RAAS Blockade and Nephropathy
At the time of publication of the study by Lewis et al in 1993, there were multiple other ongoing trials treating people with either T1DM or T2DM and microalbuminuria and one with normotensive, nonalbuminuric T2DM that have confirmed the finding of a decrease in nephropathy and expanded the observation to other ACE inhibitors, suggesting that this is a class effect.59,84–87 The introduction of the ARB class provided an opportunity for large trials to assess renal and CV benefits.
Three trials, the Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria (IRMA-2) study, the Reduction of End Points in Non-Insulin Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan (RENAAL) study, and the Irbesartan Type 2 Diabetic Nephropathy Trial (IDNT) demonstrated that ARBs can impact the progression of diabetic nephropathy in T2DM at all stages of renal disease, ranging from microproteinuria to overt nephropathy and ESRD.61–63 These studies clearly demonstrated that this effect was in addition to that attributable to BP control alone and was associated with a delay in the need for dialysis or kidney transplant by at least 2 years. This benefit was confirmed in the HOPE study, which included 1808 people with diabetes treated with ramipril, and in the 1059 ACE-intolerant patients treated with telmisartan in the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND).88,89 Differences between the specific agents for RAAS blockade have really not been addressed in clinical trials. The Efficacy of Telmisartan Compared With Losartan in Reducing Proteinuria in Hypertensive Type 2 Diabetic Patients With Overt Nephropathy (AMADEO) study showed that telmisartan was more effective than losartan in reducing proteinuria in T2DM patients with nephropathy, but such comparisons have not been further explored.90 These clinical trials have led to the adoption of ACE inhibitors or ARBs as first-line therapy both for hypertension and for treatment of albuminuria in patients with diabetes.
Not all diabetic nephropathy has been prevented by treatment with ACE inhibitors or ARBs, thus studies have been designed to test whether combination ACE/ARB therapy may be more beneficial and to ascertain a threshold below which BP lowering provides no further benefit. The HOT study suggested that for high-risk patients (ie, those with diabetes), it may be beneficial to lower BP even if it is already within the “normal” range.91 This was formally tested in the recent Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, which did not show such a benefit for the composite of CV events but did demonstrate a significant decrease in the incidence of macroalbuminuria in the intensive therapy group (4733 patients followed for 4.7 years), which attained an average systolic BP of 119.3 mm Hg (95% confidence interval [CI], 118.9–119.7). However, there was no difference between the groups in the frequency of end-stage renal disease or the need for dialysis.92 In contrast, the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study, which randomized 5569 people to the addition of a fixed combination of perindopril and indapamide demonstrated a reduction in the risks of death and major macrovascular or microvascular complications.93 Comparison of these two trial populations has not revealed an explanation for this discrepancy in effect. Combination ACE/ARB therapy was tested in the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET), with the combination of ramipril and telmisartan showing superior control of albuminuria as compared with the individual therapies for the general study group. However, the data on the diabetes subgroup of 9612 people (3220 treated with combination therapy) have not yet been released.94
RAAS Blockade and Retinopathy
The role of the RAAS in diabetic retinopathy has not been as well studied as that in the kidney, thus evidence for RAAS inhibition in retinopathy is still much weaker than for nephropathy. Several recently published studies, the Daily-Dose Consensus Interferon and Ribavirin: Efficacy of Combined Therapy (DIRECT) trial, the Renin-Angiotensin System Study (RASS), and the ADVANCE Retinal Measurements (AdRem), have provided evidence that RAAS inhibition may also be beneficial in diabetic retinopathy.95–97
The AdRem study is a substudy of ADVANCE, involving the 1602 patients with T2DM from ADVANCE centers with access to retinal cameras between 2001 and 2008. At baseline and the final visit, 7-field stereoscopic retinal photographs were taken and graded by blinded readers (gradeable baseline and final photographs from 1241 patients). Progression of ≥2 steps in the Early Treatment of Diabetic Retinopathy Study (ETDRS) classification (using the eye with worst grading) was the primary outcome. Fewer patients on BP-lowering treatment (n=623) experienced incidence or progression of retinopathy compared with patients taking placebo (n=618), but the difference was not significant (odds ratio [OR], 0.78; 95% CI, 0.57–1.06; P=.12).95 BP-lowering treatment did specifically reduce the occurrence of macular edema (OR, 0.50; 95% CI, 0.29–0.88; P=.016) and arteriovenous nicking compared with placebo (OR, 0.60; 95% CI, 0.38–0.94; P=.025). These results must be interpreted cautiously as there was no reduction (P=.27) in the incidence and progression of retinopathy in the intensive glucose control (n=630) as compared with standard glucose control group. In contrast, the ACCORD Eye Study Group found that 4 years of intensive glycemic control or combination therapy for dyslipidemia but not intensive BP control slowed the progression of diabetic retinopathy in the subgroup of 2856 of 10,251 participants who underwent eye evaluations.98
Data from studies with type 1 diabetes mellitus (T1DM) appear to shed some light on these discrepancies as they suggest that RAAS blockade is most effective when initiated early in the development of retinopathy. The Diabetic Retinopathy Candesartan Trials Programme (DIRECT) was designed to assess whether the ARB, candesartan, could reduce the incidence and progression of retinopathy in T1DM.96 Participants with normotensive, normoalbuminuric T1DM without retinopathy were recruited to the DIRECT-Prevent 1 trial and those with existing retinopathy were recruited to DIRECT-Protect 1. The primary end points were incidence and progression of retinopathy and were defined as at least a two-step and at least a three-step increase on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, respectively. In these two studies, candesartan was able to reduce the incidence of retinopathy but did not provide a beneficial effect on retinopathy progression.99 Progression of retinopathy occurred in 127 (13%) participants in the candesartan group vs 124 (13%) in the placebo group. The hazard ratio for candesartan vs placebo was 0.82 (95% CI, 0.67–1.00; P=.0508) for incidence of retinopathy and 1.02 (95% CI, 0.80–1.31; P=.85) for progression of retinopathy.
However, these results were modest, however, raising the question as to how early in the development of retinopathy does the initiation of the RAAS blockade need to occur. The Renin-Angiotensin System Study (RASS), a multicenter diabetic nephropathy primary prevention trial, evaluated the severity and response to therapy of retinopathy in 285 normoalbuminuric patients with T1DM, who would not normally have been treated with RAAS blockade.97 Retinopathy was present in 64% of participants and was not related to albumin excretion rate, BP, serum creatinine, or glomerular filtration rate. However, all renal anatomical end points were associated with increasing severity of diabetic retinopathy, while controlling for other risk factors. These data demonstrate a significant association between diabetic retinopathy and preclinical morphologic changes of diabetic nephropathy in T1DM patients. The participants were then randomized to receive losartan (100 mg daily), enalapril (20 mg daily), or placebo and followed for 5 years. A total of 90% and 82% of patients had complete renal biopsy and retinopathy data, respectively.100 As compared with placebo, the odds of retinopathy progression by two steps or more was reduced by 65% with enalapril (OR, 0.35; 95% CI, 0.14–0.85) and by 70% with losartan (OR, 0.30; 95% CI, 0.12–0.73), independent of changes in BP, thus demonstrating a specific benefit of early RAAS blockade in the progression of retinopathy.
There are beginning to emerge data to support the role of the RAAS in these observed clinical effects, using the model of oxygen-induced retinopathy (OIR) in rats and cultured bovine retinal endothelial cells (BRECs) and bovine retinal pericytes (BRPs). Aldosterone stimulated proliferation and tubulogenesis in BRECs and exacerbated angiogenesis in OIR, which was attenuated with spironolactone. The MR and aldosterone-modulated retinal inflammation, with leukostasis and MCP-1 mRNA and protein in OIR being reduced by spironolactone and increased by aldosterone. A functional retinal MR-aldosterone system was evident with MR expression, translocation of nuclear MR, and aldosterone synthase expression, which was modulated by RAAS blockade. These data demonstrate that there is a functional RAAS in the retina and that further studies are needed to determine the optimal timing of therapy to help prevent both onset and progression of diabetic retinopathy.101
Angry fat also plays a role in retinal disease through modulation of inflammatory cytokines and adiponectin levels. The adiponectin knockout mice have been valuable for studying mechanisms of not just nephropathy but also retinopathy. When neonatal mice were subjected to ischemia-induced retinopathy, pathological retinal neovascularization during ischemia was more common in the adiponectin knockout mice than controls. This effect could be attenuated by provision of adiponectin knockout mice through adenovirus-mediated overexpression of adiponectin or treatment of wild-type (WT) mice with TZDs, which are known to increase adiponectin levels, while the TZDs had no effect on ischemia-induced pathological retinal vessel formation in the adiponectin knockout mice. Pioglitazone reduced TNF-α expression in ischemic retina in WT mice but not in APN-knock out mice.102,103 These data support the clinical trial data, that RAAS blockade is effective in combating diabetic retinopathy when started early in the disease process.
RAAS Blockade and CV Disease
RAAS blockade, in the form of ACE inhibitors, were introduced in the United States in 1981 for hypertension management. The recognition that RAAS blockade could prevent or slow diabetic nephropathy led to the design of trials with progression of renal disease as an end point that were not adequately powered to detect CV events. Large trials are either ongoing or recently completed that may provide CV outcomes data in patients with diabetes treated with RAAS blockade as first-line therapy.
The UKPDS-BP control substudy demonstrated that lowering BP decreased macrovascular complications, including mortality; however, it was not powered to ascertain a difference between treatment with captoprilor atenolol. Subsequently, the diabetic subgroup of the Captopril Prevention Project (CAPPP), in a prespecified analysis, demonstrated that first-line therapy with captopril resulted in a decrease in the primary end point, fatal and nonfatal myocardial infarction and stroke as well as other CV deaths, as compared with the conventional therapy group (relative risk, 0.59; P=.018).91 Studies such as ACCORD, ADVANCE, ONTARGET, and TRANSCEND were then designed to investigate the CV benefits of RAAS blockade with ACE inhibitors, ARBs, or the combination of both.
The ADVANCE trial is an international multicenter study of 11,140 people with type 2 diabetes who were randomized to treatment with a fixed combination of perindopril and indapamide or matching placebo, in addition to current therapy.104 The primary end points were composites of major macrovascular and microvascular events, defined as death from CV disease, nonfatal stroke or nonfatal myocardial infarction, and new or worsening renal or diabetic eye disease, and analysis was by intention to treat. After a mean of 4.3 years of follow-up, the relative risk of a major macrovascular or microvascular event was reduced by 9% (P=.04). The separate reductions in macrovascular and microvascular events were similar but were not independently significant. The relative risk of death from CV disease was reduced by 18% (P=.03) and death from any cause was reduced by 14% (P=.03). There was no evidence that the effects of the study treatment differed by initial BP level or concomitant use of other treatments at baseline. While ADVANCE showed a benefit on mortality and macrovascular events, ACCORD did not.92 As with the nephropathy data, the reasons for this discrepancy are not yet apparent. It is not yet known whether the ACE/ARB combination will provide any greater CV benefit as the data from the diabetic subgroup are not yet available from ONTARGET. TRANSCEND, which studied candidates eligible for ONTARGET who were intolerant to ACE inhibitors, also has a large diabetic subgroup from whom the data are not yet available.
A potential challenge in demonstrating a CV benefit of RAAS blockade in diabetes is that it may need to be initiated very early, to block the effects of the angry fat, and be of long duration to prevent the end-organ damage in the heart. Nonetheless, once heart failure is present, RAAS inhibition clearly has an impact on multiple CV outcomes, whether the person has diabetes mellitus or not.105 The argument for early RAAS blockade to prevent the development of heart failure is well grounded in animal data. The aging mouse model has been used to demonstrate that chronic RAAS inhibition reduces cardiac fibrosis, which would then help to prevent the diastolic dysfunction that progresses to heart failure.106 This effect is likely mediated both through inhibition of the local and circulating RAAS. An overactive cardiac RAAS promotes heart remodeling through the development of left ventricular hypertrophy (LVH) and myocardial fibrosis and leads to an increase in perivascular inflammation that is associated with worsening of the myocardial fibrosis.107 Increased activity of the circulating RAAS, such as that promoted by the angry fat, contributes to the development of volume overload and vasoconstriction, with consequent increases in left ventricular diastolic filling pressures and increased stress on the stiff heart.108,109 Despite the clearly beneficial effects of RAAS blockade on the underlying pathophysiology, the clinical trial data do not yet show the expected benefits on CV outcomes. Thus, many questions remain as we work to determine a clinical strategy for optimal RAAS blockade. The fact that none of our current therapies provide complete RAAS inhibition raises the possibility that the addition of a DRI to the currently utilized combinations may have further benefit.110 Studies are ongoing to test this strategy.