Medical Research Laboratory M (Diabetes and Endocrinology), Institute of Experimental Clinical Research, Aarhus University Hospital, Aarhus, Denmark
Introduction
Diabetic nephropathy is the most important cause of end-stage renal failure in the Western world. It is preceded by increased urinary albumin excretion (UAE) in the microalbuminuric range (30300 mg/ 24 h, i.e. incipient nephropathy), often in association with hypertension. Antihypertensive treatment with angiotensin-converting-enzyme inhibitors (ACEIs) is effective in preventing or postponing the development of overt nephropathy (i.e. UAE >300 mg/24 h) [1]. Other antihypertensive drugs, such as calcium channel blockers (CCBs), may also be effective in the treatment of diabetic kidney disease, but their preventive effect is controversial. In addition, it is still unknown whether dihydropyridine CCBs and non-dihydropyridine CCBs are equally effective. Further, the safety of CCB treatment in diabetics has been debated, since increased incidence of cardiovascular mortality has been reported during nisoldipine treatment in non-insulin-dependent diabetes mellitus (NIDDM). Thus, this paper will present an updated review of experimental and clinical data concerning the renoprotective effects of CCBs in patients with insulin-dependent diabetes mellitus (IDDM) and NIDDM, and briefly discuss safety considerations. The few studies examining the effect of CCBs in a mixture of IDDM and NIDDM patients will not be discussed in this review.
Animal models of diabetic nephropathy
Experimental models used for the study of diabetic nephropathy have been heterogeneous in terms of animal species; some studies investigating rat strains with [26] or without [712] partial nephrectomy, and other studies using Beagle dogs [13,14]. Furthermore, both dihydropyridine CCBs and non-dihydropyridine CCBs have been administered, with considerable differences in study duration and CCB dosage.
Several experimental studies have compared the efficacy of a dihydropyridine CCB and an ACEI [6,11,1517] in preventing the progression of diabetic renal disease in normotensive [6,11,17] or spontaneously hypertensive rats (SHR) [15,16]. In none of these studies was an effect achieved on UAE, glomerular hypertrophy, or glomerulosclerosis in response to lacidipine [1517] or nifedipine [6,11], in contrast to the effects with ACEI treatment. However, in one study lacidipine treatment significantly reduced ocular albumin vascular clearance [15], indicating a beneficial effect on diabetic retinal microvascular changes. In addition, one study reported lacidipine to abolish diabetes-associated early renal hyperfiltration and hyperperfusion to the same degree as ACEI treatment on short-term basis, while no long-term effect was observed on UAE or glomerulosclerosis [16]. Our group reported nitrendipine to normalize UAE in normotensive, diabetic rats and to reduce renal and glomerular hypertrophy when treatment was initiated right after diabetes induction [9,18]. Furthermore, nitrendipine treatment for 6 weeks, after a period of 3 months with untreated diabetes, reduced UAE, while no effects on manifest renal and glomerular enlargement were observed [10]. In diabetic SHR nitrendipine treatment failed to show any impact on the progression of diabetic, renal changes, which could be caused by a delayed reduction in systemic blood pressure [18].
In a long-term study with diltiazem, a non-dihydropyridine CCB, in alloxan-diabetic Beagle dogs [13,14] CCB-treatment was found equally effective in comparison with the ACEI lisinopril, in preventing the development of focal glomerulosclerosis and mesangial volume expansion, and in normalizing UAE. When both treatments were combined an additional effect was observed [13,14]. This observation is in accordance with a study in streptozotocin-diabetic rats, where diltiazem was found to normalize UAE concomitantly with a reduction in systemic blood pressure and also the preservation of heparan sulfate in the glomerular basement membrane was observed [12]. In contrast, other studies reported no renoprotective effect of verapamil, a non-dihydropyridine CCB similar to diltiazem, despite a reduction in systemic blood pressure [24].
Only one experimental study has compared the renoprotective effect of a dihydropyridine CCB and a non-dihydropyridine CCB, namely nifedipine and diltiazem. They were found to be equally effective in reducing UAE in diabetic SHR, while no such effect was observed with hydralazine therapy [7]. However, only few animals were randomized to each treatment group in this study [7].
Thus, experimental studies have reported conflicting results concerning the effects of CCBs on the progression of diabetic glomerulopathy, although several studies showed some renoprotective effect of both dihydropyridine and non-dihydropyridine CCBs. It may be hypothesized that the antiproteinuric effect is dependent on an attenuation of the diabetes-induced glomerular and renal hypertrophy and mesangial volume expansion, which could explain some of the divergent findings [19]. All CCBs appear to dilate the afferent arteriole, while their effects on the efferent arteriole and glomerular capillary pressure appear to be variable. Thus, CCBs renoprotective effect in hypertensive animals could be dependent on a concomitant reduction in systemic blood pressure. Finally, partial or subtotal nephrectomy was used in some studies [26], and this may cause changes in renal autoregulatory mechanisms causing increased intraglomerular pressure that is not sufficiently reduced by CCBs, despite a concomitant reduction in systemic blood pressure. Although the results obtained in animal studies can not directly be extrapolated to humans, further investigation is needed, with special reference to the effect of CCBs on renal morphological changes and the potential role of a combination of CCBs and ACEIs.
Insulin-dependent diabetic patients
Studies investigating the effect of CCBs in IDDM patients with incipient or overt, diabetic nephropathy are few, and they have almost uniformly been performed on a short-term basis.
Among the studies focusing on the effect of dihydropyridine CCBs in IDDM patients with incipient nephropathy, the authors of one study reported that nifedipine reduced UAE and glomerular filtration rate (GFR) in normotensive IDDM patients without influencing systemic arterial blood pressure after 1 year [20], while the authors of a second study reported a 40% increase in UAE following 6 weeks of nifedipine treatment [21]. However, the study by Mimran et al. [21] included only few patients in each group, and the study by Schnack et al. [20] showed a significant reduction in UAE following 12 months of nifedipine treatment when compared to baseline values, but no difference was observed when compared to placebo-treated, diabetic patients by the end of the study. In another study comparing nifedipine treatment with an ACEI, both treatments were capable of attenuating the development of overt nephropathy, although lisinopril was found to be most effective when the yearly increase in UAE was measured [22]. Since nifedipine is a slow-acting first generation dihydropyridine CCB, it may cause oscillations in systemic blood pressure, with a repercussion on intraglomerular vessels, causing increased intraglomerular pressure. The effect of second-generation dihydropyridine CCBs, such as nitrendipine, has only been reported in one study in IDDM patients with incipient nephropathy, where nitrendipine and the ACEI enalapril were found to reduce UAE to a similar extent following a 1-year treatment [23].
In IDDM patients with overt nephropathy, the efficacy of CCBs in preventing the progression of renal disease has been compared with that of ACEIs in several reports [2427]. All these studies failed to demonstrate an antiproteinuric effect of any of the CCBs investigated. In a study by Rossing et al. [24], nisoldipine was compared with lisinopril, and only lisinopril was found to significantly reduce UAE during the first year of treatment. Interestingly, nisoldipine treatment led to a better preservation of GFR than ACEI therapy. This observation is important since in overt diabetic nephropathy preservation of GFR is considered to be a better primary endpoint than a potential antiproteinuric effect. After 4 years of follow-up the preservation of GFR was similar between the two treatment groups, and no significant difference in UAE was observed [27]. The failure of nisoldipine [24,27], isradipine [26], and nifedipine [25] to reduce UAE could be explained by impaired proximal tubular reabsorption mechanisms observed in dihydropyridine CCB treated diabetic patients [25]. Thus, despite similar reductions in blood pressures observed with dihydropyridine CCBs and ACEI treatment in these studies, only ACEI treatment was able to reduce UAE. However, the preservation of GFR, as reported in nisoldipine and lisinopril treated patients [24,27], indicates that both ACEI and dihydropyridine CCBs exert a renoprotective effect in IDDM patients with overt nephropathy.
Non-insulin-dependent diabetic patients
The impact of CCBs on the development or progression of diabetic nephropathy has been investigated more frequently in NIDDM patients than in IDDM patients. Most studies have compared the effect of a CCB with that of an ACEI, although few studies compared dihydropyridine CCBs with non-dihydropyridine CCBs.
In NIDDM patients with incipient nephropathy and moderate hypertension, three well-designed studies compared the effect of a dihydropyridine CCB with an ACEI on the progression of renal disease. Patients were followed for at least one year. Dihydropyridine CCB and ACEI treatment were reported to be equally effective in terms of reducing UAE, concomitantly with a reduction in systemic blood pressure [2830]. One short-term study [31] also reported comparable effects of a dihydropyridine CCB, nicardipine, and enalapril, in preventing the progression of diabetic nephropathy. In contrast, lisinopril was reported to induce a greater reduction of UAE than nifedipine in hypertensive NIDDM patients with incipient nephropathy [32], but the study results are difficult to evaluate since an additional antihypertensive treatment with diuretics was given as lisinopril failed to render patients normotensive. Thus, in several studies dihydropyridine CCBs and ACEI were reported to reduce UAE to a similar extent, and in one study nitrendipine and enalapril were found to induce an increase in GFR of comparable magnitude, concomitantly with a reduction in UAE [33].
Similarly consistent reports with dihydropyridine CCBs have not been demonstrated for NIDDM patients with overt nephropathy. In three studies with dihydropyridine CCBs the authors failed to observe an antiproteinuric effect, despite a reduction in systemic blood pressure [3436], while in one short-term, placebo-controlled study nicardipine and captopril were reported to be equally effective in reducing UAE [37]. Of concern is a study reporting a 50% increase in UAE in isradipine-treated NIDDM patients, while a 30% reduction was observed with captopril [35]. It has to be noted, however, that this study in African Americans [35] was of only short duration. The prevalence of diabetes and the responsiveness to antihypertensive drugs are known to be influenced by ethnic background. Therefore the extrapolation of findings in this study [35] to the condition of Caucasian patients may be of limited value.
At the time when the ABCD-trial [38] was terminated prematurely, concern arose as to the safety of CCBs as antihypertensive drugs in diabetic patients, since increased cardiovascular morbidity was reported in nisoldipine-treated hypertensive NIDDM patients. As proposed by the authors of that study, this observation could be due to a protective effect of ACEI more than a hazardous effect of nisoldipine. In the ABCD-trial, nisoldipine and enalapril were reported to be similarly effective in slowing the progression of renal disease in NIDDM patients after 5 years of treatment [39]. In view of the very few long-term studies and the heterogeneity of data and study designs, it is premature to firmly comment on the effectiveness and safety of dihydropyridine CCBs in NIDDM patients with overt nephropathy.
In contrast the available reports on the effects of non-dihydropyridine CCBs in NIDDM patients with overt nephropathy are more consistent. In no less than six studies, five from the same institution, found the authors a significant reduction in proteinuria and an attenuation of declining GFR when verapamil [4043] or diltiazem [44,45] were compared with an ACEI. In these studies, CCBs were as effective as ACEIs, and superior to the effect of a ß-blocker [41]. In a recently published paper by Bakris et al. [43] a more marked decrease in UAE was observed when verapamil was combined with trandolapril than with either agent alone, despite similar reductions in blood pressure.
Conclusions and outlook
In this review we have updated the large amount of published data on the renal effects of CCBs in human and experimental diabetes. Despite some conflicting results most studies showed lowering effects of dihydropyridine CCBs on UAE in IDDM patients with incipient nephropathy. In IDDM patients with overt nephropathy dihydropyridines had no effect on proteinuria, but more importantly slowed the decline in renal function. Dihydropyridine CCBs appear to be effective in NIDDM patients with incipient nephropathy while their efficacy in overt nephropathy remains uncertain. In contrast, the beneficial effect of non-dihydropyridine CCBs in NIDDM patients with overt nephropathy appears to be well established. Furthermore, new experimental data support the notion that some dihydropyridine CCBs, in addition to effects on UAE, also affect early glomerular changes. Thus both dihydropyridine and non-dihydropyridine CCBs may be useful in the treatment of incipient and overt diabetic nephropathy. Both the ABCD-trial [38] and the FACET-study [46] were terminated due to a reported increase in cardiovascular events in NIDDM patients treated with a dihydropyridine CCB. However, both studies recorded cardiovascular events as secondary end-points, and failed to distinguish between a deleterious effect of CCB-treatment or a protective effect of ACEI treatment, or a combination of both. A recent review of CCBs effect on cardiovascular outcome in diabetic patients concluded that CCBs had an important place in antihypertensive treatment [47]. The ongoing ALLHAT study, which has included 15 000 diabetic patients, addresses the important issue whether some antihypertensive drugs provide better cardiovascular outcomes than others [48]. The ABCD-trial showed no differences in the effect of nisoldipine and enalapril on the progression of diabetic nephropathy after five years of treatment [39]. Only one study has investigated the long-term renoprotective effect of a CCB, namely nisoldipine, in IDDM patients. It was found that nisoldipine was as effective as an ACEI in preserving kidney function [27]. Although ACEI represent the drug of first choice in the treatment of hypertension in diabetic patients with or without incipient nephropathy, a combination of two or more drugs is often required to attain a sufficient reduction in blood pressure. CCBs may carry an advantage over other antihypertensive drugs in combination with ACEIs. Despite the premature termination of the ABCD-trial and the FACET-study, no change in the use of CCBs has been recommended after these studies were published [49]. Finally, the Syst-Eur trial reported the finding that nitrendipine reduced mortality and cardiovascular events in NIDDM patients [50]. No serious adverse effects of CCBs have been reported in IDDM patients. Future studies are warranted to fully characterize the effects of CCBs on renal haemodynamics and morphology. Similarly, the role of CCB treatment in combination with an ACEI in diabetic patients with various levels of renal impairment requires further investigation.
Notes
Correspondence and offprint requests to: Birgitte Nielsen MD, Medical Research Laboratory M (Diabetes and Endocrinology), Institute of Experimental Clinical Research, Aarhus University Hospital, DK-8000 Aarhus C, Denmark. E-mail: BirgitteNielsen{at}dadlnet.dk.
References