Potential changes in the cardiometabolic risk reduction landscape
Researchers in four trials presented their findings during Monday’s Late-Breaking Science session, “New Frontiers in Cardiometabolic Risk Reduction.” They found:
- A novel ANGPTL-4 MAb reduced triglycerides by over 50%.
- Orforglipron, an oral GLP-1RA, significantly reduced OSA severity regardless of PAP use.
- Single dose of phase 1 gene therapy reduced serum triglycerides.
- Novel GLP-1 + glucagon RA did not increase cardiovascular risks vs. placebo.
Novel ANGPTL-4 MAb reduced triglycerides by over 50%
A first-in-class monoclonal antibody against angiopoietin-like protein 4 (ANGPTL4) showed a dose-dependent reduction of fasting triglycerides of more than 50% in a phase 2b trial over 12 weeks. Three doses of MAR001, 300 mg, 450 mg and 900 mg, reduced fasting triglycerides by 39.1%, 40.9% and 45.5%, respectively, across the entire trial population of individuals with elevated fasting triglycerides. In a subset of participants with fasting triglycerides ≥300 ml/dL, MAR001 reduced fasting triglycerides by 52.8%, 53.7% and 57.2% (p<0.001 for all).
ANGPTL4 inhibits lipoprotein lipase, a key step in the metabolism of triglyceride-rich lipoproteins. Blocking ANGPTL4 upregulates lipoprotein lipase activity, boosting the metabolism of lipoproteins rich in triglycerides and reducing fasting triglyceride levels.
Michelle O’Donoghue, MD, MPH
“At week 12, we observed a dose-dependent reduction in fasting triglyceride concentrations with MAR001 compared to placebo,” said principal investigator Michelle O’Donoghue, MD, MPH, McGillycuddy-Logue Endowed Chair in cardiology at Brigham and Women’s Hospital, associate professor of medicine at Harvard University in Boston and senior investigator for the TIMI Study Group. “Those effects were maintained through to week 24 as well. Notably, there were no safety concerns. We didn’t see any increase in adverse events, no liver function test abnormalities and no adverse effects on any measures of hyperglycemia.”
O’Donoghue noted that some approaches leading to similar changes in lipoprotein lipase activity have also shown adverse effects on some markers of hyperglycemia. These adverse hyperglycemia-related effects were not seen with MAR0001.
TYDAL-TIMI 78 is a two-part phase 2b double-blind randomized controlled trial comparing MAR001 vs. placebo in 235 participants with fasting triglycerides ≥150 mg/dL and remnant fasting cholesterol (RC) ≥30 mg/dL. The median baseline triglyceride concentration was 249.5 mg/dL.
In addition to the reductions in fasting triglycerides, placebo-adjusted changes in RC were -37.3%, -39.1% and -40.8% for the 300 mg, 450 mg and 900 mg dose arms (p<0.001 for all) across the entire study population.
“Triglyceride reductions appeared to be even more pronounced in individuals with higher baseline triglyceride concentrations,” O’Donoghue said. “There is biologic rationale for that. It is also why MAR0001 is going to be explicitly studied now in a population with severe hypertriglyceridemia. This is a novel therapeutic target, and it is encouraging to see a marked reduction in triglycerides with a signal toward greater efficacy in those with higher baseline triglycerides who are at higher risk for complications like pancreatitis. Thus far, we haven’t seen any adverse effects, and it appears to have a favorable tolerability profile.”
The trial was published simultaneously in the New England Journal of Medicine.
Early gene therapy trial in hypertriglyceridemia showed major reduction in serum triglyceride levels
The results for an in vivo CRISPR-Cas9 gene editing targeting hepatic angiopoietin-like protein 3 (ANGPTL3) in individuals with severe hypertriglyceridemia showed a 62.8% drop in serum triglycerides at 30 days. There were no serious treatment-related adverse events and no changes in liver function.
Ashish Sarraju, MD, FACC, FASPC
“Safety was reassuring,” said Ashish Sarraju, MD, FACC, FASPC, director of the Inherited Lipid Disorders Center and director of research in preventive cardiology at the Cleveland Clinic’s Miller Family Heart, Vascular & Thoracic Institute in Ohio. “It was well-tolerated, and the triglyceride reduction was encouraging, about 63% in a group that started off at a very high baseline median level of over 1000 mg/dL. This forms the basis for studying this approach in larger trials for severe hypertriglyceridemia.”
CTX310 is an infused lipid nanoparticle that delivers CRISPR-Cas9 gene editing therapy targeting ANGPTL3, a key regulator of hepatic lipid metabolism. The therapy reduced the ANGPTL3 gene in a manner that mimics naturally occurring variants associated with lower levels of serum triglycerides, low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (ApoB) while reducing free fatty acid flux to the liver. This analysis looked specifically at effects of CTX on ANGPTL3, triglycerides, LDL-C, ApoB, non-high density lipoprotein (HDL) cholesterol, triglyceride-rich lipoprotein cholesterol.
The multicenter trial recruited 10 individuals with median baseline triglycerides of 1,067.7 mg/dL and 20.2% hepatic fat fraction. The mean age of participants was 56.5 years; 60% were males, and all had type 2 diabetes.
All individuals received a single infusion of CTX310 based on body weight. Primary efficacy endpoints included percent changes over time for ANGPTL3, triglycerides, triglyceride-rich lipoprotein cholesterol, non-HDL cholesterol, LDL-C and Apo B. Primary safety endpoints included adverse events and changes in liver function testing.
At 30 days, ANGPTL3 declined by a mean of 65.3% and serum triglycerides fell by a mean of 62.8%. Triglycerides dropped sharply in the first two weeks after infusion and generally remained flat over the next 30 days. The only serious adverse event was hospitalization for acute-on-chronic left shoulder pain and full-thickness supraspinatus tendon tear (rotator cuff injury). There were no serious adverse events deemed related to CTX310, and the only infusion-related reaction was grade 2 low back pain in an individual already taking acetaminophen for back pain. There were no allergic or localized reactions to the infusion and no elevation in liver function testing.
“We are still very early in the drug development process for gene editing therapy,” Sarraju said. “The data so far are promising in terms of safety and efficacy, but they are still at an early stage. The next larger phase trials are being planned to assess safety and efficacy in larger populations. These data represent a new frontier for drug development for severe hypertriglyceridemia.”
First positive ATTAIN-OSA results for oral GLP-1RA
Orforglipron, an oral glucagon-like peptide-1(GLP-1) receptor agonist (RA), showed significant reductions in sleep apnea severity in adults with moderate-to-severe obstructive sleep apnea (OSA) who did not have diabetes, regardless of whether they routinely used a positive airway pressure (PAP) device. The drug reduced apnea-hypopnea index (AHI) by >17 respiratory events/hour and hypoxic burden by >70% from baseline. Orforglipron, approved for weight loss management in the United States earlier in 2026, is the first oral GLP-1RA to show positive results in OSA. An injectable GLP-1RA was approved for OSA in 2024.
Vaishnavi Kundel, MD, MS
“We have tirzepatide, an injectable dual GLP-1 and GLP-1RA, so the results for orforglipron are exciting, as it is one of the first oral pharmacologic agents investigated for patients with OSA and overweight or obesity, without diabetes. If approved, it will expand the OSA treatment landscape,” said Vaishnavi Kundel, MD, MS, associate professor of pulmonary, critical care and sleep medicine at the Icahn School of Medicine at Mount Sinai in New York City.
“In addition to reduction in AHI, we saw a significant reduction in hypoxic burden, a newer metric that has been more strongly linked to cardiovascular risk in sleep apnea. There were also reductions concurrently in C-reactive protein, body weight and blood pressure. If approved for sleep apnea, orforglipron would provide an oral pharmacologic therapy and could potentially be used alone or in combination with other therapies, such as CPAP (continuous positive airway pressure],” she said.
ATTAIN-OSA randomized two global cohorts of adults with moderate-to-severe OSA and body mass index ≥27 kg/m2, without diabetes, to the maximum tolerated dose of orforglipron, 12 mg, 24 mg or 36 mg, or placebo. Study 1 participants (363 individuals) were not on PAP therapy; Study 2 participants (349 individuals) were current PAP users who intended to continue treatment. The primary endpoint was change in AHI from baseline to week 52. Secondary endpoints included change in hypoxic burden, patient-reported outcomes, body weight, high-sensitivity C-reactive protein (hsCRP) and systolic blood pressure.
At 52 weeks, there was a significant reduction in AHI events/hour for orforglipron vs. placebo: Study 1: -17.8% vs. -4.5%; Study 2: -17.3% vs. -5.3%; p<0.001 for both. Sleep apnea-specific hypoxic burden showed even sharper declines: Study 1: -71.8% vs. -25.8%; Study 2: -72.0% vs. -28.9%; p<0.001 for both. Participants taking orforglipron also showed significant improvements in other OSA measures, body weight and hsCRP vs. placebo. Systolic blood pressure changes were -7.5 mmHg with orforglipron vs. -1.7 mmHg with placebo (Study 1) and -7.0 mmHg vs. -2.2 mmHg (Study 2), respectively.
The most frequently reported adverse events with orforglipron were gastrointestinal-related. The overall safety profile was consistent with orforglipron’s known safety profile.
“A lot of clinicians are already using tirzepatide for the management of patients with moderate-to-severe sleep apnea and overweight or obesity,” Kundel said. “This trial provides promising evidence for the potential use of orforglipron as an oral GLP-1 option for moderate-to-severe OSA.
ATTAIN-OSA was published simultaneously in the Journal of the American Medical Association.
No increased cardiovascular risk with dual GLP-1RA + glucagon RA in people with overweight and obesity
New phase 3 results demonstrated no increased cardiovascular risk with survodutide, a dual-acting GLP-1 receptor agonist (RA) plus glucagon RA compared to placebo. SYNCHRONIZE-CVOT assessed a five-component cardiovascular outcome in a broad population of individuals living with overweight or obesity with or without diabetes. The investigational agent showed noninferiority vs. placebo in both modified intent-to-treat and on-treatment analyses. There were more gastrointestinal adverse events with survodutide vs. placebo, and the overall safety profile was consistent with existing GLP-1RAs.
Biykem Bozkurt, MD, PhD, FAHA
“This new drug class demonstrated cardiovascular safety while showing substantial effects on several interconnected metabolic abnormalities that contribute to cardiovascular disease,” said Biykem Bozkurt, MD, PhD, FAHA, Mary and Gordon Cain Chair in the Winters Center for Heart Failure Research, and senior dean of faculty at Baylor College of Medicine in Houston, Texas. “The broader SYNCHRONIZE clinical development program has demonstrated substantial improvements in body weight, body composition, visceral adiposity, liver fat and metabolic disease. SYNCHRONIZE-CVOT adds a critical dimension by providing evidence of cardiovascular safety with this novel dual receptor agonist.”
GLP-1RAs have transformed the management of obesity, type 2 diabetes and cardiovascular disease. However, despite these advances, patients continue to face significant residual cardiovascular risk, underscoring the need for additional therapeutic strategies, Bozkurt said. Adding glucagon RA may target complementary metabolic pathways to reduce visceral fat, cardiac fibrosis and epicardial fat, improve kidney function, improve liver fat metabolism, increase energy expenditure and reduce fibrosis.
The global trial randomized and treated a total of 5,507 participants across 524 centers in 34 countries to either once-weekly 3.6 mg or 6.0 mg subcutaneous survodutide or placebo. All participants had a body mass index (BMI) ≥27 and established cardiovascular disease and/or at least two weight-related complications or risk factors for cardiovascular disease or BMI ≥30 with established cardiovascular disease or chronic kidney disease or ≥2 established risk factors for cardiovascular risk. The mean age of participants was 60.8 years, and 39.8% were female. Across all sites, about 79% self-identified as white, 12% as Hispanic, 6% as Black and 12% as Asian.
The primary endpoint was time to first occurrence of a five-point major adverse cardiovascular event (MACE) composite or any of the component events: cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, ischemia-related coronary revascularization or ischemic heart failure event. Major secondary endpoints included time to occurrence of a three-point MACE including cardiovascular death, nonfatal stroke or nonfatal myocardial infarction, or any of the events and adverse events.
Survodutide demonstrated noninferiority for the five-point MACE vs. placebo with HR 0.89 (95% CI: [0.67, 1.18]) in a modified intent-to-treat analysis and HR 0.75 (95% CI: [0.53, 1.06]) by on-treatment analysis, p<0.0001 for both. The three-point MACE also showed noninferiority vs. placebo, HR 0.84 (95% CI: [0.60, 1.18], p<0.0001) and HR 0.76 (95% CI: [0.51, 1.116]) for modified intent-to-treat and on-treatment analyses respectively.
GI events were more frequent with survodutide vs. placebo, including discontinuation due to GI adverse events, 20.0% and 1.9%, respectively. These adverse events are important considerations for tolerability, dose escalation and long-term maintenance of therapy, Bozkurt noted. There were no unexpected safety concerns.
“As additional evidence becomes available, glucagon receptor and GLP-1 receptor dual agonists may expand our therapeutic options for patients, especially with visceral adiposity and associated cardiometabolic conditions,” Bozkurt said. “The broader message for clinical practice is that obesity treatment and cardiovascular prevention are increasingly interconnected. Our goal should be to address the underlying metabolic drivers of disease while demonstrating that our therapies are both effective and safe.”
SYNCHRONIZE-CVOT was published simultaneously in The Lancet.
