Comparative Safety of Glucagon-Like Peptide 1 Receptor Agonists (GLP-1-RAs) in Type 2 Diabetes and Chronic Weight Management: A Real-World Data Study

Abstract

Purpose: This study assessed serious clinical outcomes comparing glucagon-like peptide 1 receptor agonists (GLP-1-RAs) with sodium glucose co-transporter 2 inhibitors (SGLT2-Is) in patients with type 2 diabetes (T2DM) and patients without diabetes using two chronic weight management (CWM) regimens.

Methods: We performed a new user, active comparator cohort study in a large, national U.S. claims database. Adults who initiated GLP-1-RAs, SGLT2-Is, naltrexone/bupropion (NalBup), or phentermine/topiramate (PhenTop) from 1 January 2016 to 31 December 2023 were included. Potential confounding was controlled using propensity score weighting for 82 clinical and demographic covariates, and risk ratios (RRs) were estimated.

Results: This study included 330,684 GLP-1-RA users and 264,277 SGLT2-I users with T2DM. Among CWM patients without diabetes, we studied over 25,000 GLP-1-RA users, 5019 NalBup users, and 3841 PhenTop users. In both indications, GLP-1-RA users had higher rates of hospitalizations for gallbladder and biliary diseases with RRs ranging from 1.14 (95% CI: 1.06-1.22) in T2DM patients to 3.32 (95% CI: 1.44-7.64) in CWM patients. No reduction in the rate of cardiovascular events was observed for GLP-1-RA users with RRs ranging from 0.92 (95% CI: 0.37-2.25) in CWM patients to 1.03 (95% CI: 0.99-1.08) in T2DM patients. In T2DM patients, GLP-1-RA users had a lower rate of acute liver injury (RR: 0.76; 95% CI: 0.64-0.91).

Conclusions: This study corroborates an increased risk of hospitalization for gall bladder and biliary conditions among users of GLP-1-RAs and found similar rates as comparators of MI or stroke when GLP-1-RAs were used for T2DM or CWM. This real-world study complements placebo-controlled trials and can further inform prescribing decisions.

Protocol registration: The study protocol was pre-registered at the Center for Open Science's Real-World Evidence Registry and is publicly accessible online (https://doi.org/10.17605/OSF.IO/PSY74).

Keywords: GLP‐1‐RA; SGLT2; diabetes; naltrexone‐bupropion; phentermine‐topiramate; safety; weight management.

FIGURE 1

Adjusted (weighted) Kaplan–Meier cumulative incidence curves for gallbladder and biliary disease hospitalization.

FIGURE 2

Adjusted (weighted) Kaplan–Meier cumulative incidence curves for myocardial infarction or stroke hospitalization.

FIGURE 3

p‐value functions of rate ratios for thyroid cancer. GLP‐1‐RA, glucagon‐like peptide 1 receptor agonists; NalBup, naltrexone hydrocholoride/bupropion hydrochloride; PhenTop, phentermine/topiramate extended‐release; SGLT2‐I, sodium glucose co‐transporter 2 inhibitors. Solid line: Comparing GLP‐1‐RA to SGLT2‐I; Dotted line: Comparing GLP‐1‐RA to PhenTop; Dashed line: Comparing GLP‐1‐RA to NalBup. This plot displays all p‐values for a range of possible rate ratios. The probabilities shown are for the observed data given each hypothesized RR. The axis values of this plot can be used to infer confidence limits at varying levels of confidence. For example, X‐axis values at the 0.05 level of the Y‐axis represent the 95% confidence interval limits. Similarly, the X‐axis values at the 0.10 level of the Y‐axis represent the 90% confidence interval limits. The peak of each curve represents the study point estimate (rate ratio). The two‐sided null hypothesis p‐value (familiar for its common use in statistical significance testing) is the Y‐axis value at which the X‐axis value is 1 (e.g., two‐sided p ~ 0.1 when comparing GLP‐1‐RA to NalBup).