The effect of dapagliflozin on alanine aminotransferase as a marker of liver inflammation: updated results from the ABCD dapagliflozin audit
Keywords:dapagliflozin, real-world, alanine aminotransferase (ALT), non-alcoholic fatty liver disease, SGLT-2
Introduction: People with type 2 diabetes are known to be at increased risk of non-alcoholic fatty liver disease (NAFLD). There is increasing evidence of diabetes treatments with benefits of also improving NAFLD. Although mostly focused on glucagon-like peptide 1 agonists, sodium-glucose linked transporter 2 inhibitors may also have some promise in improving markers of NAFLD.
Method: Data were extracted from the ABCD nationwide dapagliflozin audit tool. Alanine aminotransferase (ALT) was available in these data and was used as a marker of liver inflammation. Patients were stratified based on baseline ALT levels to see if this predicted response to treatment.
Results: 1,873 patients were included for analysis (mean±SD age 58.7±10 years, 60.8% male, median duration of diabetes 3.5 years (IQR 1.5–9)) and were followed up in this study for an average of 11.4 months. Where known (n=280), 60.8% of these were Caucasian. Baseline HbA1c was 78±17.2 mmol/mol, weight 102.1±22.5 kg and body mass index (BMI) 34.2±7.6 kg/m2. Median ALT reduction overall was 4 U/L (95% CI 3 to 4; p<0.001). Reductions in weight (3.2 kg; 95% CI 2.9 to 3.5), BMI (0.9 kg/m2, 95% CI 0.6 to 1.2) and HbA1c (10.8 mmol/mol, 95% CI 10.1 to 11.5) (0.9%, 95% CI 0.8% to 1.0%) were all significant (p<0.001). Where ALT was elevated at baseline (>19 U/L female; >30 U/L male), the median reduction in ALT was 5 U/L in women (95% CI 4 to 6; p<0.0001) and 10 U/L in men (95% CI 8 to 11; p<0.0001). Stratified into three groups by ALT using the male reference range and twice this, there were reductions in ALT in all groups, which was greatest (24 U/L 95% CI 20 to 27) in the subgroup with baseline ALT >59 U/L.
Conclusion: Our observational data suggest significant reductions in ALT as a possible marker of liver inflammation in those taking dapagliflozin. This appears to be greatest in those with the most elevated levels at baseline.
Targher, G., et al., Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care, 2007. 30(5): p. 1212-8.
Targher, G., G. Marchesini, and C.D. Byrne, Risk of type 2 diabetes in patients with non-alcoholic fatty liver disease: Causal association or epiphenomenon? Diabetes & metabolism, 2016. 42(3): p. 142-156.
Hazlehurst, J.M., et al., Non-alcoholic fatty liver disease and diabetes.
Metabolism, 2016. 65(8): p. 1096-108.
Rinella, M.E., Nonalcoholic fatty liver disease: a systematic review. Jama, 2015. 313(22): p. 2263-73.
Bril, F. and K. Cusi, Management of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes: A Call to Action. Diabetes Care, 2017. 40(3): p. 419-430.
Musso, G., et al., Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials. Diabetologia, 2012. 55(4): p. 885-904.
Suzuki, A., et al., Values and limitations of serum aminotransferases in clinical trials of nonalcoholic steatohepatitis. Liver Int, 2006. 26(10): p. 1209-16.
Ferrannini, E., et al., Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care, 2010. 33(10): p. 2217-24.
Furtado, R.H.M., et al., Dapagliflozin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus and Previous Myocardial Infarction. Circulation, 2019. 139(22): p. 2516-2527.
Jabbour, S.A., et al., Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24-week, multicenter, randomized, double-blind, placebo-controlled study. Diabetes Care, 2014. 37(3): p. 740-50.
Kato, E.T., et al., Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus. Circulation, 2019. 139(22): p. 2528-2536.
Mosenzon, O., et al., Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial. Lancet Diabetes Endocrinol, 2019. 7(8): p. 606-617.
Wilding, J., et al., Dapagliflozin therapy for type 2 diabetes in primary care: Changes in HbA1c, weight and blood pressure over 2 years follow-up. Prim Care Diabetes, 2017. 11(5): p. 437-444.
Wilding, J.P., et al., Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann Intern Med, 2012. 156(6): p. 405-15.
Wilding, J.P.H., et al., Glycaemic, weight, and blood pressure changes associated with early versus later treatment intensification with dapagliflozin in United Kingdom primary care patients with type 2 diabetes mellitus. Diabetes Res Clin Pract, 2019. 155: p. 107791.
Armstrong, M.J., et al., Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: individual patient data meta-analysis of the LEAD program. Alimentary pharmacology & therapeutics, 2013. 37(2): p. 234-242.
Choi, D.H., et al., Effect of Dapagliflozin on Alanine Aminotransferase Improvement in Type 2 Diabetes Mellitus with Non-alcoholic Fatty Liver Disease. Endocrinology and metabolism (Seoul, Korea), 2018. 33(3): p. 387-394.
Shimizu, M., et al., Evaluation of the effects of dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on hepatic steatosis and fibrosis using transient elastography in patients with type 2 diabetes and non-alcoholic fatty liver disease. Diabetes, obesity & metabolism, 2019. 21(2): p. 285-292.
Bajaj, H.S., et al., SGLT2 inhibitors and incretin agents: Associations with alanine aminotransferase activity in type 2 diabetes. Diabetes & metabolism, 2018. 44(6): p. 493-499.
Prati, D., et al., Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med, 2002. 137(1): p. 1-10.
Suga, T., et al., SGLT1 in pancreatic alpha cells regulates glucagon secretion in mice, possibly explaining the distinct effects of SGLT2 inhibitors on plasma glucagon levels. Mol Metab, 2019. 19: p. 1-12.
Qiang, S., et al., Treatment with the SGLT2 inhibitor luseogliflozin improves nonalcoholic steatohepatitis in a rodent model with diabetes mellitus. Diabetology & metabolic syndrome, 2015. 7: p. 104-104.
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