ACE gene polymorphism and losartan treatment in type 2 diabetic patients with nephropathy.
Losartan treatment reduced renal outcomes in proteinuric patients with type 2 diabetes in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. It is unknown whether an insertion (I)/deletion (D) polymorphism in the angiotensin I-converting enzyme (ACE) gene predicts renal outcomes and death and influences the effect of losartan in these patients. Pharmacogenetic analyses were performed comparing losartan with placebo administered with conventional blood pressure-lowering therapy in 1435 (95%) of the 1513 RENAAL study patients. The primary endpoint was the composite of doubling of baseline serum creatinine concentration, end-stage renal disease (ESRD) or death. Cox regression models were stratified on baseline proteinuria and included treatment, geographic region, ACE/ID genotype, and treatment x genotype interaction. Within the placebo group, subjects with the ID or DD genotype were more likely than those with the II genotype to reach the composite endpoint (by 17.5% and 38.1%, respectively, P = 0.029) or its individual components. Within the losartan group, genotype did not correlate with reaching the composite endpoint. Compared with placebo, however, losartan reduced the risk of reaching the composite endpoint by 5.8% (95% confidence interval, -23.3, 28.0), 17.6% (3.8, 29.4), and 27.9% (7.0, 44.1) among those with the II, ID, and DD genotypes, respectively. Similar trends were demonstrated for the individual endpoints. In conclusion, proteinuric type 2 diabetic patients with the D allele of the ACE gene have an unfavorable renal prognosis, which can be mitigated and even improved by losartan.
Parving
Hans-Henrik
HH
Department of Medical Endocrinology, Department 2132, Rigshospitalet, University Hospital of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark. hhparving@dadlnet.dk
de Zeeuw
Dick
D
Cooper
Mark E
ME
Remuzzi
Giuseppe
G
Liu
Nancy
N
Lunceford
Jared
J
Shahinfar
Shahnaz
S
Wong
Peggy H
PH
Lyle
Paulette A
PA
Rossing
Peter
P
Brenner
Barry M
BM
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D006801:Humans; D019808:Losartan / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D011110:Polymorphism, Genetic
D047228:Angiotensin II Type 1 Receptor Blockers; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A; D019808:Losartan