Daily Endocrinology Research Analysis
Two pivotal NEJM randomized trials advanced cardiometabolic care: olezarsen (APOC3 antisense) markedly lowered triglycerides and reduced acute pancreatitis in severe hypertriglyceridemia, while evolocumab reduced first major cardiovascular events in high-risk patients without prior MI or stroke. A multinational analysis in The Lancet Diabetes & Endocrinology showed heart failure mortality declines lag behind coronary and cerebrovascular mortality in people with and without diabetes, underscoring
Summary
Two pivotal NEJM randomized trials advanced cardiometabolic care: olezarsen (APOC3 antisense) markedly lowered triglycerides and reduced acute pancreatitis in severe hypertriglyceridemia, while evolocumab reduced first major cardiovascular events in high-risk patients without prior MI or stroke. A multinational analysis in The Lancet Diabetes & Endocrinology showed heart failure mortality declines lag behind coronary and cerebrovascular mortality in people with and without diabetes, underscoring a need to prioritize heart failure prevention.
Research Themes
- RNA-targeted lipid therapeutics and pancreatitis prevention
- Primary prevention of atherosclerotic events with PCSK9 inhibition
- Global epidemiology of cardiovascular mortality in diabetes with focus on heart failure
Selected Articles
1. Olezarsen for Managing Severe Hypertriglyceridemia and Pancreatitis Risk.
Two double-blind RCTs (n=1061) show that monthly olezarsen (50 or 80 mg) reduces triglycerides by roughly 50–72 percentage points vs. placebo at 6 months and lowers acute pancreatitis incidence (rate ratio 0.15). Safety was generally similar, though liver enzyme elevations, thrombocytopenia, and dose-dependent hepatic fat increase were more frequent at 80 mg.
Impact: Demonstrates, for the first time in large randomized trials, that APOC3 antisense therapy not only lowers triglycerides but also reduces acute pancreatitis—a clinically meaningful outcome in severe hypertriglyceridemia.
Clinical Implications: Olezarsen offers a potent option to reduce triglycerides and pancreatitis risk in severe hypertriglyceridemia. Clinicians should monitor liver enzymes, platelets, and hepatic fat, especially with higher doses, and consider patient selection for maximal benefit.
Key Findings
- At 6 months, placebo-adjusted TG reductions ranged from −49.2 to −72.2 percentage points across trials and doses (P<0.001).
- Acute pancreatitis incidence was significantly lower with olezarsen (mean rate ratio 0.15, 95% CI 0.05–0.40).
- Greater reductions in APOC3, remnant cholesterol, and non-HDL cholesterol vs. placebo.
- Adverse events overall were similar, but liver enzyme elevations, thrombocytopenia, and a dose-dependent hepatic fat increase were more frequent at 80 mg.
Methodological Strengths
- Two parallel, double-blind, randomized, placebo-controlled trials with prespecified endpoints
- Consistent efficacy across two independent studies and multiple lipid parameters
Limitations
- Increased liver enzymes, thrombocytopenia, and hepatic fat with higher dose raise safety monitoring needs
- Primary outcome focused on lipid change at 6 months; longer-term safety and outcomes beyond 12 months require confirmation
Future Directions: Evaluate long-term clinical outcomes, optimize dosing to balance efficacy and safety, and assess use in pancreatitis-prone subgroups and in combination with other lipid-lowering agents.
BACKGROUND: Patients with severe hypertriglyceridemia have an increased risk of acute pancreatitis. The efficacy and safety of olezarsen, an antisense oligonucleotide targeting apolipoprotein C-III messenger RNA, have not been established in this population. METHODS: We conducted two double-blind, randomized, placebo-controlled trials (CORE-TIMI 72a and CORE2-TIMI 72b). Patients with severe hypertriglyceridemia were assigned in a 1:1:1 ratio to receive olezarsen at a dose of 50 mg, olezarsen at a dose of 80 mg, or placebo monthly for 12 months. The primary outcome was the percent change from baseline in the triglyceride level at 6 months, reported as the difference between each olezarsen dose group and the placebo group (placebo-adjusted change). Secondary lipid outcomes included the percent change from baseline in the triglyceride level at 12 months and in the levels of apolipoprotein C-III, remnant cholesterol, and non-high-density lipoprotein (non-HDL) cholesterol at 6 months and 12 months. Acute pancreatitis events were assessed across both trials. RESULTS: A total of 1061 patients were included in the primary analysis (617 in the CORE-TIMI 72a trial and 444 in the CORE2-TIMI 72b trial). At 6 months, the placebo-adjusted least-squares mean change from baseline in the triglyceride level was -62.9 percentage points in the olezarsen 50-mg group and -72.2 percentage points in the olezarsen 80-mg group in the CORE-TIMI 72a trial and was -49.2 percentage points in the olezarsen 50-mg group and -54.5 percentage points in the olezarsen 80-mg group in the CORE2-TIMI 72b trial (P<0.001 for all comparisons of olezarsen with placebo). Decreases in the levels of triglycerides, apolipoprotein C-III, remnant cholesterol, and non-HDL cholesterol were greater with olezarsen than with placebo (P<0.001 for all comparisons). The incidence of acute pancreatitis was lower with olezarsen than with placebo (mean rate ratio, 0.15; 95% confidence interval, 0.05 to 0.40; P<0.001). The incidence of any adverse events appeared to be similar across trial groups. Elevations in liver-enzyme levels and thrombocytopenia (platelet count, <100,000 per microliter) were more common with the 80-mg dose of olezarsen, and a dose-dependent increase in the hepatic fat fraction was noted. CONCLUSIONS: Among patients with severe hypertriglyceridemia, treatment with olezarsen led to a significantly greater reduction in the triglyceride level at 6 months and in the incidence of acute pancreatitis than placebo. (Funded by Ionis Pharmaceuticals; CORE-TIMI 72a and CORE2-TIMI 72b ClinicalTrials.gov numbers, NCT05079919 and NCT05552326.).
2. Evolocumab in Patients without a Previous Myocardial Infarction or Stroke.
In 12,257 high-risk patients without prior MI or stroke, evolocumab reduced 5-year 3-point MACE (HR 0.75) and 4-point MACE (HR 0.81) versus placebo, with no safety signal. This extends PCSK9 inhibitor benefit to primary prevention in atherosclerosis and diabetes.
Impact: Defines primary prevention efficacy of PCSK9 inhibition, offering robust evidence to broaden lipid-lowering strategies beyond statins for high-risk patients without prior events.
Clinical Implications: Consider PCSK9 inhibitors in high-risk patients (atherosclerosis or diabetes with elevated LDL-C) without prior MI or stroke to reduce first MACE. Shared decision-making should weigh cost, access, and LDL-C targets.
Key Findings
- 3-point MACE reduced (HR 0.75; 95% CI 0.65–0.86; P<0.001) over median 4.6 years.
- 4-point MACE reduced (HR 0.81; 95% CI 0.73–0.89; P<0.001).
- No between-group differences in safety events were detected.
Methodological Strengths
- Large, international, double-blind randomized, placebo-controlled design
- Hard clinical endpoints with long median follow-up (4.6 years)
Limitations
- Predominantly White population (93%) may limit generalizability
- Economic and access considerations not addressed in trial context
Future Directions: Assess cost-effectiveness and implementation in diverse health systems; explore combinations with other novel lipid-lowering agents and stratify by baseline LDL-C and polyvascular disease.
BACKGROUND: The proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor evolocumab reduces the risk of major adverse cardiovascular events (MACE) among patients with a previous myocardial infarction, stroke, or symptomatic peripheral artery disease. The effect of evolocumab on the risk of MACE among patients without a previous myocardial infarction or stroke is unknown. METHODS: We conducted an international, double-blind, randomized, placebo-controlled trial of evolocumab in patients with atherosclerosis or diabetes and without a previous myocardial infarction or stroke who had a low-density lipoprotein cholesterol level of at least 90 mg per deciliter. Patients were randomly assigned in a 1:1 ratio to receive evolocumab at a dose of 140 mg every 2 weeks or placebo. The two primary end points were a composite of death from coronary heart disease, myocardial infarction, or ischemic stroke (3-point MACE) and a composite of 3-point MACE or ischemia-driven arterial revascularization (4-point MACE). RESULTS: A total of 12,257 patients were randomly assigned to receive evolocumab (6129 patients) or placebo (6128) and were included in the efficacy analyses. The median age of the patients was 66 years, 43% were women, and 93% were White. The median follow-up was 4.6 years. A 3-point MACE event occurred in 336 patients (5-year Kaplan-Meier estimate, 6.2%) in the evolocumab group, as compared with 443 (8.0%) in the placebo group (hazard ratio, 0.75; 95% confidence interval [CI], 0.65 to 0.86; P<0.001). A 4-point MACE event occurred in 747 patients (5-year Kaplan-Meier estimate, 13.4%) in the evolocumab group, as compared with 907 (16.2%) in the placebo group (hazard ratio, 0.81; 95% CI, 0.73 to 0.89; P<0.001). No evidence of a between-group difference was seen in the incidence of safety events. CONCLUSIONS: PCSK9 inhibition with evolocumab led to a lower risk of first cardiovascular events than placebo among patients with atherosclerosis or diabetes and without a previous myocardial infarction or stroke. (Funded by Amgen; VESALIUS-CV ClinicalTrials.gov number, NCT03872401.).
3. Time trends in mortality from heart failure and atherosclerotic cardiovascular disease in people with and without diabetes: a multi-national population-based study.
Across nine jurisdictions and 1.30 billion person-years, CHD and cerebrovascular mortality declined, but heart failure mortality declined less (and even rose in Ontario). Excess CHD mortality associated with diabetes diminished in some regions, yet excess heart failure mortality did not, signaling a persistent heart failure burden.
Impact: Provides robust, multi-country evidence that heart failure mortality lags behind other CVD improvements and that diabetes-related excess heart failure mortality persists, informing policy and guideline priorities.
Clinical Implications: Clinicians and systems should intensify heart failure prevention and management in both diabetic and non-diabetic populations, integrating SGLT2 inhibitors and GLP-1RAs where indicated and optimizing hypertension, ischemia, and CKD care.
Key Findings
- Among 2.92 million CVD deaths over 1.30 billion person-years, CHD mortality fell by −11.5% to −32.3% over 5 years across jurisdictions.
- Heart failure mortality declined less than CHD and cerebrovascular mortality, with an increase observed in Ontario.
- Excess CHD mortality associated with diabetes decreased in 3/9 jurisdictions; excess heart failure mortality associated with diabetes did not decline in any.
Methodological Strengths
- Large-scale, multi-national administrative datasets with cause-specific mortality over two decades
- Consistent analytic framework using Poisson regression stratified by diabetes status
Limitations
- Observational design subject to coding changes and residual confounding across jurisdictions
- Diabetes ascertainment and treatment uptake not uniformly captured
Future Directions: Dissect contributors to heart failure mortality (e.g., HFpEF vs. HFrEF, comorbidity patterns), quantify the impact of contemporary therapies, and evaluate health system interventions to close the heart failure mortality gap.
BACKGROUND: Contemporary trends in cardiovascular disease (CVD) cause-specific mortality by diabetes status are inadequately described. We examined trends by diabetes status in coronary heart disease (CHD), cerebrovascular disease, and heart failure mortality, and mortality rate ratios (people with diabetes versus those without diabetes) across nine high-income jurisdictions. METHODS: We assembled CVD cause-specific mortality data from nine administrative datasets (Europe [n=5], Australia [n=1], Canada [n=2], and South Korea [n=1]), spanning 2000-23. Using Poisson regression, we estimated mortality rates by diabetes status and mortality rate ratios. FINDINGS: There were 2·92 million CVD deaths over 1·30 billion person-years of follow-up. In all jurisdictions and in both people with and without diabetes, the total CVD and CHD mortality rates fell across the observed time period. The 5-year percent changes in CHD mortality ranged from -11·5% to -32·3%. Reductions in heart failure mortality were smaller than those for CHD mortality (except in Scotland) and smaller than those for cerebrovascular mortality (except in Scotland and Denmark). Heart failure mortality increased in Ontario, Canada. The excess CHD mortality associated with diabetes (mortality rate ratio ~2·0) fell in three of nine jurisdictions and was stable or uncertain in the remainder. No jurisdiction had a fall in excess heart failure mortality associated with diabetes. INTERPRETATION: Declines in heart failure mortality in both people with and without diabetes were less marked than were declines in CHD and cerebrovascular disease mortality in most jurisdictions. Heart failure mortality rate ratios have not decreased. A greater focus on reducing heart failure mortality in people with and without diabetes might be required. FUNDING: US Centers for Disease Control and Prevention, Diabetes Australia Research Program, Victoria State Government Operational Infrastructure Support Program.