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)

Abstract

Aim: 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. Methods: Sixty-eight patients completed the 6-year follow-up and had an end-ofstudy (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.Results: 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 = À0.48, 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. Conclusions: 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

Hepatic steatosis and advanced hepatic fibrosis are independent predictors of long‐term mortality in acute myocardial infarction

“…63,64 In fact, the plethora of upcoming trials in the search for the first US Food and Drug Administration-approved medication for non-alcoholic steatohepatitis has led to promising data that describe the combined improvement in both liver and cardiovascular-related outcomes with the use of drugs such as peroxisome proliferator-activated receptor agonists, glucagon-like peptide-1 receptor agonists and sodiumglucose co-transporter-2 inhibitors. 17,[65][66][67][68] Several studies on peroxisome proliferator-activated receptor agonists and sodium-glucose cotransporter-2 inhibitors have also shown the reduction in liver biochemistry and/or hepatic fat content or fibrosis, as well as the improvement in cardiovascular outcomes, such as high-density lipoprotein levels and triglycerides, which are independent of diabetes status. [69][70][71] The present evidence on the combined improvement of hepatic steatosis and cardiovascular risk with current therapeutics appears promising; however, future mechanistic studies are warranted to explore the causal relationship between the two entities independent of metabolic bystanders, as well as the design of randomized controlled trials of pharmacological agents on the effect of hepatic steatosis in patients with AMI, will be an important next step.…”

“…Targeting common biological mechanisms of metabolic dysregulations that underlie hepatic steatosis and coronary artery disease, through exercise and dietary modifications, can help establish the unified goal in addressing liver and cardiovascular‐related endpoints 63,64 . In fact, the plethora of upcoming trials in the search for the first US Food and Drug Administration‐approved medication for non‐alcoholic steatohepatitis has led to promising data that describe the combined improvement in both liver and cardiovascular‐related outcomes with the use of drugs such as peroxisome proliferator‐activated receptor agonists, glucagon‐like peptide‐1 receptor agonists and sodium‐glucose co‐transporter‐2 inhibitors 17,65‐68 . Several studies on peroxisome proliferator‐activated receptor agonists and sodium‐glucose co‐transporter‐2 inhibitors have also shown the reduction in liver biochemistry and/or hepatic fat content or fibrosis, as well as the improvement in cardiovascular outcomes, such as high‐density lipoprotein levels and triglycerides, which are independent of diabetes status 69‐71 .…”

AWARE. A web application to rapidly assess cardiovascular risk in Type 2 Diabetes Mellitus.

“…Thanks to the intrinsic low risk of hypoglycaemia associated with GLP-1 RA of SGLT2i, these drugs allow to safely achieve the recommended A1c levels, even in patients with advanced diabetes, thus allowing more aggressive treatment of T2DM. Recently, several small studies in newly diagnosed T2DM patients showed that the use of a combination of multiple drugs with complementary mechanisms of action (metformin, pioglitazone, and exenatide) provides better outcomes compared with the sequential treatment with conventional medications (39)(40)(41). In conclusion, we believe that the use of the web app AWARE to evaluate CV risk and implement more aggressive earlier treatment with newer medications could represent a step forward to help preventing chronic severe and invalidating complications and premature death in T2DM.…”

Pioglitazone in diabetic kidney disease: forgotten but not gone

“…Early intensive triple therapy with MET, PIO and exenatide was shown to produce greater and more durable A1C reductions in patients with new-onset T2D compared to sequential add-on therapy with MET followed by SU and then basal insulin; patients treated with triple combination therapy experienced less hepatic steatosis and fibrosis compared to those in the conventional therapy group [ 162 , 163 ]. Improvement of painful diabetic neuropathy and corneal nerve regeneration were also demonstrated, while the generalizability of these results in other diabetic microvascular complications is anticipated [ 164 ].…”