Journal of Human Hypertension (1997) 11, 35–38  1997 Stockton Press. All rights reserved 0950-9240/97 $12.00

Effects of an ACE inhibitor combined with a calcium channel blocker on progression of diabetic nephropathy

G Bakris1,2 and D White1 1Department of Preventive Medicine, Rush Hypertension Center, Rush Presbyterian-St Luke’s Medical Center, Chicago, IL; and 2Division of Nephrology, University of Illinois Medical Center, Chicago, IL, USA

It is clear that angiotensin-converting enzyme (ACE) (b) conversely, addition of an ACE inhibitor to a dihydro- inhibitors slow progression of diabetic nephropathy to a pyridine CCB (DCCB) yields effects on proteinuria simi- greater extent than other antihypertensive agents when lar to the ACE inhibitor alone. Therefore, addition of an blood pressure (BP) is reduced to levels below 140/90 ACE inhibitor to a DCCB demonstrates protection mm Hg. Recent studies also demonstrate that nondihy- against the effects of DCCB alone. Addition of an ACE dropyridine calcium channel blockers (NDCCBs) slow inhibitor to a NDCCB does not potentiate the preser- progression of diabetic nephropathy in people with pre- vation of renal morphology associated with progression existing renal insufficiency secondary to non-insulin of diabetic nephropathy when compared to either of its dependent diabetes mellitus. The combined effects of components alone. Conversely, a DCCB/ACE inhibitor both a CCB and ACE inhibitor have recently been exam- combination yields morphologic results similar to the ined in both animal models of diabetes as well as ACE inhibitor alone. Taken together these results sug- patients with established diabetic nephropathy. These gest that ACE inhibitors when combined with a NDCCB studies demonstrate the following points: (a) at compa- result in greater reductions in proteinuria, and similar rable BP levels, a combination of an ACE inhibitor with preservation of renal morphology when compared to a NDCCB result in a greater reduction in proteinuria either of its components alone. when compared to either components alone; and

Keywords: calcium antagonist; ACE inhibitor; diabetic nephropathy; proteinuria

Introduction the antihypertensive agent used.4,5 More recently, however, studies with angiotensin-converting Diabetic nephropathy will occur in approximately enzyme (ACE) inhibitors demonstrate a marked 40% of the more than 16 million diabetic patients 1 slowing in the progression of nephropathy, an effect, in the United States. This number of patients is in part, independent of blood pressure (BP) comparable to the number with heart failure, cre- reduction.6–9 This associated effect may be due to ating a major public health problem in the US. More- unique properties of ACE inhibitors. These include over, the morbidity associated with diabetic nephro- a reduction in glomerular permeability to glycated pathy is quite high. Such patients have a higher risk albumin as well as a reduction in intraglomerular from cardiovascular events, infection, death and pressure.9–12 limb loss secondary to gangrene, when compared to the general population. In addition, these patients Few long-term studies with calcium channel have a higher incidence of depression when com- blockers (CCBs) have been carried out to assess their pared to the normal population; this is especially effects on progression of diabetic nephropathy. true once they start dialysis. Lastly, from a socio- CCBs have diverse effects on progression of diabetic economic standpoint, delaying the onset of dialysis nephropathy. Dihydropyridine CCBs (nifedipine- would save approximately $55 000 per patient per like agents), in general, do not reduce surrogate mar- year.2,3 Slowing progression of diabetic nephropathy kers of renal disease progression. Specifically, they 13–18 will potentially have far reaching positive results for do not reduce proteinuria. Moreover, in animal not only patients with this problem but society in studies they do not prevent development of glo- general. merulosclerosis.15–18 Interestingly, this lack of pro- To date, all studies in patients with diabetic tection occurs in the presence of adequate BP nephropathy demonstrate that a reduction of arterial reduction. pressure to levels less than 140/90 mm Hg, slows Conversely, in both clinical and experimental progression to end stage renal disease regardless of studies, nondihydropyridine CCBs have been shown to reduce proteinuria and prevent glomerulo- sclerosis.12,15,16–18,19–24 Furthermore, some studies demonstrate a similar benefit with some CCBs com- Correspondence: Dr G Bakris, Departments of Preventive and 4,8,19,23,25 Internal Medicine, Rush University Hypertension Center, 1725 pared to an ACE inhibitor. This differential West Harrison, Suite #117, Chicago, IL 60612, USA effect of CCBs on renal membrane permeability and Effects of an ACE inhibitor G Bakris and D White 36 glomerular scarring has been attributed to several dependent diabetes.4–6 Patients with non-insulin etiologies including: a differential distribution of dependent diabetes have also received positive calcium channels and specific effects on synthesis benefits from ACE inhibitors. However, the data is of various matrix proteins.26 The specific effects of less consistent. either ACE inhibitors or CCBs alone or combined CCBs must be viewed as a heterogeneous group of will be discussed. antihypertensive agents. For simplicity they can be divided into two groups, dihydropyridine or (non- ACE inhibitors heart rate lowering) agents and nondihydropyridine (heart rate lowering CCBs). The effects of these two Mesangial matrix expansion is the earliest morpho- subclasses on renal permeability and glomerular logic change to occur in people with diabetic morphology are divergent. nephropathy.27 Animal studies have shown specific There are over 20 animal studies with dihydropyr- effects of ACE inhibitors on mesangial matrix pro- idine CCBs demonstrating no reduction in glomeru- tein synthesis. Specifically, ACE inhibitors have lar scarring or proteinuria.15,16,24,26 These studies been shown to reduce the increased synthesis of have been carried out not only in animal models of fibronectin, laminin and collagen IV synthesis in diabetes but also in models of renal insufficiency. animal models of diabetes.28 This attenuated syn- Conversely, animal studies with nondihydropyrid- thesis in matrix proteins correlates with a reduction ine CCB (NDCCB) generally demonstrate a uniform in proteinuria and a reduction in glomerulosclerosis preservation of renal morphology and an attenuated in all animal models studied. rise in the amount of proteinuria.15,16,24,26 The Very few human studies have attempted to evalu- reasons for these differences are diverse and may ate the correlation between the development of glo- relate to direct effects on glomerular permeability. merulosclerosis and changes in proteinuria. This These animal data are, in part, supported by long has been assessed in animal models. In a recent term clinical studies with NDCCBs. Studies of study, Taft et al29 followed patients for 4 years. greater than 2 years duration demonstrate a faster Patients had a biopsy prior to follow-up and a rate of decline in renal function in groups ran- repeated biopsy at the end of this time period.29 domized to dihydropyridine calcium channel block- Patients had their BPs treated with regiments that ers compared to ACE inhibitors.4,6,28,31 One excep- either contained ACE inhibitors or other conven- tion, however, is a recent 3-year study in non- tional therapy. At the end of this time period they insulin dependent diabetic patients randomized to were unable to show a significant difference in the either an ACE inhibitor or amlodipine.25 In this amount of mesangial expansion of glomeruloscl- small study there were similar reductions in albumi- erosis between the groups. However, the group nuria and similar stabilization of renal function as receiving the ACE inhibitor tended to have less assessed by change in glomerular filtration rate glomerulosclerosis and interstitial fibrosis. There- between the two groups. This is the only long-term fore, one could interpret this data as an insufficient study with a long-acting dihydropyridine CCB follow-up time in a small number of patients to which shows a similar benefit to ACE inhibition on assess a meaningful change. However, a recent surrogate end points. Conversely, all clinical studies analysis of all such small studies was performed.24 with either verapamil or diltiazem demonstrate This analysis showed that a reduction in proteinuria reductions in proteinuria and a slowed progression correlated with a blunted increase in glomerular of disease to levels similar to those seen with ACE scarring. inhibitors. This data however, was established in ACE inhibitors reduce glomerular permeability as people with chronic renal insufficiency secondary manifested clinically by their reduction in pro- to non-insulin dependent diabetes. teinuria. Three separate meta-analyses demonstrate that ACE inhibitors reduce proteinuria to a degree ACE/CCB combinations greater than what would be predicted by BP reduction alone.4–6 Both animal and human studies Recent animal studies have taken advantage of the demonstrate that this reduction in proteinuria is due renal effects seen with both ACE inhibitors and to a reduction in diabetes induced increases in CCBs, by combining them in lower doses to achieve glomerular permeability. similar levels of BP control.18,19,32,33 These combi- ACE inhibitors largely decrease protein shunting nations have recently been studied with regard to at the membrane level as well as increase or help to their effects on proteinuria and progression to glo- restore the loss of anionic charge selectivity. As a merulosclerosis. Recent animal studies in remnant result, these drugs decrease the leakage of glycated kidney models have evaluated the effects of both the albumin through the membrane. When glycated dihydropyridine and NCCCB in combination with albumin is exposed to normal cells it results in an ACE inhibitor vs either of the components alone cellular injury, in part, through free radical gener- on progression to glomerulosclerosis and pro- ation.10 Hence, reduced exposure of glycated albu- teinuria. These studies were performed in the rem- min to the renal cells should provide protection nant kidney model as well as a hypertensive model against injury. in the rat. Studies using amlodipine and benazapril Clinically, ACE inhibitors have also shown an alone or in combination demonstrate no protection advantage over other BP agents on slowing pro- against the increases in proteinuria with amlodipine gression of diabetic nephropathy.7–9,30 However, the or glomerulosclerosis while the ACE inhibitor pre- preponderance of the data is in patients with insulin vents both processes.33 Combinations of these Effects of an ACE inhibitor G Bakris and D White 37 agents, however, demonstrate a protection similar to hypertensive agents on the kidney. Arch Intern Med that seen with the ACE inhibitor both in terms of 1995; 155: 1073–1082. changes in proteinuria and glomerular morphology. 5 Weidmann P et al. Therapeutic efficacy of different This observation has also been seen with the antihypertensive drugs in human diabetic nephro- felodipine/enalapril combination.34 pathy: an updated meta-analysis. Nephrol Dial Transpl 1995; 10 (Suppl 9): 39–45. Combinations of verapamil and the ACE inhibitor 6 Gansevoort RT et al. Antiproteinuric effect of blood trandolopril have also been studied to explore the pressure lowering agents: a meta-analysis of compara- unique effects of these agents on renal morphology. tive trials. Nephrol Dial Transplant 1995; 10: 1963– Studies in SHR stroke prone rats were designed not 1974. to lower arterial pressure, but to assess whether 7 Lewis EJ, Hunsicker LG, Bain RP, Rohde RD for the either of these agents, alone or combined, conferred Collaborative Study Group. The effect of angiotensin unique protection to the kidney.32 At the end of 11 converting enzyme inhibition on diabetic nephro- weeks the study demonstrated that while the indi- pathy. N Engl J Med 1993; 329: 1456–1462. vidual components lowered proteinuria, combi- 8 Bakris GL et al. Effects of nondihydropyridine calcium nation therapy resulted in a greater reduction in pro- antagonists on progression of nephropathy resulting from noninsulin dependent diabetes: a six year follow- teinuria. Moreover, the combination group was the up study prospective study. Kidney Int 1996; 50: only group that provided protection against pro- 1641–1650. gression to glomerulosclerosis. Thus, combination 9 National High Blood Pressure Education Program therapy with agents shown to be effective, individu- Working Group on Hypertension and Renal Disease. ally, in reducing proteinuria and glomerular mor- 1995 Update of the working group reports on chronic phologic injury may have potentiating effects when renal failure and renovascular hypertension. Arch used in combination even at lower doses. A recent Intern Med 1996; 156: 1938–1949. clinical study in patients with non-insulin depen- 10 Bakris GL. Microalbuminuria: Prognostic Implications. dent diabetes corroborates these observations.23 A Cur Opinion Nephrol Hypertens 1996; 7 (in press). detailed discussion of these studies is beyond the 11 Kilaru P, Bakris GL. Microalbuminuria and progress- ive renal disease. J Hum Hypertens 1994; 8: 809–817. scope of this paper, however the reader is referred 35 12 Brown SA, Walton CL, Crawford P, Bakris GL. Long- to a recent review. term effects of different anti-hypertensive regimens on Further work needs to be done to assess the actual renal hemodynamics and proteinuria. Kidney Int 1993; mechanisms of benefit as well as the utility of these 43: 1210–1218. combinations in clinical situations. However, it 13 Abbott K, Smith AC, Bakris GL. Effects of dihydropyri- appears that we have entered a new era of therapy dine calcium antagonists on albuminuria in diabetic where combinations of drugs used in lower doses subjects. J Clin Pharmacol 1996; 36: 274–279. may have greater benefit than either of its compo- 14 Bakris GL, Smith AC. Effects of sodium intake on albu- nents alone. min excretion in patients with diabetic nephropathy treated with long-acting calcium antagonists. Annals of Int Med 1996; 125: 201–203. Conclusion 15 Bakris GL, Williams B. ACE inhibitors and calcium antagonists alone or combined: is there a difference on It is clear that BP reduction is important in slowing progression of diabetic renal disease? J Hypertens the progression of renal disease. However, specific 1995; 13 (Suppl 2): S95–S101. classes of drugs such as ACE inhibitors and NDCCB 16 Bakris GL. Hypertension in diabetic patients: an over- have demonstrated clear utility to effect surrogate view of interventional studies to preserve renal func- end points such as proteinuria to a level greater than tion. Am J Hypertens 1993; 6 (Suppl 4): 140S–147S. what would be predicted by BP reduction alone. 17 Griffin KA, Picken MM, Bidani AK. Deleterious effects Certain combinations of these agents have also of calcium channel blockade on pressure transmission shown greater utility than either of the individual and glomerular injury in rat remnant kidneys. J Clin components with regard to proteinuria reductions. Invest 1995; 96: 793–800. Therefore, in the difficult to treat hypertensive, dia- 18 Picken M, Griffin K, Bakris GL, Bidani A. Comparative effects of four different calcium antagonists on pro- betic patient, or any patient with large amounts of gression of renal disease in a remnant kidney model. proteinuria, it is important to keep these concepts J Am Soc Nephrol 1996; 7: 1586 (Abstract). in mind and use them in therapeutic management 19 Gaber L, Walton C, Brown S, Bakris GL. 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