What is the best first‑line antihypertensive for isolated diastolic hypertension in an otherwise healthy adult?

Best Antihypertensive for Isolated Diastolic Hypertension

Start with chlorthalidone 12.5-25 mg once daily as first-line therapy for isolated diastolic hypertension in otherwise healthy adults. 1, 2

Primary Recommendation: Thiazide Diuretics

Chlorthalidone is the optimal first choice based on the strongest cardiovascular outcomes evidence from the ALLHAT trial, which enrolled over 50,000 patients and demonstrated superiority over ACE inhibitors for stroke prevention (15% lower risk) and over calcium channel blockers for heart failure prevention (38% lower risk). 1, 2, 3, 4

• Chlorthalidone has a longer half-life (40-60 hours) compared to hydrochlorothiazide, providing superior 24-hour blood pressure control, particularly overnight diastolic pressure reduction. 3
• The dose of 25 mg chlorthalidone is more potent than 50 mg hydrochlorothiazide for diastolic blood pressure lowering. 3
• If chlorthalidone is unavailable, use hydrochlorothiazide 25 mg daily, which has demonstrated cardiovascular benefit in multiple placebo-controlled trials. 5, 4

Alternative First-Line Options

If thiazide diuretics are not tolerated, switch to amlodipine 5-10 mg once daily as the preferred alternative. 1, 2

• Long-acting dihydropyridine calcium channel blockers are equally effective as thiazides for all cardiovascular events except heart failure, where thiazides remain superior. 1, 2
• CCBs are particularly useful if the patient develops angina or cannot tolerate diuretic-related side effects. 1, 5

ACE inhibitors (lisinopril 10-40 mg daily) or ARBs (losartan 50-100 mg daily) are reasonable alternatives, particularly if the patient later develops diabetes, chronic kidney disease, or albuminuria. 2, 5, 6

• However, ACE inhibitors were less effective than CCBs in preventing heart failure and stroke in head-to-head comparisons. 1
• For nonblack patients without compelling indications, ACE inhibitors remain acceptable first-line options. 6, 7

Treatment Initiation Strategy

For Stage 1 diastolic hypertension (BP 130-139/80-89 mmHg):

• Start with single-agent chlorthalidone 12.5-25 mg once daily. 1, 2
• Titrate dosage after 2-4 weeks if blood pressure remains uncontrolled. 1, 2
• Add a second agent from a different class if monotherapy fails at maximum tolerated dose. 1

For Stage 2 diastolic hypertension (BP ≥140/90 mmHg or ≥10 mmHg above target):

• Initiate two first-line agents from different classes simultaneously, preferably as a single-pill combination. 1, 2, 5
• Preferred combinations include: thiazide + ACE inhibitor, thiazide + CCB, or ACE inhibitor + CCB. 5, 7

Agents to Avoid as First-Line

Beta-blockers should NOT be used as first-line therapy for isolated diastolic hypertension unless specific comorbidities exist (e.g., angina, recent MI, heart failure). 1, 5

• Beta-blockers were significantly less effective than diuretics for prevention of stroke (30% lower risk with thiazides) and cardiovascular events in network meta-analyses. 1
• They are particularly less effective in older adults for stroke prevention. 1

Alpha-blockers are not first-line agents because they are less effective for CVD prevention than thiazide diuretics. 1, 8

Monitoring and Safety

Check electrolytes and renal function within 7-14 days after initiating thiazide diuretics, then at least annually. 2, 5, 8

• Maintain potassium >3.5 mmol/L to avoid increased ventricular ectopy. 8
• Thiazide-induced hypokalemia is associated with increased blood glucose; treating hypokalemia may reverse glucose intolerance. 3

Reassess blood pressure monthly after medication initiation or changes until target BP <130/80 mmHg is achieved, then every 3-5 months once controlled. 2, 5

Common Pitfalls to Avoid

Do not combine ACE inhibitors with ARBs, as this increases adverse events including hyperkalemia and acute kidney injury without additional cardiovascular benefit. 5, 8

Avoid using hydrochlorothiazide when chlorthalidone is available, as chlorthalidone has superior outcomes data and longer duration of action. 2, 8, 3

NSAIDs blunt the antihypertensive effects of thiazides; counsel patients to avoid routine NSAID use. 3

Thiazide-induced hyperuricemia does not contraindicate continued use, especially if the patient is taking allopurinol or has no history of gout. 3