Table 3.

Summary of the clinical evidence of PPAR agonists in dyslipidemia.

Disease	Target	Drug Name	Clinical Phase (Sample Size)	Main Findings/Primary Endpoint	Reference/Clinical Trial Identifier
Dyslipidemia	PPARα	Pemafibrate	III (225)	▪ Reduced triglycerides and liver enzymes ▪ Incidence of adverse drug reaction was lower in the pemafibrate group compared to the fenofibrate group	[118]
			III (526)	▪ Pemafibrate were comparable to high-dose fenofibrate (200 mg/day) and superior to low-dose fenofibrate (100 mg/day) in reducing triglycerides ▪ Adverse effects of pemafibrate was comparable to placebo	[119]
			III (166)	▪ Reduced triglycerides, non-HDL and remnant lipoprotein cholesterol apolipoprotein (Apo) B100, ApoB48, ApoCIII levels, and HOMA-IR. ▪ Increased HDL-cholesterol,ApoA-I, and fibroblast growth factor 21. ▪ Adverse effects of pemafibrate was comparable to placebo	[120]
			III (189)	▪ Decreased triglycerides ▪ Incidence of adverse events was not associated with estimated glomerular filtration rate in dyslipidemic patients with CKD.	[121]
	PPARα, PPARγ	Rosiglitazone and/or fenofibrate	NA (41)	▪ Rosiglitazone alone did not affect triglyceride level.	[122]
	PPARβ/δ	GW501516	II (268)	▪ Increased HDL-cholesterol, APOA-I ▪ Reduced LDL-cholesterol, triglycerides, APOB, free fatty acids	[125]
			IV (13)	▪ Decreased plasma triglycerides, fatty acid, APOB-100, APOB-48, and cholesteryl ester transfer protein activity. ▪ Decreased VLDL-APOB by increasing its fractional catabolism and of APOC-III by decreasing its production rate ▪ Reduced VLDL-to-LDL conversion and LDL-APOB production ▪ Increased HDL-cholesterol, APOA-II, and LpA-I:A-II concentrations by increasing APOA-II and LpA-I:A-II production	[126]
		Seladelpar	II (181)	▪ Reduced APOB-100, LDL-cholesterol, triglycerides, non-HDL-cholesterol, free fatty acids, liver enzymes and CRP ▪ Increased HDL-cholesterol ▪ Reduced number of patients with MetS and higher LDL-cholesterol	[128]
		Seladelpar and/or statins	II (166)	▪ Reduced small and very small LDL particles, and large VLDL ▪ Increased large LDL and HDL ▪ Combined therapy of seladelpar and atorvastatin had complementary effects in improving lipid profile.	[129]
	Dual PPARα/γ	Muraglitazar	II & III-Completed (330)	▪ Primary endpoint: Percent change of triglycerides from baseline	NCT00245388
	Dual PPAR α/δ	Elafibranor	II (94)	▪ Reduced triglycerides and GGT ▪ Increased HDL-cholesterol	[73]
Diabetic dyslipidemia	Dual PPARα/γ	Saroglitazar	III (109)	▪ Reduced triglycerides, LDL, VLDL, total cholesterol, and APOB ▪ No severe adverse event	[130]
			III (302)	▪ Reduced triglycerides, non-HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol, total cholesterol, APOB, and fasting plasma glucose ▪ No severe adverse event	[131]
Familial dysbetalipoproteinemia	PPARα	Fenofibrate or gemfibrozil	NA (146)	▪ Response to fibrate differed based on hypertriglyceridemia subtypes ▪ Hypertriglyceridemia due to lipoprotein lipase deficiency and glycerol kinase deficiency did not respond to fibrate ▪ Palmar xanthomas and hypertriglyceridemia due to APOE resistance responded well to fibrate	[134]
		Bezafibrate	NA (14)	▪ Reduced triglycerides and increased HDL-cholesterol ▪ Changed cholesterol distribution from small- to large-sized LDL and from large- to small-sized HDL	[135]
		Bezafibrate + Statins	NA (15)	▪ Bezafibrate with statin reduced post-fat load triglyceride, APOB and estimated glomerular filtration rate. ▪ Fasting levels of non-HDL-cholesterol, total cholesterol, and HDL-cholesterol were improved with combined therapy.	[136]
X-linked adrenoleukodystrophy	PPARα	Bezafibrate	NA (10)	▪ No reduction in very-long-chain fatty acids	[137]
CPT II and VLCAD deficiencies.	PPARα	Bezafibrate	NA (10)	▪ Reduced LDL, triglycerides, and free fatty acids ▪ No change in palmitate oxidation, fatty acid oxidation and heart rate during exercise did not improve clinical symptoms in patients with CPTII and VLCAD deficiencies	[138]
Familial hypercholesterolemia	PPARβ/δ	Seladelpar	II (13)	▪ Five patients had a ≥ 20% LDL-C decrease from baseline, while another five had a decrease of <15%. ▪ Proprotein convertase subtilisin/kexin type 9 (PCSK9) elevated by seladelpar.	[139]
Familial combined hyperlipidemia	PPARγ	Pioglitazone + lipid-lowering drugs	NA (26)	▪ Increased whole body glucose disposal, myocardial glucose utilization, myocardial blood flow, HDL-cholesterol and adiponectin ▪ Reduced insulin	[140]
			NA (22)	▪ Reduced triglycerides, glucose, and ALT ▪ Increased adiponectin, total and subcutaneous adipose tissues, soleus intracellular lipids	[141]
HIV-associated dyslipidemia and lipodystrophy syndrome	PPARα	Fenofibrate + fish oil	II (100)	▪ Combined therapy of fenofibrate and fish oil significantly reduced triglycerides.	[143]
		Fenofibrate	NA (55)	▪ Reduced triglycerides	[144]
			NA (36)	▪ Reduced triglycerides, APOC-III, total cholesterol, APOB, non-HDL-cholesterol, and triglyceride/APOA1 ratio ▪ Increased HDL-cholesterol, LDL sizes and LDL resistance to oxidation	[145]
			II (99)	▪ Increased HDL-cholesterol ▪ Brachial flow mediated dilation, CRP, IL-6, and D-dimer were unaffected.	[146]
			NA (191)	▪ Decreased triglycerides and total cholesterol ▪ Increased non-HDL-cholesterol ▪ Combined therapy with fenofibrate, niacin, low-saturated-fat diet, exercise, and exercise led to additional benefits on lipid profile compared to all monotherapies.	[147]
		Fenofibrate + Pravastatin	III (174)	▪ Combined therapy of fenofibrate and pravastatin could improve lipid profile and were well-tolerated.	[148]
		Fibrate	NA (245)	▪ Reduced triglycerides and total cholesterol	[149]
			NA (656)	▪ Reduced triglycerides and total cholesterol	[150]
		Bezafibrate	NA (130)	▪ Reduced triglycerides, total, and LDL-cholesterol	[151]
	PPARα, PPARγ	Fenofibrate, pioglitazone	NA (14)	▪ Pioglitazone, but not fenofibrate, improved insulin resistance, blood pressure, and lipid profile.	[152]
	PPARγ	Pioglitazone	III (130)	▪ Increased limb fat deposition, but did not improve lipid profile	[153]
		Rosigltazone	NA (96)	▪ No improvement in lipoatrophy	[155]
			NA (39)	▪ Increased subcutaneous and visceral abdominal fat ▪ Improved insulin sensitivity and adiponectin ▪ Did not affect CRP and flow-mediated vasodilation	[156]
			II (71)	▪ Did not improve carotid intima media thickness, inflammatory markers and endothelial activation markers	[157]
	Pan-PPAR	Tetradecylthioacetic acid	NA (10)	▪ Tetradecylthioacetic acid with diet intervention reduced total cholesterol, LDL cholesterol, triglycerides, LDL/HDL cholesterol ratio, and TNF-α	[159]
Dyslipidemia due to spinal cord injury	PPARα	Fenofibrate	II and III -Completed (23)	▪ Primary endpoint: Triglyceride level compared to baseline after two month fenofibrate treatment	NCT02455336