Background Renal function declines progressively in patients who have diabetic nephropathy, and the decline may be slowed by antihypertensive drugs The purpose of this study was to determine whether captopril has kidney-protecting properties independent of its effect on blood pressure in diabetic nephropathy Methods We performed a randomized, controlled trial comparing captopril with placebo in patients with insulin-dependent diabetes mellitus in whom urinary protein excretion was > or = 500 mg per day and the serum creatinine concentration was Results Two hundred seven patients received captopril, and 202 placebo Serum creatinine concentrations doubled in 25 patients in the captopril group, as compared with 43 patients in the placebo group (P = 0007) The associated reductions in risk of a doubling of the serum creatinine concentration were 48 percent in the captopril group as a whole, 76 percent in the subgroup with a baseline serum creatinine concentration of 20 mg per deciliter (177 mumol per liter), 55 percent in the subgroup with a concentration of 15 mg per deciliter (133 mumol per liter), and 17 percent in the subgroup with a concentration of 10 mg per deciliter (884 mumol per liter) The mean (+/- SD) rate of decline in creatinine clearance was 11 +/- 21 percent per year in the captopril group and 17 +/- 20 percent per year in the placebo group (P = 003) Among the patients whose base-line serum creatinine concentration was > or = 15 mg per deciliter, creatinine clearance declined at a rate of 23 +/- 25 percent per year in the captopril group and at a rate of 37 +/- 25 percent per year in the placebo group (P = 001) Captopril treatment was associated with a 50 percent reduction in the risk of the combined end points of death, dialysis, and transplantation that was independent of the small disparity in blood pressure between the groups Conclusions Captopril protects against deterioration in renal function in insulin-dependent diabetic nephropathy and is significantly more effective than blood-pressure control alone

The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The collaborative study group

Background Renal function declines progressively in patients who have diabetic nephropathy, and the decline may be slowed by antihypertensive drugs. The purpose of this study was to determine whether captopril has kidney-protecting properties independent of its effect on blood pressure in diabetic nephropathy. Methods We performed a randomized, controlled trial comparing captopril with placebo in patients with insulin-dependent diabetes mellitus in whom urinary protein excretion was ≥ 500 mg per day and the serum creatinine concentration was ≤ 2.5 mg per deciliter (221 μmol per liter). Blood-pressure goals were defined to achieve control during a median follow-up of three years. The primary end point was a doubling of the base-line serum creatinine concentration. Results Two hundred seven patients received captopril, and 202 placebo. Serum creatinine concentrations doubled in 25 patients in the captopril group, as compared with 43 patients in the placebo group (P =0.007). The associated reductions in risk...

https://www.nejm.org/doi/pdf/10.1056/NEJM199311113292004

The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy.

Objective: To determine whether tight control of blood pressure with either a beta blocker or an angiotensin converting enzyme inhibitor has a specific advantage or disadvantage in preventing the macrovascular and microvascular complications of type 2 diabetes. Design: Randomised controlled trial comparing an angiotensin converting enzyme inhibitor (captopril) with a beta blocker (atenolol) in patients with type 2 diabetes aiming at a blood pressure of < 150/ < 85 mm Hg. Setting 20 hospital based clinics in England, Scotland, and Northern Ireland. Subjects: 1148 hypertensive patients with type 2 diabetes(mean age 56 years, mean blood pressure 160/94 mm Hg). Of the 758 patients allocated to tight control of blood pressure, 400 were allocated to captopril and 358 to atenolol. 390 patients were allocated to less tight control of blood pressure. Main outcome measures: Predefined clinical end points, fatal and non-fatal, related to diabetes, death related to diabetes, and all cause mortality. Surrogate measures of microvascular and macrovascular disease included urinary albumin excretion and retinopathy assessed by retinal photography. Results: Captopril and atenolol were equally effective in reducing blood pressure to a mean of 144/83 mm Hg and 143/81 mm Hg respectively, with a similar proportion of patients (27% and 31%) requiring three or more antihypertensive treatments. More patients in the captopril group than the atenolol group took the allocated treatment: at their last clinic visit, 78% of those allocated captopril and 65% of those allocated atenolol were taking the drug (P < 0.0001). Captopril and atenolol were equally effective in reducing the risk of macrovascular end points. Similar proportions of patients in the true groups showed deterioration in retinopathy by two grades after nine years (31% in the captopril group and 37% in the atenolol group) and developed clinical grade albuminuria greater than or equal to 300 mg/l (5% and 9%). The proportion of patients with hypoglycaemic attacks was not different between groups, but mean weight gain in the atenolol group was greater (3.4 kg v 1.6 kg). Conclusion: Blood pressure lowering with captopril or atenolol was similarly effective in reducing the incidence of diabetic complications. This study provided no evidence that either drug has any specific beneficial or deleterious effect, suggesting that blood pressure reduction in itself may be more important than the treatment used.

Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39

Diabetes mellitus is a disease of metabolic dysregulation, most notably abnormal glucose metabolism, accompanied by characteristic long-term complications. The complications that are specific to diabetes include retinopathy, nephropathy, and neuropathy. Patients with all forms of diabetes of sufficient duration, including insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM), are vulnerable to these complications, which cause serious morbidity (Table 1 and Table 2). Retinopathy is so characteristic of diabetes that its presence has been incorporated into the nosologic definition of NIDDM. Only hyperglycemia of sufficient magnitude to be associated with retinopathy is classified as NIDDM, while lower levels of hyperglycemia that are . . .

Long-term complications of diabetes mellitus

Background Treatment of hypertension with diuretics, beta-blockers, or both leads to improved outcomes. It has been postulated that agents that inhibit the renin–angiotensin system confer benefit beyond the reduction of blood pressure alone. We compared the outcomes in older subjects with hypertension who were treated with angiotensin-converting–enzyme (ACE) inhibitors with the outcomes in those treated with diuretic agents. Methods We conducted a prospective, randomized, open-label study with blinded assessment of end points in 6083 subjects with hypertension who were 65 to 84 years of age and received health care at 1594 family practices. Subjects were followed for a median of 4.1 years, and the total numbers of cardiovascular events in the two treatment groups were compared with the use of multivariate proportional-hazards models. Results At base line, the treatment groups were well matched in terms of age, sex, and blood pressure. By the end of the study, blood pressure had decreased to a similar exte...

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A Comparison of Outcomes With Angiotensin-Converting--Enzyme Inhibitors and Diuretics for Hypertension in the Elderly

STUDY OBJECTIVE--To assess the effectiveness of inhibition of angiotensin converting enzyme in preventing diabetic nephropathy. DESIGN--Randomised follow up study of normotensive diabetics with persistent microalbuminuria (30-300 mg/24 hours) treated with enalapril or its matched placebo for one year. Double blind for first six months, single blind for last six months. SETTING--Diabetic clinic in tertiary referral centre. PATIENTS--Treatment group and placebo group each comprised 10 normotensive diabetics with persistent microalbuminuria. INTERVENTIONS--Treatment group was given enalapril 20 mg daily and controls matched placebo. Patients were given antihypertensive treatment after one year. END POINT--Albumin excretion, arterial pressure, and renal function. MAIN RESULTS--In last three months of trial three of 10 patients taking placebo had diabetic nephropathy (albumin excretion greater than 300 mg/24 hours). No patients taking enalapril developed nephropathy and five showed normal albumin excretion (less than 30 mg/24 hours) (p = 0.005, Mann-Whitney test). Mean arterial pressure was reduced by enalapril throughout study (p less than 0.005) but increased linearly with placebo (p less than 0.05). Albumin excretion decreased linearly with enalapril but not placebo. An increase in albumin excretion with placebo was positively related to the increase in mean arterial pressure (r = 0.709, p less than 0.05, Spearman's rank test). With enalapril total renal resistances and fractional albumin clearances improved progressively (time effect, p = 0.0001). CONCLUSION--Inhibition of angiotensin converting enzyme prevents development of nephropathy in normotensive diabetics with persistent microalbuminuria. This may be due to reduction in intraglomerular pressure and to prevention of increased systemic blood pressure. Future studies should compare long term effects of inhibitors of converting enzyme with other antihypertensive drugs.

https://www.bmj.com/content/bmj/297/6656/1092.full.pdf

Prevention of diabetic nephropathy with enalapril in normotensive diabetics with microalbuminuria.

The effects of a long term reduction in blood pressure on the kidney function of normotensive diabetic patients who had persistent microalbuminuria (30-300 mg albumin/24 hours) were studied in two groups of 10 such patients before and during six months of treatment with either 20 mg enalapril or placebo daily. Treatments were assigned randomly in a double blind fashion. Before treatment both groups had similar clinical characteristics, weight, diet, total glycosylated haemoglobin, median albumin excretion rate (enalapril group 124 mg/24 h, placebo group 81 mg/24 h), and mean arterial pressure (enalapril group 100 (SD 8) mm Hg, placebo group 99 (6) mm Hg). During treatment weight, urinary urea excretion, and total glycosylated haemoglobin remained unchanged. The mean arterial pressure decreased in the enalapril group but not in the placebo group (enalapril group 90 (10) mm Hg, placebo group 98 (8) mm Hg). The median albumin excretion rate also fell in the enalapril group but not in the placebo group (enalapril group 37 mg/24 h, placebo group 183 mg/24 h.) The glomerular filtration rate rose in the enalapril group from 130 (23) ml/min/1.73 m2 to 141 (24) ml/min/1.73 m2, and total renal resistances and fractional albumin clearance decreased while fractional albumin clearance increased in the placebo group. These results show that in patients who have diabetes but not hypertension a reduction in blood pressure by inhibition of converting enzyme for six months can reduce persistent microalbuminuria, perhaps by decreasing the intraglomerular pressure.

Converting enzyme inhibition and kidney function in normotensive diabetic patients with persistent microalbuminuria.

Coronary artery disease may be difficult to detect in diabetic patients. This study was designed to determine the specificity and sensitivity of three non-invasive tests. Accordingly, the results of 48-h ambulatory electrocardiogram (ECG) monitoring, maximal ECG exercise test, and intravenous dipyridamole myocardial thallium scintigraphy were compared in 59 middle-aged diabetic patients who were consecutively selected for suspected coronary artery disease. All patients also underwent coronary angiography, which was performed regardless of the results of the non-invasive tests. Twenty patients (34%) had significant coronary lesions, i.e. stenosis equal to or greater than 70%, and 16 of these 20 patients (80%) had double or triple vessel disease. Sensitivity and specificity were, respectively, 25% and 88% for ambulatory ECG monitoring, 75% and 77% for the exercise test and 80% and 87% for thallium myocardial scintigraphy. This observation strongly supports the use of non-invasive tests for the detection of coronary artery disease in those diabetic patients at high risk of such disease. As the exercise test is cheaper and more widely available than thallium myocardial scintigraphy it should be used as a first line examination. Dipyridamole myocardial scintigraphy may provide an alternative solution for those patients who cannot perform maximal exercise, or with atypical clinical presentation.

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Detection of coronary artery disease in diabetic patients.

The antihypertensive efficacy of enalapril and its effects on the metabolism and kidney function were investigated in 11 insulin-dependent diabetic subjects with uncomplicated mild to moderate hypertension. During a short-term single-blind controlled trial, one daily dose of 20 or 40 mg enalapril significantly reduced both systolic and diastolic blood pressure. In the supine position, mean systolic blood pressure declined from 169 ± 6 to 142 ± 6 mmHg ( P P During 1 yr of treatment, the antihypertensive efficacy of enalapril did not decline,and no clinical side effects were observed. Inhibition by enalapril of angiotensin-converting enzyme did not modify daily insulin requirements, glycemic control, uricemia, or lipid metabolism; kalemia and the markers of diabetic nephropathy were not significantly altered. These results suggest that enalapril once daily should be used as the first step inthe treatment of diabetic patients with mild to moderate hypertension.

Effects of enalapril in insulin-dependent diabetic subjects with mild to moderate uncomplicated hypertension.

Blood glucose levels were compared in eight type I diabetic subjects who were given closed-loop infusions of insulin by intraperitoneal (i.p.) and intravenous (i.v.) routes, in a cross-over randomized study. After a test meal, plasma glucose peaks were significantly higher with i.p. than with i.v. infusion (174 ± 22 versus 129 ± 29 mg/dl) and marked hypoglycemia occurred after 180 min in five of eight subjects. These observations appear to be the consequence of a 60-min lag in insulin rise with i.p. administration. Because of this difference in plasma glucose rise, twice as much insulin was administered i.p. than with i.v. Plasma insulin rose to similar values in both cases. Therefore, with present closed-loop systems, i.p. insulin infusion does not lead to better control of glucose levels than i.v. infusion and does not prevent hyperinsulinism. Adjustments of the artificial B-cell algorithms and the injection of a bolus dose must be tested so that the potential advantages of the i.p. route may be achieved.

H. Leblanc

Papers

Prevention of diabetic nephropathy with enalapril in normotensive diabetics with microalbuminuria.

Converting enzyme inhibition and kidney function in normotensive diabetic patients with persistent microalbuminuria.

Detection of coronary artery disease in diabetic patients.

Effects of enalapril in insulin-dependent diabetic subjects with mild to moderate uncomplicated hypertension.

Glycemic Control with Closed-Loop Intraperitoneal Insulin in Type I Diabetes