Traditional and Novel Targets for Lipid-Lowering Medications: Reimagining the Fight Against Atherosclerosis

Traditional and Novel Targets for Lipid-Lowering Medications: Reimagining the Fight Against Atherosclerosis

By Geoffrey Onchiri Mosota,
Dip. Clin. Med. & Surg., BSc (Applied Microbiology), MBA (Strategic Management)
Founder, Native Inspire Africa | Clinician & Researcher, Boyani Medical Centre
Published: October 2025

Introduction: The Evolving Landscape of Cardiovascular Prevention

Atherosclerotic cardiovascular disease (ASCVD) remains the world’s leading cause of death despite remarkable advances in lipid management. The challenge today is not merely to lower cholesterol, but to do so precisely, safely, and sustainably across diverse populations.

Lipidology has evolved from enzyme inhibition to molecular reprogramming—spanning statins, monoclonal antibodies, RNA-silencing drugs, and even gene-editing therapies. The future is being defined not by the number on a lipid panel, but by the depth of metabolic correction achieved within each individual.

1. The Traditional Landscape: Proven Tools That Still Matter

Statins remain the cornerstone of lipid therapy, inhibiting HMG-CoA reductase and reducing LDL-C by 30–50%, with consistent reductions in cardiovascular events.

Other key agents include:

Ezetimibe – inhibits NPC1L1, blocking intestinal cholesterol absorption.

Bile Acid Sequestrants (e.g., colesevelam) – enhance hepatic LDL receptor recycling.

Fibrates – activate PPAR-α, reducing triglycerides and modestly raising HDL-C.

Niacin – once favored for HDL elevation but now limited by tolerability issues.

These therapies remain essential—particularly across resource-limited settings like much of sub-Saharan Africa, where biologics are financially inaccessible yet cardiovascular risk remains high.

Clinical Insight (Africa Focus):
Generic statins and ezetimibe remain cost-effective lifesavers. Integrating these into primary care programs, alongside lifestyle interventions and community screening, can drastically reduce premature cardiovascular deaths.

2. The Modern Revolution: PCSK9, ANGPTL3, and Beyond

The discovery of PCSK9 reshaped lipidology. Inhibitors such as evolocumab and alirocumab prevent LDL receptor degradation, achieving up to 60% LDL-C reduction even in statin-intolerant patients.

Meanwhile, ANGPTL3 inhibitors (like evinacumab) enhance lipoprotein lipase activity—lowering both LDL-C and triglycerides, an unprecedented dual benefit for familial hypercholesterolemia.

Recent analyses published in the European Heart Journal (Ballantyne & Norata, 2025; DOI: 10.1093/eurheartj/ehaf606) highlight that combining these biologics with traditional statins yields not only additive lipid reductions but also synergistic plaque stabilization.

Clinical Insight:
For African tertiary centers, selective use of PCSK9 inhibitors in high-risk familial hypercholesterolemia or statin-resistant cases can redefine secondary prevention outcomes.

3. The Next Frontier: RNA-Based and Genetic Therapies

The lipid-lowering horizon has expanded into genetic medicine.

Inclisiran (siRNA) silences hepatic PCSK9 mRNA, enabling twice-yearly dosing and near-perfect adherence.

ARO-ANG3 and Vupanorsen silence ANGPTL3 and APOB mRNA, recalibrating lipid metabolism at the molecular level.

CRISPR-Cas9–based editing of PCSK9 or ANGPTL3 is under investigation for one-time gene correction with lifelong benefits.

These therapies represent a paradigm shift—from managing biochemistry to rewriting the genetic architecture of lipid disorders.

Clinical Insight:
While such therapies remain out of reach for most developing nations, ongoing genomic research in African populations will be key in ensuring future inclusivity in global precision medicine.

4. Oral Non-Statin Innovations: Simplicity Meets Science

For patients intolerant to statins or injections, oral non-statin options offer new flexibility:

Bempedoic Acid – inhibits ATP-citrate lyase upstream of HMG-CoA reductase, providing LDL-C reduction without muscle-related effects.

Obicetrapib – a next-generation CETP inhibitor rekindling HDL research.

Thyromimetics and PPARδ agonists – enhance lipid turnover and metabolic health simultaneously.

These oral agents may democratize lipid control, especially when integrated with digital adherence systems.

5. Lipids, Inflammation, and the Microbiome: The Systems Biology Connection

Lipid metabolism cannot be separated from inflammation, circadian rhythm, and gut microbial health.

A 2025 Advances in Nutrition meta-analysis (Setayesh et al., DOI: 10.1016/j.advnut.2025.100526) revealed that probiotic and synbiotic supplementation in prediabetic and diabetic individuals significantly reduced CRP, IL-6, and TNF-α—showing that gut-targeted interventions can attenuate systemic inflammation and improve lipid homeostasis.

This underscores that cardiovascular prevention now extends beyond LDL-C numbers—into the microbiome, sleep–wake cycles, and mitochondrial function.

Clinical Insight:
Fermented foods and probiotic-rich diets—common in African traditional cuisines—can be leveraged in preventive cardiometabolic strategies, bridging modern science with indigenous nutrition.

6. Frailty, Strength, and Cardiovascular Resilience

A large UK-based cohort study (Lancet Healthy Longevity, 2025; DOI: 10.1016/j.lanhl.2025.100740) found that frailty correlates with longer hospital stays and higher in-hospital mortality, even among adults aged 18–40.

Frailty is not just a geriatric concept—it mirrors the systemic inflammation and sarcopenia that parallel lipid and metabolic dysfunction. Strength training, nutrition, and adequate protein intake thus emerge as adjunct cardiovascular therapies.

7. Metformin and Longevity: A Reality Check

Long viewed as a “longevity molecule,” metformin’s promise beyond diabetes has waned.
A 2025 review (Ageing Research Reviews, DOI: 10.1016/j.arr.2025.102817) concluded that evidence for lifespan extension in healthy populations is weak, despite clear benefits in diabetics.

Nonetheless, its AMPK activation and anti-inflammatory effects maintain relevance in metabolic and lipid regulation—especially in combination with intermittent fasting or statins.

Clinical Insight:
Metformin remains vital in African metabolic care—not as an anti-aging pill, but as a foundational insulin-sensitizing, anti-inflammatory agent synergistic with lipid-lowering therapy.

8. Vaccination and Cardiovascular Prevention

A 2025 consensus from the European Heart Journal (DOI: 10.1093/eurheartj/ehaf606) emphasized vaccination as an emerging cardiovascular prevention tool—not only against infections like influenza and COVID-19 but also against major adverse cardiovascular events in high-risk groups.

Clinical Insight:
Integrating influenza and COVID-19 vaccination into hypertension and diabetes clinics could reduce cardiovascular admissions—an affordable yet underutilized preventive measure across Africa.

9. The Promise of Precision Medicine

Genetic profiling, lipidomics, and digital biomarkers are redefining cardiovascular therapy.
Machine learning now predicts optimal responders to specific drugs, while wearable data integrate circadian patterns, lipid rhythms, and inflammation trends.

This fusion of genomics and technology aligns seamlessly with the Native Inspire Africa vision — harmonizing nature, science, and personalized prevention.

10. Conclusion: Integrating Molecules, Microbes, and Mindset

From the first statin pill to gene-silencing therapies, the battle against atherosclerosis has moved from the bloodstream to the genome.

Yet, the future will not belong solely to laboratories—it will emerge from the synergy of pharmacology, nutrition, exercise, circadian alignment, and microbial balance.

True cardiovascular resilience lies in precision medicine with a human touch—a philosophy Native Inspire Africa continues to champion.

Key Takeaways

LDL-C reduction remains the most validated route to ASCVD prevention.

Statins and ezetimibe are foundational, but RNA-based and genetic therapies are redefining lipid care.

Microbiome-targeted strategies and circadian alignment amplify drug efficacy.

Vaccination, strength training, and metabolic correction expand the frontiers of prevention.

Future lipidology will merge molecular precision with holistic health, redefining cardiovascular longevity.

By Geoffrey Onchiri Mosota
Dip. Clin. Med. & Surg., BSc (Applied Microbiology), MBA (Strategic Management)
Founder – Native Inspire Africa | Clinician & Researcher, Boyani Medical Centre
Clinician–Researcher in Metabolic and Infectious Diseases | October 2025