Rita Rachmani

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

The effect of spironolactone, cilazapril and their combination on albuminuria in patients with hypertension and diabetic nephropathy is independent of blood pressure reduction: a randomized controlled study

Objective  The effect of spironolactone, cilazapril and their combination on albuminuria was examined in a randomized prospective study in female patients with diabetes and hypertension.

Metformin in patients with type 2 diabetes mellitus: reconsideration of traditional contraindications

BACKGROUND: The strict limiting criteria for the use of metformin in diabetes mellitus stem largely from reports, in the 1970s, of mortality and lactic acidosis associated with phenformin. Data about metformin are less clear and are based mainly on case reports. The aim of this study was to evaluate the safety of continued use of metformin in patients with contraindications to this agent. PATIENTS: Some 393 patients with type 2 diabetes mellitus (serum creatinine 130-220 &mgr;mol/l) were studied. Among them were 266 patients with coronary heart disease (CHD), 94 with congestive heart failure (CHF), and 91 with chronic obstructive pulmonary disease (COPD), all of whom had been treated with metformin. The patients were randomized to either continue or to stop metformin and were then followed for 4 years. RESULTS: Analysis was by intention-to-treat. The patients who stopped taking metformin showed a rise in body mass index and in hemoglobin A1c significantly greater than those who continued the drug. There were no cases of lactic acidosis. Lactic acid values did not differ in the two groups and correlated only with serum creatinine and body mass index. Microvascular diabetic complications, cardiovascular events, and cardiovascular and total mortality were identical in the two groups. CONCLUSIONS: Diabetic patients who are treated with metformin and who tolerate the drug well may continue taking it, even when mild renal impairment develops, possibly up to serum creatinine levels of 220 &mgr;mol/l. There is also no apparent reason why patients with CHD, CHF, and COPD should discontinue metformin.

Teaching patients to monitor their risk factors retards the progression of vascular complications in high-risk patients with Type 2 diabetes mellitus—a randomized prospective study

Aims Intensive management of risk parameters in diabetic patients may retard the progression of both micro‐ and macrovascular complications. Intensified care requires expert staff and is expensive. The aim of the present study was to examine whether sharing the therapeutic responsibility with the patients will improve the outcome.

Considerations about the threshold value of microalbuminuria in patients with diabetes mellitus: lessons from an 8-year follow-up study of 599 patients

OBJECTIVE To examine the validity of the time honored threshold value for microalbuminuria of 30 mg/24 h, by analyzing an 8-year follow-up data of 599 patients with diabetes mellitus type 2, normal blood pressure and base-line albumin excretion rate (AER) </=30 mg/24 h. PATIENTS The patients were allocated to three groups according to the baseline values of AER. Group I: 0-10 mg/24 h; Group II: 10.1-20 mg/24 h; Group III: 20.1-30 mg/24 h. RESULTS Progression to microalbuminuria during follow-up occurred in 25.3, 47.3 and 85.3% of the patients in Group I, II and III, respectively. Compared to Group I, the risk to progress to microalbuminuria was 2. 34 (95% CI 1.32-4.43, P=0.029) in patients of Group II and 12.36 (95% CI 8.9-16.5, P=0.0001) in Group III. The average annual decline in glomerular filtration rate (GFR) was 1.19, 1.64 and 2.52 ml/min per year, respectively in the three groups. The correlation between baseline AER values and subsequent decline in GFR was exponential without a clear threshold value. Compared to Group I, the odds ratio for any cardiovascular end point (e.g. death, non-fatal myocardial infarction etc.) was 1.9 (95% CI 0.8-2.5, P=0.22) for patients of Group II and 9.8 (95% CI 6.7-12.3, P=0.001) for Group III. CONCLUSIONS The present study shows that patients with baseline AER values of 20.1-30 mg/24 h show an accelerated decline in GFR and significantly higher risk for cardiovascular events than patients with AER values below 20 mg/24 h. Though AER is obviously a continuous variable, the arbitrary threshold value for screening and for preventive strategies should probably be set at 20 rather than at 30 mg/24 h.

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.

Losartan and lercanidipine attenuate low‐density lipoprotein oxidation in patients with hypertension and type 2 diabetes mellitus: A randomized, prospective crossover study

Lipoprotein oxidation, dyslipidemia, and hypertension are important underlying causes of accelerated atherosclerosis in patients with diabetes mellitus. The potential of antihypertensive medications to reduce lipid oxidation is, therefore, an important determinant in the choice of agents for patients with diabetes mellitus. The aim of this study was to compare the lowering effect of a new dihydropyridine calcium antagonist, lercanidipine, with that of the first angiotensin‐receptor blocker, losartan, on low‐density lipoprotein (LDL) oxidation.

Effect of an α-Adrenergic Blocker, and ACE Inhibitor and Hydrochlorothiazide on Blood Pressure and on Renal Function in Type 2 Diabetic Patients with Hypertension and Albuminuria

α-Adrenergic blockers are potential alternative antihypertensive agents for diabetic patients. Data on their relative efficacy and their effect on kidney function and albuminuria are very limited however. 76 patients with diabetes type 2, hypertension (≧140/90 mm Hg) and albuminuria (≧30 mg/24 h) were randomized into three groups to receive cilazapril (2.5–10 mg), doxazosin (2–8 mg) or both. Patients of the first and second groups received a single agent for 4 months, the agents were then crossed for an additional period of 4 months followed by the addition of hydrochlorothiazide (25 mg) for a third 4-month period. Blood pressure was monitored monthly, creatinine clearance and HbA1c were measured before and at the end of each treatment period. Patients of the third group received reduced doses of cilazapril and doxazosin for 4 months. Hydrochlorothiazide was then added for the subsequent 4 months. There was a significant decline in blood pressure values during the first period in all groups. Cilazapril: systolic blood pressure (SBP) 160 ± 6 to 149 ± 5 mm Hg; diastolic blood pressure (DBP): 101 ± 3 to 94 ± 3 mm Hg (p = 0.001). Albuminuria declined from 350 ± 105 to 205 ± 96 mg/24 h (p = 0.001), creatinine clearance (CrCl) was unchanged. Doxazosin: SBP: 160 ± 7 to 151 ± 6 mm Hg; DBP: 97 ± 4 to 90 ± 4 mm Hg (p = 0.001). Albuminuria 373 ± 121 to 322 ± 107 mg/24 h (p = 0.065) and CrCl 87 ± 7 to 91 ± 6 ml/min. The combination of both agents at half doses was equipotent or superior to either drug alone. Cross-over of cilazapril and doxazosin reproduced the hypotensive effect and reversed the antialbuminuric effect. The addition of hydrochlorothiazide resulted in a further decline of 6–14 mm Hg in SBP and 3–11 mm Hg in DPB.

Teaching and motivating patients to control their risk factors retards progression of cardiovascular as well as microvascular sequelae of Type 2 diabetes mellitus— a randomized prospective 8 years follow‐up study

Aims  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.

The effect of acarbose on insulin resistance in obese hypertensive subjects with normal glucose tolerance: a randomized controlled study

Aim:  Acarbose, a glucose oxidase inhibitor, delays the absorption of glucose thus reducing post‐prandial blood glucose level, haemoglobin A1c (HbA1c) and insulin resistance in patients with diabetes mellitus and in subjects with impaired glucose tolerance. The effect of acarbose in subjects with normal glucose tolerance (NGT) has hitherto not been examined. The aim of the present study was to examine the effect of acarbose in obese hypertensive subjects with NGT.