LDL-C The Only Causal Risk Factor for ASCVD

Why low-density lipoprotein-cholesterol, the only causal risk factor for atherosclerotic cardiovascular disease, is still overlooked and underestimated

Continuous patient and physician education and shared decision-making between them is necessary for implementation of guidelines on low-density lipoprotein cholesterol (LDL-C)-lowering strategies to prevent atherosclerotic cardiovascular disease (ASCVD).

• Despite numerous studies proving the role of LDL-C in ASCVD etiology, LDL-C, the most important causal risk factor remains overlooked and underestimated.

Over 200 studies on nutrition, cardiovascular disease (CVD) prevention and pharma trials on new drugs recognized LDL-C as the only causal risk factor for ASCVD

• Seven Countries Study, Framingham Heart Study, and Münster Heart Study (PROCAM): Identified LDL-C as a risk factor for CVD and indicated role in ASCVD
• Several studies on statins (4S study, Cheung et al, Fulcher et al) show similar results in association of lower LDL-C levels with reduction of major adverse cardiovascular events (MACE) and risk of coronary revascularization procedures and better survival outcomes

On Top Statin Therapy: Influenced change in LDL-C target levels, especially in high-risk patients, as ezetimibe and PCSK9 inhibitors added to statin reduced LDL-C levels and significantly reduced MACE

• IMPROVE-IT: Ezetimibe added to statin led to an additional 24% reduction in LDL-C levels and lowered LDL-C than previously recommended, leading to a better outcome
• FOURIER and ODYSSEY Outcomes: PCSK9 inhibitors added to statin significantly reduced MACE incidence in patients with LDL-C levels well below guideline recommendations and patients with the highest risk of coronary artery disease benefited the most in reducing incidence of nonfatal myocardial infarction and coronary revascularization

Low LDL-C in Familial Hypercholesterolemia (FH)

• Heterozygous and homozygous FH lead to high LDL-C levels and high ASCVD risk in youth; highest doses of combination lipid-lowering therapy (LLT) is most often used in treatment.

Initiate LLT as early as possible

• Clinical benefit of LLT arises mainly from LDL-C lowering and ASCVD risk can be reduced 50–80% based on treatment adherence and level of LDL-C reduction.
• All physicians and patients should work to lower LDL-C by initiating LLT as early as possible and maintain long-term therapy to sustain very low LDL-C levels.

Guidelines vs real world: Maximum statin and combination therapy dose not often used

• Gould registry: Only 36.5% of patients in the USA receive optimized medical treatment in secondary prevention post-myocardial infarction (MI)
  • Only 67.5% and 11% of doctors think LDL-C should be <50 mg/dL and <55 mg/dL, respectively and 30% and fewer than 10% of patients reach LDL-C <70 mg/dL and <55 mg/dL, respectively.
  • Combination therapy use is limited: 1-year post-MI, 61.8% of patients received high-intensity statin therapy; ezetimibe was added in 8.5% of patients, and PCSK9 inhibitors in 3.1% of patients
• DA VINCI study: In 1 year, 20% and 38% of very high-risk patients used high-intensity statins, 9% used combination therapy, and only 1% used PCSK9 inhibitors; over half to two-thirds of patients did not achieve LDL-C targets
• Danish registry: Intensive LLT led to target LDL-C levels in 43.4–47.7% of post-MI patients in 6–12 months, which remains unsatisfactory
• Registry databases: About 50% of patients receive LLT in secondary prevention, but <50% reach LDL-C levels <70 mg/dL
• American College of Cardiology National Cardiovascular Data Registry-Practice Innovation and Clinical Excellence registry: Low LLT use was seen in patients with high LDL-C and a different risk profile
• Review of LLT use and outcomes in European patients with dyslipidemia and a high and very high ASCVD risk over a 5-year period: Inadequate treatment with LLT, 46–92% patient adherence, and suboptimal LDL-C control were seen

Adherence to statins and LLT is a common issue in both primary and secondary prevention due to patient, clinician, and healthcare system related factors

• Gould Registry: Patients and physicians were ignorant about disease, causes, target LDL-C levels and long-term therapy importance
• German data: Decreased statin adherence from 85.5% on discharge to 11.7% after 3 months and 15.7% after 12 months, similar to ezetimibe, increased MACE incidence in patients on combination therapy
• French national healthcare database: High-intensity LLT was used in only half of patients with MI and 40% remained non-adherent during follow-up, but each 10% increase in adherence improved outcomes with 7–16% MACE reduction
• Poor patient motivation and cognition, inaccurate health beliefs, lack of clinical follow up, adverse outcomes and complex strategies lead to poor LLT adherence.
• Nocebo effect can greatly impact statin discontinuation, and side-effects and symptoms did not vary significantly when taking statin or placebo in SAMSON, but were lower when patients were not receiving treatment.
• International Atherosclerosis Society surveys: Disagreement among physicians on LDL-C targets and safety of statins and low LDL-C values owing to cultural differences and gaps and beliefs of perception about LLT
• Prospective cluster randomized trial: Physicians’ adherence was lower for pharmacotherapy up-titration and the lowest when initiating therapy
• EUROASPIRE V: Rather than intensifying LLT to reach the goal, down-titration is common at follow up
• Kolandaivelu et al: In Europe, poor adherence of vascular medications attribute to ~10% of CV events, making non-adherence a new risk factor for ASCVD

Health care systems and LLT

• Various healthcare systems have different accessibility and availability of drugs, cost or reimbursement of medication and time spent with the patient.
• Finnish study: Risk of statin discontinuation declines with a lower medical cost and is lower if costs are almost completely reimbursed by the healthcare system
• Slone survey: Herbal remedies taken by ~16% of outpatients may lead to less statin absorption, interact with other drugs, and affect some medical conditions
• Over 40% of patients rely on online information, so healthcare systems and official medical associations should increase social network presence by offering medical information through mobile applications and pocket cards.

How to overcome discrepancy between target and achieved LDL-C

• Guidelines should be liberal, offer more open solutions, and consider any treatment that safely lowers LDL-C levels after insights into global registries.
• Support less frequent LLT dosing if acceptable, adapt health literature to improve patient education, and support physicians to act on a personalized approach.
• Provide patients access to LLT, as it is the cheapest and most cost-effective way to prevent ASCVD and urge patient organizations that have a significant impact on health systems policies to educate people about their illness and therapy.
• Develop a network of specialized lipid clinics under the auspices of the EAS and provide access to educational materials on its website to improve diagnosis, treatment, and achieve LDL-C targets.

For additional details, please refer the source publication, Ferhatbegović L, et al