Combination therapy with pioglitazone/exenatide/metformin reduces the prevalence of hepatic fibrosis and steatosis: The efficacy and durability of initial combination therapy for type 2 diabetes (EDICT)
Funding information: Astra Zeneca; National Institute of Diabetes and Digestive and Kidney Diseases, Grant/Award Numbers: 1R01DK103841-01A1, R01DK107680; American Diabetes Association (ADA), Grant/Award Number: R01DK24092-34
To compare the efficacy of triple therapy (metformin/exenatide/pioglitazone) versus stepwise conventional therapy (metformin → glipizide → glargine insulin) on liver fat content and hepatic fibrosis in newly diagnosed, drug-naïve patients with type 2 diabetes.
Sixty-eight patients completed the 6-year follow-up and had an end-of-study (EOS) FibroScan to provide measures of steatosis (controlled attenuation parameter [CAP] in dB/m) and fibrosis (liver stiffness measurement [LSM] in kPa); 59 had magnetic resonance imaging-proton density fat fraction (MRI-PDFF) to measure liver fat.
At EOS, HbA1c was 6.8% and 6.0% in triple and conventional therapy groups, respectively (P = .0006). Twenty-seven of 39 subjects (69%) receiving conventional therapy had grade 2/3 steatosis (CAP, FibroScan) versus nine of 29 (31%) in triple therapy (P = .0003). Ten of 39 (26%) subjects receiving conventional therapy had stage 3/4 fibrosis (LSM) versus two of 29 (7%) in triple therapy (P = .04). Conventional therapy subjects had more liver fat (MRI-PDFF) than triple therapy (12.9% vs. 8.8%, P = .03). The severity of steatosis (CAP) (r = 0.42, P < .001) and fibrosis (LSM) (r = −0.48, P < .001) correlated inversely with the Matsuda Index of insulin sensitivity, but not with percentage body fat. Aspartate aminotransferase (AST) to Platelet Ratio Index (APRI), non-alcoholic fatty liver disease fibrosis score (NFS), plasma AST, and alanine aminotransferase (ALT) all decreased significantly with triple therapy, but only the decrease in plasma AST and ALT correlated with the severity of steatosis and fibrosis at EOS.
At EOS, subjects with type 2 diabetes treated with triple therapy had less hepatic steatosis and fibrosis versus conventional therapy; the severity of hepatic steatosis and fibrosis were both strongly and inversely correlated with insulin resistance; and changes in liver fibrosis scores (APRI, NFS, Fibrosis-4, and AST/ALT ratio) have limited value in predicting response to therapy.
CONFLICT OF INTEREST
RAD is a member of the Scientific Board and Speakers Bureau of Astra Zeneca. RAD has also received research grants from AstraZeneca. EC is on the Bayer Pharma Advisory Board. None of the other authors have any conflicts of interest to declare.
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TABLE S1 Patient characteristics and laboratory tests at study end. Treatment failure represents the percentage of patients with HbA1c > 6.5% despite maximum therapy. Values represent the mean ± SEM
Table S2 Effect of Conventional Therapy and Triple Therapy on plasma AST and ALT levels stratified into tertiles according to baseline ALT and AST concentration. EOS = End of Study. Values represent the mean ± SEM
Table S3 Standardized beta coefficient of multivariate linear regression model
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FIGURE S1 Relationship between liver fat content (MRS-PDFF) and liver fibrosis score (LSM)
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FIGURE S2 Relationship between log (1/HOMA-IR) and log liver fibrosis score (LSM)
|dom14650-sup-0004-FigureS3.jpgJPEG image, 263.3 KB||
FIGURE S3 Relationship between log (1/HOMA-IR) and liver fat content (CAP) by FibroScan
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