Pegozafermin: An “Entriguing” New Therapy for High Triglycerides

In contrast to high levels of low-density lipoprotein cholesterol (LDL-C), where reduction invariably results in clinical benefit (irrespective of the therapy/therapies used), the impact of lowering elevated triglyceride (HTG) levels has been the proverbial “tough nut to crack”. This is largely reflective of TGs status as a biomarker of CVD risk rather than directly causative in the process.  Hence, the LDL mantra “lower is better” does not apply to TG, as recently demonstrated in PROMINENT (and other studies).  Rather, successful TG lowering treatments must effectively combat the proinflammatory, prothrombotic and pro-oxidative stress associated with the HTG state, as exemplified by icosapent ethyl (IPE) in REDUCE-IT.

Now, a new study offers considerable promise in treating another adverse consequence of HTG, non-alcoholic fatty liver disease (NAFLD); this condition affects 1 in 4 adults worldwide and is projected to increase to 1 in 3 adults by 2030 owing to the continued rise in obesity, Type 2 diabetes and the Metabolic Syndrome.  In addition to increased CVD, complications of NAFLD include nonalcoholic steatohepatitis, cirrhosis and liver cancer.  While lifestyle therapies resulting in weight reduction of 10% and greater reduce liver fat, no drugs have been approved by the FDA for NAFLD (see the recent American Heart Association Statement led by my colleague, Dr. Bart Duell).  

The new study entitled “ENTRIGUE”, examined pegozafermin, an analog of human fibroblast growth factor 21 (FGF21) that upon chemical modification (glycopegylation), permits a longer half-life to suppress de novo lipogenesis and to upregulate fatty acid oxidation, thereby reducing atherogenic lipids/lipoproteins/apolipoproteins.  Specifically, among volunteers with severe HTG (500-2,000 mg/dL), weekly (or twice monthly) subcutaneous injections effectively lowered TG (median reduction, 44% compared to placebo) over the 8-week study period; ~80% reduced TG levels to less than 500 mg/dL.  Impressively, there was significant reduction in liver fat as quantified by the MRI protein density fat fraction (Figure), with nearly 1 in 4 subjects normalizing their liver fat content during this short timeframe.  Equally important was that pegozafermin was well tolerated and no major adverse safety signals were observed.

Make sure to check out this paper published online in Nature Medicine and led by my academic colleagues Dr. Deepak Bhatt and lipid luminaries, Drs. Harold Bays and John Kastelein.  I suspect that we will be hearing more about this exciting FGF21 analog in the not-too-distant future.

Michael Miller, MD is a cardiologist and Chief of Medicine at the Corporal Michael J Crescenz VA Medical Center and Professor of Medicine at the Hospital of the University of Pennsylvania. Dr. Miller is Scientific Advisor to Amarin, Inc and 89bio. Prior to his arrival in Philadelphia, he was Professor of Cardiovascular Medicine, Epidemiology and Public Health at the University of Maryland School of Medicine. He is the author of numerous scientific publications and several books, including Heal Your Heart published by Penguin Random House. Check him out on twitter: @mmillermd1

Nutrition & Dietary Approaches to Prevent/Treat Cardiovascular Disease

This past week, I was delighted to receive my copy of “Prevention and Treatment of Cardiovascular Disease: Nutritional and Dietary Approaches” an important new book edited by my colleagues Drs. Michael Wilkinson, Michael Garshick and Pam Taub that focuses on lifestyle strategies for optimizing cardiovascular health.

There are numerous excellent contributions encompassing plant-based, Mediterranean and other popular diets, intermittent fasting/restrictive feeding, dietary recommendations for diabetes, metabolic syndrome, heart failure, atrial fibrillation and many other cardiovascular/inflammatory disorders.

Our contribution entitled, “Lifestyle Approaches to Lowering Triglycerides” was led by Dr. Stephen Hankinson (former University of Maryland medicine resident, currently affiliated with Brigham & Women’s Hospital).

Listed below are some of the numerous “pearls” throughout the book. It is a superb resource for anyone interested in evidence-based medicine as it relates to nutrition and cardiovascular risk reduction.

1. Overwhelmingly, consumption of whole foods enriched in dietary macronutrients have a more pronounced benefit on heart disease risk factors (such as high blood pressure/ cholesterol) than dietary supplements, for whom minimal if any such evidence exists.
2. Inadequate intake of selenium is associated with adverse effects on the cardiovascular system including oxidative stress and inflammation. Excellent sources of selenium include Brazil nuts, oysters and yellowfin tuna.
3. Low levels of magnesium may increase aortic valve calcification (due to buildup of calcium within cardiac and smooth muscle cells). Make sure to include green leafy vegetables, legumes, seeds and whole grains in your diet to maintain healthy magnesium levels.
4. A review of 50 studies evaluating more than 500,000 men and women found that adherence to a Mediterranean diet correlated with a 31% reduced risk of developing the Metabolic Syndrome over a 6-year period.
5. The DASH (Dietary Approaches to Stop Hypertension) is among the most effective non-pharmacologic treatment for high blood pressure with average reductions in systolic pressure (~11 mmHg) and similar to that observed with a single blood pressure medicine.
6. When controlled for total caloric intake, a ketogenic diet does not result in greater weight loss than other diets.
7. In the REGARDS (REasons for Geographic And Racial Differences in Stroke) study, a primary plant based diet (vegetables, fruits, beans, fish) was associated with a 41% lower likelihood of developing heart failure over an approximate 9 year follow-up period.
8. In contrast to popular belief, corn oil has a more profound effect on lowering LDL levels than olive oil (11% vs 4%).
9. A mildly caloric restrictive diet (12% reduction in daily calories) was associated with significant weight loss (average, 16.5 lbs) as well as improvement in cholesterol, blood pressure, insulin sensitivity and inflammation over a 2-year period.
10. Time restrictive eating (6-10 hour window of eating followed by a 14-18 hour fast) reduces risk of cardiometabolic diseases by promoting weight loss and improving sleep.
11. In women with early-stage breast cancer, overnight fasting of 13 (or more) hours was associated with an improved cancer prognosis, longer sleep duration and better glycemic control.
12. In men and women with Metabolic Syndrome, 12-weeks of time restrictive eating (10 hour feeding window) resulted in significant reductions in waist circumference, blood pressure and LDL cholesterol.
13. In more than 1100 men and women with psoriasis, dietary intervention that included a structured exercise program to promote weight loss resulted in a 75% improvement in psoriatic skin lesion severity.
14. In obese men and women with a history of atrial fibrillation, 10% weight loss resulted in a 46% likelihood of sustained normal (sinus) rhythm without medication over ~5 years of follow-up.

Dr. Michael Miller is Professor of Cardiovascular Medicine at the University of Maryland School of Medicine in Baltimore, Maryland and author of multiple books and book chapters related to heart disease prevention and treatment.

Got High Triglycerides? Check out our New Decision Pathway from the American College of Cardiology

For decades, triglycerides (TGs) took the proverbial back seat in the lipid/lipoprotein hierarchy.  In recent years, however, TGs have gained increasing traction as a bonafide and independent biomarker of cardiovascular risk based on a series of well conducted epidemiologic and genetic (Mendelian randomization) studies.

Earlier this month, the American College of Cardiology released a new document that systematically outlines a series of decision trees that clinicians and health care professionals might consider when treating patients with elevated TG levels.  It was a great privilege to work with colleagues and “lipid luminaries” in an highly engaging effort spearheaded by Drs. Salim Virani and Pam Morris.

Listed below are some of the highlights of the document that can be accessed by clicking here.

1. Lifestyle interventions should be initiated in adults with fasting triglyceride levels of 150 mg/dL or non-fasting triglycerides of 175 mg/dL or higher.
2. Among lifestyle recommendations for treating high triglycerides, weight loss is among the most robust (10-20% reductions on average) with up to 70% reductions potentially achievable.
3. Dietary recommendations to lower elevated triglyceride levels include switching from a low-fat, high carbohydrate diet to a higher-fat (predominantly mono/polyunsaturated) and low-carb diet (30-40% of calories).
4. In men and women with the metabolic syndrome, a high protein/weight loss diet (greater than 25% of energy intake/500 calorie per day deficit) is associated with ~35% reduction in triglycerides.
5. Physical activity and exercise may contribute up to a 30% reduction in triglyceride with both resistance training and aerobic activity contributing to these effects.
6. Excess alcohol consumption, especially with pre-existing high triglyceride levels can precipitate pancreatitis.

Dr. Michael Miller is Professor of Cardiovascular Medicine at the University of Maryland School of Medicine in Baltimore, Maryland. 

Lift Weights to Lose Weight

 

A new study shows that lifting weights/resistance training 2 or more days a week for as little as 30 minutes per session is associated with or a 20-30% lower risk of developing obesity over a 6 year period. In addition to traditional weight machines and free weights, muscle strengthening/tone activities include full body squats, pushups, planks and other core exercises.

This study adds to the growing evidence that muscle toning exercises are cardioprotective.  Among the first studies to demonstrate heart protection was the “Harvard Health Professionals’ Follow-Up Study, which found that weight training for at least 30 minutes each week resulted in a 23% lower risk of a heart attack or death from heart disease”**

Shown below are several other reasons why weight/resistance training aimed at muscle toning should be part of your overall physical fitness prescription to improve cardiometabolic health by reducing the following:

1. Type 2 diabetes: A study of nearly 4700 adults found that moderate weight training that resulted in increases in muscle mass (assessed by bench and leg press) reduced the risk of developing Type 2 diabetes by 32% over an 8-year period.
2. Conversion from Pre-diabetes to Type 2 diabetes: Another study of men and women with prediabetes (fasting glucose between 100-125 mg/dL) found resistance training (1 hour thrice weekly) to reduce conversion to Type 2 diabetes by 65%!
3. High Cholesterol: A Study of more than 7300 men found that ~1 hour of resistance training per week was associated with a 32% lower risk of high cholesterol (equal to or greater than 240 mg/dL) over ~20 years of followup.
4. Quitting Smoking: A study funded by the National Cancer Institute found that men and women who engaged in two 1-hour sessions of resistance training over a 12-week smoking cessation program were 2x as likely to successfully quit than their non- weight lifting counterparts.

Dr. Michael Miller is Director, Center for Preventive Cardiology at the University of Maryland Medical Center in Baltimore.

**from “Heal Your Heart: The Positive Emotions Prescription to Prevent and Reverse Heart Disease”