July 18, 2025

Episode 394: 402. Cardiovascular Risk Factors, Zilebesiran, Shared Decision Making

15 minutes

https://www.nejm.org/doi/10.1056/NEJMoa2415879?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed

Key Findings:

Classic Risk Factors: The five risk factors examined were hypertension, hyperlipidemia, underweight and overweight or obesity, diabetes, and smoking. These factors are estimated to account for about 50% of the global burden of cardiovascular disease.

Lifetime Risk Estimates:

Among individuals free of these risk factors at age 50, the lifetime risk of cardiovascular disease was 13% for women and 21% for men.

For those with all five risk factors, the lifetime risk jumped to 24% for women and 38% for men.

Significance of Risk Factor Modification:

Adjusting certain risk factors during midlife, particularly managing hypertension and quitting smoking, led to the most significant gains in life expectancy free of disease.

For instance, controlling hypertension between ages 55 and 60 yielded the most additional life-years free of cardiovascular disease.

Quitting smoking during the same period was associated with the most additional life-years free of death from any cause.

https://jamanetwork.com/journals/jama/fullarticle/2834632

Study Design:

This was a phase 2, randomized, double-blinded trial with participants enrolled from 150 sites across 8 countries. The study spanned from January 2022 to June 2023, with analyses completed by March 2024.

Participants received indapamide, amlodipine, or olmesartan as background therapy. Those with a specified range of 24-hour mean ambulatory systolic blood pressure (SBP) were then randomized to receive either a single subcutaneous dose of 600 mg zilebesiran or placebo.

Efficacy Results:

At 3 months, zilebesiran significantly reduced the 24-hour mean ambulatory SBP compared to placebo across all cohorts:

Indapamide: -12.1 mmHg

Amlodipine: -9.7 mmHg

Olmesartan: -4.5 mmHg

Similar reductions were observed in office SBP measurements at 3 months.

https://pubmed.ncbi.nlm.nih.gov/40578930/

Primary Outcomes:

Discontinuation of Opioid Therapy: Patients in the greater SDM group were less likely to discontinue opioid therapy 3 months post-baseline compared to those in the lesser SDM group (Relative Risk: RR of 0.56).

Opioid Prescribing Frequency: Over a 12-month period, patients in the greater SDM group experienced more frequent opioid prescriptions (RR of 1.24).

Secondary Outcomes:

Physical Function: Interestingly, physical function was slightly worse in the greater SDM group, but this difference was not deemed clinically significant.

Back-related Disability: Both greater opioid use and SDM were associated with increased back-related disability and worse physical function, yet these findings were also not clinically significant.

No significant SDM x opioid therapy interaction effects were observed, indicating that more frequent opioid use coupled with SDM did not lead to better patient outcomes in pain, function, or health-related quality of life (HRQOL).

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