CME INDIA Presentation by Dr. Anil Kumar Virmani, MD, DRM, FICP, FIACM, FACP, FDI, FRSSDI, FICCMD, FISH, CCIO, FISC, FRCP(LONDON), Dean elect, Indian college of cardiology & metabolic diseases, Faculty, Regional Yorkshire foundation teaching program, UK, Executive council member (east zone), RSSDI, Jamshedpur.

Based on a presentation at RSSDI-Jharkhand at Dhanbad, Jan 2024.

Management of Dyslipidaemia - Current Concepts Physicians Must Know

Indian Scenario 1-3

  • Approximately 10%-25% of myocardial infarctions (MI) in India occur before the age of 40, and more than 50% of coronary artery disease (CAD)-related deaths in the country happen before the age of 50.
  • Worryingly, there is a significant prevalence of dyslipidemia among Indians, as per the National Cholesterol Education Programme (NCEP) guidelines.
  • According to the ICMR-INDIAB 17 study published in The Lancet, Diabetes & Endocrinology on June 7, 2023, a staggering 81.2% of subjects exhibit at least one lipid abnormality. This includes 66.9% with decreased HDL-C levels, 29.5% with hypertriglyceridemia, and 11.8% with elevated small dense LDL-C levels. Dyslipidemia and abdominal obesity are notably higher among urban residents.

2004 study but very relevant

Management of Dyslipidaemia - Current Concepts Physicians Must Know

How you define hypercholesterolemia 4-6

Total Cholesterol > 200mg/dL
LDL(c) > 190 mg. %;                                  
               > 160 mg.% with one major risk factor, OR        
               > 130mg.% and/or Non-HDL-C > 160 mg.% with two CV risk factors
Primary Isolated Hypercholesterolemia: LDL(c) > 190 mg.% & Normal Triglycerides (< 150 mg.%)
LDL(c) > 400 mg.% is suggestive of HoFH

Impact of Lipids on Cardiovascular Health

  • Exposure to LDL cholesterol in early adulthood has been identified as a significant predictor of cardiovascular events later in life, irrespective of LDL levels in middle age.
  • Evidence from four studies conducted in the United States—ARIC, CARDIA, the Framingham Heart Study Offspring Cohort, and MESA—supports the notion that maintaining optimal LDL levels during both young and middle age can play a crucial role in minimizing the lifetime risk of cardiovascular events.
  • The findings of a study by Zhang et al. (published in JAMA Cardiology in 2021) highlight the association between cumulative exposure to low-density lipoprotein cholesterol during young adulthood and middle age, emphasizing the heightened risk of cardiovascular events. This suggests the need for a paradigm shift towards targeting high LDL levels earlier in life to effectively reduce the cumulative burden of atherosclerosis.

Know about Residual Risk

  • The PESA study revealed a significant association between hypertriglyceridemia and subclinical atherosclerosis, as well as vascular inflammation in individuals with low to moderate cardiovascular disease (CVD) risk.
  • In patients diagnosed with Type 2 Diabetes (T2D), Chronic Kidney Disease (CKD) stages 3 to 5, and incident Diabetic Nephropathy (DN), circulating levels of triglycerides and cholesterol transported in triglyceride-rich lipoproteins led to an elevated risk of death with cardiovascular disease when the Remnant-C level was greater than or equal to 30 mg/dL.
  • Notably, the highest risk was observed in patients with elevated levels of both remnant-C and LDL-C, with an odds ratio of 1.696 (95% confidence interval, 1.613-1.783). This underscores the importance of considering both remnant-C and LDL-C levels in assessing the risk of cardiovascular events in these patient populations.
Management of Dyslipidaemia - Current Concepts Physicians Must Know

Prescribing the appropriate combination of lipid-lowering therapy to achieve a patient’s target LDL-C level involves a straightforward approach:

  1. Conduct an ASCVD Risk Assessment: Begin by performing a comprehensive atherosclerotic cardiovascular disease (ASCVD) risk assessment to establish the patient’s goal LDL-C level. This assessment helps tailor the treatment plan to the individual’s specific cardiovascular risk.
  2. Determine Percentage LDL-C Reduction: Evaluate the percentage reduction in LDL-C necessary to reach the identified goal. This step ensures a personalized approach based on the patient’s unique lipid profile and risk factors.
  3. Initiate Combination Therapy: If a substantial reduction in LDL-C is required or if there are concerns about potential adverse events, consider initiating initial combination therapy. This approach may involve using two or more lipid-lowering agents simultaneously to achieve the desired reduction in LDL-C levels.
  4. Consider Dual- or Triple-Combination Therapy for High-Risk Patients: Recognize that patients at high or very high ASCVD risk may benefit from dual- or triple-combination therapy. Combining different classes of lipid-lowering medications can enhance efficacy and address multiple aspects of lipid metabolism, providing a more robust approach for individuals with elevated cardiovascular risk.

Management of Dyslipidaemia - Current Concepts Physicians Must Know

Aggressive LDL-C Lowering

  • While certain older retrospective, case-control, and prospective longitudinal studies suggest a potential association between statins and LDL-C lowering with cognitive impairment or dementia, the majority of observational studies and data from randomized trials do not support this conclusion. This holds true over varying trial durations, ranging from a median of 1.6 to 6.0 years of follow-up.
  • The risk of hemorrhagic stroke associated with statin therapy in patients without a history of cerebrovascular disease is minimal and consistently lacks statistical significance. Notably, there is no evidence indicating that the use of PCSK9 inhibitors or ezetimibe increases the risk of bleeding. Moreover, assessments from both randomized studies and mendelian inheritance studies, evaluating patients or populations with lifelong low LDL-C levels, do not suggest an enhanced vulnerability to hemorrhagic stroke. Limited evidence is available to support the idea that achieving very low levels of LDL-C heightens the risk of hemorrhagic stroke.
  • However, it is evident that lower LDL-C levels are correlated with a decreased risk of overall stroke and stroke recurrence, primarily attributable to a reduction in ischemic stroke. The concern about the risk of hemorrhagic stroke should not dissuade clinicians from treating LDL-C to guideline-recommended, risk-stratified targets.

Management of Dyslipidaemia - Current Concepts Physicians Must Know

Know the Super Hero

Management of Dyslipidaemia - Current Concepts Physicians Must Know

Bempedoic Acid: Clear role

Management of Dyslipidaemia - Current Concepts Physicians Must Know

Why inclisiran is deemed ‘life changing’?

  • In 2021, the initial small interfering RNA (siRNA) agent received approval as a supplementary treatment to statins for individuals with clinical cardiovascular disease (CVD) or heterozygous familial hypercholesterolemia.
  • On July 10, 2023, the FDA extended the indication of Inclisiran as an adjunct to statins, now encompassing primary prevention. This expansion applies to patients using statins for primary dyslipidemia, particularly those with high-risk comorbidities such as diabetes, even in the absence of a history of cardiovascular events.

When to think for LDL Apheresis?

Management of Dyslipidaemia - Current Concepts Physicians Must Know

Path Ahead

Management of Dyslipidaemia - Current Concepts Physicians Must Know

High TG

Management of Dyslipidaemia - Current Concepts Physicians Must Know

Lipoprotien (a), Is it real danger?

  • It is recommended to measure Lp(a) at least once in all adults to identify individuals at high cardiovascular risk. Additionally, screening is advised in youth with a history of stroke, a family history of elevated Lp(a), or premature atherosclerotic cardiovascular disease (ASCVD) without other identifiable risk factors. Family cascade screening for high Lp(a) is also recommended in the context of familial hypercholesterolemia, a family history of (very) high Lp(a), and a family history of ASCVD.
  • Currently, there are no commercially available Lp(a)-specific lowering drug therapies. Consensus panel recommendations for managing high Lp(a) concentrations include early and aggressive management of modifiable cardiovascular risk factors. Lipoprotein apheresis may be considered for patients with very high Lp(a) and progressive cardiovascular disease despite optimal management of risk factors. However, aspirin and niacin are not recommended for lowering Lp(a).
  • In clinical development, several Lp(a)-specific lowering agents show promise:
    • Pelacarsen, an antisense oligonucleotide therapy with monthly dosing. Outcome results from a phase 3 study are expected in 2025.
    • Olpasiran, utilizing small-interfering RNA (siRNA) technology with longer-acting effects. A dose-finding study has recently been completed.
    • SLN360, another siRNA technology with longer-acting effects, has completed its phase 1 study.

Learning Points

LDL-c is CAUSAL for ASCVD & is the PRIMARY TARGET → the lower, the better → the earlier, the better → the longer, the better.
Once at LDL-c Goal, NON-HDL should be targeted → “CO- PRIMARY” Target.
Lp(a) is an Emerging Target requiring intensification of therapy.
Getting to Guideline recommended goals and STAYING there will prevent CV Events.

References:

  1. Prabhakaran D, Jeemon P, Roy A. Cardiovascular diseases in India: Current epidemiology and future directions. Circulation 2016; 133:1605-20.
  2. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP). Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285:2486-97.
  3. Joshi SR, Anjana RM, Deepa M, Pradeepa R, Bhansali A, et al. Prevalence of dyslipidemia in urban and rural India: The ICMR–INDIAB Study. PLoS ONE 2014; 9:e96808.
  4. Updated NCEP III Guidelines; J Am Med Dir Assoc 2005.
  5. European Heart Journal, 2023 May 2 ehad 197. Ibrahim MA, Asuka E, Jialal I, Hypercholesterolemia [Updated 2023, April 23.
  6. J Clin Lipidol, 2022 Nov-Dec : 16(6); 813-821.
  7. Ference BA, Graham I, Tokgozoglu L, Catapano AL. Impact of Lipids on Cardiovascular Health: JACC Health Promotion Series. J Am Coll Cardiol. 2018 Sep 4;72(10):1141-1156. doi: 10.1016/j.jacc.2018.06.046. PMID: 30165986.
  8. Zhang Y, Pletcher MJ, Vittinghoff E, et al. Association between cumulative low-density lipoprotein cholesterol exposure during young adulthood and middle age and risk of cardiovascular events. JAMA Cardiol. 2021;Epub ahead of print.
  9. Raposeiras-Roubin S, Rosselló X, Belén Oliva B, Fernández-Friera L, Mendiguren JM, Andrés V, Bueno H, Sanz J, Martínez de Vega V, Abu-Assi E, Iñiguez A, FernándezOrtiz A, Ibáñez B, Fuster V. Triglycerides and residual atherosclerotic risk. J Am Coll Cardiol 2021;77:3031–3041.
  10. Dahai U et al, “Remnant Cholesterol and Cardiovascular Mortality in Patients With Type 2 Diabetes and Incident Diabetic Nephropathy”, The Journal of Clinical Endocrinology & Metabolism, Volume 106, Issue 12, December 2021, Pages 3546–3554.
  11. Aggressive LDL-C Lowering and the Brain: Impact on Risk for Dementia and Hemorrhagic Stroke: A Scientific Statement From the American Heart Association.Larry B. Goldstein, MD, FAHA, Chair, Peter P. Tothet al, on behalf of the American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; Council on Peripheral Vascular Disease; and Stroke Council.Arteriosclerosis, Thrombosis, and Vascular Biology Volume 43, Issue 10 Oct 2023.


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