Introduction and Objectives: SGLT2 inhibitors (SGLT2i) lower the plasma glucose concentration in T1DM patients. However, they cause an increase in plasma ketone concentration and risk of ketoacidosis. The aim of the present study is to examine whether pioglitazone amplifies the decrease in HbA1c and prevents the increase in plasma ketone concentration caused by dapagliflozin in T1DM patients. Methods: After a 4-week run in period, 60 T1DM patients received dapagliflozin 10 mg for 12 weeks. At week 16 patients were randomized to receive in double blind fashion pioglitazone (45 mg) or matching placebo for an additional 16 weeks. Results: T1DM patients were 42±3 years of age, 30% female, BMI=26.8±0.7, HbA1c=8.5±0.2%, insulin dose= 63±4 units, and eGFR=114±6 ml/min. Dapagliflozin caused -0.63±0.18%, and -0.56±0.11% decrease from baseline in HbA1c at week 16 in subjects receiving pioglitazone and placebo, respectively (both p<0.001). At week 32, the decrease from baseline in HbA1c was -0.86±0.3 and -0.44±0.17 in subjects receiving pioglitazone and placebo, respectively. Thus, the HbA1c was -0.42±0.12 lower in subjects receiving pioglitazone versus placebo (p<0.05). Plasma ketone concentration increased above baseline by 0.12±0.03 mM and 0.14±0.03 mM at week 16 in subjects receiving pioglitazone and placebo, respectively (both p<0.05). At week 32 plasma ketone concentration remained elevated above baseline in subjects receiving placebo (0.15±0.03 mM, p<0.05), and decreased below baseline (-0.06±0.02mM, p<0.05) in subjects receiving pioglitazone. Thus, the difference in plasma ketone concentration between subjects receiving pioglitazone and placebo at week 32 was -0.19±0.3, p<0.001. Conclusion: Addition of pioglitazone to SGLT2i in T1DM patients amplifies the decrease in HbA1c and prevents the increase in plasma ketone caused by SGLT2i, allowing long-term cardiovascular and renal outcome studies to be carried out safely in T1DM patients. Disclosure M. Abdul-Ghani: None. G. Baskoy: None. A. Nakhleh: None. S. Abdelgani: None. F. Al-Mulla: None. M. Abu-farha: None. F. Alajmi: Consultant; Novo Nordisk. Research Support; Novo Nordisk. Speaker's Bureau; Novo Nordisk. T. Alessa: None. R.A. DeFronzo: Advisory Panel; AstraZeneca, Novo Nordisk, Boehringer-Ingelheim, Intarcia Therapeutics, Inc., Aardvark, Renalytix, Corcept Therapeutics, Alnylam Pharmaceuticals, Inc. Research Support; Boehringer-Ingelheim, AstraZeneca, 89bio, Inc., Amgen Inc., Medality, Corcept Therapeutics. Speaker's Bureau; AstraZeneca, Corcept Therapeutics, Renalytix. N. Shehadeh: Research Support; Abbott. Advisory Panel; AstraZeneca, Eli Lilly and Company, Boehringer-Ingelheim. Research Support; Novo Nordisk Foundation. Funding The study was funded by JDRF grant to MAG. Astrazeneca provided dapagliflozin.

中文翻译：

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138-OR：吡格列酮可增强 1 型糖尿病患者 HbA1c 的降低并防止达格列净引起的血浆酮升高


简介和目的：SGLT2 抑制剂 (SGLT2i) 降低 T1DM 患者的血浆葡萄糖浓度。然而，它们会导致血浆酮浓度增加和酮症酸中毒的风险。本研究的目的是检查吡格列酮是否会放大 T1DM 患者 HbA1c 的降低并防止达格列净引起的血浆酮浓度升高。方法：经过 4 周的磨合期，60 名 T1DM 患者接受达格列净 10 mg，持续 12 周。第 16 周时，患者被随机分配接受双盲方式吡格列酮（45 mg）或匹配的安慰剂治疗，持续 16 周。结果：T1DM患者年龄为42±3岁，30%为女性，BMI=26.8±0.7，HbA1c=8.5±0.2%，胰岛素剂量=63±4单位，eGFR=114±6ml/min。在接受吡格列酮和安慰剂的受试者中，达格列净在第 16 周时使 HbA1c 较基线分别降低 -0.63±0.18% 和 -0.56±0.11%（均 p<0.001）。第 32 周时，接受吡格列酮和安慰剂的受试者的 HbA1c 相对于基线的下降分别为 -0.86±0.3 和 -0.44±0.17。因此，与安慰剂相比，接受吡格列酮治疗的受试者的 HbA1c 降低了 -0.42±0.12（p<0.05）。第16周时，接受吡格列酮和安慰剂的受试者血浆酮浓度分别高于基线0.12±0.03 mM和0.14±0.03 mM（均p<0.05）。第32周时，接受安慰剂的受试者血浆酮浓度仍高于基线（0.15±0.03 mM，p<0.05），而接受吡格列酮的受试者血浆酮浓度降至基线以下（-0.06±0.02mM，p<0.05）。因此，第32周时接受吡格列酮和安慰剂的受试者之间的血浆酮浓度差异为-0.19±0.3，p<0.001。 结论：T1DM 患者在 SGLT2i 中添加吡格列酮可放大 HbA1c 的降低，并防止 SGLT2i 引起的血浆酮升高，从而可以在 T1DM 患者中安全地进行长期心血管和肾脏结局研究。披露 M. 阿卜杜勒-加尼：无。 G.巴斯科伊：没有。 A. 纳赫勒：没有。 S.阿卜杜勒加尼：没有。 F. Al-Mulla：没有。 M. Abu-farha：没有。 F. Alajmi：顾问；诺和诺德。研究支持；诺和诺德。议长局；诺和诺德。 T.阿莱莎：没有。 R.A.德弗龙佐：顾问小组；阿斯利康、诺和诺德、勃林格殷格翰、Intarcia Therapeutics, Inc.、Aardvark、Renalytix、Corcept Therapeutics、Alnylam Pharmaceuticals, Inc. 研究支持；勃林格殷格翰、阿斯利康、89bio, Inc.、安进公司、Medality、Corcept Therapeutics。议长局；阿斯利康、Corcept Therapeutics、Renalytix。 N. Shehadeh：研究支持；雅培。顾问小组；阿斯利康、礼来公司、勃林格殷格翰。研究支持；诺和诺德基金会。资助 该研究由 JDRF 向 MAG 提供的资助。阿斯利康提供达格列净。