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 (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.

Fig. 1

Ratios to baseline at end-of-treatment for hsCRP with semaglutide and comparators by trial. ‘On-treatment without rescue medication’ data from the full analysis set. Ratios to baseline were analyzed using a mixed model for repeated measurements with treatment as categorical fixed effect and baseline hsCRP value (log-transformed) as covariate, all nested within visit, and an unstructured residual covariance matrix on log-transformed values. CI confidence interval; exenatide ER exenatide extended-release; ETR estimated treatment ratio; hsCRP high-sensitivity C-reactive protein; N number of subjects with available hsCRP data; s.c. subcutaneous

Fig. 2

Ratio to baseline at end-of-treatment for hsCRP by trial according to clinical cutoffs. Panel (a) shows SUSTAIN 3 data, panel (b) PIONEER 1 data, panel (c) PIONEER 2 data, and panel (d) PIONEER 5 data. ‘On-treatment without rescue medication’ data from the full analysis set. Ratios to baseline were analyzed using a mixed model for repeated measurements with treatment by hsCRP groups as categorical fixed effects and baseline hsCRP value (log-transformed) as covariate, all nested within visit, and an unstructured residual covariance matrix on log-transformed values. Clinical cut-offs used in this analysis were < 1.0, ≥ 1.0 to ≤ 3.0, and > 3.0 mg/L. CI confidence interval; ETR estimated treatment ratio; exenatide ER exenatide extended-release; hsCRP high-sensitivity C-reactive protein; N number of subjects with available hsCRP data; s.c. subcutaneous

Fig. 2

Ratio to baseline at end-of-treatment for hsCRP by trial according to clinical cutoffs. Panel (a) shows SUSTAIN 3 data, panel (b) PIONEER 1 data, panel (c) PIONEER 2 data, and panel (d) PIONEER 5 data. ‘On-treatment without rescue medication’ data from the full analysis set. Ratios to baseline were analyzed using a mixed model for repeated measurements with treatment by hsCRP groups as categorical fixed effects and baseline hsCRP value (log-transformed) as covariate, all nested within visit, and an unstructured residual covariance matrix on log-transformed values. Clinical cut-offs used in this analysis were < 1.0, ≥ 1.0 to ≤ 3.0, and > 3.0 mg/L. CI confidence interval; ETR estimated treatment ratio; exenatide ER exenatide extended-release; hsCRP high-sensitivity C-reactive protein; N number of subjects with available hsCRP data; s.c. subcutaneous

Fig. 3

Mediation of hsCRP by change in HbA_1c and/or body weight. Panel (a) shows mediation of hsCRP by HbA_1c, panel (b) by body weight, and panel (c) by HbA_1c and body weight combined, all according to trial and with pooled semaglutide arms versus comparators. The indirect effect is the effect of semaglutide versus comparator on change in hsCRP that was caused by its effect through change on HbA_1c and/or BW. The direct effect is the effect of semaglutide versus comparator on change in hsCRP independent of change in HbA_1c and/or BW. The total effect was calculated by adding the indirect effect to the direct effect. The proportion mediated was calculated by dividing the indirect effect by the total effect × 100. Data from the ‘on-treatment without rescue medication’ period. Mediation was analyzed with mixed models for repeated measurements, adjusted for relevant mediators at baseline: HbA_1c (panel a), BW (panel b), BW and HbA_1c (panel c); and furthermore adjusted for additional covariates at baseline: log(hsCRP), age, sex, eGFR (Chronic Kidney Disease–Epidemiology Collaboration 2009), body mass index, statins (yes/no), insulin treatment (PIONEER 5 analyses only), metformin treatment (SUSTAIN 3 and PIONEER 5 analyses only), and HbA_1c (panel b only). Mediator data were only taken from the visits where hsCRP was assessed for estimation of the direct effect. BW body weight; CI confidence interval; eGFR estimated glomerular filtration rate; HbA_1c glycated hemoglobin; hsCRP high-sensitivity C-reactive protein