Effects of high dose aleglitazar on renal function in patients with type 2 diabetes.
BACKGROUND
Aleglitazar is a new, balanced dual peroxisome proliferator-activated receptor (PPAR)α/γ agonist designed to optimize lipid and glycemic benefits and minimize PPAR-related adverse effects.


METHODS
SESTA R was a 26-week, randomized, double-blind, multicenter study comparing the effects of a supratherapeutic dosage of aleglitazar (600 μg/day) with pioglitazone (45 mg/day) on change in measured GFR (mGFR) in 174 patients with type 2 diabetes and normal to mildly impaired renal function (estimated GFR [eGFR] 60 to 120 ml/min/1.73 m(2)).


RESULTS
In 118 patients with evaluable GFR measurements, baseline mean (± SD) mGFR was 97.6 ± 17.5 ml/min/1.73 m(2) in the aleglitazar group and 101.9±21.6ml/min/1.73m(2) in the pioglitazone group. Mean percent change from baseline mGFR was -16.9% (90% confidence interval -22.0 to -11.5) with aleglitazar and -4.6% (-10.15 to 1.35) with pioglitazone, a mean treatment difference of -13.0% (-19.0 to -6.5). The 17% decrease from baseline in mGFR was consistent with the 19% decrease in eGFR Modification of Diet in Renal Disease (MDRD) observed with aleglitazar, which reached a plateau after 4weeks, with no further progression until treatment discontinuation. Following aleglitazar withdrawal, eGFR values returned to pretreatment levels within the 4-8-week follow-up, which suggests reversible hemodynamic changes in renal function.


CONCLUSIONS
Despite the increased incidence of expected, dose-dependent PPAR class side effects (e.g., peripheral edema, weight gain, and congestive heart failure) limiting further development of this supratherapeutic dosage of aleglitazar (600 μg/day), these data, together with the data from the dose-ranging SYNCHRONY study, suggest aleglitazar may be a potential new treatment for cardiovascular risk reduction in post-acute coronary syndrome patients at the therapeutic 150 μg daily dose.
Herz
Matthias
M
F. Hoffmann-La Roche AG, Basel, Switzerland. matthias.herz@roche.com
Gaspari
Flavio
F
Perico
Norberto
N
Viberti
Giancarlo
G
Urbanowska
Teresa
T
Rabbia
Michael
M
Wieczorek Kirk
Dominika
D
D000293:Adolescent; D000328:Adult; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010080:Oxazoles / Q000008:administration & dosage / Q000009:adverse effects*; D011379:Prognosis; D051437:Renal Insufficiency / Q000139:chemically induced* / Q000503:physiopathology; D012189:Retrospective Studies; D013876:Thiophenes / Q000008:administration & dosage / Q000009:adverse effects*; D055815:Young Adult
D010080:Oxazoles; D013876:Thiophenes; C542437:aleglitazar