The effect of combined treatment with canagliflozin and teneligliptin on glucose intolerance in Zucker diabetic fatty rats

Oguma, Takahiro; Kuriyama, Chiaki; Nakayama, Keiko; Matsushita, Yasuyuki; Yoshida, Kumiko; Kiuchi, Satoko; Ikenaga, Yuka; Nakamaru, Yoshinobu; Hikida, Kumiko; Saito, Akira; Akita, Keiichi; Oka, Kozo; Ueta, Kiichiro; Shiotani, Masaharu

doi:10.1016/j.jphs.2015.03.006

Cited by 26 publications

(14 citation statements)

References 31 publications

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“…Finally, an effect independent of SGLT1 inhibition might have also partially influenced the results as described above. In the current study, further elevation of plasma active GLP-1 levels was observed by addition of teneligliptin, a DPP4 inhibitor, supporting the results of previous animal studies [10,11]. This finding appears to suggest a benefit of co-treatment of canagliflozin with DPP4 inhibitors for elevating circulating GLP-1 levels.…”

Section: Discussionsupporting

confidence: 91%

“…One patient cells located mainly in the mucosal membrane of the lower small intestine [10]. The remarkable elevation of plasma active GLP-1 levels was noted especially with co-administration of dipeptidyl peptidase 4 (DPP4) inhibitors, which block GLP-1 degradation [11]. Although a tendency toward an increase in circulating active GLP-1 by canagliflozin is reported also in healthy subjects [9], there is as yet no evidence demonstrating the effect of canagliflozin on circulating active GLP-1 in patients with type 2 diabetes.…”

Section: Originalmentioning

confidence: 99%

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

et al. 2017

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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...

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Section: Discussionsupporting

confidence: 91%

Section: Originalmentioning

confidence: 99%

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

et al. 2017

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“…Another possible mechanism underlying the effect of the combination on postprandial glucose is that it might enhance GLP‐1 secretion. Oral administration of 100 mg of canagliflozin increased plasma total GLP‐1 after breakfast in Japanese patients with T2DM, probably because of a weak inhibitory effect of canagliflozin against SGLT1 . Although we did not measure GLP‐1 levels in the present study, the combination of teneligliptin and canagliflozin may increase active GLP‐1 levels, representing a beneficial effect of this combination.…”

Section: Discussionmentioning

confidence: 67%

Long‐term safety and efficacy of canagliflozin as add‐on therapy to teneligliptin in Japanese patients with type 2 diabetes

Kadowaki

Inagaki

Kondo

et al. 2017

Diabetes Obesity Metabolism

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AimTo evaluate the long‐term safety and efficacy of canagliflozin as add‐on therapy in patients with type 2 diabetes mellitus (T2DM) who had inadequate glycaemic control with teneligliptin monotherapy.MethodsThis open‐label 52‐week study was conducted in Japan. Patients received canagliflozin 100 mg added to teneligliptin 20 mg orally once daily for 52 weeks. The safety endpoint was the incidence of adverse events (AEs). The efficacy endpoints included changes in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG) and body weight from baseline to week 52 (with last observation carried forward).ResultsOverall, 153 patients entered the treatment period and 142 completed the study. The overall incidence rates of AEs and drug‐related AEs were 69.9% and 22.9%, respectively. Most AEs and drug‐related AEs were mild or moderate in severity. There were no previously undescribed safety signals. The mean changes in HbA1c, FPG and body weight were −0.99% (95% confidence interval [CI] −1.12 to −0.85), −38.6 mg/dL (95% CI −43.4 to −33.9) and −3.92% (95% CI −4.53 to −3.31), respectively. These effects were maintained for 52 weeks without attenuation. HbA1c and body weight were both decreased in 82.24% of patients at the end of the treatment period. Reductions in postprandial glucose were observed at weeks 24 and 52.ConclusionsNo new safety risks with this combination were identified, and sustained improvements in HbA1c, FPG and body weight were observed. The findings suggest that long‐term co‐administration of canagliflozin with teneligliptin is well tolerated and effective in Japanese patients with T2DM who have inadequate glycaemic control on teneligliptin alone.

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“…A recent clinical study of canagliflozin found delayed intestinal glucose absorption accompanied by increased plasma GLP-1 levels in healthy subjects (Polidori et al, 2013). Furthermore, the combined treatment with canagliflozin and teneligliptin, a DPP4 inhibitor, increased plasma active GLP-1 (aGLP-1) levels in diabetic rats (Oguma et al, 2015). Because plasma GLP-1 levels were not potentiated in SGLT2-deficient mice after a meal challenge (Powell et al, 2013), it has been suggested that GLP-1 elevation by canagliflozin is mediated by a mechanism other than the inhibition of SGLT2.…”

Section: Introductionmentioning

confidence: 99%

Intestinal Sodium Glucose Cotransporter 1 Inhibition Enhances Glucagon-Like Peptide-1 Secretion in Normal and Diabetic Rodents

Oguma¹,

Nakayama²,

Kuriyama³

et al. 2015

J Pharmacol Exp Ther

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The sodium glucose cotransporter (SGLT) 1 plays a major role in glucose absorption and incretin hormone release in the gastrointestinal tract; however, the impact of SGLT1 inhibition on plasma glucagon-like peptide-1 (GLP-1) levels in vivo is controversial. We analyzed the effects of SGLT1 inhibitors on GLP-1 secretion in normoglycemic and hyperglycemic rodents using phloridzin, CGMI [3-(4-cyclopropylphenylmethyl)-1-(b-Dglucopyranosyl)-4-methylindole], and canagliflozin. These compounds are SGLT2 inhibitors with moderate SGLT1 inhibitory activity, and their IC 50 values against rat SGLT1 and mouse SGLT1 were 609 and 760 nM for phloridzin, 39.4 and 41.5 nM for CGMI, and 555 and 613 nM for canagliflozin, respectively. Oral administration of these inhibitors markedly enhanced and prolonged the glucose-induced plasma active GLP-1 (aGLP-1) increase in combination treatment with sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, in normoglycemic mice and rats. CGMI, the most potent SGLT1 inhibitor among them, enhanced glucose-induced, but not fat-induced, plasma aGLP-1 increase at a lower dose compared with canagliflozin. Both CGMI and canagliflozin delayed intestinal glucose absorption after oral administration in normoglycemic rats. The combined treatment of canagliflozin and a DPP4 inhibitor increased plasma aGLP-1 levels and improved glucose tolerance compared with single treatment in both 8-and 13-week-old Zucker diabetic fatty rats. These results suggest that transient inhibition of intestinal SGLT1 promotes GLP-1 secretion by delaying glucose absorption and that concomitant inhibition of intestinal SGLT1 and DPP4 is a novel therapeutic option for glycemic control in type 2 diabetes mellitus.

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The effect of combined treatment with canagliflozin and teneligliptin on glucose intolerance in Zucker diabetic fatty rats

Cited by 26 publications

References 31 publications

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

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

Long‐term safety and efficacy of canagliflozin as add‐on therapy to teneligliptin in Japanese patients with type 2 diabetes

Intestinal Sodium Glucose Cotransporter 1 Inhibition Enhances Glucagon-Like Peptide-1 Secretion in Normal and Diabetic Rodents

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