What would be a reasonable third antihypertensive agent for a patient with diabetes on lisinopril (Angiotensin-Converting Enzyme inhibitor) and amlodipine (Calcium Channel Blocker)?

Third Antihypertensive Agent for Diabetic Patients on Lisinopril and Amlodipine

A thiazide-like diuretic should be added as the third antihypertensive agent for a patient with diabetes who is already on lisinopril (ACE inhibitor) and amlodipine (calcium channel blocker). 1

Rationale for Adding a Thiazide-like Diuretic

• The American Diabetes Association recommends a three-drug regimen consisting of an ACE inhibitor/ARB, a calcium channel blocker, and a thiazide-like diuretic when blood pressure targets are not achieved with two medications 1
• This combination (ACE inhibitor + CCB + thiazide-like diuretic) is specifically recommended in treatment algorithms for patients with diabetes and hypertension 1
• Long-acting thiazide-like diuretics such as chlorthalidone and indapamide are preferred over standard thiazides due to their superior cardiovascular event reduction 1
• This three-drug combination targets different and complementary pathophysiological mechanisms of hypertension, providing more comprehensive blood pressure control 1

Considerations for Thiazide-like Diuretics

• Monitor for metabolic effects including glucose control, as thiazides can cause modest elevations in blood glucose, though this effect is dose-dependent and less significant with modern lower dosing regimens 2, 3
• Check serum potassium and renal function at baseline and at least annually when combining an ACE inhibitor with a diuretic 1
• Start with lower doses of thiazide-like diuretics to minimize metabolic side effects while still achieving antihypertensive benefits 2, 4

Alternative Options if Thiazide-like Diuretics Are Contraindicated

If thiazide-like diuretics are contraindicated or not tolerated:

• Consider a mineralocorticoid receptor antagonist (spironolactone) as an alternative third agent, especially for resistant hypertension 1
• When adding a mineralocorticoid receptor antagonist to an ACE inhibitor, careful monitoring of potassium levels is essential due to increased risk of hyperkalemia 1, 5
• Beta-blockers can be considered as an alternative third-line agent, though they may have less favorable metabolic effects in diabetic patients 1, 3

Blood Pressure Targets and Monitoring

• The target blood pressure for most patients with diabetes is <130/80 mmHg 1, 5
• After adding the third agent, continue to monitor blood pressure regularly to assess efficacy 1
• If blood pressure targets are still not achieved on three classes of antihypertensive medications (including a diuretic), consider referral to a specialist with expertise in blood pressure management 1

Common Pitfalls to Avoid

• Never combine an ACE inhibitor (lisinopril) with an ARB or direct renin inhibitor, as this increases adverse effects without providing additional benefit 1, 5
• Avoid using non-dihydropyridine calcium channel blockers (verapamil, diltiazem) with the current regimen as they may have overlapping effects with amlodipine 1
• Don't discontinue the ACE inhibitor in a diabetic patient unless absolutely necessary, as it provides specific renoprotective benefits beyond blood pressure control 6

Following this evidence-based approach will optimize blood pressure control while providing cardiovascular and renal protection in patients with diabetes.