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.
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.
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.