What Can Linked Electronic Health Records and Death Data Tell Us About Drug Safety?

Approximately 76 million people in the U.S. live with obesity. In addition to changes in diet and exercise, treatment for this chronic disease often includes antiobesity medications (AOMs). 

Some previously marketed AOMs caused adverse cardiovascular (CV) effects, ranging from increased blood pressure or heart rate to major adverse CV events, including myocardial infection, stroke, or CV death. Understanding the long-term CV safety of AOMs is critical, especially since AOMs must be taken for long periods of time. The populations using these medicines are often younger adults who are otherwise healthy, and they are more likely to be women, for whom CV research has lagged relative to men.

In their study, Exponent's Catherine Rogers Murray, Dustin Burns, Heather Watson, Jeff Swaney, Samuel Spevack, Emma Moynihan, and David Dore along with their co-authors evaluated the long-term, real-world CV safety of the AOM naltrexone/bupropion (NB-ER). The Food and Drug Administration approved NB-ER in 2014, and the European Medicines Agency in 2015, for the treatment of obesity in adults or for treatment in certain overweight adults with CV risk factors.

The authors conducted an active-comparator, new-user cohort study using electronic health records (EHRs), health insurance claims, and mortality data aggregated from U.S. health systems. The project began with the authors separately conducting an emulation of a similar published randomized control trial (RCT) in which they compared the trial's results to results from the EHR data using their study design. The authors' approach replicated the published trial, and the team proceeded with their primary analysis of estimating the effect of NB-ER on the occurrence of major CV events. Both analyses are reported in their publication.

They compared the rate of major adverse CV events over an average of 4.7 years of follow-up between 12,475 recipients of NB-ER versus 12,171 recipients of another AOM, lorcaserin. Whereas lorcaserin was removed from the U.S. market in 2020 due to potential carcinogenicity, the authors chose it as the primary comparator because there is no evidence of CV effects of lorcaserin, and recipients of that drug were most similar to recipients of NB-ER, reducing bias. They found that recipients of NB-ER compared to lorcaserin were not at an increased risk of major adverse CV events, such as CV death, nonfatal myocardial infarction, or nonfatal stroke. 

Although they note that a particular strength of their study was the rich clinical information garnered from EHRs, the authors did cite some limitations common to observational studies, including confounding by factors not included in EHRs, such as socioeconomic status. Although the authors recommend that "[c]ausal interpretations for the cardiovascular safety of NB-ER should be evaluated further in a prospective, randomized, blinded, controlled clinical trial," there was strong evidence that patients initiating NB-ER compared with lorcaserin were not at an increased risk of major adverse CV events.

From the publication: "In this analysis of EHR data, our findings suggest that patients initiating NB-ER were not at an increased risk of major adverse CV events or its components compared to patients initiating lorcaserin."