Triglycerides: A New Frontier in Detecting, Treating Disease
In recent years, researchers have been studying whether measuring triglycerides—tiny fat particles that support the structure of cells and metabolism—in low-density lipoprotein (LDL) cholesterol could improve risk predictions for cardiovascular disease and lead to new treatments.
Studying ways to improve predictions and treatments could potentially benefit one in four American adults who have elevated triglycerides and provide novel therapies for people with inherited metabolic disorders.
As a first step to exploring therapies to lower dangerously high triglyceride levels, Dr. Anna Wolska, a scientist in NHLBI’s Lipoprotein Metabolism Laboratory, developed a peptide, or tiny molecule, that could lower triglyceride levels in mice by more than 80% within a few hours.
“This peptide is unlike any molecule I’ve seen before,” said Dr. Matt Devalaraja, founder of Protean Bio. “If it behaves anything close to what it does in mice, we have a drug in here.”
With support from the NIH Small Business Innovation Research program, Devalaraja received a $2 million grant to launch studies to investigate how the peptide could treat acute pancreatitis, an inflammation of the pancreas that can result from high triglyceride levels.
In about four years, Devalaraja envisions the therapy will be ready to test in a small phase 2 study with patients. In the meantime, he and the researchers will continue to study the peptide in the lab and through a preliminary, phase 1 “proof-of-concept” study.
The hope is that people ultimately could take the therapy as an oral pill and see their triglyceride levels fall within hours. For instances when a person needs hospital care, this type of treatment could be life-saving.
Triglyceride levels also help physicians predict which patients with acute pancreatitis will experience multi-organ failure and require intensive care. For every 10 patients with severe acute pancreatitis, about four experience organ failure. Among these patients, about one dies. Due to extreme triglyceride levels, the pancreas starts to shut down and sets off a series of inflammatory responses.
“You just instantly make very high triglyceride levels, that are blocking the pancreatic vascular system, disappear,” Devalaraja said about the best outcome for the therapy. “Then the patient survives.”
Devalaraja explained that while basic scientific discoveries like these unite researchers, their real joy comes from thinking about how findings from the lab could be translated into therapies to help patients. Especially those, like people with severe acute pancreatitis, who have limited treatment options. While larger phase 3 trials for this treatment are still years away, the researchers remain optimistic about the peptide and molecules like it.
As a precursor to this research, Dr. Alan Remaley, an NHLBI senior investigator, and Wolska have been studying ways triglyceride levels could potentially improve cardiovascular disease risk predictions.
On July 25, at the American Association for Clinical Chemistry’s annual conference, Wolska received a distinguished abstract award for, and presented findings about, using a new equation that the team developed based on the standard lipid panel for estimating LDL triglyceride content.
“We aren’t at the end of the journey,” said Remaley. He explained false peaks or summits can often appear in research. “We can see the top of the mountain—we think.”
Faces Behind the Discovery
An “up and coming star,” according to Polish Cultural Institute New York, and one of the Polish Forbes’ Women “23 Women to Watch in 2023,” NHLBI’s Dr. Anna Wolska is making strides both within and outside the lab. Wolska is a staff scientist in the Lipoprotein Metabolism Laboratory run by NIH senior investigator Dr. Alan Remaley.
Wolska began research in lipoprotein metabolism as a student at the Medical University of Gdansk in Poland. There weren’t many opportunities to continue her research post-graduation, though, so she started emailing scientists she had cited in her Ph.D. thesis. One person she contacted in the U.S. was Remaley, but she didn’t realize she had emailed an NIH investigator until he replied.
“He responded right away,” Wolska recalled. “I was [so excited I was] jumping up and down in my apartment.”
She first came to Remaley’s lab as a volunteer funded by an International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) grant in 2014 and then stayed as a postdoc in 2015, progressing to a research fellow in 2020 and most recently a staff scientist as of 2021.
“I try to run my lab like a democracy,” Remaley said. “A lot of credit belongs to the [lab members] and I just help empower them.”
Through this system of freedom and support, Wolska developed a peptide that lowers triglyceride levels, as well as an equation that uses data from the standard lipid panel to calculate low-density lipoprotein (LDL) triglycerides.
LDL cholesterol is currently used to calculate atherosclerosis cardiovascular disease risk, but Wolska’s research found that LDL triglyceride levels might be more accurate predictors.
Fifty-plus years of eminent NIH investigators associated with the lipoprotein metabolism lab have made these discoveries possible. “This research is multigenerational,” Remaley said, beginning in the 1950s (at what was known then as the National Heart Institute) with Dr. Donald Fredrickson, who would later serve as NHLBI scientific director and ultimately NIH director. Scientist Emeritus Dr. Edward Korn, another former NHLBI scientific director, discovered lipoprotein lipase, the key enzyme that hydrolyzes triglycerides.
“One day, I’ll pass the baton to [Wolska] or someone else,” Remaley said, adding that basic science works because many generations of scientists continue to improve upon their predecessors’ knowledge.
“It’s just incredible what we can do here,” Wolska added. “[NIH] really is the best place to do research.”