PCSK9 inhibitors are amazing medications that lower cholesterol by about 60% on their own, or 80-85% as part of triple therapy. Yet, only 1% of eligible patients use PCSK9 inhibitors today. Aside from cost, the biggest barrier is that they’re are all injectibles, not pills.

The FDA just approved Merck’s Lipfendra (enlicitide), the first oral PCSK9 inhibitor. Enlicitide lowered LDL by 56%-60%, about the same as injections like Repatha.

This article covers how enlicitide stacks up against statins, how much it lowers LDL and the rest of your lipid panel, what it costs, and what we know so far about insurance coverage.

Lipfendra lowered LDL cholesterol by 56-60%

Lipfendra was tested in a phase 3 trial with 2,912 adults, the CORALreef Lipids trial. Lipfendra lowered LDL cholesterol by 56% to 60% on top of existing statin therapy. That’s essentially equivalent injectable PCSK9 inhibitors, which lower LDL by about 60%.

At 24 weeks in CORALreef Lipids, enlicitide lowered LDL, non-HDL cholesterol, ApoB, and Lp(a) together.

In the trial, 67.5% of people on Lipfendra hit both a 50%-or-greater LDL drop and an LDL under 55 mg/dL, versus 1.2% on placebo. Layered on a statin, that pushes many people into the 20s and 30s mg/dL, levels a statin alone rarely reaches.

What’s more, Lipfendra moves the whole atherogenic panel, not just LDL. In the trial, it reduced Lp(a) by 24%, which is especially meaningful since the Lp(a)-specific drugs are still in clinical trials.

The ApoB and non-HDL reductions largely correspond to the LDL drop (these quantities are correlated and measure the same underlying particles in different ways).

Why an oral PCSK9 inhibitor matters

The barrier to PCSK9 inhibitors is the injection. Roughly 6 million Americans have high LDL despite a statin, and qualify for a PCSK9 inhibitor, yet only about 1% take one. Some of that is prior authorization and cost, but a lot of it is the needle, the pharmacy trip, and refrigeration. (About 86 million US adults have high cholesterol in total, and conceivably PCSK9 inhibitors will start being used as a monotherapy as they become more convenient and cost comes down.)

All PCSK9 inhibitors before Lipfendra were injections. A pill removes the most common reason people never start.

A once-daily pill fits into the same routine as a statin. What’s more, AstraZeneca has its own oral PCSK9 inhibitor (AZD0780) in trials, so this is likely the start of a category rather than a a singular drugs.

PCSK9 inhibitors vs statins

PCSK9 inhibitors and statins aren’t rivals: they’re usually used together and lower ApoB/LDL via different mechanisms. Statins tell the liver to make less cholesterol, which prompts it to pull more LDL out of the blood. PCSK9 inhibitors block a protein that destroys the liver’s LDL receptors, so those receptors survive and keep clearing LDL. Because the mechanisms differ, the effects of statins and PCSK9 inhibitors stack. For the full mechanism comparison, see PCSK9 inhibitors vs statins.

Added to a statin, an oral PCSK9 inhibitor reaches the same LDL reduction as the injections, and goes well past what a statin or statin-plus-ezetimibe delivers.

How much will Lipfendra cost?

Lipfendra’s list price is $315 for a 30-day supply, or about $3,780 a year. That’s below the roughly $5,850 list price of the injectable PCSK9 inhibitors.

However, list price isn’t what most people pay. As a brand-new drug, Lipfendra won’t be on every formulary yet, and insurers are likely to wrap it in the same prior authorization they use for the injectable PCSK9 inhibitors, meaning a documented statin trial first. Whether your plan treats it as a preferred oral option or gates it like an injectable will decide your out-of-pocket cost more than the list price does. We track the rules in insurance coverage of PCSK9 inhibitors.

What to ask your doctor

If your LDL or ApoB is still above target on your current regimen, these are the questions worth raising: Am I on a maximally tolerated high-intensity statin? Would adding ezetimibe get me to goal, or do my numbers warrant a PCSK9 inhibitor? Now that there’s an oral option, does that change the calculus if a shot was the sticking point? And does my plan cover Lipfendra, or does it want an injectable first?

See also: PCSK9 inhibitors lower LDL by about 60%, PCSK9 inhibitors vs statins, and insurance coverage of PCSK9 inhibitors.