CardioNerds Dr. Rick Ferraro, Director of the #CardsJC Journal Club and cardiology fellow at Johns Hopkins and Dr. Tommy Das, Program Director of the CardioNerds Academy and cardiology fellow at Cleveland Clinic join Academy fellow and episode lead Dr. Julie Power, chief fellow at the University of Minnesota to learn all about the link between LDL-C and cardiovascular events and disparities in care from Dr. Keith Ferdinand, Professor of Medicine and Chair in Preventative Cardiology at Tulane University School of Medicine.
As we’ve learned in prior episodes, LDL-C plays a key role in lipid pathophysiology. But how does it lead to cardiovascular events? LDL-C directly leads to plaque expansion and deposition in the arterial intima. Increasing levels of LDL-C are directly related to worsening plaque burden, a principle exhibited powerfully by the dose-dependent nature of coronary atherosclerosis in patients with underlying mutations leading to LDL-C elevation, such as familial hypercholesterolemia.
Importantly, the treatment of atherosclerosis and implementation of lipid-lowering therapies are not uniform, with significant disparities throughout the community. The message is clear: Reducing LDL-C is of paramount significance in the prevention and treatment of coronary atherosclerosis and ensuring equitable access to care is critical to addressing the societal burden of cardiovascular disease and improving the health of our communities.
There is no CME associated with this episode. To get free CME from other CardioNerds episodes, please visit VCU Health here.
Relevant disclosure: Dr. Ferdinand reported severing as a consultant for Medtronic, Amgen, and Novartis.
Pearls – LDL, Cardiovascular Events, & Disparities in Care
- LDL-C is a major stimulant for the initiation and progression of atherosclerosis.
- The lower the LDL-C level, the greater the clinical benefit in both primary and secondary ASCVD prevention.
- Our healthcare systems continue to have major disparities in access to quality care and it is essential to reduce barriers to cardiovascular wellness for all communities.
- Lowering LDL-C in individuals at high cardiovascular risk, especially in those with familial hypercholesterolemia, prevents ASCVD events.
Quotables – LDL, Cardiovascular Events, & Disparities in Care
“Empower patients to be partners in their care”Dr. Keith Ferdinand
Show notes – LDL, Cardiovascular Events, & Disparities in Care
1. What is the link between LDL-C and cardiovascular events?
- LDL-C is a major stimulant for the initiation and progression of atherosclerosis. The key events in the initiation of ASCVD are the retention and accumulation of cholesterol-rich lipoproteins within the arterial intima at sites with a predilection for plaque formation. As serum levels of LDL-C increase, the probability of intimal retention of LDL leading to the development of atherosclerotic plaque increases in a dose-dependent manner .
- The WOSCOPS trial demonstrated genes associated with lower LDL-C levels are also associated with a three-fold reduction in the risk of cardiovascular disease per unit reduction in LDL-C .
- The Emerging Risk Factors Collaboration (ERFC) and Prospective Studies Collaboration reported plasma LDL-C was associated with increased risk of non-fatal MI or CHD death .
- Statins uniformly reduce atherosclerotic risk across varying levels of baseline LDL-C and are first line therapy for primary and secondary prevention of ASCVD.
- In high-risk individuals and secondary prevention populations, AHA/ACC guidelines recommend 50% reductions in LDL-C, regardless of baseline, to < 70 mg/dL, using a combination of statins, ezetimibe, and PCSK9 inhibition .
- Intravascular ultrasound studies of coronary atherosclerosis involving statin-treated patients demonstrated that progression of coronary atherosclerotic plaque volume can be arrested once an LDL-C of 70 mg/dL is reached [4, 10, 11].
- The effect of LDL-C on the risk of ASCVD is both causal and cumulative over time; therefore, lowering the LDL-C level early will lead to greater reductions in the lifetime risk of ASCVD. Each millimole per liter reduction in LDL-C reduces the relative risk of ASCVD events by ∼10% in the first year of treatment and ∼20–25% after 5 years .
2. What is Familial Hypercholesterolemia?
- Familial hypercholesterolemia (FH) is an autosomal co-dominant disorder that results from a mutation in an LDL receptor gene, ApoB gene, or PCSK9 gene. FH is characterized by markedly elevated levels of LDL-C and premature atherosclerosis.
- Siblings who inherit an FH mutation have markedly elevated plasma LDL-C levels and a corresponding markedly elevated lifetime risk of ASCVD as compared to their unaffected siblings, providing powerful evidence that LDL causes ASCVD.
- Heterozygous FH affects between 1:200 and 1:300 people worldwide and when untreated is characterized by LDL-C levels >190. FH should be considered in adults with LDL-C levels > 190 mg/dL or total cholesterol levels > 310 mg/dL .
- Homozygous FH is a much rarer condition, with an extreme phenotype characterized by untreated plasma LDL-C levels above >400 from birth and almost universal development of ASCVD and xanthomas in childhood or early adolescence. Statins can be started as early as 8-10 years of age. PCSK-9 inhibitors may also be used. LDL apheresis is also a common treatment option .
- To learn more about personalized ASCVD risk assessment and FH, enjoy CardioNerds Episode #98: Personalized Risk Assessment for Cardiovascular Prevention with Dr. Amit Khera.
3. What is the interaction of LDL-C with other ASCVD risk factors?
- There are numerous risk factors for ASCVD: hypertension, diabetes mellitus, tobacco smoking, and more. Patients with more risk factors have a higher absolute rate of ASCVD in comparison with persons with fewer risk factors .
- However, reduction in LDL-C is associated with the same proportional risk reduction of ASCVD, regardless of the presence or absence of these other risk factors .
- Statin therapy reduces vascular event rates, including major coronary events, stroke, and coronary revascularization by 15-25% for each 1 mmol/L reduction in LDL-C .
4. How do we best support the cholesterol management and cardiovascular health needs of underserved and low-resource communities?
- We must recognize and work together to address CV health disparities from both the individual and population levels.
- Reduced adherence to statin therapy among eligible patients is associated with increased mortality. Minority patients, those with low income, and those with barriers to health literacy have been found to be less likely to adhere to statins, signaling important disparities that must be addressed further. The reasons are likely multifactorial and require a multipronged approach to address.
- Team care delivered in nontraditional locations shows promise, but the cost-effectiveness and sustainability of these approaches need to be studied further .
- Barriers to treatment in low-resource communities exist at multiple levels: educational opportunities, environment, limited access to healthy food options, access to healthcare providers, transport to healthcare facility organization and practice settings where care occurs, and governmental health policy. Focus is needed on developing cross-sectional partnerships to target multiple barriers [13, 16]
- Programs need early-stage investigators committed to disparities research to bridge these findings to clinical practice and formulation of health policy.
- To learn about the use of community based participatory research to meaningfully engage and empower the community in addressing these barriers, enjoy CardioNerds Episode #131 with Dr. LaPrincess Brewer and Dr. Norrisa Haynes.
- To learn about strategies to engage minority patients in clinical trials, enjoy CardioNerds Episode #135 with Dr. Clyde Yancy.
5. What are some other benefits and consequences of lowering LDL-C?
- Intensive LDL-C lowering is associated with a greater reduction of all-cause mortality in addition to CV mortality .
- LDL-C lowering has exhibited protective effects against cerebrovascular events.
- The ODYSSEY trial in 2019 demonstrated that PCSK-9 therapy decreased the risk of stroke in patients with recent ACS and dyslipidemia; however, this was regardless of LDL-C levels achieved.
- There is no evidence for an increased risk of cognitive impairment (PROSPER trial) or hemorrhagic stroke with lower LDL-C levels.
References – LDL, Cardiovascular Events, & Disparities in Care
- Baigent C, Blackwell L, Emberson J, et al. Efficacy and Safety of More Intensive Lowering of LDL Cholesterol: A Meta-Analysis of Data from 170,000 Participants in 26 Randomised Trials. Lancet. 2010; 376: 1670–81.
- Damask A, Steg PG, Schwartz GG et al. Patients With High Genome-Wide Polygenic Risk Scores for Coronary Artery Disease May Receive Greater Clinical Benefit From Alirocumab Treatment in the ODYSSEY OUTCOMES Trial. Circulation. 2020 Feb 25;141(8):624-636.
- Duran EK, Aday AW, Cook NR, et al. Triglyceride-Rich Lipoprotein Cholesterol, Small Dense LDL Cholesterol, and Incident Cardiovascular Disease. J Am Coll Cardiol. 2020 May 5; 75(17):2122-2135.
- Ference BA, Yoo W, Alesh I, et al. Effect of Long-Term Exposure to Lower Low-Density Lipoprotein Cholesterol Beginning Early in Life on the Risk of Coronary Heart Disease: a Mendelian Randomization Analysis. Journal of the American College of Cardiology. 2012; 60: 2631-9.
- Goldberg AC, Hopkins PN, Toth PP, et al. Familial Hypercholesterolemia: Screening, Diagnosis and Management of Pediatric and Adult Patients: Clinical Guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011; 5:133–40.
- Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/ AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;73: e285–350.
- Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020; 41: 111–88.
- Mihaylova B, Emberson J, Blackwell L, et al. The Effects of Lowering LDL Cholesterol with Statin Therapy in People at Low Risk of Vascular Disease: Meta-analysis of Individual Data from 27 Randomised Trials. Lancet. 2012; 380: 581-90.
- Navarese EP, Robinson JG, Kowalewski M, et al. Association Between Baseline LDL-C Level and Total and Cardiovascular Mortality after LDL-C Lowering: A Systematic Review and Meta-analysis. JAMA. 2018; 319 (15): 1566-1579.
- Nicholls SJ, Ballantyne CM, Barter PJ, et al. Effect of Two Intensive Statin Regimens on Progression of Coronary Disease. N Engl J Med. 2011; 365: 2078–2087.
- Nissen SE, Nicholls SJ, Sipahi I, et al. ASTEROID Investigators. Effect of Very High-intensity Statin Therapy on Regression of Coronary Atherosclerosis: the ASTEROID Trial. JAMA. 2006; 295: 1556–1565.
- Ridker, PM. LDL Cholesterol: Controversies and Future Therapeutic Directions. Lancet. 2014; 384: 607-617.
- Schultz WM, Kelli HM, Lisko JC, et al. Socioeconomic Status and Cardiovascular Outcomes: Challenges and Interventions. Circulation. 2018. 137 (20): 2166–2178
- Shepherd J, et al. Prevention of Coronary Heart Disease with Pravastatin in Men with Hypercholesterolemia”. The New England Journal of Medicine. 1995. 333 (20): 1301-1308.
- Valdes-Marquez E, Parish S, Clarke R, et al. Relative Effects of LDL-C on Ischemic Stroke and Coronary Disease: a Mendelian Randomization Study. Neurology. 2019; 92: e1176–87.
- Whelton PK, Einhorn PT, Muntner P, et al. Research Needs to Improve Hypertension Treatment and Control in African Americans. Hypertension. 2016.
Keith C Ferdinand, MD, is Professor of Medicine at the Tulane University School of Medicine and the Tulane Heart and Vascular Institute in New Orleans, Louisiana. He was previously Professor of Clinical Pharmacology at Xavier University, New Orleans and Clinical Professor of Medicine at Emory University, Atlanta, Georgia. Dr. Ferdinand received his medical degree from the Howard University College of Medicine in Washington, DC. He is board-certified in internal medicine and cardiovascular disease, certified in the subspecialty of nuclear cardiology, and a specialist in clinical hypertension certified by the American Society of Hypertension.
Dr. Julie Power @JuliettePower44 is a cheif cardiology fellow at the University of Minnesota. She completed medical school at Drexel University in Philadelphia followed by residency training at Allegheny General Hospital in Pittsburgh where she also served a Chief Resident. In addition to a continued involvement in medical education, Julie plans to pursue additional training in interventional cardiology after her general cardiology fellowship. In her free time, she enjoys spending time with family and friends, including exploring Minnesota with her boyfriend, Steve.