Cardiologists generally hate the idea of statin side effects. That’s because they believe most older people should be taking drugs such as atorvastatin, lovastatin, rosuvastatin or simvastatin to prevent heart disease. They fear that reports of statin side effects might discourage people from such medications. Guideline committees that enthusiastically promote statins often suggest that statin side effects are imaginary. Even so, there is a grudging recognition that many people complain or refuse to take such meds. As a result, doctors are pleased by the latest development, bempedoic acid (Nexletol). A study in JAMA suggests it is an alternative to statins for people who report that they cannot tolerate such drugs. What about Nexletol side effects?
Enthusiasm for Nexletol (Bempedoic Acid) in Lieu of Statins:
Dr. Steve Nissen is one of the country’s most recognized cardiologists. (His photo is at the top of the page.) He has served as President of the American College of Cardiology (ACC) and has been in leadership roles at the Cleveland Clinic for decades. Dr. Nissen has been a frequent guest on The People’s Pharmacy nationally syndicated public radio show. He is a huge statin enthusiast.
His most recent publications, though, involve bempedoic acid. He and his colleagues published a major study of Nexletol in the New England Journal of Medicine (April 13, 2023). It was titled:
“Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients”
The Results of the CLEAR (Cholesterol Lowering via Bempedoic Acid an ACL-Inhibiting Regimen) Trial:
In this article, Dr. Nissen and his colleagues acknowledge that:
“…7 to 29% of patients report adverse musculoskeletal effects that prevent them from using statins or limit their ability to receive guideline-recommended doses.”
They recruited 13,970 patients who “had, or were at high risk for, cardiovascular disease.” Half got placebo and half got Nexletol.
The envelope please:
“…the risk of a primary end-point event (death from cardiovascular causes, nonfatal myocardial infarction [heart attack], nonfatal stroke, or coronary revascularization [angioplasty/stent]) was significantly lower by 13% with bempedoic acid than with placebo after a median of 40.6 months of follow-up, with an absolute between-group difference in incidence of 1.6 percentage points.”
Let’s break that down for you in greater detail. Of the 6,978 patients recruited to the placebo arm of the study, 927 or 13.3% experienced one of the above cardiovascular events. Of the 6,992 volunteers on Nexletol, 819 or 11.7% experienced a major adverse cardiovascular event (MACE). That is an absolute difference of 1.6% after about 40 months.
Nexletol Side Effects:
Dr. Nissen and his colleagues report this about Nexletol side effects:
“The overall incidences of adverse events, serious adverse events, and adverse events leading to discontinuation of the trial regimen did not differ meaningfully between the bempedoic acid group and the placebo group.”
Of course the word “meaningfully” is all important. In this large study, Nexletol side effects compared to placebo broke out this way:
Liver enzyme elevations: 3% for people on placebo and 4.5% for people on Nexletol
Kidney “events”: 8.6% for people on placebo and 11.5% for people on Nexletol
Uric acid elevations: 5.6% for people on placebo and 10.9% for people on Nexletol
Gout: 2.1% for people on placebo and 3.1% for people on Nexletol
Gallbladder disease: 1.2% for people on placebo and 2.2% for people on Nexletol
Fast Forward to June, 2023, and a Subgroup Analysis:
Dr. Nissen and his colleagues published a new analysis of bempedoic acid in JAMA on June 24, 2023:
“Bempedoic Acid for Primary Prevention of Cardiovascular Events
in Statin-Intolerant Patients”
A new analysis of more than 4,000 of the original study volunteers who were at high risk for heart disease but did not yet have it, shows that bempedoic acid can reduce deaths and heart attacks for them. Follow-up over nearly 40 months revealed that 5.3% of those on the drug experienced a heart attack, stroke, coronary revascularization or death from cardiovascular causes. Among those on placebo, that figure was 7.6%, yielding a relative risk reduction of 30%.
The researchers calculate that 43 people need to take the medicine for that period of time for one person to avoid a bad outcome. This is known at the number needed to treat (NNT).
If we just focus on heart attacks (nonfatal or fatal), there were 29 (1.4%) in the group on Nexletol. That was out of 2,100 participants in the bempedoic acid group.
Of the 2,106 people in the placebo group, there were 47 (2.2%) nonfatal or fatal heart attacks. That is an absolute difference of 0.8%.
What About Nexletol Side Effects in the Subgroup Analysis?
Not surprisingly, Nexletol side effects were quite similar in this report to those in the earlier publication. However, elevated uric acid levels were a bit more common in this analysis (12.1% in those on Nexletol vs 6.3% in those on placebo).
We were fascinated to discover that muscle pain (“myalgias”) was more common in the placebo group than in the group getting Nexletol. How that happened is a bit mysterious. Does bempedoic acid have some analgesic activity? We don’t know.
Other Nexletol Side Effects:
If you go to the official prescribing information you discover some odd discrepancies. The FDA-mandated warning about high uric acid levels notes that people who had normal uric acid levels at baseline experienced substantially higher uric acid levels after participating in the clinical trials. 26% of the patients on Nexletol had high uric acid levels. Those on placebo also developed “hyperuricemia” but at a lower level (9.5%). This puzzles us.
We’d like to know:
- Why did people on placebo experience elevated uric acid levels and
- Why did those in Dr. Nissen’s trial develop this problem at a rate so much lower than those in the clinical trials for FDA approval?
Another Nexletol Side Effect–Tendon Rupture:
In Dr. Nissen’s clinical trial muscle pain was less common in those on Nexletol than in those on placebo.
But in the clinical trials the drug company sponsored to get FDA approval:
“…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.”
Additional Nexletol Side Effect Information:
The FDA requires this information about “clinical trial experience”:
“Adverse reactions led to discontinuation of treatment in 11% of NEXLETOL-treated patients and 8% of placebo-treated patients. The most common reasons for NEXLETOL treatment discontinuation were muscle spasms (0.5% versus 0.3% placebo), diarrhea (0.4% versus 0.1% placebo), and pain in extremity (0.3% versus 0.0% placebo).”
In two studies, muscle spasms occurred in 3.6% of those on Nexletol and 2.3% of the people taking placebo. Pain in an extremity (leg or arm) occurred in 3.0% of those taking Nexletol and 1.7% of those receiving placebo.
Some Other Odd Nexletol Side Effects:
The FDA required this in the official prescribing information:
“NEXLETOL was associated with an increased risk of benign prostatic hyperplasia (BPH) or prostatomegaly in men with no reported history of BPH, occurring in 1.3% of NEXLETOL-treated patients versus 0.1% of placebo-treated patients. The clinical significance is unknown.”
In other words, bempedoic acid was linked to an enlarged prostate gland in men. No explanation was given.
“Postmarketing Experience:”
This is a wastebasket category in drug prescribing information. These adverse reactions often go to the FDA’s MedWatch data collection system. We have spoken to FDA executives who dismiss these reports as meaningless. We disagree, but it is hard to determine how common such side effects are, since they were not caught in the clinical trials.
At the time of this writing, the FDA lists “HYPERSENSITIVIY: angioedema, wheezing, rash, and urticaria” (itching) in the postmarketing experience category. Such allergic reactions can be serious. We suspect that other Nexletol side effects will be added over time.
Final Words About Nexletol Side Effects Vs. Statin Side Effects:
How does Nexletol compare to statins when it comes to side effects? If I were to put words into Dr. Nissen’s mouth (though I shouldn’t), I would say that Nexletol reduced the risk of heart attacks, cardiovascular deaths, and “all-cause” mortality. The NNT was 43. In other words, 43 people would need to take Nexletol for several years for one person to avoid a cardiovascular event.
That’s actually better than statins, according to Dr. John Abramson in his book, Sickening.
In it he offers these stats on statins for primary prevention:
- “no significant reduction in mortality (the overall risk of death)
- “small (though statistically significant) reduction in the risk of nonfatal heart attack and stroke — 140 people with low risk (less than 20 percent for five-year risk) must take a statin for five years to prevent one nonfatal event (NNT = 140)”
Statin Side Effects?
What about statin side effects? Although many organizations, such as the United States Preventive Services Task Force and the Cholesterol Treatment Trialists’ Collaboration, maintain that most statin side effects are imaginary, visitors to this website beg to disagree. They have reported a lot more than muscle pain and weakness. In addition to “myalgia,” we have described myopathy and myositis at this link. For a substantial number of people these muscle diseases are incapacitating!
Other statin side effects can be found at this link. They include cataracts, diabetes, pancreatitis, joint pain, nausea, indigestion, muscle spasms, cognitive impairment, respiratory tract infections, headache and insomnia. A rare, but potentially life-threatening, condition called rhabdomyolysis can damage muscle tissue and lead to kidney disease.
For “statin intolerant patients” with a risk for heart disease, Nexletol may indeed represent a reasonable alternative.
