetes. Continuous glucose monitoring, insulin dosing, and insulin withdrawal tests (IWT) for measurement of glucose and ketogenesis during insulinopenia were completed during insulin-only (Baseline), SGLT2 inhibitor, and combination (SGLT2 inhibitor + GRA) therapy periods. RESULTS Average glucose and percent time with glucose in range (70–180 mg/dL) improved with combination therapy versus Baseline and SGLT2 inhibitor (131 vs. 150 and 138 mg/dL [P < 0.001 and P = 0.01] and 86% vs. 70% and 78% [P < 0.001 and P = 0.03], respectively) without increased hypoglycemia. Total daily insulin use decreased with combination therapy versus Baseline and SGLT2 inhibitor (0.41 vs. 0.56 and 0.52 units/kg/day [P < 0.001 and P = 0.002]). Peak β-hydroxybutyrate levels during IWT were lower with combination therapy than with SGLT2 inhibitor (2.0 vs. 2.4 mmol/L; P = 0.048) and similar to levels reached during the Baseline testing period (2.1 mmol/L). Participants reported enhanced treatment acceptability and satisfaction with combination therapy. CONCLUSIONS Glucagon antagonism enhances the therapeutic effects of SGLT2 inhibition in type 1 diabetes. Combination therapy improves glycemic control, reduces insulin dosing, and suggests a strategy to unlock the benefits of SGLT2 inhibitors while mitigating the risk of diabetic ketoacidosis.

中文翻译：

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SGLT2 抑制剂和胰高血糖素受体拮抗剂联合治疗 1 型糖尿病：随机临床试验


目的 研究钠-葡萄糖协同转运蛋白 2 (SGLT2) 抑制剂和胰高血糖素受体拮抗剂 (GRA) 的胰岛素辅助治疗对 1 型糖尿病胰岛素减少期间血糖、胰岛素使用和生酮的影响。研究设计和方法 在一项随机、双盲、安慰剂对照、交叉试验中，我们评估了 SGLT2 抑制剂辅助治疗（达格列净每天 10 毫克）单独治疗以及与 GRA 沃拉格列单抗（每周 70 毫克）联合治疗对 12 名成人的疗效。 1 型糖尿病。在仅胰岛素（基线）、SGLT2抑制剂和联合（SGLT2抑制剂+GRA）治疗期间完成了连续血糖监测、胰岛素剂量和胰岛素戒断试验（IWT），以测量胰岛素减少期间的血糖和生酮作用。结果 与基线和 SGLT2 抑制剂相比，联合治疗的平均血糖和血糖处于范围 (70–180 mg/dL) 的时间百分比有所改善（131 vs. 150 和 138 mg/dL [P < 0.001 和 P = 0.01] 和 86%） vs. 70% 和 78% [P < 0.001 和 P = 0.03]，分别），但低血糖没有增加。与基线和 SGLT2 抑制剂相比，联合治疗的每日总胰岛素使用量减少（0.41 vs. 0.56 和 0.52 单位/公斤/天 [P < 0.001 和 P = 0.002]）。联合治疗期间 IWT 期间的 β-羟基丁酸峰值水平低于 SGLT2 抑制剂（2.0 vs. 2.4 mmol/L；P = 0.048），并且与基线测试期间达到的水平相似（2.1 mmol/L）。参与者报告称联合治疗的治疗可接受性和满意度有所提高。结论 胰高血糖素拮抗作用增强了 SGLT2 抑制对 1 型糖尿病的治疗效果。 联合疗法可改善血糖控制，减少胰岛素剂量，并提出一种策略来释放 SGLT2 抑制剂的益处，同时降低糖尿病酮症酸中毒的风险。