Kowa Pharmaceuticals America Research Articles

Impact of Vitamin B6 Intake on the Risk of Diabetic Retinopathy—Analysis from Multicenter Prospective Study of Japanese Patients with Type 2 Diabetes

Vitamin B6 has been expected to prevent the progression of diabetic retinopathy. Previous studies reported that treatment with vitamin B6 protected against capillary dropout in a mouse model of diabetes and low serum vitamin B6 levels were associated with retinal vein occlusion in healthy individuals. However, data on this topic in patients with diabetes are sparse. As part of a nationwide cohort study we investigated the relationship between vitamin B6 intake and the incidence of diabetic retinopathy in Japanese patients with type 2 diabetes aged 40-70 years with HbA1c≥6.5%. The present analysis was conducted among 22Japanese patients with type 2 diabetes from outpatient clinics in 59 university and general hospitals in Japan. Analyzed were 1516 responders to a baseline dietary survey assessed by the Food Frequency Questionnaire based on food groups. Primary outcome was the 8-year risk of a diabetic retinopathy event. Cox regression analyses estimated hazard ratios (HRs) for dietary intake adjusted for age, gender, body mass index, HbA1c, smoking, energy intake, and other confounders. Mean vitamin B6 intake in quartiles ranged from 0.9 to 2.0 mg/day and half of participants had vitamin B6 intake less than the recommended dietary allowance according to dietary reference intakes in Japan (males 1.4 mg/day; females 1.2 mg/day). Patients in higher quartiles included those with significantly high energy, vegetable, meat and fish intakes (p for trend< 0.01, < 0.01, < 0.01, and < 0.01, respectively). After adjusting for confounders, hazard ratios for diabetic retinopathy in the 2nd, 3rd, and 4th quartiles of vitamin B6 intake compared with the 1st quartile were 1.2 (95% confidence interval 0.8-1.7, p=0.36), 0.9 (0.6-1.3, p=0.51), and 0.51 (0.31-0.88, p=0.01), respectively. We clarified that the decreased incidence of diabetic retinopathy in Japanese patients with type 2 diabetes was associated with high vitamin B6 intake. Disclosure C. Horikawa: None. R. Aida: None. S. Tanaka: None. Y. Yoshimura: None. R. Kawasaki: None. T. Moriya: None. A. Araki: None. H. Sone: Research Support; Self; Novo Nordisk Inc., Eli Lilly and Company, MSD K.K., Chugai Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Sanofi, Kowa Pharmaceuticals America, Inc., Eisai Inc..

Incorporating Depression Screening into Diabetes Clinics across the T1DX Learning Collaborative

Objective: Depression contributes to suboptimal health outcomes amongst people with type 1 diabetes (T1D). The ADA standards of care recommend regular psychosocial screening, however these guidelines are not universally implemented. Aim: Demonstrate feasibility of expanding depression screening across clinics in the national T1D Exchange Learning Collaborative (T1DX-LC) using a quality improvement (QI) approach. Methods: Six clinics in T1DX-LC participated in bi-monthly calls and three learning sessions for depression screening. Sites shared existing resources and used QI methodology to design iterative plan-do-study-act cycles to develop or refine existing processes and adopt interventions in their respective contexts around the following themes: 1) consistent screening and referral criteria, 2) integration of screening into work flow, 3) acceptance from families and staff, 4) adequate social work and psychology referral resources, and 5) incorporation of health information technology. Results: Screening increased from baseline of 10% across sites to 60% of eligible patients at all sites over 18 months (Figure). Discussion: Through the T1DX-LC, a network of centers were successful at completing depression screening in alignment with ADA standards of care. Sites expanded screening to individuals with type 2 diabetes and additional centers are joining the screening intervention. Disclosure S. Majidi: None. M.C. Jolly: None. G.T. Alonso: None. D.A. Buckingham: None. A.B. Cabrera: None. M.A. Clements: Speaker's Bureau; Self; Medtronic. Advisory Panel; Self; Glooko, Inc.. A. Garrity: None. K.A. Gibbs: None. B. Glick: None. K. Hong: None. M.K. Kamboj: None. K.L. Lambert: None. J. Lee: Consultant; Self; Unitio. P.V. Nadkarni: None. R. McDonough: None. A.L. Ohmer: None. N. Rioles: None. K.R. Stanek: None. S. Thomas: None. R.S. Weinstock: Research Support; Self; Medtronic MiniMed, Inc., Mylan, Kowa Pharmaceuticals America, Inc., Diasome Pharmaceuticals, Inc., Calibra Medical, Dexcom, Inc., Ultradian Diagnostics LLC., JAEB Center For Health Research, JDRF, National Institute of Diabetes and Digestive and Kidney Diseases. S. Corathers: None.

Comparative Study on Glucose Metabolism Before and After Surgery in Patients with Adrenal Cushing's Syndrome

Adrenal Cushing’s syndrome (CS) is caused by cortisol-producing adrenal adenoma (CPA) and is frequently accompanied with impaired glucose tolerance (IGT) or diabetes mellitus (DM). Previous cross-sectional studies showed that glucose metabolism disorders in CS are characterized by insulin resistance and insufficient β-cell compensation. However, because of the rarity of CS, there are few studies that assessed whether glucose metabolism disorders could be ameliorated by surgical treatment. We evaluated the changes in glucose metabolism before and after surgery for CPA. The participants were 11 (10 female and 1 male) patients with overt adrenal CS, treated with unilateral adrenalectomy for CPA between 20and 2017. Patients with pre-diagnosed DM were excluded. A 75 g oral glucose tolerance test (OGTT) was performed before and after surgery. Using the data from OGTT, insulin resistance and insulin secretion indices were calculated. After surgery, cortisol secretion and body mass index decreased significantly (24 h urinary free cortisol: 582 [321-743] to 31.3 [23.6-40.6] μg/day, p = 0.001, and 25.8 [20.6-26.2] to 21.4 [19.6-24.2], p = 0.0077, respectively). The type of OGTT was largely improved (normal glucose tolerance/IGT/DM: 2/8/1 to 8/3/0). The immunoreactive insulin and glucose levels during the OGTT decreased significantly. The homeostatic model assessment of insulin resistance decreased significantly (2.4 [1.4-2.8] to 1.0 [0.6-1.1], p = 0.002), and the Matsuda index increased significantly (3.0 [2.3-4.5] to 8.2 [6.3-11.4], p < 0.001). In addition, the insulinogenic and disposition indices increased significantly (0.70 [0.22-1.51] to 1.22 [0.78-1.64], p = 0.04, and 609.1 [237.8-1095.2] to 1286.0 [1034.6-1857.6], p = 0.001, respectively). In conclusion, our study showed that insulin resistance and insulin secretion were largely ameliorated after surgery for CPA, indicating that β cell dysfunction caused by cortisol overproduction is reversible. Disclosure K. Miyoshi: None. Y. Tsurutani: Research Support; Self; Astellas Pharma US, Inc.. Speaker's Bureau; Self; Astellas Pharma US, Inc., Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda. A. Suzuki: None. T. Takiguchi: None. C. Sugisawa: None. J. Saito: None. T. Nishikawa: None.

Self-Monitoring of Blood Glucose (SMBG) in Youth with Poorly Controlled Type 2 Diabetes (T2D) in the TODAY Study

Objective: Determine if SMBG increased after starting insulin in T2D youth with poor glycemic control in the TODAY study. Methods: Youth with recent onset T2D (n=699) were randomized to receive metformin ± rosiglitazone (rosi) or intensive lifestyle. They were asked to perform SMBG daily (supplies provided). When they reached primary outcome (PO; A1c ≥8% over 6 mon or inability to wean from temporary insulin due to metabolic decompensation), metformin (not rosi) was continued, daily insulin glargine started; dosing was intensified as needed. A1c and SMBG data for 2 year before and after PO were analyzed. SMBG% was defined as percent of days between visits when the meter was used ≥1 time. Results: Of 319 youth who reached PO, 298 started insulin and 282 had SMBG data. At PO, mean (SD) age was 15.8±2.3 year, 65.3% female, 38.3% non-Hispanic black, 16.3% Hispanic, 7.1% non-Hispanic white, BMI 35.5±7.9 kg/m2, and A1c 9.6±2.0%. Median SMBG% was 40% at PO which increased to 49% at 6 mo and fell to 41% at 1 year; 22% of youth tested ≥80% of days at PO, which increased to 25% at 6 mo and fell to 19% at 1 year. Compared with those who tested <80% at PO, youth who tested ≥80% were younger, with lower BMI and A1c. Use of SMBG was associated with ≥1% reduction in A1c at 6 and 1 year after insulin initiation (Figure). Conclusion: Adherence to SMBG was poor but associated with lower A1c. Research is needed on interventions to help youth with T2D reach A1c goals. Disclosure R.S. Weinstock: Research Support; Self; Medtronic MiniMed, Inc., Mylan, Kowa Pharmaceuticals America, Inc., Diasome Pharmaceuticals, Inc., Calibra Medical, Dexcom, Inc., Ultradian Diagnostics LLC., JAEB Center For Health Research, JDRF, National Institute of Diabetes and Digestive and Kidney Diseases. B. Braffett: None. C.L. Chan: None. N.T. Chang: None. M.W. Haymond: Advisory Panel; Self; Zealand Pharma A/S. Other Relationship; Self; Xeris Pharmaceuticals, Inc.. B. Schwartzman: None.

Test Strip–Positive Proteinuria and Its Combination with Low eGFR Are Predictive of Treatment-Required Eye Diseases in Japanese Patients with Diabetes Mellitus

Proteinuria or low eGFR was separately shown to be associated with the development of retinopathy in patients with diabetes. However, it remains unclear whether semi-quantitatively assessed proteinuria by test strips either combined or not combined with low eGFR is predictive of incident retinopathy, especially in its advanced stages.To clarify this, we utilized ICD-10 and medical treatment codes from a nationwide claims database that included 6,100 participants (1,074 women, mean age 49.3 y, HbA1c 6.9%) classified as having diabetes mellitus or treatment-required diabetic eye diseases (TRDED) during an 8-y period. Urinary protein was assessed by test strip and a result of ≥1+ indicated proteinuria, which reportedly corresponds to a urine protein concentration of ≥30 mg/dL. Multivariate Cox regression model was used to identify predictors of TRDED. During the study period, 147 patients developed TRDED (4.5/1000 person-years). Cox analysis showed that proteinuria was a significant and independent predictor of TRDED but not the serum creatinine level. Hazard ratios (HRs) for proteinuria, low eGFR (defined as <45 mL/min/1.73m2) and HbA1c (per 1% increment) for incident TRDED were 2.37(95% CI, 1.59-3.53), 3.95(1.56-10.01), and 1.73(1.55-1.94), respectively. Compared with participants with neither proteinuria nor low eGFR, those with proteinuria but not low eGFR and those with both proteinuria and low eGFR had 2.21 (1.46-3.34) and 13.82(5.50-34.71), respectively, times higher risk for TRDED. These results implied that proteinuria worked synergistically with low eGFR but the interaction was not statistically significant. These findings demonstrated that semi-quantitatively assessed proteinuria using test strips is quick and useful for assessing the risk of development of advanced retinopathy especially in combination with reduced eGFR. Disclosure M. Yamamoto: None. K. Fujihara: None. T. Osawa: None. M. Harada: None. M. Ishizawa: None. H. Ishiguro: Research Support; Self; MSD K.K., Sanofi K.K., Eli Lilly and Company. H. Suzuki: None. H. Seida: None. N. Yamanaka: None. Y. Matsubayashi: None. H. Sone: Research Support; Self; Novo Nordisk Inc., Eli Lilly and Company, MSD K.K., Chugai Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Sanofi, Kowa Pharmaceuticals America, Inc., Eisai Inc..

Biological Actions of Glucagon Gene-Derived Peptides in the Peripheral Nervous System of Mice

Background: Glucagon gene-derived peptides are produced as glucagon-like peptide 1 (GLP-1) in intestinal L cells and glucagon in pancreatic α cells, and play an important physiological role. However, the physiological roles of those peptides in various tissues are not fully elucidated. In this study, we examined the physiological roles of these peptides in the peripheral nervous system (PNS). Methods: Expression of glucagon receptor in the PNS was examined in 18-21 week-old C57BL6/J (WT) mice utilizing immunohistochemical staining. Neurite outgrowth was assessed after 24-48 hours of primary culture of dorsal root ganglion (DRG) neurons supplemented with or without glucagon (10⁻⁷ to 10⁻⁵ mol/l). Furthermore, the sensory function of the plantar pedis was evaluated by thermal plantar test in glucagon gene deficient mice (gcg+/⁻, gcg⁻/⁻) of 8, 12, 18, 24, and 30 week-old. Results: The immunohistological staining validated the expression of glucagon receptor in most DRG neurons and satellite glial cells. In the primary culture of DRG neurons, the neurite length was significantly increased in the group cultured with glucagon. (control: 761.4±294.9 μm/cell, glucagon 10⁻⁵ mol/l: 2276.5±835.6 μm/cell, p <0.01). The thermal plantar test revealed a hypersensitivity in 12 week-old gcg-/- mice (WT: 8.8 second, gcg ⁺/⁻: 6.9, gcg⁻/⁻: 5.5, p < 0.01: WT vs. gcg⁻/⁻) and in 18 week-old gcg-/- and gcg+/- mice (WT: 8.8, gcg⁺/⁻: 7.1, gcg⁻/⁻: 6.6, p < 0.01: WT vs. gcg⁺/⁻ or gcg⁻/⁻). However, the hypersensitivity disappeared in 24 week-old mice (WT: 8.4, gcg+/-: 8.9, gcg⁻/⁻: 8.5). Discussion: These data suggested that glucagon may have a protective role for DRG neurons. Further investigation should be performed to elucidate the role of glucagon gene-derived peptides in the PNS in the future. Disclosure M. Motegi: None. T. Himeno: None. H. Kamiya: Other Relationship; Self; MSD K.K., Ono Pharmaceutical Co., Ltd., Sanofi K.K., AstraZeneca, Astellas Pharma KK, Eli Lilly and Company, Novartis Pharma K.K., Dainippon Sumitomo Pharma Co., Ltd, Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceutical Co., Ltd, Ono Pharmaceutical Co., Ltd.. H. Shimoda: None. M. Kato: None. Y. Yamada: None. E. Miura-Yura: None. M. Kondo: None. S. Tsunekawa: None. Y. Kato: Speaker's Bureau; Self; Merck Sharp & Dohme Corp., Sanofi, Takeda Pharmaceutical Company, Eli Lilly Japan. Y. Hayashi: Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Kissei Pharmaceutical Co., Ltd., Takeda Pharmaceuticals Co., Ltd., Novartis Pharma K.K., Novo Nordisk A/S, Astellas Pharma US, Inc. J. Nakamura: Other Relationship; Self; Astellas Pharma US, Inc., AstraZeneca, Ono Pharmaceutical Co., Ltd., MSD K.K., Kyowa Hakko Kirin Co., Ltd., Kowa Pharmaceuticals America, Inc., Sanofi K.K., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Mitsubishi Tanabe Pharma Corporation, Eli Lilly and Company, Novartis Pharma K.K., Pfizer Inc..

Impact of Carbohydrate Intake on Obesity in Japanese Patients with Type 2 Diabetes—An Analysis of the JDCP Registry

While the clinical relevance of a low carbohydrate diet for obese patients with diabetes is still a matter of debate, the optimal amount of carbohydrates has not yet been elucidated. Therefore, we investigated the association between obesity and the carbohydrate intake while considering the physical activity (PA) levels in patients with type 2 diabetes. Japanese patients with type 2 diabetes in a nation-wide registry who completed a lifestyle survey, but were not administered insulin therapy (N=1111, mean age 61.7 y, mean BMI 24.4 kg/m2) were included in this cross-sectional study. The carbohydrate intake and PA were evaluated by the Brief-type self-administered Diet History Questionnaire and the International Physical Activity Questionnaire, respectively. Participants were stratified into two groups according to whether they were above or below the PA of 1380 MET min/week which is the level recommended by the Japan Diabetes Society and WHO, as well as into tertiles according to their carbohydrate intake. The odds ratio (OR) for obesity (defined as BMI ≥25 kg/m2) in each combined category was determined by a multivariate logistic regression model. The mean daily intake of energy, carbohydrate, protein, and fat was 1695 kcal, 233g, 69g, and 44g, respectively, and the median PA was 1386 MET min/week. ORs for obesity in participants whose carbohydrate intake was in the top tertile (≥ 253g/day) and a PA of <1380 MET min/week compared to those whose carbohydrate intake was in the bottom tertile (< 196 g/day) and a PA of ≥ 1380 MET min/week was 1.8 (95% CI, 1.2-2.9, p=0.01). However, the association became non-significant when adjusted by energy intake instead of the amount of fat and protein. In conclusion, a daily carbohydrate intake of more than approx. 250 g was significantly associated with obesity in combination with an inactive state in Japanese patients with type 2 diabetes, even though the energy intake might have as strong impact as carbohydorate intake. Disclosure S. Matsunaga: None. H. Sone: Research Support; Self; Novo Nordisk Inc., Eli Lilly and Company, MSD K.K., Chugai Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Sanofi, Kowa Pharmaceuticals America, Inc., Eisai Inc.. K. Tsuda: None. Y. Oshida: None. S. Sasaki: None. J. Satoh: Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Pfizer Inc., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd.. Y. Hayashino: None. R. Nishimura: Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Astellas Pharma US, Inc., Eli Lilly and Company, Abbott, Medtronic, MSD K.K., Novo Nordisk A/S, Sanofi, Takeda Development Center Asia, Pte. Ltd., Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.. N. Tajima: None.

A Novel Severity Classification of Diabetic Polyneuropathy Based on Nerve Conduction Study and ECG

In this study, we propose a novel DPN severity classification based on coefficient of variance of R-R interval on ECG (CVRR) and nerve conduction study (NCS). The subjects consisted of 182 patients (mean age 58.9 years-old; duration of diabetes 10.2 years, HbA1c 9.72% and BMI 26.0) with type 2 diabetes admitted to our hospital from 2015 to 2017. Based on NCS and CVRR during rest, the subjects were classified into six categories as follows; 1) N0C0: sural nerve sensory action potential (SP)>5μV and tibial nerve compound motor action potential (CP)>5mV + CVRR>2%, 2) N1C0: SP<5 and CP>5 + CVRR>2, 3) N2C0: SP<5 and CP<5 + CVRR>2, 4) N0C1: SP>5 and CP>5 + CCRR<2, 5) N1C1: SP<5 and CP>5 + CVRR<2 and 6) N2C1: SP<5 and CP<5 + CR<2. We examined the relationship between each category with urinary albumin excretion rate (logarithmic transformation: LogACR), eGFR, presence/absence of nephropathy (ACR>300mg/gCre and/or eGFR<30) or retinopathy, and PWV as an index of arteriosclerosis. For statistical analysis, one-way analysis of variance (ANOVA), multiple comparison (Tukey), covariance analysis and logistic regression analysis were used. The one-way analysis revealed significant differences between each category in terms of age, the duration of diabetes, LogACR, eGFR and PWV. LogACR and PWV were significantly higher in the N2C1 than in the N0C0 (p<0.05). Even after correction with age, duration and gender, a significant difference (p=0.008) between groups was observed in LogACR and a trend in PWV (p=0.068). In the logistic regression analysis corrected by age, duration and gender, the odds ratio (OR) for retinopathy was 5.36 in N0C1, 11.10 in N1C0, 8.23 in N1C1 and 11.78 in N2C1 compared with N0C0 (p<0.01). The OR for nephropathy in N0C1 was 6.56, 7.91 in N1C1, 15.54 in N2C0 and 23.55 in N2C1 (p<0.05). Severity classification of DPN based on NCS and CVRR during rest was well co-related to other diabetic complications, suggesting the usefulness of this novel classification to evaluate the severity of DPN. Disclosure H. Shimoda: None. H. Kamiya: Other Relationship; Self; MSD K.K., Ono Pharmaceutical Co., Ltd., Sanofi K.K., AstraZeneca, Astellas Pharma KK, Eli Lilly and Company, Novartis Pharma K.K., Dainippon Sumitomo Pharma Co., Ltd, Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceutical Co., Ltd, Ono Pharmaceutical Co., Ltd.. A. Watarai: None. T. Himeno: None. Y. Shibata: None. M. Motegi: None. M. Kato: None. Y. Yamada: None. E. Miura-Yura: None. M. Kondo: None. S. Tsunekawa: None. Y. Kato: Speaker's Bureau; Self; Merck Sharp & Dohme Corp., Sanofi, Takeda Pharmaceutical Company, Eli Lilly Japan. J. Nakamura: Other Relationship; Self; Astellas Pharma US, Inc., AstraZeneca, Ono Pharmaceutical Co., Ltd., MSD K.K., Kyowa Hakko Kirin Co., Ltd., Kowa Pharmaceuticals America, Inc., Sanofi K.K., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Mitsubishi Tanabe Pharma Corporation, Eli Lilly and Company, Novartis Pharma K.K., Pfizer Inc..

Incidence and Risk Factors for Amputation in Patients with Diabetes in Japan—Historical Cohort Study Using a Nationwide Claims Database

Since amputation of a lower extremity predisposes patients with diabetes to a lower quality of life and higher rates of cardiovascular events and mortality, identifying predictors of amputation is of clinical relevance in diabetes management. Although the incidence of amputation is known to be much lower in East Asians compared to those in Western countries, there has been no large cohort study of the accurate incidence of amputations in East Asians. Thus we analyzed data from a nationwide claims database involving 17,288 individuals with diabetes in Japan (2942 women, mean age 50.2 y, HbA1c 7.2%) from 2008-16. During a mean follow-up period of 5.3 y, 16 amputations occurred (0.17/1000 person-years), which was about one tenth of the typical rates reported by Western countries. Multivariate Cox regression analysis showed that age and HbA1c were independent predictors of amputation (hazard ratio (HR) 1.11(95% CI 1.03-1.19) and 1.43(1.13-1.81), respectively). Compared with those age <58 y and with HbA1c <8%, the HR for those age ≥58 y and HbA1c ≥8% was 32.0 (7.72-133.5). Kaplan-Meyer analysis confirmed the strikingly high risk in this category (Figure). Our results implied large differences in incidence and risk profiles for amputation in Japanese patients with diabetes, suggesting the need for ethnic group-specific strategies to prevent diabetic foot disease. Disclosure M. Kaneko: None. K. Fujihara: None. M. Yamamoto: None. M. Kitazawa: None. M. Ishizawa: None. T. Osawa: None. M. Harada: None. Y. Matsubayashi: None. T. Yamada: None. H. Sone: Research Support; Self; Novo Nordisk Inc., Eli Lilly and Company, MSD K.K., Chugai Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Sanofi, Kowa Pharmaceuticals America, Inc., Eisai Inc..

Inhibitory Effects of Intranasal Insulin Administration on Fat Oxidation during Exercise Are Diminished in Overweight Young Individuals

Endurance training at a level (FATmax) that raises the maximal fat oxidation rate (max FOR) may contribute to body weight loss in obese individuals. However, max FOR and FATmax are reduced in subjects with obesity and/or with insulin resistance compared with those without. On the other hand, in humans, intranasal insulin administration increases the concentration of insulin in cerebrospinal fluid when peripheral effects are absent, resulting in reduced food intake and body weight. However, it remains unclear whether insulin delivery to the brain affects fat oxidation during exercise. In this study, we examined the effects of nasal insulin administration on max FOR during exercise in 11 normal-weight (N group) and seven overweight (O group) young individuals. On two separate days, either 40 IU regular insulin (INS) or normal saline, as placebo (PL), was randomly administered intranasally after overnight fasting, and then each participant underwent a graded exercise test. Indirect calorimetry was used to assess max FOR during exercise and FATmax. Blood insulin and glucose levels did not change after insulin administration. In the N group, max FOR tended to decrease in the INS trial (p = 0.050); FATmax and the total amount of fat oxidation during exercise were significantly smaller in the INS trial than in the PL trial. Max FOR was significantly smaller in the O group than in the N group (p = 0.021) and was not influenced by insulin administration. Blood adrenaline levels increased by exercise tended to be reduced by insulin administration in the N group only. In conclusion, intranasal insulin administration reduces fat oxidation during exercise without increasing peripheral insulin levels, possibly via the suppression of sympathetic nerve activity. The inhibitory effects of intranasal insulin administration on fat oxidation during exercise are diminished in overweight subjects, suggesting cerebral insulin effects are attenuated in this population. Disclosure H. Yokoyama: None. R. Takeda: None. E. Kawai: None. A. Ota: None. E. Morita: None. D. Imai: None. Y. Suzuki: None. T. Morioka: Consultant; Self; Ono Pharmaceutical Co., Ltd.. Research Support; Self; Novartis Pharma K.K., MSD K.K., Eli Lilly and Company, Sanofi K.K., Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Takeda Pharmaceuticals U.S.A., Inc., Novo Nordisk Inc., Kowa Pharmaceuticals America, Inc., Astellas Pharma US, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Sumitomo Dainippon Pharma Co., Ltd. M. Emoto: Speaker's Bureau; Self; Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Sumitomo Dainippon Pharma Co., Ltd.. Research Support; Self; Astellas Pharma Inc, Ono Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceutical Company Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation. M. Inaba: None. K. Okazaki: None.

Role of Hyaluronic Acid on Apolipoprotein A1 and HDL-Mediated Cholesterol Efflux in Macrophages

Diabetic macroangiopathy are characterized by increased arterial stiffness and hyaluronic acid (HA) deposition in the large elastic arteries. It is noteworthy that systemic inhibition of HA synthesis by 4-methylumbelliferone interferes with the protective function of the endothelial glycocalyx, thereby facilitating leukocyte adhesion, inflammation, and progression of atherosclerosis. Apolipoprotein A1 (ApoA1) and High-density lipoprotein (HDL) mediates cholesterol efflux, which is the initial and rate-limiting step of reverse cholesterol transport preventing from atherosclerosis. The aim of the present study was to investigate the role of HA on ApoA1 and HDL-mediated cholesterol efflux in macrophages. Murine J774.1 macrophages and human THP-1 macrophages were labeled with 3H-cholesterol and incubated with ApoA1 (10 μg/ml) for 24 hours or HDL (50 μg/ml) for 4 hours. The percentage cholesterol efflux was calculated by dividing the media-derived radioactivity by the sum of the radioactivity in the media and the cells. The effect of HA on the cholesterol efflux was studied, adding that into the medium before the analysis of the cholesterol efflux. Under the existence of medium molecular weight HA (75-350 kDa), the HDL-mediated cholesterol efflux had significantly increased by 10.9% (n=4, p<0.01) in J774.1 macrophages. We also researched the relationship between HA and ATP-binding cassette transporter G1 (ABCG1), because expression of ABCG1 enhances cholesterol efflux to HDL. Predictably, HA significantly increased ABCG1 mRNA expression in macrophage (n=4, p<0.01), determined by Real-time Quantitative RT-PCR. These data suggest that HA increases HDL-mediated cholesterol efflux via ABCG1 in macrophages and the difference of molecular weight on HA may influence ApoA1 and HDL-mediated cholesterol efflux. The relationship between HA and cholesterol efflux might be one of the important mechanisms to prevent progression of atherosclerosis and diabetic macroangiopathy. Disclosure K. Matsuki: None. M. Ogura: None. M. Harada-Shiba: Advisory Panel; Self; Aegerion Pharmaceuticals. Speaker's Bureau; Self; Amgen Inc., Astellas Pharma US, Inc., Sanofi, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Daiichi Sankyo Company, Limited, MSD K.K.. Research Support; Self; Sanofi, Aegerion Pharmaceuticals, Kowa Pharmaceuticals America, Inc..

Prevalence of Sexual Dysfunction and Its Related Factors in Male Japanese Patients with Diabetes

Background: Sexual dysfunction affects the quality of life and is related to mortality among patients with diabetes (DM). The aim of the study was to assess the prevalence of erectile dysfunction (ED) and ejaculation disorder (EJD) and their related factors in male Japanese patients with DM. Methods: This single-center, cross-sectional analysis was performed as a part of a study by our Diabetes Center between October 2013 and January 2014 (response rate, 91%). Of 7920 patients, women, patients with neither type 1 DM (T1D) nor type 2 DM (T2D), an unknown type of DM, and those for whom information was incomplete were excluded. The remaining male patients, 315 with T1D (49 ± 15 years) and 2732 with T2D (65 ± 12 years), were analyzed. They responded to questionnaires regarding subjective symptoms associated with diabetic complications, including ED and EJD, lifestyle, and depression symptoms (PHQ-9 score). A multivariable logistic regression model was used to examine factors related to ED and EJD. Results: The prevalence of sexual dysfunction was significantly higher in patients with T2D (35.9%; ED + EJD 8.5%, only ED 25.8%, only EJD 1.7%) than in those with T1D (21.9%; ED + EJD 5.6%, only ED 12.2%, only EJD 4.1%). Multivariable logistic regression analysis showed that ED was independently associated with the presence of abnormal bowel movement and retinopathy in patients with T1D and age, the presence of proliferative retinopathy (PDR), heart failure, frequent urination, dysuria, dysautonomia, long sleeping hours, and a high PHQ-9 score in those with T2D. EJD was independently associated with PDR in patients with T1D and T2D and the presence of dysautonomia, frequent urination, dysuria, and abnormal bowel movement in patients with T2D. Conclusions: Sexual dysfunction is not rare in male Japanese patients with DM. In daily clinical practice, attention should be paid to patients at a high risk of sexual dysfunction with a variety of complicated symptoms and conditions due to DM. Disclosure Y. Kondo: None. T. Nakagami: None. J. Oya: None. Y. Hasegawa: None. A. Ito: None. N. Hirota: None. R. Tsuzura: None. A. Katamine: None. R. Yoshimura: None. J. Miura: None. Y. Uchigata: None. T. Babazono: Research Support; Self; Abbott, Arkray, Inc.. Speaker's Bureau; Self; Asahi Kasei Corporation, AstraZeneca. Research Support; Self; Baxter, Becton, Dickinson and Company, Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; Eli Lilly and Company. Research Support; Self; Kowa Pharmaceuticals America, Inc., Kissei Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., MSD K.K., Nippon Boehringer Ingelheim Co. Ltd.. Board Member; Self; Japan Diabetes Society. Research Support; Self; Johnson & Johnson Diabetes Institute, LLC., Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd.. Speaker's Bureau; Self; Otsuka Holdings Co., Ltd.. Research Support; Self; Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Takeda Canada Inc., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceuticals U.S.A., Inc., Teijin Pharma Limited, Terumo Medical Corporation.

Association of Anti-GAD Antibody Positivity Measured by RIA and ELISA with Clinical Characteristics in Patients with Type 1 Diabetes

Background: Serum anti-GAD antibody (GADA) is a diagnostic marker of immune-mediated type 1 diabetes mellitus. Discrepancies have been reported between GADA positivity assessed by radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA). To analyze heterogeneity in type 1 diabetes, this study investigated patients with this discrepancy. Subjects and Method: This study included 65 patients with acute-onset type 1 diabetes (AT1D) and 32 with slowly progressive type 1 diabetes (SPIDDM), all weakly positive (1.5-10 U/mL) for GADA, as measured by RIA in 2013-2015. GADA was measured in the same samples, stored at -80°C, by ELISA in 2016-2017. GADA concentrations ≥ 5 U/mL and < 5 U/mL on ELISA were defined as positive and negative, respectively. Postprandial C-peptide was measured at the time of RIA. Results: Of the patients with A1TD and SPIDDM, 86% and 59%, respectively, were ELISA-positive. Duration of diabetes did not differ significantly between positive and negative patients in each subtype. Postprandial C-peptide index was significantly lower in positive than negative patients with SPIDDM (0.39±0.48 vs. 1.56±1.16, p<0.001), but not with AT1D. HLA was assessed in 15 patients with SPIDDM, nine positive and six negative for GADA. Seven of the nine positive, but none of the five negative, patients had HLA-DR9 (p=0.007). HLA was also assessed in 39 patients with AT1D, 33 positive and six negative for GADA. Eleven of the 33 positive, but none of the six negative, patients had HLA-DR9 (p=0.158). Discussion: In SPIDDM patients weakly positive for GADA by RIA, ELISA positivity was significantly associated with lower insulin secretion, suggesting that more cytotoxic epitopes of GAD are recognized by ELISA than by RIA. ELISA positivity in SPIDDM is associated with HLA-DR9, a haplotype linked to cytotoxicity against pancreatic β-cells. Measuring GADA by RIA and ELISA may predict insulin secretion in patients with SPIDDM. Disclosure S. Takagi: Stock/Shareholder; Self; Astellas Pharma Inc., Mitsubishi Tanabe Pharma Corporation. J. Miura: None. S. Hoshina: None. Y. Uchigata: None. T. Babazono: Research Support; Self; Abbott, Arkray, Inc.. Speaker's Bureau; Self; Asahi Kasei Corporation, AstraZeneca. Research Support; Self; Baxter, Becton, Dickinson and Company, Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; Eli Lilly and Company. Research Support; Self; Kowa Pharmaceuticals America, Inc., Kissei Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., MSD K.K., Nippon Boehringer Ingelheim Co. Ltd.. Board Member; Self; Japan Diabetes Society. Research Support; Self; Johnson & Johnson Diabetes Institute, LLC., Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd.. Speaker's Bureau; Self; Otsuka Holdings Co., Ltd.. Research Support; Self; Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Takeda Canada Inc., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceuticals U.S.A., Inc., Teijin Pharma Limited, Terumo Medical Corporation.

Dipstick Proteinuria as a Predictor of End-Stage Renal Disease in Japanese Adults With and Without Diabetes Mellitus (DM)

Although proteinuria is an established potent predictor of the initiation of dialysis, it is unclear whether the impact and clinical relevance of widely used dipstick proteinuria on dialysis differs between adults with and without DM. To clarify this, we longitudinally analyzed a nationwide claim-based database that included 138,554 people aged 18-72 y in Japan. Urinary protein was assessed by test strip, the results of which ± corresponds to ≥15 mg/dL. During the 7-y period, there were 46 and 20 incident cases of dialysis among people with and without DM, respectively. Multivariate Cox analysis showed that, among people without proteinuria, those with DM had a 3.4-fold increased dialysis risk than those without DM whereas, even among individuals without DM, dipstick proteinuria confers a far higher risk of around 20 fold (Table, upper). DM and dipstick proteinuria seemed to additively affect (Table, middle) the initiation of dialysis although those with both DM and proteinuria did not have a significantly higher risk of dialysis than those without DM but with proteinuria (Table, lower). Proteinuria detected by dipstick confers a far higher risk of subsequent dialysis than diabetes per se, but clinicians should be aware of the greatly increased risk for dialysis in those with both DM and dipstick proteinuria, which implies the necessity of intensified interventions.Table Adjusted HRs (95% CI) for initiation of dialysis in individuals with and without DM according to presence or absence of dipstick proteinuria(events / n)Non-DM (46/128,529)DM (20/10,015)Dipstick proteinuriaHR (95% CI)P-valueHR (95% CI)P-value-ref3.37 (1.02-11.1)0.046± or moreref1.98 (0.76-5.13)0.16-ref3.51 (1.35-9.46)<0.01± or more19.0 (10.5-34.3)<0.0135.7 (14.1-90.1)<0.01-0.(0.03-0.10)<0.010.19 (0.07-0.48)<0.01± or moreref1.88 (0.79-4.49)0.15Adjusted for age, sex, BMI, WC, SBP, HbA1c, smoking, HDL-C, LDL-C, TG Disclosure A. Furuya: None. K. Fujihara: None. T. Osawa: None. M. Yamamoto: None. M. Harada: None. M. Ishizawa: None. H. Seida: None. N. Yamanaka: None. Y. Matsubayashi: None. H. Sone: Research Support; Self; Novo Nordisk Inc., Eli Lilly and Company, MSD K.K., Chugai Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Sanofi, Kowa Pharmaceuticals America, Inc., Eisai Inc..

Impacts of the Kumamoto Earthquake 2016 on Glycemic Control in Diabetic Patients

In April 14th and 16th, 2016, Kumamoto area was severely damaged by massive M7 class earthquakes. To examine the effects of these earthquakes on glycemic control and stress factors in diabetic outpatients regularly cared in diabetic clinic of Kumamoto University Hospital, sequential HbA1c, glycated albumin, other biochemical parameters, life style associated questionnaire and Impact of Event Scale-Revised (IES-R) scores were analyzed. A total of 557 patients were enrolled and data were collected from 13 months before to 13 months after the earthquakes. In patients with type 1 diabetes (T1D) or specific types of diabetes due to other causes, glycemic control was not altered during the observational period. This glycemic stability in T1D may result from self-management of insulin doses (increase in 7% and decrease in 20% of patients). In patients with type 2 diabetes (T2D), HbA1c was decreased by 0.11% (from 7.33% to 7.22%) at 1-2 months after the earthquakes compared to that before the earthquakes, and increased at 3-4, 6-7 and 12-13 months after the earthquakes. The reduction of HbA1c at after 1-2 months in T2D was associated with “quick restoration of life-lines” and “sufficiency of sleep.” The glycemic deterioration at after 3-4 months was related to “shortage of antidiabetic agents” and “insufficient amount of food”, and at after 12-13 months that was connected to “large-scale partial destruction of houses” and “changes in working environments.” IES-R, representing disaster associated stress levels were positively correlated with “age”, “delayed restoration of life-lines”, “self-managements of antidiabetic agents” and “increased amount of activity”, and negatively associated with “early restoration of life-lines” and “sufficiency of sleep.” Thus, the glycemic control, associated factors and stress levels are altered in chronological order. Post-disaster diabetic medical care must consider these corresponding points in accordance with the time period. Disclosure T. Kondo: None. N. Miyakawa: None. H. Motoshima: None. N. Ishii: None. M. Igata: None. K. Yoshinaga: None. D. Kukidome: None. T. Senokuchi: None. J. Kawashima: None. T. Matsumura: None. E. Araki: Speaker's Bureau; Self; Astellas Pharma US, Inc., MSD K.K., Kowa Pharmaceuticals America, Inc., Sanofi, Novo Nordisk Inc.. Research Support; Self; Astellas Pharma US, Inc., MSD K.K., Ono Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Takeda Pharmaceuticals U.S.A., Inc., Daiichi Sankyo Company, Limited, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Sanofi, Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd., Taisho Toyama Pharmaceutical Co..

Increased Cardiovascular Risk in Patients with Diabetes, Statin-Controlled LDL Cholesterol, and Residual Hypertriglyceridemia

High triglyceride (TG) levels are common in type 2 diabetes (T2D). We evaluated T2D patients at high risk for CV events who had statin-controlled LDL cholesterol (LDLc) to determine whether the presence of high TG levels contribute to residual CV risk. We combined data from the Southern California and Northwest regions of Kaiser Permanente to identify adults on statin therapy with LDLc 40-100 mg/dL, no other lipid therapies, and with T2D and a prior diagnosis of myocardial infarction, ischemic stroke, peripheral artery disease or at least one other CV risk factor. Patients were grouped into high (200-499 mg/dL, n=5,542) or normal (<150 mg/dL, n=22,411) TGs in 2010 and followed them through December 2016 to compare the adjusted incidence rates and rate ratios of first non-fatal MI, non-fatal stroke, unstable angina, coronary revascularization, death, and their composite. Models were adjusted for demographic and clinical characteristics using generalized linear models with Poisson errors. Over mean follow-up of 5 years, patients with high TG were at increased risk of CV outcomes (Table). High TG levels independently increase CV risk in T2D patients with statin-controlled LDLc. The ongoing CV outcome trial, REDUCE-IT, will determine if high dose pure prescription eicosapentaenoic acid reduces CV risk among statin users with persistently high TG levels, including T2D patients. Disclosure G. Nichols: Research Support; Self; Boehringer Ingelheim GmbH, Amarin Corporation, Janssen Pharmaceuticals, Inc., Sanofi. S. Philip: Stock/Shareholder; Self; Amarin Corporation. Employee; Self; Amarin Corporation. C.B. Granowitz: Employee; Self; Amarin Corporation. K. Reynolds: Research Support; Self; Amarin Corporation, Novartis Pharmaceuticals Corporation, Amgen Inc., CSL Behring. S. Fazio: Consultant; Self; Amarin Corporation, Akcea Therapeutics, Amgen Inc., Kowa Pharmaceuticals America, Inc..

Mechanisms of Therapeutic Effects of Conditioned Media from Cultured Dental Pulp Stem Cells on Diabetic Polyneuropathy

Stem cell transplantation is expected to become a novel therapy for diabetic polyneuropathy. Dental pulp stem cells (DPSC) are an attractive cell source because they can be easily isolated from teeth extracted for general orthodontic reasons. We reported earlier that DPSC transplantation was effective for diabetic polyneuropathy. However, most of the transplanted DPSCs from this study are gone from the transplanted site and the mechanism of cell transplantation may have been due to the abundant secreted factors from stem cells. We confirmed that conditioned media from DPSCs (DPSC-CM) ameliorated diabetic polyneuropathy. We, therefore, examined the mechanism of therapeutic effects of DPSC-CM on diabetic polyneuropathy. DPSCs were isolated and cultured from the mandibular incisors of 6-week-old male Sprague-Dawly (SD) rats. Diabetes was induced at 6-weeks by administering STZ. DPSC-CM was administered to the unilateral hindlimb skeletal muscles of both the diabetic and normal rats 8 weeks after the administration of STZ, and the measurements were performed 4 weeks after DPSC-CM administration. Administration of DPSC-CM significantly improved the delay of the sciatic nerve motor/sensory conduction velocity and reduced sciatic nerve blood flow in diabetic rats. TNF-α and CD68 gene expression in the sciatic nerves tended to increase in the diabetic group, which showed a decreasing trend by administration of DPSC-CM. Capillary density in the hindlimb skeletal muscle was decreased in diabetic rats. DPSC-CM significantly increased capillary/muscle ratio in the hindlimb skeletal muscles in the diabetic rats. It was revealed that intramuscular administration of DPSC-CM was effective for diabetic polyneuropathy at least in part by improving nerve/muscle blood flow and suppressing inflammation. These results indicate that DPSC-CM could be a novel therapy for diabetic polyneuropathy. Disclosure E. Makino: None. N. Nakamura: None. M. Miyabe: None. M. Ito: None. S. Kanada: None. M. Hata: None. T. Saiki: None. H. Kamiya: Other Relationship; Self; MSD K.K., Ono Pharmaceutical Co., Ltd., Sanofi K.K., AstraZeneca, Astellas Pharma KK, Eli Lilly and Company, Novartis Pharma K.K., Dainippon Sumitomo Pharma Co., Ltd, Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceutical Co., Ltd, Ono Pharmaceutical Co., Ltd. J. Nakamura: Other Relationship; Self; Astellas Pharma US, Inc., AstraZeneca, Ono Pharmaceutical Co., Ltd., MSD K.K., Kyowa Hakko Kirin Co., Ltd., Kowa Pharmaceuticals America, Inc., Sanofi K.K., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Mitsubishi Tanabe Pharma Corporation, Eli Lilly and Company, Novartis Pharma K.K., Pfizer Inc.. K. Miyazawa: None. S. Goto: None. T. Matsubara: None. K. Naruse: None.

Glycemic Factors Related to Depression in Adults with Type 1 Diabetes

Objective: To compare glycemic factors (home glucose monitoring, glucose variability, A1c) in adults with type 1 diabetes (T1D) with probable depression to those without depression in a real world setting. Methods: Adults with T1D at our diabetes center are routinely screened for depression with the PHQ2. If the PHQ2 score is >3, PHQ9 is completed. Medical records were reviewed including device downloads for adults with PHQ9 scores =10 (“depressed”) and age-matched “not depressed” controls (PHQ2 scores =3). Patients with T1D duration <1 year, GFR =30 mL/min/1.73m2, hemoglobinopathy or dementia were excluded. Results: Of 1292 adults screened, 83 (6.4%) were depressed, and compared to an age-selected group of 171 non-depressed T1D adults (age range 18-72 years, 86% white, 8% black, 99% non-Hispanic, 42% Medicaid). Depressed [mean (SD) PHQ9 score 16.8 (4.3)] did not differ from non-depressed on age [41.7 (15.6) vs. 41.8 (15.7) years], BMI [29.3 (8.8) vs. 28.9 (6.2) kg/m2], T1D duration [21.2 (13.4) vs. 22.0 (15.0) years], or % male [42.2 vs. 40.9]. Meter downloads were available for 215/254 patients (74% of depressed, 90% of non-depressed). The depressed group had higher A1c [9.6% (2.3) vs. 8.6% (1.8) p<0.001], and fewer glucose tests/day [2.8 (2.3) vs. 3.6 (2.5) p=0.048] based on meter downloads. Prior work found that depression did not relate to self-reported glucose monitoring in T1D adults. The groups did not differ on meter % coefficient of variation (CV; mean 42%) or % with hypoglycemia (glucose reading <54 mg/dL). Continuous glucose monitoring (CGM) was used by 38 patients; CGM % CV was also not different in those depressed [35.0 (6.2), n=5] vs. non-depressed [36.0 (6.0), n=33]. The depressed group using CGM had lower A1c, suggesting that CGM use should not be withheld in the presence of depression. The small number of patients using CGM is a limitation. Conclusion: Adults with T1D and probable depression had higher A1c, less meter use, fewer glucose readings/day, but no difference in glucose variability (% CV) or hypoglycemia (<54 mg/dL). Disclosure I. Egbuonu: None. P.M. Trief: Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. C.A. Roe: None. R.S. Weinstock: Research Support; Self; Medtronic MiniMed, Inc., Mylan, Kowa Pharmaceuticals America, Inc., Diasome Pharmaceuticals, Inc., Calibra Medical, Dexcom, Inc., Ultradian Diagnostics LLC., JAEB Center For Health Research, JDRF, National Institute of Diabetes and Digestive and Kidney Diseases.

Efficacy and Safety of Evolocumab in Patients with Type 2 Diabetes Mellitus and Hypercholesterolemia or Mixed Dyslipidemia

Aim: To examine the efficacy of 12 weeks of monthly evolocumab (EvoMab) 420 mg vs. placebo (Pbo) in lowering LDL-C in those with type 2 diabetes mellitus (T2DM) and hypercholesterolemia or mixed dyslipidemia and on statin therapy. Methods: Patients ≥18 years with T2DM, HbA1c <10%, on stable pharmacotherapy for diabetes for ≥6 months, and taking a statin were eligible; 421 were randomized (2:1 EvoMab:Pbo) and dosed. Co-primary endpoints: mean % change in LDL-C from baseline to week 12 and mean % change in LDL-C from baseline to the mean of weeks 10 and 12. Additional measures included change in non-HDL-C, LDL-C goals, and measures of glycemic control. Results: Mean participant age (SD) was 62 (8) years; 44% women; 77% Caucasian. In modified, intent to treat analyses (all randomized and dosed patients) EvoMab significantly reduced LDL-C and non-HDL-C vs. Pbo, and did not impact glycemic control. The incidence of AEs was comparable between EvoMab and Pbo, with no clinically meaningful differences in serious AEs. See Table.Table.Placebo(N=141)Evolocumab(N=280)Baseline LDL-C (mg/dL), mean (SD)110.4 (33.0)108.6 (31.0)Baseline non-HDL-C (mg/dL), mean (SD)145.5 (33.9)144.6 (34.9)Any adverse event (AE), n (%)52 (36.9)110 (39.3)Serious AE, n (%)2 (1.4)14 (5.0) 14 (5.0)14 (5.0)aMean of Weeks 10 and 12LipidsPercent change from baseline in LDL-C, mean (SE)–0.8 (1.8)–65.0 (1.3)bPercent change from baseline in non-HDL-C, mean (SE)–0.(1.6)–56.6 (1.2)bAchievement of LDL-C < 70 mg/dL, n, %20 (14.8)253 (92.7)bAchievement of ≥50% reduction in LDL-C, n, %1 (0.7)230 (84.2)bWeek 12Glycemic ControlChange from baseline in FSG in mg/dL, median (Q1, Q3)4.0(–15.0, 29.0)5.0(–13.5, 29.5)Change from baseline in HbA1c in percent, median (Q1, Q3)0.1(–0.2, 0.5)0.1(–0.2, 0.5)aNo pattern in differences in serious AEs was observed. Chronic obstructive pulmonary disease was the only serious AE reported by ≥ 1% of patients in the evolocumab treatment group.bP < 0.0001 for evolocumab versus placebo comparisonFSG, fasting serum glucose; HbA1c, glycated hemoglobin; LDL-C, low-density lipoprotein cholesterol; non-HDL-C, non-high-density lipoprotein cholesterol; SE, standard errorFunding: Amgen Inc. Conclusion: In statin-treated patients with T2DM and hypercholesterolemia or mixed dyslipidemia, evolocumab safely and effectively lowered LDL-C. Disclosure R.S. Rosenson: Other Relationship; Self; Akcea Therapeutics, Amgen Inc., AstraZeneca, Eli Lilly and Company, The Medicines Company, Regeneron Pharmaceuticals, Inc., Sanofi US, Kowa Pharmaceuticals America, Inc., UpToDate. M.L. Daviglus: Advisory Panel; Self; Amgen Inc. P. Reaven: Research Support; Self; AstraZeneca, Amgen Inc., Bristol-Myers Squibb Company. P. Pozzilli: Research Support; Self; Sanofi. Speaker's Bureau; Self; Eli Lilly and Company. Research Support; Self; Merck Sharp & Dohme Corp. H. Bays: Research Support; Self; Amgen Inc. M. Monsalvo: Employee; Self; Amgen Inc.. Stock/Shareholder; Self; Amgen Inc. M. Elliott: Employee; Self; Amgen Inc.. Stock/Shareholder; Self; Amgen Inc. R. Somaratne: Employee; Self; NGM Biopharmaceuticals. Stock/Shareholder; Self; NGM Biopharmaceuticals. Y. Handelsman: Consultant; Self; Amarin Corporation. Speaker's Bureau; Self; Amarin Corporation. Board Member; Self; American Association of Clinical Endocrinologists. Consultant; Self; Amgen Inc.. Research Support; Self; Amgen Inc.. Speaker's Bureau; Self; Amgen Inc.. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Gan & Lee Pharmaceuticals. Consultant; Self; Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc.. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc.. Research Support; Self; Lexicon Pharmaceuticals, Inc.. Consultant; Self; Merck & Co., Inc.. Research Support; Self; Merck & Co., Inc.. Consultant; Self; Novo Nordisk Inc.. Research Support; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc., Regeneron Pharmaceuticals, Inc.. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi.

Influence of SGLT2 Inhibitor on Resting Heart Rate (RHR) and Factors Related to Its Changes

An elevated resting heart rate (RHR) is a risk factor for vascular complications in patients with and without type 2 diabetes mellitus (T2DM). Recently, the beneficial effects of SGLT2 inhibitors (SGLT2i) on cardiovascular and renal events were reported in large-scale clinical trials. However, their mechanisms are not fully clarified. This study aimed to investigate the effect of SGLT2i on RHR and the clinical factors that affect changes in RHR in patients with T2DM. Analyzed were 419 T2DM patients on diet and exercise therapy who received an SGLT2i, tofogliflozin (TOFO), or a placebo as initial monotherapy in two TOFO phase 2 and 3 studies. Adipose tissue insulin resistance (Adipo-IR) was calculated by the product of fasting free fatty acid and fasting insulin. Differences in heart rate-related variables between TOFO and the placebo were analyzed with an ANCOVA model. Multivariate analysis was performed to clarify independent factors that were associated with changes in RHR. Baseline characteristics were: male (67%), age (mean: 58 years), HbA1c (8.1%), BMI (26 kg/m2), RHR (66 bpm), eGFR (84 mL/min/1.73m2) and Adipo-IR (32.5 pmol/L•mmol/L). Concerning the effects on RHR, TOFO reduced RHR levels (least squares mean: -1.7 and -1.1 bpm, p<0.01 vs. baseline, p<0.vs. placebo) at weeks 12 and 24, respectively. Changes in quartiles of RHR from baseline to 24 weeks were 7.7, 0.7, -3.7, and -11.2, respectively. The change in RHR at week 24 did not correlate with changes in HbA1c, body weight and systolic blood pressure; however, it was correlated with baseline RHR levels (r = -0.37) and the change in Adipo-IR (r = 0.39) significantly. Multivariate analysis indicated that higher RHRs and Adipo-IR levels at baseline were independently associated with a greater reduction in RHR. Our results showed that the beneficial effects of the SGLT2i on cardiovascular and renal events may be associated with suppression of the sympathetic nervous system by improvement in Adipo-IR and amelioration of hyperinsulinemia. Disclosure Y. Matsubayashi: None. T. Nojima: Employee; Self; Kowa Company,LTD. A. Yoshida: Employee; Self; Kowa Pharmaceutical Co. Ltd. H. Suganami: Employee; Self; Kowa Company, Ltd.. T. Yamada: None. K. Fujihara: None. S. Tanaka: None. K. Kaku: Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation, MSD K.K.. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Ono Pharmaceutical Co., Ltd.. Advisory Panel; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. Speaker's Bureau; Self; Taisho Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceuticals, Japan Inc., Kowa Pharmaceuticals, Japan Inc.. Advisory Panel; Self; Astellas, Japan Inc. H. Sone: Research Support; Self; Novo Nordisk Inc., Eli Lilly and Company, MSD K.K., Chugai Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Sanofi, Kowa Pharmaceuticals America, Inc., Eisai Inc..