PNPLA3 Risk Allele Association With ALT Response to Semaglutide Treatment

Abstract

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are approved for treatment of type 2 diabetes mellitus (T2DM) and weight loss in people with overweight, and semaglutide is in phase 3 clinical trials for treatment of nonalcoholic fatty liver disease (NAFLD). GLP-1RAs reduce alanine aminotransferase (ALT) levels, and in phase 2 trials, semaglutide resulted in histologic improvement in steatohepatitis.1Armstrong M.J. et al.Lancet. 2016; 387: 679-690Abstract Full Text Full Text PDF PubMed Scopus (1275) Google Scholar,2Newsome P.N. et al.N Engl J Med. 2021; 384: 1113-1124Crossref PubMed Scopus (666) Google Scholar Genetics may modify response to NAFLD treatment. In one recent systematic review, the PNPLA3-rs738409-G genotype associated with increased hepatic steatosis and fibrosis was associated with lower response to omega-3 fatty acids and dapagliflozin but greater response to lifestyle interventions.3Boeckmans J. et al.Liver Int. 2023; Google Scholar To our knowledge, no studies have investigated the impact of PNPLA3 genotype on GLP-1RA treatment effect. Notably, several weight-independent pathways by which GLP-1RAs decrease steatohepatitis, including lipid transport, beta oxidation, and de novo lipogenesis, are altered in the PNPLA3-rs738409-G variant, suggesting that the PNPLA3 genotype may modify GLP-1RA treatment effects.4Luukkonen P.K. et al.J Hepatol. 2022; 76: 526-535Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Our primary aim was to evaluate whether the PNPLA3 genotype affects treatment response to semaglutide. We conducted a retrospective study of consecutive patients treated with semaglutide at Michigan Medicine before January 1, 2022. Genetic data were available through the Michigan Genomics Initiative, in which research participants were genotyped on the Illumina HumanCoreExome v.12.1 array with genotypes imputed to the Trans-Omics for Precision Medicine reference panel using Michigan Imputation Server v.1.5.7.5Das S. et al.Nat Geney. 2016; 48: 1284-1287Crossref PubMed Scopus (1861) Google Scholar,6Zawistowski M. et al.Cell Genom. 2023; 3100257Google Scholar Patients were excluded if semaglutide treatment lasted for <3 months, semaglutide dosage was <1.0 mg weekly, or if another GLP-1RA was started following semaglutide treatment. The index date was the first date of semaglutide treatment, and follow-up dates were defined as 6 (3–9), 12 (9–18), or 24 (18–36) months after the index date, with ranges allowed to minimize missingness. The primary outcome was change in ALT during follow-up, with ALT defined either as a continuous variable or as a 17-point reduction, which is associated with histologic improvement.7Huang D.Q. et al.Clin Gastroenterol Hepatol. 2022; 21: 2682-2685.e4Abstract Full Text Full Text PDF Scopus (8) Google Scholar,8Loomba R. et al.Gastroenterology. 2019; 156: 88-95.e5Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar The primary predictor was PNPLA3-rs738409 genotype, defined as CC or CC/GG. Continuous variables were compared via nonparametric Wilcoxon rank sum testing. Depending on statistical assumptions, categorical variables were evaluated using either chi-square or Fisher exact tests. Univariable and multivariable logistic regression analyses were performed to examine the relationship between PNPLA3 genotype and decrease in ALT. Regression sensitivity analyses were performed after excluding patients taking oral semaglutide, those with normal baseline ALT, or both groups. A cutoff of P < .05 was used for statistical significance. For each analysis, participants with missing data were excluded. A total of 220 patients met inclusion criteria (Supplementary Table 1). The average age was 59.2 years, and 141 (64.1%) were female. Mean baseline body mass index (BMI) was 36.9 kg/m2; 172 (78.2%) had T2DM, 184 (83.6%) had dyslipidemia, 180 (81.8%) had hypertension, and 77 (35.0%) had nonalcoholic fatty liver disease (International Classification of Diseases, 9th Revision, 571.8 or 10th Revision, K74.0 or K75.81). Mean baseline ALT was 29 (95% confidence interval [CI], 26–32) and 35 (95% CI, 30–40) (P = .10) in patients with PNPLA3-rs738409-CC vs CG or GG genotypes, respectively. Average semaglutide treatment duration was 1.6 years. Most (93.6%) took subcutaneous semaglutide, with the most common doses being 1 mg (45%), 2.4 mg (24%), and 2 mg weekly (17%); the remainder (6.4%) took oral semaglutide. PNPLA3-rs738409 genotype was CC, CG, and GG in 126, 81, and 13 patients, respectively. Of the patients, 47% had taken another GLP-1RA within the last 6 months, with the primary reasons for switching to semaglutide being inadequate glycemic control or weight loss, change in insurance coverage, or supply shortage of the previous GLP-1RA. There was no significant difference in PNPLA3-rs738409 genotype between those who had vs had not previously taken another GLP1-RA (P = .60). There was no difference between ALT or BMI 12 months before semaglutide initiation vs at baseline, overall or based on PNPLA3 genotype. After 6 months of semaglutide treatment, change in ALT did not significantly differ across dichotomized PNPLA3 genotype. However, 1 year after semaglutide initiation, ALT decreased more in people carrying at least 1 PNPLA3 risk allele: a mean ALT decrease of 9.0 (95% CI, 4.5–13.4) vs 2.5 (95% CI, –0.1 to 5.1) U/L in individuals with the CG/GG vs CC CC genotype (P = .012). A similar pattern held at 2 years, with a mean ALT decrease of 10.0 (95% CI, 6.1–13.8) and 2.2 (95% CI, –1.1 to 5.4] U/L in the CG/GG vs CC genotypes, respectively (P = .031). BMI changes were similar across PNPLA3 genotype (mean BMI decrease, 7.0% vs 6.3% in CC and CG/GG genotypes, respectively; P = .93), and in an interaction model, the BMI-PNPLA3 interaction term was not significant. We conducted logistic regression analyses evaluating the odds of a decrease in ALT at 12 or 24 months based on PNPLA3 genotype (Supplementary Table 2). In univariable analysis, PNPLA3 group (CC vs CG/GG) was associated with odds ratios of 3.04 (95% CI, 1.30–7.08; P = .010) and 2.81 (95% CI, 1.20–6.60; P = .018) of having a 17-point decrease in ALT at years 1 and 2, respectively. We conducted additional analyses adjusted for age, sex, TM6SF2-rs58542926 genotype, and HSD17B13- rs72613567 genotype (model 1); model 1 variables plus change in BMI and diabetes status (model 2); and model 2 variables plus prior use of GLP-1RA use (model 3). Finally, we conducted an analysis including only individuals with elevated baseline ALT (>19/30 U/L in women/men, respectively). In all analyses, the associations between carriage of PNPLA3 risk alleles and halving of ALT were consistent. Change in BMI strongly correlated with ALT response, whereas change in hemoglobin A1c and low-density lipoprotein did not (data not shown). Change in year 2 vs baseline Fibrosis 4 scores was not affected by PNPLA3 genotype (data not shown). Among patients receiving semaglutide, ALT decreased more in people with PNPLA3 risk alleles despite similar baseline ALT. Study limitations include the surrogate outcome of ALT change, though the threshold we used does correlate with histologic reduction in steatohepatitis.2Newsome P.N. et al.N Engl J Med. 2021; 384: 1113-1124Crossref PubMed Scopus (666) Google Scholar,7Huang D.Q. et al.Clin Gastroenterol Hepatol. 2022; 21: 2682-2685.e4Abstract Full Text Full Text PDF Scopus (8) Google Scholar Also, many patients had near-normal baseline ALT. In addition, our cohort was small, and only 13 people had the PNPLA3-rs738409-GG genotype. Finally, not all patients had NAFLD, though the prevalence was likely high based on high prevalence of obesity (80%) and T2DM (78%). People with PNPLA3-rs738409-G risk alleles may represent a select group for treatment with GLP-1RAs because they are at high baseline risk of progression to cirrhosis9Chen V.L. et al.Gastroenterology. 2023; 164: 966-977.e17Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar and also because they may experience greater decreases in ALT, which needs to be correlated further with response, in large clinical trials, using noninvasive tests and liver histology. Figure 1. The Michigan Genomics Initiative includes Matthew Zawistowski and Sebastian Zöllner from the Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan. The authors acknowledge the Michigan Genomics Initiative participants, Precision Health at the University of Michigan, the University of Michigan Medical School Central Biorepository, the University of Michigan Advanced Genomics Core, and the University of Michigan Medical School Data Office for Clinical and Translational Research for providing data and specimen storage, management, processing, and distribution services and the Center for Statistical Genetics in the Department of Biostatistics at the School of Public Health for genotype data curation, imputation, and management in support of the research reported in this manuscript. Esteban Urias, MD (Data curation: Lead; Formal analysis: Lead; Writing – original draft: Lead). Nicholas Tedesco, MS (Formal analysis: Lead; Writing – review & editing: Equal). Antonino Oliveri, PhD (Formal analysis: Supporting; Writing – review & editing: Supporting). Chinmay Raut, BS (Formal analysis: Supporting; Writing – review & editing: Supporting). Elizabeth K. Speliotes, MD, PhD, MPH (Formal analysis: Supporting; Writing – review & editing: Equal). Vincent L. Chen, MD, MS (Conceptualization: Lead; Formal analysis: Supporting; Supervision: Lead; Writing – review & editing: Lead). Supplementary Table 1Baseline Clinical Characteristics of the PNPLA3-rs738409 GenotypeVariablers738409-CC (n = 126)rs738409-CG or GG (n = 94)P valueDemographics Age, y, mean (SD)(n = 220)59.3 (11.3)59.0 (10.9).58 Female, n (%)(n = 220)80 (63.5)61 (64.9).94 Race/ethnicity, n (%)(n = 220)Asian5 (4.0)4 (4.3).061Black18 (14.3)5 (5.3)Hispanic2 (1.6)6 (6.4)White95 (75.4)77 (81.9)Other6 (4.8)2 (2.1) Prior GLP-1RA treatment, n (%)(n = 220)62 (49.2)42 (44.7).60Metabolic comorbidities Baseline body mass index, kg/m2, mean (SD)(n = 204)37.4 (7.0)36.3 (6.0).45 Type 2 diabetes, n (%)(n = 220)97 (77.0)75 (79.8).74 Dyslipidemia, n (%)(n = 215)106 (84.1)78 (83.0).93 Hypertension, n (%)(n = 215)101 (80.2)79 (84.0).58 Nonalcoholic fatty liver disease diagnosis code, n (%)(n = 215)37 (29.4)40 (42.6).06Laboratory values, mean (SD) Alanine aminotransferase, U/L (n = 195)29.4 (17.1)34.8 (25.9).19 Aspartate aminotransferase, U/L (n = 177)26.4 (10.6)29.4 (17.7).62 Alkaline phosphatase, U/L (n = 177)85.6 (26.3)85.8 (29.3).87 Total bilirubin, mg/dL (n = 177)0.53 (0.25)0.53 (0.23).80 Albumin, mg/dL (n = 183)4.41 (0.26)4.38 (0.26).27 Platelet count, K/μL (n = 151)259.8 (60.0)268.6 (72.7).52 Creatinine, mg/dL (n = 196)0.97 (0.27)0.96 (0.32).34NOTE. Descriptive statistics are shown based on PNPLA3-rs738409 genotype.SD, standard deviation. Open table in a new tab Supplementary Table 2Associations Between PNPLA3-rs738409-G Carriage and Reduction in Alanine AminotransferaseModelYear 1Year 2Odds ratioP valueOdds ratioP valuePrimary analysis: all patients Univariable (n = 165)3.04 (1.30–7.08).0102.81 (1.20–6.60).018 Model 1 (n = 165)3.30 (1.38–7.91).0073.20 (1.30–7.83).011 Model 2 (n = 127)3.95 (1.27–12.33).0183.75 (1.14–12.33).030 Model 3 (n = 127)3.65 (1.13–11.73).0303.63 (1.06–12.35).039Sensitivity analysis: exclude patients with normal baseline ALT Univariable (n = 106)4.05 (1.63–10.07).0033.67 (1.47–9.16).005 Model 1 (n = 106)4.32 (1.68–11.13).0024.16 (1.58–10.95).004 Model 2 (n = 86)5.21 (1.57–17.25).0074.72 (1.37–16.26).014Model 3 (n = 86)4.73 (1.39–16.06).0134.58 (1.29–16.28).019Sensitivity analysis: include only subcutaneous semaglutide Univariable (n = 154)3.89 (1.51–10.03).0053.59 (1.38–9.32).009 Model 1 (n = 154)4.15 (1.58–10.93).0043.98 (1.49–10.69).006 Model 2 (n = 121)4.74 (1.38–16.36).0144.78 (1.29–17.71).019 Model 3 (n = 121)4.61 (1.29–16.47).0195.01 (1.28–19.58).020NOTE. Effects are shown per allele of PNPLA3-rs738409-G. Normal baseline ALT was defined as <19/30 U/L for women/men, respectively. Model 1: adjusted for TM6SF2-rs58542926-T and HSD17B13-rs72613567-TA genotypes, age, and sex. Model 2: adjusted for model 1 covariates, change in body mass index from year 1 or 2 vs baseline, and diabetes status. Model 3: adjusted for model 2 covariates and recent (<6 months) use of a glucagon-like peptide-1 receptor agonist other than semaglutide. Open table in a new tab NOTE. Descriptive statistics are shown based on PNPLA3-rs738409 genotype. SD, standard deviation. NOTE. Effects are shown per allele of PNPLA3-rs738409-G. Normal baseline ALT was defined as <19/30 U/L for women/men, respectively. Model 1: adjusted for TM6SF2-rs58542926-T and HSD17B13-rs72613567-TA genotypes, age, and sex. Model 2: adjusted for model 1 covariates, change in body mass index from year 1 or 2 vs baseline, and diabetes status. Model 3: adjusted for model 2 covariates and recent (<6 months) use of a glucagon-like peptide-1 receptor agonist other than semaglutide.

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