What should be added to losartan (angiotensin II receptor antagonist) and amlodipine (calcium channel blocker) for uncontrolled hypertension in a patient with diabetes?

Management of Uncontrolled Hypertension in Diabetes: Adding a Thiazide-like Diuretic

For a patient with uncontrolled hypertension on losartan and amlodipine who also has diabetes, a thiazide-like diuretic (chlorthalidone or indapamide) should be added as the next agent. 1, 2

Rationale for Adding a Thiazide-like Diuretic

The American Diabetes Association guidelines specifically address this scenario under "Resistant Hypertension," which is defined as blood pressure ≥140/90 mmHg despite therapy with three antihypertensive medications including a diuretic 1. Your patient is already on two of the recommended first-line agents:

1. An ARB (losartan) - which is appropriate for patients with diabetes
2. A dihydropyridine calcium channel blocker (amlodipine)

The missing component from the recommended three-drug regimen is a thiazide-like diuretic. Adding this third agent follows the evidence-based treatment algorithm for hypertension in diabetes 1, 2.

Medication Selection

• Preferred agents: Chlorthalidone or indapamide are the preferred thiazide-like diuretics due to their longer duration of action and stronger evidence for cardiovascular event reduction 1, 2
• Alternative: Hydrochlorothiazide if the preferred agents are unavailable
• Dosing: Start with low doses (e.g., chlorthalidone 12.5 mg daily) and titrate as needed 3

Monitoring After Adding the Thiazide Diuretic

• Check serum creatinine, eGFR, and potassium within 2-4 weeks of initiating therapy 1
• Monitor for potential adverse effects:
  • Electrolyte disturbances (hypokalemia, hyponatremia)
  • Metabolic effects (hyperglycemia, hyperlipidemia)
  • Volume depletion symptoms

If Blood Pressure Remains Uncontrolled

If blood pressure remains uncontrolled despite optimized doses of all three agents (ARB, CCB, and thiazide-like diuretic), the next step would be to add a mineralocorticoid receptor antagonist (spironolactone) 1, 2. This approach is supported by evidence showing that mineralocorticoid receptor antagonists are effective for resistant hypertension in patients with type 2 diabetes when added to existing treatment with an ARB, thiazide-like diuretic, and dihydropyridine calcium channel blocker 1.

Important Considerations

• Maximize current medications: Ensure losartan is at the maximum tolerated dose (typically 100mg daily) before adding additional agents 4
• Adherence assessment: Consider medication adherence testing if blood pressure remains uncontrolled despite multiple medications 1
• Avoid certain combinations: Do not combine ACE inhibitors with ARBs as this increases adverse effects without additional benefit 1, 2
• Blood pressure goal: Target BP <130/80 mmHg for patients with diabetes 1, 2
• Regular monitoring: Continue annual monitoring of renal function and electrolytes 1

Additional Supportive Evidence

Research has shown that adding a thiazide diuretic to ARB therapy provides superior blood pressure reduction compared to simply increasing the ARB dose alone 4. The ADHT trial demonstrated that adding amlodipine to either an ACE inhibitor or ARB significantly improved blood pressure control in patients with diabetes and hypertension 5, supporting the multi-drug approach you're already using.

When comparing amlodipine to losartan in hypertensive patients with diabetes, amlodipine demonstrated an improved pattern of pulse wave reflection 6, suggesting complementary mechanisms that support their combined use.