Oral Cholesterol Medication Shows Promise as Alternative to Injectable Treatments

Among people with previous heart attack or stroke, or those at high risk for cardiovascular events, a daily oral medication may offer an effective alternative to injections of PCSK9 inhibitors for lowering low-density lipoprotein cholesterol. The investigational drug enlicitide demonstrated up to 60% reduction in LDL cholesterol in a phase 3 trial presented at the American Heart Association's Scientific Sessions 2025, with sustained reductions maintained at 52 weeks of treatment.

This oral medication represents a potential breakthrough for patients who struggle to reach guideline-recommended cholesterol targets despite currently available therapies. Many individuals remain at unnecessary risk of stroke and heart attack because they cannot achieve adequate cholesterol control with existing treatments. The study found that enlicitide produced results nearly identical to those achieved with injectable antibodies alirocumab and evolocumab, while showing numerically better outcomes than the siRNA medication inclisiran.

After 24 weeks of daily treatment, participants taking enlicitide experienced a 53% reduction in non-HDL cholesterol, a 50% reduction in ApoB protein, and a 28% reduction in Lp(a) lipoprotein. Importantly, seven out of ten participants taking enlicitide achieved both at least a 50% reduction in LDL-C and levels below 70 mg/dL, while more than two-thirds reduced their LDL-C by at least 50% and achieved levels below 55 mg/dL. The safety profile was comparable to placebo, with similar rates of serious side effects and only a small proportion of participants leaving the study early due to adverse effects.

The CORALreef Lipids trial enrolled 2,912 adults with an average age of 63 years, 39% of whom were women. All participants had experienced a previous heart attack or stroke or were assessed to be at intermediate or high risk of cardiovascular events within the next decade. Despite being on stable lipid-lowering therapy, including statins for 97% of participants and additional cholesterol absorption inhibitors for 26%, all participants had LDL levels above recommended targets at the study's outset.

Researchers note that while these findings are promising, the ongoing CORALreef outcomes trial will determine whether the substantial LDL reductions achieved with enlicitide actually translate to reduced major cardiovascular events. The study data was collected between August 2023 and July 2025 at 168 health care centers across 14 countries, providing a robust international dataset. Additional information about the American Heart Association's scientific standards and financial policies is available at https://www.heart.org.