Diabetes Research and Clinical Practice - Volume 120 - Supplement 1

OL05-5

Effects of SGLT2 inhibitor luseogliflozin under different dietary

formula in type 2 diabetes: A randomized, controlled

exploratory trial

Hitoshi KUWATA

1,2

, Masahiro IWASAKI

, Shigeto KANADA

Daisuke YABE

–

*, Yutaka SEINO

1,2

Yutaka Seino Distinguished

Center for Diabetes Research, Kansai Electric Power Medical Research

Institute,

Center for Diabetes, Endocrinology and Metabolism,

Kansai Electric Power Hospital,

Center for Metabolism and Clinical

Nutrition, Kansai Electric Power Hospital,

Medical Corporation

Heishinkai OCROM Clinic, Osaka, Japan

Effects of SGLT2 inhibitors (SGLT2i) under different dietary

formula need to be investigated as a case of ketoacidosis due to

SGLT2i use under strict carbohydrate restriction was reported.

This study was designed to determine safety and efficacy of

SGLT2i luseogliflozin under 3 different dietary formula

in patients with type 2 diabetes. Twenty four patients with

type 2 diabetes were randomly assigned to tree groups and

received either one of the three different delivery meals for

14 days (i.e. Day 1 to Day 14) [Group A, high glycemic index

meals with 55% energy from carbohydrate; group B, low

glycemic index meals with 55% energy from carbohydrate;

and group C, high glycemic index meals with 40% energy from

carbohydrate]. The patients in all three groups also received

luseogliflozin once daily for last 7 days (i.e. Day 8 to Day 14).

Daily glycemic profiles were analyzed during Days 6

–

7 and

–

14 using continuous glucose monitoring devices; and

changes of biochemical parameters were investigated using

blood samples withdrawn on Days 8 and 15. Luseogliflozin

improvedmean (mg/dL) [A 142.9 to 127.7*; B 129.9 to 115.2*; and

C 130.4 to 111.4* (*, p < 0.05 hereafter)] and AUC (mg/dL x min)

[A 6849 to 6121*; B 6226 to 5521*; and C 6247 to 5340*] in all

groups, while it has little effects on SD (mg/dL) [A 39.5 to 35.2; B

31.9 to 30.6; and C 27.7 to 27.6]. Levels of glucagon (pg/mL) [A

152.6 to 154.6; B 144.4 to 142.9; and C 152.0 to 150.3] were

unaffected by luseogliflozin. Total ketones (

mol/L) [A 590.5 to

752.3*; B 596.9 to 689.8; and C 599.1 to 744.7*] were increased

by luseogliflozin but comparable among three groups. Of 23

patients who received luseogliflozin, 2 mild adverse events,

frequent urination and drowsiness occurred in one patient in

A. These results suggest SGLT2i can be safely and effectively

used under mild carbohydrate restriction and low glycemic

index, while long-term safety and efficacy of SGLT2i, in asso-

ciation with different dietary formula, need to be determined.

OL05-6

Use of the Japanese health insurance claims database to

assess safety of SGLT2 inhibitors in the management of

diabetes

Daisuke YABE

, Rie NISHIKINO

, Nauta YAMANAKA

Chie ITO

, Yutaka SEINO

Kansai Electric Power Medical Research

Institute,

Japan Medical Data Center Co., Ltd., Japan

Aims:

A considerable number of serious adverse events (SAEs)

were reported in patients receiving SGLT2 inhibitors (SGLT2i)

clinically in Japan during the early stage of their use. These

included urinary tract infections (UTI), genital infections (GI),

hypoglycemia and dehydration in addition to acute myocar-

dial and cerebral infarctions (MI and CI). While announcement

of the recommendations for appropriate use of SGLT2i

seemingly reduced SAEs substantially in Japan, safety of

SGLT2i remains to be shown in actual clinical practice.

Methods:

Incidence of UTI, GI, hypoglycemia, dehydration, MI

and CI was compared in patients receiving SGLT2i or other

OADs. The index date was defined as the prescription date

of the first claim for a new OAD during the target period

from April, 2014 through May, 2015. An anti-diabetic drug

was considered new if there were no claims for the medi-

cation during the prior 6 months. The observation period

started on the index date and ended at the occurrence of one of

the following events, whichever was earliest: (i) UTI, GI,

hypoglycemia, dehydration, MI and CI, (ii) initiation of

another new antidiabetic drug, insulin or GLP-1, (iii) end of

observation period and (iv) end of eligibility.

Results:

Cox proportional hazard models (CPHM) comparing

the adjusted risk of UTI and GI with age and gender as

independent variables revealed that SGLT2i was associated

with higher hazard risks (HR) of UTI [SGLT2i n = 2,615 and other

OADs n = 6,250; HR 1.4 (95%CI 1.1

–

1.9), p = 0.0122] and GI

[SGLT2i n = 2,675 and other OADs n = 6,390; HR 2.5 (95%CI 1.6

–

3.8), p < 0.0001]. CPHM comparing the age- and gender-

adjusted risk of hypoglycemia revealed no significant increase

in HR of all hypoglycemia [SGLT2i n = 2,711 and other OADs

n = 6,492; HR 1.6 (95%CI 0.3

–

9.5), p = 0.6203]. CPHM comparing

the age- and gender-adjusted risk of dehydration revealed

that SGLT2i was associated with higher hazard risks (HR)

of dehydration [SGLT2i n = 2,646 and other OADs n = 6,293;

HR 1.4 (95%CI 1.0

–

1.9), p = 0.0239], while CPHM comparing

the adjusted risk of MI and CI with age, gender, and risk

comorbidities as independent variables revealed that SGLT2i

did not significantly elevate HR of MI [SGLT2i n = 2,686 and

other OADs n = 6,450; HR 1.3 (95%CI 0.4

–

4.7), p = 0.6868] and CI

[SGLT2i n = 2,657 and other OADs n = 6,324; HR 1.0 (95%CI 0.4

–

2.2), p = 0.9488].

Conclusion:

The announcement of the recommendations

reduced SAEs such as hypoglycemia, MI and CI substantially

in Japan. However, UTI and GI should be screened and

appropriately treated, if exist, in all patients receiving SGLT2i.

The Pancreatic Islet and Bariatric Surgery

OL06-1

Clock gene dysregulation induced by chronic endoplasmic

reticulum stress disrupts

-cell function

Yasuharu OHTA

, Akihiko TAGUCHI

, Takuro MATSUMURA

Hiroko NAKABAYASHI

, Masaru AKIYAMA

, Risa SUETOMI

Akie YANAI

, Koh SHINODA

, Yukio TANIZAWA

Division of

Endocrinology, Metabolism, Hematological Science and Therapeutics,

Department of Bio-Signal Analysis, Yamaguchi University, Graduate

School of Medicine,

Divison of Neuroanatomy, Department of

Neuroscience, Yamaguchi University, Graduate School of Medicine,

Japan

Wolfram syndrome, caused by the WFS1 mutation and

characterized by insulin-dependent diabetes mellitus, is one

of the prototypical human endoplasmic reticulum (ER) dis-

eases. In addition, recent studies have suggested that gluco-

toxicity and lipotoxicity induce ER stress responses resulting

-cell failure. One environmental condition that is gaining

greater appreciation as a risk factor for type 2 diabetes (T2DM)

is circadian rhythm disruption, and various animal studies

support the concept that clock genes have an essential

function in the endocrine pancreas. Herein, we demonstrate

potential mechanisms whereby chronic ER stress can predis-

pose

-cells to failure via clock gene dysregulation. To newly

identify mechanisms underlying the

-cell dysfunction in

diabetic Wfs1-/- Ay/a mice, we performed microarray analyses

and discovered a decrease in albumin D-element binding

protein (Dbp) expression and an increase in nuclear factor

interleukin 3 (Nfil3)/E4 binding protein 4 (E4bp4) expression in

Wfs1-/- Ay/a islets as compared to non-diabetic Ay/a islets. As

expected, Ddit3 (Chop) expression was up-regulated inWfs1-/-

Ay/a islets as compared to Ay/a islets. No other clock genes,

including Arntl (Bmal1), showed altered expressions. The

Quantitative real-time PCR analysis of isolated islets revealed

that levels of Dbp and Nfil3/E4bp4 expression had decreased

about 3-fold and increased about 3-fold, respectively, in

Wfs1-/- Ay/a as compared to WT islets. MIN6 cells treated

with 1 µM thapsigardin (TG) for 24 h showed a marked

Oral Presentations / Diabetes Research and Clinical Practice 120S1 (2016) S40

–

S64

S52