Boeder Schafer C, Thomas Robert L, Le Roux Melissa J, Giovannetti Erin R, Gregory Justin M, Pettus Jeremy H
Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA.
Ian M. Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University School of Medicine, Nashville, TN.
Diabetes Care. 2025 Jan 1;48(1):52-60. doi: 10.2337/dc24-0212.
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.
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.
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.
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.
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）辅助胰岛素治疗对1型糖尿病胰岛素缺乏期间血糖、胰岛素使用及酮体生成的影响。
在一项随机、双盲、安慰剂对照、交叉试验中，我们评估了辅助SGLT2抑制剂治疗（每日达格列净10毫克）单独使用以及与GRA药物volagidemab（每周70毫克）联合使用对12名1型糖尿病成年患者的影响。在仅使用胰岛素（基线）、SGLT2抑制剂及联合治疗（SGLT2抑制剂+GRA）期间，完成了连续血糖监测、胰岛素给药以及胰岛素撤药试验（IWT），以测量胰岛素缺乏期间的血糖和酮体生成情况。
与基线和SGLT2抑制剂治疗相比，联合治疗使平均血糖及血糖处于目标范围（70-180毫克/分升）的时间百分比得到改善（分别为131与150和138毫克/分升[P<0.001和P=0.01]，以及86%与70%和78%[P<0.001和P=0.03]），且低血糖发生率未增加。与基线和SGLT2抑制剂治疗相比，联合治疗使每日胰岛素总用量减少（分别为0.41与0.56和0.52单位/千克/天[P<0.001和P=0.002]）。IWT期间联合治疗的β-羟基丁酸峰值水平低于SGLT2抑制剂治疗（分别为2.0与2.4毫摩尔/升；P=0.048），且与基线测试期间达到的水平相似（2.1毫摩尔/升）。参与者报告联合治疗的可接受性和满意度更高。
胰高血糖素拮抗作用可增强SGLT2抑制在1型糖尿病中的治疗效果。联合治疗改善了血糖控制，减少了胰岛素用量，并提示了一种在减轻糖尿病酮症酸中毒风险的同时发挥SGLT2抑制剂益处的策略。
