Women’s Health: Lipid Changes Over a Lifetime and Their Implications

Lipids, including LDL cholesterol, HDL cholesterol, and triglycerides, play pivotal roles in women’s health. Their levels fluctuate throughout life due to various factors, such as hormonal changes, lifestyle, and medical conditions.

Importance of the Heart Calcium Score

The Heart Calcium Score, also known as the Coronary Artery Calcium (CAC) Score, is an essential tool in modern heart health. It helps evaluate the presence and extent of calcified plaque in the coronary arteries, offering critical insights into a person’s risk of cardiovascular diseases.

BALANCE: Olezarsen for Familial Chylomicronemia Syndrome

Olezarsen is an investigational drug that tackles triglycerides by blocking the production of apolipoprotein C-III (apoC3). ApoC3 normally hinders the liver’s ability to remove triglycerides from the blood. By reducing apoC3, Olezarsen allows the liver to work more effectively, lowering triglyceride levels. This can significantly reduce the risk of pancreatitis, a dangerous condition caused by high triglyceride levels in the blood.

What is Insulin Resistance?

Insulin resistance is a condition in which the body’s cells become less responsive to the effects of insulin, a hormone produced by the beta cells in the pancreas. Insulin is central for regulating blood sugar (glucose) levels, facilitating the uptake of glucose by cells for energy.

Leqvio – 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.

Diabetes & Cardiovascular Disease

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death among patients with diabetes. Therefore, managing ASCVD risk is crucial in preventing the progression of atherosclerosis and reducing serious events like heart attacks and strokes in individuals with diabetes.

ORION: Gene Silencing, PCSK9 & LDL Cholesterol

Leqvio (Inclisiran) has received FDA approval as an additional therapy to diet and maximally tolerated statin medications for adults diagnosed with either heterozygous familial hypercholesterolemia (HeFH) or severe ASCVD who require further reduction of LDL cholesterol.

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.

GT

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.

GT

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.

GT