AMSTERDAM — In type 1 diabetic patients with diabetic nephropathy, 40 mg/day of lisinopril appears to be the ideal dose for renoprotection, Dr. Katrine J. Schjoedt said in a poster presentation at the annual meeting of the European Association for the Study of Diabetes.
Angiotensin converting enzyme inhibitors such as lisinopril are considered first-line agents for renoprotection in patients with type 1 diabetes who have nephropathy, because these drugs reduce albuminuria in addition to lowering blood pressure. The currently recommended 20 mg/day dose of lisinopril is based on the drug's blood pressure-lowering effect; the optimal dose for renoprotection has not been established, said Dr. Schjoedt of the Steno Diabetes Center, Gentofte, Denmark.
To evaluate whether additional renoprotective effects could be obtained with higher doses of lisinopril, 56 type 1 diabetic patients with diabetic nephropathy were taken off all ongoing antihypertensive therapy and put on fixed doses (median 60 mg/day) of slow-release furosemide for the entire study. After a 2-month washout period, the patients were randomized to receive 20, 40, or 60 mg/day of lisinopril for 2 months.
The 49 patients who completed the trial had a mean age of 49 years and a diabetes duration of 33 years; two-thirds of them were men. At baseline, they had a mean blood pressure of 142/74 mm Hg, a mean urinary albumin excretion rate of 362 mg/24 hours, and a mean estimated glomerular filtration rate of 75 mL/min per 1.73 m
The mean urinary albumin excretion rate fell by 71% from baseline with 40 mg lisinopril, by 70% with 60 mg, and by 63% with 20 mg. All of the reductions from baseline were significant. The 40-mg group and the 60-mg group both had significant reductions in urinary albumin excretion rate, compared with the 20-mg group, but the difference between the 60-mg and 40-mg groups was not significant.
“High [40 mg] doses of lisinopril offer additional renoprotection in comparison to the currently recommended dose [20 mg]. Ultrahigh [60 mg] doses do not offer any further beneficial effect,” Dr. Schjoedt remarked.
All three dose groups also had significant reductions in blood pressure from baseline: Systolic pressure fell by 10, 13, and 12 mm Hg and diastolic pressure fell by 6, 8, and 7 mm Hg with lisinopril doses of 20, 40, and 60 mg/day, respectively. In addition, there was a dose-dependent reduction in estimated glomerular filtration rate, from 75 mL/min per 1.73 m
Adverse events leading to study dropout were an increase in plasma creatinine in two patients (one on the 20-mg dose and one on the 60-mg dose), high blood pressure in one patient in the 60-mg group, mild dizziness in two patients (on 40 mg and 60 mg), mild diarrhea in one (on 40 mg), and restless legs in one (on 20 mg). There were dose-dependent decreases in hemoglobin (down to 7.8 mmol/L with the 60- and 40-mg doses, compared with 8.3 mmol/L at baseline), and a significant increase in hemoglobin A1c in the 60-mg group (rising to 8.9%, compared with 8.6% at baseline).
Nonetheless, Dr. Schjoedt concluded, “high doses of lisinopril are generally well tolerated and safe.”
High doses of lisinopril offer additional renoprotection. Ultrahigh doses offer no additional benefit. DR. SCHJOEDT