Lipids

Leqvio, a Revolutionary Cholesterol Medication

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in the United States and worldwide. In the US alone, a person dies from cardiovascular-related causes every 33 seconds. Therefore, it is crucial to develop new therapies that aim to reduce the risk of cardiovascular disease.

New FDA approval: fish oil (vascepa) for cardiovascular risk reduction

Vascepa is a form of omega-3 fish oil named icosapent ethyl. It was first approved by the FDA in 2012 for the treatment of severe hypertriglyceridemia, as defined by blood triglyceride levels >500 mg/dL.

The FDA has now added a second indication for Vascepa. It can be utilized in patients with established cardiovascular disease or in those who have diabetes plus two or more other risk factors (e.g., hypertension, hypercholesterolemia, smoking, kidney dysfunction) for cardiovascular disorder. Before treatment, patients must also have baseline triglyceride measures >150 mg/dL.

This significant approval comes after reviewing the results of REDUCE-IT, a landmark randomized clinical trial published in NEJM, January 2019. REDUCE-IT confirmed significant cardiovascular outcome reduction of 25% in patients receiving icosapent ethyl when added to statin therapy.

I anticipate widespread use of the fish oil, icosapent ethyl, especially in patients with diabetes, who, by its nature of insulin resistance, frequently have both the increased risk of ASCVD and high triglycerides. Clinicians should be aware of possible induction or worsening of atrial fibrillation, atrial flutter, and bleeding with Vascepa, particularly in the predisposed individuals.

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Interaction of ACAT with MTTP in making Lipoprotein B

Blood lipid particles, formally called lipoproteins, are essential for carrying and transporting triglycerides and cholesterol to various body tissues. Lipoproteins that contain B48 and B100 apoproteins are two decisive players. B48-Lipoprotein (Lp B48) is synthesized in the gastrointestinal tract, whereas B100-Lipoprotein (Lp B100) is made in the liver.

In this review article, the authors propose a feasible model of how Lp B48 and Lp B100 are created in the endoplasmic reticulum of enterocytes and hepatocytes. ACAT is responsible for converting free cholesterol into cholesteryl ester (CE), while MTTP is responsible for uploading CE and triglycerides into B48- or B100-Lipoproteins.

Clinician’s knowledge of Lp B48 and Lp B100 physiology is vital as both lipoproteins are – directly or indirectly – involved in all forms of dyslipidemias (Fredrickson classifications I – V)

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From obesity and triglycerides to pancreatitis

Obesity rates are rising worldwide. Acute pancreatitis is also on the rise. The authors of the current study followed prospectively about 120,000 individuals. As expected, they found a high correlation between BMI and acute pancreatitis events. Investigators also observed that hypertriglyceridemia could explain about 22-30% of the relationship between obesity and pancreatitis.

The results of the study, although not new, confirm prior research and knowledge that obesity leads to insulin resistance, which in turn elevates blood triglyceride concentration. Hypertriglyceridemia is a well-known specific cause of acute pancreatitis, especially when triglyceride measurements are above 500 mg/dL.

Clinically, it is essential to screen obesity patients for hypertriglyceridemia. A fasting lipid panel is a simple and inexpensive laboratory test that can provide significant insights into the patient’s risk of insulin resistance and pancreatitis.

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More bad news for Niacin

The New England Journal of Medicine first published the results of the HPS2-THRIVE randomized clinical trial in 2014. Niacin addition to statin therapy did not improve cardiovascular outcomes. Instead, the trial found an increased rate of adverse events.

Last month, Clinical Therapeutics published a detailed analysis of the trial’s adverse events. Authors found that niacin addition significantly increased the risk of new-onset diabetes, worsening of diabetes, severe bleeding, and serious infections by about 30%, 55%, 40%, and 20% respectively.

The above adverse outcomes were more pronounced in the first year after the start of niacin. The infection rate was an exception, which stayed elevated throughout the trial. Investigators followed and analyzed a group of 25,000 patients with high baseline risk for the vascular disease over four years.

Based on HPS2-THRIVE data, it is difficult to justify the clinical use of niacin from the cardiovascular standpoint.

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A future of high triglycerides

Familial chylomicronemia syndrome is rare. Its prevalence is about 1 in 1 million. It is characterized by defective or deficient lipoprotein lipase (LPL) enzyme, severely high triglycerides, and recurrent pancreatitis. Apoprotein C3 antagonizes LPL activity leading to hypertriglyceridemia. Much effort has been done to target Apo C3 pharmacologically. Now we have an anti-sense inhibitor to the hepatic Apo C3 mRNA, called volanesorsen.

This phase 3, double-blind randomized clinical trial shows that volanesorsen lowers both Apo C3 and triglycerides remarkably.  Apo C3 is decreased by 25.7 mg/dL and triglycerides by about 1700 mg/dL (Δ80% reduction). Low platelet count and injection site reactions were seen more commonly with volanesorsen than placebo.  Although the study was designed to evaluate changes in triglyceride levels, clinical outcomes (pancreatitis) are also expected to improve.

Study findings are of major importance as it provides us with another tool and pathway of lowering elevated triglycerides. Hypertriglyceridemia, commonly found in patients with metabolic syndrome, is a well-established independent risk factor for cardiovascular events. I anticipate that the antisense inhibitor technology will also be tested in patients with metabolic syndrome, insulin resistance, prediabetes, and diabetes; as these conditions are far more prevalent than familial chylomicronemia syndrome.

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2019 NLA scientific statement: Lp(a) – key points

The various large meta-analysis, Mendelian randomizations, and prospective population-based studies have found the Lipoprotein (a) to be an independent risk factor for atherosclerosis, aortic valve stenosis, and thrombosis. Lp(a) test is considered to be high when its value is >50 mg/dL or >100 nmol/L. These measures correspond to the top 20th percentile of the general population.

Currently, there are no approved specific therapies for Lp(a). The NLA does not recommend the use of Niacin, HRT (hormonal replacement therapy) or Lomitapide (microsomal triglyceride transfer protein inhibitor). Recent trials such as FOURIER and ODYSSEY have shown that addition of PCSK9 inhibitors to Statin therapy can lower Lp(a) by 30%.

However, various guidelines including 2018 AHA/ACC and 2019 NLA scientific statement recommend the use of PCSK9 inhibitors only in the context of uncontrolled LDLc/non-HDLc in patients at high-risk or very-high-risk for ASCVD events.

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Lipoprotein(a) is an independent ASCVD risk

Blood Lipoprotein(a) measurements are genetically determined.  Lifestyle, physical activity or dietary habits do not change its levels.  Epidemiologically, Lp(a) has been found to be an independent risk factor for poor ASCVD outcomes.  Lp(a) is a promoter of atherosclerosis, thrombosis and aortic valve stenosis.

In this meta-analysis of 7 statin-outcome randomized clinical trials, authors showed that baseline and on-statin treatment Lp(a) levels correlated positively and linearly with ASCVD events: the higher the Lp(a) measurements, the higher the cardiovascular outcomes.

Development of specific drug therapies in reducing Lp(a) are needed.  These therapies would then be tested in outcome driven ASCVD clinical trials.

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New drug development for hypercholesterolemia

The study shows that bempedoic acid, when added to statin therapy, reduces LDLc levels further. Bempedoic acid is an inhibitor of ATP citrate lyase, an important enzyme of cholesterol and fatty acid synthesis.

A group of 2300 patients with either established cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) were followed for about 12 months.  Baseline LDLc was 103 mg/dL.  Mean LDLc reduction with bempedoic acid was about 20 mg/dL.

These results are meaningful as it is well-established that the lower the LDLc the lower the ASCVD outcomes.  No increased adverse events were seen with the ATP Citrate lyase inhibitor compared to placebo.

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ACLY variants vs. cardiovascular outcomes

ATP citrate lyase is a key enzyme in cholesterol and fatty acid biosynthesis. It helps convert citrate to Acetyl CoA, the precursor to endogenous lipid genesis. Recent studies have shown that pharmacological inhibition of ATP citrate lyase causes a 30% reduction in LDLc, 50% reduction when combined with ezetimibe, and an extra 20% LDLc lowering when added to statin therapy.

This major Mendelian randomization study revealed that genetic variants in the ACLY gene led to similar clinical and biochemical outcomes as HMGCR variants. This provides a theoretical basis that medical inhibition of ATP citrate lyase could have similar cardiovascular benefits as statin therapies.

Mendelian randomization is considered nature’s randomized “clinical trial”. About 800,000 participants were included and analyzed.

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Addition of PCSK9 inhibitor Alirocumab further lowers CVD events.

In ODYSSEY trial, the addition of PCSK9 inhibitor, Alirocumab to high-intensity statin further reduced cardiovascular events by 15% in patients with very-high baseline CVD risk (prior ACS) and elevated atherogenic cholesterol particles. Atherogenicity was defined by LDLc ≥70 mg/dL, non-HDLc ≥100 mg/dL, or Apo B ≥80 mg/dL.

About 19,000 patients with acute coronary syndrome 1-12 months prior to study initiation were followed for 3 years. The study target was final LDLc between 25-50 mg/dL. Similar to FOURIER 2017 results, ODYSSEY 2018 adds more evidence to the notion “the lower the LDLc, the lower ASCVD events”

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