Sridhar Vikas S, Odutayo Ayodele, Garg Satish, Danne Thomas, Doria Alessandro, Mauer Michael, Davies Michael J, Banks Phillip, Girard Manon, Cherney David Z I
Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.
Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada.
J Am Soc Nephrol. 2025 May 1;36(5):890-900. doi: 10.1681/ASN.0000000540. Epub 2024 Nov 1.
Poor glycemic control in type 1 diabetes and CKD is associated with a higher risk of CKD progression. In a subgroup of inTandem participants with type 1 diabetes and CKD, adding sotagliflozin to insulin reduced HbA1c, body weight, and systolic BP without increasing severe hypoglycemia, compared with adding placebo. In participants with type 1 diabetes and CKD, sotagliflozin did not significantly increase the risk of DKA, however, there were a small number of diabetic ketoacidosis events.
This analysis evaluated the efficacy and safety of sotagliflozin, a dual sodium-glucose cotransporter 1 and 2 inhibitor, added to insulin in patients with type 1 diabetes and CKD.
We used data from the 52-week pooled inTandem 1 and 2 trials and the 24-week inTandem 3 trial to assess the effects of sotagliflozin (200 mg [inTandem 1 and 2 only] or 400 mg daily) versus placebo on glycated hemoglobin (HbA1c; primary end point), body weight, systolic BP, insulin dose, and safety end points including adjudicated severe hypoglycemia and diabetic ketoacidosis (DKA), stratified by CKD.
CKD was identified in 237/1575 inTandem 1 and 2 participants and 228/1402 inTandem 3 participants. At week 24, significant, placebo-adjusted reductions in HbA1c were observed—inTandem 1 and 2: non-CKD subgroup (sotagliflozin 200 mg: −0.4%, 95% confidence interval [CI], −0.4 to −0.3; 400 mg: −0.4%, 95% CI, −0.5 to −0.3) and CKD subgroup (sotagliflozin 200 mg: −0.4%, 95% CI, −0.6 to −0.1; 400 mg: −0.3%, 95% CI, −0.5 to −0.1). For systolic BP, there was a significant reduction at week 24 with sotagliflozin in the non-CKD subgroup, but no effect in the CKD subgroup in inTandem 1 and 2. At week 52, the incidence of severe hypoglycemia was lower with sotagliflozin (7% on 200 mg and 4% on 400 mg) compared with placebo (17%) in the CKD subgroup of inTandem 1 and 2, whereas the incidence of severe hypoglycemia was 5%–6% across non-CKD subgroups. The incidence of adjudicated DKA at week 52 was 1%, 5%, and 3% for placebo, 200, and 400 mg in the CKD subgroup compared with 0%, 3%, and 4% in the non-CKD subgroup, respectively. The results were generally similar in inTandem 3, except systolic BP was significantly reduced with sotagliflozin versus placebo in CKD and non-CKD subgroups.
In participants with type 1 diabetes and CKD, sotagliflozin treatment had similar HbA1c, body weight, and systolic BP lowering effects as in participants with type 1 diabetes without CKD. In addition, sotagliflozin was associated with a lower to neutral risk of severe hypoglycemia and did not significantly increase the risk of DKA among a small number of DKA events.
: NCT02384941, NCT02421510, NCT02531035.
1型糖尿病合并慢性肾脏病（CKD）患者血糖控制不佳与CKD进展风险较高相关。在inTandem研究中1型糖尿病合并CKD的亚组参与者中，与添加安慰剂相比，在胰岛素治疗基础上加用索格列净可降低糖化血红蛋白（HbA1c）、体重和收缩压，且不增加严重低血糖的发生风险。在1型糖尿病合并CKD的参与者中，索格列净未显著增加糖尿病酮症酸中毒（DKA）风险，不过发生了少量糖尿病酮症酸中毒事件。
本分析评估了在1型糖尿病合并CKD患者中，在胰岛素治疗基础上加用双钠-葡萄糖协同转运蛋白1和2抑制剂索格列净的疗效和安全性。
我们使用了为期52周的inTandem 1和2试验以及为期24周的inTandem 3试验的数据，以评估索格列净（200 mg[仅inTandem 1和2]或每日400 mg）与安慰剂相比，对糖化血红蛋白（HbA1c；主要终点）、体重、收缩压、胰岛素剂量以及包括判定的严重低血糖和糖尿病酮症酸中毒（DKA）在内的安全性终点的影响，并按CKD进行分层。
在inTandem 1和2试验的1575名参与者中有237人、inTandem 3试验的1402名参与者中有228人被诊断为CKD。在第24周时，观察到HbA1c有显著的、经安慰剂校正的降低——inTandem 1和2试验：非CKD亚组（索格列净200 mg：-0.4%，95%置信区间[CI]，-0.4至-0.3；400 mg：-0.4%，95% CI，-0.5至-0.3）和CKD亚组（索格列净200 mg：-0.4%，95% CI，-0.6至-0.1；400 mg：-0.3%，95% CI，-0.5至-0.1）。对于收缩压，在inTandem 1和2试验的非CKD亚组中第24周时索格列净使其显著降低，但在CKD亚组中无此作用。在第52周时，inTandem 1和2试验的CKD亚组中，索格列净组严重低血糖的发生率低于安慰剂组（200 mg组为7%，400 mg组为4%，而安慰剂组为17%），而非CKD亚组中严重低血糖的发生率为5% - 6%。CKD亚组中第52周时判定的DKA发生率，安慰剂组为1%，200 mg组为5%，400 mg组为3%，而非CKD亚组分别为0%、3%和4%。inTandem 3试验的结果总体相似，只是在CKD和非CKD亚组中，索格列净组与安慰剂组相比收缩压显著降低。
在1型糖尿病合并CKD的参与者中，索格列净治疗在降低HbA1c、体重和收缩压方面与1型糖尿病无CKD的参与者相似。此外，索格列净与严重低血糖的低至中性风险相关，且在少量DKA事件中未显著增加DKA风险。
NCT02384941、NCT02421510、NCT02531035。
