Introduction
Diabetes mellitus is rapidly increasing in its worldwide prevalence and is currently estimated to affect 7-8% of the US population.1 In 2005, 1.5 million new cases of diabetes were diagnosed in people aged 20 years or older in the US. In the not-so- distant past, type-2 diabetes mellitus was viewed as a seemingly benign condition, at least in the elderly, with little effect on life expectancy and/or renal function.2 It is now obvious that type-2 diabetes must be taken every bit as seriously as type-I diabetes, in part, because of its associated renal and cardiovascular complications.3 In fact, diabetes is the most common cause of end-stage renal disease (ESRD) in the US, accounting for 44% of new incident cases. In the US the number of persons who began treatment for ESRD relating to diabetes increased 162% from 1990 to 2003 (16,649-43,638 cases).4-5 This trend is also present in Japan, Australia, and New Zealand, as well as in most European countries.6
Incidence and prevalence counts for ESRD in the US are expected to increase by 44% and 85%, respectively, from 2000 to 2015.7 In kind, the proportion of ESRD patients derived from diabetes is expected to go up considerably during this time span. The increasing incidence and prevalence of diabetic nephropathy relates to a projected doubling of the number of patients with diabetes as well as a greater life expectancy and therefore more opportunity for late complications to present. Caring for patients with ESRD is costly, with more than US$18 billion per year currently spent in the US alone. The cost associated with the management of ESRD is expected to surpass US$28 billion by 2010.4 This epidemic is by no means exclusive to the US with similar economic figures being reported by other heavily industrialised countries.
Background
It has become a clinical imperative to treat diabetic nephropathy both early and aggressively. This has proven to be no easy task since these patients typically have difficult-to-manage hypertension and, moreover, debate still continues as to the optimal drug or drug class(es) to be used.8 To this end, two trials: the Irbesartan Diabetic Nephropathy Trial (IDNT) and The Reduction in End-Points in NIDDM with the Angiotensin-II Antagonist Losartan Study (RENAAL) were conceived and carried out in the mid- to late-1990s as a means to studying the effect of angiotensin-receptor blocker (ARB)-based therapy on renal failure progression in diabetic nephropathy.9-10
These trials both succeeded in demonstrating that ARB therapy with either losartan or irbesartan could slow the progression of renal disease (at equal levels of blood pressure [BP] reduction) more so than non-renin-angiotensin-system (RAS) anti-hypertensive therapies.9-10
The favourable results of these two studies provided the rationale for the preferred use of ARBs in the treatment of diabetic nephropathy.5 These studies made two important clinical observations: first, it was noted that baseline systolic BP was a stronger predictor of adverse renal outcomes than was diastolic BP in patients with type-2 diabetes-related nephropathy. As such, the risk for ESRD or death increased by 6.7% for every 10mm/Hg rise in baseline systolic BP.11 Second, in this type-2 diabetic population with nephropathy, baseline albuminuria was the major predictor for ESRD and the early anti-proteinuric effect of either losartan or irbesartan best forecast long-term renoprotection.
For example, in RENAAL patients with albuminuria >3g/g creatinine had a 1.92-fold higher risk for the cardiovascular end-point and a 2.70-fold higher risk for heart failure (HF) compared with patients with more modest degrees of albuminuria <1.5g/g creatinine. Modelling of the initial six-month change in risk parameters showed that albuminuria reduction was the sole parameter that predicted cardiovascular outcome with an 18% and 27% reduction in cardiovascular risk and HF, respectively, for every 50% fall in albuminuria.12 Proteinuria damages the kidney through multiple linked pathways, including induction of tubular chemokine expression, complement activation that then provokes interstitial inflammatory cell infiltration, and sustained fibrogenesis. Chemoattractants and adhesive molecules for inflammatory cells are upregulated by this glut of protein - processes that occur via activation of NF-B-dependent and NF-B-independent pathways.13
Perspective
A series of questions arise concerning therapy with the ARB drug class in diabetic nephropathy including:8
- Are the observed findings with irbesartan and losartan, in the IDNT and RENAAL trials respectively, reflective of a class effect?
- Does ethnicity influence the renoprotective effects of ARBs?
- Do ARBs offer superior protection to angiotensin-converting enzyme (ACE) inhibitor therapy in the setting of diabetic nephropathy?
- Is there an incremental benefit that arises from the addition of an ACE inhibitor to an ARB in diabetic nephropathy?
Class Effect
The first of these questions is a difficult one. Acceptance of the concept of a class-effect mandates rejecting the fact that ARBs are structurally and physicochemically different with compound-specific pharmacokinetics, tissue-penetration characteristics, and potency.14-16 Unfortunately, a true operational definition for 'class effect' does not exist for ARBs or, for that matter, any class of drugs. Instead a related term 'class labelling' is the terminology preferred by the US Food and Drug Administration (FDA). Further complicating the issue of class effect with ARBs is the innate difficulty in establishing dose-equivalence for the various pathobiologic effects of ARBs, such as BP reduction, renal protection, and/or an anti-proteinuric effect.
By definition, since all ARBs reduce BP there must be a class effect for this aspect of their action. True dose-equivalence for BP control has never been determined amongst the various ARBs; however, equivalent doses can be approximated by matching the upper and lower boundaries for dosing amongst the various compounds in the class. The issue of class effect becomes more unsettled when renal protection is the sought-after goal with ARB therapy. ARB-related nephroprotection relates to both BP control and reduction in urine protein excretion. The latter may be the most critical facet of how these compounds provide renoprotection. If such is the case then dose-equivalence for anti-proteinuric effects must be established before one ARB is substituted for another.
To date, this has not been an exercise undertaken with any rigour. When such comparisons are made, a number of confounding variables need to be controlled for: including differences in compound pharmacokinetics (renally-cleared or not), the degree to which BP is reduced and/or the dose of an ARB.17-18 As an example of the latter, ultra-high dosing of irbesartan (900mg/day), in a BP independent manner, reduced urine albumin excretion by 15% more than did a 300mg/day dose of this compound. Thus, unless formally studied it is uncertain as to what represents comparable anti-proteinuric doses amongst the various ARBs and/or ACE inhibitors.
Ethnicity and ARB Effect
In a post-hoc analysis of the RENAAL study, losartan retained its renoprotective properties in all ethnic groups studied. Treatment-induced change in albuminuria at month-six predicted the longer-term renoprotective effect in a similar manner for black, Asian, Hispanic and white patients. However, the RENAAL study was not powered to study variations (or not) in ethnic responses; thus, prospective trials are needed where the specific aim with ARB therapy is to explore whether the renal protection provided is comparable among different ethnic groups.20
ACE Inhibitor Versus ARB Therapy
This question can only be speculated on since the available evidence supporting one drug class (ACE inhibitors) over another (ARBs) is indeterminate and these drug classes have been sparingly studied head-to- head in renal disease. In one study, subjects with type-2 diabetes and early-stage nephropathy received either the ARB telmisartan (80mg/day) or the ACE inhibitor enalapril (20mg/day). The primary endpoint in this study was the change in the glomerular filtration rate (GFR) over a treatment period of five years. After five years, each drug similarly reduced BP and urine protein excretion with a GFR change that was little different between treatment groups ((17.5ml/minute/1.73m2 versus 15ml/minute/ 1.73m2 in the telmisartan and enalapril-treated subjects, respectively).21 These findings although suggestive of 'equivalence' do not apply per se to the more advanced stage of nephropathy, which characteristically has much greater levels of urine protein excretion.
What is currently lacking with ACE inhibitors is a hard end-point study in type-2 diabetic nephropathy.14 The absence of such a study is conspicuous when the RENAAL and IDNT trial results are considered, since these studies have provided the foundation for the use of ARBs in diabetic nephropathy.14,22 It is an accepted fact that ACE inhibitors and ARBs comparably reduce BP.6,11 However; comparability is yet to be established in the instance of renal disease, although the last decade has seen a wealth of information to appear, which would suggest that ACE inhibitors are renoprotective.23
Does the absence of hard end-point data for ACE inhibitors in type-2 diabetic nephropathy matter? Common sense would suggest that these two drug classes, if anything, would be interchangeable in how they afford renoprotection. What might influence the clinician's choice of one of these drug classes? Ideally, a study to ascertain the long-term renoprotective effect(s) of each class in diabetic nephropathy would provide some resolution to this debate; however, such a study is unlikely to ever be carried out. Alternatively, careful review of the available literature, although not definitive by any means, can provide guidance. As such, a recent systematic review of randomised clinical trials in this area has found that ACE inhibitors are the only agents with proven renal benefit in patients who have diabetes with no nephropathy and the only agents with proven survival benefit in patients who have diabetes with nephropathy;24-25 however, the relative effects of ACE inhibitors and ARBs on survival are unknown due to the lack of adequate head-to-head trials.
If a physician believes therapy should be strongly influenced by clinical trial findings, then the preferred treatment in this patient population should be an ARB in that proof-of-concept studies exist;9-10 otherwise, the selection of a drug class ,as has often been the case, is predicated on a physician's past experience and individual perspective on the literature.
Combination ACE Inhibitor and ARB Therapy
The practice of combining an ACE inhibitor and ARB is becoming increasingly more popular even as we struggle to gather the necessary experimental evidence to support the use of this combination.26 Whereas, the evidence is less than compelling in support of combined ACE inhibitor and ARB therapy for improving BP control, the benefits of this combination in renal disease are more appealing. The effect of combination therapy on protein excretion has been probed in a number of studies and the findings are positive (in several instances independent of additional BP reduction).27
The Combination Treatment of Angiotensin-II Receptor Blocker and Angiotensin-converting-Enzyme Inhibitor in Non-Diabetic Renal Disease (COOPERATE) study provided the first long-term trial results addressing the effect of dual blockade (the ARB losartan and the ACE inhibitor trandolapril) on primary renal end-points.
This study of 263 patients with non-diabetic renal disease demonstrated that 23% of patients reached the primary end-point during treatment with either monotherapy, whereas only 11% of patients on losartan (100mg) and trandolapril (3mg) doubled their serum creatinine or reached ESRD during a median of three-years of follow-up.28
As intriguing as this study might be, additional studies involving more diverse patient populations are required to determine whether long-term cardiovascular and renal outcomes are more favourably impacted with combination, rather than monotherapy. Finally, the optimal dose and time of administration relationship, as well as the specific drug make-up, of an ACE inhibitor and ARB combination is yet to be determined. It is clear however, that dose titration of an RAS blocker to a maximally effective dose, followed by add-on therapy of the other drug class, incrementally reduces urine protein excretion.29 Despite the considerable uncertainty surrounding the use of combination ACE inhibitor and ARB therapy, such dual blockade is in most instances safe and well-tolerated beyond the increased risk of developing hyperkalemia.30
Pharmacoeconomics
Within trial analytic and Markov model economic evaluations of the RENAAL and IDNT, and IRbesartan in type-2 diabetes with Micro-Albuminuria-2 (IRMA-2) studies suggest that treatment with ARBs in patients with type-2 diabetes with overt or incipient nephropathy confers health gains and net cost savings compared with conventional (amlodipine and standard non-ACE inhibitor) antihypertensive therapy.31-32
For reimbursement and reference pricing decisions, there is a need for a head-to-head comparison of an ACE inhibitor with ARBs to model all possible costs and effects of ACE inhibitors and ARBs. An element that might warrant inclusion in such an analysis is how these drugs lessen the risk of developing new-onset diabetes.33-34
Conclusions
Diabetic nephropathy is a global problem with no obvious end in sight. Healthcare expenditures for this disease are significant and spiralling upward. To date, there is no established method to reduce the primary rate of development of diabetic nephropathy; rather, current practice typically addresses diabetic nephropathy when it is already present either in the form of microalbuminuria or as the more advanced disease state, which is marked by macroproteinuria and declining renal function. Important elements to the treatment plan for diabetic nephropathy include meticulous BP control and reduction in urine protein excretion to levels below 1g/day. With regards to the latter, ACE inhibitors and/or ARBs are of considerable importance. In type-2 diabetic nephropathy the ARBs losartan and irbesartan remain the initial agents of choice; however, ACE inhibitors are not without a significant basis for use in diabetic nephropathy.