Combining Antihypertensive Agents in Early Diabetic Nephropathy

C.K. Christensen, MD

M.M. Pedersen, MD

C.E. Mogensen, MD

Second University Clinic of Internal Medicine,

Aarhus Kommunehospital, DK-8000 Aarhus C, Denmark

Reprint requests: C.K. Christensen, Second University Clinic of Internal Medicine, Aarhus Kommunehospital, DK-8000 Aarhus C, Den- mark.

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Antihypertensive treatment induces a fall in urinary protein and albumin excretion in insulin-dependent diabetic (IDDM) patients with both incipient,‘s2 and overt nephropathy. 3r4 These observations indicate that protein excretion in some way reflects the level of the systemic blood pressure, probably via parallel changes in intraglomerular pressure. Accordingly, antihypertensive agents may reduce high intraglomerular pressure during exercise in patients with diabetic nephropathy. 5,6 More importantly, clinical studies have shown that antihypertensive treatment can reduce the rate of fall in GFR consider- ably in the overt stage of diabetic nephropathy,3s4 and even more optimistic results have been published in diabetics with incipient nephropathy.‘v2

ACE inhibitors have been shown to have a beneficial effect on kidney function both in the early2s6 and more advanced stages of diabetic nephropathy. 7-9 However, studies using ACE inhibitors in combination with selective beta-blockers and diuretics in the early phase of diabetic nephrop- athy has not been performed, but may be rational, since both early cardiac hyperfunction1° and increased extracellular volume” may be present in these patients with abnormal renal hemodynamics.12

We have, therefore, undertaken a triple treatment study adding an ACE inhibitor to a conventional antihypertensive program consisting of a selective beta-blocker and a thiazide diuretic.

INCLUSION CRITERIA, PATIENTS, METHODS, STUDY DESIGN AND STATISTICS

To meet the inclusion criteria, IDDM patients: 1) were undergoing ongoing treatment with a cardioselective beta-blocker (metoprolol) and a thiazide (bendroflumethiazide); 2) had persistently elevated urinary albumin excre- tion, but at levels below 600 pg/min; and 3) were less than 50 years of age. Eight men fulfilled the inclusion criteria and were included in the study. Their clinical data are presented in Table 1; the mean age was 36 years, and mean diabetes duration 26 years.

The test parameters were as follows: 1) blood pressure (measured auscul- tatorily); 2) glomerular filtration rate (GFR) and renal plasma flow (RPF) determined by constant infusion techniques using 1125-iothalamate and V3’- hippuran, respectively, as markers;13 and 3) urinary albumin excretion (UAE) measured from the clearance samples by radioimmunoassay.14 The design was open. Enalapril, 20 mg/day, was added to metoprolol(50-200 mg/24 h) and bendroflumethiazide (2.5-7.5 mg/24 h) during a 6 month period. At this point, enalapril was discontinued and the patients were followed further for 3 months. The doses of metoprolol and bendroflumethiazide were constant for at least 3 months prior to the start of the study and through the observation period. Medication compliance was controlled by contact with the hospital at the start of the study, every week during the first 4 weeks of enalapril, and monthly thereafter.

Parametric statistics were performed and a paired t-test was used. The results are presented as mean 2 SD except for UAE, which is expressed as geometric mean x/k tolerance factor due to log-transformation. Mean blood pressure (MAP) was calculated by adding l/3 of the pulse pressure to the diastolic blood pressure.

RESULTS

Data from the study is presented in Table 2. Good compliance was noted throughout the study, and no side-effects were seen.

MULTIPLEANTIHYPERTENSIVESIN DIABETIC NEPHROPATHY 89

TABLE 1 Clinical Data in Eight IDDM Men with Early Diabetic Nephropathy

Age (yea@

38 f 6

Diabetes Duration

(yea@

26 f 5

HbAlc (Oh)

8.4 * 0.8

Retlnopathy: Background/ Proliferation

6W2P

Insulin Dose (W/kg/24 h)

0.65 f 0.18

Body Mars Index

(kg/m*)

25.5 f 3.4

Blood Pressure Systolic (SBP), diastolic (DBP), and mean (MAP) blood pressure measurements were slightly but insig- nificantly (2p values between 510%) reduced during the period when enalapril was added to the conventional antihy- pertensive treatment with metoprolol and bendroflumethia- zide. After discontinuation of enalapril, blood pressure rose significantly.

Kidney Function Glomerular filtration rate (GFR) was initially slightly but significantly reduced from a mean of 121 ml/min to 113 mllmin. Thereafter, GFR was stable. Renal plasma flow (RPF) did not change during enalapril therapy. A tendency towards a decrease in RPF was seen 3 months after enalapril was stopped, but RPF was otherwise stable.

Urinary Albumin Excretion On enalapril, the urinary albumin excretion rate (UAE) was reduced from 174 to 70 @min. Three months after discontinuation of enalapril, movement toward an increase in UAE was seen; however, the rise was not significant (2p = 8%).

Metabolic Control No changes in HbA,c were seen through- out the study periods when enalapril was added, or thereafter.

DISCUSSION The present study demonstrates that combination therapy with three different antihypertensive agents in relatively low doses can be carried out with good compliance and without side effects. In spite of efficient long-term antihypertensive treatment with a selective beta-blocker and a thiazide (mean MAP below 100 mmHg), UAE was reduced to less than half baseline when enalapril was added. This effect was obtained without significant reduction in MAP, although tendency to-

ward a minor reduction was noted (Table 2). During the addition of enalapril, kidney function was stable apart from an initial small decrease in GFR. RPF was unchanged, and metabolic control was uninfluenced.

The results suggest that ACE inhibition reduces the intra- glomerular pressure, and consequently UAE. Apparently the marked reduction in UAE was not explained by an additional antihypertensive effect of enalaprtl, but may be mediated by intrarenal changes e.g., an altered balance between afferent and efferent arteriolar resistance, or a direct effect on glomer- uli. In diabetic nephropathy the intraglomerular pressure may be increased, reflecting the degree of diabetic renal involve- ment, as well as systemic blood pressure level.

From the literature, the beneficial effect of antihypertensive agents on slowing the progression of diabetic renal disease has appeared, with favourable effects observed for all antihy- pertensive drugs tested. 14,7-s The common denominator for these studies seems to be blood pressure reduction, and not the drug used, although theoretically, advantages, disadvan- tages, and side-effects of different agents may be important.

At present, short-term studies have suggested that both ACE inhibitors and cardioselective beta-blockers combined with diuretics may be useful in slowing the progression of diabetic nephropathy, and a combination of these three agents may be advantageous. The treatment endpoint with respect to blood pressure in young IDDM patients appears to be approximately 13585 mmHg (-MAP = 100 mmHg), as the rate of progression has been shown to be reduced consider- ably when blood pressure was reduced to this level.3-4

It is concluded that ACE inhibitors, added to conventional antihypertensive treatment with selective beta-blockers and a diuretic were well tolerated and had a marked effect on UAE in spite of only minor or no changes in hemodynamic parame- ters. This triple treatment program seems to be a useful and

TABLE 2 Blood Pressures, Kidney Function, Urinary Albumin Excretion, and Metabolic Control in 8 IDDM Patients with Early Nephropathy Throughout the Study

GFR RPF SBP MAP DBP (mllmin11.73 m2) (mllmin11.73 m2) UAE HbAic

(mmHg) (mmHg) (mmHg) n=7 n=7 (pg/min) (Oh) __~_

Before 129 * 11 99f8 84 + 7 121 + 22 460 + 36 174.6x/+2.4 8.4 f 0.8

First 123 i 10 94 * 9 80 i 7 113 i 23’ 450 i 51 106.0x/+2.0 8.6 rt 1.6 3 months

First 123 zt 10 94 f 9 79 + 9 ,i:,:‘, 466 i 56 70.0xk2.3t 9.0 f 1.7 6 months

3 months 135 * 11A 104 i 8~ 88zt77r 116 zt 30 437 f 63 113.5x/+2.0 8.5 f 1.1 Post

A indicates significant difference between first 6 months and 3 months post’ ( A = < 5%). *indicates difference between values before and during addition of enalapril (’ = < 5%; i = < 1%).

CHRISTENSEN ETAL.

rational regimen for preserving kidney function in diabetics

with early nephropathy.

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3. Mogensen CE: Long-term antihypertensive treatment inhibiting progression of diabetic nephropathy. Br Med J 285:885-688, 1982.

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8. Romanelli G, Giustina A, Cimino A, et al: Short term effect of captopril on microalbuminuria induced by exercise in normoten- sive diabetics. Br Med J 298:285-288,1989.

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