Effects of liraglutide versus sitagliptin on circulating cardiovascular biomarkers, including circulating progenitor cells, in individuals with type 2 diabetes and obesity: Analyses from the LYDIA trial

Abstract

The mechanisms behind the beneficial cardiovascular effects of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) compared with dipeptidyl peptidase‐4 inhibitors (DPP4is) remain largely unknown, despite both targeting the incretin pathway to improve glycaemic control. In these prespecified secondary analyses of the LYDIA trial, we examined the impact of the GLP‐1RA liraglutide (1.8 mg once‐daily) and the DPP4i sitagliptin (100 mg once‐daily) on circulating cardiovascular biomarkers associated with atherosclerotic risk, including circulating progenitor cells (CPCs). LYDIA was a 26‐week, randomized, active‐comparator trial in 61 adults with type 2 diabetes and obesity (mean ± SD: age 43.8 ± 6.5 years, body mass index 35.3 ± 6.4 kg/m2, HbA1c 7.5% ± 0.83% [58.5 ± 9.1 mmol/mol]). Vascular endothelial growth factor (VEGF) and stromal cell‐derived factor‐1‐alpha (SDF‐1ɑ), both of which are implicated in endothelial function, were higher at 26 weeks with liraglutide therapy compared with sitagliptin (mean between‐group difference [95% CI]: 77.03 [18.29, 135.77] pg/mL, p = .010; and 996.25 [818.85, 1173.64] pg/mL, p < .001, respectively). There were no between‐group differences in CPCs, nitric oxide, C‐reactive protein, interleukin‐6, tumour necrosis factor alpha and advanced glycation end‐products. These analyses suggest a favourable impact of liraglutide on VEGF and SDF‐1ɑ levels compared with sitagliptin. These factors may therefore be implicated in the differential cardiovascular effects observed between these agents in large cardiovascular outcome trials. However, these are secondary analyses from a previous trial and thus hypothesis‐generating. Purposive trials are required to examine these findings further.

Impact of semaglutide on high-sensitivity C-reactive protein: exploratory patient-level analyses of SUSTAIN and PIONEER randomized clinical trials

“…In addition, analysis of a 52-week phase 2 trial investigated once-daily ≤ 0.4 mg doses of s.c. semaglutide (N = 957) and the STEP phase 3 trials investigated s.c. semaglutide 2.4 mg dose in subjects with overweight and obesity with or without type 2 diabetes (total N = 4684); these trials identified consistent reductions in hsCRP with once-daily semaglutide ≤ 0.4 mg and once-weekly s.c. semaglutide 2.4 mg [ 28 – 32 ]. An analysis of subjects with type 2 diabetes and obesity in the LYDIA trial found there was no significant difference in the effects of liraglutide on hsCRP compared with the dipeptidyl peptidase-4 inhibitor sitagliptin [ 33 ]. However, a recent meta-analysis, which included data from 40 randomized controlled trials in subjects with type 2 diabetes, found significant improvements with GLP-1RAs compared with standard diabetes therapies (including sulfonylureas, insulins, dipeptidyl peptidase-4 inhibitors, thiazolidinediones) and placebo in several clinical biomarkers, including CRP, tumor necrosis factor-alpha, and adiponectin (markers of inflammation) and malondialdehyde (a marker of oxidative stress) [ 34 ].…”

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

“…Furthermore, in small placebo-controlled randomized controlled trials, the combination of metformin and liraglutide may reduce the levels of the most atherogenic LDL subfraction and C-reactive protein in patients with coronary artery disease and new onset type 2 diabetes [7]. Compared to sitagliptin, liraglutide was also found to increase VEGF, which is a mediator of angiogenesis and might attenuate the adverse consequences of large vessel atherosclerosis by inducing the formation of collateral vessels in obese type 2 diabetic patients [8]. As recently summarized by Ussher et al, GLP-1RA-mediated cardiovascular protection could be mainly attributed to their vascular anti-inflammatory and anti-atherosclerotic actions, alongside improvements in heart glucose metabolism, fibrosis, oxidative stress, cardiomyocytes viability, and, even though to a small extent, in blood pressure [9].…”

Obesity and Endothelial Function

“…This finding suggests that a GLP-1 receptor agonist has beneficial effects on endothelial function by promoting brown adipocyte differentiation. However, the results of clinical studies regarding the effects of GLP-1 receptor agonists on endothelial function have been conflicting [ 174 , 175 , 176 , 177 ]. In addition, there is no information on the effects of semaglutide on endothelial function.…”