RAS Blockade for Every Diabetic Patient: Pro and Con
Luis M Ruilope, MD, and Anna Solini, MD, PhD, presented a pro/con argument article in the May 2011 edition of Diabetes Care. They were tackling the question of whether renin-angiotensin system (RAS) inhibitors should be used in every patient with type 1 diabetes or type 2 diabetes. The suggestion that this could be done comes from the known role of RAS blockade in blood pressure regulation and organ protection.
The counter argument to this is that RAS inhibitors should not necessarily be used in every patient; there could be better options for achieving the same goal, including calcium-channel blockers—alone or in combination with ACE inhibitors.
The arguments will be summarized here.
- According to the European Society of Hypertension and the European Society of Cardiology, the first monotherapy given to a diabetic patient with elevated blood pressure and with the presence of micro- or macroalbuminuria should be an RAS suppressor. This can be an ACE inhibitor or an angiotensin receptor blocker (ARB).
- RAS suppressors have a capacity to control blood pressure alone or in combination. The Avoiding Cardiovascular events through Combination therapy in Patients Living with Systolic Hypertension study (ACCOMPLISH) showed “very positive and early results” for the use of RAS suppressors in combination with a diuretic and or a calcium channel blocker.
- RAS suppressors have a capacity to prevent and regress target organ damage (TOD). Preventing new onset microalbuminuria is a part of preventing TOD (specifically, protecting the renal system) in diabetes patients, and this is dependent on controlling blood pressure and suppressing RAS (as shown by the Bergamo Nephrologic Diabetes Complications Trial [BENEDICT] and the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation [ADVANCE] studies).
Lowering albuminuria using RAS inhibitors also protects the cardiovascular system (as shown by the Losartan Inteventaion For Endpoint reduction in hypertension [LIFE] study, as well as in the Reduction of End Points in Type 2 Diabetes With the Angiotensin II Antagonist Losartan [RENAAL] study).
- RAS suppressors have a capacity to protect patients with a high global cardiovascular risk. Meta-analysis of the Heart Outcomes Prevention Evaluation (HOPE), European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA), and Prevention of Events with Angiotensin-Converting Enzyme Inhibition (PEACE) studies showed that patients with diabetes have a similar risk level as nondiabetic patients in situation of secondary prevention. For those nondiabetic patients, RAS inhibitor administration is mandatory to prevent cardiovascular events and death. Therefore, regardless of renal outcome (and whether RAS suppression does not protect renal function in the absence of albuminuria), RAS inhibitors should be mandatory.
- The nephroprotective effect of RAS inhibitors is still up for debate. BENEDICT is the only RCT addressing the primary prevention of diabetic nephropathy (through preventing microalbuminuria). In it, ramipril significantly reduced microalbuminuria incidence in type 2 diabetes patients over a 5-year follow-up period--but the results have not been replicated.
- There is scant trial evidence for the superiority of RAS inhibitors in reducing cardiovascular risk when compared to other antihypertensive medications. Many clinical trials recently have concluded that the 4 main classes of drugs—diuretics, RAS-active compounds, calcium channel blockers, and β-blockers—“have a substantially identical antihypertensive efficacy.”
Additionally, it should be pointed out that the ethnicity of the patient needs to be taken into account when beginning an antihypertensive therapy. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study and LIFE study showed that a diuretic-based therapy is better than an RAS suppressor for black hypertensive patients without renal disease or heart failure.
- While RAS inhibitors are said to have cardioprotective mechanisms beyond lowering blood pressure, these other mechanisms may not significantly reduce the cardiovascular risk of a patient with diabetes. There is little clinical trial evidence for more cardioprotective effects of RAS inhibitors, although there is cellular and animal model evidence of the anti-inflammatory and antiproliferative properties of RAS-active compounds.
It can be said that RAS inhibitors provide nephroprotection--better than other antihypertensive agents--but there isn’t evidence to be able to say that they provide better cardioprotection.
The most important aspect of blood pressure control in patients with diabetes is actually lowering the blood pressure to goal. Most physicians will reflexively place a diabetic patient on a RAS-inhibitor at the first sign of hypertension. However, the first step should be measuring kidney function and albuminuria.
Microalbuminuria (30-300 mcg/mg) is not a surrogate for diabetic nephropathy, but rather a marker of inflammation. Other causes of microabluminuria include poor glucose control, poorly controlled blood pressure, elevated cholesterol, a high salt diet, and infection. Physicians should address these other etiologies of microalbuminuria and monitor for improvement.
Rather than assuming the patient has early signs of diabetic nephropathy and automatically treating with a RAS blocker, patients should be assessed for other causes of microalbuminuria. If a diabetic patient has macroalbuminuria (>300 mcg/mg), then there is an indication to treat with an ACE or ARB.