The results of clinical trials have been controversial as to whether angiotensin-converting enzyme inhibitors (ACEI) alone or angiotensin receptor blockers (ARB) alone or ACEI combined with ARB therapy are preferable in patients with chronic kidney disease with proteinuria.
A new meta-analysis by Piero Ruggenenti and Giuseppe Remuzzi, MD, recently published in The Lancet, shows that dual blockade of the renin-angiotensin system (RAS) is the most effective means of preventing the development of end-stage renal disease (ESRD) in patients with diabetes and kidney disease. When individualized by careful dose adjustment, combination therapy should be the most effective tool for renal protection.
A meta-analysis of antihypertensive medications in patients with diabetes showed that combination therapy with ACEI and ARB ranked first in preventing ESRD in 43,256 patients with diabetes and kidney disease, followed by ACEI and ARB alone. This analysis showed that the benefit of treatment was independent of blood pressure control and was associated with improvements in proteinuria.
Calcium channel blockers (CCB) did not appear to have any perceived renal protective effect, while renin inhibitors were associated with progression of renal disease. Comparative analyses showed lower mortality with ACEIs (either alone or in combination with CCB), ARBs or diuretics compared to non-RAS inhibitors.
Evidence suggests that improved patient survival with ACEI-based drugs is not a myth. Previous data from a meta-analysis of the same population showed that ACEI-treated diabetic patients reduced all-cause mortality and cardiovascular mortality.
However, due to the well-known limitations of network meta-analyses, data on the renoprotective effects of dual RAS blockade have reignited the debate about the role of ACEI and ARB combination in the prevention and treatment of diabetic nephropathy.
The combined treatment strategy is more effective in RAS inhibition compared to the other agents alone (even at the maximum recommended dose). Since the progression of renal disease is largely mediated by angiotensin II (AngII), dual blockade of RAS synergistically blocks AngII production and activation, which can more effectively reduce proteinuria and prevent or even reverse glomerulosclerosis, glomerular interstitial injury and tubular damage.
The benefits of RAS dual blockade in humans were first reported in the CALM study. The study included 199 patients with hypertension, type 2 diabetes and microproteinuria, and 12 weeks of combination therapy was more effective in reducing proteinuria compared to patients treated with candesartan or lenopril alone.
Many subsequent studies have found that in patients with type 1 and type 2 diabetes mellitus with microalbuminuria or massive proteinuria, the combination of ACEI and ARB was more effective in reducing proteinuria than ACEI or ARB treatment alone. Because lowering proteinuria is associated with lower renal and cardiovascular events, the outstanding proteinuria-lowering effect of RAS dual blockade is expected to translate into long-term effective renal and cardiovascular protection, especially in patients with diabetic nephropathy.
These expectations were challenged by the VA NEPHRON D study, a randomized controlled trial comparing combination therapy (ACEI lenopril and ARB losartan) with losartan alone in 1448 patients with type 2 diabetes and overt nephropathy.
Unfortunately, this study was stopped prematurely for safety and non-value reasons, leading many diabetologists and nephrologists to abandon the dual RAS blockade strategy, classifying it as a harmful intervention for diabetic patients. Even medical regulatory bodies (e.g., the European Committee for Medicinal Drugs) have not recognized the novel protective role of dual therapy for ESRD, limiting RAS combination therapy.
In fact, at the time of closure of the VA NEPHRON D study, dual RAS blockade had reduced ESRD events by 34% compared to colesartan alone, an effect that had never been obtained before. The decreased risk was associated with a significant reduction in proteinuria.
In the RENAAL study, the proteinuria-lowering effect of losartan compared to the placebo group was similar to the reduction in risk of ESRD. However, the therapeutic effect was seen in small amounts at 2.2 years of follow-up and was only statistically significant at 3.2 years. When the VA NEPHRON D study was stopped and the RENALL trial was prematurely stopped, the renoprotective effect of losartan may have been inevitably missed as well.
In the RENALL study, patients may have been tested more intensively and without forced increases in therapeutic dose, which prevented unexpected adverse events in the VA NEPHRON D study and made the study free of safety concerns.
Suggestions for diabetologists and nephrologists to consider a combination treatment strategy of ACEI and ARB
The fact that adverse events (e.g., hypotension, hyperkalemia, acute kidney injury AKI) led to premature study closure lost the opportunity to demonstrate a clinically relevant renoprotective effect. Indeed, excessive blood pressure decreases may promote cardiovascular events and AKI, especially in elderly diabetic patients.
Moreover, complete RAS blockade may blunt renal vascular adaptation (autoregulation) and reduce perfusion pressure, which extremely reduces glomerular pressure and perfusion, and AKI and hyperkalemia may follow, especially when renal perfusion is further impaired, such as with renal vascular disease (affecting more than 20% of diabetic patients), or when dehydration, bleeding, heart failure, trauma, sepsis and other co-morbid diseases.
The excess adverse events associated with dual RAS blockade in the VA NEPHRON D study can be explained by treatment-related and potentially reversible hemodynamic effects. Convincingly, the recommended low-dose combination of ACEI and ARB resulted in effective RAS blockade without excessive drop in blood pressure and with minimal adverse effects. In this context, the ongoing VALID study was designed to verify whether half doses of ACEI and ARB are more effective than alone in slowing GFR reduction and delaying the onset of ESRD.
While awaiting the results of the VALID study, we recommend that diabetologists and nephrologists, as well as healthcare administrators, reconsider the strategy of ACEI in combination with ARB, as this strategy may be the most effective means to safely reduce or prevent the progression of chronic proteinuric nephropathy, providing individualized doses and tolerances. This approach has been shown to stabilize renal function and prevent ESRD.
Based on these data, it is painful to learn that colleagues have abandoned dual blockade strategies out of fear of patients developing AKI or other complications being charged, just as they have abandoned chemotherapy out of fear of febrile neutropenia in cancer patients. Of course, the dual blockade strategy requires more care on the part of the clinician to ensure that RAS blockade is discontinued promptly in the event of acute disease, but the benefits of this therapy warrant the extra effort.