In patients with history of atherosclerotic CV disease, current guidelines recommend a target of LDL-C levels < 55 mg/dl [1]. These recommendations were supported by the recent Korean trial of patients with atherosclerotic CV disease, showing that targeting LDL-C levels < 55 mg/dl resulted in decreased risk of CV events at 3 years compared with targeting LDL-C levels of < 70 mg/dl; HR 0.67; 95% CI, 0.52 to 0.86; P=0.002 [2]. Meanwhile, using health record data from 8 large US health systems, Navar et al [3] have shown that only 22.6% of patients with atherosclerotic CV disease attain the target LDL-C values < 55 mg/dl.  Furthermore, even with using high intensity statins + ezetimibe, 40% of these patients still fail to meet an LDL-C < 55 mg/dl [3]. To achieve such LDL-C objective, combination lipid-lowering therapy is frequently required, including high-intensity statin plus ezetimibe plus a PCSK9 inhibitor. Unfortunately, there is underutilization of the potent PCSK9 inhibitors likely due to their high cost and need for parenteral administration [4].  Enlicitide (code MK-0616) is an orally administered macrocyclic peptide that binds to PCSK9 and blocks its interaction with the LDL-C receptor [5]. This results in increased availability of LDL-C receptors and enhanced clearance of LDL-C. To facilitate its absorption from the intestine, enclicitide is formulated with a permeation enhancer, sodium caprate, to allow its passage through tight junctions between intestinal epithelial cells [6]. Enlicitide has low bioavailability of 2% [5]. Its excretion takes place via the kidneys [7]. Because food intake affects pharmacokinetics of enlicitide, this agent should be administered in the morning on an empty stomach with water and withhold food and beverages for 30 minutes [5,8]. Enlicitide is currently under investigation in various phase 3 clinical trials. Three of these trials were recently published and summarized in table 1 [8-10]. The main purpose of this article is to review available data regarding enlicitide and to provide an appraisal on its efficacy and safety as a new lipid-lowering drug. 

Enlicitide in Patients with Cardiovascular Disease and High Cardiovascular Risk: The Coralreef Trial

The CORALreef trial is the largest randomized study (n=2909) to evaluate effects of enlicitide on lipid profile in patients with history of major CVD with LDL-C ≥55 mg/dl (58% of subjects) and those at high risk to develop CVD with LDL-C of ≥70 mg/dl (42% of subjects) [8]. Approximately 50% of patients had diabetes, and 97% were already on statins of high and moderate intensity, and 25% on ezetimibe [8]. Participants were randomized in a 2:1 ratio to enlicitide 20 mg or placebo for 52 weeks [8].

Enlicitide in Patients with Heterozygous Familial Hypercholesterolemia

In the CORALreef HeFH phase 3 trial, Ballantyne et al [9] evaluated the effect of enlicitide in 303 patients with HeFH (table 1). 27.6% of patients had history of major CV disease and 12% had type 2 diabetes [9]. From a mean baseline of LDL-C of 119 mg/dl, reductions in LDL-C levels at 24 week (primary outcome) was like the larger CORALreef trial, -58.2% and 2.6% in the enlicitide and placebo groups, respectively; between group difference -59.4% (95% CI, -65.6 to -53.2; P<0.001) (table 1) [9]. At 52 weeks, the corresponding difference was -61.5% (95% CI, -69.4 to -53.7; P<0.001) [9]. At 24 weeks, achievement of the target LDL-C levels of < 55 mg/dl coupled with a reduction of ≥50% of LDL-C from baseline occurred in 67.3% with enlicitide versus 1.0% with placebo [9]. These percentages are almost identical to those recorded in the CORALreef trial mentioned above [9]. Likewise, as seen in table 1, the reduction in non-HDL-C and Lp(a) levels by enlicitide were similar in the CORALreef and COLAReef HeFH trials.

Effects of Enlicitide on LDL-C Levels and Other Lipoproteins

From a mean baseline LDL-C levels of 96 mg/dl, the mean percent change in LDL-C values was -57.1% and 3.0% with enlicitide and placebo, respectively at 24 weeks [8]. Thus, at 24 weeks, the adjusted between-group difference was -58.8% (95% CI, -61.8 to -50.7; P<0.001). At 52 weeks, the between group difference was -47.6 (95% CI, -52.7 to –42.5; P< 0.001) [8]. Maximal effect on LDL-C lowering was observed after 4 weeks followed by a plateau or minimal rebound [8]. At 24 weeks, achievement of the target LDL-C levels of < 55 mg/dl with a reduction of ≥50% of LDL-C from baseline occurred in 67.5% of patients receiving with enlicitide versus 1.2% of subjects randomized to placebo [8]. The reduction in LDL-C levels was similar in different patient subgroups classified by age, gender, ethnicity, diabetes status, and baseline LDL-C levels [8]. Enlicitide was associated with significant reduction in atherogenic lipoproteins compared with placebo at 24 weeks. Thus, difference versus placebo was - 53.4% (95% CI, -55.5 to -51.2) for non-HDL-C, -50.3% (95% CI, -52.1 to -42.5) for apo B, and -28.2 (95% CI, -30.3 to -26.3) for Lp(a) [8]. Enlicitide significantly increased HDL-C levels more than placebo, between group difference at 24 weeks was 6.9% (95% CI, 5.6 to 8.1) [8]. Regarding serum triglycerides, enlicitide has a mild but statistically significant effect, with reduction of 14.9% (95% CI, 5.6 to 8.1%) versus placebo [8].

Enlicitide versus Ezetimibe And/Or Bempedoic Acid

In the CORALreef AddOn trial, Catapano et al [10] compared efficacy and safety of enlicitide 20 mg/d versus ezetimibe 10 mg/d, bempedoic acid 180 mg/d, or ezetimibe + bempedoic acid in statin-treated patients (n=301). Included patients had either history of established CVD and LDL-C levels ≥ 55 mg/dl, or at intermediate to high CV risk with LDL-C ≥70 mg/dl (table 1) [10]. For unclear reasons, the duration of this phase 3, randomized trial was only 56 days. From a mean baseline LDL-C levels of 91.6 mg/dl, enlicitide was superior to other 3 comparators in reducing LDL-C values. Thus, at day 56, the decrease in LDL-C concentrations from baseline was -64.6% with enlicitide, -6.3% with bempedoic acid, -27.8% with ezetimibe and -36.5% with ezetimibe + bempedoic acid (P< 0.001 versus 3 comparators) [10]. Likewise, reductions in ApoB and non-HDL-C levels were greater with enlicitide (all P< 0.001) (table 1) [10].

Advantages

Available studies suggest that enlicitide consistently lower LDL-C levels like the 2 injectable PCSK9 inhibitors, evolocumab and alirocumab [11,12]. However, contrary to the 2 agents, enlicitide is administered orally. This represents great convenience for patients who have needle phobia and avoid the skin adverse effects of injections.  In addition, it has a reassuring safety profile over one year of use with no concerning safety signals that emerged in any trial so far.

Limitations of Enlicitide

First limitation of enlicitide is the lack of data regarding its impact on CV events and mortality. Second, patients included in enlicitide trials were relatively “healthy” because they were selected based on multiple exclusion criteria and therefore results may not be applied to all patients with atherosclerotic CVD. For instance, exclusion criteria were the presence of uncontrolled diabetes defined as HbA1c ≥9.0%, triglycerides levels ≥ 400 mg/dl, and hepatic disease [8].  While enlicitide is excreted via the kidneys, its safety has not been adequately evaluated in patients with chronic kidney disease (CKD). In fact, in the CORALreef trial only 16% of patients had an estimated glomerular filtration rate (eGFR) < 60 ml/min [8].

No doubt, enlicitide is a welcome addition to lipid-lowering therapy. This new PCSK9 inhibitor provides consistent reductions in LDL-C and non-HDL-C levels of approximately 50%, and more modest reduction in Lpa of approximately 28%. Moreover, the drug has excellent safety record up to 1 year of use. Thus, efficacy and safety of enlicitide closely mimic those of injectable PCSK9 inhibitors. Being orally administered once daily provides an attractive advantage over the currently available parenteral PSCK9 inhibitors. Future studies are needed to establish the long-term safety and efficacy of enlicitide and its effects on CV outcomes and mortality. In addition, safety of enlicitide in various patient groups need to be studied such as patients with CKD, liver disease, the elderly, and in various ethnic minorities.

Conflict Of Interest

The author has no conflict of interest to declare.

Table 1: Phase 3 Trials Of Enlicitide.

LDL-CL low-density lipoprotein cholesterol, non-HDL-C: non-high density lipoprotein cholesterol, HeFH: heterozygous familial hypercholesterolemia, CVD: cardiovascular disease.

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