C O M M E N T A R Y
teinuric renal disease (29) and in patients with diabetes that the ACE inhibitor enalapril can directly decrease the permeability characteristics of the capillary basement membrane (17). An increase in selectivity, allowing larger molecules BEN H. BROUHARD, MD to pass through the membrane, occurs during the course of the disease process. Enalapril will directly decrease permepproximately 30-40% of patients decreases in this measurement have been ability characteristics of the glomerular with diabetes mellitus will suc- used as a frequent outcome measure for basement membrane and therefore recumb to end-stage renal disease many clinical studies. Other investigators strict passage of molecules through this (1). Furthermore, diabetic nephropathy would argue that microalbuminuria poorly semipermeable membrane (17). Such accounts for 25% of all new cases of reflects the histological changes of mesan- studies have been conducted with neuuremia in the Western world (2). The gial matrix expansion, the hallmark of pro- tral dextran molecules and therefore the pathogenesis of diabetic nephropathy is gressive disease (9). Nevertheless, microal- charge effect of the various endogenous multifactorial, including metabolic con- buminuria (or proteinuria), GFR, and proteins has not been considered. Thus, trol (3) which has been recognized for blood pressure are the frequently moni- ACE inhibitors may produce the effect of years and the recently investigated ad- tored clinical end points of antihyperten- decreasing proteinuria by a direct action on the glomerular basement membrane. vanced glycosylation end products (4). sive trials. Other contributing factors include puNot only have ACE inhibitors been berty (4) and, perhaps most importantly, used to lower blood pressure and stabilize blood pressure control. CLINICAL STUDIES— When antihy- protein excretion and GFR but also to preSince the landmark studies of pertensive therapy is contemplated there vent the development of renal dysfunction. Parving et al. (6) in 1983 demonstrating a are various classes of drugs from which Mathiesen et al. (23) used captopril to treat decline in the rate of deterioration in renal to choose. The most commonly studied 21 patients who had microalbuminuria function with reduction of elevated blood of these is the angiotensin-converting en- and were normotensive; they were compressure, adequate blood pressure control zyme (ACE) inhibitors. Numerous ex- pared with a similar group of untreated has become the standard of medical prac- perimental (10,11) and human studies patients. After 4 yr, albumin excretion in tice for the hypertensive diabetic subject. (12-27; Table 1) have suggested that the treated group decreased from 82 to 57 Thus, for patients with hypertension and this group of antihypertensives can ade- mg/day, whereas the untreated group indiabetes mellitus, when to treat and what quately control blood pressure and de- creased from 105 to 166 mg/day antihypertensive to treat with become im- crease proteinuria in patients with dia- (P < 0.05). Seven of the untreated patients portant questions. A recent review by betic nephropathy. Furthermore, these progressed to overt nephropathy; none of Mogensen et al. (7) have suggested main- studies would also suggest that renal the treated group did so. Blood pressure tenance of a mean arterial pressure of function is maintained over the time and metabolic control (HbAlc) remained 90-95 mmHg to maintain or decrease mi- course of the study. However, as noted in unchanged in both groups. These authors croalbuminuria (in adults) and 100-105 Table 1, most of these studies have fol- concluded that use of ACE inhibition can mmHg to maintain glomerular filtration lowed relatively few patients for short prevent progression of nephropathy, as rate (GFR), providing fair metabolic con- periods of time. Nevertheless, studies in- measured by albumin excretion, in nortrol is also achieved (HbAlc 8.5-9.0%). volving other disease processes have also motensive diabetic subjects. Another class of drugs that have Because the excretion of even small indicated that ACE inhibitors are useful been recently studied are the calcium amounts of albumin (30 jxg/min) has been in slowing the progression of renal dischannel blockers. Again, as noted in Taproposed as a harbinger of future deterio- ease (28). Furthermore, it has been ble 2, the number of patients studied is ration in renal function (8), increases or shown in an experimental model of prosmall and the time of follow-up limited. The data for nicardipine and diltiazem demonstrate that renal function is preFROM THE CLEVELAND CLINIC CHILDREN'S HOSPITAL, CLEVELAND, OHIO. served and proteinuria decreased (Table ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO BEN H. BROUHARD, MD, DEPARTMENT OF 2). In short-term studies, nifedipine may PEDIATRICS, CLEVELAND CLINIC CHILDREN'S HOSPITAL, 9500 EUCLID AVENUE, CLEVELAND, OH 44195. actually increase proteinuria (14,26). However, a year-long study from the Mel-
Antihypertensive Therapy for Patients With Diabetes Mellitus
A
918
DIABETES CARE, VOLUME 15, NUMBER 7, JULY 1992
Commentary
Table 1—Use of angiotensin-converting enzyme inhibitors in patients with diabetes REF.
Pts.
DRUG
TAGUMA ET AL. 12
CAPTOPRIL
MARRE ET AL. 13
ENALAPRIL
MlMRAN ET AL. 1 4
CAPTOPRIL
PARVING ET AL. 15
CAPTOPRIL
BABA ET AL. 16
ENALAPRIL
MORELLl ET AL. 17
ENALAPRIL
STORNELLO ET AL. 18
CAPTOPRIL
BjORCK ET AL. 19
ENALAPRIL
RUDBERG ET AL. 2 0
ENALAPRIL
DURATION (WK)
10 10 7 15 7 20 12 22
8 24 6 52 4 12 4 8 24
6(BP)
CHANGE IN PROTEINURIA
10.6-6.1 G/DAY 124-37 ITIG/DAY 8 6 - 5 7 |JLG/MIN 390-300 IJ-G/MIN
32-22 Mg/MiN 2.2-1.8 MG/DAY 833-433 M-G/MIN 2.0-1.1 G/DAY 26-17 |JLG/MIN
CHANGE IN RENAL FUNCTION*
4.7-5.0 MG/DL 130-141 ML/MIN 149-140 ML/MIN 112-108 ML/MIN 93-99 ML/MIN 73-73 ML/MIN 113-109 ML/MIN 159-171 IAMOL/L 130-119 ML/MIN 125-130 ML/MIN
24 30-10 JJLG/MIN 6 (NL BP) 4.1-2.6 G/DAY 1.39-1.36 ML/S LISINOPRIL 8 BAKRIS 2 1 6 3 4 - 2 4 |AG/MIN 10 MELBOURNE GROUP 22 52 138-123 ML/MIN PERINDOPRIL 8 2 - 5 7 |AG/DAY 21 128-120 ML/MIN CAPTOPRIL MATHIESEN ET AL. 2 3 208 12 STORNELLO ET AL. 2 4 420-266 |XG/MIN 116-108 ML/MIN ENALAPRIL 3 CAPTOPRIL HOMMEL ET AL. 2 5 16 1389-1075 JXG/MIN 99-93 ML/MIN 12 14 CAPTOPRIL BjORCK ET AL. 2 6 2.9-2.8 G/DAY 10.35-5.5 ML- MIN" 1 • YR"1 104 12 4.5-3.4 G/DAY CAPTOPRIL VALVO ET AL. 2 7 57-51 ML/MIN 26 *Renal function has been variously measured as change in serum creatinine concentration (mg/dl), clearance (ml/min, u,mol/h, ml/s), or decline in clearance over time (ml • min"1 • yr~l).
bourne group would indicate that there is have produced conflicting results. When relatively little change in both proteinuria compared with ACE inhibitors, metropolol and renal function (22). The difference in was shown to be less effective (1.4-1.6 the results of these studies may relate to g/day) than the ACE inhibitor (1.6-0.79 the time in the disease process at which the g/day) in reducing proteinuria after 8 wk patients were studied. The patients of De- (18). In a separate study atenolol demarie and Bakris (26), who were evaluated creased proteinuria to a similar degree after a relatively short time, demonstrated compared with an ACE inhibitor (420greater amounts of proteinuria, whereas 269 jjig/min and 420 to 266 |xg/min, rethe Melbourne group (22) investigated pa- spectively) (24). tients with much lesser amounts of albumin excretion. Other classes of antihypertensives have been less well studied. Two studies MECHANISMS— The mechanisms have evaluated (3- blocking agents that by which these classes of drugs decrease
proteinuria and preserve renal function also appear to be somewhat different. ACE inhibitors have been shown experimentally to decrease glomerular capillary perfusion pressure (10). This is achieved by decreasing efferent arteriolar resistance to a greater extent than afferent resistance resulting in a decrease in perfusion pressure and single nephron GFR. This has been shown experimentally in renal ablation models of progressive renal disease (30) and the streptozocin model of diabetes (10). In fact, Anderson et al. (27) compared an ACE inhibitor to triple therapy of hydrochlorothiazide, re-
Table 2—Use of calcium channel blockers in patients with diabetes mellitus
REF.
DRUG
MELBOURE 22 MlMRAN ET AL. 1 4
NlFEDIPINE
DEMARIE ET AL. 26
NlFEDIPINE
DEMARIE ET AL. 2 8
DlLTIAZEM
BAKRIS 21
DlLTIAZEM
STORNELLO ET AL. 18
NlCARDIPINE
BABA ET AL. 16
NlCARDIPINE
NlFEDlPlNE
DURATION
CHANGE IN
CHANGE IN RENAL
PTS.
(WK)
PROTEINURIA
FUNCTION
23 22
52 6 6 6 6
41-33 |XG/MIN
150-136 ML/MIN
14 14
8 12 7
86-122 (XG/MIN 2.8-5.3 G/DAY
2.7-1.3 G/DAY
4
4.1-2.8 G/DAY 833-324 JJLG/MIN
4
32-18 LLG/MIN
81-87 jiM/L 159-212 JJLMOL/L
NC 1.39-1.41 ML/S 113-115 ML/MIN 93-103 ML/MIN
NC, no change.
DIABETES CARE, VOLUME 15, NUMBER 7, JULY 1992
919
Commentary
serpine, and hydralazine. The ACE inhibitor decreased proteinuria and preserved structure (i.e., decreased glomerular sclerosis) and function (i.e., maintenance GFR) in animals with both diabetes and surgically induced progressive renal disease. Although equally effective in lowering blood pressure, triple therapy maintained neither structure nor function as well as the ACE inhibitors and did not lower glomerular perfusion pressure, thus indicating a central role for intraglomerular pressure in progressive diabetic nephropathy. These investigators concluded that antihypertensive therapy may be somewhat specific for preserving renal function over and above the overall general effect of lowering systemic pressure. In contrast, Yoshida et al. (31) demonstrated in the renal ablation model of progressive renal disease that both triple therapy and an ACE inhibitor lowered systemic blood pressure equally and decreased glomerular sclerosis, despite the ACE inhibitor significantly decreasing glomerular capillary pressure, whereas the rats treated with triple therapy showed no effect on capillary pressure. Thus, these investigators propose that intrarenal glomerular hemodynamics may not be etiologically important in the progression of renal disease. They have presented data suggesting that glomerular hypertrophy is a better predictor of future development of sclerosis. These investigators hypothesize that therapy with either an ACE inhibitor or triple therapy can decrease glomerular hypertrophy, which progresses to sclerosis. Although studies are limited in evaluating parameters of ongoing hypertrophy, in a diabetic model certainly it is known that glomerular hypertrophy and GFR increase at the onset of the disease process, both in human and experimental animals. Whether such hypertrophy at the onset or late in the course of the disease can progress to sclerosis and declining renal function await further study. Little work has been done in evaluating basic mechanisms of action of cal-
920
cium channel blockers in an experimental model of diabetes mellitus. Epstein (34) noted that the renal hemodynamic response to calcium antagonist depends on the prevailing factors determining basal renal vascular tone. Data from studies of other models would suggest that this class of drugs decrease afferent arteriolar tone without change in efferent arteriolar resistance (35). Anderson et al. (32) in preliminary studies in the streptozocin-induced rat showed an increase in albuminuria after treatment with nifedipine compared with either hydralazine or an ACE inhibitor. Neither single nephron glomerular filtration rate nor plasma flow or glomerular capillary pressure were affected by the calcium channel antagonist. More studies are needed to define the mechanisms of action and potential usefulness of other calcium channel blockers in this model of insulin-dependent diabetes mellitus. In summary, when choosing an antihypertensive regimen for a patient with diabetes, the most critical issue is the decrease in blood pressure. Although any class of antihypertensive drug may be used for blood pressure and will be effective, ACE inhibitors and some calcium entry blockers may have specific advantages over other classes of drugs. Thus, the weight of experimental and clinical evidence would suggest that an ACE inhibitor probably should be the initial treatment of choice if the patient's renal function can permit such therapy. If the GFR is compromised, hyperkalemia and perhaps even worsening of renal function may occur. If a calcium channel blocker is used, it may be more appropriate to choose nicardipine or diltiazem rather than nifedipine, but, again, it must be realized that the underlying mechanisms whereby these agents act to retard progression of the disease is not fully appreciated. In addition, other studies such as the study of Mathiesen et al. (23) must be performed to address the question of how early to begin therapy. The time at which the patient develops proteinuria or hypertension may be too late.
Thus, should the patient be started at the onset of the disease? In children, should this be after the onset of puberty? Can such antihypertensive therapy overcome the effects of poor metabolic control? What is the role of hyperlipidemia in the progression of diabetic nephropathy? Thus, the question of the effects of the antihypertensive therapy on circulating lipid concentrations become important. Clearly, the issue of antihypertensive therapy for the diabetic subject is becoming more complex than just effective lowering of systemic blood pressure. References 1. Andersen AR, Christiansen JS, Andersen JK, Dreiner S, Deckert T: Diabetic nephropathy in type I (insulin-dependent) diabetes: an epidemiological study. Diabetologia 14:363-70, 1978 2. Lane PH, Steffes MW, Mauer SM: Renal histologic changes in diabetes mellitus. Sem Nephrol 10:254-59, 1990 3. Bilous RW, Mauer SM, Sutherland DER, Najarian JS, Goetz FC, Steffes MW: The effects of pancreas transplantation on the glomerular structure of renal allografts in patients with insulin-dependent diabetes. N Engl J Med 321:80-85, 1989 4. Makita Z, Radoff S, Rayfield EJ, Yang Z, Skolnik E, Delaney V, Friedman EA, Cerami A, Vlassara H: Advanced glycosylation end products in patients with diabetic nephropathy. N Engl J Med 325: 836-42, 1991 5. Kostraba JN, Dorman JS, Orchard TJ, Becker DJ, Okki Y, Ellis D, Doft BH, lopey LA, La Porte RE, Drash AL: Contribution of diabetes duration before puberty to development of microvascular complications in 1DDM subjects. Diabetes Care 12:686-93, 1989 6. Parving H-H, Smidt UM, Andersen AR, Svendsen PA: Early aggressive antihypertensive treatment reduces rate of decline in kidney function in diabetic nephropathy. Lancet 1:1175-78, 1983 7. Mogensen CE, Hansen KW, Pedersen MM, Christensen CK: Renal factors influencing blood pressure threshold and choice of treatment for hypertension in IDDM. Diabetes Care 14 (Suppl. 4): 13-
DIABETES CARE, VOLUME 15,
NUMBER 7, JULY
1992
Commentary
26, 1991 8. Mogensen CE: Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N EnglJ Med 310:356-60, 1984 9. Steffes MW, Osterby R, Chavers B, Mauer SM: Mesangial expansion as a central mechanism for loss of kidney function in diabetic patients. Diabetes 38:1077-81, 1989 10. Zatz R, Dunn BR, Meyer TW, Anderson A, Rennke HG, Brenner BM: Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest 77: 1925-30, 1986 11. Anderson S, Rennke HG, Garcia DL, Brenner BM: Short and long-term effects of antihypertensive therapy in the diabetic rat. Kidney Int 36:526-36, 1987 12. Taguma Y, Kitamoto Y, Futaki G, Ueda H, Monma H, Ishizaki M, Takahashi H, Sekino H, Sasaki Y: Effect of captopril on heavy proteinuria in azotemic diabetics. N EnglJ Med 313:1617-20, 1985 13. Marre M, Leblanc H, Suarez, Guyenne T-T, Menard J, Passa P: Converting enzyme inhibition and kidney function in normotensive diabetic patients with persistent microalbuminuria. Br Med] 294: 1448-52, 1987 14. Mimran A, Insua A, Ribstein J, Bringer J, Monnier L: Comparative effect of captopril and nifedipine in normotensive patients with incipient diabetic nephropathy. Diabetes Care 11:850-53, 1988 15. Parving H-H, Hommel E, Nielsen MD, Giese J: Effects of captopril on blood pressure and kidney function in normotensive insulin dependent diabetics with nephropathy. Br Med J 299:53336, 1989 16. Baba T, Murabayashi S, Takebe K: Comparison of the renal effects of angiotensin converting enzyme inhibitor and calcium antagonist in hypertensive type 2 (noninsulin-dependent) diabetic patients with microalbuminuria: a randomized controlled trial. Diabetohgia 32:40-44, 1989
DIABETES CARE, VOLUME 15, NUMBER 7, JULY 1992
17. Morelli E, Loon N, Meyer T, Peters W, Myers BD: Effects of converting-enzyme inhibition on barrier function in diabetic glomerulopathy. Diabetes 39:76-82, 1990 18. Stomello M, Valvo EV, Scapellato L: Hemodynamic, renal, and humoral effects of the calcium entry blocker nicardipine and converting enzyme inhibitor captopril in hypertensive type II diabetic patients with nephropathy. J Cardiovas Pharmacol 14:851-55, 1989 19. Bjorck S, Mulec H, Johnsen SA, Nyberg G, Aurell M: Contrasting effects of enalapril and metoprolol on proteinuria in diabetic nephropathy. Br Med J 300: 904-907, 1990 20. Rudberg S, Aperia A, Freyschuss U, Persson B: Enalapril reduces microalbuminuria in young normotensive type I (insul i n - d e p e n d e n t ) diabetic patients irrespective of its hypotensive effect. Diabetologia 33:470-76, 1990 21. Bakris GL: Effects of diltiazem or lisinopril on massive proteinuria associated with diabetes mellitus. Ann Intern Med 112:707-708, 1990 22. Melbourne Diabetic Nephropathy Study Group: Comparison between perindopril and nifedipine in hypertensive and normotensive diabetic patients with microalbuminuria. BrMedJ 302:210-16, 1991 23. Mathiesen ER, Hommel E, Giese J, Parving H-H: Efficacy of captopril in postponing nephropathy in normotensive insulin dependent diabetic patients with microalbuminuria. Br Med] 303:81-87, 1991 24. Stornello M, Valvo EV, Scapelato L: Comparative effects of enalapril, atenolol and chlorthalidone on blood pressure and kidney function of diabetic patients affected by arterial hypertension and persistent proteinuria. Nephron 58:52-57, 1991 25. Hommel E, Parving H-H, Mathiesen E, Edsberg B, Nielsen MD, Giese J: Effect of captopril on kidney function in insulindependent diabetic patients with nephropathy. Br Med J 293:467-70,
1986 26. Bjorck S, Nyberg G, Mulec H, Granerus G, Herlitz H, Aurell M: Beneficial effects of angiotensin converting enzyme inhibition on renal function in patients with diabetic nephropathy. BrMedJ 293:47174, 1986 27. Valvo EN, Bedogna V, Casagrande P, Antiga L, Zamboni M, Bommartini F, Oldrizei L, Rugiu C, Maschio G: Captopril in patients with type II diabetes and renal insufficiency: systemic and renal hemodynamic alteration. Am J Med 85:34448, 1988 28. Demarie BK, Bakris GL: Effects of different calcium antagonists on proteinuria associated with diabetes mellitus. Ann Intern Med 113:987-88, 1990 29. Remuzzi A, Puntoriere S, Battaglia D, Bertani J, Remuzzi G: Angiotensin converting enzyme inhibition ameliorates glomerular filtration of macromolecules and water and lessens glomerular injury in the rat. J Clin Invest 85:541-49, 1990 30. Anderson A, Meyer TW, Rennke HG, Brenner BM: Control of glomerular hypertension limits glomerular injury in rats with reduced renal mass.J Clin Invest 76:612-19, 1985 31. Anderson S, Rennke HG, Brenner BM: Therapeutic advantage of converting enzyme inhibitors in arresting progressive renal disease associated with systemic hypertension in the rat. J Clin Invest 77: 1993-2000, 1986 32. Yoshida Y, Kawamura T, Ikoma M, Fogo A, Ichikawa 1: Effects of antihypertensive drugs on glomerular morphology. Kidney Int 36:626-35, 1989 33. Anderson S, Rennke HG, Zoyas MA, Brenner BM: Chronic calcium channel blockade fails to lower glomerular pressure and albuminuria in diabetic rats. Clin Res 39:247A, 1991 34. Epstein M: Preface. J Am Soc Nephrol 1:S1, 1990 35. Loutzenhiser R, Epstein M: Renal microvascular actions of calcium antagonists. J Am Soc Nephrol LS3-S12, 1990
921
teinuric renal disease (29) and in patients with diabetes that the ACE inhibitor enalapril can directly decrease the permeability characteristics of the capillary basement membrane (17). An increase in selectivity, allowing larger molecules BEN H. BROUHARD, MD to pass through the membrane, occurs during the course of the disease process. Enalapril will directly decrease permepproximately 30-40% of patients decreases in this measurement have been ability characteristics of the glomerular with diabetes mellitus will suc- used as a frequent outcome measure for basement membrane and therefore recumb to end-stage renal disease many clinical studies. Other investigators strict passage of molecules through this (1). Furthermore, diabetic nephropathy would argue that microalbuminuria poorly semipermeable membrane (17). Such accounts for 25% of all new cases of reflects the histological changes of mesan- studies have been conducted with neuuremia in the Western world (2). The gial matrix expansion, the hallmark of pro- tral dextran molecules and therefore the pathogenesis of diabetic nephropathy is gressive disease (9). Nevertheless, microal- charge effect of the various endogenous multifactorial, including metabolic con- buminuria (or proteinuria), GFR, and proteins has not been considered. Thus, trol (3) which has been recognized for blood pressure are the frequently moni- ACE inhibitors may produce the effect of years and the recently investigated ad- tored clinical end points of antihyperten- decreasing proteinuria by a direct action on the glomerular basement membrane. vanced glycosylation end products (4). sive trials. Other contributing factors include puNot only have ACE inhibitors been berty (4) and, perhaps most importantly, used to lower blood pressure and stabilize blood pressure control. CLINICAL STUDIES— When antihy- protein excretion and GFR but also to preSince the landmark studies of pertensive therapy is contemplated there vent the development of renal dysfunction. Parving et al. (6) in 1983 demonstrating a are various classes of drugs from which Mathiesen et al. (23) used captopril to treat decline in the rate of deterioration in renal to choose. The most commonly studied 21 patients who had microalbuminuria function with reduction of elevated blood of these is the angiotensin-converting en- and were normotensive; they were compressure, adequate blood pressure control zyme (ACE) inhibitors. Numerous ex- pared with a similar group of untreated has become the standard of medical prac- perimental (10,11) and human studies patients. After 4 yr, albumin excretion in tice for the hypertensive diabetic subject. (12-27; Table 1) have suggested that the treated group decreased from 82 to 57 Thus, for patients with hypertension and this group of antihypertensives can ade- mg/day, whereas the untreated group indiabetes mellitus, when to treat and what quately control blood pressure and de- creased from 105 to 166 mg/day antihypertensive to treat with become im- crease proteinuria in patients with dia- (P < 0.05). Seven of the untreated patients portant questions. A recent review by betic nephropathy. Furthermore, these progressed to overt nephropathy; none of Mogensen et al. (7) have suggested main- studies would also suggest that renal the treated group did so. Blood pressure tenance of a mean arterial pressure of function is maintained over the time and metabolic control (HbAlc) remained 90-95 mmHg to maintain or decrease mi- course of the study. However, as noted in unchanged in both groups. These authors croalbuminuria (in adults) and 100-105 Table 1, most of these studies have fol- concluded that use of ACE inhibition can mmHg to maintain glomerular filtration lowed relatively few patients for short prevent progression of nephropathy, as rate (GFR), providing fair metabolic con- periods of time. Nevertheless, studies in- measured by albumin excretion, in nortrol is also achieved (HbAlc 8.5-9.0%). volving other disease processes have also motensive diabetic subjects. Another class of drugs that have Because the excretion of even small indicated that ACE inhibitors are useful been recently studied are the calcium amounts of albumin (30 jxg/min) has been in slowing the progression of renal dischannel blockers. Again, as noted in Taproposed as a harbinger of future deterio- ease (28). Furthermore, it has been ble 2, the number of patients studied is ration in renal function (8), increases or shown in an experimental model of prosmall and the time of follow-up limited. The data for nicardipine and diltiazem demonstrate that renal function is preFROM THE CLEVELAND CLINIC CHILDREN'S HOSPITAL, CLEVELAND, OHIO. served and proteinuria decreased (Table ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO BEN H. BROUHARD, MD, DEPARTMENT OF 2). In short-term studies, nifedipine may PEDIATRICS, CLEVELAND CLINIC CHILDREN'S HOSPITAL, 9500 EUCLID AVENUE, CLEVELAND, OH 44195. actually increase proteinuria (14,26). However, a year-long study from the Mel-
Antihypertensive Therapy for Patients With Diabetes Mellitus
A
918
DIABETES CARE, VOLUME 15, NUMBER 7, JULY 1992
Commentary
Table 1—Use of angiotensin-converting enzyme inhibitors in patients with diabetes REF.
Pts.
DRUG
TAGUMA ET AL. 12
CAPTOPRIL
MARRE ET AL. 13
ENALAPRIL
MlMRAN ET AL. 1 4
CAPTOPRIL
PARVING ET AL. 15
CAPTOPRIL
BABA ET AL. 16
ENALAPRIL
MORELLl ET AL. 17
ENALAPRIL
STORNELLO ET AL. 18
CAPTOPRIL
BjORCK ET AL. 19
ENALAPRIL
RUDBERG ET AL. 2 0
ENALAPRIL
DURATION (WK)
10 10 7 15 7 20 12 22
8 24 6 52 4 12 4 8 24
6(BP)
CHANGE IN PROTEINURIA
10.6-6.1 G/DAY 124-37 ITIG/DAY 8 6 - 5 7 |JLG/MIN 390-300 IJ-G/MIN
32-22 Mg/MiN 2.2-1.8 MG/DAY 833-433 M-G/MIN 2.0-1.1 G/DAY 26-17 |JLG/MIN
CHANGE IN RENAL FUNCTION*
4.7-5.0 MG/DL 130-141 ML/MIN 149-140 ML/MIN 112-108 ML/MIN 93-99 ML/MIN 73-73 ML/MIN 113-109 ML/MIN 159-171 IAMOL/L 130-119 ML/MIN 125-130 ML/MIN
24 30-10 JJLG/MIN 6 (NL BP) 4.1-2.6 G/DAY 1.39-1.36 ML/S LISINOPRIL 8 BAKRIS 2 1 6 3 4 - 2 4 |AG/MIN 10 MELBOURNE GROUP 22 52 138-123 ML/MIN PERINDOPRIL 8 2 - 5 7 |AG/DAY 21 128-120 ML/MIN CAPTOPRIL MATHIESEN ET AL. 2 3 208 12 STORNELLO ET AL. 2 4 420-266 |XG/MIN 116-108 ML/MIN ENALAPRIL 3 CAPTOPRIL HOMMEL ET AL. 2 5 16 1389-1075 JXG/MIN 99-93 ML/MIN 12 14 CAPTOPRIL BjORCK ET AL. 2 6 2.9-2.8 G/DAY 10.35-5.5 ML- MIN" 1 • YR"1 104 12 4.5-3.4 G/DAY CAPTOPRIL VALVO ET AL. 2 7 57-51 ML/MIN 26 *Renal function has been variously measured as change in serum creatinine concentration (mg/dl), clearance (ml/min, u,mol/h, ml/s), or decline in clearance over time (ml • min"1 • yr~l).
bourne group would indicate that there is have produced conflicting results. When relatively little change in both proteinuria compared with ACE inhibitors, metropolol and renal function (22). The difference in was shown to be less effective (1.4-1.6 the results of these studies may relate to g/day) than the ACE inhibitor (1.6-0.79 the time in the disease process at which the g/day) in reducing proteinuria after 8 wk patients were studied. The patients of De- (18). In a separate study atenolol demarie and Bakris (26), who were evaluated creased proteinuria to a similar degree after a relatively short time, demonstrated compared with an ACE inhibitor (420greater amounts of proteinuria, whereas 269 jjig/min and 420 to 266 |xg/min, rethe Melbourne group (22) investigated pa- spectively) (24). tients with much lesser amounts of albumin excretion. Other classes of antihypertensives have been less well studied. Two studies MECHANISMS— The mechanisms have evaluated (3- blocking agents that by which these classes of drugs decrease
proteinuria and preserve renal function also appear to be somewhat different. ACE inhibitors have been shown experimentally to decrease glomerular capillary perfusion pressure (10). This is achieved by decreasing efferent arteriolar resistance to a greater extent than afferent resistance resulting in a decrease in perfusion pressure and single nephron GFR. This has been shown experimentally in renal ablation models of progressive renal disease (30) and the streptozocin model of diabetes (10). In fact, Anderson et al. (27) compared an ACE inhibitor to triple therapy of hydrochlorothiazide, re-
Table 2—Use of calcium channel blockers in patients with diabetes mellitus
REF.
DRUG
MELBOURE 22 MlMRAN ET AL. 1 4
NlFEDIPINE
DEMARIE ET AL. 26
NlFEDIPINE
DEMARIE ET AL. 2 8
DlLTIAZEM
BAKRIS 21
DlLTIAZEM
STORNELLO ET AL. 18
NlCARDIPINE
BABA ET AL. 16
NlCARDIPINE
NlFEDlPlNE
DURATION
CHANGE IN
CHANGE IN RENAL
PTS.
(WK)
PROTEINURIA
FUNCTION
23 22
52 6 6 6 6
41-33 |XG/MIN
150-136 ML/MIN
14 14
8 12 7
86-122 (XG/MIN 2.8-5.3 G/DAY
2.7-1.3 G/DAY
4
4.1-2.8 G/DAY 833-324 JJLG/MIN
4
32-18 LLG/MIN
81-87 jiM/L 159-212 JJLMOL/L
NC 1.39-1.41 ML/S 113-115 ML/MIN 93-103 ML/MIN
NC, no change.
DIABETES CARE, VOLUME 15, NUMBER 7, JULY 1992
919
Commentary
serpine, and hydralazine. The ACE inhibitor decreased proteinuria and preserved structure (i.e., decreased glomerular sclerosis) and function (i.e., maintenance GFR) in animals with both diabetes and surgically induced progressive renal disease. Although equally effective in lowering blood pressure, triple therapy maintained neither structure nor function as well as the ACE inhibitors and did not lower glomerular perfusion pressure, thus indicating a central role for intraglomerular pressure in progressive diabetic nephropathy. These investigators concluded that antihypertensive therapy may be somewhat specific for preserving renal function over and above the overall general effect of lowering systemic pressure. In contrast, Yoshida et al. (31) demonstrated in the renal ablation model of progressive renal disease that both triple therapy and an ACE inhibitor lowered systemic blood pressure equally and decreased glomerular sclerosis, despite the ACE inhibitor significantly decreasing glomerular capillary pressure, whereas the rats treated with triple therapy showed no effect on capillary pressure. Thus, these investigators propose that intrarenal glomerular hemodynamics may not be etiologically important in the progression of renal disease. They have presented data suggesting that glomerular hypertrophy is a better predictor of future development of sclerosis. These investigators hypothesize that therapy with either an ACE inhibitor or triple therapy can decrease glomerular hypertrophy, which progresses to sclerosis. Although studies are limited in evaluating parameters of ongoing hypertrophy, in a diabetic model certainly it is known that glomerular hypertrophy and GFR increase at the onset of the disease process, both in human and experimental animals. Whether such hypertrophy at the onset or late in the course of the disease can progress to sclerosis and declining renal function await further study. Little work has been done in evaluating basic mechanisms of action of cal-
920
cium channel blockers in an experimental model of diabetes mellitus. Epstein (34) noted that the renal hemodynamic response to calcium antagonist depends on the prevailing factors determining basal renal vascular tone. Data from studies of other models would suggest that this class of drugs decrease afferent arteriolar tone without change in efferent arteriolar resistance (35). Anderson et al. (32) in preliminary studies in the streptozocin-induced rat showed an increase in albuminuria after treatment with nifedipine compared with either hydralazine or an ACE inhibitor. Neither single nephron glomerular filtration rate nor plasma flow or glomerular capillary pressure were affected by the calcium channel antagonist. More studies are needed to define the mechanisms of action and potential usefulness of other calcium channel blockers in this model of insulin-dependent diabetes mellitus. In summary, when choosing an antihypertensive regimen for a patient with diabetes, the most critical issue is the decrease in blood pressure. Although any class of antihypertensive drug may be used for blood pressure and will be effective, ACE inhibitors and some calcium entry blockers may have specific advantages over other classes of drugs. Thus, the weight of experimental and clinical evidence would suggest that an ACE inhibitor probably should be the initial treatment of choice if the patient's renal function can permit such therapy. If the GFR is compromised, hyperkalemia and perhaps even worsening of renal function may occur. If a calcium channel blocker is used, it may be more appropriate to choose nicardipine or diltiazem rather than nifedipine, but, again, it must be realized that the underlying mechanisms whereby these agents act to retard progression of the disease is not fully appreciated. In addition, other studies such as the study of Mathiesen et al. (23) must be performed to address the question of how early to begin therapy. The time at which the patient develops proteinuria or hypertension may be too late.
Thus, should the patient be started at the onset of the disease? In children, should this be after the onset of puberty? Can such antihypertensive therapy overcome the effects of poor metabolic control? What is the role of hyperlipidemia in the progression of diabetic nephropathy? Thus, the question of the effects of the antihypertensive therapy on circulating lipid concentrations become important. Clearly, the issue of antihypertensive therapy for the diabetic subject is becoming more complex than just effective lowering of systemic blood pressure. References 1. Andersen AR, Christiansen JS, Andersen JK, Dreiner S, Deckert T: Diabetic nephropathy in type I (insulin-dependent) diabetes: an epidemiological study. Diabetologia 14:363-70, 1978 2. Lane PH, Steffes MW, Mauer SM: Renal histologic changes in diabetes mellitus. Sem Nephrol 10:254-59, 1990 3. Bilous RW, Mauer SM, Sutherland DER, Najarian JS, Goetz FC, Steffes MW: The effects of pancreas transplantation on the glomerular structure of renal allografts in patients with insulin-dependent diabetes. N Engl J Med 321:80-85, 1989 4. Makita Z, Radoff S, Rayfield EJ, Yang Z, Skolnik E, Delaney V, Friedman EA, Cerami A, Vlassara H: Advanced glycosylation end products in patients with diabetic nephropathy. N Engl J Med 325: 836-42, 1991 5. Kostraba JN, Dorman JS, Orchard TJ, Becker DJ, Okki Y, Ellis D, Doft BH, lopey LA, La Porte RE, Drash AL: Contribution of diabetes duration before puberty to development of microvascular complications in 1DDM subjects. Diabetes Care 12:686-93, 1989 6. Parving H-H, Smidt UM, Andersen AR, Svendsen PA: Early aggressive antihypertensive treatment reduces rate of decline in kidney function in diabetic nephropathy. Lancet 1:1175-78, 1983 7. Mogensen CE, Hansen KW, Pedersen MM, Christensen CK: Renal factors influencing blood pressure threshold and choice of treatment for hypertension in IDDM. Diabetes Care 14 (Suppl. 4): 13-
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26, 1991 8. Mogensen CE: Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N EnglJ Med 310:356-60, 1984 9. Steffes MW, Osterby R, Chavers B, Mauer SM: Mesangial expansion as a central mechanism for loss of kidney function in diabetic patients. Diabetes 38:1077-81, 1989 10. Zatz R, Dunn BR, Meyer TW, Anderson A, Rennke HG, Brenner BM: Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest 77: 1925-30, 1986 11. Anderson S, Rennke HG, Garcia DL, Brenner BM: Short and long-term effects of antihypertensive therapy in the diabetic rat. Kidney Int 36:526-36, 1987 12. Taguma Y, Kitamoto Y, Futaki G, Ueda H, Monma H, Ishizaki M, Takahashi H, Sekino H, Sasaki Y: Effect of captopril on heavy proteinuria in azotemic diabetics. N EnglJ Med 313:1617-20, 1985 13. Marre M, Leblanc H, Suarez, Guyenne T-T, Menard J, Passa P: Converting enzyme inhibition and kidney function in normotensive diabetic patients with persistent microalbuminuria. Br Med] 294: 1448-52, 1987 14. Mimran A, Insua A, Ribstein J, Bringer J, Monnier L: Comparative effect of captopril and nifedipine in normotensive patients with incipient diabetic nephropathy. Diabetes Care 11:850-53, 1988 15. Parving H-H, Hommel E, Nielsen MD, Giese J: Effects of captopril on blood pressure and kidney function in normotensive insulin dependent diabetics with nephropathy. Br Med J 299:53336, 1989 16. Baba T, Murabayashi S, Takebe K: Comparison of the renal effects of angiotensin converting enzyme inhibitor and calcium antagonist in hypertensive type 2 (noninsulin-dependent) diabetic patients with microalbuminuria: a randomized controlled trial. Diabetohgia 32:40-44, 1989
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17. Morelli E, Loon N, Meyer T, Peters W, Myers BD: Effects of converting-enzyme inhibition on barrier function in diabetic glomerulopathy. Diabetes 39:76-82, 1990 18. Stomello M, Valvo EV, Scapellato L: Hemodynamic, renal, and humoral effects of the calcium entry blocker nicardipine and converting enzyme inhibitor captopril in hypertensive type II diabetic patients with nephropathy. J Cardiovas Pharmacol 14:851-55, 1989 19. Bjorck S, Mulec H, Johnsen SA, Nyberg G, Aurell M: Contrasting effects of enalapril and metoprolol on proteinuria in diabetic nephropathy. Br Med J 300: 904-907, 1990 20. Rudberg S, Aperia A, Freyschuss U, Persson B: Enalapril reduces microalbuminuria in young normotensive type I (insul i n - d e p e n d e n t ) diabetic patients irrespective of its hypotensive effect. Diabetologia 33:470-76, 1990 21. Bakris GL: Effects of diltiazem or lisinopril on massive proteinuria associated with diabetes mellitus. Ann Intern Med 112:707-708, 1990 22. Melbourne Diabetic Nephropathy Study Group: Comparison between perindopril and nifedipine in hypertensive and normotensive diabetic patients with microalbuminuria. BrMedJ 302:210-16, 1991 23. Mathiesen ER, Hommel E, Giese J, Parving H-H: Efficacy of captopril in postponing nephropathy in normotensive insulin dependent diabetic patients with microalbuminuria. Br Med] 303:81-87, 1991 24. Stornello M, Valvo EV, Scapelato L: Comparative effects of enalapril, atenolol and chlorthalidone on blood pressure and kidney function of diabetic patients affected by arterial hypertension and persistent proteinuria. Nephron 58:52-57, 1991 25. Hommel E, Parving H-H, Mathiesen E, Edsberg B, Nielsen MD, Giese J: Effect of captopril on kidney function in insulindependent diabetic patients with nephropathy. Br Med J 293:467-70,
1986 26. Bjorck S, Nyberg G, Mulec H, Granerus G, Herlitz H, Aurell M: Beneficial effects of angiotensin converting enzyme inhibition on renal function in patients with diabetic nephropathy. BrMedJ 293:47174, 1986 27. Valvo EN, Bedogna V, Casagrande P, Antiga L, Zamboni M, Bommartini F, Oldrizei L, Rugiu C, Maschio G: Captopril in patients with type II diabetes and renal insufficiency: systemic and renal hemodynamic alteration. Am J Med 85:34448, 1988 28. Demarie BK, Bakris GL: Effects of different calcium antagonists on proteinuria associated with diabetes mellitus. Ann Intern Med 113:987-88, 1990 29. Remuzzi A, Puntoriere S, Battaglia D, Bertani J, Remuzzi G: Angiotensin converting enzyme inhibition ameliorates glomerular filtration of macromolecules and water and lessens glomerular injury in the rat. J Clin Invest 85:541-49, 1990 30. Anderson A, Meyer TW, Rennke HG, Brenner BM: Control of glomerular hypertension limits glomerular injury in rats with reduced renal mass.J Clin Invest 76:612-19, 1985 31. Anderson S, Rennke HG, Brenner BM: Therapeutic advantage of converting enzyme inhibitors in arresting progressive renal disease associated with systemic hypertension in the rat. J Clin Invest 77: 1993-2000, 1986 32. Yoshida Y, Kawamura T, Ikoma M, Fogo A, Ichikawa 1: Effects of antihypertensive drugs on glomerular morphology. Kidney Int 36:626-35, 1989 33. Anderson S, Rennke HG, Zoyas MA, Brenner BM: Chronic calcium channel blockade fails to lower glomerular pressure and albuminuria in diabetic rats. Clin Res 39:247A, 1991 34. Epstein M: Preface. J Am Soc Nephrol 1:S1, 1990 35. Loutzenhiser R, Epstein M: Renal microvascular actions of calcium antagonists. J Am Soc Nephrol LS3-S12, 1990
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