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

Abstract

BackgroundGlycemic 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.MethodsA 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.ResultsCompared 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).ConclusionsAleglitazar, 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.

Safety of Antidiabetic Therapies on Bone

“…In T2DM patients, aleglitazar improved the lipid profile and decreased levels of cardiovascular markers of inflammation and clotting (67; 68). The observed adverse events were characteristic of either PPARγ or PPARα agonists; however, when compared to pioglitazone-PPARγ-mediated effects, such as edema and weight gain, these were less severe.…”

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).…”

Nutrition, metabolism, and targeting aging in nonhuman primates

“…Dual peroxisome proliferator-activated receptor α/γ agonists may be even more efficient in reducing cardiovascular events in diabetic patients as they confer both the insulin sensitizing effects of PPARγ agonism and lipid lowering effects associated with PPARα agonism. In diabetic rhesus monkeys, dual PPAR α/γ agonists like Aleglitazar and TAK559 have been shown to correct hyperinsulinemia and result in a less atherogenic lipoprotein profile without adversely affecting liver function, body weight or fluid retention as observed with other selective PPAR agonists 89,90 . The beneficial effects of these classes of drugs on lipid profiles and glucoregulatory function in the context of metabolic dysfunction are reminiscent of the outcomes of CR 91,92 .…”