Enlicitide is an orally administered proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor under investigation in phase 3 clinical trials. In the largest enlicitide trial (CORALreef) including patients with established or at high-risk of developing cardiovascular disease (CVD) already on statins, the changes in low-density lipoproptein cholesterol (LDL-C) levels after 24 weeks were -57.1% and 3.0% with enlicitide and placebo, respectively. Enlicitide decreased levels of the atherogenic non-high density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (apo B) and lipoprotein a [Lp(a)]; difference from placebo -53.4%, -50.3%, and -28.2%, respectively. Similar results were obtained in another phase 3 clinical trial of patients with heterozygous familial hypercholesterolemia (HeFH). In a third randomized trial lasting only 56 days, enlicitide was more effective than ezetimibe, bempedoic acid, and ezetimibe + bempedoic acid in decreasing LDL-C levels with reductions of -64.6%, -27.8%, -6.3%, and -36.5% versus baseline, respectively. Enlicitide was well tolerated for up to 1 year of use, with adverse effects and drug discontinuation rates comparable to placebo. Enlicitide is a promising addition to lipid lowering therapy due to its ease of administration orally coupled with high efficacy and safety. Further studies are needed to examine long-term safety of enlicitide and its impact on CV outcomes and mortality. 

In patients with history of atherosclerotic CV disease, current guidelines recommend a target of LDL-C levels < 55 P=0.002>

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].

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>

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>

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>

Table 1: Phase 3 trials of enlicitide

Abbreviations in table 1.

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

Appraisal of enlicitide

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 CORA Lreef trial only 16% of patients had an estimated glomerular filtration rate (eGFR) < 60>

Conclusions and future needs

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.