May 08, 2017
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Canagliflozin improves adipose tissue function in type 2 diabetes

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AUSTIN, Texas — In adults with type 2 diabetes, the SGLT2 inhibitor canagliflozin improved adipose tissue function, independent of weight loss, when compared with glimepiride therapy for 52 weeks, W. Timothy Garvey, MD, FACE, said during a presentation.

“It’s well known that type 2 diabetes and obesity are pro-inflammatory states associated with insulin resistance and increased risk of cardiovascular disease and premature death,” Garvey, professor of medicine and chair of the department of nutrition sciences at the University of Alabama at Birmingham, said at the American Association of Clinical Endocrinologists Annual Scientific and Clinical Congress. “We also know that at least part of the pathophysiology involves chronic hyperglycemia and obesity, which can lead to impaired adipose tissue function. This can be characterized by altered production of adiposity-related hormones, adipokines, as well as cytokines and chemokines that promote inflammation, endothelial dysfunction, oxidative stress and insulin resistance.”

Timothy Garvey
W. Timothy Garvey

By inhibiting the co-transporter in the proximal lumin of the kidney, canagliflozin (Invokana, Janssen) also puts into motion a “big impact” on other systemic events in metabolism, Garvey said. These include altered substrate oxidation, changes in energy balance and hepatic metabolism. However, the links between renal effects and systemic effects have not been clearly elucidated, he noted.

In a post hoc, exploratory analysis of a phase 3, double-blind, randomized controlled trial, Garvey and colleagues analyzed serum samples from randomly selected patients receiving 300 mg daily canagliflozin (n = 100; mean age 59 years; 48% men; 87% white; mean HbA1c, 7.8) or glimepiride (n = 100; mean age, 58 years; 55% men; 80% white; mean HbA1c, 7.7%) for 52 weeks without rescue therapy. Researchers assessed levels of the adipokines serum leptin, adiponectin and leptin-to-adiponectin ratio; the pro-inflammatory cytokines C-reactive protein, interleukin-6 (IL-6) and tumor necrosis factor alpha; and the chemokines plasminogen activator inhibitor-1 (PAI-1), vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1).

Primary endpoints included change from in baseline in HbA1c and body weight at 52 weeks; and changes from baseline in adipokines, cytokines and chemokines at 52 weeks, each adjusted for treatment group, HbA1c and effects by country.

At 52 weeks, the least squares mean (LSM) change in HbA1c was –0.99% with canagliflozin vs. –0.91% with glimepiride; LSM change in body weight was –4.1 kg with canagliflozin vs. 0.7 kg with glimepiride.

Compared with glimepiride therapy, patients assigned canagliflozin saw a mean 26% decrease in serum leptin (LSM change, –1.65 vs 2.14 ng/mL) and a mean 17% increase in serum adiponectin (LSM change, 0.74 vs –0.02 g/mL). Patients assigned canagliflozin also experienced a 23% reduction in serum IL-6 (–0.3 vs 0.2 pg/mL) and a 9% increase in median serum TNF alpha (0.1 vs –0.1 pg/mL) when compared with glimepiride therapy.

There were no between-group differences observed for C-reactive protein, PAI-1, VCAM-1 or MCP-1, Garvey said.

Garvey noted that the change in leptin correlated with the change in body weight (r 0.35) only; however, the changes in adiponectin and IL-6 were not correlated with the observed change in HbA1c, body weight or lipids.

“We conclude that these collective results suggest that canagliflozin may improve adipose tissue function, increasing adiponectin and decreasing the inflammatory posture of the adipocytes as reflected by a decrease in IL-6, independent of weight loss, and these may reflect favorably on cardiometabolic health,” Garvey said.

The direct effects of canagliflozin on cardiovascular outcomes will be available following the completion of the ongoing CANVAS study in June, Garvey said. – by Regina Schaffer

Reference:

Garvey, WT, et al. Abstract #252. Presented at: AACE Annual Scientific and Clinical Congress; May 3-7, 2017; Austin, Texas.

Disclosures: Garvey reports serving on advisory boards for Alexion, Eisai, Merck, Novo Nordisk, Takeda and Vivus, and receiving research support from Astra Zeneca, Elcelyx, Lexicon, Merck, Novo Nordisk, Pfizer and Weight Watchers.