Mordchai Ravid

Long-Term Stabilizing Effect of Angiotensin-Converting Enzyme Inhibition on Plasma Creatinine and on Proteinuria in Normotensive Type II Diabetic Patients

Diabetic nephropathy is the single most important cause of end-stage renal failure in the western world. It accounts for 15% to 25% of all renal failure in patients receiving chronic dialysis [1]. About 40% of type I and 20% of type II diabetics develop clinically important nephropathy [2-4]. However, the ratio of type II to type I diabetics is 10 to 1, and the number of patients with chronic renal failure due to type II disease exceeds that of type I [4-6]. Therefore, an obvious need exists to evaluate treatments that may delay the progress of nephropathy in type II diabetes. However, most studies of diabetic renal disease have hitherto focused on type I diabetes. Available data suggest that effective antihypertensive treatment is the best inhibitor of diabetic nephropathy [7-10]. Angiotensin-converting enzyme inhibitors have been found more effective than placebo and -adrenergic blocking agents in hypertensive as well as in normotensive diabetics with early and advanced nephropathy [11-15]. Some classes of calcium antagonists effectively decrease urinary protein excretion and may preserve renal function. However, analysis of several studies shows that, although the effects of angiotensin-converting enzyme inhibitors are consistent, those of calcium antagonists vary [16-18]. Short-term studies showed a clear antiproteinuric effect of captopril and of enalapril on the diabetic kidney, probably independent of the antihypertensive effect of these agents [14, 15, 19]. However, the outcome of long-term intervention and the possibility of a true alteration of the natural course of the disease were unknown. We did a relatively long-term, 5-year study of the effect of the angiotensin-converting enzyme inhibitor, enalapril, on the course of diabetic nephropathy in normotensive, type II diabetic patients with microalbuminuria and normal renal function. Our report describes a randomized, placebo-controlled, double-blind study on 94 diabetic patients. Methods Patients A total of 108 patients with type II diabetes mellitus, diagnosed according to World Health Organization criteria [20] who attended six clinics in the Tel Aviv area were recruited during 1986 and gave informed consent to participate in the study. The inclusion criteria were as follows: age less than 50 years; duration of diabetes mellitus of less than 10 years with no evidence of systemic, renal, cardiac, or hepatic diseases; body mass index less than 27 kg/m2; normal blood pressure values on two consecutive examinations (systolic, 140 mm Hg; diastolic, 90 mm Hg; mean blood pressure < 107 mm Hg); serum creatinine, < 123 mol/L (1.4 mg/dL); and microalbuminuria (urinary protein excretion of 30 to 300 mg/24 h) on two consecutive visits without evidence of urinary tract infection. Initially, there were 49 men and 59 women, ages 34 to 49 years (mean age [SD], 44 4 years). The duration of diabetes was 0.5 to 9.1 years (mean duration [SD], 6.7 1.6 years). Sixteen patients received insulin, 43 were taking oral hypoglycemic agents, and 49 were using diet to control their diabetes. Protocol The protocol was approved by the hospital review board. After a 2-month pretreatment period, the patients were randomly allocated to receive either 10 mg enalapril (Teva Pharmaceutical Industries, Ltd., Petach Tikwa, Israel) daily or placebo in a double-blind manner. The placebo tablets were similar but not identical to enalapril. Randomization was done using a table of random numbers [21]. The follow-up period was terminated, for each patient, exactly 5 years after his or her randomization, and the data were submitted for evaluation. The patients were seen by their family physicians approximately every 3 to 4 months. On these visits, fasting blood glucose, glycosylated hemoglobin, serum creatinine, serum electrolyte levels, and albuminuria in 24-hour urine samples were determined. Blood pressure was measured by mercury sphygmomanometers with the patients sitting after a 5-minute rest; the average of two determinations was recorded. The diastolic pressure was determined at Korotkoff phase V. If systolic blood pressure values of 145 mm Hg, or diastolic values of 95 mm Hg, were found on two consecutive occasions, treatment with long-acting nifedipine (Pressolate, Agis Industries Ltd., Yeruham, Israel) was initiated. Funduscopy was done yearly by an ophthalmologist, and the presence of diabetic retinopathy was recorded. Measurements Glucose and creatinine levels were determined by routine automated methods. Glycosylated hemoglobin levels were measured by affinity chromatography with a commercial kit (Isolab, Biochemical Methodology, Drower 4350, Akron, Ohio). The albumin excretion rate was measured on 24-hour urine samples by an automated immunoturbidimetric assay [22]. Sixteen to 20 fasting blood glucose determinations and 15 to 20 glycosylated hemoglobin values were available for each patient. For each patient, the correlation coefficients between fasting blood glucose and glycosylated hemoglobin levels were between 0.60 and 0.84. The mean blood pressure values were calculated for each patient (mean pressure defined as diastolic value plus one third of the pulse pressure). The reciprocal creatinine value (100/creatinine value) was calculated for each visit [23], and the decline in renal function was expressed as a percentage of the initial value. The course of renal function, of the mean blood pressure, and of urinary protein excretion were plotted against time (separately) for the enalapril and the placebo groups. Statistical Analysis All data were expressed as mean (SD) and ranges. Significance was defined as P < 0.05. To test for adequate randomization, the enalapril and placebo groups were compared with respect to mean age, mean duration of diabetes, as well as mean baseline values of albuminuria, serum creatinine, glycosylated hemoglobin, and mean blood pressure using pooled variance Student t-tests for independent groups as well as one-way analysis of variance. To compare the annual means of the various measurements between the two groups and within each group, one between-group factor and one repeated measures factor were used in analysis of variance. The rate of decrease of reciprocal creatinine levels and the rate of increase of albuminuria were calculated by linear regression analysis. Results Five patients, 2 taking enalapril and 3 taking placebo left the study during the first year. Six patients (4 taking enalapril and 2 taking placebo) developed a disturbing cough, and the treatment was discontinued. Three patients (1 on enalapril and 2 on placebo) were lost to follow-up during the third and fourth years. The final analysis was therefore done on 94 patients, of whom 49 received enalapril and 45 received placebo. Age, male/female ratio, duration of diabetes, and the other baseline data of the two groups are shown in Table 1. No statistically significant differences existed between the initial characteristics of the enalapril and the placebo groups. Table 1. Baseline Data from 94 Type II Diabetic Patients with Microalbuminuria* During the first year of treatment, the urinary albumin excretion in the enalapril group decreased from an initial mean of 143 mg/24 h to an annual mean of 122 mg/24 h. Values greater than 300 mg/24 h were recorded in only two patients. Subsequently, a minimal but steady increase occurred in mean daily albumin excretion of these patients, with a fourth-year mean of 136 mg/24 h and a fifth-year mean of 140 mg/24 h. In six patients, albuminuria exceeded 300 mg/24 h. In contrast, among the placebo-treated patients, a steady, gradual increase occurred in mean daily albuminuria. The initial albumin value was 123 mg/24 h, the first-year mean was 134 mg/24 h, and the fifth-year value was 310 mg/24 h. Albumin values were greater than 300 mg/24 h in 19 patients and greater than 1 mg/24 h in three patients. The difference between the mean values of daily albuminuria in the two groups became statistically significant after the first year. However, the difference in the rate of change in proteinuria from baseline was statistically significant at the end of the first year (P < 0.05). These data are shown in Figure 1 and are numerically detailed in the Appendix Table. If the development of overt proteinuria ( 300 mg/24 h) is considered clinically important, the risk for developing this degree of proteinuria within 5 years of follow-up was 19/45 (42%) in the placebo group compared with 6/49 (12%) in the enalapril group. Therefore, enalapril treatment resulted in an absolute risk reduction of 30 percentage points for the development of overt proteinuria (95% CI, 15% to 45%; P < 0.001) for a 5-year period. Appendix Table. Initial and Annual Averages of Blood Chemistry Values for the 5-Year Follow-up in the Enalapril- and Placebo-Treated Groups* Figure 1. Proteinuria during 5-year follow-up in diabetics treated with enalapril or placebo. P P P Renal function, expressed as reciprocal creatinine (100/cr) remained unchanged in the enalapril group during the first 2 years of follow-up. From the third year onward, a small, nonsignificant but systematic decrease was recorded. The decrease was 1% of the initial value during the 5 years. In the placebo-treated group, a gradual, steady decrease of about 2% occurred in renal function each year. The difference between the initial and mean fifth-year values was 13% (P < 0.05). The difference between the mean rate of decrease of reciprocal creatinine among the enalapril- and the placebo-treated groups became significant after the second year. These data are shown in Figure 2 and are outlined in the Appendix Table. Figure 2. Reciprocal creatinine (100/cr) levels expressed as percentage of initial value, during 5 years of follow-up in placebo-and enalapril-treated type II diabetics. P P The mean blood pressure in the enalapril-treated patients decreased slightly from an initial value of 99 mm Hg to 96 mm Hg during the first year

Use of Enalapril To Attenuate Decline in Renal Function in Normotensive, Normoalbuminuric Patients with Type 2 Diabetes Mellitus: A Randomized, Controlled Trial

The concept of microalbuminuria has had a major impact on diabetes research and clinical care of patients with diabetes [1-5]. Initial albuminuria is regarded by most researchers as an independent predictor of subsequent progression of nephropathy and risk for cardiovascular morbidity and mortality [6-8]. Angiotensin-converting enzyme (ACE) inhibitors have been found to attenuate progression of nephropathy in both types of diabetes in hypertensive [9-12] and normotensive patients [13-15] with microalbuminuria. They were also found to lower urinary albumin excretion in normotensive and normoalbuminuric patients with type 1 diabetes [16]. The relation between albuminuria and later progression of nephropathy in these patients has not been established, possibly because of short follow-up periods. No data are available on the effect of early introduction of ACE inhibitors in normotensive and normoalbuminuric patients with type 2 diabetes mellitus. We designed a randomized, double-blind, placebo-controlled trial of the effect of ACE inhibition on the course of nephropathy in 156 patients with type 2 diabetes. These patients had normal blood pressure and normal urinary albumin excretion at baseline. Methods Patients Potential candidates were identified through the computerized records of the central regional laboratory for the northern part of the greater Tel-Aviv area. Persons with hyperglycemia and normal urinalysis results were located through their family physicians. Consent was sought once eligibility was established. Inclusion criteria were age younger than 60 years; age 40 years or older at diagnosis; duration of diabetes mellitus less than 10 years with no clinical evidence of malignant, autoimmune, hepatic, cardiovascular, or renal disease; body mass index less than 30 kg/m2; normal blood pressure on at least two consecutive visits (systolic pressure 140 mm Hg and diastolic pressure 90 mm Hg; mean pressure 107 mm Hg); serum creatinine concentration of 123 mol/L or less; and urinary albumin excretion of 30 mg/24 h or less. All baseline data were obtained twice during the run-in prerandomization period. Patients were eligible only if values within the predetermined range were found on both examinations. The average of the values was used as the baseline value. A total of 255 patients who had type 2 diabetes according to World Health Organization criteria [17] and attended one of eight clinics in the greater Tel-Aviv area were found to be eligible and were contacted during 1990 and 1991. Of these patients, 214 gave informed consent to participate. Twenty patients were excluded during the observation period: Six had blood pressure values above normal, 5 had microalbuminuria, 3 had serum creatinine concentrations above the trial criterion, 1 patient developed unstable angina pectoris, and 5 withdrew consent. Of the 194 patients included in the study, 102 were women and 92 were men (mean age SD, 54.9 3.2 years [range, 37 to 59 years]). The known duration of diabetes was 0 to 9 years (mean duration, 5.75 2.8 years). Patients were instructed to use the standard isocaloric diet recommended by the Israeli Diabetic Association, and 69 study patients used diet alone to control their hyperglycemia. Pharmacologic therapy for diabetes was insulin in 34 patients and oral hypoglycemic agents in 91 patients. Protocol The protocol was approved by the hospital review board. After a 2-month observation period, patients were randomly assigned in a double-blind manner to receive enalapril (Assia-Riezel Ltd., Ramat-Gan, Israel), 10 mg/d, or placebo. Ninety-seven patients were assigned to receive enalapril, and 97 were assigned to receive placebo. Randomization was done centrally by telephone with a random number table [18]. Patient allocation to placebo or enalapril was recorded and kept by one of the authors. The placebo tablets were similar in appearance to the enalapril tablets. The medications, which came in sealed, numbered packages, were centrally prepared and were given to the patients at each visit by one nurse who was otherwise not involved in the study. Patients were followed by their family physicians, who were unaware of allocation. Two semiannual prescheduled visits took place each year, and interim visits were scheduled as clinically indicated. At the semiannual visits, hemoglobin A1c values, serum creatinine concentrations, serum electrolyte levels, and 24-hour albumin excretion and urinary creatinine concentrations were measured. Blood pressure was measured by the physicians twice at each visit by using mercury sphygmomanometers with the patients seated after a 5-minute rest; physicians recorded the average of the two values. The diastolic pressure was determined at Korotkoff phase V. If a systolic blood pressure of 145 mm Hg or more or a diastolic blood pressure of 95 mm Hg or more was found, measurements were repeated weekly. If elevated values persisted on two consecutive visits, a long-acting calcium-channel blocker (diltiazem or verapamil), hydrochlorothiazide, or both were administered. If systolic blood pressure values of 100 mm Hg or less were repeatedly found, the enalapril dosage was reduced to 5 mg/d (half of a 10-mg enalapril tablet or half of a placebo tablet). Fundoscopy was done yearly by an ophthalmologist, and the presence of retinopathy was recorded. For each patient, follow-up was terminated 6 years after randomization. Measurements All blood and urine samples were examined by a central laboratory. Assays were not changed during the study period. Glycosylated hemoglobin values were measured by affinity chromatography with a commercial kit (Isolab, Biochemical Methodology, Akron, Ohio). The normal range of this assay is a hemoglobin A1c value of 3.5% to 5.6% and an intra-assay and interassay coefficient of variability of less than 3%. Urinary albumin concentration was measured twice in 24-hour urine samples by an automated immunoturbidimetric method [19]. This procedure has intra-assay and interassay coefficients of variability of 5.9% and 7.6%, respectively. Creatinine concentrations were determined by using the automated method of Bartels and colleagues [20]. Creatinine clearance, normalized for 1.73 m2 of body surface area, was calculated for each visit by using the standard formula (urine creatinine x urine volume/plasma creatinine). The mean blood pressure (defined as the diastolic pressure plus one third of the pulse pressure) was calculated at each visit. Statistical Analysis Data are expressed as the mean (SD) with ranges. A P value less than 0.05 was considered significant. On the basis of the assumptions that 15% of normotensive, normoalbuminuric patients with type 2 diabetes will develop microalbuminuria during 6 years and that treatment with enalapril will reduce the risk for microalbuminuria by 12%, we calculated that 69 patients were required in each group for a type 1 error of 0.05 and a power of 0.80 [21]. To test for adequate randomization and to compare the patients who completed the trial with those who did not complete the trial, the enalapril and placebo groups and the 38 patients who dropped out were compared for mean age; mean duration of diabetes; and mean baseline albumin excretion, creatinine clearance, glycosylated hemoglobin value, and blood pressure by using pooled-variance Student t-tests for independent groups and one-way analysis of variance. To compare the annual means of the various measurements between the two groups and within each group, one between-group factor and one repeated-measures factor were used in analysis of variance. For variables shown to be different by analysis of variance, unpaired t-tests were used for between-group parallel annual means and paired t-tests were used for comparison of intragroup sequential annual means. The rate of decrease of creatinine clearance and the rate of increase of albumin excretion were computed by doing linear regression analysis with all of the semiannual values included in the equation. Urinary albumin values were logarithmically transformed before analysis. The degree of albuminuria at baseline was used as a covariate. The funding source had no involvement in the design, conduct, or reporting of the trial. Results Figure 1 shows the flow of participants during the trial. Thirty-eight patients did not complete the trial. Five patients died (3 in the enalapril group and 2 in the placebo group); death was related to coronary heart disease in 3 patients, stroke in 1 patient, and ovarian carcinoma in 1 patient. Six patients violated the protocol (2 patients in the enalapril group stopped taking their medication for more than 6 months, and 4 patients in the placebo group took an ACE inhibitor prescribed by consultant physicians for more than 6 months). Ten patients were lost to follow-up (6 in the enalapril group and 4 in the placebo group). The trial medication was discontinued in 12 patients: Six developed a disturbing cough (4 in the enalapril group and 2 in the placebo group), 4 had an allergic skin reaction (2 in the enalapril group and 2 in the placebo group), 1 patient in the enalapril group developed leukopenia, and 1 patient in the placebo group developed hyperkalemia. Finally, 5 patients developed severe urinary tract infections that had a detectable influence on renal function (2 in the enalapril group and 3 in the placebo group). A total of 156 patients completed the trial, of whom 77 received enalapril and 79 received placebo. Figure 1. Flow of participants through the trial. Baseline data for the two groups and for patients who did not complete the trial are shown in Table 1. The baseline characteristics of patients in the study groups and those who dropped out did not differ significantly. A modest but steady decrease in hemoglobin A1c values was seen in the enalapril and the placebo groups and may reflect the change in attitude toward glucose control among family physicians in the early 1990s. However, t

Treatment of High-Risk Patients with Diabetes: Motivation and Teaching Intervention: A Randomized, Prospective 8-Year Follow-Up Study

The aim of this study was to examine whether motivating patients to gain expertise and closely follow their risk parameters will attenuate the course of microvascular and cardiovascular sequelae of diabetes. A randomized, prospective study was conducted of 165 patients who had type 2 diabetes, hypertension, and hyperlipidemia and were referred for consultation to a diabetes clinic in an academic hospital. Patients were randomly allocated to standard consultation (SC) or to a patient participation (PP) program. Both groups were followed by their primary care physicians. The mean follow-up was 7.7 yr. The SC group attended eight annual consultations. The PP patients initiated on average one additional consultation per year. There were 80 cardiovascular events (eight deaths) in the SC group versus 47 events (five deaths) in the PP group (P = 0.001). The relative risk (RR) over 8 yr for a cardiovascular event in the intervention (PP) versus the control (SC) group was 0.65 (95% confidence interval, 0.89 to 0.41). There were 17 and eight cases of stroke in the SC and PP groups, respectively (P = 0.05). RR for stroke was 0.47 (95% confidence interval, 0.85 to 0.32). In the SC group, 14 patients developed overt nephropathy (four ESRD) versus seven (one ESRD) in the PP group (P = 0.05). Throughout the study period, BP, LDL cholesterol, and hemoglobin A1c were significantly lower in the PP than in the SC patients. Well informed and motivated patients were more successful in obtaining and maintaining good control of their risk factors, resulting in reduced cardiovascular risk and slower progression of microvascular disease.

Monitoring Kidney Function and Albuminuria in Patients With Diabetes

It is beyond doubt that patients with diabetes are at high risk of developing renal and cardiovascular disease. Both outcomes have significant clinical implications and are associated with high additional costs. Several traditional (blood pressure, HbA1c, cholesterol) and novel cardiovascular biomarkers (C-reactive protein, pro-brain natriuretic peptide) are at hand to identify those individuals who will develop end-stage renal or cardiovascular disease, as early as possible. The traditional biomarkers have been successfully applied in clinical practice and have proven their clinical usefulness. Renal biomarkers, in particular, albuminuria and estimated glomerular filtration rate (eGFR), have been added to the biomarker armamentarium. Both are indeed associated with renal and cardiovascular disease in individuals with diabetes and may be used to identify individuals at risk of long-term complications. Although identifying individuals at risk is important, even more important is the question whether we can lower this risk by changing renal biomarkers through pharmacological (or other) intervention. This overview describes the performance of albuminuria and eGFR in predicting renal and cardiovascular disease. In the second part, the relationship between treatment-induced changes in these two renal biomarkers and renal and cardiovascular outcome will be described.nn### AlbuminuriannThe relationship between albuminuria and renal and cardiovascular disease has been well established. Its association was first described in patients with type 1 diabetes (1,2). Several studies followed these initial reports and confirmed the significance of albuminuria in predicting long-term renal prognosis. Data from prospective trials showed that patients with type 2 diabetes appear to progress from micro- to macroalbuminuria to end-stage renal disease (ESRD), similar to the earlier reports of patients with type 1 diabetes. The Reduction in End Points in Non-Insulin Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan (RENAAL) showed that albuminuria is the most critical baseline predictor for ESRD (3). Similar data …

Use of a mild sedative helps to identify true non-dippers by ABPM: a study in patients with diabetes mellitus and hypertension.

BackgroundThe interplay between the continuity or quality of sleep and diurnal variation in blood pressure has not been directly examined before. We examined the influence of a mild, non-hypotensive sedative on nocturnal dipping. DesignThis was a randomized, single-blind study. SettingThe study took place in an out-patient clinic in an academic hospital. InterventionZolpidem 10u2009mg or placebo was given randomly for the first or second night, and ambulatory blood pressure monitoring was instigated for 48u2009h. PatientsThe populuation under study comprised 96 male patients with type 2 diabetes mellitus and hypertension (mean age 54±6 years, mean blood pressure 158/94±9/6u2009mmHg). Main outcome measureNocturnal dipping (nocturnal blood pressure ≥10% lower than daytime pressure) was found in 71% of the patients taking the sedative compared with 27% of those on placebo (P=0.001). ResultsOn placebo, non-dippers and dippers had similar profiles of cardiovascular risk parameters. In contrast, non-dippers taking zolpidem had significantly higher values for most cardiovascular risk parameters compared with dippers: higher systolic blood pressure, higher low-density lipoproteins, lower high-density lipoproteins, higher serum creatinine, a higher urinary albuminu2009:u2009creatinine ratio, higher serum insulin and insulin resistance. ConclusionThe use of a mild sedative during ambulatory blood pressure monitoring may help to identify the patients with a very high cardiovascular risk. These are the patients with a blunted nocturnal hypotension despite sedation.

Late doxorubicin cardiotoxicity.

The occurrence of late congestive heart failure (CHF) as the first clinical manifestation of doxorubicin-induced cardiac toxicity is unusual in children and very rare in adults. However, subclinical cardiac dysfunction is commonly detected in children years after treatment with doxorubicin containing regimens. We report a 58 year old woman who developed stage IV CHF 7 years after completion of doxorubicin treatment for carcinoma of the ovary. Occult cardiac dysfunction was first demonstrated by radionuclide angiography 6 years prior to the occurrence of the clinical manifestations. This unique course of the disease and the management of the CHF are discussed.

Treatment of Diabetic Perforating Ulcers (Mal Perforant) with Local Dimethylsulfoxide

Perforating foot ulcers constitute a major problem in diabetics with peripheral neuropathy for which no specific therapy is available. Twenty patients with chronic, resistant mal perforant were treated by local application of dimethylsulfoxide (DMSO) solution. Complete healing of the ulcers was achieved in 14 patients following 4–15 weeks of daily treatment. Partial resolution was observed in another four patients, and in the remaining two there was no effect. A control group, equal in number, was treated conventionally. Complete healing of the ulcers took place in only two patients. The therapeutic effect of DMSO most probably results from an increase in tissue oxygen saturation via a combined mechanism of local vasodilatation, decreased thrombocyte aggregation, and increased oxygen diffusion. Local DMSO is effective, simple, devoid of systemic side effects, and inexpensive. It should be employed for diabetic foot ulcers prior to the consideration of surgical measures. J Am Geriatr Soc 33:41, 1985

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.

Agranulocytosis Associated with Enalapril

An 83-year-old patient developed agranulocytosis following six months of enalapril 10 mg/d. The patient also had received verapamil for three years. Upon discontinuation of both drugs the white blood cell count was rapidly restored. Cases of agranulocytosis due to angiotensin-converting enzyme inhibitors, mainly captopril, have been previously described. We could, however, find no single case associated with verapamil. This, and the very long exposure of the patient to verapamil, support the assumption that this life-threatening complication might have been caused by enalapril.

Dual Blockade of the Renin-Angiotensin System in Diabetic Nephropathy

The accelerated progression of atherosclerosis in diabetes is most probably the end result of the cumulative impact of the major risk factors that are more prevalent in diabetic subjects, namely obesity and dyslipidemia, the derangement in carbohydrate metabolism (hyperglycemic environment, hyperinsulinism, and insulin resistance), a prothrombotic tendency, and, perhaps most important, microalbuminuria and hypertension (1–5). At least two additional cardiovascular risk factors are probably more pronounced in diabetes; they are endothelial dysfunction (6) and an inflammatory reaction in the affected blood vessels mediated by the proinflammatory interleukins and expressed by elevated levels of C-reactive protein (7).nnMicroalbuminuria is often the first clinical manifestation of early microvascular derangement. In type 2 diabetes, it is the hallmark of subsequent diabetic nephropathy and a surrogate marker of cardiovascular disease and increased cardiovascular mortality (8). Furthermore, the presence of microalbuminuria predicts a worse outcome after percutaneous coronary intervention. The 2-year mortality after percutaneous coronary intervention in diabetic patients with microalbuminuria was increased by 85% compared with individuals with normal urinary albumin excretion (9). Microalbuminuria is associated with echocardiographic evidence of left ventricular hypertrophy and identifies overall cardiovascular risk also in hypertensive nondiabetic patients (10,11). It is therefore mandatory to screen all diabetic as well as nondiabetic hypertensive patients for the presence of microalbuminuria. Indeed, all the relevant professional associations have included annual screening for microalbuminuria in their recommendations (12,13). Treatment strategies aimed at reducing urinary albumin excretion were found to be effective in retarding the progression of renal disease, as manifested by prolongation of the time to doubling of serum creatinine and postponement of end-stage renal disease and the need to renal replacement therapy (14–17).nnFurthermore, the magnitude of early decline in albuminuria in response to a given therapeutic intervention is a reliable predictor …