Long-term renoprotective effects of losartan in diabetic nephropathy: interaction with ACE insertion/deletion genotype?
OBJECTIVE
Several observational follow-up studies have found that the D allele of the insertion (I)/deletion (D) polymorphism of the ACE gene (ACE/ID) is associated with an increased risk of renal function loss, even during ACE inhibition. Therefore, we investigated the long-term effect of the angiotensin II subtype-1 (AT1) receptor antagonist losartan (100 mg o.d.) on kidney function in II and DD type 1 diabetic patients with diabetic nephropathy.


METHODS
A total of 54 hypertensive type 1 diabetic patients with diabetic nephropathy homozygous for the insertion (n = 26) or the deletion (n = 28) allele were included in the study. After a 4-week washout, the patients received losartan (tablet, 100 mg o.d.) and were followed prospectively with a mean follow-up period of 36 months. Patients and investigators were blinded to ACE genotypes. At baseline, after 2 and 4 months and every 6 months thereafter, glomerular filtration rate (GFR), albuminuria, and 24-h blood pressure were determined.


RESULTS
At baseline, GFR, albuminuria, and blood pressure were similar in the two genotype groups, II versus DD: mean (SD), 86 (22) vs. 88 (24) ml. min(-1). 1.73 m(-2); median (interquartile range), 1,134 (598-2,023) vs. 1,451 (893-1,766) mg/24 h; and mean (SD), 156/82 (17/9) vs. 153/80 (17/11) mmHg, respectively. GFR decreased similarly in both genotype groups, versus DD, respectively (P = 0.4): geometric mean (95% CI), 2.9 (2.0-4.2) vs. 3.4 (2.3-5.1) ml. min(-1). year(-1). Albuminuria and arterial blood pressure were significantly reduced during the study; no differences were noted between groups. During follow-up, albuminuria was decreased by 75% (95% CI 59-85) and 73% (56-83) in the II and DD groups, respectively (P < 0.01 vs. baseline). Mean systolic and diastolic blood pressures were 139/74 mmHg (14/8) in both genotype groups during the study (P < 0.01 vs. baseline).


CONCLUSIONS
In contrast to previous observational studies with ACE inhibitors, long-term treatment with losartan has similar beneficial renoprotective effects on progression of diabetic nephropathy in hypertensive type 1 diabetic patients with ACE II and DD genotypes.
Andersen
Steen
S
Steno Diabetes Center, Copenhagen, Denmark. stan@dadlnet.dk
Tarnow
Lise
L
Cambien
Francois
F
Rossing
Peter
P
Juhl
Tina R
TR
Deinum
Jaap
J
Parving
Hans-Henrik
HH
D000328:Adult; D000419:Albuminuria / Q000453:epidemiology; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure; D008076:Cholesterol, HDL / Q000097:blood; D003404:Creatinine / Q000097:blood; D004251:DNA Transposable Elements; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000235:genetics / Q000517:prevention & control*; D005260:Female; D005838:Genotype; D005919:Glomerular Filtration Rate; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D019808:Losartan / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D011188:Potassium / Q000097:blood; D012307:Risk Factors; D017384:Sequence Deletion
D000959:Antihypertensive Agents; D008076:Cholesterol, HDL; D003404:Creatinine; D004251:DNA Transposable Elements; D006442:Glycated Hemoglobin; D019808:Losartan; D007703:Peptidyl-Dipeptidase A; D011188:Potassium