HDL Cholesterol and Cardiovascular Risk - Rethinking the 'Good Cholesterol' Narrative

The long-standing narrative that high-density lipoprotein (HDL) cholesterol is unequivocally "good" is unraveling under the weight of recent scientific evidence. For decades, HDL has been marketed as a cardiovascular savior, with therapies aimed at elevating its levels dominating lipid management strategies. However, a growing body of clinical trials and meta-analyses now challenges this simplistic view, revealing a nuanced relationship between HDL and cardiovascular risk. For investors in biopharma stocks targeting HDL-related therapies, these findings signal a paradigm shift-and a potential minefield of unmet expectations.

The HDL Paradox: Function Over Concentration

Recent studies have dismantled the assumption that higher HDL cholesterol (HDL-C) levels directly translate to lower cardiovascular risk. A 2025 meta-analysis of HDL particle subclasses found that total and small HDL particles (HDL-p) are negatively associated with all-cause mortality in cardiovascular disease (CVD) patients, while large HDL-p showed a positive association. This suggests that the functional properties of HDL-such as reverse cholesterol transport and anti-inflammatory activity-are more critical than mere concentration. Small HDL-p, for instance, for instance, has higher protein content and atheroprotective potential compared to larger, lipid-dense particles.

Compounding this complexity is the emergence of a U-shaped relationship between HDL-C and atherosclerotic cardiovascular disease (ASCVD) risk. While moderate increases in HDL-C reduce risk, extremely high levels may paradoxically elevate it. This challenges the conventional wisdom that "more is better" and raises questions about the validity of HDL-C as a standalone biomarker. As one review notes, HDL-C levels may not reliably reflect functional capacity, as they primarily measure larger, cholesterol-loaded particles.

Clinical Trial Failures and the HDL Drug Dilemma

The biopharma sector's attempts to capitalize on HDL's perceived benefits have been marred by repeated clinical trial failures. Niacin, once hailed as a HDL-boosting panacea, showed no cardiovascular benefit when added to statin therapy and was associated with adverse effects. Similarly, CETP inhibitors like torcetrapib and dalcetrapib either increased mortality or failed to demonstrate efficacy. These setbacks have left investors wary of HDL-targeting drugs, particularly as newer therapies like PCSK9 inhibitors and RNA interference (RNAi) drugs gain traction. According to market research, the market is shifting toward LDL-focused therapies.

Anacetrapib and evacetrapib, CETP inhibitors with more favorable profiles, remain in development, but their outcomes are uncertain. Meanwhile, the market is shifting toward LDL-focused therapies. PCSK9 inhibitors, for example, have demonstrated robust LDL-C reduction but face challenges related to high costs and competition from cheaper alternatives like bempedoic acid. The long-acting cholesterol-lowering drugs market, valued at $1.529 billion in 2024, is projected to grow at a 6.0% CAGR through 2032, but this growth is contingent on overcoming reimbursement barriers and patent cliffs.

Investment Risks in HDL-Targeting Biopharma

The financial landscape for HDL/lipid therapy developers is fraught with challenges. Companies like HLS Therapeutics, which relies on Vascepa and bempedoic acid for growth, reported a $3.92 million net loss in Q3 2025 despite increased prescriptions. High R&D costs, regulatory uncertainties, and the need for real-world evidence to justify premium pricing further strain biopharma firms. For instance, NewAmsterdam Pharma's Obicetrapib and Arrowhead Pharmaceuticals' Zodasiran, while promising in clinical trials, must navigate complex approval pathways and market acceptance hurdles.

Investors must also contend with macroeconomic headwinds. U.S. drug pricing policies, including Medicare/Medicaid reforms, threaten to erode profit margins. Additionally, the rise of biosimilars and generics-such as the impending patent expirations for blockbuster cholesterol drugs-could reduce revenues by up to 80% post-launch. The lipid nanoparticle (LNP) technology used in RNA-based therapies, while innovative, adds another layer of complexity due to high production costs and scalability issues.

A Call for Caution and Strategic Reassessment

For investors, the key takeaway is clear: HDL-focused therapies are no longer a sure bet. The scientific community's pivot toward HDL functionality and LDL-centric approaches has left many HDL-targeting drugs in limbo. While the global lipid disorder treatment market is projected to grow, from $30.48 billion in 2025 to $43.223 billion by 2030, this growth will likely be driven by LDL-lowering agents rather than HDL-boosting ones.

Biopharma companies must now balance innovation with cost-effectiveness. Digital health integration, patient adherence programs, and strategic M&A could mitigate risks, but success hinges on demonstrating superior value through real-world outcomes. For investors, the lesson is to prioritize therapies with robust clinical evidence and scalable business models-those that address unmet needs without relying on the outdated "good cholesterol" narrative.

In the end, the HDL story is a cautionary tale of how quickly scientific consensus can shift. For biopharma, the path forward lies not in chasing outdated metrics but in embracing the complexity of lipid biology-and the markets that follow.