What is the first-line therapy for a newly diagnosed patient with hypertension (HTN), considering potential comorbidities such as diabetes or impaired renal function?

First-Line Therapy for Hypertension

For most adults with newly diagnosed hypertension, initiate treatment with a thiazide-like diuretic (preferably chlorthalidone 12.5-25 mg daily), which has the strongest evidence for reducing cardiovascular mortality, stroke, and heart failure compared to other drug classes. 1, 2

Treatment Initiation Strategy Based on Blood Pressure Stage

Stage 1 Hypertension (130-139/80-89 mmHg):

• Begin with single-agent therapy and titrate dosage before adding sequential agents to reach BP target <130/80 mmHg 3, 1
• Patients with elevated BP and high cardiovascular risk (≥10% over 10 years) should start pharmacological treatment after 3 months of lifestyle intervention if BP remains ≥130/80 mmHg 3

Stage 2 Hypertension (≥160/100 mmHg):

• Initiate with two first-line agents of different classes, either as separate medications or fixed-dose combination 3, 1
• This approach more effectively achieves adequate BP control in patients with markedly elevated pressures 3

First-Line Medication Classes

Thiazide-Like Diuretics (Preferred):

• Chlorthalidone 12.5-25 mg once daily is the optimal choice based on superior cardiovascular outcomes data and longer duration of action 1
• Chlorthalidone demonstrated superiority over lisinopril in preventing stroke and over amlodipine in preventing heart failure 1
• Hydrochlorothiazide 12.5-25 mg once daily (maximum 50 mg) is an acceptable alternative with lesser potency but still effective BP reduction 1
• Thiazide diuretics are significantly better than calcium channel blockers for prevention of heart failure 1

Alternative First-Line Options:

• ACE inhibitors (e.g., lisinopril), ARBs, or dihydropyridine calcium channel blockers (e.g., amlodipine) are acceptable alternatives when thiazides cannot be used 3, 1, 2
• These four drug classes have demonstrated reduction in cardiovascular events in large randomized trials 2

Special Population Considerations

Patients with Diabetes:

• If albuminuria present (UACR ≥30 mg/g): ACE inhibitor or ARB is mandatory first-line therapy to reduce proteinuria and slow kidney disease progression 3, 4
• For UACR ≥300 mg/g: ACE inhibitor or ARB is strongly recommended 3
• If no albuminuria: Use standard first-line drugs (thiazide diuretics, ACE inhibitors, ARBs, or calcium channel blockers) 3
• For diabetes with established coronary artery disease: ACE inhibitors or ARBs are recommended first-line 3

Patients with Chronic Kidney Disease:

• ACE inhibitor or ARB is recommended first-line, with ARB if ACE inhibitor not tolerated 3
• Continue ACE inhibitor or ARB therapy even as kidney function declines to eGFR <30 mL/min/1.73 m² for cardiovascular benefit 3, 4

Black Patients:

• Thiazide diuretic or calcium channel blocker are more effective than ACE inhibitors or ARBs when used as monotherapy 1, 4
• ACE inhibitors are 36% less effective than calcium channel blockers and 30% less effective than thiazides for stroke prevention in this population 1
• The American College of Cardiology specifically recommends initiating with thiazide diuretic or calcium channel blocker for Black patients without heart failure or chronic kidney disease 1

Patients with Coronary Artery Disease:

• ACE inhibitors or ARBs are recommended first-line therapy 3

Combination Therapy Approach

When Single-Agent Therapy is Insufficient:

• Progress to two-drug combination: RAS blocker (ACE inhibitor or ARB) plus either dihydropyridine calcium channel blocker or thiazide-like diuretic 3, 4
• Fixed-dose single-pill combinations are recommended to improve adherence 3

If BP Not Controlled with Two Drugs:

• Increase to three-drug combination: RAS blocker + dihydropyridine calcium channel blocker + thiazide-like diuretic, preferably in single-pill combination 3, 4

Resistant Hypertension (Not Controlled on Three Drugs):

• Consider adding mineralocorticoid receptor antagonist 3, 4
• Refer to specialist with expertise in BP management 3, 4

Medications to Avoid as First-Line

Beta-Blockers:

• Not recommended for uncomplicated hypertension due to inferior efficacy, particularly for stroke prevention in older adults 3, 1
• Beta-blockers are 36% less effective than calcium channel blockers and 30% less effective than thiazides for stroke prevention 1
• Reserved for specific indications: prior MI, active angina, or heart failure with reduced ejection fraction 3

Alpha-Blockers:

• Not recommended as first-line therapy due to inferior cardiovascular disease prevention compared to thiazides 1

Critical Contraindications and Monitoring

Never Combine:

• ACE inhibitors with ARBs: increased risk of hyperkalemia, syncope, and acute kidney injury without added cardiovascular benefit 3, 4
• ACE inhibitor or ARB with direct renin inhibitor: lack of benefit and increased adverse events 3, 4

Pregnancy Considerations:

• ACE inhibitors and ARBs are absolutely contraindicated in pregnancy 3, 4
• For pregnant women: use dihydropyridine calcium channel blockers (extended-release nifedipine), labetalol, or methyldopa 3

Essential Monitoring:

• Monitor serum creatinine, eGFR, and potassium within 7-14 days after initiation of ACE inhibitors, ARBs, or diuretics, then at least annually 3, 4
• Maintain potassium levels >3.5 mmol/L when using thiazide diuretics to avoid increased ventricular ectopy 1
• Follow-up within 7-14 days after medication initiation or dose changes, with goal of achieving BP target within 3 months 4

Blood Pressure Targets

• Target <130/80 mmHg for most adults <65 years 4, 2
• Target systolic BP 120-129 mmHg in most adults if well tolerated 3
• Target systolic BP <130 mmHg for adults ≥65 years 4

Lifestyle Modifications (Essential Adjunct)

All patients should receive intensive lifestyle counseling alongside pharmacotherapy 3, 4:

• Sodium restriction to <1500 mg/day or reduction of at least 1000 mg/day 3
• Increased dietary potassium intake (3500-5000 mg/day) 3
• Weight loss if overweight/obese (target BMI 20-25 kg/m²) 3, 4
• Aerobic exercise 90-150 minutes/week or isometric resistance 3 sessions/week 3, 4
• Alcohol limitation to ≤2 drinks/day in men, ≤1/day in women 3
• DASH-like diet rich in fruits, vegetables, whole grains, and low-fat dairy products 3, 4