Redefining low-density lipoprotein cholesterol targets: How low can we safely go?

Low-density lipoprotein cholesterol (LDL-C) is a pivotal determinant in the pathogenesis of atherosclerosis and the progression of atherosclerotic cardiovascular disease (ASCVD). Extensive empirical evidence derived from statin-based trials, PCSK9 inhibitors, and novel RNA-targeted therapies consistently demonstrates that incremental reductions in LDL-C correlate with proportional decreases in major adverse cardiovascular events (MACEs).[1] With the advent of long-term data, including sustained LDL-C reduction through inclisiran over 6–7 years (with an average reduction of approximately 50%) and a reassuring safety profile, the paradigm of “the lower, the better” is gaining widespread endorsement. This article delves into human physiology, genetic insights, and findings from clinical trials to evaluate the safety of LDL-C reduction, the benefits of achieving very low LDL-C levels, and the long-term risk benefit balance of intensive LDL-C lowering strategies.[2] HUMAN PHYSIOLOGY AND LOW-DENSITY LIPOPROTEIN CHOLESTEROL Cholesterol is indispensable for maintaining cell membrane integrity and functions as a precursor for bile acids, fat-soluble vitamins, and steroid hormones. Plasma cholesterol, either absorbed from the gut or synthesized by the liver, is transported through lipoproteins (chylomicrons, very low-density lipoprotein [VLDL], LDL, and high-density lipoprotein). Since mammalian nucleated cells have the capacity to synthesize cholesterol de novo, the physiological role of LDL particles is primarily to redistribute cholesterol to peripheral tissues, rather than to supply a critical requirement. It is well established that LDL-C levels in newborns are significantly lower than those in older children or adults. In a study of 122 newborns, the mean LDL-C was 23 mg/dL (standard deviation: 10 mg/dL), with approximately one-third having LDL-C at or below 13 mg/dL levels entirely consistent with normal growth and development, and multiple studies have shown that healthy neonates typically have LDL-C levels in the 30–70 mg/dL range, with a subset falling below 30 mg/dL.[3,4] These findings suggest that very low LDL-C levels are physiologically compatible with normal growth and survival. GENETIC CONDITIONS ASSOCIATED WITH VERY LOW LDL CHOLESTEROL Several rare genetic disorders are associated with chronically very low LDL-C levels providing human “experiments of nature” that inform our understanding of long-term tolerance to low LDL-C [Table 1].Table 1: Genetic conditions associated with very low-density lipoprotein cholesterolPCSK9 is expressed in multiple tissues, including the kidney, liver, intestine, and brain. Remarkably, a compound heterozygote harboring loss-of-function PCSK9 mutations exhibited a serum LDL-C of 14 mg/dl yet remained free of cardiovascular disease, retained normal fertility, and demonstrated no neurocognitive impairments. Individuals with PCSK9 loss-of-function mutations display an increased density of LDL receptors on hepatocyte surfaces, facilitating enhanced LDL-C clearance from the circulation and resulting in lifelong reductions in LDL-C. Notably, these individuals remain in good health and experience a significant reduction in cardiovascular events over extended long-term follow-up.[5] Familial combined hypolipidemia (FHBL2), a rare disorder caused by mutations in the ANGPTL3 gene, is characterized by substantial reductions in all apo-B and apoA-1 containing lipoproteins, with some homozygous carriers achieving LDL-C levels as low as 27 mg/dL.[6] These two conditions, PCSK9 loss of function mutations and FHBL2, provide compelling evidence that extremely low LDL C levels can be achieved safely, without significant comorbidities, while conferring robust cardiovascular protection. Collectively, these observations reinforce the concept that LDL C can be pharmacologically or genetically reduced to very low levels, approaching 14 mg/dL in the context of PCSK9 deficiency, resulting in significant cardiovascular risk reduction, without causing serious adverse effects. IMPACT OF ACHIEVING VERY LOW LDL CHOLESTEROL LEVELS ON ATHEROSCLEROTIC CARDIOVASCULAR DISEASE EVENTS Atherosclerosis is a multifactorial disease influenced by a range of risk factors, with LDL-C playing a central pathogenic role. In an atherogenic environment, oxidized LDL infiltrates the arterial intima, initiating inflammatory cascades, promoting endothelial dysfunction, and ultimately driving the formation and progression of atherosclerotic lesions. Observational studies have consistently demonstrated a continuous positive association between LDL-C levels and the risk of ASCVD, extending well below the average LDL-C levels seen in contemporary populations, without a clearly defined lower threshold. The LDL-C level at which cardiovascular event rates are predicted to approach zero is approximately 57 mg/dL for primary prevention and 30 mg/dL for secondary prevention.[7] HMG-CoA reductase inhibitors (statins), NPC1L1 inhibitors (ezetimibe), and PCSK9 inhibitors (evolocumab and alirocumab) are cornerstone pharmacologic therapies that effectively lower LDL-C levels and reduce the incidence of atherosclerotic cardiovascular events.[8] Multiple prospective randomized controlled trials have shown that, in both primary and secondary prevention populations, greater reductions in LDL-C correlate with a greater reduction in MACEs. The Cholesterol Treatment Trialists’ Collaboration, in a meta-analysis of 174,149 participants across 27 statin trials, found that each 1-mmol/L (39 mg/dL) reduction in LDL-C was associated with a 21% reduction in the risk of MACEs. This relationship remained consistent regardless of age, sex, or comorbid conditions such as chronic kidney disease and diabetes, and across the groups with varying baseline LDL-C levels.[1] Notably, this continuous reduction in cardiovascular risk per 1-mmol/L decrease in LDL-C persists even at very low LDL-C levels, achievable with the addition of nonstatin therapies.[9,10] More intensive lipid-lowering strategies using nonstatins have extended benefit to even lower LDL-C levels. In the IMPROVE-IT trial, adding ezetimibe to high-dose statin brought LDL-C to ~54 mg/dL, reducing cardiovascular events over 7 years.[11] The FOURIER trial (statin + PCSK9 inhibitor evolocumab) achieved a median LDL-C of 30 mg/dL, with some patients reaching <10 mg/dL, and demonstrated a significant reduction in ASCVD events over 2.2 years.[12] The ODYSSEY trial (statin + alirocumab) achieved an average LDL-C of ~48 mg/dL and similarly demonstrated reduced event rates during follow-up of 2.8 years.[13] Robust long-term evidence from the ORION-8 open-label extension (OPE) of the RNA-based PCSK9-silencing agent inclisiran shows sustained and potent LDL-C lowering (~50% mean reduction) maintained over up to 6.8 years, with no attenuation of efficacy and no emergent safety signals.[14-16] Thus, the accumulated evidence substantiates that intensive LDL-C reduction well beyond conventional targets consistently results in clinically meaningful reductions in ASCVD risk. IMPACT ON ATHEROMA REGRESSION Prospective clinical trials provide compelling evidence of a direct relationship between achieved LDL-C levels and the rate of atherosclerotic progression. These studies demonstrate that the angiographic progression of atherosclerosis closely mirrors chronic LDL-C exposure. Reversal of atherosclerosis with aggressive lipid lowering trial This landmark study randomized 654 patients with symptomatic coronary artery disease and baseline stenosis ≥20% on coronary angiography to either high-dose atorvastatin (80 mg/day) or pravastatin (40 mg/day). Intravascular ultrasound assessment revealed that coronary atherosclerosis progression was virtually halted in the atorvastatin group, which achieved an on-treatment LDL-C of 79 mg/dL. Importantly, this study established that atherosclerosis progression is minimal or absent when LDL-C is ≤67 mg/dL.[7,17] Global assessment of plaque regression with a PCSK9 antibody as measured by intravascular ultrasound trial This trial assessed the effect of PCSK9 inhibition with evolocumab on atheroma volume in patients already receiving statin therapy. Key findings included:[18] LDL-C reduction: 36.6 mg/dl in the evolocumab group versus 93.0 mg/dl in controls Percent atheroma volume: 0.95% decrease versus 0.05% increase Normalized total atheroma volume: 5.8 mm3 decrease versus 0.9 mm3 decrease Plaque regression rates: 64.3% versus 47.3% (difference: 17%). The Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound study also demonstrated a linear relationship between achieved LDL-C levels and atherosclerosis regression, with significant effects observed across a wide LDL-C spectrum from 110 mg/dL down to as low as 20 mg/dL. Long-term evolocumab data – fourier open-label extension Extended follow-up from the FOURIER-OLE confirmed that LDL-C reductions maintained over up to 8 years correlate with sustained plaque stabilization, reinforcing the durability of aggressive LDL-C lowering strategies.[19] Inclisiran (RNA-based PCSK9 silencing) Although long-term imaging data with inclisiran are not yet available, its durable LDL-C reduction (~50% mean reduction over 6.8 years) and favorable lipoprotein profile, including lower apoB-containing particles, suggest a similar potential for sustained plaque stabilization or regression under very low LDL-C therapy.[14-16] IMPACT ON ALL-CAUSE MORTALITY Evidence from randomized trials and genetic studies indicates that the incidence of cardiovascular events follows a log-linear relationship with LDL-C concentration, both at extremely low and high levels. Cardiovascular risk rises with higher LDL-C and declines with lower LDL-C, with the magnitude of risk reduction remaining consistent, regardless of whether LDL-C lowering is achieved through statins, ezetimibe, PCSK9 inhibitors, or lifestyle interventions. Notably, data from the IMPROVE-IT and FOURIER trials demonstrate that the relationship between LDL-C reduction and cardiovascular event reduction aligns with the regression line established from meta-analyses of statin trials, reinforcing the principle that “lower is better” for LDL-C. The FOURIER trial observed reductions in cardiovascular events even at LDL-C levels as low as 10 mg/dL. In the ODYSSEY OUTCOMES trial,[13] among patients eligible for ≥3 years of follow-up, alirocumab reduced all-cause mortality by 22%. A post hoc analysis revealed that mortality continued to decrease with LDL-C reduction down to 30 mg/dL, though whether this trend persists below 30 mg/dl remains to be confirmed. Long-term data further support the safety and efficacy of profound LDL-C lowering: FOURIER-OLE:[19] Parent and extension data for evolocumab show that LDL-C reductions were maintained over up to 8.6 years, with persistent reductions in major cardiovascular events, including at very low LDL-C levels (<20 mg/dl), without a significant increase in adverse safety endpoints. Inclisiran ORION-8:[14-16] Long-term RNA-based PCSK9 silencing demonstrates durable LDL-C reduction, excellent tolerability, and no new safety signals over multiple years, indicating sustained cardiovascular benefit without compromising long-term survival. Collectively, these findings strongly suggest that lowering LDL-C to very low levels does not compromise safety or overall survival. On the contrary, achieving profound LDL-C reduction may offer maximal cardiovascular protection. SAFETY CONSIDERATIONS OF ACHIEVING VERY LOW LDL CHOLESTEROL LEVELS The long-term safety of pharmacologically achieved very low LDL-C remains a critical consideration for researchers and clinicians. Data from the IMPROVE-IT trial[20] demonstrate that over a 6-year follow-up, individuals achieving LDL-C <30 mg/dL experienced no excess adverse events compared with those with higher LDL-C. Similarly, the FOURIER trial demonstrated consistent safety profiles across achieved LDL-C strata, including among patients with LDL-C <10 mg/dL. Longer-term follow-up from FOURIER-OLE[21] confirmed that safety outcomes remained statistically comparable even among participants with LDL-C <20 mg/dL. Consistent with the parent trial, MACE incidence continued to decrease progressively, with average LDL-C levels down to <20 mg/dL and even <10 mg/dL (median: 7 mg/dL). When combining results from the parent FOURIER trial and FOURIER-OLE, representing up to 8.6 years of follow-up, there is no evidence of excess adverse events, despite progressively lower LDL-C levels coinciding with reduced cardiovascular events.[19] Similarly, the ORION-8 long-term extension of inclisiran therapy[14-16] reported favorable tolerability over up to 6.8 years, with limited injection site reactions and no evidence of accumulating adverse events or loss of efficacy. In addition, genetic phenotypes associated with lifelong very low LDL-C, such as PCSK9 loss-of-function mutations and ANGPTL3 hypolipidemia, show no consistent pattern of increased noncardiovascular morbidity, supporting the biological safety of extremely low LDL-C over a lifetime. Taken together, these findings suggest that sustained very low LDL-C does not appear to pose significant harm while still offering maximal cardiovascular benefit. GUIDELINE RECOMMENDATIONS ON VERY LOW LDL CHOLESTEROL TARGETS Current professional society guidance closely aligns with these observations. The 2018 American College of Cardiology (ACC)/American Heart Association (AHA)/Multisociety Cholesterol Guideline emphasizes LDL-C reduction guided by therapy intensity and risk category rather than strict lower safety limits.[19,22] Recent updates from the ACC/AHA/ Multisociety Cholesterol Guideline emphasize aggressive LDL-C lowering in high-risk patients using a threshold-based approach. In individuals with established ASCVD, the goal is ≥50% LDL-C reduction and levels <55 mg/dL, with escalation to nonstatin therapies (ezetimibe and PCSK9 inhibitors) if this is not achieved. Importantly, these guidelines clearly state that no lower safety threshold for LDL-C has been identified, and very low levels (<25 mg/dL) should not prompt de-escalation of therapy if treatment is well tolerated. This directly supports the concept of “lower for longer” to maximize cardiovascular risk reduction.[23] The new guideline extends additional support that “lower (LDL-C) for longer is better.” Similarly, the ESC/EAS dyslipidemia guidelines recommend aggressive LDL-C goals of <55 mg/dL for very high-risk patients and <40 mg/dL in selected extremely high-risk individuals.[11] National and regional guidelines broadly align with international recommendations supporting intensive LDL-C lowering in high-risk populations. The Lipid Association of India expert consensus recommends an LDL-C goal of <50 mg/dL in very high-risk or secondary prevention patients, with optional targets of ≤30 mg/dL in extreme risk individuals such as those with recurrent cardiovascular events or polyvascular disease.[24] Similarly, the Cardiological Society of India dyslipidemia guidelines advise LDL-C targets of <55 mg/dL for very high-risk patients, <70 mg/dL for high-risk individuals (e.g., diabetes or hypertension), and <100 mg/dL for the general population.[25] Importantly, current guideline frameworks do not define a lower safety threshold for LDL-C and recommend that very low achieved levels should not prompt de-escalation of therapy in high-risk patients in the absence of adverse effects. Expert consensus, including the National Lipid Association’s “lower for longer” paradigm, suggests that LDL-C levels <25 mg/dL and even <10–20 mg/dL in very high-risk populations are biologically plausible, safe, and associated with continued ASCVD risk reduction, supporting targets of <55 mg/dL and even <40 mg/dL in selected extreme-risk patients.[26-29] CONCLUSION The totality of human evidence, including physiological, genetic, randomized controlled trials, long-term extensions, and emerging RNA-based therapy data, supports the principle that lower LDL-C levels confer greater cardiovascular protection, even at levels far below traditional targets. Sustained and aggressive LDL-C reduction over many years consistently leads to significant ASCVD risk reduction, without being associated with persistent long-term safety concerns. Recent guidance from the National Lipid Association reinforces the “lower for longer” paradigm, emphasizing cumulative LDL-C exposure as a critical determinant of cardiovascular risk. Advances in lipid-lowering therapies, such as PCSK9 monoclonal antibodies and siRNA-based agents like inclisiran, have made durable and profound LDL-C reduction increasingly achievable. Contemporary recommendations from the ACC/AHA/Multisociety Cholesterol Guidelines reinforce that very low LDL-C levels are both attainable and safe, with no defined lower limit restricting therapy in high-risk individuals. While ongoing long-term surveillance remains essential, particularly for newer RNA-based therapies, accumulating clinical trial data and real-world evidence are likely to further substantiate the safety and efficacy of maintaining very low LDL-C levels. As this evidence base grows, clinical practice may increasingly prioritize lifetime LDL-C exposure reduction over fixed minimum targets, particularly in individuals at the highest cardiovascular risk. Authors’ contributions Alok Kumar Singh led the conception and drafting of the editorial, and Jyoti Aggarwal provided critical revisions and intellectual input. Both the authors approved the final manuscript and agreed to be accountable for its content.