What is the best combination of blood pressure (BP) medications for a patient with hypertension and possible comorbidities such as diabetes (Diabetes Mellitus) or kidney disease (Impaired Renal Function)?

Best Combination Blood Pressure Medications

For most patients with hypertension requiring combination therapy, the preferred regimen is a RAS blocker (ACE inhibitor or ARB) combined with a dihydropyridine calcium channel blocker or a thiazide/thiazide-like diuretic, preferably as a single-pill combination. 1

Initial Combination Therapy Strategy

Combination therapy is recommended as initial treatment for most patients with confirmed hypertension (BP ≥140/90 mmHg), with exceptions for patients aged ≥85 years, those with symptomatic orthostatic hypotension, moderate-to-severe frailty, or elevated BP (120-139/70-89 mmHg) with specific indications. 1

Preferred Two-Drug Combinations:

• ACE inhibitor + dihydropyridine calcium channel blocker (e.g., lisinopril + amlodipine) 1, 2
• ARB + dihydropyridine calcium channel blocker (e.g., losartan + amlodipine) 1, 2
• ACE inhibitor + thiazide/thiazide-like diuretic (e.g., lisinopril + chlorthalidone) 1
• ARB + thiazide/thiazide-like diuretic (e.g., losartan + chlorthalidone) 1

Single-pill combinations are strongly recommended over separate pills to improve adherence. 1, 2

Population-Specific Recommendations

Patients with Diabetes and Albuminuria (UACR ≥30 mg/g):

Start with an ACE inhibitor or ARB as the foundation, combined with either a dihydropyridine calcium channel blocker or thiazide-like diuretic. 1 This combination reduces progressive kidney disease risk while controlling blood pressure. 1

• ACE inhibitors and ARBs have superior antiproteinuric effects compared to other antihypertensive classes in diabetic kidney disease. 1
• Either ACE inhibitors or ARBs can be used; they appear equally effective in type 2 diabetes with macroalbuminuria. 1
• Diuretics potentiate the beneficial effects of ACE inhibitors and ARBs in diabetic kidney disease. 1

Patients with Chronic Kidney Disease (eGFR <60 mL/min/1.73 m²):

For patients with albuminuria, use ACE inhibitor or ARB as the base, combined with a loop diuretic (if eGFR <30 mL/min/1.73 m²) or thiazide-like diuretic (if eGFR ≥30 mL/min/1.73 m²). 1

• Continue ACE inhibitor or ARB therapy even as eGFR declines to <30 mL/min/1.73 m², as this may provide cardiovascular benefit without significantly increasing end-stage kidney disease risk. 1
• Thiazide diuretics lose diuretic efficacy when eGFR <30 mL/min/1.73 m², but chlorthalidone may retain some antihypertensive effect through vasodilation. 3

Black Patients:

Initial combination should include a thiazide-type diuretic or calcium channel blocker, as monotherapy with ACE inhibitors or ARBs produces smaller blood pressure reductions in Black patients. 4, 5 However, combining a diuretic with an ACE inhibitor or ARB eliminates racial differences in blood pressure response. 5

Patients with Coronary Artery Disease:

ACE inhibitors or ARBs are recommended as first-line therapy, combined with a dihydropyridine calcium channel blocker or thiazide-like diuretic. 1

Three-Drug Combination Therapy

When BP is not controlled with two drugs, escalate to a three-drug combination: RAS blocker + dihydropyridine calcium channel blocker + thiazide/thiazide-like diuretic, preferably as a single-pill combination. 1, 6

Example regimen: Lisinopril 40 mg + amlodipine 10 mg + chlorthalidone 25 mg daily 6

Critical Contraindications

Never combine an ACE inhibitor with an ARB - this dual RAS blockade increases risks of hyperkalemia, acute kidney injury, and syncope without providing additional cardiovascular benefit. 1, 2, 6

Avoid combining beta-blockers with thiazides as first-line therapy due to increased risk of developing diabetes. 1

Diuretic Selection: Important Nuances

Among thiazide-type diuretics, chlorthalidone is preferred over hydrochlorothiazide based on stronger outcome data and greater potency. 1, 7, 8, 9

• Chlorthalidone 25 mg is more potent than hydrochlorothiazide 50 mg, particularly for overnight blood pressure reduction. 7
• Chlorthalidone demonstrated superiority over lisinopril in preventing stroke and over amlodipine in preventing heart failure in the ALLHAT trial. 7, 8
• Chlorthalidone has pleiotropic effects beyond BP reduction, including favorable effects on cholesterol levels. 9
• Indapamide is an alternative thiazide-like diuretic with no negative impact on glucose or lipid metabolism. 9

Monitoring Requirements

Monitor serum creatinine/eGFR and potassium at baseline, 1-2 weeks after initiation or dose adjustment, and regularly thereafter when using ACE inhibitors, ARBs, or diuretics. 1, 2, 6

Reassess blood pressure 2-4 weeks after medication initiation or adjustment, with a goal of achieving target BP within 3 months. 1, 6

Beta-Blocker Role

Beta-blockers should only be added to combination therapy when there are specific compelling indications: angina, post-myocardial infarction, heart failure with reduced ejection fraction, or heart rate control. 1 They are not recommended as routine antihypertensive agents without these conditions. 1

Resistant Hypertension (Fourth-Line Agent)

If BP remains ≥140/90 mmHg on optimal doses of three drugs (RAS blocker + calcium channel blocker + thiazide diuretic), add spironolactone 25-50 mg daily as the preferred fourth agent. 6 Monitor potassium closely when combining with ACE inhibitor or ARB. 6