Type 2 diabetes mellitus(T2DM)is one of the most prevalent chronic metabolic disorder characterized by insulin resistance and relative insulin deficiency.PPARδactivation has been reported to have several beneficial e...Type 2 diabetes mellitus(T2DM)is one of the most prevalent chronic metabolic disorder characterized by insulin resistance and relative insulin deficiency.PPARδactivation has been reported to have several beneficial effects in alleviating dyslipidemia and insulin resistance.GW501516,a synthetic PPARδagonist,was developed to target hyperlipidemia and reported to alleviating insulin resistance in T2DM.Studies indicate that PPARδactivation by GW501516 can reduce adiposity,enhanceβ-oxidation of fatty acids,and improve insulin sensitivity in T2DM animal models.Despite its therapeutic promise,potential carcinogenic effects also have been reported.Therefore,a comprehensive non-targeted and targeted lipidomics study was carried out to evaluate the regulatory effect of GW501516 in the plasma of db/db mice.The results revealed that GW501516 is effective in reducing the accumulation of lipids in the fatty acid metabolism pathway and lipid classes including triglycerides and phosphatidylglycerols.Furthermore,activation of PPARδby GW501516 demonstrated a beneficial effect on improving circulating cholesterol homeostasis.However,while the levels of hexosylceramides and sphingomyelin were partially reversed,ceramide levels,which are negatively associated with insulin sensitivity,were significantly elevated by GW501516.Despite these mixed outcomes,the study highlights both the promising therapeutic potential of PPARδactivation in metabolic disorders and the safety concerns regarding long-term clinical use.The findings provide valuable insights into the impact of GW501516-induced PPARδactivation on lipid metabolism in T2DM,contributing to a better understanding of its therapeutic potential and risks.展开更多
Background GW117(N-(2-(6-chloro-7-deuteromethoxynaphthalen-1-yl)ethyl)acetamide)is a dual-acting agent(MT1/MT2 agonist,5-HT_(2C)antagonist)with prior evidence of antidepressant efficacy and favourable safety.Aims To p...Background GW117(N-(2-(6-chloro-7-deuteromethoxynaphthalen-1-yl)ethyl)acetamide)is a dual-acting agent(MT1/MT2 agonist,5-HT_(2C)antagonist)with prior evidence of antidepressant efficacy and favourable safety.Aims To preliminarily evaluate the efficacy and safety of GW117 in major depressive disorder(MDD)and to explore the optimal dosing.Methods A total of 280 eligible patients aged 18-65years with MDD were randomly assigned(1:1:1:1)to8 weeks of double-blind treatment with fixed doses of GW117 tablets(20,40,60 mg/day)or placebo.The primary endpoint was the change from baseline to Week 8 in the total score of the Hamilton Rating Scale for Depression-17item(HAMD-17).Key secondary endpoints included changes in the Montgomery-?sberg Depression Rating Scale(MADRS)total score over the same period.Results In the full analysis set(n=276),GW117 showed numerically greater reductions versus placebo in the HAMD-17 and MADRS total scores,as well as higher response rates at Week 8.However,these differences did not reach statistical significance,potentially due to a high placebo response and other contributing factors.In a post hoc analysis of an optimal subgroup(baseline HAMD-17>24 or insomnia factor>4),GW117 showed efficacy in improving multidimensional symptoms,including insomnia.The 20 mg dose demonstrated a significant3.66-point greater reduction in MADRS(p=0.026)and a23.16%higher response rate(p=0.013)compared with placebo.GW117 was well-tolerated,with no cases of alanine aminotransferase or aspartate aminotransferase exceeding 3×the upper limit of normal and no concerning safety signals reported.Conclusions This exploratory study found that GW117demonstrated encouraging antidepressant efficacy and a favourable safety profile in patients with MDD.Although differences versus placebo did not reach statistical significance in the overall population,GW11720 mg monotherapy showed significant improvements in multidimensional depressive symptoms,including insomnia,in the optimal response subgroup.No hepatotoxicity was reported,supporting its promising therapeutic potential for further clinical development.展开更多
基金the financial support by Hong Kong Research Grants Council(No.T12-101/23-N)National Natural Science Foundation of China(No.22206160)。
文摘Type 2 diabetes mellitus(T2DM)is one of the most prevalent chronic metabolic disorder characterized by insulin resistance and relative insulin deficiency.PPARδactivation has been reported to have several beneficial effects in alleviating dyslipidemia and insulin resistance.GW501516,a synthetic PPARδagonist,was developed to target hyperlipidemia and reported to alleviating insulin resistance in T2DM.Studies indicate that PPARδactivation by GW501516 can reduce adiposity,enhanceβ-oxidation of fatty acids,and improve insulin sensitivity in T2DM animal models.Despite its therapeutic promise,potential carcinogenic effects also have been reported.Therefore,a comprehensive non-targeted and targeted lipidomics study was carried out to evaluate the regulatory effect of GW501516 in the plasma of db/db mice.The results revealed that GW501516 is effective in reducing the accumulation of lipids in the fatty acid metabolism pathway and lipid classes including triglycerides and phosphatidylglycerols.Furthermore,activation of PPARδby GW501516 demonstrated a beneficial effect on improving circulating cholesterol homeostasis.However,while the levels of hexosylceramides and sphingomyelin were partially reversed,ceramide levels,which are negatively associated with insulin sensitivity,were significantly elevated by GW501516.Despite these mixed outcomes,the study highlights both the promising therapeutic potential of PPARδactivation in metabolic disorders and the safety concerns regarding long-term clinical use.The findings provide valuable insights into the impact of GW501516-induced PPARδactivation on lipid metabolism in T2DM,contributing to a better understanding of its therapeutic potential and risks.
文摘Background GW117(N-(2-(6-chloro-7-deuteromethoxynaphthalen-1-yl)ethyl)acetamide)is a dual-acting agent(MT1/MT2 agonist,5-HT_(2C)antagonist)with prior evidence of antidepressant efficacy and favourable safety.Aims To preliminarily evaluate the efficacy and safety of GW117 in major depressive disorder(MDD)and to explore the optimal dosing.Methods A total of 280 eligible patients aged 18-65years with MDD were randomly assigned(1:1:1:1)to8 weeks of double-blind treatment with fixed doses of GW117 tablets(20,40,60 mg/day)or placebo.The primary endpoint was the change from baseline to Week 8 in the total score of the Hamilton Rating Scale for Depression-17item(HAMD-17).Key secondary endpoints included changes in the Montgomery-?sberg Depression Rating Scale(MADRS)total score over the same period.Results In the full analysis set(n=276),GW117 showed numerically greater reductions versus placebo in the HAMD-17 and MADRS total scores,as well as higher response rates at Week 8.However,these differences did not reach statistical significance,potentially due to a high placebo response and other contributing factors.In a post hoc analysis of an optimal subgroup(baseline HAMD-17>24 or insomnia factor>4),GW117 showed efficacy in improving multidimensional symptoms,including insomnia.The 20 mg dose demonstrated a significant3.66-point greater reduction in MADRS(p=0.026)and a23.16%higher response rate(p=0.013)compared with placebo.GW117 was well-tolerated,with no cases of alanine aminotransferase or aspartate aminotransferase exceeding 3×the upper limit of normal and no concerning safety signals reported.Conclusions This exploratory study found that GW117demonstrated encouraging antidepressant efficacy and a favourable safety profile in patients with MDD.Although differences versus placebo did not reach statistical significance in the overall population,GW11720 mg monotherapy showed significant improvements in multidimensional depressive symptoms,including insomnia,in the optimal response subgroup.No hepatotoxicity was reported,supporting its promising therapeutic potential for further clinical development.
