According to a review in the British Journal of Clinical Pharmacology, hypertension, a silent threat affecting over 1.13 billion people globally, is a major risk factor for heart disease and other health problems. Current management, with lifestyle changes and medication, faces challenges, with many struggling to control blood pressure. However, hope emerges! Re-evaluating older drugs and exploring new ones like ARNIs show promise. The future lies in personalized medicine, with research on genes like UMOD paving the way for tailoring treatment based on individual needs. By optimizing existing strategies and embracing advancements, we can conquer this silent killer and reclaim health for future generations.

Key Points

Global Burden:

• Over 1.13 billion people worldwide have hypertension.

• It significantly increases the risk of cardiovascular disease, chronic kidney disease, diabetes, and obesity.

• The prevalence is over 60% in individuals over 60, making it a leading cause of death.

Management Challenges:

• Many patients struggle to achieve adequate blood pressure control.

• Factors include suboptimal treatments, resistance to medications, aging populations, and rising comorbidities.

• Poor adherence to medication regimens is a major hurdle.

Optimizing Current Approaches:

• Re-evaluating older antihypertensive drugs shows promise for immediate improvement.

• Medications like spironolactone and amiloride are effective for treatment-resistant hypertension.

Emerging Pharmacological Advancements:

• Endothelin receptor antagonists (ERAs) show promise in lowering blood pressure and reducing proteinuria.

• SGLT2 inhibitors, used for diabetes, also reduce blood pressure and offer renal benefits.

• Dual Angiotensin Receptor-Neprilysin Inhibitors (ARNIs), like Entresto, are a game-changer, effectively lowering blood pressure and arterial stiffness.

The Future of Personalized Medicine:

• Pharmacogenomics can personalize treatment plans based on individual genetic responses to medications.

• Studies on the UMOD gene suggest tailoring therapy based on a patient's unique genetic makeup.

• Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) are promising targeted therapies for lowering blood pressure.

Overall:

• Hypertension management is evolving, with new therapeutic strategies showing promise.

• Novel approaches offer broader cardiovascular and renal protection.

• More research is needed to integrate these advances into guidelines with a focus on primary blood pressure control endpoints.

Hypertension isn't just a medical condition; it's a pervasive health crisis, silently ensnaring millions across the globe. According to European guidelines, hypertension is defined by an office systolic blood pressure (SBP) of ≥140 mmHg and/or diastolic blood pressure (DBP) of ≥90 mmHg. Shockingly, it afflicts 1.13 billion people globally, with projections indicating a 15-20% surge by 2025. This staggering prevalence isn't merely a statistic; it's a grim reality that demands urgent attention and action.

The Comorbidity Conundrum: A Complex Nexus

Hypertension seldom operates in isolation; it intertwines with a complex web of comorbidities, including chronic kidney disease, diabetes mellitus, and obesity. This intricate interplay exacerbates the severity of hypertension, amplifying the risk of cardiovascular disease and other adverse health outcomes. The ramifications extend far beyond individual health, permeating societal well-being and straining healthcare systems worldwide.

Unveiling the Alarming Reality

Recent data from the United States paints a sobering picture of hypertension management. The proportion of adults with adequately controlled hypertension has plummeted to less than 45%, signaling a troubling decline in effective blood pressure control. This downward trend is accompanied by a surge in hypertension-related cardiovascular mortality rates, underscoring the urgent need for comprehensive and sustainable interventions.

Strategies for Confronting Hypertension

Lifestyle Interventions: Building a Foundation for Health

Lifestyle modifications serve as the bedrock of hypertension management, empowering individuals to take charge of their health destiny. Regular exercise, balanced diet, salt restriction, weight management, and smoking cessation constitute the cornerstone of lifestyle interventions, offering a proactive approach to blood pressure control and overall well-being.

Pharmacotherapy: Harnessing the Power of Medications

While lifestyle interventions lay the groundwork, pharmacotherapy provides a crucial adjunct in the fight against hypertension. A diverse array of antihypertensive agents, ranging from angiotensin-converting enzyme (ACE) inhibitors to calcium channel blockers (CCBs), offers tailored solutions to address individual needs and preferences. Optimization of medication regimens, adherence promotion, and vigilant monitoring are essential components of effective pharmacotherapy.

Exploring Novel Pharmacological Frontiers

In the pursuit of innovation, researchers are venturing into uncharted territories, exploring novel pharmacological avenues to combat hypertension. Endothelin Receptor Antagonists (ERAs) and SGLT2 Inhibitors emerge as promising candidates, offering unique mechanisms of action and potential synergies in blood pressure reduction and cardiovascular protection. These innovative therapies hold the promise of reshaping the landscape of hypertension management and improving patient outcomes.

Novel Antihypertensive Agents: SGLT2 Inhibitors

SGLT2 inhibitors, primarily used in type 2 diabetes, have shown effects on blood pressure reduction. Studies like EMPA-REG BP trial and others demonstrate a reduction in SBP and DBP, particularly during the daytime. They have shown potential for reducing cardiovascular events and have various proposed mechanisms, including osmotic diuresis, metabolic alterations, weight loss, and improved endothelial function. Additionally, SGLT2 inhibitors have shown renal protective effects, benefiting renal outcomes across different levels of kidney function and albuminuria.

Unraveling the Dual Inhibition: SGLT1 and SGLT2

SGLT1, or Sodium-Glucose Co-Transporter 1, plays a crucial role in glucose absorption within the small intestine and accounts for only about 10% of glucose reabsorption in the kidneys. Inhibiting SGLT1 effectively delays glucose absorption, resulting in reduced postprandial blood glucose levels. Moreover, this inhibition has been associated with a decreased rate of cardiovascular events, making it an exciting target for medical research. The SCORED trial, a monumental effort, involved 10,584 patients diagnosed with T2DM and a range of albuminuria levels (from less than 30 to over 300 mg/g) and an estimated glomerular filtration rate (eGFR) ranging from 25 to 60 mL/min/1.73m². These participants were randomly assigned to receive sotagliflozin at a dosage of 200 mg per day or a placebo. Though the trial faced an early termination due to financial constraints, it yielded remarkable results. Sotagliflozin demonstrated a 16% reduction in the primary endpoint, a composite of the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, when compared to the placebo.

Safety Concerns with SGLT2 Inhibitors

While the benefits of SGLT2 inhibitors are undeniable, it's crucial to address the recognized side effects associated with these agents. These include genital and urinary infections that can progress to pyelonephritis due to increased glycosuria, occurring in approximately 4-6% of patients treated. Furthermore, studies, particularly the CANVAS trial, have highlighted an increased incidence of peripheral amputations (toes, feet, or legs) and bone fractures. Another potential risk is acute kidney injury, often associated with hypovolemia. Rare but severe complications include diabetic ketoacidosis and Fournier's gangrene, which necessitate careful consideration.

The Role of Dual Angiotensin Receptor-Neprilysin Inhibitors (ARNIs) in Hypertension Management

In recent years, dual angiotensin receptor-neprilysin inhibitors (ARNIs) have emerged as a potential game-changer in the treatment of hypertension and its associated conditions. Before delving into the role of ARNIs in hypertension management, it's crucial to grasp the underlying mechanisms of hypertension. The Renin-Angiotensin-Aldosterone System (RAAS) plays a pivotal role in regulating blood pressure. RAAS activation leads to salt and water retention, vasoconstriction, sympathetic activation, and cardiovascular remodeling. Neprilysin, a membrane-bound enzyme, is instrumental in breaking down vasoactive peptides, including A- and B-type natriuretic peptides.

The Power of ARNIs: Sacubitril/Valsartan

The journey to find the most effective ARNI was not without its challenges. The initial contender, omapatrilat, showed promise but was discontinued due to the risk of angioedema. However, this setback paved the way for the emergence of sacubitril/valsartan (LCZ696) as the first-in-class ARNI. This revolutionary medication combines the angiotensin receptor blocker (ARB) valsartan and the neprilysin inhibitor prodrug AHU377.

The Paradigm-HF Trial: A Milestone in ARNI Research

The groundbreaking PARADIGM-HF trial marked a significant turning point in ARNI research. It demonstrated the superiority of ARNI treatment over ACE inhibition alone in improving outcomes for patients dealing with heart failure and a reduced ejection fraction. This milestone study led to the licensing of sacubitril/valsartan, marketed as Entresto by Novartis, as the sole licensed ARNI. A recent meta-analysis of 12 multicenter, double-blind Randomized Controlled Trials (RCTs), involving 3,816 patients, compared Entresto with valsartan alone and Entresto with olmesartan alone concerning blood pressure reduction. The results revealed that Entresto, when administered at dosages ranging from 100 to 400 mg per day, led to a more significant reduction in both office systolic blood pressure (SBP) and diastolic blood pressure (DBP) when compared to ARB treatment alone. Moreover, Entresto proved more effective at lowering 24-hour SBP.

ARNIs and Arterial Stiffness: A Crucial Link

Aging often brings about arterial stiffness and salt sensitivity, both of which contribute to the development of hypertension and its complications. Increased arterial stiffness leads to systolic hypertension, widening pulse pressure, and increased central aortic pressure. Additionally, increased salt sensitivity contributes to the development of nocturnal hypertension, disrupting the normal nocturnal blood pressure dipping pattern. These changes raise the risk of developing treatment-resistant hypertension, end-organ damage, and an increased likelihood of heart failure with preserved ejection fraction (HFpEF). The PARAMETER study, designed to investigate the effect of Entresto on arterial stiffness compared to ARB monotherapy, focused on newly diagnosed, untreated hypertensive patients aged 60 or above. These patients displayed features of increased arterial stiffness, with high systolic blood pressure and pulse pressure values. They were randomly assigned to receive either Entresto (200 mg per day) or olmesartan (20 mg per day) for 12 weeks. The results were striking, with Entresto significantly reducing central aortic SBP more than olmesartan while exhibiting similar effects on central aortic pulse pressure and brachial SBP. Interestingly, Entresto also improved 24-hour ambulatory central aortic and brachial SBP, with the most prominent effects observed during sleep.

Pharmacogenomics: A Personalized Approach

It has become increasingly clear that individual responses to antihypertensive medications are strongly influenced by genetic factors. Genome-wide association studies (GWAS) have significantly advanced our knowledge in this field, helping to identify specific genes related to hypertension development and the prediction of responses to antihypertensive agents. One such gene of interest is UMOD, which encodes for uromodulin, a protein exclusively expressed in the kidney. Studies have highlighted the association between single-nucleotide polymorphisms in the UMOD gene and renal function, as well as hypertension. This insight opens up the possibility of tailoring treatment based on an individual's uromodulin genotype. Clinical studies are underway to determine whether patients with a high-uromodulin genotype respond better to loop diuretic therapy, providing a personalized and more effective approach to hypertension management.

Antisense Oligonucleotides and Small Interfering RNAs: Targeted Therapy

Within the RAAS, angiotensin production primarily originates from the cleavage of angiotensinogen (AGT), a serum globulin produced in the liver. Deleting angiotensinogen can significantly reduce the stimulation of angiotensin receptors. This can be achieved through the use of antisense oligonucleotides (ASO) and small interfering RNA (siRNA), both of which target RNA through base pairing. Animal studies have demonstrated the effectiveness of ASOs and siRNAs in lowering blood pressure, with long-lasting effects. In a recent first-in-human study, a siRNA called ALN-AGT01, which targets hepatic AGT synthesis, showed promising results. Patients with hypertension experienced dose-dependent reductions in serum AGT, accompanied by a reduction of over 10.0 mmHg in mean 24-hour systolic blood pressure after just 8 weeks following a single dose administration. Further studies are currently underway to explore the potential of this innovative approach.

Conclusions: The Evolving Landscape of Hypertension Management

In conclusion, the management of hypertension is undergoing a significant transformation. While optimizing the use of existing antihypertensive agents offers benefits, there remains a substantial need for novel therapeutic strategies. Some pharmacological approaches show promise, particularly those with broader cardiovascular and renal protection. However, the incorporation of these novel agents into hypertension guidelines is currently hindered by the paucity of clinical trials focusing on primary blood pressure endpoints.As we navigate the evolving landscape of hypertension management, we encounter a myriad of challenges and opportunities. Embracing innovation, optimizing existing therapies, and prioritizing individualized care is imperative in our quest to conquer hypertension and safeguard global health.

Reference Article

Hunter, P. G., Chapman, F. A., & Dhaun, N. (2021). Hypertension: Current trends and future perspectives. British Journal of Clinical Pharmacology, 87(10), 3721-3736. https://doi.org/10.1111/bcp.14825

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