Enlicitide Cuts LDL-C Regardless of Kidney Function

For patients with reduced kidney function, a group at elevated cardiovascular risk that often falls short of lipid targets, the oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor enlicitide (Lipfendra; Merck) lowered low-density lipoprotein cholesterol (LDL-C) at least as much as it did in patients with preserved kidney function. A pooled analysis of the phase 3 CORALreef Lipids (NCT05952856) and CORALreef HeFH (NCT05952869) trials were presented at the American Society of Nephrology’s Kidney Week 2026 in Denver, Colorado.¹

In it, patients with an estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m² had a placebo-adjusted LDL-C reduction of 65.9% at week 24, and 80.5% of those treated with enlicitide reached an LDL-C below 70 mg/dL.¹

The FDA approved enlicitide 20 mg once daily in July 2026 as an adjunct to diet and exercise to reduce LDL-C in adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH). The approval was based on placebo-adjusted week 24 LDL-C reductions of 56% in CORALreef Lipids and 59% in CORALreef HeFH.^2,3

Consistent Lipid Lowering Across eGFR Groups

The analysis pooled 3212 participants from both trials comparing enlicitide 20 mg once daily with placebo. Of these, 2924 had an eGFR of 60 or higher, and 288 had an eGFR below 60. Investigators assessed:

• LDL-C change at weeks 24 and 52;
• non–high-density lipoprotein cholesterol (non–HDL-C), apolipoprotein B (ApoB), and lipoprotein(a) [Lp(a)] at week 24;
• LDL-C goal attainment; and
• adverse events through week 52.¹

In patients with eGFR below 60, placebo-adjusted LDL-C reductions were 65.9% at week 24 and 64.2% at week 52. In patients with eGFR of 60 or higher, the reductions were 62.3% and 56.8%, respectively. Enlicitide significantly reduced non–HDL-C, ApoB, and Lp(a) versus placebo in both groups (all P < .001). At week 24, 74.9% of enlicitide-treated patients with eGFR below 60 reached an LDL-C below 55 mg/dL, nearly identical to the 74.7% seen with eGFR of 60 or higher. The corresponding rates for an LDL-C below 70 mg/dL were 80.5% and 81.5%.¹

"It has shown both efficacy and safety in patients with reduced eGFR," Christie M. Ballantyne, MD, of Baylor College of Medicine, first author of the analysis, said in a comment to Pharmacy Times.

Safety was comparable to placebo, including in patients with eGFR below 60, according to the investigators. The abstract did not report adverse event rates by eGFR group. It also did not give separate results for patients with eGFR below 30 or those receiving dialysis.¹

What the Label Says About Kidney Function

Enlicitide is minimally metabolized. After intravenous administration it is primarily eliminated via glomerular filtration, with about 73% of a dose recovered in urine. Even so, the prescribing information projects only 5%, 11%, and 26% higher steady-state exposure in patients with mild, moderate, and severe renal impairment, respectively. It also reports single-dose exposure is 17% and 75% higher in patients with end-stage renal disease when enlicitide is given before and after hemodialysis. The label describes none of these increases as clinically meaningful and includes no renal dosage adjustment.³

Patients with chronic kidney disease (CKD) commonly take several cardiometabolic medications. For them, the label reports that enlicitide did not affect exposure to lisinopril (Zestril, AstraZeneca; Prinivil, Merck), digoxin, warfarin, atorvastatin (Lipitor; Pfizer), levothyroxine, or oral semaglutide (Wegovy; Novo).³

Counseling Points for Patients With CKD

Administration is where pharmacists will spend most of their counseling time. Patients should swallow the tablet whole on an empty stomach in the morning with water, black coffee, or plain tea. They should then wait at least 30 minutes before other food or drink. Taking enlicitide 30 minutes after a meal cut steady-state exposure (AUC) by 48%.³

"In the phase 3 clinical trial program, there was good adherence to taking the medication first thing in the morning before food. It can be taken with other medications at the same time," Ballantyne said. "The drug has a long half-life, so taking occasional doses non-fasting or missing an occasional dose is unlikely to make a major impact on efficacy."

The label advises taking a missed dose as soon as possible, at least 30 minutes before the next food or drink other than water, black coffee, or plain tea, and not taking 2 doses on the same day.³

"Enlicitide provides a new nonstatin oral option [that] has been shown to be more effective than currently available nonstatin therapies with similar efficacy to the injectable monoclonal antibodies that target PCSK9," Ballantyne said.

For now, pharmacists should present enlicitide as an LDL-C–lowering therapy. The CORALreef Outcomes (NCT06008756) trial has enrolled more than 14,500 participants and is evaluating whether the drug reduces cardiovascular morbidity and mortality; that benefit has not yet been established.²

REFERENCES

1. Ballantyne C, Zhuo M, Banka P, et al. Enlicitide, an oral PCSK9 inhibitor, for lipid lowering: pooled analysis of the phase 3 CORALreef Lipids and HeFH trials by baseline eGFR. Abstract TH-OR037. Presented at: ASN Kidney Week 2026; October 22, 2026; Denver, CO.

2. Antrim A, Halpern L. FDA approves enlicitide, the first oral PCSK9 inhibitor for high cholesterol. Pharmacy Times. Updated July 17, 2026. Accessed October 22, 2026. https://www.pharmacytimes.com/view/fda-approves-enlicitide-the-first-oral-pcsk9-inhibitor-for-high-cholesterol

3. Lipfendra (enlicitide) tablets. Prescribing information. Merck Sharp & Dohme LLC; 2026. Accessed October 22, 2026. https://www.merck.com/product/usa/pi_circulars/l/lipfendra/lipfendra_pi.pdf