bluuebunny/crossref_metadata_2025 huggingface dataset:
Systems Medicine Derived Biomarkers to Assess How Canagliflozin Delays Progression of Diabetic Kidney Disease
Authors: HEERSPINK HIDDO LAMBERS. , PERCO PAUL , LEIERER JOHANNES , HANSEN MICHAEL K. , HEINZEL ANDREAS , MAYER GERT
Published: June 2018

The SGLT2 inhibitor canagliflozin (CANA) slows progression of kidney function decline in type 2 diabetes. In this translational study, we determined in silico potential mechanisms of action (MoA) and identified representative candidate biomarkers to assess in vivo how CANA may delay progression of diabetic kidney disease (DKD). These biomarkers were then validated in a CANA clinical trial. A CANA MoA network model was constructed based on an in vitro transcriptomics experiment in human proximal tubular cells and molecular features linked to SGLT2 inhibitors from scientific literature. This model was mapped onto an established DKD network model that describes molecular processes of disease progression. Overlapping areas in both networks were subsequently used to select candidate biomarkers that change with CANA therapy and may be used to monitor CANA response. These biomarkers were measured in 296 plasma samples of the 2-year CANTATA-SU clinical trial comparing CANA with glimepiride. Forty-four proteins present in the CANA MoA molecular model overlapped with proteins in the DKD network model. These proteins were considered candidates serving as proxy for monitoring impact of CANA on DKD pathophysiology. For ten of these, scientific evidence was available suggesting that they are involved in DKD progression. Of these, CANA 300 mg decreased plasma levels of tumor necrosis factor receptor 1 (TNFR-1; 9.2%, p<0.01), interleukin 6 (IL6; 26.6%, p=0.01), matrix metalloproteinase 7 (MMP7; 24.9%, p=0.01), and fibronectin 1 (FN1; 14.9%, p=0.02) during two years follow-up. Changes in TNFR-1 at 1 year independently associated with eGFR decline over 2 years (p=0.0234). This study successfully applied a network-based systems biology analysis to select biomarkers for monitoring kidney response to CANA. CANA significantly reduced plasma levels of TNFR-1, IL6, MMP7, and FN1 suggesting CANA reverses molecular processes related to inflammation, extracellular matrix and fibrosis.

Disclosure

H.L. Heerspink: Consultant; Self; AbbVie Inc., AstraZeneca. Advisory Panel; Self; Boehringer Ingelheim GmbH. Consultant; Self; Janssen Research & Development, Fresenius SE & Co. KGaA. Advisory Panel; Self; Merck & Co., Inc.. Consultant; Self; Mitsubishi Tanabe Pharma Corporation. P. Perco: None. J. Leierer: None. M.K. Hansen: Employee; Self; Janssen Research & Development. A. Heinzel: None. G. Mayer: None.
Short-Term Effects of a Sodium-Glucose Linked Transporter 2 Inhibitor on Left Ventricular Relaxation in Nondiabetic Hypertensive Patients
Authors: KRYSTEL KELLY EBO ETOUA , MBANYA JEAN CLAUDE , SOBNGWI EUGÈNE , LILIANE MFEUKEU KUATE
Published: June 2018

Background: The rapid beneficial effects of Empagliflozin on cardiovascular mortality and hospitalization rate for heart failure in subjects with type 2 diabetes Mellitus raised some questions related to a potential intrinsic effect on the heart. We conducted this study in a population of nondiabetic hypertensive patients in order to look out for short-term effects on left ventricular relaxation.

Methods: We carried out a single arm non-randomized clinical trial. Each patient received 25mg of empagliflozin as add-on therapy once daily for six weeks. We included nondiabetic hypertensive patients on stable anti-hypertensive medication for at least 12weeks with diastolic dysfunction haven given their informed consent. The outcome measures were to evaluate the left ventricular relaxation, to determine changes in the nycthemeral blood pressure profile and to evaluate the electrocardiographic profile before and after the treatment. The primary endpoint was the increase in velocity of the lateral mitral annulus e’ at Doppler echocardiography.

Results: A total of 11 patients were treated. Nine patients had significant improvement of their mitral profiles E/A from 0.71 [0.58-0.75] to 0.82 [0.79-0.93] cm/s (p= 0.008). The velocity e’ that was impaired in 5 patients improved by 22% in 4 patients. The effect of empagliflozin was non-significant on blood pressure at ABPM. On the electrocardiogram we observed a significant decrease in the PR interval from 200 [157-200] to 160 [143-186] ms, p= 0.04.

Conclusion: Daily intake of 25mg Empagliflozin is associated with an early improvement of the left ventricular relaxation in nondiabetic hypertensive patients without significant reduction in blood pressure. This suggests an intrinsic myocardial action of Empagliflozin to investigate.

Disclosure

E. Krystel Kelly: None. J. Mbanya: Advisory Panel; Self; GlaxoSmithKline plc.. Speaker's Bureau; Self; Novo Nordisk A/S, Sanofi, Servier. E. Sobngwi: None. M. Liliane: None.
Dapagliflozin Improves Insulin Sensitivity in the Obese Prediabetic Canine
Authors: PASZKIEWICZ REBECCA L. , BERGMAN RICHARD N. , BEDIAKO ISAAC ASARE , MKRTCHYAN HASMIK J. , SASHI GOPAUL V. , YANG HSIU-CHIUNG , LUNDBORG EVA , KIM STELLA , FORMENTINI IVAN , KOLKA CATHRYN M.
Published: June 2018

SGLT2 inhibition has positive effects on glucose balance, reducing fasting and postprandial glucose levels, however little is known about the effects of SGLT2 inhibitors on lipid levels. PKPD simulation for this canine model was applied for dose selection of dapagliflozin (dapa). Seven dogs were fed a high fat diet for 6 weeks, then received a single low dose of streptozotocin (18.5mg/kg) to induce mild type 2 diabetes. Animals were exposed to dapa (n=4, 1.25mg/kg) or placebo (n=3) once per day for 6 weeks, while remaining on the high fat diet. Animals were then subjected to the intravenous glucose tolerance test (IVGTT) to assess glucose tolerance and insulin response to glucose, and the euglycemic hyperinsulinemic clamp protocol in conjunction with tracer infusions to evaluate adipose tissue, skeletal muscle and hepatic insulin sensitivity. In the IVGTT, modeling techniques are used to estimate the acute insulin response to a glucose bolus, which was not altered with dapa treatment, but insulin sensitivity was significantly improved compared to placebo-treated animals (dapa 0.54±0.22, control -0.95±0.51mU/l-1.minute-1, p=0.05). The glucose infusion required for euglycemia during steady state in the clamp was decreased with dapa (dapa -3.0±1.05, control 1.53±1.28 mg/minute/kg, change from pre-drug timepoint, P=0.038), supporting the IVGTT results. Urinary glucose disposal rate during the clamp was inconsistent. There is a trend towards higher FFA levels in dapa-treated animals under noninsulin stimulated conditions (P=0.054). These may be a regulator of hepatic glucose production, or reflect a switch towards lipid utilization. We conclude that 6 weeks of dapa treatment improves insulin sensitivity in a canine model of mild type 2 diabetes. Further studies on lipid metabolism, body fat deposition and insulin clearance are on-going.

Disclosure

R.L. Paszkiewicz: None. R.N. Bergman: Advisory Panel; Self; Ingredion, Inc.. Research Support; Self; AstraZeneca. Consultant; Self; GI Dynamics Inc.. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Consultant; Self; Novo Nordisk A/S. I. Asare Bediako: None. H.J. Mkrtchyan: None. V. Gopaul: Employee; Self; AstraZeneca. H. Yang: Employee; Self; AstraZeneca. E. Lundborg: Employee; Self; AstraZeneca. S. Kim: None. I. Formentini: Employee; Self; AstraZeneca. C.M. Kolka: Research Support; Self; AstraZeneca.
Which Is Better? High-Dose Metformin Alone or Combination of Low-Dose Metformin and Linagliptin on Glycemic Variability in Japanese Type 2 Diabetes Patients with Insufficient Glycemic Control with Low-Dose Metformin Alone—A Randomized, Crossover, Pilot Study
Authors: TAKAHASHI HIROSHI , NISHIMURA RIMEI , UTSUNOMIYA KAZUNORI
Published: June 2018

The aim of this study is to investigate the effect of high dose metformin or combination of low dose metformin and linagliptin on glycemic variability (GV) in Japanese type 2 diabetes (T2D) patients with insufficient glycemic control with low dose metformin alone in a cross-over study using continuous glucose monitoring (CGM). This study was conducted in T2D outpatients (7%< HbA1c <10%) receiving low dose metformin (750-1000 mg) alone. All patients were assigned to metformin 1500 mg monotherapy (high dose metformin; HMET) or combination of metformin 750 mg and linagliptin 5 mg (low dose metformin and DPP-4; LMET+DPP-4) in a cross-over fashion and underwent CGM assessments more than 4 weeks after change of treatment. 24-hour data were collected for comparison after they had had the same retort pouch foods. Mean glucose level, standard deviations of glucose (SD), glucose coefficient of variation (%CV), mean amplitude of glucose excursions (MAGE), pre-meal glucose levels, and 3-hour postprandial glucose area under the curve (AUC, >160 mg/dL) were compared between HMET and LMET+DPP-4 groups by using t-test. The study enrolled a total of 11 patients with T2D (men/women, 8/3; age, 51.9 ± 9.8 years; BMI, 26.3 ± 3.0 kg/m2; HbA1c, 7.6 ± 0.4%; and metformin dose 750/1000 mg, 6/5). Of the CGM-derived GV metrics for the HMET vs. LMET+DPP-4, mean glucose level, SD, MAGE and %CV were not significantly different (p=0.946, 0.394, 0.865, 0.290). Again, while the pre-breakfast glucose level were not significantly different between the groups (p=0.432), the AUC after breakfast was significantly smaller in LMET+DPP-4 vs. HMET (5004 ± 3220 vs. 7712 ± 5177; p=0.047). A comparison of GV with HMET vs. LMET+DPP-4 suggested that LMET+DPP-4 may reduce post-breakfast GV to a greater degree than HMET in Japanese patients with T2D receiving low dose metformin monotherapy.

Disclosure

H. Takahashi: 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.. K. Utsunomiya: None.
Apabetalone (RVX-208) Lowers Major Adverse Cardiovascular Events (MACE) in Diabetes Mellitus Patients with CVD by Attenuating Monocyte Adhesion to Endothelial Cells
Authors: TSUJIKAWA LAURA , KULIKOWSKI EWELINA , CALOSING CYRUS , WASIAK SYLWIA , GILHAM DEAN , HALLIDAY CHRISTOPHER , JOHANSSON JAN O. , SWEENEY MICHAEL , WONG NORMAN C.
Published: June 2018

Apabetalone (RVX-208) leads to a 57% relative risk reduction of MACE in patients with diabetes mellitus (DM) and CVD. To test whether RVX-208, an inhibitor (BETi) of epigenetic readers bromodomain extra-terminal (BET) proteins lowers CVD by affecting genes mediating monocyte adhesion to endothelial cells in response to high glucose(HG) and dietary metabolite trimethyl-amine oxide (TMAO). Cultured THP-1 monocytes, HUVEC endothelial cells and primary human hepatocytes (PHH) were exposed to varying amts of glucose and TMAO. Results showed that HG (25.6 mM) induced Very Late Antigen-4 (VLA-4) mRNA, a gene mediating THP-1 adhesion by 1.3-fold and RVX-2suppressed it >50%. BETi blocked TMAO induction of VLA-4 mRNA by >50% in THP-1. In HUVECs RVX-2abrogated HG induction of E-selectin and MYD88 mRNA by 2- and 1.3-fold, respectively and lowered TMAO induction of both mRNAs by >50%. Microbiome action on dietary phospholipids followed by hepatic flavin mono-oxygenase-3 (FMO3) processing yields TMAO. In PHH exposed for 24 hours to RVX-208, FMO3 mRNA was lower by 40% but it also suppressed a transcriptional regulator of FMO3, farnesoid X receptor (FXR). BETi for 6 hours suppressed both FXR mRNA and protein within 6 hours by >80% suggesting a direct effect of BETi on the FXR gene. Furthermore, in ChiP assays BRD4, a BET protein, dissociated immediately from FXR DNA upon exposure to RVX-208. BRD4 guides a complex containing RNA pol II along active genes, its dissociation would halt transcription of the gene.

In summary, Apabetalone inhibits HG and TMAO enhanced adhesion of THP-1 to HUVECs, this process mimics a step in CVD pathogenesis. RVX-2suppresses cellular adhesion genes; VLA-4 in THP-1 and both E-selectin plus MYD88 in HUVECs. BETi blocks TMAO activity and its production by inhibiting FXR expression, a regulator of FMO3 gene transcription. Rapid actions of BETi in dissociating BRD4 from FXR DNA suggests a direct effect of RVX-2on transcription of this gene.

Disclosure

L. Tsujikawa: None. E. Kulikowski: Employee; Self; Resverlogix Corp.. C. Calosing: None. S. Wasiak: Employee; Self; Resverlogix Corp. D. Gilham: Employee; Self; Resverlogix Corp.. Stock/Shareholder; Self; Resverlogix Corp.. C. Halliday: None. J.O. Johansson: Employee; Self; Resverlogix Corp., Artery Therapeutics, Inc. M. Sweeney: Employee; Self; Resverlogix Corp. N.C. Wong: Stock/Shareholder; Self; Resverlogix Corp..
The Effect of Gliptins to Improve Functional Outcome after Stroke in Mice Is Mediated by the CXCR4/SDF-1α Pathway
Authors: CHIAZZA FAUSTO , TAMMEN HARALD , PINTANA HIRANYA , LIETZAU GRAZYNA , COLLINO MASSIMO , NYSTROM THOMAS , KLEIN THOMAS , DARSALIA VLADIMER , PATRONE CESARE
Published: June 2018

Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) decrease hyperglycemia by inhibiting glucagon-like peptide-1 (GLP-1) cleavage. Gliptins can also improve stroke outcome in rodents independently of GLP-1R. However, the underlying mechanisms are unknown. Stromal cell-derived factor-1α (SDF-1α) is a DPP-4 substrate and CXCR4 agonist that promotes beneficial effects in injured brains. However, SDF-1α involvement in gliptin-mediated neuroprotection is unproven. We aimed to determine whether gliptins improve stroke outcome via SDF-1α/CXCR4 and identify additional targets behind the efficacy. Adult, male C57bl6/j mice (n=101) underwent transient focal cerebral ischemia. Linagliptin was administered for 3 days or 3 weeks. The CXCR4-antagonist AMD3100 was administered starting a day before ischemia. Stroke outcome was assessed by measuring upper-limb function and brain tissue damage. Levels of active GLP-1, gastric inhibitory polypeptide (GIP) and SDF-1α were quantified by ELISA in serum and brain. Mass spectrometry was used to identify additional gliptin-mediated effectors in brain tissue samples. Sustained, post-ischemic treatment with linagliptin reduced motor impairment (p003C0.01) and tissue damage (p003C0.05). Linagliptin increased serum levels of GLP-1 (p003C0.0001), GIP (p003C0.05) and SDF-1α (p003C0.05). However, only SDF-1α levels were increased in the brain (p003C0.001). Linagliptin also decreased the presence of neurogranin-derived peptides and peptides from an isoform of myelin basic protein (MBG, p003C0.05). The inhibition of SDF-1α/CXCR4 pathway diminished the positive effects of linagliptin on stroke outcome (not different from vehicle). We propose a gliptin-mediated neuroprotective mechanism via SDF-1α, which could affect Ca2+ homeostasis, altering neurogranin and MBG processing and potentially decreasing calpain activity. These results provide new insights into restorative gliptin-mediated effects against stroke.

Disclosure

F. Chiazza: Other Relationship; Self; Boehringer Ingelheim GmbH. H. Tammen: Consultant; Self; Boehringer Ingelheim GmbH. H. Pintana: Other Relationship; Self; Boehringer Ingelheim GmbH. G. Lietzau: Other Relationship; Self; Boehringer Ingelheim GmbH. M. Collino: None. T. Nystrom: Research Support; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk A/S. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. T. Klein: Employee; Self; Boehringer Ingelheim GmbH. V. Darsalia: Other Relationship; Self; Boehringer Ingelheim GmbH. C. Patrone: Other Relationship; Self; Boehringer Ingelheim GmbH.
The Novel Use of Nanotechnology Structured Water Magnalife to Control Blood Glucose Level in Type 2 Diabetic Patients
Authors: SAMI ALI K.M. , AMIN KAWA H. , KURMANJI MOHAMMED T.
Published: June 2018

Introduction: Nanotechnology structured water is a new type of water that is produced using special modulators to change and add new properties to water molecules.

Objectives: To find out the effect of drinking nanotechnology structured water on blood glucose levels in patients with type 2 diabetes mellitus.

Patients and Methods: Type-2 diabetes mellitus patients (n=387) with only oral hypoglycemic drugs were blindly divided into 2 groups. Group A (191 patients) supplied with nanotechnology structured water and group B (196 patients) supplied with ordinary bottled water. Water bottles were unlabeled and patients were unaware of the type of water given to them. Blood glucose level was measured as Glycated Hemoglobin (HbA1c) in the same laboratory. Tests were done before starting drinking the water given to the patients as baseline then measured at the end of the third month of drinking the given water in a daily dose of (500 ml /25 kg of body weight).

Results: At the end of the the study, only 352 patients were followed (35 patients dropped out for different reasons). Group A (n=183) (aged 24 to 76, mean 50.2) years with male to female (56.3%: 43.7%), and group B (n=169) (aged 30 to77, mean49.3) years with male to female (49.1%:50.9%). Group A showed significant difference between baseline HbA1c 8.1%+/-1.38 vs. HbA1c after 3 months 6.6%+/-0.85 (p<0.001). While group B showed no significant difference in pre-post HbA1c tests 7.9% +/-1.36 vs. 7.8% +/-1.16 (p=0.274). The percentage of Patients with HbA1c<7 in group A increased from (25.1%) at baseline to (61.2%) after 3 months, while in group B, the percentage of patients with HbA1c <7 decreased from (27.2%) to (19.5%).

Conclusion: Nanotechnology structured water magnalife offers a new way to achieve better control of blood sugar in type 2 diabetic patients. However, further studies are needed to study the long term use of nano-water for the possibility to gradually decrease the needed doses of hypoglycemic agents or to stop them.

Disclosure

A.K. M. Sami: None. K.H. Amin: None. M.T. Kurmanji: None.
Central Obesity but Not BMI Related to Hypoglycemic Efficacy of Metformin—Subanalysis of MARCH Study
Authors: YANG ZHAOJUN , WANG XIN , WANG NA , JIN XIAN , ZHANG JINPING , ZHANG XUELIAN , YANG WENYING
Published: June 2018

Objective: MARCH study(Metformin and AcaRbose in Chinese as the initial Hypoglycaemic treatment) was a nationwide, multicenter, randomized controlled trial in China (Chinese Clinical Trial Registry, number ChiCTR-TRC-08000231), and confirmed that Acarbose was non-inferior to Metformin in terms of hypoglycemic effectiveness among Chinese patients with newly-diagnosed type 2 diabetes. The purpose of this paper was to understand the association between the efficacy of Acarbose and Metformin and the parameters reflected body weight.

Method: A total of 788 participants from MARCH database were included in this analysis. The participants were divided into four BMI groups(BMI 19-23.9, 24-25.9, 26-27.9, and 28-30kg/m2) and four weight loss groups according to quartile of weight change from the baseline, and two central obesity groups according to IDF criteria(i.e., waist circumference >=90cm in male, >=80cm in female), respectively. ANCOVA was used to assess the association of the above obesity categories with the changes of HbA1c from baseline in Acarbose group and Metformin group respectively, with treatment and center as factors, and baseline HbA1c as a covariate.

Result: There was no significant difference in change from baseline HbA1c within the acarbose group (0.98%,0.95%,1.20%,1.14%,p=0.1476) as well as the metformin group (1.08%,1.12%,1.20%,1.32%,p=0.2918) when patients were stratified by BMI quartile. The reduction in HbA1c was greater in patients with central obesity than those without in Metformin treatment group[1.26%(95% CI:1.15%-1.37%) vs.0.98%(95% CI:0.81%-1.15%),p=0.0059], but there was no significant difference among patients with and without central obesity for HbA1c reduction in acarbose treatment group[1.10%(95% CI:0.98%-1.21%) vs. 0.97%(95% CI:0.81%-1.13%),p=0.2037].

Conclusion: The hypoglycemic efficacy of acarbose is not associated with the obesity status. In contrast, Metformin was more effective in patients with central obesity.

Disclosure

Z. Yang: None. X. Wang: None. N. Wang: None. X. Jin: None. J. Zhang: None. X. Zhang: None. W. Yang: None.
An Observational Study to Evaluate Change in Dose Requirement of Standard Glucose Lowering, Lipid Lowering, and Antihypertensive Therapy Treated with SGLT2 Inhibitor (Canagliflozin) over One Year, in Fifty T2DM Patients
Authors: GUPTA VISHAL , TELI VAISHALI
Published: June 2018

Objective: To evaluate effect of Canagliflozin (CA) on dose of other commonly co-administered antidiabetic, antihypertensive (AH) and lipid lowering drugs (AL) over a period of 12 months.

Methodology: Fifty diabetes patients receiving glucose lowering therapy, AH and LL were treated with CA for a period of 12months. These patients were followed up at months 3, 6 and 12 for routine metabolic assessment and subsequent amendment in drug therapy. In the present study we evaluated the change in doses of background antidiabetic, AH and AL medication 12 months after CA therapy. Data was represented as Mean + 2 SD with 95% CI, a p value of 0.or lower was considered significant. Paired t test was used to compare average dose of all drug classes at baseline and end of 12 months.

Results: There was a significant reduction in average dose of Gliclazide from 172.5 ± 62.16mg at baseline to 141.25 ± 64.24mg at the end of 12 month (p= 0.05) The average dose of metformin reduced from 1.19 ± 0.53g at baseline (BS) to 1.± 0.51g at the end of 12 month (p= 0.18, not significant NS), Sitagliptin was reduced from 75.78 ± 26.56mg at BS to 75 ± 29.09mg at the end of 12 month (p= 0.91, NS). Basal insulin reduced from 27.14 ± 14.46IU at BS to 25.85 ± 28.63IU at the end of 12 month (p= 0.91, NS) Rosuvastatin slightly increased from 19.16 ± 4.53mg at BS to 19.79 ± 6.35mg at the end of 12 month (p= 0.57, NS) Among AH therapy, average dose of Telmisartan reduced from 43.33 ± 23.94mg at BS to 37.61 ± 22.39mg at the end of 12 month (p= 0.42, NS), Valsartan reduced from 103.33 ± 52.45mg at BS to 93.33 ± 54.82mg at the end of 12 month (p= 0.65, NS) and Cilnidipine reduced from 15 ± 5.27mg at BS to 17 ± 11.59mg at the end of 12 month (p= 0.62, NS).

Conclusion: Canagliflozin was associated with reduced requirements of gliclazide after one year of therapy in type 2 diabetes patients.

Disclosure

V. Gupta: None. V. Teli: None.
Assessment of Adverse Renal Effects 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 a SGLT2 inhibitor for the treatment of T2DM. Adverse renal effects were assessed in adults with T2DM receiving ERTU relative to placebo (PBO) or active comparators in pooled analyses of 7 randomized, double-blind, Phase 3 trials. Patients (N=4859) received ERTU 5 mg (n=1716), ERTU 15 mg (n=1693), or non-ERTU (PBO, glimepiride or sitagliptin; n=1450) for up to 2 years. Mean age was 57.8 years, 25.8% were ≥65 years old and 51.8% were males. Mean eGFR was 85.3 mL/min/1.73 m2 and ∼12% had moderate renal impairment (RI; eGFR <60 mL/min/1.73 m2). The mean duration of T2DM was 7.9 years and mean baseline A1C was 8.2%.

The incidence of renal-related AEs was low across the groups (ERTU 5 mg, 0.6%; ERTU 15 mg, 0.8%; non-ERTU, 0.4%); few were serious (0.1% in all groups) or led to treatment discontinuation (0.1%, 0.2% and 0.1%, respectively). Subgroup analyses demonstrated that in patients with moderate RI, renal-related AEs were more frequent in the ERTU groups relative to the non-ERTU group (ERTU 5 mg, 3.6%; ERTU 15 mg, 2.1%; non-ERTU, 1.1%). Incidence of renal-related AEs was similar across groups for patients ≥65 years old (excluding those with moderate RI at baseline) (ERTU 5 mg, 0.3%; ERTU 15 mg, 1.0%; non-ERTU, 0.8%) or those using diuretics (ERTU 5 mg, 1.2%; ERTU 15 mg, 0.8%; non-ERTU, 0.8%) or ACE/ARB (ERTU 5 mg, 0.9%; ERTU 15 mg, 0.9%; non-ERTU, 0.5%).

Independent blinded adjudication for causality was performed for pre-specified renal-related AEs and renal laboratory changes from baseline. Four patients had renal events that were adjudicated as causally related to study medication (“possible” or “very likely”; 1 in the ERTU 5 mg group, 2 in the ERTU 15 mg group and 1 in the non-ERTU group).

In conclusion, there was no increased risk of adverse renal effects in patients with T2DM receiving ERTU relative to PBO or active comparators, except in those with baseline moderate RI.

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..
Suppression of Ketogenesis in Type 1 Diabetes Is Not Delayed by SGLT2 Inhibitor Therapy
Authors: SIEBEL STEPHAN , PATEL NEHA S. , GALDERISI ALFONSO , CARRIA LORI R. , TAMBORLANE WILLIAM V. , SHERR JENNIFER
Published: June 2018

Enthusiasm for SGLT2 inhibitors as adjunctive agents for T1D has been tempered by increased risk of DKA, especially in pump treated patients susceptible to interruptions of basal insulin due to infusion site failures. Our insulin interruption study showed that failure to recognize early metabolic decompensation in SGLT2i-treated T1D patients relates to blunted increases in plasma glucose (PG) rather than accelerated ketogenesis (Δ PG 99±13 vs. 197±24 mg/dL, p<0.002; Δ free fatty acids [FFA] 0.8±0.1 vs. 0.7±0.1 and Δ β-hydroxy-butyrate [BHB] 1.5±0.2 vs. 1.2±0.2 mmol/L) before and after SGLT2i therapy. We report herein whether correction of early ketogenesis by a rescue dose of rapid-acting insulin is adversely affected by SGLT2i use. Ten adults [age 23±5 years, A1c 7.4±0.8%] had insulin interruption studies pre- and post 3 weeks of canagliflozin therapy. After a 6-hour suspension, a 0.2 unit/kg SQ bolus of aspart was given. PG, FFA and BHB levels were monitored for 150 minutes. PG fell from 314±42 to 183±17mg/dl pre- vs. 186±73 to 117±33mg/dL post SGLT2i use. The fall in FFA and BHB levels were unaffected by SGLT2i therapy(Figure). These data indicate that SGLT2i treatment does not impair suppression of increased FFA and BHB levels due to interruption of basal insulin infusion. Turning ketogenesis off, as well as on, does not appear to be affected by SGLT2i use.

Disclosure

S. Siebel: None. N.S. Patel: Consultant; Self; Janssen Pharmaceuticals, Inc.. A. Galderisi: None. L.R. Carria: None. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceuticals U.S.A., Inc. J. Sherr: Consultant; Self; Medtronic MiniMed, Inc.. Advisory Panel; Self; Insulet Corporation, Eli Lilly and Company, Bigfoot Biomedical.
A Pilot, Head-to-Head Comparison of Hydroxychloroquine (HCQ) with Pioglitazone (PIO) as Third-Line Agents in Type 2 Diabetic Patients Failing Metformin and a Sulfonylurea (SU)
Authors: HSIA STANLEY H. , DURAN PETRA , DAVIDSON MAYER B.
Published: June 2018

Type 2 diabetes is characterized by insulin resistance and inflammation. HCQ, a commonly used anti-inflammatory drug for rheumatoid arthritis and lupus, is associated with a lower risk of new-onset type 2 diabetes and reports of hypoglycemia in diabetic patients. PIO, an effective 3rd-line agent in patients failing metformin and SUs, has several side effects (e.g., weight gain, fluid retention, fractures) while HCQ has relatively few. We compared 15 patients taking HCQ 400 mg daily with 7 patients taking PIO 45 mg daily, with baseline HbA1c levels of 7.5-11.0% on maximum-tolerated doses of metformin and a SU, in a randomized controlled trial. Glucose control, insulin resistance, and inflammation (highly-sensitive C-reactive protein, hsCRP) were measured at baseline, 2 and 4 months.Results (Mean ± SD)MonthHbA1c (%)Weight (kg)Homeostasis Model Assessment (HOMA) % SensitivityhsCRP (mg/L)HCQPIOHCQPIOHCQPIOHCQPIO08.6 ± 1.09.1 ± 0.785.7 ± 14.383.7 ± 18.2109 ± 97102 ± 876.2 ± 6.78.8 ± 7.227.5 ± 0.96.8 ± 0.385.4 ± 13.986.2 ± 17.485 ± 61170 ± 1385.5 ± 5.92.2 ± 2.047.4 ± 0.96.3 ± 0.285.4 ± 14.587.0 ± 17.996 ± 74180 ± 1364.2 ± 3.83.3 ± 3.7pa<0.0001<0.00010.760.020.500.060.670.001pb0.00010.0040.010.054 a p value for the change from 0 to 4 months by 1-way repeated ANOVA; b p value for the difference between groups by 2-way repeated ANOVA.

Baseline characteristics were not significantly different between groups. Both drugs were well tolerated and significantly improved glucose control; PIO was more effective than HCQ but also caused significantly more weight gain. PIO increased insulin sensitivity while HCQ did not; PIO also significantly decreased hsCRP. HCQ may be beneficial in uncontrolled type 2 diabetic patients as a 3rd-line agent.

Disclosure

S.H. Hsia: Research Support; Self; AstraZeneca, Bayer AG, Bristol-Myers Squibb Company, Cirius Therapeutics, Eli Lilly and Company, Intarcia Therapeutics, Inc., Ionis Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Merck & Co., Inc., National Institute of General Medical Sciences, PhaseBio Pharmaceuticals, Inc., Sanofi-Aventis, TaiwanJ Pharmaceuticals Co., Ltd., Theracos, Inc., Tobira Therapeutics, VTV Therapeutics. P. Duran: None. M.B. Davidson: Employee; Self; Insulin Algorithms, Inc.
The Elevation of Hematocrit after Administration of SGLT2 Inhibitors Does Not Correlate with Plasma Osmolarity in Japanese Subjects with Type 2 Diabetes
Authors: WADA YOSHIHARU , HAMAMOTO YOSHIYUKI , IWASAKI YORIHIRO , NAKATANI YOSHIHISA , FUJIKAWA JUN , HONJO SACHIKO , AIZAWA-ABE MEGUMI , HAMASAKI AKIHIRO
Published: June 2018

It has been reported that hematocrit is elevated after administration of sodium-glucose cotransporter 2 (SGLT2) inhibitors. However, it remains controversial whether this elevation is caused by its diuretic effect. In this study, we aimed to clarify the mechanism of hematocrit elevation by examining the correlation between hematocrit and several parameters reflecting diuretic effects in subjects with type 2 diabetes who were treated with SGLT2 inhibitors. A total of 70 subjects (male: n=45, age: 53.5±10.1 SD years, BMI: 29.3±4.5 kg/m2, HbA1c: 8.8±1.2%) with type 2 diabetes who were newly administered SGLT2 inhibitors from June 2014 to March 2017 were retrospectively identified from our database. Changes in HbA1c, hematocrit, urine specific gravity, uric acid, serum creatinine and plasma osmolarity levels between before and 30, 60, 90 and 120 days after the administration of the drugs were evaluated. Plasma osmolarity was calculated by the formula (2 x (Na[mEq/l] + K[mEq/l])) + (BUN[mg/dl] / 2.8) + (glucose[mg/dl] / 18). HbA1c was significantly decreased (30d: -0.57±0.53%; p=0.0vs. basal value, 60d: -0.88±1.04; p=0.002, 90d: -0.65±1.10; p<0.001, 120d: -0.79±1.22; p<0.001). Hematocrit was increased immediately after and remained high over 120 days (1.3±2.1%; p=0.05, 1.5±3.0; p=0.44, 2.5±2.8; p=0.002, 2.1±2.6; p=0.005). Urine specific gravity was also increased (0.007±0.01g/ml; p<0.001, 0.003±0.010; p=0.02, 0.004±0.009; p=0.03, 0.007±0.011; p<0.001). However, uric acid (30d: -0.10±0.80mg/dl; p=0.70), serum creatinine (0.04±0.07mg/dl; p=0.32) and plasma osmolarity (0.87±4.34mOsm/l; p=0.31) did not show change. No correlations were observed between changes in hematocrit and serum creatinine, uric acid or plasma osmolarity.

In conclusion, our data indicate that the elevation of hematocrit after the administration of SGLT2 inhibitors is unlikely to be caused by hemo-concentration via diuretic effect.

Disclosure

Y. Wada: None. Y. Hamamoto: None. Y. Iwasaki: None. Y. Nakatani: None. J. Fujikawa: None. S. Honjo: None. M. Aizawa-Abe: None. A. Hamasaki: None.
Clinical Parameters, Fuel Oxidation, and Glucose Kinetics in T2D Patients Treated with Dapagliflozin plus Saxagliptin Combination
Authors: QIN YUEJUAN , ADAMS JOHN M. , MARTINEZ ROBERT A. , PINO ANTONINO DI , JOBORI HUSSEIN AL , ALI ALI M. , TRIPLITT CURTIS L. , DEFRONZO RALPH A. , CERSOSIMO EUGENIO
Published: June 2018

To investigate mechanisms responsible for the clinical and metabolic benefits observed with SGLT2i plus DPP-4i therapy, we randomized 30 T2D patients (A1c=8.6±0.2%, BMI=33.1±1.9) to receive dapagliflozin 10 mg [DAPA], dapagliflozin/saxagliptin 10/5 mg [DAPA/SAXA] or placebo [PCB]. Baseline OGTT, glucose kinetics (3-3H-glucose), indirect calorimetry, HbA1c, FPG, FFA, insulin, and glucagon were repeated after 16 weeks of therapy.

Results: Insulin secretion (δI/δG)0-120 min during OGTT increased (p<0.05) in DAPA (+0.6±0.1) and DAPA/SAXA (+0.6±0.1), but not in PCB (-0.4±0.20). The Matsuda Index improved (p<0.01) in DAPA (+0.6±0.20) and DAPA/SAXA (+0.7±0.1), but not in PCB (-0.1±0.2). The Disposition Index [IS/IR] increased (p<0.05) in DAPA (δ0.23±0.03) and DAPA/SAXA (δ 0.2±0.02), but not in PCB (δ0.03±0.04). The increase in fasting plasma glucagon in PCB (+37±4) and DAPA (+20±2) was blunted (p<0.05) in combo (-7±4 pg/ml). There were no significant changes in fasting plasma FFA.

Conclusion: DAPA/SAXA combination therapy was associated with improved glycemic control vs. DAPA due to the attenuation of the rise in EGP. Further, the increase in glucose Ox in combination with inhibition of lipid Ox and glucagon secretion inhibit ketone production which may reduce the risk of DKA. Addition of SAXA improves insulin secretion and prevents the glucagon elevation induced by DAPA.

CharacteristicsPCBDAPADAPA/SAXAp-valueδ BMI (Kg/m2)+0.16±0.27-0.58±0.42-0.77±0.01*<0.05δ HbA1c (%)+0.6±0.2-1.4±0.1-1.7±0.2*<0.01δ FPG (mg/dl)+35±3-59±6-68±8*<0.001Mean OGTT Glu (mg/dl)+41±6-73±8-86±7*<0.001δ Basal EGP (mg/kg.min)+0.26±0.04+0.19±0.04-0.06±0.05**<0.01δ Lipid Ox (%)-8±6+16±3+10±2*<0.001 & ***<0.05δ Glucose Ox (%)+5±4-31±3-17±2*<0.001 &***<0.001*= DAPA & DAPA/SAXA vs. PCB; **=DAPA/SAXA vs. DAPA & PCB; ***=DAPA vs. DAPA/SAXA EGP=Endogenous Glucose Production; Ox: Oxidation

Disclosure

Y. Qin: None. J.M. Adams: None. R.A. Martinez: None. A. Di Pino: None. H. Al Jobori: None. A.M. Ali: None. C.L. Triplitt: Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Eli Lilly and Company. Consultant; Self; Sanofi, Novo Nordisk Inc. R.A. DeFronzo: Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc.. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc. E. Cersosimo: Research Support; Self; AstraZeneca, VeroScience, LLC.. Speaker's Bureau; Self; AstraZeneca, Sanofi, Janssen Pharmaceuticals, Inc., Eli Lilly and Company.
Euglycemic DKA as an Initial Presentation of Immunotherapy-Induced Insulin-Dependent Diabetes
Authors: IYER PRIYANKA , THOSANI SONALI N.
Published: June 2018

New onset insulin dependent diabetes (DM) has been reported in cancer patients (pts) receiving immunotherapy (IO). Typically, pts have Grade 3 hyperglycemia (CTCAE) and sometimes DKA. Euglycemic DKA has been reported in pts on empagliflozin (Empa). We present a unique case of euglycemic DKA as initial presentation for immunotherapy induced insulin dependent DM. Pt is a 68 year old man without preexisting DM started on nivolumab for metastatic prostate cancer. Following 2 doses of nivolumab, he developed fatigue, weight loss and Grade 2 hyperglycemia for which he was started on metformin, glipizide, and Empa by his outside physician. His BG levels ranged from 130-200 mg/dL on these therapies. Nivolumab treatment was stopped due to significant adverse effects. On return visit to our clinic, approximately 3 months after initial hyperglycemia, pt complained of persistent fatigue, weight loss and a new fruity odor in his breath. Labs revealed BG of 134mg/dl, bicarb of 19 mEq/L (23-30mEq/L), anion gap (AG) of 17mEq/L (4-14mEq/L). Urine ketones were positive and c-peptide level was 0.3ng/ml (0.8- 3.85ng/ml). Pt was advised to immediately stop Empa and follow-up with local ER. When he presented to local ER, approximately 4 days later, he was hyperglycemic with glucose 316 mg/dL, and labwork consistent with classic DKA. Pt was initiated on basal bolus insulin regimen and had resolution of DKA.IO mediated DM results from immune mediated islet cell destruction leading to rapidly progressive insulin deficiency. When suspected, these pts should be evaluated for beta cell dysfunction and insulin should be used for glycemic control. This case highlights that SGLT2 therapy should be used with caution in patients with hyperglycemia on immunotherapy as it could mask the diagnosis of DKA. In addition, this case shows that patients taken off of immunotherapy may develop delayed glycemic complications and may need long term monitoring.

Disclosure

P. Iyer: None. S.N. Thosani: Consultant; Spouse/Partner; Boston Scientific Corporation, Medtronic. Speaker's Bureau; Spouse/Partner; AbbVie Inc..
Placental DNA Methylation of miR-548 and WWTR1 Genes Influence Insulin Sensitivity during Pregnancy
Authors: HIVERT MARIE-FRANCE , BRIGGS CATHERINE M. , CARDENAS ANDRES , PERRON PATRICE , BOUCHARD LUIGI
Published: June 2018

Insulin sensitivity decrease in pregnancy is a physiologic adaptation to derive nutrients for the growing fetus. The placenta has a major role in this phenomenon, but exact mechanisms remain unknown. A better understanding of the placental role in maternal insulin sensitivity regulation could help us reveal pathophysiologic pathways of gestational diabetes. We tested associations between insulin sensitivity and DNA methylation (DNAm) across the genome in 439 placenta samples from our prospective cohort Gen3G using Illumina EPIC arrays. Women were recruited at 1st trimester of pregnancy and performed a 2-hour 75g oral glucose tolerance test (OGTT) at 24-28 weeks: we measured glucose and insulin levels at each OGTT point to calculate Matsuda insulin sensitivity index. We applied standard quality control procedures for DNAm arrays analyses and adjusted for technical batch effects. We tested 720,077 individual CpGs using robust linear regression on M-values (adjusted for maternal age, BMI, smoking, parity, gestational age at birth, and child sex) and used Bonferroni to account for multiple testing. We found that maternal insulin sensitivity was associated with DNAm in placenta at 318 CpGs across the genome (P<6.94 x10-8). Among these, we found differentially methylated CpGs at loci well known for their role in diabetes (TCF7L2, SPRY2), brown adipose tissue regulation (PRDM16), and near the Prolactin Receptor. Mendelian Randomization (MR) analyses supported that placental DNAm causally influence maternal insulin sensitivity at 28 CpGs (P<0.05). Among these, our two strongest MR associations (FDR adjusted P<0.05) pointed at CpGs near miR-548 (P=5.6x10-5) and WWTR1 (P=9.8x10-5), a gene implicated in PPARalpha regulation and previously associated with preeclampsia. Our findings highlight the role of placenta epigenetic regulation in insulin sensitivity during pregnancy and reveal novel potential biologic targets implicated in gestational metabolic disorders.

Disclosure

M. Hivert: None. C.M. Briggs: None. A. Cardenas: None. P. Perron: Research Support; Self; Merck & Co., Inc., Pfizer Inc., Novo Nordisk Inc.. Speaker's Bureau; Self; Sanofi. Research Support; Self; AstraZeneca. L. Bouchard: None.
HD-6277, a Selective GPR40 Agonist, Can Improve Beta-Cell Signaling and Insulin Secretion
Authors: KANG SEUNG JUN , KIM CHUN HWA , CHOI HYO SUN , YANG GOEUN , LEE SUN HEE , LIM KWAN SOO , PARK MIN AH , KIM DOO YOUNG , YANG JIN , RHEE JAE KEOL , KIM DAEHOON
Published: June 2018

The free fatty acid receptor 1 (FFAR1/GPR40) mediates fatty acid-dependent augmentation of glucose-induced insulin secretion (GIIS) in pancreatic β-cells. The objective of the studies described here was to examine the pharmacological properties of HD-6277 in cell based assay and preclinical models of T2D. Insulin secretion was evaluated in INS-1 cells, HD-6277 (0.1∼10 μM) treated group enhanced more insulin secretion than sulfonylurea added condition. HD-6277 (100 mg/kg) did not induced hypoglycemia even combinational treatment with Metformin (50 mg/kg) in Sprague-Dawley rats. Goto-Kakizaki (GK) rats have known as type 2 diabetic model with secondary failure and apoptosis of pancreatic beta-cell. HD-6277 and glimepiride were administered to GK rats of 8 (young) and 26 (old) weeks old, respectively. Glucose tolerance tests (GTT) were performed at the starting and the ending point of the chronic administration. Administration of HD-6277 and glimepiride improved glycemic control and insulin secretion, compared to vehicle control groups in young GK rats, however, chronic administration of glimepiride cause loss of glycemic control efficacy, whereas HD-6277 did not. At the end of chronic administration, glimepiride-treated group demonstrated poor glycemic control and insulin secretion during GTT than HD-6277-treated group. In administration of HD-6277 and glimepiride to old GK rats, HD-6277-treated group has showed ameliorate in glycemic control than vehicle group, however glimepiride-treated group did not.

Thus, repeated administration of HD-6277 can preserves pancreatic islets, improves beta cell function and attenuates diabetes.

Disclosure

S. Kang: Employee; Self; Hyundai Pharm. corp. C. Kim: Employee; Self; Hyundai Pharm. corp.. H. Choi: None. G. Yang: Employee; Self; Hyundai Pharm. CORP. S. Lee: Employee; Self; Hyundai Pharm. CORP. K. Lim: Employee; Self; Hyundai Pharm. corp. M. Park: Employee; Self; Hyundai Pharm.corp. D. Kim: Employee; Self; Hyundai Pharm. CORP. J. Yang: Employee; Self; Hyundai Pharm. corp. J. Rhee: Employee; Self; Hyundai Pharm. corp. D. Kim: Employee; Self; Hyundai Pharm. Corp..
Pharmacodynamics Post-Hoc Analysis of Glucose Kinase Activator Dorzagliatin (HMS5552)—Twelve Weeks Treatment in T2D Patients in China
Authors: ZHU DALONG , ZHAO YU , TANG CUI , TIANXIN HU , LI YONG-GUO , ZHAO GUIYU , HOU XINGHUA , ZHANG YI , CHEN LI ,   HMM0201 STUDY GROUP
Published: June 2018

In a phase II study, dorzagliatin, a novel glucokinase activator (GKA), demonstrated significant HbA1c reduction and safety profile in Chinese T2D patients. Two hundred fifty eight (258) T2D patients were randomly assigned to 5 groups (50mg BID, 75mg BID, 75mg QD, 100mg QD and placebo) for a 12 weeks treatment. Compared with placebo group, HbA1c changes from baseline was significantly lower in the 100mgQD (0.69%, P<0.05), 50mgBID (0.79%, P<0.01) and 75mgBID (1.12%, P<0.001) groups. Post-hoc analyses of the phase II results were conducted to investigate the effects of dorzagliatin on the composite response rate (defined as reaching HbA1c<7.0%, no weight gain and no hypoglycemia), efficacy response β cell functions (HOMA-IR and Disposition Index), and efficacy response in stratified subgroups. Post-hoc analysis showed that the composite response rate was 28.3% (P < 0·05) and 35.4% (P < 0·001), respectively for 50mgBID and 75mgBID groups. It was significantly higher than the placebo group. HOMA-IR and Disposition Index was improved at Week 12 for the 75 mg BID group compared with placebo. Improvement of HOMA-IR was maintained at Week 13, one week after treatment discontinuation. Subjects were stratified into subgroups according to their medical history, disease history, gender, age and BMI. In drug naïve subjects, HbA1c change from baseline was -0.85% in 75mgQD (P<0.05), -0.95% in 100mgQD (P<0.01), -1.04% in 50mgBID (P<0.01), -1.21% in 75mgBID (P<0.001), and -0.17% in placebo group. Significant HbA1c reduction was also observed in 75mgBID (-0.97%, P<0.05) in the subjects who were previously treated with other antidiabetic drugs. No significant trends were observed on HbA1c in subgroups stratified by disease history, gender, age and BMI. The post-hoc analysis demonstrated dorzagliatin provided a comprehensive disease management in T2D patients with benefits of β cell function and insulin resistance improvement in the early stage T2D patients.

Disclosure

D. Zhu: None. Y. Zhao: None. C. Tang: None. H. Tianxin: None. Y. Li: None. G. Zhao: None. X. Hou: None. Y. Zhang: None. L. Chen: None.
Effects of Teneligliptin (Teneli) on Glycemic Indices in Type 2 Diabetes (T2DM) Subjects Uncontrolled with Metformin (Met) and Glimepiride (Glim) Combination
Authors: MAHAPATRA HARIBALLAV , MISHRA SUSANT , KHUNTIA MONALISA , JENA BISWARANJAN , DAS SREEYA , JENA APURBA R. , PADHI RAJESH K. , SAHOO ABHAY K. , MAHAPATRA RAMABALLAV , MAHAPATRA LAXMINARAYAN
Published: June 2018

Objective: People with diabetes gradually require increasing dose of medications to achieve good control. We studied the glycemic response of adding Teneligliptin (Teneli) in T2DM subjects with high HbA1c despite being on stable doses of Met and Glim dose.

Methods: In this retrospective study T2DM subjects, who were on fixed doses of Met 1000 to 2000mg and Glim 1 to 6mg daily for 3 months were considered. Subjects with an HbA1c between 8-11% and who were prescribed Teneli 20mg OD for at least 6 months, were shortlisted. Those taking insulin or antidiabetic drugs other than Glim+Met or those whose dose was up-titrated during the study period were excluded. We compared HbA1c, fasting (FPG), postprandrial (PPG) plasma glucose, total cholesterol (TC), triglyceride (TG), HDL, LDL, systolic (SBP) and diastolic (DBP) blood pressure at baseline and after 6months of Teneli initiation.

Results: Data of 562 subjects (229, 41% females), who met the inclusion criteria were extracted for analysis from the hospital records. Mean age of the sample was 52.6 (95% CI: 51.7-53.4) years and duration of diabetes was 7.8 (6.6-8.3) years. Addition of Teneli resulted in a drop in HbA1c from 9.6% (8.2-10.6) to 8.8% (7.1-9.4) (p<0.05). FPG decreased from 158.8 (154.3-163.2) to 127.8 (124.5-131.1) and PPG from 236.4 (230.7-242.0) to 191.0 (186.0-196.0) respectively (p <0.05). Teneli also improved lipid parameters significantly, particularly TC and TG. With Tenali, SBP declined from 136.8 (134.8-137.9) to 129.5 (128.1-130.9) and DBP from 83.1 (82.2-83.9) to 81.0 (80.2-81.9). There was no incidence of severe hypoglycemia, though 18 (3.2%) cases of suspected hypoglycemia were managed at home.

Conclusion: Adding Teneli to Met and Glim combination showed promising role in improving glycemic parameters, lipid components and blood pressure. Low hypoglycemia risk makes the drug a suitable add-on option for those with high HbA1c values.

Disclosure

H. Mahapatra: None. S. Mishra: None. M. Khuntia: None. B. Jena: None. S. Das: None. A.R. Jena: None. R.K. Padhi: None. A.K. Sahoo: None. R. Mahapatra: None. L. Mahapatra: None.