What is the best initial medication for a patient with hypertension, considering comorbidities such as diabetes, kidney disease, coronary artery disease, or peripheral artery disease?

Best Initial Blood Pressure Medication

For most patients with hypertension, start with a thiazide-like diuretic (chlorthalidone 12.5-25 mg daily) as first-line monotherapy, but immediately switch to ACE inhibitors or ARBs as first-line agents when specific comorbidities are present: diabetes with albuminuria, chronic kidney disease, heart failure, or coronary artery disease. 1

Blood Pressure Severity Determines Single vs. Combination Therapy

• Stage 1 hypertension (140-159/90-99 mmHg): Begin with single-agent therapy 1
• Stage 2 hypertension (≥160/100 mmHg): Immediately initiate two-drug combination therapy, as this achieves control faster and improves adherence 2, 1

First-Line Medication Selection for Uncomplicated Hypertension

Chlorthalidone is superior to hydrochlorothiazide and should be the preferred thiazide diuretic based on:

• Strongest outcome data for reducing cardiovascular mortality and morbidity 1
• Superior 24-hour blood pressure control compared to hydrochlorothiazide at equivalent doses 3
• Proven efficacy in landmark trials (SHEP, ALLHAT) demonstrating reduced stroke and cardiovascular events 4
• Starting dose: chlorthalidone 12.5-25 mg once daily 1, 5

Alternative first-line options include ACE inhibitors (lisinopril 10 mg daily), ARBs (losartan 50 mg daily), or calcium channel blockers (amlodipine 5 mg daily), though these lack the mortality benefit demonstrated with thiazides 1, 6, 7, 8

Comorbidity-Driven Medication Selection (Critical Decision Points)

Diabetes Mellitus

• With albuminuria (UACR ≥30 mg/g): ACE inhibitor (lisinopril 10 mg daily) or ARB (losartan 50 mg daily) is mandatory first-line therapy to reduce progressive kidney disease 2, 9
• Without albuminuria: Thiazide diuretics, ACE inhibitors, ARBs, or calcium channel blockers are all appropriate 2
• Target blood pressure: <130/80 mmHg 2

Chronic Kidney Disease

• ACE inhibitor or ARB is first-line therapy regardless of diabetes status 2, 1
• Use ARB if ACE inhibitor not tolerated 2
• Continue therapy even as eGFR declines to <30 mL/min/1.73m² for cardiovascular benefit 9

Heart Failure

• Reduced ejection fraction: Guideline-directed beta blockers (carvedilol, metoprolol succinate, bisoprolol) plus ACE inhibitor or ARB 2
• Preserved ejection fraction: Diuretics for volume overload, add ACE inhibitor or ARB for additional blood pressure control 2

Coronary Artery Disease

• ACE inhibitor or ARB is first-line therapy 2, 1, 6
• For stable angina: Add beta blocker, then dihydropyridine calcium channel blocker for additional control 2
• Post-MI: Guideline-directed beta blocker plus ACE inhibitor 2

Peripheral Artery Disease

• Use standard first-line agents (thiazides, ACE inhibitors, ARBs, or calcium channel blockers) 2

Two-Drug Combination Therapy for Stage 2 Hypertension

Preferred combination: Chlorthalidone 12.5-25 mg + lisinopril 10 mg daily based on ALLHAT trial data showing superior cardiovascular outcomes 1

Alternative combinations:

• Chlorthalidone 12.5-25 mg + amlodipine 5 mg daily 1
• ACE inhibitor or ARB + calcium channel blocker 1, 6

Fixed-dose single-pill combinations are strongly preferred to improve adherence 6

Critical Contraindications and Monitoring

ACE Inhibitors/ARBs

• Absolutely contraindicated in pregnancy due to fetal injury and death 1
• Avoid in history of angioedema or bilateral renal artery stenosis 1
• Monitor serum creatinine/eGFR and potassium at least annually, more frequently if eGFR <60 mL/min/1.73m² 2, 9
• Never combine ACE inhibitor + ARB or add direct renin inhibitor, as this increases adverse events without benefit 2, 9, 6

Thiazide Diuretics

• Monitor electrolytes, particularly potassium, which decreases in dose-dependent manner 10
• Use caution in patients with preexisting diabetes or gout, though cardiovascular benefits outweigh metabolic concerns 10
• Low-dose therapy (12.5-25 mg) minimizes metabolic side effects while maintaining efficacy 5, 10

Titration and Follow-Up Strategy

• Recheck blood pressure within 1 month after initiating therapy 1
• Aim to achieve target blood pressure within 3 months 1
• For single-agent therapy: Increase to full dose before adding second agent 1
• For two-drug therapy: Escalate to triple therapy (RAS blocker + calcium channel blocker + thiazide diuretic) if blood pressure remains ≥140/90 mmHg after 2-4 weeks 1, 6

Common Pitfalls to Avoid

• Do not delay pharmacological therapy for lifestyle modifications alone in patients with blood pressure ≥140/90 mmHg 1, 6
• Do not use hydrochlorothiazide when chlorthalidone is available, as chlorthalidone has superior 24-hour control and better cardiovascular outcomes 1, 3
• Avoid therapeutic inertia: Failing to intensify treatment when blood pressure remains uncontrolled is a major barrier to achieving targets 1
• Do not maximize single-agent dose before adding second agent in patients with Stage 2 hypertension—start with combination therapy immediately 2, 1