Why it may be unwise to stop ACEIs or ARBs too early

Wisam Younis, Pharm.D.
Program manager, Clinical Pharmacy Outcomes
Providence Health Plan

Uncontrolled hypertension, especially in patients with diabetes, is a major risk factor for cardiovascular disease and microvascular complications. Diabetic nephropathy is the leading cause of end-stage renal disease, occurring in 20 to 40 percent of patients with diabetes.1

Due to the renal protective properties of ACE inhibitors (ACEIs), and angiotensin receptor blockers (ARBs), the American Diabetes Association recommends that patients with diabetes who have persistent elevated albuminuria (30 mg a day or greater), or who require antihypertensive drug therapy, should be placed on an ACEI or ARB as a first-line therapy unless contraindicated by angioedema or pregnancy.1

The recently published Eighth Joint National Committee high blood pressure guidelines make a similar recommendation to initiate or add on ACEIs or ARBs for patients with hypertension and chronic kidney disease, with or without diabetes to improve kidney outcomes.2

For people with diabetes and hypertension without kidney disease who are not African American, JNC 8 recommends calcium channel blockers, thiazide diuretics, ACEIs or ARBs as initial antihypertensive therapy. This is based on moderate evidence to demonstrate comparable effects on overall mortality and cardiovascular, cerebrovascular and kidney outcomes. For the general African American population, calcium channel blockers and thiazide diuretics are recommended as initial treatment. However, based on expert opinion, the American Diabetes Association continues to prefer ACEI or ARBs as initial therapy for all people with diabetes who require antihypertensive therapy.

An ACEI or ARB should be initiated at a low dose then titrated gradually to higher doses as needed and tolerated. ACEI and ARB therapies should not be combined.

Although providers usually initiate an ACEI or ARB in their patients with hypertension and diabetes, they commonly discontinue these agents when the patient’s renal function begins to decline and serum potassium levels start to rise. Unfortunately, this is just when these medications may bring the most benefit.

An acute elevation in serum creatinine may be seen within two to five days after initiating an ACEI or ARB, especially in patients with chronic kidney disease. However, an ACEI or ARB can be safely continued in this population and may improve renal function even if serum creatinine stabilizes at a higher level than normal.

Studies have not defined an appropriate serum creatinine level for cases in which the use of an ACEI or ARB is contraindicated. A randomized, controlled trial published in the New England Journal of Medicine, however, reports of renal protection in patients with advanced chronic renal insufficiency and serum creatinine values between 3.1 and 5.0 mg/dL when compared to placebo, independent of lowering blood pressure.3

The National Kidney Foundation recommends:

  • Hypertensive patients with diabetes and chronic kidney disease stages 1-4 should be treated with an ACEI or an ARB, usually in combination with a diuretic.
  • In most patients, the ACEI or ARB can be continued if serum potassium is at or below 5.5 mEq/L or if GFR is not rapidly declining (30 percent under baseline within four months).

In addition, it is recommended that patients who suffer an acute kidney injury unrelated to ACEI continue the therapy when kidney function returns to baseline or is stabilized.

The pharmacodynamics of ACEIs and ARBs increases the risk of hyperkalemia. However, this risk can be significantly reduced by:

  • Decreasing the dosage of ACEI or ARB
  • Discontinuing potassium-sparing diuretics
  • Discontinuing potassium supplementation
  • Restricting dietary potassium intake
  • Initiating a low-dose loop diuretic

Other drugs, such as NSAIDs, that may decrease kidney function and increase hypertension and hyperkalemia risk also should be taken into account.

For patients who don’t tolerate ACEIs, the first alternative should be ARBs. Again, due to the lack of strong evidence on additional cardiovascular benefits and the added adverse effects, ACEI and ARB therapies should not be combined.4,5

  1. American Diabetes Association, www.diabetes.org. Accessed Nov. 14, 2013
  2. 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8). JAMA. E1-E14, 2013
  3. Hou FF, Zhang X, et al. Efficacy and Safety of Benazepril and Advanced Chronic Renal Insufficiency. N Engl J Med 2006; 354:131
  4. National Kidney Foundation. KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 update. Am J Kidney Dis. 60(5):850-886, 2012.
  5. National Kidney Foundation. KDOQI Clinical Practice Guideline on Hypertension and Antihypertensive Agents in Chronic Kidney Disease. Am J Kidney Dis. 43:S1-S290, 2004