Combined Blockade of the Renin System: An Example of Hormesis

“The hermetic dose‐response may be reliably described as a being a stimulation in the low dose zone, followed by an inhibitory response at higher doses.” ¹

The renin‐angiotensin system is a well‐characterized vasoactive hormonal system that plays a crucial physiologic role for control of arterial pressure, intravascular volume, and serum potassium. Inhibition of this system through angiotensin‐converting enzyme (ACE) inhibition or angiotensin II receptor blockade (ARB) is highly beneficial for control of hypertension, amelioration of heart failure, and prevention of progression of diabetic nephropathy. ² , ³ , ⁴ Development of the direct renin inhibitor (DRI), aliskiren, has been added as another effective renin system inhibitor for use in these diseases. ⁵ , ⁶ If partial blockade of the renin‐angiotensin system (RAS) is beneficial through use of one of these drug classes, more complete antagonism might, theoretically, be even better. ⁷ This hypothesis is the rationale for clinical trials in which 2 or 3 classes for blockade of the RAS (ACE inhibitors, ARBs, or a DRI) have been compared with various control groups. For overall blockade of the RAS, a single class might be considered “low dose” and the combination of 2 or 3 together as “high dose.” Several previous trials have compared the combination of an ACE inhibitor and ARB with either one alone; the results, however, have not uniformly supported a favorable effect for theis combination. ⁸

The Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints (ALTITUDE) trial studied high‐risk, type 2 diabetic patients by comparing the addition of the DRI, aliskiren, or placebo in patients already on recommended treatment including either an ACE inhibitor or ARB. ⁹ A total of 8606 participants were enrolled. Nearly all were taking either an ACE inhibitor or ARB when entering the trial. ¹⁰ In December 2011, Novartis, maker of aliskiren, issued a media release announcing that the ALTITUDE trial was terminated on advice from the Data Monitoring Committee. Patients in the aliskiren arm of the trial had a higher occurrence of stroke, hypotension, renal impairment, and hyperkalemia. ¹¹ On April 20, 2012, the Food and Drug Administration issued a warning that aliskiren was contraindicated for treatment of diabetes and in those with chronic renal disease when given in combination with an ACE inhibitor or ARB, and that the combination drug containing aliskiren and valsartan would no longer be available as of July 2012. ¹²

Another recently published large trial, the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), studied the effect of combining an ACE inhibitor, ramipril, and an ARB, telmisartan, in participants at high risk for cardiovascular disease because of multiple risk factors, diabetes, and/or target organ damage. ¹³ The combination of ramipril and telmisartan was not superior to either drug alone for prevention of events, but adverse events, including hypotension, were significantly more frequent in the combination compared with either an ACE inhibitor or ARB alone. Another feature of ONTARGET was the overall J‐U curve of events in relation to blood pressure on treatment. ¹⁴

The pattern of a biphasic response to a medication or radiation has been named “hormesis” and identifies what may be a widespread biologic phenomenon. In experimental studies, hormesis has been observed in the biphasic response of hypertensive rats to a blueberry (antioxidant) diet with increased reactive oxygen pathways on brief treatment, but reduced reactive oxygen pathways with sustained diet treatment. ¹⁵ In this study, the short exposure was harmful and the sustained exposure was beneficial with regard to oxidative stress. Another example of time‐dependent hormesis is the transient initial reduction in glomerular filtration rate followed by later improvement in renal function when patients with diabetic nephropathy are treated with ACE inhibitors or ARBs. ¹⁶

ALTITUDE studied diabetic hypertensives and ONTARGET studied those at high risk for cardiovascular disease due to a combination of risk factors and target organ pathology. It seems likely that the hormedic effect of near‐complete blockade of the RAS will be increased in the high‐risk groups, such as those enrolled in these trials with high risk states including diabetic nephropathy, and may be less likely in healthier groups. Nonetheless, hormesis should be considered in selecting antihypertensive medications and doses for high‐risk patients, for new clinical trials, and for designing new clinical guidelines or advisories.