bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk of Foot Ulcer and Lower Extremity Amputation among Participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC)
Authors: BOYKO EDWARD J. , ZELNICK LEILA , BRAFFETT BARBARA , POP-BUSUI RODICA , COWIE CATHERINE C. , LORENZI GAYLE M. , GUBITOSI-KLUG ROSE , ZINMAN BERNARD , BOER IAN DE
Published: June 2018

We examined whether prior intensive glycemic control during the DCCT reduced the risk of diabetic foot ulcer (DFU) and lower extremity amputation (LEA) among participants with type 1 diabetes in the EDIC study. DFU and LEA occurrence were determined by physical examination during annual EDIC follow-up visits that began about one year following DCCT completion. We also assessed DFU and LEA risk by neurovascular measurements, diabetes characteristics, and clinical factors. Data were available from 23 years of EDIC follow-up. Recurrent DFU was defined if reported on a different limb in subsequent years or the same limb in non-consecutive years. Multivariable Cox models were used to estimate the association of intensive glycemic control and other time-updated risk factors with incident or total (incident + recurrent) DFU or incident LEA. Incident DFU was observed in 86 of the 699 former intensive and 109 of the 7former conventional treatment participants (HR 0.78, 95% CI 0.59 to 1.03). Total DFU numbered 117 in intensive (7.3/1000 person-years (p-y)) and 153 in conventional treatment participants (9.6/1000 p-y) for a significant risk reduction (HR 0.76, 95% CI 0.60 to 0.97, p=0.03). Incident LEA occurred in 15 intensive (1.0/1000 p-y) compared to 21 conventional treatment participants (1.4/1000 p-y, HR 0.70, 95% CI 0.36 to 1.36, p=0.30). Greater HbA1c, lower eGFR, albuminuria, confirmed clinical neuropathy, lower nerve conduction velocity, abnormal cardiovascular autonomic function, proliferative retinopathy, and macular edema were independently associated (p<0.05) with higher risk of incident DFU and LEA. Current smoking was associated with higher risk of LEA only. Ankle-brachial index measured continuously was not associated with risk of either outcome. We conclude that intensive glycemic control decreases the risk of DFU, the most important antecedent in the causal pathway to LEA.

Disclosure

E.J. Boyko: None. L. Zelnick: None. B. Braffett: None. R. Pop-Busui: Research Support; Self; AstraZeneca. C.C. Cowie: None. G.M. Lorenzi: Advisory Panel; Self; Intarcia Therapeutics, Inc.. R. Gubitosi-Klug: None. B. Zinman: Consultant; Self; Novo Nordisk A/S, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Sanofi, Merck & Co., Inc., Abbott. I. de Boer: Research Support; Self; Medtronic, Abbott. Consultant; Self; Boehringer Ingelheim GmbH, Ironwood Pharmaceuticals, Inc..
Gemigliptin in Diabetic Kidney Disease in Asian Indians with Type 2 Diabetes in Real-Life Scenarios—Insights from Gem Study
Authors: SHAH KIRAN , PATANGE SONALI A. , GANDHI ALKA P.
Published: June 2018

Diabetic Kidney disease is strongly associated with cardiovascular events, premature mortality and ESRD. Gemigliptin can be used without dose adjustment in patients with renal failure. The current study aimed to assess the possible renoprotective effects of gemigliptin, using albuminuria and eGFR as indicators. This was a multi-center real-world retrospective analysis of 146 DPP-4 inhibitor naïve type 2 diabetic patients with established moderate DKD (eGFR between 30 to 45ml/min/1.73m2 over last 3 months) with diabetic retinopathy who received gemigliptin 50 mg once daily for 24 weeks in addition to anti-hyperglycemic, anti-hypertensives and statins. Goodness of fit was examined using SPSS statistics 20 and ANOVA was conducted to interpret the results. Baseline characteristics were: 71(48.6%) males and 75 (51.4%) females, the mean age was 60.81 ± 7.42 years, mean duration was 11.92 ± 3.3 years, mean BMI was 26.54 ± 2.59kg/m2. Gemigliptin showed significant improvements in glycaemia, renal and lipid parameters with no deterioration in retinopathy, liver enzymes and with no hypoglycemic episodes and was weight neutral. In the present study, gemigliptin reduced albuminuria independent of age, gender, duration of diabetes, Hba1c, eGFR and SBP. It could ameliorate diabetic nephropathy by reducing urine albumin excretion and mitigating the reduction of eGFR in diabetic patients.

Mean changes in various efficacy parameters at week 24 of the overall study periodParametersAt Baseline (n=146)At 6 months (n=146)% change from Baseline to 6 monthsP valueFBS192.90 ± 52.64129.99 ± 19.4632.6Significant (<0.001)PPBS248.72 ± 62.75170.55 ± 23.0031.4Significant (<0.001)HbA1c9.22 ± 1.517.68 ± 0.571.5Significant (<0.001)UACR306.61 ± 77.17228.36 ± 45.8525Significant (<0.001)Albuminuria521.2 ± 62.2342.4 ± 51.334.2Significant (<0.001)eGFR37.37 ± 5.8641.76 ± 5.5212Significant (<0.001)Serum Creatinine1.70 ± 0.231.55 ± 0.218.8Significant (<0.001)

Disclosure

K. Shah: None. S.A. Patange: None. A.P. Gandhi: None.
Combination of SGLT2 Inhibitor and Novel Selective PPARα Modulator, Tofogliflozin (Tofo) and Pemafibrate (Pema), Improves Survival Rate in STAM Mice as a Diabetic NASH Model
Authors: YANO WATARU , TAKIZAWA TOSHIAKI , SASAKI YUSUKE , ASAHIYAMA MASATO , KAMIYA WAKANA , NAKAGAWA TAKASHI , YAMAZAKI HIROYUKI , INOUE KEISUKE , MIZUNO KEN , SAKAI JURO , KODAMA TATSUHIKO , TANAKA TOSHIYA
Published: June 2018

Patients with type 2 diabetes have a high prevalence of nonalcoholic fatty liver disease (NAFLD) which is emerging as a major public health concern in the world. Nonalcoholic steatohepatits (NASH), a severe form of NAFLD, can progress to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). To establish the effective therapeutic method for NASH, we evaluate the therapeutic potential of the combination of SGLT2 inhibitor, tofogliflozin (Tofo), and a novel selective PPARα modulator (SPPARMα), pemafibrate (Pema), in STAM mice as a diabetic animal model of NASH to HCC. STAM mice were administered Tofo and Pema from 6 weeks of age. After 3 weeks of treatment, plasma triglyceride (TG) level was tended to reduce with 0.1 mg/kg Pema monotherapy, and decreased significantly to normal level in combination with 10 mg/kg Tofo. Blood glucose (BG) level was not altered in Pema-treated group, but lowered significantly with the combination therapy. Histological analysis of the liver revealed a tendency to reduce lipid droplet size and ballooning degeneration in Pema group. The combination of Pema and Tofo exhibited the synergistic effects on lipid droplet size and ballooning significantly. Liver TG content was also decreased in mice with the combination therapy. The survival rate of control group was decreased to 10% at 22 weeks of age. STAM mice with Pema in diet showed a tendency to increase the survival rate (30%) and the combination of Pema and Tofo significantly improved the survival rates (50%) compared to control group. Also, both of treated groups markedly reduced the number of tumors in the liver. These results suggested that, in addition of lipid metabolism, glycemic control might play an important role in the treatment of NASH. Combination therapy of SGLT2 inhibitor and SPPARMα would be a potent therapeutic strategy for the treatment of NAFLD, NASH and HCC.

Disclosure

W. Yano: Employee; Self; Kowa Company, LTD. T. Takizawa: Employee; Self; Kowa Company, LTD. Y. Sasaki: Employee; Self; Kowa Company, Ltd. M. Asahiyama: Employee; Self; Kowa Company, Ltd.. Employee; Spouse/Partner; Kowa Company, Ltd.. W. Kamiya: None. T. Nakagawa: Employee; Self; Kowa Company, LTD. H. Yamazaki: Employee; Self; Kowa Company, LTD. K. Inoue: Employee; Self; Kowa Company, LTD. K. Mizuno: Employee; Self; Kowa Company, LTD.. J. Sakai: None. T. Kodama: Consultant; Self; Kowa Company, Ltd. T. Tanaka: Research Support; Self; Kowa Company, Ltd..
Physiological Responses to Daily Use of Beta-Three Adrenergic Receptor Agonist, Mirabegron
Authors: O'MARA ALANA , CYPESS AARON , CERO CHERYL , JOHNSON JAMES W. , LINDERMAN JOYCE D. , LEITNER BROOKS , FLETCHER LAURA , BRYCHTA ROBERT , KAPURIA DEVIKA , MCGEHEE SUZANNE , ROTMAN YARON
Published: June 2018

Background: Brown Adipose Tissue (BAT) in adult humans has become increasingly recognized to contribute to energy consumption and modulate metabolism. To date, BAT stimulation has predominately relied on cold exposure. However, long-term cold exposure is impractical as a treatment option for obesity and diabetes. Thus, we investigated if a chronic pharmacotherapeutic approach could stimulate BAT and contribute to metabolic health.

Methods: In an ongoing study, 6 healthy female volunteers received 4 weeks of daily mirabegron (Myrbetriq, Astellas Pharma) 100 mg, a β3 adrenergic receptor (AR) agonist. Acute responses were determined by comparing effects before and then five hours after dosing. Chronic changes were assessed after 4 weeks of treatment. The primary endpoint was the change in BAT metabolic activity measured by 18F-FDG PET/CT. Secondary endpoints included resting energy expenditure (REE), insulin and glucose sensitivity, liver steatosis, and cardiovascular stimulation.

Results: Acute effects of mirabegron included consistent increases in rate pressure product (RPP), REE, and serum non-esterified fatty acids (NEFA) (p<0.05, p=0.06, p<.05). After 4 weeks, there was a wide range of changes in BAT volume (41 ± 223 mL, p=0.86). Body weight was unchanged (0.3 ± 0.62 kg). Several physiological responses after chronic treatment were blunted, including smaller mirabegron-induced increases in RPP, NEFA, and REE. Yet, there were significant increases in sleeping EE (72 ± 23 kcal/d, p=0.03), insulin sensitivity (1.5 ± .6 (mU/L*min, p=0.05), and liver steatosis (30 ± 10 dB/m, p = 0.04) after 4 weeks.

Conclusions: Acute treatment with mirabegron in women successfully activates BAT thermogenesis. Preliminary data show chronic treatment resulted in a blunting of several responses, consistent with physiological attenuation of β-AR signaling. The increases in sleeping EE and improved insulin sensitivity suggest chronic mirabegron treatment may help alleviate metabolic disease.

Disclosure

A. O'Mara: None. A. Cypess: None. C. Cero: None. J.W. Johnson: None. J.D. Linderman: None. B. Leitner: None. L. Fletcher: None. R. Brychta: None. D. Kapuria: None. S. McGehee: None. Y. Rotman: None.
The SGLT2 Inhibitor Tofogliflozin Reduces Weight in People with Type 2 Diabetes due to Fluid Loss Initially and to Lipolysis in Late
Authors: YOSHIDA AKIHIRO , KUSAKABE HIROMI , TAKAMURA TOSHINARI , KAKU KOHEI , SUGANAMI HIDEKI
Published: June 2018

It is well recognized that sodium/glucose cotransporter 2 inhibitors (SGLT2i) are associated with weight loss in people with type 2 diabetes. However, the time-dependent associations of weight loss with the anthropometric and body fluid measurements and serum parameters during SGLT2i intervention remain unclear. Thus, we aimed to clarify weight loss-related factors, carefully focusing on the clinical process during the long-term intervention with a SGLT2i, tofogliflozin in people with type 2 diabetes. We analyzed data from 775 people with type 2 diabetes that participated in tofogliflozin phase 3 trials. Participants received tofogliflozin (20, or 40 mg; n = 235, and 540, respectively) orally once daily for 52 weeks. The correlation analysis was performed at week 4, 24 and 52. Baseline characteristics showed men (66 %), age (mean: 58 years), HbA1c (8.0 %), BMI (26 kg/m2) and eGFR (84 mL/min/1.73m2). Tofogliflozin significantly reduced body weight at week 4, 24 and 52 (mean: -1.4, -3.0 and -3.0 kg, respectively). At week 4, weight loss was negatively correlated with both the change in body fluid measures (hematocrit, RBC count, serum creatinine level, and uric acid level) and beta-hydroxybutyrate (BHB). At week 24, weight loss was positively correlated with anthropometric measurements (waist and hip circumferences) and hepatic enzymes levels, and negatively correlated with adiponectin, HDL-C, and BHB levels, but not with body fluid measures. Although the values at week 52 were in concert with the results at week 24, there was a modest but significant correlation between weight loss and BHB level. Our results clarified that tofogliflozin reduces weight, especially that of visceral fat in people with type 2 diabetes, at least due to fluid loss initially and to lipolysis in late. Weight loss might contribute to decrease in the hepatic enzymes, whereas it also accompanies an increase in beta-hydroxybutyrate, the safety issue of which to be investigated in future.

Disclosure

A. Yoshida: Employee; Self; Kowa Pharmaceutical Co. Ltd. H. Kusakabe: Employee; Self; Kowa Pharmaceutical Co.Ltd. T. Takamura: 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. Suganami: Employee; Self; Kowa Company, Ltd..
Initial Beta-Hydroxybutyrate Elevation in Relation to Subsequent Weight Loss in Type 2 Diabetes via the SGLT2 Inhibitor Tofogliflozin
Authors: SATO YUICHI , NUNOI KIYOHIDE , KAKU KOHEI , YOSHIDA AKIHIRO , SUGANAMI HIDEKI
Published: June 2018

The elevation of ketones is clinically concerned in the use of SGLT2 inhibitor (SGLT2i), however little is known about the association between that elevation and subsequent clinical process. We aimed to clarify the association of the initial beta-hydroxybutyrate (BHB) elevation via the SGLT2i, tofogliflozin with subsequent weight loss in type 2 diabetes participants. Analyzed were 774 type 2 diabetes participants who received tofogliflozin in two phase 3 studies. The participants were divided into four groups according to the quartiles for their change in BHB after 4 weeks of tofogliflozin therapy. The adjusted assessments of variables were analyzed using an analysis of covariance model with the quartiles, their baseline values, age, sex, and eGFR as covariates. BHB levels significantly increased (mean: +107.1 µmol/L) from baseline to week 4. Those changes in the first (Q1), second (Q2), third (Q3), and fourth (Q4) quartiles, respectively, were -33.7, +31.4, +98.0, and +331.1 µmol/L. Glycemic control at baseline was poorer, while CPI was lower within the higher quartiles. The difference of BHB changes among the quartiles was maintained during tofogliflozin therapy. At week 52, the increase of BHB levels from baseline was significant (+142.7 µmol/L) in Q4, but not changed in Q1. The weight loss at week 52 in Q4 (least square mean: -3.6 kg) was greater than in Q1 (-2.4 kg) although the improvement of hyperglycemia was identical. Furthermore, the reduction in waist circumference and increase in adiponectin were greater in Q4. And the increase in fasting free fatty acid was also greater in Q4, but not changed in Q1. The distinct response of BHB elevation was observed early after the SGLT2i, tofogliflozin therapy. The higher initial BHB elevation resulted in the greater reduction in body weight, especially fat mass via lipolysis. The progressive weight loss might be clinically associated with one of the signs of the higher ketone elevation.

Disclosure

Y. Sato: None. K. Nunoi: 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. A. Yoshida: Employee; Self; Kowa Pharmaceutical Co. Ltd. H. Suganami: Employee; Self; Kowa Company, Ltd..
SGLT2 Inhibitors Increase Bone Strength by Increasing Procollagen Type 1 Amino-Terminal Propeptide in Patients with Type 2 Diabetes
Authors: KUSUNOKI MASATAKA , NATSUME YUKIE , MIYATA TETSURO , OSHIDA YOSHIHARU
Published: June 2018

With regard to osteoporosis in diabetic patients due to SGLT2 inhibitors (SGLT2is), there is no consensus on its onset as yet. At the meeting of the European Association for the Study of Diabetes in 2015, we reported improvement of bone strength after 6-month treatment with three SGLT2is as revealed by quantitative ultrasound analysis of 115 Japanese type 2 diabetic patients. In this study, we investigated the influence of SGLT2is on the bone strength, density and quality in Japanese patients with type 2 diabetes through both quantitative ultrasound analysis and D dual-energy X-ray absorptiometry (DEXA) before and after 6-month of SGLT2i treatment. The study was conducted in 19 Japanese patients with type 2 diabetes mellitus. Treatment with luseogliflozin 2.5 mg qd or dapagliflozin 5 mg qd for 6 months resulted in significant elevation of the ultrasound-measured bone density (ratio to young adults) of the heel from 88 ± 16% to 91 ± 15% (P<0.05). On the other hand, the lumbar spine bone density and femoral bone density measured by DEXA showed no significant difference before and after the treatment. Since the bone density measured by ultrasound is regarded to be equal to the bone quality + bone density, these results suggest that the bone density, reported to account for 70% of the bone strength, was not altered by the treatment with SGLT2is. In other words, the improvement of the bone strength revealed by ultrasound analysis appears to reflect improved bone quality rather than improved bone density. The serum level of TRACP-5b (a marker of bone destruction) did not differ significantly between before and after treatment, while the serum level of total procollagen type 1 amino-terminal propeptide (P1NP) increased significantly after the treatment (from 35.2 ± 10.3 μg/L to 39.0 ± 12.8 μg/L, P<0.05). The improvement of the bone quality and elevation of bone strength following treatment with SGLT2i appears to be correlated with elevation of the serum P1NP level.

Disclosure

M. Kusunoki: Research Support; Self; Taisho Toyama Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Kaken Pharmaceutical Co., Ltd. Y. Natsume: Research Support; Spouse/Partner; Taisho Toyama Pharmaceutical Co., Ltd., Kaken Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd.. T. Miyata: None. Y. Oshida: None.
Discovery and Development of HGR4113 as a Novel Antidiabetes Oral Agent
Authors: KIM KYUNGIL , YOO SANG-KU , JO IN GEUN , LIM KEUN-WAN
Published: June 2018

HGR4113 is a novel compound that was discovered by Glaceum Inc. through a Quantitative Structure-Activity Relationship (QSAR) study on Glabridin and its derivatives. HGR4113 showed competitive antihyperglycemic effects in db/db mice without any adverse event of obesity. The test consisted of a vehicle control group (db/db mice), a test group (HGR4113 150mg/kg), and two positive control groups (Metformin 300mg/kg and Pioglitazone 75mg/kg). HGR4113 was given orally once daily for 7 days for 8 consecutive weeks (qd×7×8). During the course of this study, HGR4113 exhibited a level of efficacy highly comparable to Pioglitazone, one of the oral antihyperglycemic agents available. More importantly, however, HGR4113 demonstrated weight maintenance effects similar to Metformin in db/db mice, whereas Pioglitazone caused db/db mice to develop significant signs of obesity as a critical adverse effect.

In conclusion, our test results suggest HGR4113 as a safe and effective drug for T2DM along with further clinical development.

Disclosure

K. Kim: None. S. Yoo: Employee; Self; Glaceum. I. Jo: Employee; Self; Glaceum Incoporation. K. Lim: Employee; Self; Glaceum Inc..
Systematic Literature Review and Network Meta-analysis (NMA) of SGLT2i as Monotherapy for Type 2 Diabetes Mellitus (T2DM)
Authors: DAVIES GLENN M. , MCNEILL ANN MARIE , KRUGER ELIZA , KOWAL STACEY L. , EJZYKOWICZ FLAVIA , HANNACHI HAKIMA , CATER NILO B. , MCLEOD EUAN
Published: June 2018

Objective: Indirectly compare the efficacy and safety of ertugliflozin (ertu) from the VERTIS MONO trial to other SGLT2i when used as monotherapy.

Methods: Pubmed, EMBASE and Cochrane were searched through to end of 2016 for RCTs of 24-26 weeks duration in T2DM patients with uncontrolled A1C on no anti-hyperglycemic therapy. Comparators to ertu 5mg and 15mg were low and high doses of SGLT2i licensed in Europe and USA: canagliflozin (cana), dapagliflozin (dapa) and empagliflozin (empa). Included outcomes vs. placebo at 24-26 weeks were change in A1C, weight loss (WL), systolic (SBP), A1C <7%, urinary and genital mycotic infections, hypoglycemia and patients with ≥1 adverse event (AE). Evidence was synthesized using both fixed effect (FE) and random effects (RE) Bayesian NMA, with model selection informed by guidelines. Credible intervals (CrI), analogous to 95% confidence intervals, were used to determine significance.

Results: The NMA included 10 RCTs with FE models selected for all analyses except A1C <7% and WL. For change in A1C ertu 15mg was significantly more effective vs. dapa 10mg (mean difference (MD): -0.36%, CrI -0.65, -0.08) and empa 25mg (MD:-0.31%, CrI -0.58, -0.04). There were no other significant differences for efficacy outcomes between ertu and other SGLT2i, except a larger reduction in SBP for cana 300mg vs. ertu 15mg (MD: 3.45 mmHg, CrI 0.15, 6.76). Analyses of safety outcomes did not identify any significant differences or could not be interpreted due to scarcity of events in placebo arms preventing network convergence. The impact of inter-trial heterogeneity was tested, but remains a potential confounder.

Conclusions: In an indirect comparison ertu 5mg was comparable to other low dose SGLT2i at reducing A1C whereas ertu 15mg was more effective vs. dapa 10mg and empa 25mg. With the exception of SBP for ertu 15mg vs. cana 300mg, remaining outcomes were comparable to other SGLT2i for both ertu 5mg and 15mg.

Disclosure

G.M. Davies: Employee; Self; Merck & Co., Inc. A. McNeill: Employee; Self; Merck & Co., Inc.. Stock/Shareholder; Self; Merck & Co., Inc. E. Kruger: Employee; Self; QuintilesIMS. S.L. Kowal: None. F. Ejzykowicz: Employee; Self; Merck Sharp & Dohme Corp. H. Hannachi: Employee; Self; Merck & Co., Inc. N.B. Cater: Employee; Self; Peter Sheehan Diabetes Care Foundation, Inc. E. McLeod: Employee; Self; Pfizer Inc..
Gestational Diabetes (GDM) and Childhood Disorders of Glucose Metabolism—Hyperglycemia and Adverse Pregnancy Outcome Follow-Up Study (HAPO FUS)
Authors: BRICKMAN WENDY , CATALANO PATRICK , CLAYTON PETER E. , DEEROCHANAWONG CHAICHARN , HAMILTON JILL , LASHLEY PAULA M. , LAWRENCE JEAN M. , LEBENTHAL YAEL , MCCANCE DAVID R. , TAM WING H. , KUANG ALAN , LOWE LYNN P. , METZGER BOYD E. , SCHOLTENS DENISE , LOWE WILLIAM ,   HAPO FOLLOW-UP STUDY COOPERATIVE RESEARCH GROUP
Published: June 2018

While overt diabetes during pregnancy is associated with a higher childhood risk of altered glucose metabolism, the contribution of GDM to this disorder is less clear. Using data from HAPO FUS, we examined associations of maternal GDM not confounded by treatment with childhood glucose metabolism. Maternal glycemic status was based on a 75 g oral glucose tolerance test (OGTT) at ∼28 weeks gestation. Offspring disorders of glucose metabolism (impaired glucose tolerance or type 2 diabetes using American Diabetes Association criteria) were assessed at the HAPO FUS visit using an OGTT in 41children at mean age 11.4 (range 7.9-15.5) years. Insulin sensitivity (IS) was calculated using the Matsuda index and insulin secretion using the insulinogenic index. GDM was defined by International Association of Diabetes in Pregnancy Study Groups criteria. Among offspring of mothers with and without GDM, 10.6% and 5.2%, respectively, had a disorder of glucose metabolism. After adjusting for field center, maternal pregnancy variables and child age, Tanner stage and family history of diabetes at HAPO FUS, the odds ratio and 95% confidence interval (CI) for a disorder of glucose metabolism was 1.98 (1.44-2.74), p=3.1 x 10-5. Adjusting for maternal BMI at OGTT, child’s BMI z score, or both did not attenuate risk. Offspring of GDM mothers had lower IS (29.7 ± 12.5, mean ± SD) compared to offspring of non-GDM mothers (33.7 ± 13.8) with a mean difference of -2.1 (95% CI -3.2 - -1.0), p= 1.9 x 10-4 after adjusting for field center, maternal pregnancy variables and child age, Tanner stage and family history of diabetes at HAPO FUS. The association was attenuated but still significant after adjusting for maternal BMI and/or child BMI z score. Maternal GDM was not associated with insulinogenic index.

In summary, exposure to untreated GDM in utero is significantly and independently associated with childhood disorders of glucose metabolism, in part through insulin resistance.

Disclosure

W. Brickman: None. P. Catalano: None. P.E. Clayton: None. C. Deerochanawong: None. J. Hamilton: None. P.M. Lashley: None. J.M. Lawrence: None. Y. Lebenthal: Speaker's Bureau; Self; Novo Nordisk Inc.. Consultant; Self; Kamada. D.R. McCance: None. W.H. Tam: None. A. Kuang: None. L.P. Lowe: None. B.E. Metzger: None. D. Scholtens: None. W. Lowe: None.
Type 2 Diabetes Mellitus (T2DM) Patients with Inadequate A1C Control on Metformin (MET) + DPP-4i—A Network Meta-analysis (NMA) of the Efficacy and Safety of SGLT2i, GLP-1 Analogs, and Insulin
Authors: MCNEILL ANN MARIE , DAVIES GLENN M. , KRUGER ELIZA , KOWAL STACEY L. , EJZYKOWICZ FLAVIA , HANNACHI HAKIMA , CATER NILO B. , MCLEOD EUAN
Published: June 2018

Objective: Indirectly compare the efficacy and safety of ertugliflozin (ERTU) from the VERTIS SITA2 trial to other treatments in patients with inadequate A1C control on MET+DPP-4i.

Methods: Literature was searched up to end 2016 for RCTs in patients with A1C ≥7% on MET+DPP-4i. Included outcomes vs. placebo at 24-26 weeks were change in A1C, weight, systolic blood pressure, A1C <7%, urinary tract infections, genital mycotic infections, hypoglycemia and patients with ≥1 adverse event. Evidence synthesis used fixed effect and random effects Bayesian NMA, with model selection informed by guidelines. Credible intervals (CrI), analogous to 95% confidence intervals, were used to determine significance.

Results: Interventions compared (+background therapies) were dapagliflozin 10mg (MET+sitagliptin [SITA] and MET+saxagliptin), empagliflozin 10/25mg (MET+linagliptin), titrated canagliflozin (MET+SITA), titrated liraglutide (MET) and ERTU 5/15mg (MET+SITA). No relevant insulin RCTs were found. Added to MET+SITA, ERTU 5 and 15mg were significantly more effective than dapagliflozin 10mg (A1C mean difference [MD] 5mg -0.29%, CrI -0.56, -0.02; 15mg -0.37%, CrI -0.64, -0.10). Comparisons to other SGLT2i regimens did not find significant differences in A1C or other outcomes. The liraglutide arm of LIRA SWITCH discontinued SITA. Sensitivity analysis comparing triple therapy (MET+SITA+ERTU) vs. dual therapy (MET+liraglutide) did not find significant differences (A1C MD 5mg -0.07%, CrI -0.35, 0.22, 15mg -0.15% CrI -0.43, 0.14).

Conclusions: Amongst patients requiring triple therapy with SGLT2i added to MET+DPP-4i there was considerable heterogeneity between studies and assumptions of equivalence of background DPP-4i were required. Nonetheless, this analysis indicated that ERTU was more effective than dapagliflozin as add-on to MET+SITA and was comparable to other SGLT2i+MET+DPP-4i regimens.

Disclosure

A. McNeill: Employee; Self; Merck & Co., Inc.. Stock/Shareholder; Self; Merck & Co., Inc. G.M. Davies: Employee; Self; Merck & Co., Inc. E. Kruger: Employee; Self; QuintilesIMS. S.L. Kowal: None. F. Ejzykowicz: Employee; Self; Merck Sharp & Dohme Corp. H. Hannachi: Employee; Self; Merck & Co., Inc. N.B. Cater: Employee; Self; Peter Sheehan Diabetes Care Foundation, Inc. E. McLeod: Employee; Self; Pfizer Inc..
Changes in Energy Balance during Dapagliflozin Therapy in Type 2 Diabetes—The Energize Study
Authors: RAJEEV SURYA PANICKER , ROBERTS CARL A. , CUTHBERTSON DANIEL J. , SPRUNG VICTORIA S. , BROWN EMILY , HALFORD JASON C. , HARROLD JOANNE A. , KEMP GRAHAM J. , STANCAK ANDREJ , WILDING JOHN P.
Published: June 2018

Weight loss during SGLT2i therapy is less than predicted from urinary glucose loss. Modelling suggests a 10-15% compensatory increase in energy intake. We compared effects of 12 weeks’ dapagliflozin 10mg od vs. placebo on food intake in a double-blind, placebo-controlled study with short (1 week) and long-term (12 week) crossover periods. Food intake was measured during test meals at baseline, pre and post each crossover using the Sussex Ingestion Pattern Monitor, continuously recording intake during the meal; primary outcome was the difference after 12 weeks’ treatment. 52 patients with T2DM treated with diet or oral agents were recruited (45 completed;43% female). Median age 60y, weight 98.4 kg, BMI 34, HbA1c 59.5 mmol/mol. Analysis used a linear mixed model with the random effect as study subject and fixed effects of sex, visit, study arm and arm:visit interaction. Dapagliflozin use was associated with a reduction in HbA1c -9.73mmol/mol (95% CI 3.91, 16.27; p=0.004), and body weight (-2.84 vs. -0.87 kg) vs. placebo. There was no difference in test meal food intake between dapagliflozin and placebo at 12 weeks median difference, 2.63g (95% CI,-31.65,36.9); p=0.659 or at other time points. Dapagliflozin was not associated with a compensatory increase in food intake.

Disclosure

S. Rajeev: None. C.A. Roberts: None. D.J. Cuthbertson: None. V.S. Sprung: None. E. Brown: Research Support; Self; AstraZeneca. J.C. Halford: Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. J.A. Harrold: None. G.J. Kemp: None. A. Stancak: None. J.P. Wilding: Other Relationship; Self; Astellas, AstraZeneca, Boehringer Ingelheim GmbH, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi, Eli Lilly and Company, Orexigen Therapeutics, Inc., Merck & Co., Inc..
Evaluation of Osmotic Diuresis and Volume Depletion Events in Patients with Type 2 Diabetes Mellitus (T2DM) Receiving Ertugliflozin
Authors: PATEL SHRITA M. , HICKMAN MARY A. , FREDERICH ROBERT , LAURING BRETT , TERRA STEVEN , JOHNSON SUSAN L. , HUYCK SUSAN , MANCUSO JAMES P.
Published: June 2018

Ertugliflozin (ERTU) is an SGLT2 inhibitor for the treatment of T2DM. Osmotic diuresis (OD), volume depletion (VD) and change in renal function were assessed in adults with T2DM. Pooled analyses were performed on data from 7 randomized, double blind, Phase 3 trials in patients receiving ERTU or non-ERTU (placebo [PBO] or active comparator) for at least 26 weeks, including a PBO pool (subset; n=1544) and a broad pool (all studies; N=4859; ERTU 5 mg: n=1716; ERTU 15 mg: n=1693; non-ERTU: n=1450). Mean age was 57.8 years, 25.8% were ≥65 years old, 51.8% were male and 27.7% were on diuretics. Mean eGFR was 85.3 mL/min/1.73 m2. Mean duration of T2DM was 7.9 years and mean baseline (BL) A1C was 8.2%. BL characteristics were similar in the PBO pool.

In the broad pool, the incidence of OD events was 2.7%, 2.2%, and 1.4% with ERTU 5 mg, ERTU 15 mg, and non-ERTU, respectively; none were serious and ≤0.2% led to treatment discontinuation. The incidence of VD events was 1.9%, 1.4%, and 1.2% with ERTU 5 mg, ERTU 15 mg and non-ERTU, respectively; 0.2%, 0% and 0%, respectively, were serious and ≤0.1% led to treatment discontinuation. In patients with moderate renal impairment (RI; n=575, ∼12%), ≥65 years old, or on diuretics, ERTU led to a higher incidence of VD events than non-ERTU. In the PBO pool, the incidence of OD events was 2.9%, 2.4%, and 1.0% and the incidence of VD events was 0.8%, 1.0%, and 1.7% with ERTU 5 mg, ERTU 15 mg and PBO, respectively. There was no increase in the proportion of patients with orthostatic hypotension with ERTU treatment.

ERTU was associated with small, early decreases in eGFR that returned to or towards BL during treatment. Mean decreases in eGFR were larger in patients with BL moderate RI and returned to BL after treatment discontinuation (recently published).

ERTU is associated with OD, but does not generally lead to VD events or orthostatic hypotension. Consistent with this, observed decreases in eGFR were reversible during treatment or after discontinuation.

Disclosure

S.M. Patel: Employee; Self; Merck & Co., Inc.. Employee; Spouse/Partner; GlaxoSmithKline plc.. Stock/Shareholder; Self; Merck & Co., Inc.. Stock/Shareholder; Spouse/Partner; GlaxoSmithKline plc. M.A. Hickman: Employee; Self; Pfizer Inc.. Stock/Shareholder; Self; Pfizer Inc. R. Frederich: Employee; Self; Pfizer Inc.. Stock/Shareholder; Self; Pfizer Inc., Bristol-Myers Squibb Company. B. Lauring: Employee; Self; Merck & Co., Inc. S. Terra: Employee; Self; Pfizer Inc. S.L. Johnson: Employee; Self; Pfizer Inc. S. Huyck: Employee; Self; Merck & Co., Inc. J.P. Mancuso: Employee; Self; Pfizer Inc.. Stock/Shareholder; Self; Pfizer Inc.. Employee; Spouse/Partner; Pfizer Inc.. Stock/Shareholder; Spouse/Partner; Pfizer Inc..
Dapagliflozin Exposure Response in Japanese vs. Non-Japanese Patients with Type 1 Diabetes
Authors: SOKOLOV VICTOR , YAKOVLEVA TATIANA , UEDA SHINYA , PARKINSON JOANNA R. , PENLAND ROBERT C. , BOULTON DAVID W. , TANG WEIFENG
Published: June 2018

Dapagliflozin (DAPA), an SGLT2 inhibitor, reduces blood glucose by increasing urinary glucose excretion (UGE). The pharmacokinetics and pharmacodynamics of DAPA in Japanese and non-Japanese patients (pts) with type 1 diabetes (T1D) have been evaluated in 2 studies (Japanese: NCT01498185, n=42, DAPA 5, 10 mg or placebo [PBO] for 14 days; Non-Japanese: NCT02582814, n=70, DAPA, 1, 2.5, 5, 10 mg or PBO for 7 days). A clear dose-response for 24-hour UGE was seen in the non-Japanese study but not in the Japanese study. An exposure-response model was used to characterize the relationship between DAPA exposure and 24-hour UGE using a nonlinear mixed-effect modeling approach, and the effect of patient-level characteristics (baseline and Day 7) on this was investigated. Covariates were identified using a stepwise procedure. Average self-monitored blood glucose (SMBG) at Day 7, Day 7 change from baseline in total insulin dose, and baseline eGFR all had a significant effect on UGE; SMBG was the most influential. When these covariates are included, the model fits the data well for both populations (Figure; for the Japanese study, 1 and 2.5 mg data were simulated using median AUC from non-Japanese pts, for 5 and 10 mg median covariate values were from the Japanese study). The lack of clear dose-response in UGE in Japanese pts may primarily be caused by high SMBG, which is likely a result of greater insulin dose reductions in the Japanese study.

Disclosure

V. Sokolov: None. T. Yakovleva: None. S. Ueda: Employee; Self; AstraZeneca. J.R. Parkinson: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. R.C. Penland: Employee; Self; AstraZeneca. Stock/Shareholder; Self; Novartis Pharmaceuticals Corporation. D.W. Boulton: Employee; Self; AstraZeneca. Stock/Shareholder; Self; Bristol-Myers Squibb Company. W. Tang: Employee; Self; AstraZeneca.
Durability of Glycemic Control with Dapagliflozin vs. Saxagliptin in Patients with Inadequately Controlled Type 2 Diabetes
Authors: BAILEY CLIFFORD J. , PRATO STEFANO DEL , WEI CHERYL , SARAIVA GABRIELA LUPORINI
Published: June 2018

Type 2 diabetes (T2D) is a progressive disease requiring add-on antihyperglycemic agents to maintain glycemic goals, although how to escalate therapy remains debatable. The benefits of dapagliflozin (DAPA) over saxagliptin (SAXA) on glycemic control (GC) and weight reduction were demonstrated in a post-hoc analysis (NCT01606007). We now evaluate the failure to sustain GC—the slope of ∆A1c over time regression line (coefficient of failure [CoF])—with DAPA or SAXA add-on to metformin (MET). CoF DAPA vs. SAXA was statistically compared directly over 24 weeks (short term; NCT01606007, patients [pts] with ≥1 ∆A1c value at/post week 18) and indirectly (post-hoc analysis of placebo controlled trials) over 102 weeks (long term; NCT00528879 and NCT00121667, pts with ≥3 ∆A1c values from 3 different visits at/post week 20). A1c CoF was lower for DAPA vs. SAXA both at 24 weeks (1.38%/y greater reduction; p=0.009) and 102 weeks (0.37%/y; p=0.04) (Figure). Fewer DAPA- than SAXA-treated pts required rescue medication or discontinued study for failing to achieve GC over 24 weeks (3.4% vs. 9.4%; p=0.0191). Similarly, the placebo adjusted risk ratio of rescue or study discontinuation for DAPA was numerically lower than SAXA over 102 weeks (0.70 vs. 0.74; p=0.68). These results suggest that in T2D pts inadequately controlled on MET, addition of DAPA is associated with significantly greater durability of GC than SAXA over 102 weeks.

Disclosure

C.J. Bailey: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim GmbH, Elcelyx Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Intarcia Therapeutics, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Servier, Sanofi, Takeda Pharmaceuticals U.S.A., Inc.. Research Support; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Takeda Pharmaceuticals U.S.A., Inc.. Advisory Panel; Self; Janssen Biotech, Inc., Abbott. C. Wei: Employee; Self; AstraZeneca. G. Luporini Saraiva: Employee; Self; AstraZeneca.
Exploring Hepatic Safety of the Dipeptidyl Peptidase-4 (DPP-4) Inhibitor Vildagliptin in a Real-World Setting
Authors: WILLIAMS RACHAEL , KOTHNY WOLFGANG , SERBAN CARMEN , PALDÁNIUS PÄIVI M. , SCHLIENGER RAYMOND
Published: June 2018

Since the introduction of DPP-4 inhibitors, vildagliptin has accumulated extensive efficacy/effectiveness and safety data from various meta-analyses of clinical trials, large randomized controlled trials, non-interventional studies, and post-authorization safety studies. In this non-interventional post-authorization study, we explored if vildagliptin is associated with an increased risk of hepatic events vs. other non-insulin antidiabetic drugs (NIADs) in a real-world setting. A cohort study was performed in adult T2DM patients with a vildagliptin or NIAD prescription between January 20and June 2014 with data from five European electronic healthcare databases from the UK (CPRD), Germany and France (IMS), Denmark (OPED) and Sweden (National Registers). Patients with cancer, HIV/AIDS or insulin prior to the index date (date of first vildagliptin or NIAD prescription in the study period) were excluded. Age- and sex-adjusted incidence rate ratios (aIRRs) were estimated in current vildagliptin vs. current other NIAD users using negative binomial regression. We included 738,054 patients, of which 20,973 received vildagliptin (mean follow-up 1.4 years, 28,330 cumulative vildagliptin patient-years). The database-specific aIRR estimates for serious hepatic events were not suggestive of an increased risk with vildagliptin (range of individual aIRR: 0.29-0.55), with two data sources having an upper limit of the 95% confidence interval (CI) <1 (IMS Germany: 0.65; IMS France: 0.63). The aIRR for ALT/AST >3-times upper limit of normal (ULN) together with bilirubin >2-times ULN (only assessed in CPRD) was 0.72 (95% CI: 0.42-1.25). In this real-world setting there was no evidence of an increased risk of hepatic toxicity with vildagliptin exposure compared to other NIADs across five European databases.

Disclosure

R. Williams: Employee; Self; Clinical Practice Research Datalink, London, UK. W. Kothny: Employee; Self; Novartis AG. Stock/Shareholder; Self; Novartis AG. C. Serban: Employee; Self; Novartis AG. Stock/Shareholder; Self; Novartis AG. P.M. Paldánius: Employee; Self; Novartis AG. Stock/Shareholder; Self; Novartis AG. R. Schlienger: Employee; Self; Novartis AG. Stock/Shareholder; Self; Novartis AG.
Discovery of CPL207-280CA, an Effective and Safe GPR40 Agonist for the Treatment of Type 2 Diabetes
Authors: BAZYDLO KATARZYNA , BUDA PAWEL , MACH MATEUSZ , DZIDA RADOSłAW , STELMACH FILIP , DUBIEL KRZYSZTOF K. , PIECZYKOLAN JERZY S. , WIECZOREK MACIEJ
Published: June 2018

Activation of GPR40 (G-protein coupled receptor 40) in pancreatic beta cells may improve glycaemic control in type 2 diabetes (T2D) through enhancement of glucose-stimulated insulin secretion (GSIS). However, the most clinically advanced GPR40 agonist fasiglifam was withdrawn from phase 3 for its hepatotoxicity resulting presumably from the inhibition of pivotal bile acid transporters. Here we present a potent CPL207-280CA agonist devoid of fasiglifams drawbacks as numerous comparative in vitro and in vivo studies revealed. In Ca2+ influx assay (hGPR40), CPL207-280CA showed higher efficacy than fasiglifam (EC50=70 vs. 250 nM respectively). At 10 µM it showed 3.9-times greater enhancement of GSIS in MIN6 cells. Similarly, in Spraque Dawley (SD) rats and C57BL6 mice challenged with glucose, CPL207-280CA compared with fasiglifam at 10 mg/kg stimulated insulin secretion 2.5-times greater (AUC), without causing hypoglycaemia. CPL207-280CA (at 10 µM) subjected to off-targets’ (Safety47TM, BioMAP) and selectivity analysis showed no off-target activity, as well as in MIN6 and HepG2 cells it exhibited broader range of non toxic doses than its comparator. Finally, in hepatobiliary transporters inhibitory assays (carried out in 10 crucial transporters), CPL207-280CA displayed considerably less propensity than fasiglifam, as favourable IC50 values indicate e.g.: human bile salt export pump (Bsep), >100 and 30 µM; multidrug resistance-associated protein 2 (Mrp2), N.D. and 48 µM; organic anion transporting polypeptide (OATP) 1B1, 17.9 and 0.49 µM; organic anion transporting polypeptide (OATP) 1B3, 43 and 3.4 µM; organic anion transporting polypeptide (OATP) 1A2, 118 and 10.6 µM respectively. We conclude that CPL207-280CA is a potent enhancer of GSIS in model animals, which brings no risk of hypoglycaemia and substantially less risk of hepatotoxicity at therapeutic doses. Therefore we propose CPL207-280CA compound as an effective and safe candidate for the T2D treatment.

Disclosure

K. Bazydlo: Employee; Self; Celon Pharma S.A. P. Buda: Employee; Self; CelonPharma S.A. M. Mach: Employee; Self; Celon Pharma S.A. R. Dzida: Employee; Self; Celon Pharma S.A. F. Stelmach: Employee; Self; Celon Pharma S.A. K.K. Dubiel: Employee; Self; Celon Pharma S.A. J.S. Pieczykolan: Employee; Self; Celon Pharma.S.A. M. Wieczorek: Board Member; Self; Celon Pharma S.A..
The Efficacy of Teneligliptin with Metformin in Drug-Naïve Type 2 Subjects
Authors: CHUDASAMA DIPAK B. , SABOO BANSHI D. , PANCHAL DHARMENDRA , PATEL FENY , SAIYED MAHIRA , HASNANI DHRUVI , CHAVDA VIPUL , CHANDARANA HARDIK , GOKLANI RUTUL
Published: June 2018

Aim: To assess the efficacy of Teneligliptin with metformin in drug naïve type 2 subjects.

Objective: To assess the efficacy of Teneligliptin with metformin in drug naïve type 2 subjects. Primary outcome observe change in HbA1c, FBS and PPBS from baseline to 48 weeks. Secondary outcome is to note the change in BMI and drug safety.

Method: A retrospective analysis of data from December 2016 till December 2017 was carried out at 4 centers of a chain of Diacare-Diabetes care and Hormone Clinic. The inclusion criteria included newly detected type 2 subjects aged 50.0 +_ 7.0 years, who were Drug naïve with mean HbA1c 8.0% (7%-9%), mean Fasting value 144 mg/dl (+/- 18mg/dl) and mean post meal value 220mg/dl (+/-18mg/dl).

All vital parameters with anthropometric data was analyzed, tabulated and reviewed

Result: N=450 subjects. Reduction in HbA1c after 12 weeks was 1.2% from base line and after 24 weeks it was 1.6% and 1.0% at the end of 48 weeks. 66% of subjects were seen with HbA1c <7% at 24th week. To the rest in whom target was not achieved till 24th weeks, an interventation was added in the form of OHA along with physical exercise and diet.

Drop in BMI at 12 weeks was 0.6 kg/m2, at 24th week it was 0.8 kg/m2 and at 48th week it was 0.5kg/m2. 8% of subjects had an AE-intermittent diarrhea and no SAE was detected.

Conclusion: In real scenario, combination of tenegliptin 20mg with metformin 1000mg was associated with clinically significant reduction in HbA1c.

Disclosure

D.B. Chudasama: None. B.D. Saboo: None. D. Panchal: None. F. Patel: None. M. Saiyed: None. D. Hasnani: None. V. Chavda: None. H. Chandarana: None. R. Goklani: None.
Rapid Dose Escalation Study of Praliciguat, a Soluble Guanylate Cyclase Stimulator, in Patients with Diabetes and Hypertension
Authors: HANRAHAN JOHN P. , WAKEFIELD JAMES D. , WILSON PHEBE J. , ZIMMER DANIEL P. , MIHOVA MARINA , CHICKERING JENNIFER , RUFF DENNIS , HALL MICHAEL L. , CURRIE MARK , TODD MILNE G. , PROFY ALBERT T.
Published: June 2018

Background: Impaired nitric oxide (NO) signaling through soluble guanylate cyclase (sGC) has been associated with microvascular complications of diabetes. Praliciguat (IW-1973), an sGC stimulator that enhances NO signaling, reduced fasting plasma glucose and proteinuria in an animal model of diabetic nephropathy. In a Phase 1 clinical study in healthy adults, doses of 15-40 mg were tolerated and lowered blood pressure (BP).

Methods: This Phase 2a open-label in-clinic study assessed the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of oral praliciguat in 11 patients with type 2 diabetes mellitus (T2DM) and hypertension on stable glycemic and BP therapy. Patients received sequential 3-day dosing cycles escalating through placebo (PBO), 10, 20, 30, 40 and 50 mg praliciguat QD. Assessments included adverse events (AEs), blood chemistry, ambulatory BP and heart rate, platelet function, and reactive hyperemia index (RHI).

Results: The escalating dose regimen was generally well tolerated; there were no serious or severe AEs. Escalation in 2 patients was stopped due to asymptomatic BP lowering. Overall PK showed a median Tmax of 1-3 h, low to moderate variability, and ∼2-fold accumulation supporting QD dosing. Average 12-h daytime mean arterial BP decreased by 2 to 9 mmHg relative to time-matched PBO baseline across praliciguat dose levels, while heart rate increased 4 to 7 bpm. Notable changes from PBO baseline [mean (95% CI)] at the end of treatment were seen for fasting serum glucose [-26.5 mg/dL (-43.4, -9.5], HbA1c [-0.4% (-0.8, -0.04)], cholesterol [-43 mg/dL (-67, -20)], and body weight [-3.5 kg (-4.9, -2.0)]. Praliciguat had no effect on RHI or platelet function.

Conclusion: T2DM patients with hypertension on standard therapy showed improvements in hemodynamics and metabolic parameters in this small in-clinic study. These results support further evaluation of praliciguat in T2DM patients including those with complications.

Disclosure

J.P. Hanrahan: Employee; Self; Ironwood. J.D. Wakefield: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc.. P.J. Wilson: None. D.P. Zimmer: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc.. M. Mihova: None. J. Chickering: None. D. Ruff: None. M.L. Hall: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc. M. Currie: Employee; Self; Ironwood Pharmaceuticals, Inc. G. Milne: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc.. Employee; Spouse/Partner; Catabasis Pharmaceuticals. Stock/Shareholder; Spouse/Partner; Catabasis Pharmaceuticals. A.T. Profy: Other Relationship; Self; Ironwood Pharmaceuticals.