Effect of semaglutide on liver enzymes and markers of inflammation in subjects with type 2 diabetes and/or obesity

Abstract

Background: Obesity and type 2 diabetes are drivers of non-alcoholic fatty liver disease (NAFLD). Glucagon-like peptide-1 analogues effectively treat obesity and type 2 diabetes and may offer potential for NAFLD treatment.

Aim: To evaluate the effect of the glucagon-like peptide-1 analogue, semaglutide, on alanine aminotransferase (ALT) and high-sensitivity C-reactive protein (hsCRP) in subjects at risk of NAFLD.

Methods: Data from a 104-week cardiovascular outcomes trial in type 2 diabetes (semaglutide 0.5 or 1.0 mg/week) and a 52-week weight management trial (semaglutide 0.05-0.4 mg/day) were analysed. Treatment ratios vs placebo were estimated for ALT (both trials) and hsCRP (weight management trial only) using a mixed model for repeated measurements, with or without adjustment for change in body weight.

Results: Elevated baseline ALT (men >30 IU/L; women >19 IU/L) was present in 52% (499/957) of weight management trial subjects. In this group with elevated ALT, end-of-treatment ALT reductions were 6%-21% (P<0.05 for doses≥0.2 mg/day) and hsCRP reductions 25%-43% vs placebo (P < 0.05 for 0.2 and 0.4 mg/day). Normalisation of elevated baseline ALT occurred in 25%-46% of weight management trial subjects, vs 18% on placebo. Elevated baseline ALT was present in 41% (1325/3268) of cardiovascular outcomes trial subjects. In this group with elevated ALT, no significant ALT reduction was noted at end-of-treatment for 0.5 mg/week, while a 9% reduction vs placebo was seen for 1.0 mg/week (P = 0.0024). Treatment ratios for changes in ALT and hsCRP were not statistically significant after adjustment for weight change.

Conclusions: Semaglutide significantly reduced ALT and hsCRP in clinical trials in subjects with obesity and/or type 2 diabetes.

Figure 1

Distribution of baseline fibrosis scores (A) age‐unadjusted; and (B) age‐adjusted. FIB‐4, Fibrosis 4 Index; NFS, non‐alcoholic fatty liver disease Fibrosis Score

Figure 2

Estimated (mixed model for repeated measurements) mean ALT changes from baseline by treatment group and study visit for individuals with high baseline ALT in (A) weight management trial NCT02453711 and (B) cardiovascular outcomes trial SUSTAIN‐6. ALT, alanine aminotransferase

Figure 3

Treatment vs placebo ratios for change in ALT from baseline to weeks 28 or 52 in weight management trial NCT02453711 (A) unadjusted for change in body weight; and (B) adjusted for change in body weight. ALT, alanine aminotransferase; CI, confidence interval; OD, once daily

Figure 4

Normalisation of ALT at week 52 among subjects with elevated baseline ALT in weight management trial NCT02453711. ALT, alanine aminotransferase

Figure 5

Treatment vs placebo ratios for high‐sensitivity C‐reactive protein change from baseline to weeks 28 or 52 in weight management trial NCT02453711 (A) unadjusted for change in body weight; and (B) adjusted for change in body weight. ALT, alanine aminotransferase; CI, confidence interval; OD, once daily

Figure 6

Proportion of subjects in weight management trial NCT02453711 with metabolic syndrome at baseline, week 28 and week 52 of treatment with once‐daily semaglutide or placebo (observed data). ALT, alanine aminotransferase. Metabolic syndrome was defined as three or more of: waist circumference ≥89 cm (women) or ≥102 cm (men); triglycerides ≥1.7 mmol/L; high‐density lipoprotein‐cholesterol <1.3 mmol/L (women) or <1.04 mmol/L (men); systolic blood pressure ≥130 mmHg and diastolic blood pressure ≥85 mmHg; fasting plasma glucose ≥5.6 mm/L