Abstract
BackgroundWe explored whether clinically relevant baseline characteristics of patients with type 2 diabetes can modify the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RA) or sodium-glucose cotransporter-2 inhibitors (SGLT-2i) on the risk of major adverse cardiovascular events (MACE).MethodsWe investigated Medline and EMBASE through June 2019. We included randomized clinical trials reporting the effect of GLP-1 RA or SGLT-2i on MACE in subgroups of patients with type 2 diabetes, identified through key baseline factors: established cardiovascular disease; heart failure; chronic kidney disease; uncontrolled diabetes; duration of diabetes; hypertension; obesity; age; gender and race. Hazard ratios (HRs) and 95% confidence intervals (CIs) from trials were meta-analyzed using random-effects models.ResultsTen trials enrolling 89,790 patients were included in the analyses. Subgroup meta-analyses showed a 14% risk reduction of MACE in patients with established cardiovascular disease [GLP1-RA: HR, 0.86 (95% CI, 0.80–0.93); SGLT-2i: 0.86 (0.80–0.93)], and no effect in at-risk patients without history of cardiovascular events [GLP1-RA: 0.94 (0.82–1.07); SGLT-2i: 1.00 (0.87–1.16)]. We observed a trend toward larger treatment benefits with SGLT-2i among patients with chronic kidney disease [0.82 (0.69–0.97)], and patients with uncontrolled diabetes for both GLP1-RA or SGLT-2i [GLP1-RA: 0.82 (0.71–0.95); SGLT-2i: 0.84 (0.75–0.95)]. Uncontrolled hypertension, obesity, gender, age and race did not appear to modify the effect of these drugs.ConclusionsIn this exploratory analysis, history of cardiovascular disease appeared to modify the treatment effect of SGLT2i or GLP1-RA on MACE. Chronic kidney disease and uncontrolled diabetes should be further investigated as potential effect modifiers.
Highlights
Type 2 diabetes mellitus (T2DM) is the seventh-leading cause of death in the US and a major contributor to cardiovascular disease [1]
All drugs tested in the trials have been approved by the Food and Drug Administration (FDA) as a therapeutic option for the treatment of type 2 diabetes
Individuals with type 2 diabetes and history of cardiovascular disease showed a meaningful reduction in the risk of cardiovascular events, over an average follow-up time of 3 years of treatment with longer acting GLP1-RA or sodium-glucose cotransporter-2 inhibitors (SGLT-2i) drugs, which was not observed among patients with high cardiovascular risk and no prior cardiovascular events
Summary
Type 2 diabetes mellitus (T2DM) is the seventh-leading cause of death in the US and a major contributor to cardiovascular disease [1]. A major barrier to effective implementation of such findings is the scarcity of evidence describing the extent to which results from trials may be generalizable to all patients with T2DM [2] or whether the results may vary across subgroups of the population [3, 4]. The identification of subgroups of interest in clinical trials usually emerges from baseline characteristics of the population, which have been deemed a priori as potential treatment effect modifiers [5, 6]. We explored whether clinically relevant baseline characteristics of patients with type 2 diabetes can modify the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RA) or sodium-glucose cotransporter-2 inhibitors (SGLT-2i) on the risk of major adverse cardiovascular events (MACE)
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