New guidelines from two leading medical associations suggest that efforts to reduce bad cholesterol should focus on maintaining low levels of two key lipoproteins. Big pharma is all in, looking to improve on the standard statins to help vanquish America’s number one killer: heart disease.
Heart disease has remained America’s number one killer for a century. Recent guidelines, however, underscore the potential opportunity for pharmaceutical companies in treating a key cause of the epidemic—bad cholesterol.
Atherosclerotic cardiovascular disease (ASCVD)—characterized by a buildup of plaque in the arteries—is not a normal part of aging, John T. Wilkins, a cardiologist at Northwestern Medicine, told BioSpace, “though unfortunately it’s very normative in the U.S.”
“Cholesterol levels are a primary determinant or cause of atherosclerosis,” he continued, as the accumulation of cholesterol-containing particles within the walls of arteries can lead to heart attacks or strokes.
Recently, there have been glimmers of good news in the space.
On March 30, Merck reported that its cholesterol-lowering pill enlicitide significantly outperformed other oral non-statin drugs in patients with hypercholesterolemia—aka., high cholesterol. It also reduced low-density lipoprotein-cholesterol (LDL-C) by 64.6% from baseline at eight weeks when added to background treatment with a statin.
The results, which came months after Merck received a Commissioner’s National Priority Voucher for enlicitide in December 2025, follow on the heels of another significant development: the publication of updated guidelines by the American College of Cardiology (ACC) and the American Heart Association (AHA) for managing lipids and cholesterol.
The guidelines reintroduce specific LDL-C goals aimed at preventing a first heart attack or stroke. For those at intermediate risk, LDL-C levels should be less than 100 mg/dL, while those at high risk should aim for less than 70 mg/dL. Individuals with ASCVD should maintain an LDL-C level lower than 55 mg/dL for the secondary prevention of cardiac events, according to the document.
“What is important with the guidelines is establishing limits, with the idea that a lower level of LDL-C is better,” Joerg Koglin, senior vice president, global clinical development at Merck, told BioSpace. “When you look at the LDL goals as they are right now, approximately 70% of patients on statins don’t reach those goals.”
This offers a significant opportunity for Merck, and Big Pharma peers Amgen, AstraZeneca and Eli Lilly to step in with solutions. The ACC’s recent Annual Scientific Session served as a platform for some of these companies to provide clinical updates.
Merck targets convenience
Lifetime exposure to high LDL-C levels increases cardiac risk, Koglin said, making a longer-term assessment important. It is illogical to wait until someone is 50 years old to begin treatment because by this time, cholesterol plaques and general risk have already accumulated, he added.
The new guidance recognizes this and provides a tool designed to measure risk for ASCVD events beginning at age 30. The Predicting Risk of Cardiovascular Disease EVENTs (PREVENT) calculator for primary prevention of ASCVD is capable of estimating both 10- and 30-year risk for ASCVD events, which, in turn, influences treatment options. It is also more accurate compared with the previous calculator, which was known to overestimate risk, said Wilkins, who was an author of the new guidelines.
The calculator’s ability to estimate 30-year risk is important for two reasons, Wilkins said. First, ASCVD develops over decades, creating a long latency period, and second, poor cardiovascular health is increasing in young American adults.
This is where industry is stepping in. There is momentum building within the overall pipeline, Koglin said, with increased research activity and the emergence of new data providing both actionable insights and new treatments for the management of cholesterol.
At ACC, Merck reviewed results from its Phase III CORALreef AddOn study, in which enlicitide demonstrated a statistically significant reduction in LDL-C after eight weeks of treatment compared to current cholesterol-lowering medicines bempedoic acid, ezetimibe or bempedoic acid with ezetimibe.Enlicitide’s nature as a daily oral PCSK9 inhibitor differentiates it from existing monoclonal antibody PCSK9 drugs that require either biweekly or monthly injections. The PCSK9 injectable class of drugs includes market leader Repatha, which earned Amgen $3 billion in 2025.
This requirement of either a biweekly or monthly injection is burdensome enough to patients that Merck sees a market opportunity in launching an oral alternative, Koglin said. Analysts appear to agree. Guggenheim Partners in November pointed to results from Merck’s Phase 3 CORALreef Lipids trial, in which the data showed at least a 97% treatment adherence rate.
“We see a path for enlicitide to exceed the ~ $2.8Bn consensus currently estimates for enlicitide in 2033,” the firm wrote at the time.
Repatha does currently hold one advantage over enlicitide, however. Amgen presented data at ACC from a new subgroup of the Phase 3 Vesalius-CV showing the drug significantly reduced the risk of a first cardiovascular event in the high-risk primary prevention setting, a first for a PCSK9 inhibitor.
This statistic is not yet known for enlicitide, but Merck’s CORALreef Outcomes trial could yield such data. Primary results are due in November 2029, per ClinicalTrials.gov.
Further data from Amgen’s trial also emphasized the high unmet need remaining in this space. The five-year cardiovascular event rate in the placebo arm was 10.5%, even though these individuals would be considered low risk by physicians, Paul Burton, chief medical officer at Amgen, told BioSpace.
“There are probably 50 million people in this country who are walking around looking a lot like the Vesalius-CV population, so there’s a huge unmet need,” he said. Real-world data show that only one in five individuals on current standard-of-care medication are able to achieve the new LDL-C guidance, Burton added. “That means the vast majority of people are going to need a medicine like Repatha.”
LP(a): The next step?
An additional opportunity to reduce heart disease risk is via lipoprotein(a) (Lp(a)). Both Burton and Koglin highlighted the recommendation to monitor Lp(a)—high levels of which are associated with an increased risk for heart attack or stroke—at least once in adulthood as a significant aspect of the new guidelines. Unlike LDL-C, the primary driver for Lp(a) levels appears to be genetic, Koglin said.
This pathway is a focus for many companies, including Merck and AstraZeneca.
Last year, Merck committed nearly $2 billion biobucks to China-based Jiangsu Hengrui to partner on an investigational small molecule, HRS-5346, which targets Lp(a). Meanwhile, AstraZeneca in October 2024 linked up with the Chinese firm CSPC Pharmaceutical Group on an Lp(a) disruptor.
And Merck and AstraZeneca are not alone. Eli Lilly and Amgen are each developing their own Lp(a)-targeting therapies in-house. Lilly reported positive Phase 2 data from its investigational pill muvalaplin in November 2024, and a readout from the OCEAN(a)-Outcomes trial evaluating Amgen’s small interfering RNA therapy olpasiran is expected next year, according to Burton.
“We need additional treatment solutions,” Koglin said. “It’s almost embarrassing that ASCVD has been the leading cause of death in adults worldwide for so many years, despite all of the innovations we’ve seen in research and treatments.”
