Will Nexletol (Bempedoic Acid) Replace Statins?

Statins overwhelmingly dominate pharmacy sales. At last count, over 50 million people take statin-type cholesterol-lowering drugs such as atorvastatin, rosuvastatin and and simvastatin. That does not include all the other statins such as fluvastatin, lovastatin, pitavastin and pravastatin or combination drugs containing a statin such as Vytorin or Caduet. But many people cannot tolerate statins because of adverse reactions such as muscle pain and weakness or increases in blood glucose. That’s why there has been interest in statin alternatives such as Nexletol (bempedoic acid).

The FDA approved Nexletol in February, 2020. It never really became a big best seller. But a study published in the New England Journal of Medicine (March 4, 2023) has attracted attention. Will Nexletol replace drugs like atorvastatin, simvastatin or rosuvastatin to lower LDL cholesterol? Probably not, but for people who cannot tolerate statins, it might represent a viable alternative.

Cardiologists Call Statins the Cornerstones!

Most cardiologists are not ready to throw statins on the scrap heap of tired old medications. They perceive statins as their go-to prescriptions for heart protection.

The # 1 most prescribed drug in the United States remains atorvastatin (Lipitor). Our most recent review shows that roughly 29,359,439 Americans filled 115,271,514 million prescriptions for this statin-type cholesterol-lowering medication annually. 11,790,764 took  rosuvastatin. And more than 6 million people take simvastatin each year.

The Cost of Statins vs. Nexletol:

Most statin-type drugs are now available generically. That means they are affordable. Insurance companies are relatively happy paying for such inexpensive medications and co-pays won’t break the bank.

If you do not rely on insurance, statins are cheap! According to GoodRx.com, the cost for 90 tablets of 20 mg simvastatin tablets is about $28. The price at GoodRx of atorvastatin could range from about $6 to around $24 for 30 tablets (40 mg) with a GoodRx coupon.

The cost of Nexletol is a lot higher than generic statins! Let’s assume for a moment that your insurance company does not approve the drug. According to GoodRx, the “average retail price” for a month’s supply would be about over $500. Using a GoodRx coupon/Savings Card, the cost is likely to be around $231.

Nexletol Is NOT a Statin!

The most popular cholesterol-lowering drugs interfere with the body’s ability to make cholesterol. They are known as 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors (statins). That’s a mouthful and I won’t bore you with more statin details.

The new medication, bempedoic acid, works through a different pathway. An editorial in the New England Journal of Medicine (March 4, 2023) explains the science behind the “new” Nexletol. Let me just say it’s complicated. Here is the biochemistry.

Feel free to skip over it:

“Bempedoic acid is a prodrug: it requires conversion by the very-long-chain acyl-CoA synthetase 1 (ASCVL1) into a CoA-thioester that is the active metabolite. The CoA-thioester inhibits adenosine triphosphate citrate lyase that is in the cholesterol biosynthetic pathway upstream of HMG-CoA reductase.”

A Reader Asks a Question About Nexletol Effectiveness:

Q. I read the breathless announcements about bempedoic acid and how effective it is at lowering cholesterol. This is all well and good, but what we care about is how effective it is at preventing heart attacks and strokes!

I would love to know the NNT for primary and secondary protection as well as mortality outcomes. Cardiologists are dogmatic that lowering cholesterol is desirable, but what we care about is not getting sick and dying.

A. The NNT (number needed to treat) is a very useful way of understanding the power of a medication. As you point out, avoiding a heart attack and staying alive is more important for patients than controlling lipid levels. The NNT defines how many people would need to take a medication for one person to avoid the undesirable outcome.

Researchers published data on primary prevention in JAMA (July 11, 2023). There were 4,206 people in the study who did not have cardiovascular disease when it began, although they had high cholesterol and were at high risk. Based on the published data, 125 people without heart disease would need to take bempedoic acid for three years so that one person could avoid a heart attack. To avoid death from cardiovascular causes during those three years, 77 people would need to take the medicine. And to avoid death during the study for any reason, the NNT is 62.5. There was no protection from stroke.

The study actually included many people who did have cardiovascular disease before it began. Those results, which could be considered secondary prevention, were published in the New England Journal of Medicine (April 13, 2023).  The NNT in this situation for a fatal or nonfatal heart attack was 91 over three years, but there were no lives saved.

You can learn more about bempedoic acid and other approaches to lowering blood lipids in our eGuide to Cholesterol Control and Heart Health. This online resource is located under the Health eGuides tab.

The Bottom Line on Bempedoic Acid (Nexletol):

Muscle pain associated with statin-type cholesterol-lowering drugs has been controversial for years. Some research suggests that this side effect is relatively common while other studies report that it is no more likely than with placebo.

Bempedoic acid can lower LDL cholesterol in patients who cannot tolerate statins. The study in the New England Journal of Medicine that has generated so much press in the last week was carried out on 14,000 people who were statin intolerant.

The randomized controlled trial lasted more than three years. People taking Nexletol daily were 23% less likely to have a heart attack than those taking placebo pills. The absolute risk for a heart attack was 3.7% in the bempedoic acid group compared to 4.8% in the placebo group.

That’s a benefit, but when it comes to mortality, the results were less promising.

The authors of this impressive study report that:

“Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause.”

In other words, Nexletol did not save any lives over the three plus years of the study. Some cardiologists will say that’s not enough time to see a clinical benefit. Others point to fewer heart attacks and say that is good enough for them.

We were puzzled to note that there were 434 “deaths from any cause” among those on Nexletol and 420 “deaths from any cause” among those on placebo. The difference was not statistically significant. It was also not reassuring.

Side Effects of Bempedoic Acid:

Gout:

Patients on Nexletol had higher levels of uric acid in their urine and were more likely to develop gout or gallstones than those on placebo.

In the official prescribing information, the uric acid problem is described this way:

“In clinical trials, 26% of NEXLETOL-treated patients with normal baseline uric acid values (versus 9.5% placebo) experienced hyperuricemia [high uric acid levels] one or more times, and 3.5% of patients experienced clinically significant hyperuricemia reported as an adverse reaction (versus 1.1% placebo). Increases in uric acid levels usually occurred within the first 4 weeks of treatment initiation and persisted throughout treatment.”

Tendon Rupture:

The FDA also requires a warning about tendon rupture:

“NEXLETOL is associated with an increased risk of tendon rupture or injury. In clinical trials, tendon rupture occurred in 0.5% of patients treated with NEXLETOL versus 0% of placebo-treated patients and involved the rotator cuff (the shoulder), biceps tendon, or Achilles tendon. Tendon rupture occurred within weeks to months of starting NEXLETOL. Tendon rupture may occur more frequently in patients over 60 years of age, in those taking corticosteroid or fluoroquinolone drugs, in patients with renal failure, and in patients with previous tendon disorders.

“Discontinue NEXLETOL immediately if the patient experiences rupture of a tendon.”

It may seem as if a 0.5% incidence of tendon rupture is nothing to worry about. If it occurs, however, it can be a disastrous complication. Anyone who gets a prescription for Nexletol should ask about warning signals of tendon problems.

Other side effects of bempedoic acid may include:

• Elevated liver enzymes
• Muscle spasms
• Back pain
• Pain in an extremity
• Abdominal discomfort
• Benign prostatic hyperplasia (BPH)

We have not received many comments about Nexletol. If you have taken this drug to lower cholesterol, please share your experience in the comment section below. If you would like to read more about our thoughts on cholesterol and statins, you may want to review our eGuide to Cholesterol Control and Heart Health. It can be found under the Health eGuides tab at this link.

You will learn about an often ignored risk factor for heart disease called lipoprotein (a), also known as Lp(a). It is a big deal and statins can actually raise Lp(a) levels. A study published in BMC Cardiovascular Disorders (Dec. 30, 2022) offered some disturbing observations.

To be precise:

“After statin therapy, the mean level of Lp(a) increased by 19.3% from baseline. Lp(a) levels increased in 307 patients (62.9%) with a median elevation of 4.1 mg/dL. Patients with an increase in Lp(a) were at higher risk for MACE [major adverse cardiovascular events] than those without an increase in Lp(a).”

Conclusions:

“Severe increases in Lp(a) following statin therapy raise the risk of MACE [major adverse cardiovascular events]…”

Should you wish to learn more about Lp(a), check out our eGuide mentioned above.