Administration Of SGLT2 Inhibitor Research Articles

Abstract We071: Identifying Preventive and Therapeutic Effects of SGLT2 Inhibitor on Atrial Fibrillation

Background: The frequency and prevalence of atrial fibrillation (AF) and heart failure are expected to increase over time, which are expected to result in enormous medical expenses and socioeconomic losses. Previous studies have confirmed that SGLT2 inhibitor (SGLT2i) reduces cardiovascular mortality and hospitalization rates in heart failure patients. Also, follow-up studies have been reported that the use of SGLT2i reduces atrial fibrillation, and its administration is recommended in clinical practice guidelines. In spite of beneficial effects of SGLT2i on atrial fibrillation, the exact mechanism by which SGLT2i reduces atrial fibrillation has not been revealed. Methods: We performed experiments by creating an AF cell model using Ang II and an AF animal model using Acetylcholin-Calcium chloride. Fibrosis markers and calcium regulatory proteins were confirmed by Western blot, and the occurrence and burden of AF were evaluated by using a 1F catheter in animal models. Results: In our cell studies and animal experiments, the inhibitory effect of SGLT2i administartion on atrial fibrillation was confirmed. First, fibrosis markers tend to reduce in atrial fibrillation models treated with SGLT2i, compared to non-treated atrial fibrillation models. In addition, the phosphorylation of the calcium handling proteins, such as CaMKII, RyR2, and PLB, increased in the AF group, whereas the degree of phosphorylation in SGLT2i treated group decreased to the phosphorylation level in control group. Conclusion: In AF-induced cell and animal models, the effect of SGLT2i was shown to be highly effective against atrial fibrillation. In particular, the results indicate that administration of SGLT2i before inducing atrial fibrillation could bring out the preventive and therapeutic effects through amelioration of fibrosis and reduction of calcium handling proteins phosphorylation.

Effects of dapagliflozin on peripheral sympathetic nerve activity in standard chow- and high-fat-fed rats after a glucose load

To clarify the effects of long-term administration of SGLT2 inhibitor, a hypoglycemic agent, on basal sympathetic nerve activity (SNA) and on SNA under development of insulin resistance, we measured peripheral SNA in response to a glucose load in standard chow- (SCF) and high-fat-fed (HFF) rats treated with or without dapagliflozin for 7 weeks. We conducted an intravenous glucose administration (IVGA), and evaluated SNA microneurographically recorded in the unilateral sciatic nerve. Dapagliflozin did not affect the steady state action potential (AP) rate just before the IVGA (baseline) in both the SCF and HFF rats. After the IVGA, in the SCF rats, the AP rate in dapagliflozin-treated group transiently decreased within 20 min after the IVGA, and was significantly lower (P < 0.05) than non-treated group for 60 min. In the HFF rats, no significant difference was seen in the AP rate between dapagliflozin-treated and non-treated groups. The rate in the dapagliflozin-treated group after the IVGA was significantly lower (P < 0.05) than the baseline whereas such difference was not found in the non-treated group. In conclusion, dapagliflozin attenuate SNA in response to glucose load, and that the SNA response is different between standard chow-fed- and high-fat-fed rats.

1143-P: A Single and Chronic SGLT2 Inhibitor Administration Did Not Alter Insulin Clearance in Type 2 Diabetes

Reduced insulin clearance (IC) and hyperinsulinemia are observed in obesity with insulin resistance and considered as compensatory change against insulin resistance. On the other hand, several animal models showed that enhanced IC by genetic modification suppressed high fat diet induced weight gain and insulin resistance. Recently we found that 3-day low carbohydrate diet increased IC, suggesting low glucose availability may acutely increase IC. Given that SGLT2 inhibitors decrease glucose availability by increasing urinary glucose excretion, we hypothesized that SGLT2 inhibitors may acutely increase IC, and then induce body weight reduction and improve metabolic disorders. To test this hypothesis, we recruited 12 Japanese men with type 2 diabetes mellitus. We evaluated IC and tissue specific insulin sensitivity by hyperinsulinemic euglycemic clamp (insulin infusion rate; 40 mU/m2·min) on baseline, immediately after a single administration (n=12) and after 8-week administration (n=9) of SGLT2 inhibitor (Tofogliflozin). We also measured ectopic fat in muscle and liver and abdominal fat areas by 1H-MRS and MRI, respectively. IC was not altered immediately after a single administration of Tofogliflozin (594.7±67.7ml/min/m2 to 608.3±90.9ml/min/m2, p=0.61). Also, 8 weeks administration of Tofogliflozin did not alter IC (582.5±67.3ml/min/m2 vs. 602.3±67.0ml/min/m2, p=0.41), while body weight and subcutaneous fat area were significantly decreased by 1.7% and 6.4%, respectively. In addition, 8 weeks administration of Tofogliflozin significantly decreased HbA1c and fasting plasma glucose levels and increased fasting endogenous glucose production, while insulin sensitivity and ectopic fat in muscle and liver were not changed. In conclusion, IC was not altered after a single and 8-week administration of Tofogliflozin. Decreased body weight and improved glycemic control by chronic administration of Tofogliflozin may occur independently of IC change. Disclosure M. Sato: None. Y. Tamura: Advisory Panel; Self; Astellas Pharma Inc. Research Support; Self; Kowa Company, Ltd. Speaker’s Bureau; Self; Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd. H. Kaga: None. N. Yamasaki: None. M. Kiya: None. R. Suzuki: None. D. Sugimoto: None. S. Kadowaki: None. Y. Furukawa: None. T. Funayama: None. Y. Someya: None. R. Kawamori: None. H. Watada: Advisory Panel; Self; Abbott, Ajinomoto, Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Fuji Film, Janssen Pharmaceuticals, Inc., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Research Support; Self; Astellas Pharma Inc., Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Shionogi &amp; Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Yakult. Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Funding Kowa Company, Ltd.

SO022EVALUATION OF GLOMERULAR HEMODYNAMIC CHANGES BY SGLT2 INHIBITION IN TYPE 2 DIABETIC RATS USING IN VIVO IMAGING TECHNIQUES

Abstract Background and Aims In recent clinical trials, the SGLT2 inhibitor (SGLT2i) slowed the progression of kidney disease compared with the placebo in patients with type 2 diabetes. Improvement of glomerular hyperfiltration via tubuloglomerular feedback (TGF) is considered to be one of the possible pathways for renal protection with SGLT2 inhibition (SGLT2i) in diabetic kidney disease (DKD). We have successfully developed the novel method to measure single-nephron GFR (SNGFR) in mice using multiphoton laser microscopy and demonstrated that the adenosine/adenosine A1 receptor (A1aR) pathway plays a pivotal role in the TGF mechanism in the type 1 diabetic model, Akita mice (Kengo Kidokoro, David Z. I. Cherney et al. Circulation. 2019). It has been suggested that the mechanism of improvement effects in glomerular hyperfiltration by SGLT2i is different in type 1 diabetes and type 2 diabetes. However, the detailed regulatory mechanism of GFR by SGLT2i is not fully understood in type 2 diabetes. This study aims to clarify the effects of SGLT2i on glomerular hemodynamics in type 2 diabetic rats. Method Zucker lean (ZL) rats and Zucker diabetic fatty (ZDF) rats were used. In the first experiment, SNGFR and diameters of glomerular afferent/efferent arterioles were measured in both groups. Next, we examined the change of SNGFR and diameters of glomerular afferent/efferent arterioles, as well as urinary excretions of glucose and sodium in ZDF after a single-dose administration of SGLT2i (luseogliflozin; 10mg/kg, gavage) for 120 minutes, which generated the following three groups: SGLT2i group, SGLT2i + adenosine A1 receptor (A1aR) antagonist (8-cyclopentyl-1,3-dipropylxanthine, 1mg/kg) group, and insulin group. Results SNGFR in the ZDF group was significantly higher than in the ZL group. The diameter of the afferent arteriole and efferent arteriole was also wider in ZDF rats than in ZL rats. The SNGFR and diameter of the afferent arteriole were significantly decreased after a single-dose administration of SGLT2i in ZDF. However, there was no significant diameter change in the efferent arteriole. Moreover, a decrease of SNGFR was not observed in the A1aR antagonist group after SGLT2i administration. Urinary excretions of glucose and sodium showed a similar pattern in the SGLT2i and SGLT2i+ A1aR antagonist groups. Conclusion The adenosine/A1aR pathway plays an important role in the regulation of the tonus of the afferent arteriole and is involved in the suppression of glomerular hyperfiltration by SGLT2 inhibition in type 2 diabetes.

1135-P: Acute Increase in Endogenous Glucose Production by a Single Administration of Tofogliflozin Is Disappeared by Suppressing Its Glucose Lowering Effect in the Patients with Type 2 Diabetes Mellitus

It has been shown that a single administration of SGLT2 inhibitor (SGLT2i) to the patients with type 2 diabetes mellitus (T2DM) decreases plasma glucose (PG), but increases endogenous glucose production (EGP); however, its underlying mechanism has been totally unknown. We hypothesized that a single administration of SGLT2i lowers PG, thereby suppresses insulin level and increases glucagon level, which in turn rises EGP. To test this hypothesis, we recruited 12 Japanese patients with type 2 diabetes mellitus without taking any hypoglycemic agents (BMI 24.9±2.5 kg/m2, HbA1c 7.7±0.9%). In each patient, by [6,6-2H2]-glucose infusion, we evaluated basal EGP and EGP under the conditions with: (i) no administration of drugs (CON), (ii) single administration of a SGLT2i, Tofogliflozin (TOF), and (iii) TOF + glucose adjustment (TOF+G) in which we adjusted PG level by exogenous glucose infusion to mimic PG level during CON. In each patient, we measured EGP under three condition at 1-2 week intervals. Also, we evaluated changes in insulin, glucagon and EGP between basal period and after each 3h condition. The decrement of PG during 3h experimental period in TOF was significantly greater than that in CON, and this change was inhibited by glucose infusion (delta PG: CON; -14.6 mg/dl, TOF; -26.4 mg/dl, TOF+G; -15.6 mg/dl). In CON, EGP was decreased by 11.1%, but it was significantly increased by 4.5% in TOF. However, similar to CON, EGP was decreased by 15.7% in TOF+G. In addition, insulin level was decreased by 24% and glucagon level was increased by 36% in TOF; however, these hormonal changes were not observed in CON and TOF+G. In conclusion, acute EGP elevation by a single administration of SGLT2i was disappeared by suppression of glucose lowering effect of SGLT2i. Changes in insulin and glucagon by rapid decline of PG after SGLT2i administration may be a main inducer of EGP elevation. Disclosure N. Yamasaki: None. Y. Tamura: Advisory Panel; Self; Astellas Pharma Inc. Research Support; Self; Kowa Company, Ltd. Speaker’s Bureau; Self; Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd. H. Kaga: None. M. Sato: None. M. Kiya: None. S. Kadowaki: None. R. Suzuki: None. Y. Furukawa: None. D. Sugimoto: None. T. Funayama: None. Y. Someya: None. R. Kawamori: None. H. Watada: Advisory Panel; Self; Abbott, Ajinomoto, Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Fuji Film, Janssen Pharmaceuticals, Inc., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Research Support; Self; Astellas Pharma Inc., Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Shionogi &amp; Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Yakult. Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Funding Kowa Company, Ltd.

Inter-organ Communication Pathway Manifested by Non-physiological Stress to the Kidney in Type II Diabetic Patients -Why Are Diabetic Patients Prone to Develop Heart Failure?

It has become clear that sodium glucose cotransporter (SGLT)-2 inhibitors not only do not increase the incidence of cardiovascular events but they also reduce the duration of hospitalization for heart failure in type 2 diabetes mellitus (T2DM) patients. The administration of SGLT2 inhibitor in T2DM patients with hypertension and a fluid retention tendency lowers the blood pressure and mitigates fluid retention. It also reduces the heart rate in T2DM patients with a fast heart rate. As an explanation for the multifaceted effects of SGLT2 inhibitors on hemodynamics, we hypothesize that these agents act on the inter-organ communication pathway, which modulates the sympathetic nerve activity to the cardiovascular system.

1219-P: Enhanced Response in Serum Ketone Level in Men Compared with Women by Administration of SGLT2 Inhibitor

SGLT2 inhibitors (SGLT2is) reduce hyperglycemia and insulin levels via increased urinary glucose excretion (UGE). Reduced insulin triggers decreased tissue glucose disposal and increased lipid use followed by ketone production. The metabolic response to starvation, the production of beta-hydroxybutyrate (BHB), was reported to be influenced by sex and menopausal status in healthy persons. However, little is known of sex- and menopausal status-specific effects of SGLT2is on BHB. This study investigated the effect of the SGLT2i tofogliflozin on BHB according to sex and menopausal status in type 2 diabetes mellitus (T2DM). Analyzed were 190 T2DM patients taking tofogliflozin as initial monotherapy in a Phase 3 study. Baseline characteristics were: men (66%); premenopausal (7%) and postmenopausal women (27%), age (mean 58y), and mean HbA1c (7.8%), BMI (26kg/m2), BHB (69µmol/L) and eGFR (83mL/min/1.73m2). Sex- and menopausal status-specific differences were analyzed by multivariate analysis. Longer duration of diabetes and lower baseline HDL-C and adiponectin were noted in men while age and HbA1c, BMI, BHB and eGFR were identical between sexes. Increases in BHB at weeks 4 and 52 were: men, median +128%* and +64*, respectively (+ p&amp;lt;0.01 vs. baseline); women, +48* and +58*, respectively. Mean increases in the fasting free fatty acid-to-insulin ratio (FIR) at week 52 were +88%* for men and +53* for women. Reductions in HbA1c and fasting insulin and increases in UGE and free fatty acids at week 52 were similar between sexes. Multivariate analyses showed a greater increase in BHB at week 52 in men than in women, especially postmenopausal women. Further, FIR increased greater in men than in women. Finally, premenopausal women had a greater increase in BHB than postmenopausal women. Results suggest that the different degrees of BHB elevation between sexes via tofogliflozin may provide clinical insights into sex- and menopause-specific metabolic responses to increased lipid use via SGLT2is in T2DM. Disclosure A. Yoshida: Employee; Self; Kowa Pharmaceutical Co. Ltd. Y. Matsubayashi: None. T. Nojima: Employee; Self; Kowa Co., Ltd. H. Suganami: Employee; Self; Kowa Co., Ltd. K. Kaku: Advisory Panel; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk A/S. Speaker's Bureau; Self; Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. H. Sone: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kowa Pharmaceutical Europe Co. Ltd., Kyowa Hakko Kirin Co., Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited.

A Case of an Excessively Obese Type 2 Diabetic Woman With Significantly Improved Glycemic Control to Prepare for Pregnancy by Short-term Administration of SGLT2 Inhibitor

A Case of an Excessively Obese Type 2 Diabetic Woman With Significantly Improved Glycemic Control to Prepare for Pregnancy by Short-term Administration of SGLT2 Inhibitor