Cardiovascular safety of fixed-dose extended-release naltrexone/bupropion in clinical practice

The fixed-dose extended-release combination of naltrexone/bupropion (NB-ER) is indicated to treat overweight and obesity in adults as an adjunct to a reduced-calorie diet and increased physical activity. This study compared the rate of major adverse cardiovascular events (MACE) and its components (nonfatal acute myocardial infarction [AMI], nonfatal stroke, and cardiovascular death) between patients initiating NB-ER and those initiating lorcaserin (removed from US market in 2020; included as active comparator to minimize possible confounding by indication) in routine clinical practice.

This was a retrospective cohort study with a new-user, active-comparator design. Patients initiating NB-ER or lorcaserin were identified using Arcadia Data Research electronic health records, including insurance claims (June 2012-February 2020). Incidence rate ratios were estimated, and adjusted hazard ratios (aHRs) with 95 % confidence intervals (CIs) were estimated using a propensity score (PS)-weighted Cox proportional hazard model in an intention-to-treat analysis.

Patients initiating NB-ER (n = 12 475) or lorcaserin (n = 12 171) were followed for a mean observation period of 4.7 years. After PS weighting, baseline comorbidities, concomitant medications, lifestyle factors, and clinical measures were balanced between cohorts. MACE incidence was 0.77/1000 person-years for NB-ER and 1.03/1000 person-years for lorcaserin. Compared to lorcaserin, patients initiating NB-ER had statistically similar rates of MACE (aHR, 0.76; 95 % CI, 0.48-1.22), nonfatal AMI (aHR, 0.74; 95 % CI, 0.45-1.23), and nonfatal stroke (aHR, 1.05; 95 % CI, 0.34-3.22). No deaths were observed within 30 days of an AMI or stroke.

Patients initiating NB-ER compared with lorcaserin were not at an increased risk of MACE or its components. Conclusions from this study must be interpreted in the context of certain assumptions related to PS methodology and use of lorcaserin as an active comparator. Causal interpretations for the cardiovascular safety of NB-ER should be evaluated further in a prospective, randomized, blinded, controlled clinical trial.