Lipid-lowering therapy: Evidence and future perspective

Low-density lipoprotein cholesterol and secondary prevention

Therapy aimed at lowering low-density lipoprotein cholesterol (LDL-C) reduces the risk of atherosclerotic cardiovascular disease (ASCVD). Absolute risk stratification for the development of coronary artery disease as an outcome of elevated LDL-C has been established, alongside target lipid management levels, emphasizing the importance of strict lipid-lowering therapy. For secondary prevention, particularly in patients with acute coronary syndrome (ACS) or familial hypercholesterolemia, a target LDL-C level of <70 mg/dL is recommended for high-risk patients and <55 mg/dL for very high-risk patients, in addition to the conventional target of <100 mg/dL.

Beyond the degree of LDL-C lowering, the timing of intervention has emerged as a critical determinant of long-term cardiovascular risk. A large pooled analysis published in JAMA Cardiology demonstrated that earlier exposure to lower LDL-C levels is associated with a substantially lower lifetime risk of ASCVD, supporting the concept of “the earlier, the better” in lipid management (JAMA Cardiol 2021;6:276–285). These findings indicate that early initiation and sustained LDL-C lowering confer cumulative vascular benefits and may prevent irreversible atherosclerotic plaque development.

Statins have been the mainstay of LDL-C–lowering therapy for many years, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors became available as a potent new option in 2016. PCSK9 inhibitors include the human monoclonal antibody evolocumab, which selectively inhibits PCSK9 involved in LDL receptor metabolism, and the small interfering RNA inclisiran. In addition to markedly lowering LDL-C levels, evolocumab has been demonstrated to reduce cardiovascular events in large clinical trials. ¹ PCSK9 inhibitors are expected to provide excellent treatment adherence due to the ease of subcutaneous administration, evolocumab is administered every 2 to 4 weeks and inclisiran every 6 months, as well as their low incidence of adverse drug reactions. However, due to their relatively high drug prices, use of PCSK9 inhibitors requires careful consideration of the cost–benefit balance. Furthermore, their efficacy with long-term administration remains to be fully verified. Currently, these agents are indicated only for patients with dyslipidemia or familial hypercholesterolemia who are at high risk of cardiovascular events and whose LDL-C levels have not reached target values despite treatment with statins at the maximum tolerated dose.

The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial ¹ was a randomized, double-blind, placebo-controlled study designed to evaluate the efficacy of the PCSK9 inhibitor evolocumab in patients with cardiovascular disease (CVD). The trial included 27,564 patients with ASCVD and LDL-C levels ≥ 70 mg/dL (1.8 mmol/L) who were receiving statin therapy. The median follow-up duration was 2.2 years. The primary endpoint was a composite of cardiovascular death, myocardial infarction (MI), stroke, unstable angina, or coronary revascularization. The results showed that the risk of cardiovascular events, as defined by the primary endpoint, was significantly reduced in the evolocumab group compared with the placebo group (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.79–0.92; P < 0.001). PCSK9 inhibition with evolocumab in patients receiving statin therapy reduced LDL-C levels to a median of 30 mg/dL (0.78 mmol/L). These findings indicate that patients with ASCVD benefit from lowering LDL-C levels well below conventional targets. However, there is considerable criticism regarding the low cost-effectiveness of PCSK9 inhibitors. A key challenge moving forward will be determining which patient populations derive the greatest benefit from these expensive yet highly effective therapies.

LDL-C–lowering drug therapy in patients with lower extremity arteriosclerosis obliterans

As described earlier, lowering LDL-C levels follows the principle of “the lower, the better” in reducing the risk of cardiovascular events. This raises the question of which patient populations should receive PCSK9 inhibitors. Patients with lower extremity arteriosclerosis obliterans (ASO) represent a key target group. A subanalysis of the FOURIER trial ² reported that one of the strongest factors associated with the efficacy of evolocumab was the presence or absence of a history of peripheral arterial disease (PAD), including lower extremity ASO. The analysis demonstrated that evolocumab reduced mortality, cardiovascular events (e.g. MI), and lower extremity events (e.g. revascularization) in patients with a history of lower extremity ASO. Of the 27,564 patients included in this analysis, 3642 (13.2%) had PAD, including 1505 patients with no prior history of MI or stroke. The baseline LDL-C level was approximately 92 mg/dL, and treatment with evolocumab resulted in an LDL-C reduction of approximately 59%. Evolocumab reduced the primary endpoint consistently and significantly in both patients with PAD (HR, 0.79; 95% CI, 0.66–0.94; P = 0.0098) and those without PAD (HR, 0.86; 95% CI, 0.80–0.93; P = 0.0003). For the key secondary endpoints, the HRs were 0.73 (95% CI, 0.59–0.91; P = 0.0040) in patients with PAD and 0.81 (95% CI, 0.73–0.90; P < 0.0001) in patients without PAD. Patients with PAD were at higher baseline risk and experienced greater absolute risk reductions for both the primary endpoint (3.5% in patients with PAD vs. 1.6% in those without PAD) and the key secondary endpoints (3.5% vs. 1.4%, respectively). Evolocumab also reduced the risk of major adverse limb events in the overall population (HR, 0.58; 95% CI, 0.38–0.88; P = 0.0093). In addition, a consistent association was observed between reductions in LDL-C levels and reductions in the risk of adverse limb events (β-coefficient, P = 0.026), extending to LDL-C levels below 10 mg/dL. Therefore, in patients with PAD who are at particularly high risk of cardiovascular events, PCSK9 inhibition with evolocumab provides substantial absolute risk reduction. Accordingly, PCSK9 inhibitor therapy is especially recommended for high-risk patients, including those with ASO, whose LDL-C levels have not reached management targets with statin therapy alone.

Triglycerides and cardiovascular disease

Lower LDL-C levels are associated with a reduced risk of CVD. A meta-analysis of eight randomized controlled trials evaluating the efficacy of statin therapy demonstrated a direct relationship between achieved LDL-C levels and the risk of major cardiovascular events. ³ However, even with intensive LDL-C–lowering therapy using statins, ezetimibe (alone or in combination), or PCSK9 inhibitors, patients with dyslipidemia continue to experience residual CVD risk. This residual risk has been attributed to low HDL-C and/or elevated triglyceride (TG) levels, as well as to non-lipid factors such as inflammation of atherosclerotic plaques. ⁴

While there is strong evidence supporting the principle that “the lower, the better” applies to LDL-C, corresponding data for TG are less robust. Nevertheless, accumulating evidence suggests an association between elevated TG levels and the incidence of cardiovascular events. In the dal-OUTCOMES trial, 15,817 patients with ACS receiving statin therapy were randomized to receive either the cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib or placebo and were followed for a median of 31 months. Although dalcetrapib conferred no clinical benefit, the risk of long-term CVD increased significantly across quartiles of baseline fasting TG levels (P < 0.001), with a HR of 1.61 between the highest (>175 mg/dL) and lowest (≤80 mg/dL) quartiles. ⁵ Similarly, in the MIRACL trial, 1501 patients with ACS were randomized to receive either atorvastatin (80 mg/day) or placebo and were followed for 16 weeks. Atorvastatin significantly reduced the incidence of the primary endpoint, which included death, nonfatal acute MI, or other cardiovascular events. A subanalysis demonstrated a significant association between elevated fasting TG levels and CVD risk (P = 0.03). ⁵ Importantly, both trials showed that the relationship between TG levels and CVD risk was independent of LDL-C levels, suggesting that elevated LDL-C and TG levels are independently associated with cardiovascular events in patients with ACS.

Therapeutic agents for hypertriglyceridemia include statins, fibrates (peroxisome proliferator–activated receptor α [PPARα] agonists), and omega-3 polyunsaturated fatty acids, such as eicosapentaenoic acid and docosahexaenoic acid. ⁴ Fibrates exhibit potent TG-lowering effects, and patients with elevated serum TG levels are known to be at increased risk of cardiovascular events. However, whether fibrate therapy translates into a reduction in cardiovascular events remains controversial. Several meta-analyses have assessed the impact of fibrates on cardiovascular outcomes, with inconclusive results. Two Cochrane reviews evaluating fibrate therapy reached the following conclusions: (a) fibrates are associated with moderate evidence of reduced cardiovascular and coronary events in primary prevention, although the absolute treatment effect is modest (absolute risk reduction < 1%); and (b) fibrates may be effective for secondary prevention of a composite outcome including nonfatal stroke, nonfatal MI, and vascular death; however, this benefit appears to be dependent on the inclusion of data from clofibrate trials. ⁶

Is TG a target for cardiovascular event treatment?

Pemafibrate, a selective PPARα modulator, exhibits high selectivity for PPARα.^7,8 The phase III PROMINENT trial was conducted to evaluate the efficacy of pemafibrate in preventing the onset and recurrence of ASCVD in patients with type 2 diabetes who had elevated TG levels (200–499 mg/dL) and low HDL-C levels. This long-term, multicenter, randomized, double-blind, placebo-controlled trial was conducted in 24 countries to assess the efficacy of pemafibrate 0.2 mg in combination with statin therapy for the prevention of cardiovascular events. ⁹ The trial enrolled 10,497 participants, with a median follow-up duration of 3.4 years. Compared with placebo, pemafibrate reduced TG levels by 26.2% and increased HDL-C levels by 5.1%, but also increased LDL-C levels by 12.3%. As a result, the pemafibrate and placebo groups were comparable in terms of non–HDL-C levels, a representative marker of overall dyslipidemia-related cardiovascular risk. The two groups were also similar with respect to the incidence of the primary efficacy endpoint (nonfatal MI, ischemic stroke, coronary revascularization, or death from CVD), and no apparent benefit was observed in subgroup analyses. Although the overall incidence of adverse events was similar between the pemafibrate and placebo groups, the pemafibrate group exhibited a higher incidence of renal dysfunction and venous thromboembolism, as well as a lower incidence of nonalcoholic fatty liver disease. A recent publication has described fibrates as another “lost paradise,” alongside nicotinic acid and CETP inhibitors. ¹⁰

The PROMINENT trial demonstrated that pemafibrate treatment increased LDL-C and apolipoprotein B (apoB) levels. This increase in LDL-C may be attributable to enhanced conversion of remnant lipoproteins to LDL mediated by pemafibrate. ¹¹ Consequently, the beneficial effects of fibrates in lowering TG levels and raising HDL-C levels may have been offset by the adverse effect of increased LDL-C, resulting in neutral overall effects on cardiovascular outcomes.

It is also noteworthy that pemafibrate increases LDL-C levels in patients with low baseline LDL-C but decreases LDL-C levels in those with high baseline values. ¹² To prevent CVD, reductions in both LDL-C and TG levels are necessary. Pemafibrate lowers both LDL-C and TG levels in patients with elevated baseline levels of both lipids, such as those who have not yet initiated statin therapy. Therefore, pemafibrate may be useful for the primary prevention of CVD in patients with combined dyslipidemia, characterized by elevated TG and LDL-C levels and commonly observed in obese individuals.

The landmark REDUCE-IT trial provided compelling evidence supporting EPA as an effective therapy for residual cardiovascular risk (N Engl J Med 2019;380:11–22). In this randomized, double-blind, placebo-controlled trial, 8179 statin-treated patients with elevated TG levels (135–499 mg/dL) and either established CVD or diabetes plus additional risk factors were assigned to receive icosapent ethyl (4 g/day) or placebo. Over a median follow-up of 4.9 years, EPA therapy resulted in a 25% relative risk reduction in the primary composite cardiovascular endpoint (HR, 0.75; 95% CI, 0.68–0.83; P < 0.001), including significant reductions in cardiovascular death, MI, stroke, and coronary revascularization.

Importantly, the cardiovascular benefit of EPA observed in REDUCE-IT exceeded that expected from TG reduction alone, suggesting that its pleiotropic effects—such as anti-inflammatory, antioxidative, membrane-stabilizing, and antithrombotic actions—play a major role in cardiovascular protection. In contrast, docosahexaenoic acid (DHA) has not demonstrated comparable cardiovascular benefit and may exert different biological effects.

Based on these findings, EPA represents a key therapeutic option for secondary prevention in statin-treated patients with persistent hypertriglyceridemia and residual cardiovascular risk.

Lipoprotein(a)

Lipoprotein(a) [Lp(a)] has emerged as an important genetically determined risk factor for ASCVD. Elevated Lp(a) levels are associated with increased risks of coronary artery disease, stroke, and calcific aortic valve stenosis independent of LDL-cholesterol levels. Structurally, Lp(a) consists of a low-density lipoprotein particle covalently bound to apolipoprotein(a), a glycoprotein that shares structural homology with plasminogen. Through this structure, Lp(a) promotes both pro-atherogenic and pro-thrombotic processes, including the transport of oxidized phospholipids and interference with fibrinolysis.^13,14 Lp(a) concentrations are largely genetically determined and remain relatively stable throughout life, with substantial inter-individual and ethnic variability. Current international guidelines recommend that Lp(a) be measured at least once in adulthood to identify individuals at elevated cardiovascular risk.

Unlike LDL-C, lifestyle modification has little impact on Lp(a) levels. Conventional lipid-lowering therapies such as statins have minimal or neutral effects on Lp(a), although PCSK9 inhibitors have been shown to reduce Lp(a) concentrations by approximately 20% to 30%, which may contribute in part to their cardiovascular benefits. ¹⁵ More recently, novel RNA-targeted therapies have demonstrated remarkable Lp(a)-lowering effects. Antisense oligonucleotide therapy targeting apolipoprotein(a) synthesis, such as pelacarsen, has shown reductions of up to 80% in circulating Lp(a) levels in phase II studies. ¹⁶ Similarly, small interfering RNA therapies such as olpasiran have demonstrated profound and sustained reductions in Lp(a) concentrations in early-phase clinical trials. ¹⁷ Large outcome trials evaluating whether Lp(a) reduction translates into reduced cardiovascular events are currently underway.

Given the strong genetic determination of Lp(a) and its causal relationship with ASCVD, targeted Lp(a)-lowering therapies may represent an important future strategy for addressing residual cardiovascular risk. Integrating Lp(a) measurement into routine cardiovascular risk assessment may therefore facilitate earlier identification of high-risk individuals and enable more personalized preventive strategies.

Lp(a) has attracted increasing attention as a novel risk factor for ASCVD. Previous epidemiological studies have demonstrated that elevated Lp(a) levels are an independent risk factor for ASCVD. Lp(a) is a lipoprotein particle composed of LDL and a distinct apolipoprotein known as apolipoprotein(a) [apo(a)]. Structurally, apo(a) is covalently bound to apoB within the LDL particle. Apo(a) shares structural homology with plasminogen and is thought to interfere with plasminogen activity, thereby promoting thrombus formation. In addition, Lp(a) is believed to contribute to the initiation and progression of atherosclerosis due to its propensity to carry oxidized phospholipids and to accumulate within the vascular wall. Lp(a) levels are largely genetically determined and are independent of lifestyle factors.^13,14 Elevated Lp(a) levels are more common in individuals of African ancestry and less common in Asian populations. Consequently, it is recommended that Lp(a) be measured at least once in a lifetime. As Lp(a)-lowering therapies are anticipated to become available, their use is expected to represent a new intervention point for residual ASCVD risk. However, it remains unclear whether the principle of “the lower, the better,” which applies to LDL-C, is also applicable to Lp(a) in preventing cardiovascular events. Pelacarsen, an antisense oligonucleotide therapy that inhibits hepatic Lp(a) synthesis, has been shown in phase II studies to reduce Lp(a) levels by approximately 80%. ¹⁵ A phase III clinical trial is currently underway to evaluate the efficacy of pelacarsen in reducing cardiovascular events. This trial is expected to enroll approximately 8300 patients with a history of CVD (e.g. MI or stroke) and Lp(a) levels ≥ 70 mg/dL (150 nmol/L), with results anticipated by the end of 2026. Similarly, small interfering RNA therapies such as olpasiran have demonstrated profound and sustained reductions in Lp(a) concentrations in early-phase clinical trials. ¹⁶ PCSK9 inhibitors are typically administered to patients who have not achieved adequate LDL-C reduction with statin therapy and have also been shown to reduce Lp(a) levels by approximately 20% to 30%. ¹⁷ Therefore, the optimal therapeutic approach for patients with insufficient LDL-C reduction and elevated Lp(a) levels, whether treatment with PCSK9 inhibitors or emerging Lp(a)-lowering agents, will require further clarification following the publication of the results of the ongoing phase III trial.

Summary perspective

Collectively, contemporary evidence underscores that optimal lipid management requires not only intensive LDL-C lowering but also early initiation of therapy and targeted treatment of residual risk factors such as hypertriglyceridemia and elevated Lp(a). The integration of these therapies will represent a new paradigm in comprehensive ASCVD prevention.