Exploring Recent Guideline Updates on the Management of Hyperlipidemia | Written Recap

Viet Le, D.M.Sc., M.P.A.S., is a preventive cardiology physician assistant and an associate professor of research at the Intermountain Healthcare Heart Institute in Salt Lake City, Utah. In this Managed Healthcare Executive K-Cast video series, Le discussed primary and secondary prevention of atherosclerotic cardiovascular disease, statin intolerance and resistance, nonstatin therapy and recent hyperlipidemia guidelines and clinical trials.

Primary and secondary prevention

Primary prevention applies to individuals who have not experienced a heart attack or stroke but who have risk factors for developing atherosclerotic cardiovascular disease (ASCVD), such as diabetes, hypertension or high low-density lipoprotein cholesterol (LDL-C), Le explained. Secondary prevention concerns people who have had a heart attack or stroke or have peripheral artery disease. “You really need to get on top of the risk because they’re at high risk for a second event,” he said, and the goals in secondary prevention are “much more intensive.” Statins are a foundational therapy for lowering LDL-C, but Le said that effect is actually secondary to their effect on the arterial plaques that are characteristic of ASCVD. Statins, he said, “stabilize that plaque. They reduce inflammation around this cholesterol pimple, if you will, that’s sitting in the coronary artery.”

Statin intolerance and resistance

Le said it was important to distinguish between statin intolerance and resistance. People with statin intolerance experience harm from the drugs, such as rhabdomyolysis or fulminant liver failure, or notable symptoms, such as muscle aches. Although some patients cannot take statins because of complete intolerance, Le said there is a continuum to partial intolerance. Some patients can take a statin less frequently and still benefit from its plaque-stabilization effects, he noted. In the social media era, statins have “[received] a bad name” for causing aches and pains, he said, and clinical trial results have shown a nocebo effect.

Patients with statin resistance do not experience symptoms, Le noted. Instead, the problem is that statins do not lower LDL-C levels as much as they typically do. Instead of a 50% reduction, people with statin resistance may experience only a 25% or 10% reduction.

Nonstatin therapies

Le said several nonstatin treatments are available for patients who cannot be effectively treated with statins because of statin intolerance or resistance. The generic ezetimibe, which is sold under the brand name Zetia, reduces cholesterol absorption in the intestine and increases hepatic uptake of circulating cholesterol. Le likened ezetimibe to “a bouncer at the bar” that blocks cholesterol from being absorbed in the gut and, as a component of bile acids, in the liver. “In essence, you lose about 20% of LDL-C when you use ezetimibe, so it is a very effective medication,” Le said.

Bempedoic acid, sold under the brand name Nexletol, is another nonstatin therapy. Le noted that it is a prodrug that is activated only in the liver, so it does not affect skeletal muscle like statins do. Nexletol reduces cholesterol production by approximately 25%; this effect is reduced by approximately 10 percentage points when the drug is used in combination with a statin, according to Le. Nexletol and Zetia are sold in a combination pill, he noted, under the brand name Nexlizet. He described Nexletol as a “great first choice to start the process of reducing inflammation, stabilizing plaque and reducing inflammation” and also a great choice as monotherapy for people with statin intolerance.”

Even more substantial reductions in LDL-C are achieved with PCSK9 inhibitors, which reduce cholesterol levels by improving the activity of receptors that ferry LDL-C to the liver, where it is broken down, Le explained. The FDA has approved two PCSK9 inhibitors, Praluent (alirocumab) and Repatha (evolocumab), which are monoclonal antibodies delivered by self-administered subcutaneous injection. Leqvio (inclisiran) is small interfering RNA (siRNA) that lowers LDL-C by operating upstream and decreasing the synthesis of PCSK9 in the first place. Leqvio is also a subcutaneous injection, but it is administered by a clinician and less often, once every six months, compared with the twice-monthly schedule of Praluent and Repatha.

Le said that several factors should be considered when deciding which LDL-C-lowering therapy to use, including the diseases the patients have, whether it is for primary or secondary prevention, and the level of inflammation, as evidenced by high-sensitivity C-reactive protein levels. The PSCK9 therapies don’t affect inflammation, but Nexletol and Zetia do, he noted, so prescribing multiple therapies might be warranted. “We have patients on triple therapy or quadruple. … It sounds excessive, but given the risk of having another stroke or heart attack, as we discuss this with patients, I think most prefer not to have another event.”

The uptake of some of the LDL-C-lowering medications has been low, Le acknowledged. He said the complexity of the guidelines is partly to blame: “We’ve done it to ourselves as we developed guidelines.” Le also noted that primary care physicians are dealing with many diseases and, therefore, many sets of guidelines. He also noted that high cost and the barriers related to it, such as payer prior authorization practices, are also a factor. Aside from Zetia and the statins, all the LDL-C-lowering therapies are still protected by patents and are available only as branded products.

Guidelines

Le discussed the LDL-C guidelines for adults that were issued by the National Lipid Association in 2025 and the American Diabetes Association (ADA) guidelines. The lipid association’s guidelines, titled “LDL Cholesterol Management Simplified in Adults – Lower for Longer is Better,” argue for starting treatment early in high-risk patients and set less than 100 milligrams per deciliter (mg/dL) as the LDL-C goal for healthy adults in the general population; less than 70 mg/dL for high-risk individuals, which include those with type 2 diabetes; and less than 55 mg/dL in very high-risk individuals, which include those who have had myocardial infarction or an ischemic stroke. The ADA guidelines set a primary prevention LDL goal of less than 70 mg/dL for people with type 2 diabetes. The secondary prevention goal is 55 mg/dL.

Le discussed familial hypercholesterolemia (FH) as illustrating the advantages of the “lower for longer is better” approach to LDL-C. Individuals with FH have very high LDL-C from birth and often experience cardiovascular disease early in adulthood. Le said that if treatment had begun in infancy, “you could have moved their heart attack from their 20s to their 50s or 60s,” underscoring how lifetime LDL exposure shapes cardiovascular outcomes.

Noting that 1 in 3 patients with type 2 diabetes will have a stroke or heart attack or develop peripheral artery disease, Le said that individuals should be started on a statin when they are diagnosed with type 2 diabetes. Thereafter, their lipid levels should be monitored and therapy started sooner than has been done in the past. “It’s so important to get to less than 70 [mg/dL] in these primary prevention folks,” Le said.

Le also discussed recent European guidelines that identified normal physiologic LDL-C levels as being between 20 mg/dL and 40 mg/dL. “I am always a little jealous of the European cholesterol guideline committees,” he said. “They’re moving much quicker than we are in the U.S.”

Clinical trial results

Le discussed results from two clinical trials that illustrate the benefits of expanding the lowering of LDL-C beyond statins and also starting treatment early. The CLEAR Outcomes trial compared Nexletol with placebo among individuals who were statin intolerant. The results showed that the study participants randomly assigned to Nexletol were 13% less likely to have a major cardiovascular event (defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization) than those in the placebo group. Le noted that Nexletol was more protective for primary prevention than for secondary prevention.

The FOURIER trial compared Repatha with a placebo among individuals with atherosclerotic cardiovascular disease who were taking a statin. The trial had an open-label extension that allowed participants in the placebo group to “cross over” and be treated with the PCSK9 inhibitor. Although the LDL-C levels in the crossover group dropped to the same low level — 30 mg/dL — as those who were started in the Repatha group, they had more cardiovascular events. “They were never able to catch up in terms of protection,” Le said. “There was still a difference five years later between the original arm that received Repatha.” Le, who was an investigator for the FOURIER trial, said the results provide more evidence for the “lower for longer is better” approach that the National Lipid Association guidelines take.