Empagliflozin是一种钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂,已证明对2型糖尿病(T2D)患者具有心血管和肾脏保护作用。我们假设empaglifozin(EMPA)可以调节高脂高蔗糖(HFHS)饮食小鼠和2型糖尿病(T2D)的异位脂肪储存和心肌能量学。
C57BL/6HFHS小鼠(n=24)和T2D受试者(n=56)被随机分配到用EMPA(30mg/kg小鼠,10毫克/天的人)或安慰剂。在基线和12周时进行具有1H-MRS评估的4.7T或3TMRI-心肌脂肪(主要终点)和肝脏脂肪含量(LFC)。在人类中,标准心脏MRI与用31P-MRS测量的心肌能量学(PCr/ATP)相结合。皮下(SAT)腹部,内脏(增值税),还评估了心外膜和胰腺脂肪。主要疗效终点是EMPA和安慰剂之间的心外膜脂肪体积从基线到12周的变化。次要终点是PCr/ATP比率的差异,心肌,肝脏和胰腺脂肪含量,12周时组间的SAT和增值税。
在喂食HFHS的小鼠中,与安慰剂相比,EMPA显著改善葡萄糖耐量并增加血酮体(KB)和β-羟基丁酸酯水平(p<0.05)。与标准饮食小鼠相比,饲喂HFHS的小鼠心肌和肝脏脂肪含量增加。EMPA显著降低了55%的肝脏脂肪含量,(p<0.001),但对心肌脂肪没有影响。在人类研究中,所有56例患者的LV功能均正常,平均LVEF=63.4±7.9%。与安慰剂相比,接受EMPA治疗的T2D患者体重明显减轻(-2.6kg[-1.2;-3.7]),HbA1c改善0.88±0.74%。与安慰剂相比,EMPA组的血细胞比容和EPO水平显着增加(p<0.0001,p=0.041)。与安慰剂相比,EMPA显着增加糖尿和血浆KB水平(分别为p<0.0001,p=0.012),并显着降低肝脏脂肪含量(-27±23vs.-2±24%,p=0.0005)和内脏脂肪(-7.8%[-15.3;-5.6]vs.-0.1%[-1.1;6.5],p=0.043),但对心肌或心外膜脂肪没有影响。12周时,心肌PCr/ATP无明显变化(组间p=0.57).
EMPA有效减少小鼠和人类的肝脏脂肪,而不改变心外膜,心肌脂肪或心肌能量学,反驳SGLT2抑制剂心血管保护的节俭底物假说。试验注册NCT,NCT03118336。2017年4月18日注册,https://clinicaltrials.gov/ct2/show/NCT03118336。
Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that has demonstrated cardiovascular and renal protection in patients with type 2 diabetes (T2D). We hypothesized that empaglifozin (EMPA) could modulate ectopic fat stores and myocardial energetics in high-fat-high-sucrose (HFHS) diet mice and in type 2 diabetics (T2D).
C57BL/6 HFHS mice (n = 24) and T2D subjects (n = 56) were randomly assigned to 12 weeks of treatment with EMPA (30 mg/kg in mice, 10 mg/day in humans) or with placebo. A 4.7 T or 3 T MRI with 1H-MRS evaluation-myocardial fat (primary endpoint) and liver fat content (LFC)-were performed at baseline and at 12 weeks. In humans, standard cardiac MRI was coupled with myocardial energetics (PCr/ATP) measured with 31P-MRS. Subcutaneous (SAT) abdominal, visceral (VAT), epicardial and pancreatic fat were also evaluated. The primary efficacy endpoint was the change in epicardial fat volume between EMPA and placebo from baseline to 12 weeks. Secondary endpoints were the differences in PCr/ATP ratio, myocardial, liver and pancreatic fat content, SAT and VAT between groups at 12 weeks.
In mice fed HFHS, EMPA significantly improved glucose tolerance and increased blood ketone bodies (KB) and β-hydroxybutyrate levels (p < 0.05) compared to placebo. Mice fed HFHS had increased myocardial and liver fat content compared to standard diet mice. EMPA significantly attenuated liver fat content by 55%, (p < 0.001) but had no effect on myocardial fat. In the human study, all the 56 patients had normal LV function with mean LVEF = 63.4 ± 7.9%. Compared to placebo, T2D patients treated with EMPA significantly lost weight (- 2.6 kg [- 1.2; - 3.7]) and improved their HbA1c by 0.88 ± 0.74%. Hematocrit and EPO levels were significantly increased in the EMPA group compared to placebo (p < 0.0001, p = 0.041). EMPA significantly increased glycosuria and plasma KB levels compared to placebo (p < 0.0001, p = 0.012, respectively), and significantly reduced liver fat content (- 27 ± 23 vs. - 2 ± 24%, p = 0.0005) and visceral fat (- 7.8% [- 15.3; - 5.6] vs. - 0.1% [- 1.1;6.5], p = 0.043), but had no effect on myocardial or epicardial fat. At 12 weeks, no significant change was observed in the myocardial PCr/ATP (p = 0.57 between groups).
EMPA effectively reduced liver fat in mice and humans without changing epicardial, myocardial fat or myocardial energetics, rebutting the thrifty substrate hypothesis for cardiovascular protection of SGLT2 inhibitors. Trial registration NCT, NCT03118336. Registered 18 April 2017, https://clinicaltrials.gov/ct2/show/NCT03118336.