This review examines emerging therapies that go beyond traditional statin treatment to address residual cardiovascular risk. While statins effectively lower LDL cholesterol, many patients still face elevated risk from two other factors: lipoprotein(a) (Lp(a)) and triglycerides. The article covers new experimental drugs—including antisense oligonucleotides and monoclonal antibodies—that target Lp(a), apolipoprotein C-III, and angiopoietin-like protein 3, as well as the latest evidence on omega-3 fatty acids. Clinical outcome trials will ultimately determine whether these promising new approaches actually reduce cardiovascular events in patients.
Heart disease remains the leading cause of death worldwide, despite major progress in prevention and treatment over recent decades. The main treatable culprit is dyslipidemia—an unhealthy balance of fats in the blood—and the standard approach has been to lower "bad" LDL cholesterol using drugs called statins. This strategy works: for every 38.7 mg/dL reduction in LDL cholesterol, major vascular events drop by 23%. Yet there's a serious problem: many patients still remain at high risk even when taking these medications.
A recent European survey found that only one-third of patients taking lipid-lowering drugs actually reach the recommended LDL cholesterol target of under 70 mg/dL. Part of the issue is that patients don't always take their medications as prescribed. But even among those who do, significant risk remains. A newer class of drugs called PCSK9 inhibitors (given as injections) can reduce LDL cholesterol by 51% on top of statins and lower additional cardiovascular risk by 15%—but these drugs are expensive, which limits their widespread use.
Because of these gaps, researchers are now focusing on two other risk factors that statins barely touch: lipoprotein(a), known as Lp(a), and triglycerides (TG), a type of fat in the blood. Using a research technique called Mendelian randomization—which uses genetic information to determine cause-and-effect relationships—scientists have established that elevated levels of both are independent, causal risk factors for cardiovascular disease. Importantly, these risks persist even when LDL cholesterol is well controlled with statin therapy.
Lipoprotein(a), or Lp(a), is a unique particle that looks like an LDL cholesterol particle but has an extra protein attached to it called apolipoprotein(a). This protein is produced by the LPA gene in the liver and comes in many different sizes, ranging from 200 to 800 kDa. People with smaller versions of this protein tend to have higher Lp(a) levels in their blood.
Your Lp(a) level is largely determined by your genetics. In fact, genetic variation in the LPA gene explains about 91% of the variation in Lp(a) levels between people. Diet and lifestyle choices have very little influence on it. Lp(a) is also a major carrier of oxidized phospholipids (OxPL)—molecules that stimulate inflammation and contribute to the buildup of plaque in arteries.
Despite decades of research, scientists still don't fully understand exactly how Lp(a) is assembled, how it causes disease, or how it is cleared from the body. But the evidence linking it to heart disease is strong.
Multiple lines of evidence have identified Lp(a) as a risk factor for both atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis (narrowing of the heart's main valve). A recent meta-analysis found a statistically independent, almost linear relationship between Lp(a) levels and cardiovascular risk in patients already taking statins—meaning higher Lp(a) means higher risk, even when LDL is controlled.
Remarkably, Lp(a) has a stronger association with death from any cause than LDL cholesterol does, for a similar increase in cholesterol content. This suggests that Lp(a)'s harmful effects go beyond just its cholesterol content. Researchers calculated that reducing Lp(a) by 65.7 mg/dL would have the same effect on reducing coronary heart disease as lowering LDL cholesterol by 38.7 mg/dL—though these estimates are based on genetic epidemiological studies, so caution is warranted.
Guidelines from the European Atherosclerosis Society recommend keeping Lp(a) levels below 50 mg/dL, which is below the 80th percentile of the Danish Caucasian population. The threshold for increased risk may be lower depending on the test used and the population being studied.
Specific populations have notably higher Lp(a) levels:
One concerning finding: statins can actually increase Lp(a) levels by 9–20%, likely because they increase LPA gene expression and apo(a) production. Meanwhile, drugs targeting PCSK9 (like Evolocumab) or apoB (Mipomersen) have been shown to reduce Lp(a) levels. However, a 14% Lp(a) reduction with Evolocumab did not affect arterial wall inflammation, suggesting that greater reductions may be needed for clinical benefit.
Experimental therapies are being developed that block the liver from producing apo(a) in the first place. These drugs, called antisense oligonucleotides (ASOs), are given as subcutaneous injections (under the skin). They work by binding to the messenger RNA (mRNA) that carries the genetic instructions for making apo(a), causing that message to be destroyed before any protein can be made.
A newer version of this technology, called a ligand-conjugated ASO, is chemically modified to be taken up more efficiently by liver cells. This version—IONIS-APO(a)-LRX—is roughly 30 times more potent than the original formulation.
Clinical trial results have been impressive:
A Phase III cardiovascular outcome study is now planned. However, no evidence yet proves that lowering Lp(a) actually reduces heart attacks and strokes—that remains the critical next step to validate Lp(a) as a causal risk factor worth treating.
Apolipoprotein C-III (apoC-III) is a protein produced mainly in the liver and, to a lesser extent, in the intestine. Once in the bloodstream, it attaches to HDL cholesterol (the "good" cholesterol) and to triglyceride-rich lipoproteins (TRLs), which include chylomicrons, VLDL, and IDL—particles that carry fat through the blood.
Animal studies show that apoC-III raises triglyceride levels through several mechanisms: it inhibits lipoprotein lipase (LPL) and hepatic lipase (HL)—enzymes that normally break down triglycerides—and it increases the liver's production of VLDL. It also interferes with the removal of triglyceride-rich particles from the blood by blocking their binding to LDL receptors. Beyond fat metabolism, laboratory studies suggest apoC-III may directly activate endothelial cells (the lining of blood vessels) and promote monocyte adherence—both early steps in atherosclerosis—and it also appears to play a role in insulin resistance and pancreatic beta-cell function.
The genetic evidence for apoC-III's importance is compelling. People with gain-of-function (GOF) mutations in the APOC3 gene—meaning their bodies make too much apoC-III—have plasma triglycerides that are 32% higher than their relatives without the mutation. Conversely, people with loss-of-function (LOF) mutations, who produce less apoC-III, enjoy two benefits: 39% lower triglycerides and a 40% lower risk of heart disease.
Even more striking: a decrease of just 1 mg/dL of apoC-III in the blood is associated with a 4% reduction in cardiovascular risk, after adjusting for age and sex. Researchers studying people with near-absent apoC-III levels found they had slightly further reduced triglycerides, markedly increased HDL cholesterol, and similar LDL cholesterol compared to those with partial deficiency.
The main strategy to block apoC-III production uses antisense oligonucleotides (ASOs), similar to the approach used for Lp(a). The leading drug, Volanesorsen (also known as ISIS 304801), was initially developed for rare genetic disorders: familial chylomicronemia syndrome (FCS) and familial partial lipodystrophy (FPL), both characterized by dangerously high triglyceride levels.
In Phase II trials with weekly injections of 300 mg, Volanesorsen produced dramatic changes:
That last finding is surprising and concerning. Phase III studies (APPROACH and COMPASS) in patients with FCS or severe hypertriglyceridemia (TG > 500 mg/dL) showed an 84% reduction in apoC-III and greater than 70% reduction in triglycerides with weekly 300 mg doses. In FCS patients (who start with very low LDL at baseline of 28.2 mg/dL), LDL cholesterol increased by 139%, though non-HDL cholesterol decreased overall.
Volanesorsen also showed promise for improving insulin sensitivity, suggesting potential use in type 2 diabetes. However, the drug was found to increase the risk of thrombocytopenia (dangerously low blood platelet counts) in FCS patients, so FDA approval currently depends on the outcomes of ongoing clinical trials. Two studies are tracking long-term safety: the BROADEN study follows 60 FPL patients for 1–3 years with results expected in 2019, and the APPROACH Open Label Study follows FCS patients for 65 weeks, with completion estimated in 2020.
A next-generation ligand-based ASO (ISIS 678354) shows similar benefits without the problematic LDL increase. In Phase I/II trials with 30 mg weekly, patients experienced:
Both multiple-dose groups—whether weekly or monthly—showed reduced LDL cholesterol. A Phase II trial in patients with hypertriglyceridemia and established cardiovascular disease is expected to be completed this year.
Angiopoietin-like protein 3 (ANGPTL3) is a protein produced almost exclusively in the liver. Its job is to regulate how triglycerides are distributed between muscle tissue (where they're burned for energy) and fat tissue (where they're stored). It does this by inhibiting lipoprotein lipase (LPL) and endothelial lipase (EL), two enzymes that break down fats in the blood.
Interestingly, studies in mice suggest that inactivating ANGPTL3 changes the way apoB-containing lipoproteins (the harmful fat-carrying particles) are cleared from the circulation—without directly involving the usual LDL receptor pathway. That's important because most cholesterol-lowering drugs work through LDL receptors, so ANGPTL3 provides an alternative approach for patients who don't respond adequately to those drugs.
Complete ANGPTL3 deficiency in humans is rare but very revealing. It causes a condition called familial combined hypolipidemia, characterized by dramatically reduced levels of all three major lipids:
People with two copies of loss-of-function mutations also have higher LPL activity, lower free fatty acids, and increased insulin sensitivity compared to non-carriers. A study by Dewey and colleagues found that 246 heterozygous carriers (one copy of the mutation) had 27% lower triglycerides, 9% lower LDL cholesterol, unchanged HDL cholesterol, and a 41% reduced risk of coronary artery disease compared to 58,089 non-carriers. A meta-analysis of 19 studies covering 21 different loss-of-function variants found a 34% lower risk of coronary artery disease.
Two types of drugs targeting ANGPTL3 are in early development: monoclonal antibodies (which block the protein in the bloodstream) and antisense oligonucleotides (which block the liver from producing it in the first place). These approaches could produce different results, since antibodies only neutralize protein circulating in the blood while ASOs also block any potential functions of the protein inside cells.
Evinacumab (monoclonal antibody): In healthy adults with moderate hypertriglyceridemia or elevated LDL cholesterol (above 100 mg/dL), a single intravenous dose of 20 mg/kg reduced:
In an open-label study, 9 patients with homozygous familial hypercholesterolemia (a severe genetic condition causing extremely high LDL from birth) received Evinacumab and achieved a mean reduction of 47% in triglycerides, 49% in LDL cholesterol, and 36% in HDL cholesterol. This proves the drug works even in patients without functional LDL receptors. Phase II trials are now recruiting patients with heterozygous FH who still have high cholesterol despite maximal statin therapy, and those at risk for acute pancreatitis.
IONIS-ANGPTL3-LRX (antisense oligonucleotide): Phase I trials in healthy volunteers with hypertriglyceridemia, using 60 mg weekly, resulted in reductions of:
A Phase II trial in patients with type 2 diabetes was completed in April 2019, with results awaited. Altogether, both approaches are remarkably effective—at the highest doses, they essentially recreate the lipid profile of people born with ANGPTL3 deficiency.
Three omega-3 fatty acid (OM3FA) supplements are currently approved by the FDA for treating severe hypertriglyceridemia (triglycerides above 500 mg/dL). Despite decades of largely inconclusive studies on their cardiovascular benefits, omega-3s are still thought to protect the heart. Current research focuses on finding the most effective dose, combinations of fatty acids, and chemical formulations for optimal absorption.
The main omega-3 fatty acids in oily fish are:
Three FDA-approved prescription omega-3 drugs exist for severe hypertriglyceridemia:
For years, the evidence on omega-3s and cardiovascular outcomes was disappointing. A large meta-analysis of 77,917 participants, the ASCEND study (over 15,000 patients with diabetes), and the VITAL study (a primary prevention trial with more than 25,000 participants) all failed to show major cardiovascular benefits from omega-3 supplementation.
Then came the surprising REDUCE-IT trial. This study showed a 25% reduction in cardiovascular mortality among patients taking 4 grams of Vascepa (icosapent ethyl) daily on top of statin therapy. After one year, the drug lowered plasma triglycerides by 18%, with only a slight 3% increase in LDL cholesterol.
Based on these findings, the American Diabetes Association updated its "Standards of Medical Care in Diabetes" and now recommends Vascepa for diabetic patients with ASCVD, or for patients on statins with elevated triglycerides, to reduce cardiovascular risk. Importantly, the molecular reasons for this success are still unclear and likely go beyond merely lowering triglycerides.
The short-term EVAPORATE study is evaluating Vascepa in 80 statin-treated patients with elevated triglycerides (200–499 mg/dL), tracking the progression of low-attenuation plaque volume (a measure of dangerous arterial plaque) over 9–18 months. Several long-term studies using different omega-3 formulations and dosages (1.8–4 g daily) are also underway:
The first long-term study is expected to be completed in 2020. Additionally, MAT9001 (containing EPA and DPA) is in Phase II trials for severe hypertriglyceridemia, with data comparing it to Vascepa expected by the end of 2020.
For a significant proportion of patients, LDL cholesterol reduction with statins—and possibly ezetimibe and bile-acid sequestrants—is not enough to eliminate cardiovascular risk. Further LDL reduction is possible with PCSK9 inhibition, but the high cost of currently approved monoclonal antibodies limits widespread use. Several alternatives may provide relief in the future, including siRNA-based drugs (like LIB003) or ASOs against PCSK9 (like SPC5001). Another experimental drug, Bempedoic acid (currently awaiting FDA approval), can lower LDL cholesterol by up to 21% and may offer a more affordable option on top of statins.
The failure of therapies that target HDL cholesterol has shifted focus toward treating elevated Lp(a) and triglyceride-rich lipoproteins. Recent genetic evidence supporting Lp(a) and triglycerides as causal risk factors, combined with advances in monoclonal antibody and antisense technology, has driven major progress in developing new treatments for residual cardiovascular risk.
Key challenges remain. The initial concern that ASOs against apoC-III increase LDL cholesterol appears solved with the new generation formulation, but the risk of low platelet counts (thrombocytopenia) still needs to be resolved. Notably, this side effect appears related to apoC-III itself, not the ASO technology. The observed reduction in HDL cholesterol following ANGPTL3 targeting was expected based on human genetics—and importantly, genetic data also show a reduced risk of heart disease despite this HDL reduction.
ASOs and monoclonal antibodies do require subcutaneous injections or intravenous administration, which some patients find inconvenient. However, these injected therapies offer certain advantages over daily oral medications, particularly for patients who struggle with adherence to daily pill regimens.
This review article summarizes early-stage research, and several important caveats apply. First, most of the drugs discussed are still in Phase I, II, or early Phase III trials—meaning we don't yet know if lowering Lp(a), apoC-III, or ANGPTL3 actually translates into fewer heart attacks and strokes. The correlation between genetic variants that lower these targets and reduced risk is encouraging, but biology doesn't always match genetic predictions exactly.
Second, the estimates comparing Lp(a) reduction to LDL reduction are based on genetic epidemiological studies, not direct clinical trials, and the actual cholesterol content of Lp(a) is estimated, not measured. Third, several drugs cause significant side effects—including the LDL-raising effect of Volanesorsen and the thrombocytopenia risk—which may limit their clinical utility. Finally, the ongoing trials discussed (BROADEN, APPROACH Open Label, REDUCE-IT, EVAPORATE, STRENGTH, RESPECT-EPA, OMEMI) have completion dates ranging from 2019 to 2020 and beyond; their results could change the conclusions summarized here.
If you have cardiovascular disease, high cholesterol, or a family history of early heart attacks, here are key takeaways from this research:
Lipoprotein(a), or Lp(a), is a particle similar to LDL cholesterol but with an extra protein attached. Your Lp(a) level is mostly genetic and barely affected by diet. Higher Lp(a) is linked to increased cardiovascular risk, even when LDL is controlled. A level above 50 mg/dL is considered elevated.
Yes. Statins lower LDL cholesterol effectively, but many patients still have elevated triglycerides, which are an independent causal risk factor for heart disease. Managing triglycerides through diet, exercise, and possibly prescription omega-3s may further reduce risk, but always discuss this with your doctor.
Experimental drugs called antisense oligonucleotides block the liver from making the apo(a) protein. In clinical trials, one such drug reduced Lp(a) by up to 92% in a phase I study, and most patients reached target levels in phase II trials. However, these drugs are not yet FDA-approved, and long-term outcome studies are still needed.
ApoC-III is a protein that raises triglyceride levels by inhibiting enzymes that break down fats and by increasing the liver's production of fat particles. People with genetic mutations that reduce apoC-III have lower triglycerides and a lower risk of heart disease. Experimental drugs targeting apoC-III have shown dramatic triglyceride reductions, but safety concerns remain.
Prescription omega-3s are FDA-approved for very high triglycerides. Most large trials did not show cardiovascular benefits, but the REDUCE-IT trial found a 25% reduction in cardiovascular mortality with icosapent ethyl at 4 grams daily in high-risk patients. Over-the-counter fish oil is not a proven substitute, as studies used prescription-strength products.
Ask whether your Lp(a) level has been checked, especially if you have unexplained heart disease or a family history. Ask if non-statin medications like PCSK9 inhibitors are appropriate if your LDL remains high. Ask about triglyceride management if levels are above 500 mg/dL. Keep taking your statins, as newer treatments are add-ons, not replacements.
Original article title: The Future of Lipid-Lowering Therapy
Journal: Journal of Clinical Medicine, 2019, Volume 8, Article 1085; published 23 July 2019
DOI: 10.3390/jcm8071085
This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and does not constitute medical advice. Always consult your healthcare provider about your specific medical condition and treatment options.
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