Beyond Good and Bad: Shifting the Perspective on Cholesterol

Since 1950, heart disease has been the leading cause of death in the United States. And after decades of research, billions of dollars spent on studies related to prevention and treatment, and a clear understanding of risk factors, one person still dies every 33 seconds from cardiovascular disease. We know cardiovascular disease is multifactorial, impacted by a complex interplay of environmental, behavioral and genetic influences—yet cholesterol-lowering efforts remain the primary focus of most physicians.

But the limitations of the so-called lipid theory have been recognized for years, with dozens of studies questioning the validity of the cholesterol hypothesis. Total cholesterol is a poor predictor of heart disease, and research on the association between LDL levels and all-cause mortality yields conflicting results. Meanwhile, new studies cast further doubts on the protective effect of HDL and question whether “good cholesterol” is as good as we once thought. ^1,2,3

In other words, there’s a lot we don’t know. Even so, doctors continue to prescribe cholesterol-lowering drugs as the first line of defense—despite well-recognized adverse effects and increasing evidence that the benefits of statins have been greatly exaggerated. Research shows a weak and inconsistent relationship between statin use and the degree of LDL reduction, and a recent meta-analysis of 21 randomized clinical trials examining the efficacy of statins in decreasing total mortality and cardiovascular outcomes found the absolute benefits are modest. ^4,5,6

“To be sure, cholesterol plays a role in cardiovascular disease,” says Trish Griffin, RDN, LD, director of brand marketing for iwi life. “But to focus only on lowering cholesterol through statin therapy is short-sighted. Statins aren’t appropriate for everyone, and  cardiometabolic health isn’t a one-size-fits-all approach. This is where integrative and functional medicine practitioners have an advantage, and an opportunity to create a tailored strategy that includes nutrition, lifestyle factors and nutraceuticals to support healthy lipid profiles and compliment conventional interventions. A personalized protocol that encourages  patients to be involved in their care is more appropriate and effective for long-term change.”

Beyond good and bad: shifting the way we think about cholesterol.

This is not to say practitioners should ignore cholesterol, but that lipids should be considered from a broader perspective. Standard lipid panels offer a limited view of a complex and highly nuanced condition, and the current emphasis on lowering LDL while increasing HDL is a short-sighted and simplistic. Cholesterol doesn’t come in two varieties: there’s no such thing as “good” and “bad” cholesterol, and emerging research suggests remnant cholesterol—all cholesterol not found in HDL and LDL lipoproteins—may be an important and more accurate predictor of heart disease.

In newer studies, remnant cholesterol, not LDL, is positively associated with cardiovascular disease incidence, ^7,8,9 and increasing research points to remnant cholesterol as a stand-alone measure of heart attack and stroke risk, independent of LDL. ^10,11 It’s also a powerful predictor of metabolic syndrome, a prominent player in cardiovascular health: a recent study demonstrated the first evidence of a link between remnant cholesterol levels and metabolic syndrome, and the relationship was especially strong in women. ¹²

And while we know elevated triglycerides are strongly implicated in arteriosclerosis, metabolic syndrome and an increase in all-cause mortality, the ratio of triglycerides to HDL (TG/HDL-C) is not a common measurement—even though TG/HDL-C is considered a risk marker for metabolic syndrome and cardiovascular disease. Advanced lipid tests that measure lipoprotein particle composition such as LDL and HDL particle number and size, apolipoprotein A-I (apoA-I), apolipoprotein B (apoB) and lipoprotein(a) (Lp[a])— widely accepted risk factors for atherosclerosis, coronary artery disease and stroke—allow a more detailed assessment of cardiovascular health. ^13,14,15

Other simple, inexpensive tests can also give practitioners a fuller picture of individual risk. Elevated blood glucose contributes to endothelial dysfunction, atherosclerosis and impaired platelet function, triggers chronic low-grade inflammation, and plays a significant role in cardiovascular conditions. The link between inflammation and heart disease is well-established, and C-reactive protein (CRP) levels may indicate a patient’s likelihood of developing cardiovascular problems. Elevated homocysteine has long been considered an independent predictor of cardiovascular disease, and fibrinogen concentration is associated with increased risk. ^16,17,18

In addition to comprehensive testing, diet and lifestyle approaches form the foundation of a personalized cardiovascular protocol, along with emotional, psychological and other considerations. “From a functional medicine standpoint, it’s essential to view heart disease as more than just a physical ailment,” says Leah Linder, ND, licensed naturopathic doctor. “It encompasses emotional, psychological and spiritual dimensions as well. Patients with heart disease often experience a range of emotions, from fear and uncertainty to grief and anger. By providing compassionate, patient-centered care that acknowledges and validates these emotional experiences, we can support patients in their healing journey and empower them to actively participate in their treatment and recovery.”

And evidence-based nutraceuticals shown to promote healthy lipid profiles should play a key role in a targeted prevention plan, complimentary to and supportive of pharmaceutical interventions.

Omega-3s: diving deeper into fish oils.

Of all heart-health supplements, omega-3s are perhaps the most widely accepted and universally recommended. The cardioprotective benefits of fish oil are well known, and multiple studies link higher consumption of omega-3 fatty acids from marine sources with decreased vascular atherogenic inflammation, improved endothelial function, reduced blood pressure, less risk of metabolic syndrome and lower rates of heart disease, heart failure and sudden death. ^19,20,21 Omega-3 fatty acids are also associated with significant decrease in triglyceride levels, and some research found that fish oil supplements lowered triglycerides by as much as 25 to 34 percent. ^22,23

Although studies report slight improvements in HDL, fish oil supplements that contain EPA and DHA tend to raise LDL. In a meta-analysis of 21 studies, fish oil supplementation was linked with higher LDL levels. DHA-containing supplements, compared to EPA-containing supplements, led to more substantial LDL increases, and significant increases were seen in 71 percent of DHA-alone groups, but not in any EPA-alone studies. ^{24,25,26,27,28}

“These effects were seen in fish oil supplements, which contain both EPA and DHA,” says Griffin. “EPA-rich omega-3s sourced from sustainable algae sidestep the issues associated with fish oil, while capitalizing on the benefits.”

Most plant sources of omega-3s, like flax, walnuts and chia seeds, contain ALA, the precursor to EPA and DHA. But ALA bioconversion to EPA and DHA is inefficient, with typical conversion rates ranging from 5 percent to less than 0.5 percent. Certain species of algae, however, are naturally rich in EPA and/or DHA, and studies show the bioavailability, efficacy and cardioprotective actions of algae oil are comparable to fish oil. ^29,30,31

iwi life Heart with AlmegaPL^® algae-derived omega-s has been shown to support healthy lipid profiles, reduce triglycerides and lower remnant cholesterol—such as VLDL and IDL—without increasing LDL in the generally healthy, normolipidemic population. Derived from Nannochloropsis algae, in a unique form conjugated to polar lipids (glycolipids and phospholipids), it’s the only clinically validated, photosynthetic source of EPA on the market and has been clinically shown to maintain healthy cholesterol and triglyceride levels already within their normal range.*

In a double-blind, parallel design, randomized clinical trial, AlmegaPL supplementation lowered VLDL by 25 percent, resulting in a significant reduction in total cholesterol compared to placebo. ³² Typically, when using DHA-containing supplements like fish oils, a decrease in VLDL is accompanied by an increase in LDL. In this study, participants who took EPA-only AlmegaPL maintained constant LDL levels throughout the supplementation period.

A new clinical trial, published in February, confirmed these results and also found that AlmegaPL reduced triglycerides by 14 percent—four times the response expected from other omega-3 sources, like fish oil. ³³  In discussing the outcomes, the study’s author suggested the triglyceride-lowering response could not be attributed to the omega-3 content alone, and that the supplement’s novel molecular form appeared to offer additional benefits.

“The AlmegaPL polar lipids are engineered for improved absorption and bioavailability,” says Griffin. “This unique composition of naturally occurring polar lipids bound to fatty acids creates the formation of micelles in the stomach, facilitating easier digestion and the delivery of omega-3 fatty acids to the body.” Supported by research, polar lipid-rich oil from algae was shown to be more bioavailable thus resulting in higher blood concentrations of EPA and DHA compared to krill oil.³⁴

Besides the EPA component, algae-derived omega-3s have further advantages. Unlike fish oils, they’re appropriate for vegans and vegetarians, and they’re an excellent alternative for people who can’t eat seafood or don’t tolerate fish oils. They’re easier to digest and are associated with fewer gastrointestinal complaints like nausea or “fish burps.” And they’re an environmentally sustainable alternative to fish oil. Omega-3s from marine animal sources, including krill, damage complex marine ecosystems and impact water and limited agricultural resources. AlmegaPL is sourced from sustainable algae grown in ponds on a Texas farm, using nonarable desert land and non-potable brackish (salty) water, with sunlight as the main energy input.

Along with omega-3s, other nutraceuticals have been shown to promote healthy cholesterol levels. What to include in a cardioprotective protocol:

• Coenzyme Q10 (CoQ10). Increasing evidence points to the vital role of CoQ10 in preventing and treating cardiometabolic disorders. Studies suggest CoQ10 lowers blood pressure and improves endothelial function and may help treat heart failure. In one meta-analysis, patients with heart failure who took  CoQ10 supplements had greater exercise capacity and a decreased risk of dying compared to those who took a placebo. It’s especially important for patients taking statins, to replenish depleted CoQ10 levels and avoid the adverse effects associated with conventional cholesterol-lowering drug treatments. ^35,36,37
• Red yeast rice. Produced by fermentation of Monascus purpureus yeast, red yeast rice supplements contain compounds called monacolins. Monacolin K, thought to be the most efficacious of the monacolins, is chemically identical to the cholesterol-lowering drug lovastatin. Studies suggest red yeast rice supplements that contain monacolin K decrease total cholesterol, LDL and triglyceride levels, and these effect were also linked with significant improvements in pulse wave velocity and endothelial function. ^38,39,40
• Phytosterols. Plant sterols and stanols compete with cholesterol for absorption and have been shown to reduce total and LDL cholesterol, minus the adverse effects commonly experienced during statin use. In one systematic review and meta-analysis, phytosterol supplementation was associated with clinically significant decreases in LDL, and some research lists plant sterols among the most effective natural treatments for managing cholesterol levels. A combination of phytosterols and red yeast rice appears to have additive cholesterol-reducing benefits.^41,42,43
• Bergamot. Neohesperidin and other compounds in bergamot fruit extract have been shown to influence enzymes involved in cholesterol metabolism and absorption, and research highlights its lipid-lowering actions. In one review, bergamot supplementation reduced total cholesterol and triglycerides, with decreases in LDL levels ranging from 7 percent to over 40 percent. A recent meta-analysis found that bergamot supplementation significantly decreased total cholesterol, LDL and triglycerides, while also increasing HDL, and a 2022 meta-analysis concluded that bergamot and red yeast rice were the most effective nutraceuticals for reducing total and LDL cholesterol levels.^44,45,46,47
• Citrus flavonoids. A number of studies validate the lipid-lowering actions of specific citrus-derived flavonoids. In one trial, daily supplementation with a combination of citrus flavonoids and tocotrienols led to significant reductions in total cholesterol, LDL, triglycerides and apoB, and additional research shows citrus flavonoids may increase HDL. Tangeretin and nobiletin have an optimal molecular structure and are the most potent for reducing cholesterol, while other citrus flavonoids, such as hesperidin and naringin, have weaker effects.^48,49,50,51

*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.

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