Abstract：
OBJECTIVE: 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.
METHODS: 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.
RESULTS: Twenty-five patients with a mean age of 49 ± 7.97 years and a body mass index of 25.35 ± 2.22 kg/m2 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: Twenty-five patients with a mean age of 49 ± 7.97 years and a body mass index of 25.35 ± 2.22 kg/m2 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.
CONCLUSIONS: 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.
摘要：
目的：观察噻唑烷二酮(TZD)吡格列酮对钠-葡萄糖协同转运蛋白-2(SGLT2)抑制剂canagliflozin治疗的非肥胖T2DM患者酮体的影响。
方法：两个时期的交叉试验，每个治疗周期持续4周，有4周的冲洗期，进行了。参与者以1：1的比例随机分配接受吡格列酮联合canagliflozin（PIOGCANA组）与canagliflozin单药治疗（CANA组）。主要结果是CANA或PIOGCANA治疗前后β-羟基丁酸（β-HBA）的变化（Δ）。次要结局是血清乙酰乙酸和丙酮的Δ变化，转化为尿酮的速率，和与SGLT2抑制剂诱导的酮体产生相关的因素的Δ变化，包括非酯化脂肪酸（NEFA），胰高血糖素,胰高血糖素与胰岛素的比例，去甲肾上腺素（NA）。根据意向治疗原则进行分析。
结果：纳入25例患者，平均年龄为49±7.97岁，体重指数为25.35±2.22kg/m2。一名患者在清除期间停止研究。分析显示，两种干预措施后，血清酮体水平均显着增加，转化为尿酮的速率也升高。然而,PIOG+CANA组的酮体水平差异（乙酰乙酸除外）明显小于CANA组（219.84±80.21μmol/Lvs.317.69±83.07μmol/L,β-HBA中p<0.001；8.98±4.17μmol/Lvs.12.29±5.27μmol/L,p=0.018在丙酮中)。NEFA,胰高血糖素,胰高血糖素与胰岛素的比例，CANA和PIOG+CANA治疗后，NA也显着增加；而只有NEFA在两组之间表现出显着差异。相关分析显示，血清NEFA水平的Δ变化差异与β-HBA和乙酰乙酸酯酮的Δ变化差异之间存在显着关联。
结论：补充吡格列酮可以减轻坎格列净诱导的酮体。这种益处可能与底物NEFA减少密切相关，而不是其他因素，包括胰高血糖素，空腹胰岛素和NA。
方法：两个时期的交叉试验，每个治疗周期持续4周，有4周的冲洗期，进行了。参与者以1：1的比例随机分配接受吡格列酮联合canagliflozin（PIOGCANA组）与canagliflozin单药治疗（CANA组）。主要结果是CANA或PIOGCANA治疗前后β-羟基丁酸（β-HBA）的变化（Δ）。次要结局是血清乙酰乙酸和丙酮的Δ变化，转化为尿酮的速率，和与SGLT2抑制剂诱导的酮体产生相关的因素的Δ变化，包括非酯化脂肪酸（NEFA），胰高血糖素,胰高血糖素与胰岛素的比例，去甲肾上腺素（NA）。根据意向治疗原则进行分析。
结果：纳入25例患者，平均年龄为49±7.97岁，体重指数为25.35±2.22kg/m2。一名患者在清除期间停止研究。分析显示，两种干预措施后，血清酮体水平均显着增加，转化为尿酮的速率也升高。然而,PIOG+CANA组的酮体水平差异（乙酰乙酸除外）明显小于CANA组（219.84±80.21μmol/Lvs.317.69±83.07μmol/L,β-HBA中p<0.001；8.98±4.17μmol/Lvs.12.29±5.27μmol/L,p=0.018在丙酮中)。NEFA,胰高血糖素,胰高血糖素与胰岛素的比例，CANA和PIOG+CANA治疗后，NA也显着增加；而只有NEFA在两组之间表现出显着差异。相关分析显示，血清NEFA水平的Δ变化差异与β-HBA和乙酰乙酸酯酮的Δ变化差异之间存在显着关联。
结论：补充吡格列酮可以减轻坎格列净诱导的酮体。这种益处可能与底物NEFA减少密切相关，而不是其他因素，包括胰高血糖素，空腹胰岛素和NA。
