Effects of aleglitazar, a balanced dual peroxisome proliferator-activated receptor α/γ agonist on glycemic and lipid parameters in a primate model of the metabolic syndrome.
BACKGROUND
Glycemic control and management of dyslipidemia to reduce cardiovascular risk are major therapeutic goals in individuals with type 2 diabetes mellitus (T2DM). This study was performed to evaluate the effects of aleglitazar, a balanced dual peroxisome proliferator-activated receptor α/γ (PPARα/γ) agonist, on both lipid and glycemic parameters in obese, hypertriglyceridemic, insulin-resistant rhesus monkeys.


METHODS
A 135-day efficacy study was performed in six rhesus monkeys. After a 28-day baseline assessment (vehicle only), monkeys received oral aleglitazar 0.03 mg/kg per day for 42 days, followed by a 63-day washout period. Plasma levels of markers of glycemic and lipid regulation were measured at baseline, at the end of the dosing period, and at the end of the washout period.


RESULTS
Compared with baseline values, aleglitazar 0.03 mg/kg per day reduced triglyceride levels by an average of 89% (328 to 36 mg/dL; P = 0.0035 when normalized for baseline levels) and increased high-density lipoprotein cholesterol levels by 125% (46 to 102 mg/dL; P = 0.0007). Furthermore, aleglitazar reduced low-density lipoprotein cholesterol levels (41%) and increased levels of apolipoprotein A-I (17%) and A-II (17%). Aleglitazar also improved insulin sensitivity by 60% (P = 0.001). Mean body weight was reduced by 5.9% from baseline values with aleglitazar at this dose (P = 0.043).


CONCLUSIONS
Aleglitazar, a dual PPARα/γ agonist, has beneficial effects on both lipid and glucose parameters and may have a therapeutic role in modifying cardiovascular risk factors and improving glycemic control in patients with T2DM.
Department of Internal Medicine and Pediatrics, University of South Florida, Tampa, FL, USA. bchansen@aol.com
Barbara C
BC
Hansen
Xenia T
XT
Tigno
Agnes
A
Bénardeau
Markus
M
Meyer
Elena
E
Sebokova
Jacques
J
Mizrahi
D000284:Administration, Oral; D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood; D016633:Apolipoprotein A-II / Q000097:blood; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004195:Disease Models, Animal; D004435:Eating; D006442:Glycated Hemoglobin / Q000378:metabolism; D015228:Hypertriglyceridemia / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007333:Insulin Resistance; D008253:Macaca mulatta; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D009765:Obesity / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology; D010080:Oxazoles / Q000008:administration & dosage / Q000494:pharmacology*; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D011236:Prediabetic State / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D014280:Triglycerides / Q000097:blood; D015431:Weight Loss
D016632:Apolipoprotein A-I; D016633:Apolipoprotein A-II; D015415:Biomarkers; D001786:Blood Glucose; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D010080:Oxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D013876:Thiophenes; D014280:Triglycerides; C542437:aleglitazar
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