What are the best initial antihypertensive medications for a patient with primary hypertension and no significant comorbidities, and how should treatment be tailored for patients with diabetes, kidney disease, or older adults?

Best Initial Antihypertensive Medications

For patients with uncomplicated primary hypertension, start with ACE inhibitors, ARBs, thiazide-like diuretics (chlorthalidone or indapamide preferred), or dihydropyridine calcium channel blockers as first-line therapy, with the specific choice and whether to use monotherapy versus dual therapy determined by baseline blood pressure level and cardiovascular risk. 1, 2

Initial Treatment Strategy Based on Blood Pressure Level

For BP 140-159/90-99 mmHg: Begin with single-agent therapy in low-to-moderate risk patients without comorbidities. 2

For BP ≥160/100 mmHg: Initiate immediate dual therapy, preferably as a single-pill combination, to achieve faster blood pressure control and reduce cardiovascular events. 2

High-risk patients (established CVD, diabetes, CKD, organ damage, or age 50-80 years): Start dual therapy immediately regardless of baseline BP, even if BP is only 140-159/90-99 mmHg. 2

First-Line Medication Classes for Uncomplicated Hypertension

The four evidence-based first-line drug classes are: 1, 2

• ACE inhibitors (lisinopril, enalapril, ramipril)
• Angiotensin receptor blockers/ARBs (losartan, valsartan, telmisartan)
• Thiazide-like diuretics (chlorthalidone and indapamide are preferred over hydrochlorothiazide due to superior cardiovascular outcomes) 1
• Long-acting dihydropyridine calcium channel blockers (amlodipine, nifedipine extended-release)

Race-Based Considerations

Non-Black patients: Start with low-dose ACE inhibitor or ARB, then add dihydropyridine calcium channel blocker or thiazide-like diuretic as second agent. 1

Black patients: Start with low-dose ARB combined with dihydropyridine calcium channel blocker OR dihydropyridine calcium channel blocker combined with thiazide-like diuretic, as ACE inhibitors and ARBs are less effective as monotherapy in this population. 1

Preferred Two-Drug Combinations

When dual therapy is indicated, use these evidence-based combinations: 2

• Thiazide-like diuretic + ACE inhibitor
• Thiazide-like diuretic + ARB
• Calcium channel blocker + ACE inhibitor
• Calcium channel blocker + ARB

Tailoring Treatment for Specific Comorbidities

Diabetes with Albuminuria

ACE inhibitor or ARB at maximum tolerated dose is mandatory first-line therapy for patients with diabetes and UACR ≥30 mg/g. 1

• For UACR ≥300 mg/g: ACE inhibitor or ARB is strongly recommended (Grade A evidence). 1
• For UACR 30-299 mg/g: ACE inhibitor or ARB is recommended (Grade B evidence). 1
• Without albuminuria, standard first-line agents (thiazide-like diuretics or dihydropyridine calcium channel blockers) are equally effective. 1

Diabetes with Coronary Artery Disease

ACE inhibitors or ARBs are recommended as first-line therapy. 1

Chronic Kidney Disease

For CKD patients with albuminuria (UACR ≥30 mg/g), initiate ACE inhibitor or ARB to reduce progressive kidney disease risk. 1, 3

• Continue ACE inhibitor or ARB even as eGFR declines to <30 mL/min/1.73 m² for cardiovascular benefit, unless contraindicated. 1
• Monitor serum creatinine, eGFR, and potassium at least annually. 1
• Non-dihydropyridine calcium channel blockers (diltiazem, verapamil) reduce albuminuria and should not be used as monotherapy but combined with RAAS blockers. 3

Older Adults (Age >80 Years) and Frail Elderly

Start with monotherapy at low doses and titrate slowly, individualizing BP targets based on frailty status. 1, 2

• Simplify regimens with once-daily dosing and single-pill combinations to improve adherence. 1
• Monitor for orthostatic hypotension when initiating therapy. 2
• Target BP reduction of at least 20/10 mmHg, ideally to 140/90 mmHg, but adjust based on frailty. 1

Heart Failure with Reduced Ejection Fraction

Use ACE inhibitor (or ARB if ACE inhibitor not tolerated), beta-blocker, and diuretic/mineralocorticoid receptor antagonist. 1, 2

Stable Ischemic Heart Disease or Post-MI

Beta-blockers plus ACE inhibitor or ARB are recommended. 1

Critical Pitfalls to Avoid

Never combine ACE inhibitors with ARBs - this combination increases adverse events (hyperkalemia, syncope, acute kidney injury) without added cardiovascular benefit. 1

Do not use sequential monotherapy as default in high-risk patients - this delays BP control and increases cardiovascular risk. 2

Avoid non-dihydropyridine calcium channel blockers in heart failure with reduced ejection fraction. 1

Monitor for hyperkalemia when adding mineralocorticoid receptor antagonists to ACE inhibitor or ARB therapy - check serum creatinine and potassium regularly. 1

Resistant Hypertension (BP ≥140/90 mmHg on Three Drugs)

Add mineralocorticoid receptor antagonist (spironolactone) as fourth-line agent when BP remains uncontrolled on ACE inhibitor/ARB + thiazide-like diuretic + dihydropyridine calcium channel blocker. 1

• Alternative fourth-line agents if spironolactone contraindicated or not tolerated: amiloride, doxazosin, eplerenone, clonidine, or beta-blocker. 1
• Before diagnosing resistant hypertension, exclude medication nonadherence, white coat hypertension, and secondary causes. 1

Monitoring and Follow-Up

Schedule monthly visits until BP target (<130/80 mmHg for most patients) is achieved, typically within 3 months. 1, 2

• Monitor serum creatinine, eGFR, and potassium at least annually for patients on ACE inhibitors, ARBs, or diuretics. 1
• Check for orthostatic hypotension in elderly patients on dual therapy. 2

Essential Lifestyle Modifications

All patients require intensive lifestyle counseling regardless of medication choice: 1, 2

• Sodium restriction to <1500 mg/day (or reduce by at least 1000 mg/day)
• Increase dietary potassium to 3500-5000 mg/day
• Weight loss if overweight/obese (target at least 1 kg reduction)
• Physical activity: 90-150 minutes/week of aerobic exercise or 3 sessions/week of isometric resistance training
• Alcohol moderation: ≤2 drinks/day for men, ≤1 drink/day for women
• DASH diet: Rich in fruits, vegetables, whole grains, low-fat dairy, reduced saturated and total fat