Lipid Effects of Peroxisome Proliferator-Activated Receptor-Δ Agonist GW501516 in Subjects With Low High-Density Lipoprotein Cholesterol

Abstract

Objective-Peroxisome proliferator-activated receptor-δ-induced upregulation in skeletal muscle fatty acid oxidation would predict the modulation of lipid/lipoproteins. Methods and Results-GW501516 (2.5, 5.0, or 10.0 mg) or placebo was given for 12 weeks to patients (n=268) with high-density lipoprotein (HDL) cholesterol <1.16 mmol/L. Fasting lipids/apolipoproteins (apos), insulin, glucose, and free fatty acid were measured; changes from baseline were calculated and assessed. A second smaller exploratory study (n=37) in a similar population was conducted using a sequence of 5 and 10 mg dosing for the assessment of lipoprotein particle concentration. GW501516 demonstrated HDL cholesterol increases up to 16.9% (10 mg) and apoA-I increases up to 6.6%. Reductions were observed in low-density lipoprotein (LDL) cholesterol (−7.3%), triglycerides (−16.9%), apoB (−14.9%), and free fatty acids (−19.4%). The exploratory study showed significant reductions in the concentration of very LDL (−19%), intermediate-density lipoprotein (−52%), and LDL (−14%, predominantly a reduction in small particles), whereas the number of HDL particles increased (+10%; predominantly medium and large HDL). Conclusion-GW501516 produced significant changes in HDL cholesterol, LDL cholesterol, apoA1, and apoB. Fewer very LDL and larger LDL support a transition toward less atherogenic lipoprotein profiles. These data are consistent with peroxisome proliferator-activated receptor-δ being a potentially important target for providing cardiovascular protection in metabolic syndrome-like patients. Materials and Methods Primary Lipid Study Main Criteria for InclusionMale or female subjects aged 18 to 75 years with fasting plasma HDL-C concentration ≤45 mg/dL (≤1.16 mmol/L), plasma LDL-C levels that did not require treatment according to the National Cholesterol Education Program/Adult Treatment Panel III guidelines, and fasting plasma TG concentration ≤500 mg/dL (≤5.65 mmol/L) were eligible for the study. Individuals with diabetes mellitus, renal impairment, thyroid dysfunction, or concomitant use of lipid lowering agents were excluded. DesignThis was a multicenter, randomized double-blind, parallel, placebocontrolled study with a 2-staged design. In stage 1, patients were randomly allocated to 12 weeks of treatment with 2.5 mg, 5.0 mg, or placebo. An Independent Data Monitoring Committee was prospectively appointed to ensure participant safety during the study and additionally to review the stage 1 data to advise whether the study could continue to stage 2 with an expanded dose range. In accordance with the Independent Data Monitoring Committee recommendations, stage 2 of the study was conducted with patients randomly allocated to 12 weeks of treatment with 5.0 mg, 10.0 mg, or placebo. The lipid changes in the treatment arms common to stages 1 and 2 (5 mg and placebo) were assessed for sufficient concordance to permit pooling of data from the 2 stages. In addition to the treatment period, each stage of the study included a 2-week placebo run-in period ...

Peroxisome Proliferator Activated Receptor-δ

“…4 In healthy humans, a synthetic PPARδ agonist, GW501516, reduced postprandial plasma triglycerides, increased high-density lipoprotein, and increased muscle expression of enzymes involved in fatty acid oxidation. 5 Similar effects were observed when PPARδ was activated in obese individuals, 6,7 people with low high-density lipoprotein, 8 and those with elevated low-density lipoprotein on statin therapy. 9 PPARδ is also known to affect macrophage biology because its deletion in this cell type disrupts phagocytosis 10 and promotes insulin resistance in addition to impairing the M1 (more inflammatory) to M2 (more inflammation resolution) transition.…”

Association and Interaction ofPPARα,δ,andγGene Polymorphisms with Low-Density Lipoprotein-Cholesterol in a Chinese Han Population

“…Hansen et al (2011) and Olson et al (2012) have already found that a dual PPARa/g agonist, aleglitazar, and GW501516, a PPARd agonist, can significantly decrease LDL-C levels in humans, which suggested a potential LDL-lowering effect triggered by activating different isoforms of PPARs. The mechanism of increased removal of LDL particles could be possibly attributed to the formation of LDL with a higher affinity for the LDL receptor, followed by a more rapid catabolic rate when PPARa agonist, such as fibrate, was used for treatment (Staels et al, 1998), whereas a possible mechanism for PPARd could be due to the reduction of the Niemann-Pick C1-like 1 (NPC1L1) protein by PPARd activation in the intestine as the inhibition of NPC1L1 would lead to reduced cholesterol absorption (Riserus et al, 2008).…”

Novel investigational drugs mimicking exercise for the treatment of cachexia

“…Indeed, treatment with GW501516 results in improved circulating apolipoproteins, LDL and HDL cholesterol and hepatosteatosis (51) . Finally, administration of MBX-8025 to moderately obese subjects improves circulating lipid and cholesterol profiles (52) .…”