Once-weekly semaglutide‡ 2.

4 mg
• Overweight or obesity
(BMI ≥27 kg/m2) 1:1 N=17,604
• Established CV disease†

Semaglutide improves liver enzymes and fatty liver index in patients with obesity
• No prior history of diabetes Placebo
(HbA1c <6.5%) Scan QR code or visit the website
– below for:

and cardiovascular disease – results from the SELECT trial

Science Hub materials

https://sciencehub.novonordisk.com/congresses/aasld2024/

Sebastian M. Meyhöfer1,2, Bertrand Cariou3, Cintia Cercato4, Helen M. Colhoun5, John E. Deanfield6, Mette Skalshøi Kjær7, Ole Kleist Jeppesen7, A. Michael Lincoff8, Ildiko Lingvay9, Philip N. Newsome10, Newsome.html?cid=qr-g2ofexoofm

Stephen J. Nicholls , María De Los Angeles Quiroga Peláez , Ferruccio Santini , Arun J. Sanyal , Steven E. Kahn
11 7 12 13 14

Figure 1. SELECT trial design2,3 Figure 2. Ratio of liver enzymes to baseline over time Key result
Aim
• To assess the effects of semaglutide on liver enzymes and Once-weekly semaglutide‡ 2.4 mg ALT AST GGT
predicted hepatic steatosis in patients in the SELECT trial. 1.05 1.05 1.05
• Overweight or obesity ETD (95% CI): ETD (95% CI): ETD (95% CI):
(BMI ≥27 kg/m2) 1:1 N=17,604 –1.9 (–2.6, –1.2) –0.9 (–1.3, –0.5) –8.2 (–9.5, –6.8)
Introduction • Established CV disease† p<0.0001 p<0.0001 1.00 p<0.0001
• No prior history of diabetes Placebo 1.00 1.00
• Metabolic dysfunction-associated steatotic liver disease has (HbA1c <6.5%)

Ratio to baseline

Ratio to baseline

Ratio to baseline
been associated with increased cardiovascular (CV) risk in people 0.95
with obesity.1 †
Established CV disease: MI ≥60 days prior to screening, stroke ≥60 days prior to screening or symptomatic
PAD; NYHA class IV excluded; ‡Dose escalation was from week 4 to 16 with intervals of 4 weeks, and the 0.95 0.95
• The SELECT CV outcomes trial showed that treatment with the maintenance dose was event-driven to end of treatment period.

glucagon-like peptide-1 analog semaglutide resulted in a 20% BMI, body mass index; CV, cardiovascular; HbA1c, glycated hemoglobin; MI, myocardial infarction; 0.90
NYHA, New York Heart Association; PAD, peripheral artery disease.
reduction in the risk of major CV events in patients with overweight
or obesity and established atherosclerotic CV disease (ASCVD), and 0.90 0.90
Table 1. Baseline demographics and clinical characteristics 0.85
without diabetes.2
Semaglutide Placebo Overall
Characteristic
(n=8803) (n=8801) (N=17,604)
Methods Age, years, mean (SD) 61.6 (8.9) 61.6 (8.8) 61.6 (8.9)
0.85 0.85 0.80
0 26 52 78 104 0 26 52 78 104 0 26 52 78 104
• SELECT was a multicenter, randomized, double-blind, Sex, n (%)
Time from randomization (weeks) Time from randomization (weeks) Time from randomization (weeks)
placebo‑controlled, event-driven trial that enrolled 17,604 patients. Female 2448 (27.8) 2424 (27.5) 4872 (27.7)
– Patients aged ≥45 years were randomized (1:1) to receive Male 6355 (72.2) 6377 (72.5) 12,732 (72.3) Placebo Semaglutide
once‑weekly subcutaneous semaglutide 2.4 mg or placebo in Body weight, kg, mean (SD) 96.5 (17.5) 96.8 (17.8) 96.7 (17.7) Observed data from the in-trial period. Data are mean (± SEM). ETDs are for the treatment policy estimand. The post-baseline responses are analyzed using a mixed model for repeated measurements with treatment group as a fixed factor and baseline as a covariate, all nested within visit. Mean estimates are adjusted according to observed
addition to standard of care for CV disease prevention (Figure 1). BMI, kg/m2, mean (SD) 33.3 (5.0) 33.4 (5.0) 33.3 (5.0) baseline distribution.
Waist circumference, cm, mean (SD) 111.3 (13.1) 111.4 (13.1) 111.3 (13.1) ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; ETD, estimated treatment difference; GGT, gamma-glutamyl transferase; SEM, standard error of the mean.
Full methods have been published previously.2,3
HbA1c, %, mean (SD) 5.8 (0.34) 5.8 (0.3) 5.8 (0.3)
• This prespecified analysis assessed liver enzymes (alanine
Triglycerides, mg/dL, median (IQR) 134 (99–188) 135 (100–190) 135 (99–189)
aminotransferase [ALT], aspartate aminotransferase [AST],
HDL-C, mg/dL, median (IQR) 44 (37–52) 44 (37–52) 44 (37–52)
Figure 3. Mean change in FLI from baseline at week 104 Key result Figure 4. Mean change in body weight from baseline at week 1042 Discussion
and gamma-glutamyl transferase [GGT]) over 104 weeks.
LDL-C, mg/dL, median (IQR) 78 (61–102) 78 (61–102) 78 (61–102) Semaglutide Placebo Semaglutide Placebo
• Moreover, the fatty liver index (FLI), an algorithm based on body 0 0 • Excess body fat is a major risk factor for hepatic steatosis and
ALT, U/L, n† inflammation.
mass index, waist circumference, triglycerides, and GGT predictive
<24 4237 4273 8510 –0.9
of hepatic steatosis, was assessed over 104 weeks. –4 –2.5 – The observed decrease in FLI and liver enzymes in the

Change from baseline

≥24 4320 4290 8610
semaglutide arm is likely mediated by its concomitant and
AST, U/L, n†

Change from baseline

at week 104 (%)
Results <22 4265 4290 8555 –8 –4
significant effect on body weight loss.

at week 104 (%)

≥22 4349 4350 8699
• The observed reductions in ALT, AST, and GGT, along with
• Baseline characteristics were well balanced between study arms the substantial decrease in FLI, underscore the potential of
GGT, U/L, n† –12
(Table 1).2 semaglutide not only in addressing CV risk but also in concurrently
<30 4694 4689 9383
• ALT, AST, and GGT declined rapidly after initiation of semaglutide improving liver health.
30–<60 2846 2854 5700
treatment, reaching a nadir at 20 weeks, after which ALT and AST –16 –8
≥60 1185 1199 2384
increased over time while GGT remained stable (Figure 2).
FLI, U/L, n†
• The estimated treatment difference vs placebo at week 104 was –20 –18.6
<85 4247 4291 8538 –9.4
–1.9 U/L (95% confidence interval [CI] –2.6, –1.2; p<0.0001) for ALT; ≥85 4423 4395 8818
–0.9 U/L (95% CI –1.3, –0.5; p<0.0001) for AST; and –8.2 U/L (95% CI
–9.5, –6.8; p<0.0001) for GGT (Figure 2).
FIB-4 index, n† ETD (95% CI): –16.1 (–16.7, –15.6)
p<0.0001
–12 Conclusion
<1.17 4166 4122 8288
• The estimated treatment difference for FLI with semaglutide vs ETD (95% CI): –8.5 (–8.8, –8.3) • Semaglutide treatment resulted in a significant and rapid
≥1.17 4124 4173 8297 Observed data from the in-trial period. ETDs are for the treatment policy estimand. The responses were
placebo was –16.1 (95% CI –16.7, –15.6; p<0.0001; Figure 3). analyzed in the full analysis set using an ANCOVA with treatment as a fixed factor and baseline value as a p<0.0001 improvement in liver enzymes and FLI, suggesting a beneficial
†
Data available for 17,120 (ALT), 17,254 (AST), 17,467 (GGT), 17,356 (FLI), and 16,585 (FIB-4) patients at baseline.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; FIB-4, Fibrosis-4;
covariate. effect on liver health in patients with established ASCVD and
• Semaglutide treatment also resulted in a –9.4% mean change in ANCOVA, analysis of covariance; CI, confidence interval; ETD, estimated treatment difference; FLI, fatty Data are from the full analysis population. ETD is for the treatment policy estimand.
FLI, fatty liver index; GGT, gamma-glutamyl transferase; HbA1c, glycated hemoglobin; HDL-C, high density
liver index. CI, confidence interval; ETD, estimated treatment difference. without diabetes.
body weight over 104 weeks vs –0.9% with placebo (Figure 4). lipoprotein cholesterol; IQR, interquartile range; LDL-C, low density lipoprotein cholesterol; SD, standard deviation.

1
Clinical, Medical & Regulatory, Novo Nordisk Pharma GmbH, Mainz, Germany; 2Department of Internal Medicine 1 - Endocrinology & Diabetes, University Medical Centre Lübeck, Lübeck, Germany; 3Nantes Université, CHU Nantes, CNRS, INSERM, l’institut du thorax, Nantes, France; 4Obesity Unit, Department of Endocrinology, Hospital das
Clínicas, University of São Paulo, São Paulo, Brazil; 5Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK; 6Institute of Cardiovascular Sciences, University College London, London, UK; 7Novo Nordisk A/S, Søborg, Denmark; 8Department of Cardiovascular Medicine, Cleveland Clinic and Cleveland Clinic Lerner College References:
of Medicine of Case Western Reserve University, Cleveland, OH, USA; 9Department of Internal Medicine/Endocrinology and Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA; 10Institute of Hepatology, King’s College London and King’s College Hospital, London, UK; 11Victorian Heart
(1) Mantovani A et al. Lancet Gastroenterol Hepatol 2021;6:903–913; (2) Lincoff AM et al. N Engl J Med 2023;389:2221–2232; (3) Ryan DH et al. Am Heart J 2020;229:61–69.
Institute, Monash University, Melbourne, Victoria, Australia; 12Obesity and Lipodystrophy Centre, University Hospital of Pisa, Pisa, Italy; 13Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; 14VA Puget Sound Health Care System and University of Washington,
Seattle, WA, USA. Disclosures:
This trial was funded by Novo Nordisk A/S and is registered with ClinicalTrials.gov (NCT03574597). Editorial and administrative support was provided by Roxanna Munir, PhD, of Apollo, OPEN Health Communications, and funded by Novo Nordisk A/S, in accordance with Good Publication Practice (GPP) guidelines (www.ismpp.org/gpp-2022). ​ Sebastian M. Meyhöfer declares receiving consulting honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, esanum, Gilead, Ipsen, Lilly,
Presented at the AASLD Liver Meeting, November 15–19, 2024, San Diego, CA, USA.​ Novartis, Novo Nordisk, Sandoz, Sanofi; and research grants from AstraZeneca, Lilly, Novo Nordisk.

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