Cardiovascular and Renal Effectiveness of GLP-1 Receptor Agonists vs. Other Glucose-Lowering Drugs in Type 2 Diabetes: A Systematic Review and Meta-Analysis of Real-World Studies

Abstract

Cardiovascular outcome trials (CVOT) showed that treatment with glucagon-like peptide-1 receptor agonists (GLP-1RA) is associated with significant cardiovascular benefits. However, CVOT are scarcely representative of everyday clinical practice, and real-world studies could provide clinicians with more relatable evidence. Here, literature was thoroughly searched to retrieve real-world studies investigating the cardiovascular and renal outcomes of GLP-1RA vs. other glucose-lowering drugs and carry out relevant meta-analyses thereof. Most real-world studies were conducted in populations at low cardiovascular and renal risk. Of note, real-world studies investigating cardio-renal outcomes of GLP-1RA suggested that initiation of GLP-1RA was associated with a greater benefit on composite cardiovascular outcomes, MACE (major adverse cardiovascular events), all-cause mortality, myocardial infarction, stroke, cardiovascular death, peripheral artery disease, and heart failure compared to other glucose-lowering drugs with the exception of sodium-glucose transporter-2 inhibitors (SGLT-2i). Initiation of SGLT-2i and GLP-1RA yielded similar effects on composite cardiovascular outcomes, MACE, stroke, and myocardial infarction. Conversely, GLP-1RA were less effective on heart failure prevention compared to SGLT-2i. Finally, the few real-world studies addressing renal outcomes suggested a significant benefit of GLP-1RA on estimated glomerular filtration rate (eGFR) reduction and hard renal outcomes vs. active comparators except SGLT-2i. Further real-world evidence is needed to clarify the role of GLP-1RA in cardio-renal protection among available glucose-lowering drugs.

Effectiveness and safety of GLP-1 receptor agonists versus SGLT-2 inhibitors in type 2 diabetes: an Italian cohort study

“…In a recent systematic review and meta-analysis of RWS, no differences in the occurrence of composite CV outcomes and MACE were found between new users of SGLT-2i and GLP-1RA [ 20 ]. Indeed, the studies by Patorno et al [ 27 ], enrolling the largest population to date, and Longato et al [ 13 ] were the only ones to detect a significantly lower risk of composite CV outcome occurrence (hospitalization for MI or stroke and all-cause death or myocardial infarction or stroke, respectively) in SGLT-2i compared to GLP-1RA new users.…”

“…SGLT-2i displayed an unparalleled benefit on HF-related outcomes in randomized controlled trials regardless of the baseline cardio-renal risk of the enrolled population [ 29 ]; accordingly, a meta-analysis of RWS showed that SGLT-2i were more effective than GLP-1RA on prevention of HF worsening [ 30 ]. On the other hand, albeit to a lesser extent, GLP-1RA have also been proven beneficial, significantly reducing HF hospitalization by 11% compared to placebo in CVOT [ 2 ] and by 12% compared to other glucose-lowering drugs except for SGLT-2i in RWS [ 20 ]. Interestingly, in three nested case–control studies involving 336,334 T2D patients without previous CV disease and HF, Wright et al have recently shown that GLP-1RA were associated with a 18% risk reduction of HF compared to other glucose-lowering drugs [ 25 ].…”

“…The large and unselected population, representing the real clinical setting, and the longer follow-up duration compared to similar studies [ 20 ] represent the main strengths of this study.…”

“…The large and unselected population, representing the real clinical setting, and the longer follow-up duration compared to similar studies [20] represent the main strengths of this study. Also, besides the study specifically conducted in elderly patients by Patorno et al [14], the population enrolled in this study was averagely older (mean age 66.3 years) than that of previous RWS (mean age ranging from 50 years in [15] to 63 years in [13], adding valuable insight on a subgroup of patients widely represented in everyday clinical practice.…”

“…Currently, there are no available headto-head randomized trials comparing the effects of GLP-1RA and SGLT-2i on CV or renal outcomes; hence, despite their recognized limitations-such as the lack of randomization, low quality control surrounding data collection, and susceptibility to multiple sources of bias for comparing outcomes [12]-real-world data may provide guidance in understanding and exploiting the specific clinical properties of these two drug classes. Indeed, several real-world studies (RWS) have been recently carried out in different countries and populations mostly focusing on CV rather than kidney outcomes [13][14][15][16][17][18][19]; these studies have suggested an overall similar benefit of GLP-1 RA and SGLT-2i on CV composite endpoints [20].…”