Effect of canagliflozin treatment on hepatic triglyceride content and glucose metabolism in patients with type 2 diabetes

Abstract

Aim: To evaluate the impact of the sodium glucose co-transporter 2 inhibitor canagliflozin on intrahepatic triglyceride (IHTG) accumulation and its relationship to changes in body weight and glucose metabolism. Materials and methods:In this double-blind, parallel-group, placebo-controlled, 24-week trial subjects with inadequately controlled type 2 diabetes mellitus (T2DM; HbA1c = 7.7% AE 0.7%) from two centres were randomly assigned (1:1) to canagliflozin 300 mg or placebo. We measured IHTG by proton-magnetic resonance spectroscopy (primary outcome), hepatic/muscle/ adipose tissue insulin sensitivity during a 2-step euglycaemic insulin clamp, and beta-cell function during a mixed meal tolerance test. Analyses were per protocol. Results: Between 8 September 2014-13 June 2016, 56 patients were enrolled. Canagliflozin reduced HbA1c (placebo-subtracted change: −0.71% [−1.08; −0.33]) and body weight (−3.4% [−5.4; −1.4]; both P ≤ 0.001). A numerically larger absolute decrease in IHTG occurred with canagliflozin (−4.6% [−6.4; −2.7]) versus placebo (−2.4% [−4.2; −0.6]; P = 0.09). In patients withnon-alcoholic fatty liver disease (n = 37), the decrease in IHTG was −6.9% (−9.5; −4.2) versus −3.8% (−6.3; −1.3; P = 0.05), and strongly correlated with the magnitude of weight loss (r = 0.69, P < 0.001). Body weight loss ≥5% with a ≥30% relative reduction in IHTG occurred more often with canagliflozin (38% vs. 7%, P = 0.009). Hepatic insulin sensitivity improved with canagliflozin (P < 0.01), but not muscle or adipose tissue insulin sensitivity. Beta-cell glucose sensitivity, insulin clearance, and disposition index improved more with canagliflozin (P < 0.05).Conclusions: Canagliflozin improves hepatic insulin sensitivity and insulin secretion and clearance in patients with T2DM. IHTG decreases in proportion to the magnitude of body weight loss, which tended to be greater and occur more often with canagliflozin. K E Y W O R D Sfatty, liver, canagliflozin, insulin resistance, insulin secretion, liver, randomized trial

Incretin‐Based Therapies for the Management of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes

“…Consistent with its lack of effect on body weight, most studies have not observed a reduction of IHTG with sitagliptin (Table ). This was particularly true for all three placebo‐controlled trials, where the average decrease of IHTG in the placebo arms (~10%‐20%) was similar to the relative decrease observed with sitagliptin by Yan et al This reduction is also in agreement with the relative ~10%‐20% reduction of IHTG observed in placebo arms of other controlled trials in patients with steatohepatitis (NASH) . Relative short duration of diabetes (~4 years) may have also promoted a better response than in previous studies, although the absolute reduction in MRI‐measured liver‐fat content was relatively small (mean reduction of ~4%) and none reached resolution of HS.…”

“…Promising results have been observed for the treatment of NAFLD in animal models and in open‐label clinical trials . Recently, a placebo‐controlled RCT in patients with T2DM reported that canagliflozin promoted weight loss and improved hepatic insulin sensitivity and insulin secretion . In those with NAFLD, cangliflozin decreased intrahepatic triglycerides (IHTG) versus baseline, but this was of borderline significance when compared to placebo (−38% vs. −20%; P = 0.09).…”

A diabetologist’s perspective of non‐alcoholic steatohepatitis (NASH): Knowledge gaps and future directions

“…However, their impact on liver histology remains to be established. Table summarizes several recent RCTs in NAFLD . Taken together, this class has been remarkably consistent in causing a 2% to 3% decrease in total body weight (1.5‐3.0 kg) and in lowering plasma aminotransferases with a placebo‐corrected reduction in intrahepatic triglyceride content of 10%‐30%.…”

“…Table 2 summarizes several recent RCTs in NAFLD. [43][44][45][46][47] Taken together, this class has been remarkably consistent in causing a 2% to 3% decrease in total body weight (1.5-3.0 kg) and in lowering plasma aminotransferases with a placebo-corrected reduction in intrahepatic triglyceride content of 10%-30%. However, decreases in intrahepatic triglyceride content must be interpreted with caution because changes in liver fat on imaging may or may not reliably correlate with necroinflammation or fibrosis on histology.…”

“…Most but not all trials have failed to report an improvement in insulin sensitivity. In one study, more patients lost ≥5% of body weight and had a ≥30% reduction in liver fat on canagliflozin than with placebo (38% vs 7%, P = .009) …”