Triglyceride

Substantial Triglyceride Reduction With Plozasiran

Posted by

0


In patients with severely elevated triglyceride levels who are at risk for acute pancreatitis, the investigational drug plozasiran brought about substantial reductions in triglyceride levels in the phase 2 SHASTA-2 study. 

Most patients receiving plozasiran showed a fall in triglyceride levels to < 500 mg/dL threshold of acute pancreatitis risk. 

The safety profile of the drug was generally favorable, but it was associated with an increase in low-density lipoprotein cholesterol (LDL-C) and a transient decline in glycemic control in patients with diabetes in the study.

“Plozasiran produced significant reductions in triglyceride levels below the threshold associated with elevated risk for pancreatitis,” concluded lead investigator Daniel Gaudet, MD, PhD, professor of medicine at the University of Montreal, Canada. 

“These data support the initiation of pivotal studies of plozasiran for the treatment of severe hypertriglyceridemia,” he added. 

“Severe hypertriglyceridemia is a challenging condition for which few effective treatments are currently available,” Gaudet noted. “From the patients’ standpoint, the possibility that in the near future there could be an agent that safely and effectively lowers severely elevated triglyceride levels and reduces or eliminates the risk of developing pancreatitis is extraordinary.”

Gaudet presented the SHASTA-2 study on April 7 at the American College of Cardiology’s Annual Scientific Session, held in Atlanta, Georgia. The results were simultaneously published online in JAMA Cardiology. 

An estimated 1 in 5 US adults — and more than 2 in 5 of adults aged 60 years or older — have elevated triglycerides, defined as > 150 mg/dL, which contributes to coronary artery disease. Severe hypertriglyceridemia, defined as triglyceride levels > 500 mg/dL, can also cause pancreatitis.

Plozasiran is an investigational RNA interference therapeutic that targets the apolipoprotein C-III (ApoC-III) protein, which inhibits the liver’s ability to clear triglycerides out of the body. It works by reducing the production of ApoC-III, thereby enabling the liver to increase triglyceride clearance.

The SHASTA-2 trial included 229 patients with severe hypertriglyceridemia. Their average triglyceride level at baseline was 900 mg/dL. Most participants also had at least three of these risk factors: elevated risk for or history of cardiovascular disease, diabetes, low high-density lipoprotein cholesterol (HDL-C), and high body mass index. 

Patients were randomly assigned to one of four groups. Three groups received two injections of plozasiran at one of three doses (10 mg, 25 mg, or 50 mg); the fourth group received two injections of placebo. The first injection was given on day 1 and the second at week 12. 

The study’s primary endpoint was the change in fasting triglyceride levels from study entry to 24 weeks. This was reduced by 74% in plozasiran-treated patients compared with 17% in patients who received placebo. 

At 48 weeks, the average reduction was 58% in patients who received the highest doses of plozasiran compared with 7% for those on placebo.

The average reduction in ApoC-III was 78% for plozasiran-treated patients vs 1% for the placebo group at 24 weeks. At 48 weeks, ApoC-III levels were reduced by 48% on average among patients receiving the highest doses of plozasiran, whereas ApoC-III levels increased 4% in the placebo group.

At 24 weeks, over 90% of patients who received the higher doses (25 mg or 50 mg) of plozasiran saw their triglyceride levels fall to < 500 mg/dL. At 48 weeks, 77% of these patients still had triglyceride levels < 500 mg/dL. 

More than 50% of patients on higher doses achieved triglyceride levels of below 150 mg/dL (the normal range) at 24 weeks. 

“Significant and durable dose-dependent reductions in ApoC-III and triglycerides persisted through week 48, or 36 weeks after patients received their second dose of plozasiran,” Gaudet noted. 

In terms of other lipid parameters, dose-dependent and significant increases in HDL-C level were observed at week 24 with plozasiran, which remained significant to week 48. But the drug was also associated with dose-dependent increases in LDL-C level, which peaked after the second dose. In those receiving the highest dose (50 mg), the placebo-adjusted increase in LDL-C was 60%. LDL-C steadily declined after 24 weeks and was not significantly different from placebo values at week 48.

A phase 3 trial is now planned with the 25-mg dose.

Discussant of the study at the ACC late-breaking clinical trials session, Pradeep Natarajan, MD, MMSc, director of preventive cardiology at Massachusetts General Hospital, Boston, noted that Apo C-III loss of function mutations are associated with lowered triglycerides and reduced coronary artery disease risk without substantial changes in LDL-C levels, so he wondered why LDL-C was increased with plozasiran.

He also questioned why the drug was associated with an adverse effect on glycemic control. 

Gaudet replied that LDL-C increase may be expected as part of the mechanism of action of plozasiran but that could be treated with statins or PCSK9 inhibitors. 

He also suggested that the increases in LDL-C level may be offset by the attendant decreases in levels of triglycerides, remnant cholesterol and non–HDL-C, and the lack of increase in ApoB level seen with the drug.

On the glycemic status, Gaudet pointed out that ApoC-III has a deleterious effect on glycemic control, so ApoC-III inhibition should not cause a decline in glycemic control. “We do not see a long-term deleterious effect on glycemic control with this drug and carriers of the ApoC-III gene variants do not have problems with glycemic control,” he added. 

LDL-C Increase?

Discussing the SHASTA-2 study at an ACC press conference, Neha Pagidipati, MD, MPH, associate professor of medicine at the Duke Clinical Research Institute, Durham, North Carolina, said: ” When I look at the overall results of this study, obviously a 50% lowering of triglycerides at 48 weeks is certainly very exciting.”

But she expressed concern over the LDL-C increase, adding that understanding the mechanism of that and the potential implications will be very important.

“Going forward, this is a very exciting time for this patient population who have long been underserved and under treated and I look forward to seeing outcomes data and more safety data on this agent,” she concluded.

Pagidipati pointed out that plozasiran is one of two new agents for hypertriglyceridemia that were the subject of late-breaking clinical trials at the ACC meeting. 

The other agent, olezarsen, also targets the production of ApoC-III, but plozasiran is an RNA interfering molecule, whereas olezarsen is an antisense oligonucleotide.

She also noted that the patient populations were different in the two studies. Though all patients in SHASTA-2 had very elevated triglyceride levels, all > 500 dL/mg, in the olezarsen trial, only a small minority of patients had triglyceride levels that high, making them more of a high-risk moderate-hypertriglyceridemia population.

How to Lower Your Triglyceride Levels

Posted by

0


Having high triglyceride levels can increase your risk of heart disease. Limiting the amount of sugar, carbs, and trans fats you eat, along with regular exercise and other dietary changes, may help decrease your triglyceride levels.

Triglycerides are a type of fat found in your blood. After you eat, your body converts the calories that you don’t need into triglycerides and stores them in your fat cells to be used for energy later.

While triglycerides are an important energy supply for your body, having too many triglycerides in your blood can increase your risk of heart disease.

About 25.9% of adultsTrusted Source in the United States have elevated blood triglycerides, which is classified as having triglyceride levels over 150 mg/dL.

Having obesity or unmanaged diabetes, regularly drinking alcohol, and following a high calorie diet can all contribute to high blood triglyceride levels.

You can lower your triglyceride levels through various dietary and lifestyle changes.

Aim for a healthy-for-you weight

Whenever you eat more calories than your body needs, it turns those calories into triglycerides and stores them in fat cells.

Working toward a moderate body weight by consuming fewer excess calories can be an effective way to lower your blood triglyceride levels.

In fact, research has shownTrusted Source that losing even 5–10% of your body weight can significantly reduce your triglyceride levels.

Limit your sugar intake

While the American Heart Association recommends consuming no more than 100–150 calories of added sugar per day, one study found that the average American eats about 308 caloriesTrusted Source of added sugar daily.

Added sugar is commonly found in sweets, soft drinks, and fruit juice.

Extra sugar in your diet may be turned into triglycerides, which can lead to an increase in blood triglyceride levels, along with other heart disease risk factors.

A 2020 reviewTrusted Source that included data on 6,730 people found that those who consumed sugar-sweetened beverages regularly were over 50% more likely to have high triglycerides than those who did not.

Another study foundTrusted Source that consuming high amounts of added sugar is also associated with higher blood triglyceride levels in children.

Fortunately, several studies have shown that low carb diets can leadTrusted Source to a decrease in blood triglyceride levels.

Even a slight change, such as replacing sugar-sweetened beverages with water, could decrease triglycerides in some people.

Follow a lower-carb diet

Much like added sugar, extra calories from carbs in your diet are converted into triglycerides and stored in fat cells.

Not surprisingly, low carb diets have been linked to lower blood triglyceride levels.

A review of 12Trusted Source randomized controlled trials found that people following reduced carb diets typically saw a reduction in triglyceride levels at 6, 12, and 24 months.

Across these studies, triglyceride levels decreased the most 6 months after starting a reduced calorie diet.

A 2020 reviewTrusted Source compared low fat and low carb diets. Researchers found that 6–12 months after starting their relative diets, those on the low carb diet had greater decreases in triglyceride levels than those on a low fat diet.

Eat more fiber

Dietary fiber is found naturally in fruits, vegetables, and whole grains. It’s also found in many other plant sources, including nuts, seeds, cereals, and legumes.

Including more fiber in your diet can slow the absorption of fat and sugar in your small intestine, helping decrease your triglyceride levels.

According to one studyTrusted Source, including 117 adults with overweight or obesity, eating more dietary fiber was linked to lower triglyceride levels.

Another small study in adolescents found that consuming a high fiber cereal alongside a breakfast high in fat reduced post-meal triglyceride increasesTrusted Source by 50%.

Exercise regularly

When paired with weight loss, studies showTrusted Source that aerobic exercise is especially effective at decreasing triglycerides.

The American Heart Association recommendsTrusted Source getting at least 30 minutes of aerobic exercise 5 days per week through activities like walking, jogging, bicycling, and swimming.

The benefits of exercise on triglycerides are most apparent in long-term exercise regimens. One studyTrusted Source in people with heart disease showed that exercising for 45 minutes 5 times per week led to a significant decline in blood triglycerides.

All exercise helps reduce triglyceride levels. However, some researchTrusted Source has found that exercising at a higher intensity for a shorter amount of time is more effective than exercising at a moderate intensity for longer periods.

Limit trans fats

Artificial trans fats are added to processed foods to increase their shelf life.

Trans fats are commonly found in commercially fried foods and baked goods made with partially hydrogenated oils. They can also be found in small amounts in some animal products.

In recent years, the addition of trans fats to food has beenTrusted Source banned in the United States.

Due to their inflammatory properties, trans fats have beenTrusted Source attributed to many health problems, including increased LDL (“bad”) cholesterol levels and heart disease.

One review of 16 studies reported that replacing trans fats with polyunsaturated fats in the diet could help reduce triglyceride levels.

Aim to eat fatty fish twice weekly

Fatty fish is well known for its benefits on heart health and ability to lower blood triglycerides.

This is mostly due to its content of omega-3 fatty acids, a type of polyunsaturated fatty acid that is considered essential, meaning you need to get it through your diet.

Both the Dietary Guidelines for Americans and the American Heart Association recommendTrusted Source eating two servings of fatty fish per week to reduce the risk of heart disease and stroke.

One 2016 studyTrusted Source showed that eating salmon twice weekly significantly decreased blood triglyceride concentration.

Salmon, herring, sardines, tuna, and mackerel are a few types of fish that are especially high in omega-3 fatty acids.

Increase your intake of unsaturated fats

Studies showTrusted Source that monounsaturated and polyunsaturated fats can reduce blood triglyceride levels, especially when they’re replacing carbs in your diet.

Monounsaturated fats are found in foods like olive oil, nuts, and avocados. Polyunsaturated fats are present in vegetable oils and fatty fish, as well as nuts and seeds such as walnuts, flaxseeds, and chia seeds.

A 2019 reviewTrusted Source of 27 studies reported that while olive oil consumption does decrease triglyceride levels, it does so significantly less than other types of plant oil.

One older studyTrusted Source analyzed the diets of 452 adults in a specific population of Indigenous people in Alaska over the previous 24 hours.

It found that saturated fat intake was associated with increased blood triglycerides, while polyunsaturated fat intake was associated with lower triglyceride levels.

To maximize the triglyceride-lowering benefits of unsaturated fats, pick a heart-healthy fat like olive oil and use it to replace other types of fat in your diet, such as trans fats or highly processed vegetable oils.

Establish a regular meal pattern

Insulin resistance is another factor that can contribute to high blood triglycerides.

After you eat a meal, the cells in your pancreas send a signal to release insulin into the bloodstream. Insulin is then responsible for transporting sugar to your cells to be used for energy.

If you have too much insulin in your blood, your body can become resistant to it, making it difficult for your body to use insulin effectively. This can lead to a buildup of both sugar and triglycerides in the blood.

Setting a regular eating pattern can help prevent insulin resistance and high triglycerides. For instance, research showsTrusted Source that not eating breakfast can lead to decreased insulin sensitivity.

An American Heart Association statement suggestedTrusted Source that irregular eating patterns seemed less likely to achieve healthy cardiometabolic levels. They recommended intentional eating at regular times.

However, the evidence is mixed when it comes to meal frequency.

A 2013 studyTrusted Source demonstrated that eating three meals per day significantly decreased triglycerides compared with eating six meals per day.

However, multiple other studiesTrusted Source suggest that changes in meal frequency don’t significantly affect triglyceride concentration.

Regardless of how many meals you’re eating daily, eating regular meals can improve insulin sensitivity and lower blood triglyceride levels.

Limit alcohol intake

Alcoholic beverages are often high in sugar, carbs, and calories. If these calories remain unused, they can be converted into triglycerides and stored in fat cells.

Additionally, alcohol can increaseTrusted Source the synthesis of large, very low-density lipoproteins in the liver, which carry triglycerides into your system.

Although a variety of factors come into play, some studies showTrusted Source that moderate alcohol consumption can increase blood triglycerides by up to 53%, even if your triglyceride levels are normal to begin with.

That said, other research has linkedTrusted Source light to moderate alcohol consumption to a reduced risk of heart disease while linking binge drinking to an increased risk.

Add soy protein to your diet

Soy is rich in isoflavones, which are a type of plant compound with numerous health benefits. While widely known for its role in lowering LDL (“bad”) cholesterol, soy protein has been shownTrusted Source to reduce blood triglyceride levels.

One reviewTrusted Source of 46 studies found that regular consumption of soy protein was linked to significantly lower triglyceride levels in postmenopausal women.

Soy protein can be found in foods like soybeans (edamame), tofu, tempeh, and soy milk.

Eat more tree nuts

Tree nuts provide a concentrated dose of fiber, omega-3 fatty acids, and unsaturated fats, all of which work together to lower blood triglycerides.

One analysisTrusted Source of 61 studies showed that each daily serving of tree nuts decreased triglycerides by an average of 2.2 mg/dL (0.06 mmol/L).

Another reviewTrusted Source of 49 studies showed that eating tree nuts is associated with a modest decrease in blood triglycerides.

Tree nuts include:

  • almonds
  • pecans
  • walnuts
  • cashews
  • pistachios
  • Brazil nuts
  • macadamia nuts

However, keep in mind that nuts are high in calories. A single serving of almonds, or about 23 almonds, containsTrusted Source around 164 calories, so moderation is key.

Most studies have foundTrusted Source the greatest health benefits in individuals who consumed 3–7 servings of nuts per week.

Consult with a healthcare professional about natural supplements

Several natural supplements could have the potential to lower blood triglycerides. Always consult a doctor before starting any supplements, as they can interact with other medications.

Note especially that the Food and Drug Administration (FDA) does not regulate supplements in the same way as it regulates pharmaceuticals, and supplement quality can vary widely.

Below are a few of the main supplements that have been studied:

  • Fish oil: Well known for its potent effects on heart health, fish oil is rich in omega-3 fatty acids, which have been shownTrusted Source to decrease triglycerides and several other risk factors for heart disease.
  • Fenugreek: Though traditionally used to stimulate milk production, fenugreek seeds have also been shownTrusted Source to be effective at reducing blood triglycerides.
  • Vitamin D: Research has shown that vitamin D supplementation can helpTrusted Source reduce overall triglyceride levels.
  • Curcumin: One reviewTrusted Source of seven studies found that supplementing with curcumin could cause a significant drop in triglyceride and LDL (“bad”) cholesterol levels.

The bottom line

Dietary and lifestyle factors can have a major influence on your triglyceride levels.

Eating healthy, unsaturated fats instead of trans fats, decreasing your intake of carbs and added sugars, and exercising regularly are a few strategies that can help lower your blood triglycerides.

With a few lifestyle modifications, you can decrease your triglycerides and improve your overall health at the same time.

There’s no need to completely change your diet and lifestyle overnight. Try experimenting with a few of the tips listed above and gradually incorporating other strategies into your routine to make more long lasting, sustainable changes that are easier to stick to.

Air pollution exposure linked to heart disease risk factors

Posted by

0


Blood glucose levels, cholesterol and other risk factors for heart disease may be worsened with exposure to air pollution, especially among those with diabetes, according to study findings.

“While air pollution is linked with relatively small changes in cardiometabolic risk factors, the continuous nature of exposure and the number of people affected give us cause for concern,” Victor Novack, MD, PhD, of Soroka University Medical Center and Ben-Gurion University in Israel, said in a press release. “Even small changes in glucose levels and glycemic control can contribute to increased risk of cardiovascular disease.”

In the 10-year population-based retrospective cohort study, Novack and colleagues evaluated data from 73,117 adults living in southern Israel from 2003 to 2012 to determine the effects of both short- and intermediate-term exposure to particulate matter on serum glucose, HbA1c, triglyceride, HDL and LDL levels. Thirty-six percent of participants had diabetes.

Acute exposure to particulate matter less than 10 µm in diameter was not linked to glucose, triglyceride, or LDL or HDL levels. However, intermediate exposures (3 months) to particulate matter less than 10 µm in diameter and less than 2.5 µm in diameter were linked to increases in glucose (0.3% and 0.02%, respectively), LDL (2.32% and 1.42%, respectively) and triglyceride (0.23% and 0.37%, respectively) levels and decreases in HDL (1.13% and 1.3%, respectively).

Participants with diabetes had the strongest links between particulate matter and increases in HbA1c (3.58% for particulate matter < 10 µm in diameter and 2.93% for < 2.5 µm in diameter) and LDL (2.37% for particulate matter < 10 µm in diameter and 1.54% for < 2.5 µm in diameter).

“We found an association between air pollution exposure in the intermediate term and undesirable changes in cholesterol,” study researcher Maayan Yitshak Sade, MPH, also of Soroka University Medication Center and Ben-Gurion University, said in the release. “This suggests that cumulative exposure to air pollution over the course of a lifetime could lead to elevated risk of [CVD].” – by Amber Cox

Why a Lucky Few Can Eat to Their Heart’s Content.

Posted by

1


We all know people who seem to have been born with good genes—they may smoke, never exercise, or consume large amounts of bacon, yet they remain seemingly healthy. Now, researchers have found that individuals who carry a rare genetic mutation that controls the blood levels of certain fats, or lipids, are protected from heart disease. The result, reported here yesterday at the annual meeting of the American Society of Human Genetics, suggests that a drug mimicking this effect could prevent heart disease, a major killer.

Triglycerides are lipids that the body makes from unused calories in food and later burns as fuel. Doctors often monitor patients’ blood levels of these compounds because higher levels have been linked to a greater risk of heart disease.

One player in processing triglycerides is a protein called ApoC-III that is encoded by the gene APOC3. Five years ago, researchers discovered a mutation in APOC3 in 5% of the Amish population in Lancaster County, Pennsylvania. Those with this variant had unusually low levels of triglycerides after consuming a fat-laden milkshake. They also had only half as much ApoC-III protein in their blood, and they were less likely to develop calcification of coronary arteries, which can lead to coronary heart disease.

The Amish group was too small to allow researchers to directly link the genetic mutation to less heart disease, however. And it wasn’t clear whether the gene would show up in non-Amish people.

Now, researchers have found APOC3 mutations in the general U.S. population. They sequenced the protein-coding DNA, or exomes, of 3734 white and African-American volunteers, then combed through the data for genetic variants linked to triglyceride levels. A few people turned out to have either the Amish APOC3 mutation or one of three other variants in APOC3 that also disable this copy of the gene. When the team checked the DNA of a larger group of nearly 111,000 people, they found that about one in 200 carried one of the four APOC3 variants, reported Jacy Crosby of the University of Texas Health Science Center, Houston, who represented a large consortium called the National Heart, Lung, and Blood Institute Exome Sequencing Project.

The 500 or so people with one of these APOC3 variants not only had less ApoC-III in their blood and 38% lower triglyceride levels than the average person; they also had a 40% lower risk of coronary heart disease, whose effects include heart attacks. This result firms up the link between APOC3 and heart disease and also supports a possible prevention strategy, Crosby said: Reducing levels of the ApoC-III protein could potentially lower lipid levels and protect against heart disease. One such drug is already in clinical testing, she noted.

The new study “is exciting, but one has to be cautious” about whether such a drug will work, says geneticist Stephen Rich of the University of Virginia in Charlottesville. That’s because inhibiting ApoC-III late in life may not mimic being born with an APOC3 mutation, which protects for a lifetime, he says.