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

• Published in: Diabetes, obesity & metabolism Vol. 21; no. 4; pp. 812 - 821
• Main Authors: Cusi, Kenneth, Bril, Fernando, Barb, Diana, Polidori, David, Sha, Sue, Ghosh, Atalanta, Farrell, Kristin, Sunny, Nishanth E., Kalavalapalli, Srilaxmi, Pettus, Jeremy, Ciaraldi, Theodore P., Mudaliar, Sunder, Henry, Robert R.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.04.2019; Wiley Subscription Services, Inc
• Subjects: Adipose tissue; Aged; Antidiabetics; Beta cells; Body weight; Body weight loss; canagliflozin; Canagliflozin - therapeutic use; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Double-Blind Method; fatty; Fatty liver; Female; Glucose; Glucose Clamp Technique; Glucose metabolism; Glucose transporter; Glycated Hemoglobin A - metabolism; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells - metabolism; liver; Liver - metabolism; Liver diseases; Magnetic resonance spectroscopy; Male; Metabolism; Middle Aged; Patients; Proton Magnetic Resonance Spectroscopy; randomized trial; Secretion; Sodium; Sodium-Glucose Transporter 2 Inhibitors - therapeutic use; Treatment Outcome; Triglycerides - metabolism; Weight Loss; insulin secretion; fatty; liver; insulin resistance; randomized trial; canagliflozin
• ISSN: 1462-8902; 1463-1326; 1463-1326
• DOI: 10.1111/dom.13584

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% ± 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 with non‐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.