Omapatrilat, an Angiotensin-Converting Enzyme and Neutral Endopeptidase Inhibitor, Attenuates Early Atherosclerosis in Diabetic and in Nondiabetic Low-Density Lipoprotein Receptor–Deficient Mice

Omapatrilat inhibits both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). ACE inhibitors have been shown to inhibit atherosclerosis in apoE-deficient mice and in several other animal models but failed in low-density lipoprotein (LDL) receptor– deficient mice despite effective inhibition of the reninangiotensin- aldosterone system. The aim of the present study was to examine the effect of omapatrilat on atherogenesis in diabetic and nondiabetic LDL receptor–deficient mice. LDL receptor–deficient male mice were randomly divided into 4 groups (n = 11 each). Diabetes was induced in 2 groups by low-dose STZ, the other 2 groups served as nondiabetic controls. Omapatrilat (70 mg/kg/day) was administered to one of the diabetic and to one of the nondiabetic groups. The diabetic and the nondiabetic mice were sacrificed after 3 and 5 weeks, respectively. The aortae were examined and the atherosclerotic plaque area was measured. The atherosclerotic plaque area was significantly smaller in the omapatrilat-treated mice, both diabetic and nondiabetic, as compared to nontreated controls. The mean plaque area of omapatrilattreated nondiabetic mice was 9357 ± 7293 μm2, versus 71977 ± 34610 μm2 in the nontreated mice (P = .002). In the diabetic animals, the plaque area was 8887 ± 5386 μm2 and 23220 ± 10400 μm2, respectively for treated and nontreated mice (P = .001). Plasma lipids were increased by omapatrilat: Meanplasma cholesterol in treated mice, diabetic and nondiabetic combined, was 39.31 ± 6.00 mmol/L, versus 33.12 ± 7.64 mmol/L in the nontreated animals (P = .008). The corresponding combined mean values of triglycerides were 4.83 ± 1.93 versus 3.00 ± 1.26 mmol/L (P = .02). Omapatrilat treatment did not affect weight or plasma glucose levels. Treatment with omapatrilat inhibits atherogenesis in diabetic as well as nondiabetic LDL receptor–deficient mice despite an increase in plasma lipids, suggesting a direct effect on the arterial wall

Plasma lipids and the progression of nephropathy in diabetes mellitus type II: Effect of ACE inhibitors

Plasma lipids and the progression of nephropathy in diabetes mellitus type II: Effect of ACE inhibitors. Ninety-four normotensive type II diabetics with normal renal function and microalbuminuria were randomized to receive enalapril 10 mg/day or placebo and were followed for five years. In the patients treated by enalapril plasma creatinine values and albuminuria remained stable throughout the observation period. Their plasma total cholesterol decreased from an initial value of 245 ± 27 mg/dl to mean study value of 236 ± 29 mg/dl, and to a fifth year value of 232 ± 27 mg/dl (P < 0.001). The changes in HDL cholesterol and triglyceride values were nonsignificant. In the placebo group there was a significant increase in albuminuria and a mean decline of 13% in reciprocal creatinine values during the five years. Plasma total cholesterol increased from an initial mean value of 246 ± 24 to a mean study value of 252 ± 25 mg/dl, and to a fifth year mean value of 259 ± 32 mg/dl (P < 0.001). There was a significant correlation between both initial and mean plasma total cholesterol values, and the decline in renal function and the rise in albuminuria in the placebo treated patients. This correlation persisted after stratification for blood pressure. Treatment with enalapril did not eliminate these correlations. Cholesterol may be an additional risk factor for diabetic nephropathy. ACE inhibitors may have a modest cholesterol lowering effect in diabetic patients mediated, in part, through the decline in albuminuria