Effect of canagliflozin on circulating active GLP-1 levels in patients with type 2 diabetes: a randomized trial

Abstract

SODIUM GLUCOSE COTRANSPORTER 2 (SGLT2) inhibitors are a new class of anti-diabetic drugs that improve glycemic control by inhibiting reabsorption of glucose filtered through the renal glomerulus. SGLT2 is expressed in the S1 segment of the proximal renal tubules, and inhibition of this molecule results in a remarkable increase in urinary glucose excretion [1][2][3][4] Abstract. Canagliflozin has a robust inhibitory effect on sodium glucose transporter (SGLT)-2 and a mild inhibitory effect on SGLT1. The main purpose of this study was to investigate the effect of canagliflozin on circulating active glucagon-like peptide 1 (GLP-1) levels in patients with type 2 diabetes. Patients were randomly divided into a control group (n =15) and a canagliflozin-treated group (n =15). After hospitalization, the canagliflozin-treated group took 100 mg/day canagliflozin for the entire study, and after 3 days both groups took 20 mg/day teneligliptin for an additional 3 days. In a meal test, canagliflozin significantly decreased the area under curve (AUC) (0-120 min) for plasma glucose (PG) after 3 days when compared with that at baseline, and addition of teneligliptin to the canagliflozin-treated group further decreased it. A significant decrease in the AUC (0-120 min) for serum insulin by canagliflozin was obtained, but the addition of teneligliptin elevated the AUC, and thus abolished the significant difference from baseline. A significant increase in the AUC (0-120 min) of plasma active GLP-1 by canagliflozin-treatment compared with that at baseline was observed, and the addition of teneligliptin resulted in a further increase. However, canagliflozin-treatment did not change the AUC (0-120 min) of plasma active glucose-dependent insulinotropic peptide (GIP). In conclusions, canagliflozin-administration before meals decreased PG and serum insulin, and increased plasma active GLP-1 levels in patients with type 2 diabetes. Canagliflozin did not greatly influence plasma active GIP levels. Key words: Canagliflozin, GLP-1, GIP, SGLT1is located in a more distal region from the glomerulus compared with the location of S1. SGLT1 is responsible for approximately 10% of the glucose absorption in the kidney [2]. Among the SGLT2 inhibitors, canagliflozin also possesses a mild SGLT1 inhibitory effect [5,6]. Because SGLT1 is also expressed in the small intestine [7,8], inhibition of SGLT1 appears to cause the inhibition of glucose absorption in this location as well. In fact, it is reported that administration of canagliflozin can transiently repress the increase of postprandial plasma glucose (PG) levels probably via SGLT1 inhibition in the small intestine by a maximum of 30 % in healthy subjects [9].Interestingly, recent animal studies showed that administration of canagliflozin not only caused an increase in the glucose concentration in the lower small intestinal lumen probably by SGLT1 inhibition, but also resulted in a tendency toward an increase in the levels of plasma glucagon-like peptide (GLP)-1 (a hormone that increases insulin secr...

Effect of Sodium Glucose Cotransporter 2 Inhibitors With Low SGLT2/SGLT1 Selectivity on Circulating Glucagon-Like Peptide 1 Levels in Type 2 Diabetes Mellitus

“…Canagliflozin (mildly) and sotagliflozin (moderately) inhibit SGLT1 in the upper intestine, which suggests that these drugs should prevent (rather than promote) early phase elevation of GLP-1. However, canagliflozin does not inhibit early phase GLP-1 elevation after a meal in healthy subjects [ 26 ], and significantly promoted this effect in our study in patients with type 2 diabetes, as described above [ 46 ]. This finding is basically consistent with the postprandial elevation of GLP-1 in SGLT1-/- mice [ 27 ].…”

“…We recently investigated the effect of canagliflozin on GLP-1 levels in patients with type 2 diabetes [ 46 ]. Canagliflozin (100 mg a day) (n = 15) for 3 days significantly increased AUC 0 - 2 h of plasma aGLP1 from baseline by about two times, while no significant change was noted for 3 days observation in a control group without canagliflozin (n = 15).…”

Serum Betatrophin Levels and Clinical Features in Patients With Poorly Controlled Type 2 Diabetes

“…The detailed study protocol has been already presented [ 15 , 16 ]. In brief, this study was a randomized open-label study.…”

What does sodium‐glucose co‐transporter 1 inhibition add: Prospects for dual inhibition

“…Additionally, SGLT1 −/− mice show abnormal pancreatic islet (cyto)morphology associated with impaired insulin and glucagon release capacity, thus, SGLT1 appears to be required for normal β‐ and α‐cell function. Interestingly, a recent randomized trial in T2DM patients showed that treatment with canagliflozin, a selective SGLT2 inhibitor, increased plasma GLP‐1 levels when administered before meals . Even though canagliflozin is ∼260‐fold more selective for SGLT2 than SGLT1 (Table ), it was reported to inhibit intestinal glucose absorption because concentrations in the intestinal lumen reached 10‐times the IC 50 of SGLT1 .…”