Comparative cardiovascular safety of GLP-1 receptor agonists versus other glucose-lowering agents in real-world patients with type 2 diabetes: a nationwide population-based cohort study

Abstract

Background : Current evidence about the cardiovascular safety of glucagon-like peptide-1 receptor agonist (GLP-1ra) possesses limited generalizability to real-world patients with type 2 diabetes (T2D) in usual practice. This study aimed to investigate the comparative cardiovascular safety of GLP-1ra in head-to-head comparisons with dipeptidyl peptidase-4 inhibitor (DPP-4i), sulfonylurea (SU), and insulin in a real-world population with T2D. Methods : Adults with newly-diagnosed T2D were identified from Taiwan’s National Health Insurance Research Database in 2003-2014. A prevalent new-user cohort design was adopted to include a broad representation of real-world T2D patients being treated with GLP-1ra. The between-group comparability of baseline patient characteristics was achieved by matching on (1) initiation time of study drugs, (2) prior exposure to glucose-lowering agents, and (3) diabetes severity and complications, comorbidities, and concomitant cardiovascular medications using propensity scores. The primary outcome was a composite of cardiovascular disease (CVD) events and assessed up to the end of 2015. Cox modeling was employed to assess the association between study drugs and outcomes. Results : A total of 3,195 GLP-1ra stable users was identified in 2011-2014. 1,893, 1,829, and 1,367 GLP-1ra stable users were 1:1 matched to DPP-4i, SU and insulin users, respectively. Compared to DPP-4i, SU and insulin, the use of GLP-1ra was associated with a lower risk of composite CVD events (hazard ratio [95% confidence interval]: 0.73 [0.57-0.96], 0.76 [0.57-1.00], and 0.81 [0.62-1.07], respectively). Subgroup analyses revealed that GLP-1ra versus DPP-4i yielded a greater cardiovascular benefit in those without established CVD versus those with established CVD. Conclusions : This head-to-head comparison study extends the supporting evidence for the cardiovascular safety of GLP-1ra to a broad spectrum of real-world T2D patients using GLP-1ra.

Cardiovascular and renal outcomes with SGLT-2 inhibitors versus GLP-1 receptor agonists in patients with type 2 diabetes mellitus and chronic kidney disease: a systematic review and network meta-analysis

“…GLP-1 RAs are known to reduce blood pressure (BP) [14] and body weight [15]. Large cohort studies and meta-analyses of RCTs demonstrated that GLP-1 RAs improve cardiovascular outcomes [16][17][18][19][20] The American Diabetes Association (ADA) recommends SGLT-2 inhibitors or GLP-1 RAs in type 2 DM patients who have atherosclerotic cardiovascular disease or kidney disease [21]. However, it remains unclear if GLP-1 RAs are beneficial to type 2 DM patients with CKD as well.…”

Cost-effectiveness of GLP-1 receptor agonists versus insulin for the treatment of type 2 diabetes: a real-world study and systematic review

“…Fifth, due to limited numbers of study subjects in different individual GLP-1RA and insulin therapies, further assessment of comparative effectiveness and cost-effectiveness of treatments by the more granular level of different individual drugs would be underpowered. Moreover, given no heterogeneous treatment effects found by age, gender, or diabetes severity for GLP-1RAs versus insulin in our previous analyses [6] and limited study subjects with different patient characteristics in the present study, performing the costeffectiveness analysis stratified by different patient demographic or clinical characteristics would be infeasible. Therefore, future research with sufficient study subjects that can be classified by different individual drugs and patient characteristics is encouraged, which can provide more individualized and precise suggestions on treatment selections.…”

“…S2. The comparability of patient characteristics between two study groups was achieved by the three-step matching on (1) the index date, (2) prior exposure to GLAs in the year before the index date, and (3) patient demographic and clinical characteristics (e.g., diabetes severity, comorbidities, co-medications for cardiovascular diseases [CVDs]) using the propensity score matching approach [6]. After the matching, there were 1022 matched pairs of GLP-1RA and insulin users with no significant between-group difference in the baseline characteristics except for age, hyperlipidemia, and neuropathy (Additional file 1: Table S3).…”

“…However, the common gastrointestinal symptoms and higher drug acquisition costs of GLP-1RAs have hindered their widespread and continuous use in real-world settings [2,5]. In Taiwan's National Health Insurance program, the cost of a GLP-1RA (e.g., liraglutide) can be up to 7 times that of insulin (e.g., insulin glargine) per treatment cycle (e.g., US$108.6 versus US$15.4 per month) [6]. The trade-offs among clinical effectiveness, tolerability, and cost for GLP-1RA use have highlighted the importance of a cost-effectiveness analysis (CEA) of GLP-1RA versus insulin therapy in real-world clinical practice [2].…”

Association of Renal and Cardiovascular Safety With DPP‐4 Inhibitors vs. Sulfonylureas in Patients With Type 2 Diabetes and Advanced Chronic Kidney Disease

“…Furthermore, a two-step matching algorithm was implemented to enhance the comparability between study groups of DPP4i and SU users. 25 First, the previous utilization patterns of GLAs were considered as an important proxy for patients' underlying status of diabetes management and therefore utilized as the matching criterion. Specifically, patients exposed to the same number of GLA classes were matched first, with a maximum 90-day drug supply difference (±45 days) of prior use of DPP4is or SUs allowed for the matched pairs.…”