Merck, Amgen double down on bad cholesterol to vanquish number 1 killer

Merck's Oral Enlicitide Delivers Strong Phase 3 Results for High Cholesterol

New guidelines from the American College of Cardiology (ACC) and American Heart Association (AHA) are driving pharmaceutical companies to intensify efforts in managing high cholesterol and preventing heart disease. Merck recently reported positive Phase 3 results for its oral PCSK9 inhibitor, enlicitide, demonstrating significant LDL-C reduction in patients with hypercholesterolemia. This development, alongside Amgen's data for its injectable PCSK9 inhibitor Repatha in primary prevention, highlights the industry's commitment to addressing the substantial unmet need in cardiovascular health, with a growing focus on novel targets like lipoprotein(a) (Lp(a)).

• Merck's enlicitide, an oral PCSK9 inhibitor, demonstrated a statistically significant 64.6% reduction in low-density lipoprotein-cholesterol (LDL-C) from baseline at eight weeks in the Phase 3 CORALreef AddOn study, when added to background statin treatment. This efficacy, combined with a reported 97% treatment adherence rate from the CORALreef Lipids trial, positions it as a convenient oral alternative to existing injectable PCSK9 therapies.
• Updated guidelines from the ACC and AHA have reintroduced specific LDL-C goals, noting that approximately 70% of patients on statins do not achieve these targets. Amgen presented new subgroup data from its Phase 3 Vesalius-CV trial, showing Repatha significantly reduced the risk of a first cardiovascular event in high-risk primary prevention, underscoring the critical need for more effective cholesterol-lowering solutions.
• Beyond LDL-C, the pharmaceutical industry is increasingly targeting lipoprotein(a) (Lp(a)), a genetically driven risk factor for heart attack and stroke, with new guidelines recommending its monitoring. Merck committed nearly $2 billion to partner on an investigational Lp(a)-targeting small molecule, HRS-5346, while AstraZeneca, Eli Lilly (with muvalaplin), and Amgen (with olpasiran) are also developing therapies in this promising area.

Addressing the Unmet Need in Hypercholesterolemia Management

Current hypercholesterolemia management faces significant barriers that limit optimal patient outcomes. Real-world evidence demonstrates substantial gaps between clinical guidelines and practice implementation, with only 20% of high-risk patients achieving recommended LDL-C targets despite available therapies. These challenges span clinical efficacy, safety profiles, and healthcare system limitations.

• Suboptimal target achievement: A significant proportion of patients fail to achieve optimal LDL-C targets, experience dose-limiting side effects, or face challenges with the long-term adherence required for sustained cardiovascular benefit

• Inadequate therapy utilization: Real-world studies show that the use of lipid-lowering therapies is inadequate even among patients at higher cardiovascular risk, with combination therapies implemented in only 24% of patients

• Regulatory and guideline limitations: The impossibility of contextual updates to international guidelines and limits imposed by national regulatory authorities restrict treatment access, particularly for patients at higher cardiovascular risk

• Statin-related adverse effects: Many patients suffer from serious side effects, including a modest but significant increased risk of new-onset diabetes, along with challenges related to route of administration and unsatisfactory physicochemical characteristics

• Monitoring and prescription gaps: Most dyslipidemic coronary artery disease and post-surgical cardiac patients are not monitored for serum lipids and are not prescribed appropriate lipid-altering therapy to reach target levels

• Poor medication compliance: Long-term adherence remains challenging, with compliance further compromised by high costs and the requirement for life-long therapy

• Residual cardiovascular risk: Even with optimized LDL reduction using statins, cardiovascular disease risk is reduced by only 30%, indicating a remaining 70% residual risk and highlighting the need for more effective therapeutic approaches

• Emerging therapy challenges: Novel approaches like gene editing face obstacles including off-target effects, delivery efficiency concerns, long-term safety questions, and complex regulatory landscapes that must be navigated for mainstream clinical adoption

The Evolving Hypercholesterolemia Landscape: From PCSK9s to Lp(a) Targets

The hypercholesterolemia treatment landscape has undergone significant transformation over the past five years, marked by the emergence of novel therapeutic agents and a fundamental shift in treatment paradigms. Several breakthrough therapies have expanded the therapeutic armamentarium beyond traditional statins. PCSK9 inhibitors (alirocumab and evolocumab) have demonstrated approximately 60% LDL-C reductions, while inclisiran, a small interfering RNA molecule, achieves approximately 50% LDL-C lowering with the advantage of biannual dosing. ATP-citrate lyase inhibitors like bempedoic acid have provided additional oral treatment options, particularly valuable for statin-intolerant patients. Recent clinical trials have also validated fixed-dose combinations, with the ROSE-CH trial demonstrating that rosuvastatin/ezetimibe 10/10 mg achieved superior LDL-C reduction (-51.48%) compared to rosuvastatin monotherapy (-42.47%, P<0.001).

Clinical practice has witnessed a paradigmatic shift from moderate-intensity statin monotherapy toward early combination therapy approaches. Prescription patterns from 2023-2024 reflect this evolution, with statin monotherapy declining from 42% to 30%, while PCSK9 inhibitor utilization increased from 33% to 40%. The 2025 ESC/EAS guidelines now recommend potent early combination therapy following acute coronary syndrome, moving away from the traditional "watch and wait" approach. This shift acknowledges that a greater number of patients require combination agents to achieve optimal lipid control, particularly as treatment targets become more stringent and risk stratification incorporates novel biomarkers like lipoprotein(a) and inflammatory markers.

Despite these therapeutic advances, significant treatment gaps persist across global healthcare systems. Analysis of 131 million US adults revealed that only 23% of the primary prevention cohort receives lipid-lowering therapy, despite 47-87% being eligible under various guidelines. Utilization remains particularly low for newer agents, with ezetimibe use at 4% versus 31-74% eligibility, and PCSK9 inhibitor use at 0% versus 11-53% eligibility. Even among patients with elevated lipoprotein(a), only 22.3% had therapy modifications within 30 days of detection. Target achievement has shown modest improvements, with very high-risk Italian patients achieving LDL-C <55 mg/dL increasing from 16.3% in 2019 to 23.6% in 2022, though nearly one-third of patients still maintain LDL-C levels ≥100 mg/dL, highlighting persistent gaps between available therapies and real-world implementation.

Oral PCSK9i and Primary Prevention Reshape Lipid Management

The evolving landscape of cardiovascular risk management is being significantly shaped by new clinical guidelines and innovative therapeutic advancements. With the American College of Cardiology (ACC) and American Heart Association (AHA) emphasizing more aggressive lipid management, the pharmaceutical industry is responding with novel approaches to tackle the persistent challenge of high cholesterol and residual cardiovascular risk.

Merck's positive Phase 3 results for enlicitide, an oral PCSK9 inhibitor, represent a pivotal moment. Current PCSK9 inhibitors, while highly effective in reducing LDL-C and cardiovascular events, are injectable monoclonal antibodies. An oral formulation could dramatically improve patient convenience and adherence, potentially broadening the eligible patient population beyond those with established atherosclerotic cardiovascular disease (ASCVD) or familial hypercholesterolemia who are often statin-intolerant or inadequately controlled. This shift could redefine the competitive dynamics within the PCSK9 inhibitor class, offering a compelling alternative to existing injectable options.

Concurrently, the focus on primary prevention, exemplified by Amgen's data for Repatha, highlights a strategic move to intervene earlier in the disease continuum. Studies are exploring the benefits of PCSK9 inhibition in high-risk patients without a prior myocardial infarction or stroke, aiming to prevent initial cardiovascular events. This expansion of utility underscores the robust efficacy and safety profile of PCSK9 inhibitors, even at very low LDL-C levels.

Beyond LDL-C, the industry is increasingly recognizing lipoprotein(a) (Lp(a)) as a critical, genetically determined, independent risk factor for cardiovascular disease. While PCSK9 inhibitors offer a modest reduction in Lp(a) levels, the intensified focus on this target suggests a future where more potent, specific Lp(a)-lowering therapies, such as antisense oligonucleotides, may become integral to comprehensive risk reduction strategies. However, the high cost of PCSK9 inhibitors remains a significant consideration for healthcare systems and patient access, and the long-term outcomes specifically attributable to Lp(a) lowering by PCSK9 inhibitors, versus dedicated Lp(a) therapies, are still being fully elucidated. The convergence of new guidelines, oral therapies, and a deeper understanding of residual risk factors like Lp(a) promises a more personalized and effective approach to preventing cardiovascular disease.