Light at the End of Tunnel

A new pharmacological agent olezarsen working through a complex process involving messenger RNA leading to markedly reduced production of the protein apolipoprotein C-III [APOC3] which produces triglycerides from the liver; this has rekindled the hope of reducing the vascular events and associated problems in patients with high triglycerides. The drug which has completed pre-clinical trials (Phase 3) has been given expedited permission to go ahead in for clinical use for preventing acute pancreatitis in patients with familial severe hyper-triglyceridemias. This has rekindled the hope for getting a magic bullet which would go beyond producing just a cosmetic benefit of reducing the levels without any clinical benefit.

Can We Do Without Triglycerides?

Triglycerides are a type of fat (Lipid) found in our blood. When we eat, the body converts the calories right away into triglycerides. These are stored in the fat cells as ready form of energy as in camel’s hump.  When required these triglycerides are released for energy. They are important for life and are the main form of consumable fats. However, excess is bad.

A common cause of high triglycerides in blood is eating more calories than are needed to provide energy. This is also called hypertriglyceridemia. It is a common finding with its prevalence being at least 25% of our population of India. The data from the study from Gauri Kaul Foundation showed it to be present in more than 33% subjects evaluated in our camps across the valley.

Normal and Abnormal Ranges of Triglycerides

Normal is less than 150 mgs/dl, Borderline high 150 to 199 mgs/dl, High 200 to 499 mgs/dl and Very High more than 500 mgs/ dl.

The levels must be checked after an overnight fast. Fat from a recent meal can fallaciously increase the reading.

Common causes of High triglycerides

Overeating foods high in fat and carbohydrates, increased body weight and obesity, lack of exercise, some genetic disorders affecting breakdown of lipids, tobacco use, frequent alcohol intake, uncontrolled diabetes, Hypo- thyroidism, liver and kidney diseases, Certain drugs needed to treat HIV, breast cancer and steroids etc.

Health Problems due to High Triglycerides

Very high triglycerides (> 500mgs/dl) can cause a serious and potentially fatal condition called acute pancreatitis. It needs prompt attention and drug therapy along with general measures to prevent these serious complications.

Patients with high triglycerides (> 150 mgs/lit) are at risk of vascular events like angina and heart attacks when they have associated issues. “Triglycerides become hazardous when they are in a bad company”. They become deleterious if accompanied with;

1. low HDL cholesterol (levels < 40mgs/dl in men and > 50mgs/dl in women),
2. obesity especially truncal or abdominal (waist measurement more than 90 cm’s in males and more than 80 cm’s in women.
3. presence of diabetes mellitus 4. presence of high LDL cholesterol (more than 100 mgs/dl) and 5. blood pressure more than 140/90 mms Hg.

Best way to reduce Triglycerides is adopting a healthy life style

1. Regular Exercise, aim for at least 30 minutes on most days, in terms of steps 8000 or more steps/day. It lowers triglycerides and increases HDL cholesterol. Climb stairs, take longer route to go for work or shopping. cycling uphill is also a good way.
2. Avoid sugars and refined carbohydrates. Sugars, cakes, products made of refined flour, bakery products, Chot, girda the staple Kashmiri bread served with breakfast and tea. These all are rich sources to increase triglycerides in blood.
3. Lose weight by cutting on calories.

4.Choose Healthier Fats. Fats are essential but those obtained from plant sources like olive, mustard, canola, sesame, sunflower, peanut oils. Oils however should not be burnt to carbon while cooking

5. Fish and poultry instead of red meat.
6. Avoid trans fats. Like cooking in vanaspati ghee (hydrogenated oils), using pre-cooked tinned foods, use of creamers etc.
7. Desi Ghee or clarified butter provides some health benefits but it is important to realize that it contains saturated fats, an excess of which increases the cholesterol levels and increase the risk of heart disease if taken more than 2 to 3 spoons.
8. Alcohol in any form is unsafe for health as per the 2023 guidelines from WHO
9. Don’t Skip meals. Starving is not a solution because it leads to over eating at the next meal invariably making the triglyceride levels jump. Food items like plenty of fruits, salads, nuts, carrots should be kept around but not biscuits and bakery products to extinguish the hunger pangs.

Do we have a magic drug to reduce triglycerides?

This is an area of intense research for the last several decades. A number of drugs have undergone very credible scientific trials to see if the levels reduced towards normal i.e., < 150 mgs/dl led to improvement in outcomes like heart attacks and other related illnesses. Several drugs which include, Niacin, Fibrates (Gemfibrozil, Bezafibrate and Fenofibrate etc), fish oils and synthetic high dose omega 3 fatty acids and vitamin E etc have been used extensively without any proof of benefit. Likewise, agents like Saroglitazar (Lipaglyn and Bilypsa) have no outcomes data indicating their usefulness and no trial to this effect is going on. The reduction in levels is therefore of only cosmetic value.

What about fish oils and omega 3 fatty acids?

These agents traditionally have been considered to be safe modality to reduce triglycerides. This concept was suddenly hyped by a recent placebo-controlled trial of 2019 (REDUCE IT) showing a significant benefit in the patients consuming a very high dose of 4 gm of icosapent ethyl twice per day. The study showed a significant benefit in the patients on very high dose of omega 3 fatty acids. This led to a short-lasting boom in its use. It was however soon realised that the benefit was because of higher events in the placebo group which had a mineral oil which was producing a hazardous effect of increasing the LDL cholesterol. This finding was not duplicated in a study following it where omega 3 fatty acid with statins “STRENGTH” where the placebo had corn oil and statins. Thus, the study has punctured the enthusiasm shown by REDUCE IT. Omega 3 acids also have failed to improve the desired outcomes and only do a cosmetic reduction in levels.

End of fibrates?

In a recent large trial “PROMINENT” a very potent fibrate (Pemafibrate) vs placebo was used in a population with high Triglycerides and low HDL with a high percentage of diabetics. They were all on high doses of statins. In this typical population which we also see in our valley Pemafibrate despite a 26 % reduction in triglycerides and 5% increase in HDLc, did not improve the outcomes (heart attack, stroke, death) at all.

So how do we handle high triglycerides in 2024

Weight reduction, correcting secondary causes like obesity, hypo-thyroidism, diabetes and stopping alcohol. Population at high risk need to keep LDL cholesterol very low (< 55 mgs dl) by using appropriate doses of statins with or without ezetimibe. Patients with more than 500 mgs/dl need fibrates (fenofibrates) to prevent pancreatitis. However, current therapies for severely elevated levels of triglycerides are ineffective, with a continuing risk of life-threatening acute pancreatitis, a gap that will probably be closed by olezarsen, which has recently been granted fast-track designation by the Food and Drug Administration in USA for the treatment of the familial chylomicronemia syndrome with levels > 1000-2000 mgs/dl in spite of all current measures. Ongoing clinical trials would tell us the role of olezarsen in patients with moderate elevation (150 to 500 mgs/dl) who have risk factors for getting heart attacks with low levels of LDL cholesterol. If positive we will have an injection once in a month which will be safe and efficacious. Amen

Prof Upendra Kaul , Founder Director Gauri Kaul Foundation, Dean Academics and Research Batra Hospital and Medical Research Centre