A Scientific Sessions symposium on Sunday, June 27, provided a platform for investigators to share new insights about the role of triglycerides in cardiovascular disease (CVD).
The Importance of Triglycerides Continues to Emerge can be viewed by registered meeting attendees at ADA2021.org through September 29, 2021. If you haven’t registered for the Virtual 81st Scientific Sessions, register today to access all of the valuable meeting content.
Brian A. Ference, MD, MPhil, MSc, FACC, FESC, Professor and Director of Research in Translational Therapeutics and Executive Director, Center for Naturally Randomized Trials, University of Cambridge, United Kingdom, discussed how triglycerides factor into the development of CVD and the potential for triglyceride-lowering therapies to reduce cardiovascular events.
The magnitude and length of exposure to apolipoprotein B (apoB)-containing lipoproteins such as low-density lipoprotein (LDL), triglyceride-rich very-low-density lipoprotein (VLDL), and their metabolic remnants determine CVD risk, Dr. Ference explained.
“The benefit of any lipid-lowering therapies should be proportionate to the absolute production in apoB-containing lipoproteins and the duration of treatment, not by the corresponding reduction in triglycerides or cholesterol, or both, carried by those particles as measured by plasma triglycerides, LDL cholesterol, or non-HDL (high-density lipoprotein) cholesterol,” he said.
About 90% of all circulating apoB-containing lipoproteins are LDL particles, making a potent LDL-lowering therapy the ideal first therapy for most patients, Dr. Ference said.
Lisa R. Tannock, MD, Professor of Internal Medicine, University of Kentucky, discussed the use of fibrates and omega-3 fatty acids other than icosapent ethyl in the treatment of hypertriglyceridemia for the prevention of cardiovascular events. The benefit of using fibrates in addition to statins to reduce such events is unclear, she said.
“Statins should still be the first line of therapy, but the addition of fibrates should be considered in some patients,” Dr. Tannock said. “I would argue that some of the lack of randomized controlled trial data to support this conclusion is driven by the fact that perhaps we didn’t study the right patient population.”
Patients who have higher triglycerides and lower HDL on statin therapy should be considered for additional lipid-lowering therapy to further reduce their risk of cardiovascular events, noted Dr. Tannock, who presented promising data on the benefits of omega-3 fatty acids.
“The wide range of formulations and doses that have been used in various trials does confound things, but it suggests that EPA (eicosapentaenoic acid) but not DHA (docosahexaenoic acid) drives improvement in cardiovascular events and that greater benefits may occur with higher doses of EPA,” she said.
However, REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl – Intervention Trial) and JELIS (Japan EPA Lipid Intervention Study) indicate that omega-3 fatty acid supplementation with EPA only reduces the rate of cardiovascular events by 25% compared to mineral oil placebo, said Jean-Claude Tardif, CM, MD, FRCPC, FCCS, FACC, FAHA, FESC, FCAHS, Director, Montreal Heart Institute, Canada Research Chair in Personalized Medicine, Endowed Research Chair in Atherosclerosis, and Professor of Medicine, University of Montreal.
Dr. Tardif provided an overview of newer drugs under investigation for the management of hypertriglyceridemia.
“Replication of the pharmacogenetic response to fenofibrate in a prospectively conducted randomized cardiovascular outcomes trial would lead to a precision medicine approach to prevention,” said Dr. Tardif, referring to a polymorphism in the peroxisome proliferator-activated receptor (PPAR)-alpha gene that appears to determine response to fenofibrate.
Permafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients With Diabetes (PROMINENT), a clinical trial of 10,000 participants with type 2 diabetes, aims to determine whether the selective PPAR-alpha modulator permafibrate can reduce the risk of ischemic cardiovascular events in patients with both high triglycerides and low HDL cholesterol values, he explained.
Other potential therapies are being examined in A Study of AKCEA-APOCIII-LRx Administered to Patients With Familial Chylomicronemia Syndrome (BALANCE) and A Dose-Ranging Study With Vupanorsen (TRANSLATE-TIMI 70). BALANCE, now in phase 3, is investigating apolipoprotein C-III inhibition with AKCEA-APOCIII-LRX antisense oligonucleotide (ASO) for the reduction of plasma triglycerides in patients with familial chylomicronemia syndrome. TRANSLATE phase 2b is testing the triglyceride-lowering effect of an angiopoietin-like 3 (ANGPTL3) blockade with a monoclonal antibody or an ASO.
Stephen G. Young, MD, Distinguished Professor of Medicine, Professor of Human Genetics, University of California, Los Angeles, discussed plasma triglyceride processing by the glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1)-lipoprotein lipase (LPL) complex. GPIHBP1 captures LPL secreted by parenchymal cells and transports it to the capillary lumen, where LPL is able to access and process triglyceride-rich lipoproteins in the circulation.
“In the clinic, GPIHBP1 missense mutations—that’s amino acid substitutions—cause chylomicronemia in human patients,” Dr. Young explained. “And those missense mutations are invariably located in GPIHBP1’s LU (Ly6/uPAR) domain. They cause chylomicronemia by abolishing the binding and transport of LPL to its site of action in the capillary lumen.”
Patients with chylomicronemia typically have triglyceride levels >1,000 mg/dL, and most have had acute pancreatitis, he said.