A current evaluation of the safety of angiotensin receptor blockers and direct renin inhibitors

Abstract

The safety of angiotensin II receptor blockers (ARBs) for the treatment of hypertension and cardiovascular and renal diseases has been well documented in numerous randomized clinical trials involving thousands of patients. However, recent concerns have surfaced about possible links between ARBs and increased risks of myocardial infarction and cancer. Less is known about the safety of the direct renin inhibitor aliskiren, which was approved as an antihypertensive in 2007. This article provides a detailed review of the safety of ARBs and aliskiren, with an emphasis on the risks of cancer and myocardial infarction associated with ARBs. Safety data were identified by searching PubMed and Food and Drug Administration (FDA) Web sites through April 2011. ARBs are generally well tolerated, with no known class-specific adverse events. The possibility of an increased risk of myocardial infarction associated with ARBs was suggested predominantly because the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial reported a statistically significant increase in the incidence of myocardial infarction with valsartan compared with amlodipine. However, no large-scale, randomized clinical trials published after the VALUE study have shown a statistically significant increase in the incidence of myocardial infarction associated with ARBs compared with placebo or non-ARBs. Meta-analyses examining the risk of cancer associated with ARBs have produced conflicting results, most likely due to the inherent limitations of analyzing heterogeneous data and a lack of published cancer data. An ongoing safety investigation by the FDA has not concluded that ARBs increase the risk of cancer. Pooled safety results from clinical trials indicate that aliskiren is well tolerated, with a safety profile similar to that of placebo. ARBs and aliskiren are well tolerated in patients with hypertension and certain cardiovascular and renal conditions; their benefits outweigh possible safety concerns.

Azilsartan in Patients With Mild to Moderate Hypertension Using Clinic and Ambulatory Blood Pressure Measurements

“…Serious AEs were distributed across the AZL treatment groups and were not considered related to study drug. The safety profile is consistent with previous data for other ARBs and was confirmed in subsequent phase 3 studies …”

Angiotensin II type 1 receptor blockers increase tolerance of cells to copper and cisplatin

“…However, the ARBs Candesartan Cilexetil, Losartan and Olmesartan Medoxomil display activity against both Cu and Cp (Table 1). Interestingly, Candesartan Cilexetil and Olmesartan Medoxomil are ester prodrug versions of their parent compound Candesartan and Olmesartan, respectively, and display improved bioavailability 6869. It is therefore plausible that the uptake of these prodrugs in yeast is more efficient, and thereby is a determinant of their protective effect against Cu and Cp.…”

Single‐Center Evaluation of the Pharmacokinetics and Safety of the Angiotensin II Receptor Antagonist Azilsartan Medoxomil in Mild to Moderate Hepatic Impairment

“…Cardiovascular disease, therefore, remains a substantial health concern, and improved BP‐lowering drugs and more effective strategies for currently available antihypertensive drugs are needed . Angiotensin II receptor blockers (ARBs) are a drug class generally considered to be among the best tolerated and more effective agents in the realm of antihypertensives, even though there are some differences between individual drugs . The eighth and the most recently approved drug of the ARBs is azilsartan medoxomil (AZL‐M); it is approved at doses of 20 to 80 mg once daily (40 to 80 mg in the United States), alone or in combination with other antihypertensive agents …”

“…4 Angiotensin II receptor blockers (ARBs) are a drug class generally considered to be among the best tolerated and more effective agents in the realm of antihypertensives, even though there are some differences between individual drugs. [5][6][7][8][9][10] The eighth and the most recently approved drug of the ARBs is azilsartan medoxomil (AZL-M); it is approved at doses of 20 to 80 mg once daily (40 to 80 mg in the United States), alone or in combination with other antihypertensive agents. [11][12][13][14][15][16][17] AZL-M is a prodrug potassium salt that is rapidly hydrolyzed to the active moiety, AZL, and is not detected in plasma after oral administration.…”