Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Laboratory of Endocrinology& Metabolism, and Ministry of Education Key Laboratory of Vascular Aging, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Diabetes Obes Metab. 2024 Aug;26(8):3137-3146. doi: 10.1111/dom.15641. Epub 2024 May 3.
To examine the effects of the thiazolidinedione (TZD) pioglitazone on reducing ketone bodies in non-obese patients with T2DM treated with the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin.
Crossover trials with two periods, each treatment period lasting 4 weeks, with a 4-week washout period, were conducted. Participants were randomly assigned in a 1:1 ratio to receive pioglitazone combined with canagliflozin (PIOG + CANA group) versus canagliflozin monotherapy (CANA group). The primary outcome was change (Δ) in β-hydroxybutyric acid (β-HBA) before and after the CANA or PIOG + CANA treatments. The secondary outcomes were Δchanges in serum acetoacetate and acetone, the rate of conversion into urinary ketones, and Δchanges in factors related to SGLT2 inhibitor-induced ketone body production including non-esterified fatty acids (NEFAs), glucagon, glucagon to insulin ratio, and noradrenaline (NA). Analyses were performed in accordance with the intention-to-treat principle.
Twenty-five patients with a mean age of 49 ± 7.97 years and a body mass index of 25.35 ± 2.22 kg/m were included. One patient discontinued the study during the washout period. Analyses revealed a significant increase in the levels of serum ketone bodies and an elevation in the rate of conversion into urinary ketones after both interventions. However, differernces in levels of ketone bodies (except for acetoacetate) in the PIOG + CANA group were significantly smaller than in the CANA group (219.84 ± 80.21 μmol/L vs. 317.69 ± 83.07 μmol/L, p < 0.001 in β-HBA; 8.98 ± 4.17 μmol/L vs. 12.29 ± 5.27 μmol/L, p = 0.018 in acetone). NEFA, glucagon, glucagon to insulin ratio, and NA were also significantly increased after both CANA and PIOG + CANA treatments; while only NEFAs demonstrated a significant difference between the two groups. Correlation analyses revealed a significant association between the difference in Δchanges in serum NEFA levels with the differences in Δchanges in ketones of β-HBA and acetoacetate.
Supplementation of pioglitazone could alleviate canagliflozin-induced ketone bodies. This benefit may be closely associated with decreased substrate NEFAs rather than other factors including glucagon, fasting insulin and NA.
观察噻唑烷二酮（TZD）吡格列酮对钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂卡格列净治疗的非肥胖 2 型糖尿病（T2DM）患者酮体减少的影响。
进行了两期交叉试验，每个治疗期持续 4 周，洗脱期为 4 周。参与者按 1:1 的比例随机分配接受吡格列酮联合卡格列净（PIOG+CANA 组）或卡格列净单药治疗（CANA 组）。主要结局为 CANA 或 PIOG+CANA 治疗前后β-羟丁酸（β-HBA）的变化（Δ）。次要结局为血清乙酰乙酸和丙酮的Δ变化、转化为尿酮的比率以及与 SGLT2 抑制剂诱导酮体产生相关的因素的Δ变化，包括非酯化脂肪酸（NEFAs）、胰高血糖素、胰高血糖素与胰岛素的比值和去甲肾上腺素（NA）。分析按照意向治疗原则进行。
纳入了 25 名平均年龄为 49±7.97 岁、体重指数为 25.35±2.22kg/m²的患者。1 名患者在洗脱期内退出研究。分析显示，两种干预后血清酮体水平均显著升高，尿酮转化率升高。然而，PIOG+CANA 组的酮体水平（除乙酰乙酸外）差异明显小于 CANA 组（219.84±80.21μmol/L 比 317.69±83.07μmol/L，p<0.001；8.98±4.17μmol/L 比 12.29±5.27μmol/L，p=0.018）。CANA 和 PIOG+CANA 治疗后，NEFA、胰高血糖素、胰高血糖素与胰岛素的比值和去甲肾上腺素也明显升高；而只有 NEFA 在两组间有显著差异。相关性分析显示，血清 NEFA 水平变化的差异与β-HBA 和乙酰乙酸的酮体变化的差异之间存在显著相关性。
吡格列酮的补充可以减轻卡格列净引起的酮体。这种益处可能与减少底物 NEFA 密切相关，而不是与胰高血糖素、空腹胰岛素和 NA 等其他因素有关。
