As of 2025, hypertension remains a leading contributor to global cardiovascular morbidity and mortality, affecting over 1.28 billion individuals, according to WHO estimates.
With evolving evidence and changing population dynamics, the selection of first-line antihypertensive therapy has grown more nuanced.
Updated guidelines from the American College of Cardiology (ACC) and the European Society of Cardiology (ESC) emphasize not only blood pressure (BP) control but also cardiovascular risk reduction, medication tolerability, and protection.
Guideline Update: Beyond the BP Numbers
Both the 2023 ESC/ESH guidelines and the ACC/AHA 2024 position paper now advocate for a risk-stratified approach to hypertension treatment. Rather than targeting BP alone, these guidelines recommend initiating therapy based on total cardiovascular risk, incorporating age, comorbidities, and renal function into the decision-making process.
- In individuals under 65 with stage 1 hypertension and low CVD risk, lifestyle intervention remains the primary recommendation.
- For moderate-to-high risk patients, combination therapy at initiation is preferred—often involving a calcium channel blocker (CCB) plus either an ACE inhibitor or ARB.
Angiotensin-Converting Enzyme Inhibitors (ACEi): Still Foundational?
ACE inhibitors, such as enalapril and lisinopril, have been mainstays in hypertension therapy for decades. In 2025, their role persists, particularly in patients with diabetic nephropathy, proteinuria, or heart failure with reduced ejection fraction (HFrEF).
However, long-term data now show higher discontinuation rates due to cough and angioedema. A 2024 meta-analysis published in The Lancet concluded that ARB therapy achieves comparable cardiovascular protection with fewer adverse effects, prompting many clinicians to favor losartan, valsartan, or telmisartan as first-line agents.
According to Dr. Maria Ortiz, cardiologist at Mount Sinai Hospital, "We're now seeing a clinical shift where ARBs are increasingly being used as the primary RAAS-blocker, especially in multi-ethnic populations with higher ACEi-related intolerance."
Calcium Channel Blockers (CCBs): Preferred for Isolated Systolic Hypertension
Dihydropyridine CCBs, especially amlodipine, remain essential, particularly in elderly patients presenting with isolated systolic hypertension (ISH).
The INCLUSIVE trial, published in 2023, confirmed that amlodipine combined with an ARB led to a 42% reduction in incidence in patients over 70 compared to monotherapy. Additionally, CCBs demonstrate superior efficacy in Black and South Asian populations, where renin-angiotensin system activity is typically lower. This pharmacogenomic insight is now considered a determinant in therapy selection across diverse populations.
Thiazide-Like Diuretics: Reassessing Their Role
Once considered first-line, thiazide diuretics, especially hydrochlorothiazide, have been reevaluated due to their metabolic side effects. Instead, thiazide-like agents such as indapamide and chlorthalidone are now preferred. These agents offer longer half-lives, better 24-hour BP control, and reduced risk of new-onset diabetes.
In a 2024 Cochrane Review, indapamide showed a 21% relative risk reduction in heart failure hospitalization compared to hydrochlorothiazide.
Beta-Blockers: Reserved and Selective Use
Beta-blockers no longer serve as routine first-line therapy for uncomplicated hypertension. Nevertheless, they remain indispensable in patients with concomitant ischemic heart disease, atrial fibrillation, or heart failure. The B-SELECT trial published in JAMA Cardiology (2023) emphasized that bisoprolol outperformed older agents like atenolol in reducing cardiovascular events among patients with dual diagnoses of hypertension and coronary artery disease.
Single-Pill Combinations (SPCs): Improving Adherence, Enhancing Outcomes
Treatment adherence is a critical determinant of BP control. To that end, SPCs have become the standard of care in most high-income countries. Triple fixed-dose combinations, such as olmesartan/amlodipine/hydrochlorothiazide, have demonstrated superior BP-lowering efficacy and higher patient adherence rates. The TRIPLE-H trial (2022–2024) found that SPCs reduced clinical inertia by 60% and led to a 32% higher rate of BP target achievement in primary care settings.
Renal and Metabolic Considerations in First-Line Selection
For patients with chronic kidney disease (CKD) or diabetes, therapeutic decisions are more complex. Current consensus recommends:
- ACEi or ARB as foundational therapy to slow renal decline.
- Avoidance of diuretics in advanced CKD stages due to electrolyte disturbances.
- CCBs as second-line agents when RAAS inhibitors alone are insufficient.
Moreover, SGLT2 inhibitors, although not first-line antihypertensives, have been integrated as add-on therapy in patients with coexisting diabetes or CKD, providing modest BP reduction (~5 mmHg) and significant renal protection.
Precision Hypertension Therapy: The Future Is Here
The integration of genomic profiling and AI-driven BP pattern analysis is expected to revolutionize personalized therapy. Trials such as HYPERGEN-25 are evaluating how specific polymorphisms (such as CYP11B2, ACE gene) can predict response to ACEi vs ARB therapy. Wearable BP monitors with continuous data collection and machine learning feedback now aid clinicians in adjusting therapy more precisely, especially in resistant hypertension cases.
First-line antihypertensive therapy in 2025 is no longer a one-size-fits-all decision. As therapeutic classes evolve and comparative effectiveness research expands, individualized treatment based on clinical phenotype, ethnicity, comorbidities, and patient preference becomes paramount. The shift toward SPCs, preference for ARBs, and strategic use of pharmacogenomics reflects a mature, patient-centric approach to hypertension management.
The future of hypertension therapy lies not in discovering new drugs, but in harnessing existing treatments with greater precision and personalization.
