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

Abstract

Background Exploratory analysis to determine the effect of semaglutide versus comparators on high-sensitivity C-reactive protein (hsCRP) in subjects with type 2 diabetes. Methods Trials of once-weekly subcutaneous (SUSTAIN 3) and once-daily oral (PIONEER 1, 2, 5) semaglutide with hsCRP data were analyzed. Subjects with type 2 diabetes (N = 2482) received semaglutide (n = 1328) or comparators (placebo, n = 339; exenatide extended-release, n = 405; empagliflozin, n = 410). hsCRP ratio to baseline at end-of-treatment was analyzed overall, by clinical cutoff (< 1.0, ≥ 1.0 to ≤ 3.0, or > 3.0 mg/L), by tertile, and by estimated glomerular filtration rate in PIONEER 5 (a trial which was conducted in a population with type 2 diabetes and chronic kidney disease [CKD]). Mediation analyses assessed the effect of change in glycated hemoglobin (HbA1c) and/or change in body weight (BW) on hsCRP reductions. Results Geometric mean baseline hsCRP was similar across trials (range 2.7–3.0 mg/L). Semaglutide reduced hsCRP levels by clinical cutoffs and tertiles from baseline to end-of-treatment in all trials versus comparators (estimated treatment ratios [ETRs] versus comparators: 0.70–0.76; p < 0.01) except versus placebo in PIONEER 5 (ETR [95% CI]: 0.83 [0.67–1.03]; p > 0.05). The effect of semaglutide on hsCRP was partially mediated (20.6–61.8%) by change in HbA1c and BW. Conclusions Semaglutide reduced hsCRP ratios-to-baseline versus comparators in subjects with type 2 diabetes (not significant with CKD). This effect was partially mediated via reductions in HbA1c and BW and potentially by a direct effect of semaglutide. Semaglutide appears to have an anti-inflammatory effect, which is being further investigated in ongoing trials. Trial registrations: ClinicalTrials.gov identifiers: NCT01885208 (first registered June 2013), NCT02906930 (first registered September 2016), NCT02863328 (first registered August 2016), NCT02827708 (first registered July 2016).

Protection against stroke with glucagon-like peptide-1 receptor agonists: a comprehensive review of potential mechanisms

“…These animal data are in line with findings from human studies [ 57 , 79 – 81 ]. For instance, in a placebo-controlled study of 24 obese patients with T2DM, exenatide treatment for 12 weeks exerted an anti-inflammatory effect independent of body weight reduction, as illustrated by reduced circulating levels of various pro-inflammatory mediators such as TNF-α, IL-1β, IL-6, serum amyloid A, and MMP-9 [ 79 ].…”

Effect of Temporal Trend in Inflammatory and Cholesterol Risk on the Prognosis of Percutaneous Coronary Intervention-Treated Patients with Contemporary Statin Therapy

“…Hence, glucose-lowering therapies with anti-inflammatory effects could be the optimal strategy for diabetic patients with high inflammatory risk after PCI treatment. Recently, exploratory analysis has substantiated the effectiveness of semaglutide in reducing the inflammatory level ratio-to-baseline versus comparators in diabetes mellitus patients, potentially by a direct effect of semaglutide, independent of HbA1c or body weight reduction [31,32]. The potential anti-inflammatory effect of semaglutide could be that semaglutide could effectively lower the level of CD163, a biomarker for macrophage activation, and reversal changes in leukocyte recruitment, rolling, and adhesion/extravasation related to the inflammatory response were also observed in animal models after semaglutide treatment [33].…”

Effect of Temporal Trend in Inflammatory and Cholesterol Risk on the Prognosis of Percutaneous Coronary Intervention-Treated Patients with Contemporary Statin Therapy

“…Hence, glucose-lowering therapies with antiin ammatory effects could be the optimal strategy for diabetic patients with high in ammatory risk after PCI treatment. Recently, exploratory analysis has substantiated the effectiveness of semaglutide in reducing the in ammatory level ratio-to-baseline versus comparators in diabetes mellitus patients, potentially by a direct effect of semaglutide, independent of HbA1c or body weight reduction [31,32]. The potential anti-in ammatory effect of semaglutide could be that semaglutide could effectively lower the level of CD163, a biomarker for macrophage activation, and reversal changes in leukocyte recruitment, rolling, and adhesion/extravasation related to the in ammatory response were also observed in animal models after semaglutide treatment [33].…”