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

Ofri Mosenzon; Matthew S Capehorn; Alessandra De Remigis; Søren Rasmussen; Petra Weimers; Julio Rosenstock

doi:10.1186/s12933-022-01585-7

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

Cardiovasc Diabetol. 2022 Sep 2;21(1):172. doi: 10.1186/s12933-022-01585-7.

Authors

Ofri Mosenzon¹, Matthew S Capehorn², Alessandra De Remigis³, Søren Rasmussen³, Petra Weimers³, Julio Rosenstock⁴

Affiliations

¹ Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, PO Box 12000, Jerusalem, Israel. ofrim@hadassah.org.il.
² Clifton Medical Centre, Rotherham Institute for Obesity, Rotherham, UK.
³ Novo Nordisk A/S, Søborg, Denmark.
⁴ Velocity Clinical Research at Medical City, Dallas, TX, USA.

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 (HbA_1c) 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 HbA_1c 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 HbA_1c 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).

Keywords: Body weight; Chronic kidney disease; GLP-1RAs; HbA1c; High-sensitivity C-reactive protein; Inflammation; PIONEER; SUSTAIN; Semaglutide; Type 2 diabetes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Body Weight
C-Reactive Protein* / analysis
C-Reactive Protein* / drug effects
Diabetes Mellitus, Type 2* / drug therapy
Glucagon-Like Peptides* / pharmacology
Glycated Hemoglobin / analysis
Humans
Randomized Controlled Trials as Topic
Renal Insufficiency, Chronic / drug therapy
Treatment Outcome

Substances

Glycated Hemoglobin A
semaglutide
Glucagon-Like Peptides
C-Reactive Protein

Associated data

ClinicalTrials.gov/NCT02906930
ClinicalTrials.gov/NCT02863328
ClinicalTrials.gov/NCT02827708
ClinicalTrials.gov/NCT01885208