bluuebunny/crossref_metadata_2025 huggingface dataset:
Lixisenatide and Renal Outcomes in Patients with Type 2 Diabetes—A Post-Hoc Analysis of the ELIXA Trial
Authors: MUSKIET MARCEL A. , TONNEIJCK LENNART , HUANG YAO , LIU MINZHI , SAREMI ARAMESH , HEERSPINK HIDDO LAMBERS. , VAN RAALTE DANIËL H.
Published: June 2018

Limited data exist on long-term effects of GLP-1 receptor agonists on kidney function and albuminuria in T2D. In ELIXA, a study of cardiovascular safety of lixisenatide (Lixi) over a median follow-up of 25 months in 6068 patients (pts) with T2D and an acute coronary event ≥180 days before screening, slower progression of urinary albumin-to-creatinine ratio (UACR) was seen with Lixi vs. placebo (Pbo). In a mixed-effect model with repeated measures for comparisons between treatment (Tx) groups of changes in UACR, the interaction between Tx and baseline (BL) UACR categories was significant (p<0.01). We assessed change in estimated glomerular filtration rate (eGFR, per the 4-variable modification of diet in renal disease formula) and UACR by BL albuminuria status. eGFR was not significantly different for Lixi vs. Pbo overall or by BL albuminuria status. UACR percent change from BL was lower for Lixi vs. Pbo in pts with micro- or macroalbuminuria (Table). In a Cox proportional hazards model adjusted for BL and on-trial HbA1c, Lixi was associated with 23% lower risk for first macroalbuminuria event in pts without BL macroalbuminuria (HR 0.77; 95% CI: 0.62, 0.96; p=0.0174).

In conclusion, in pts with T2D and a recent acute coronary event, Lixi reduced UACR progression in pts with BL micro- or macroalbuminuria and was associated with lower incidence of macroalbuminuria beyond glycemic control.

Disclosure

M.A. Muskiet: Consultant; Self; Eli Lilly and Company, Novo Nordisk A/S. L. Tonneijck: Consultant; Spouse/Partner; Eli Lilly and Company. Y. Huang: Consultant; Self; Sanofi. M. Liu: Employee; Self; Sanofi. A. Saremi: Employee; Self; Sanofi US. 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. D.H. van Raalte: Advisory Panel; Self; Sanofi. Research Support; Self; Sanofi, Boehringer Ingelheim GmbH. Advisory Panel; Self; Boehringer Ingelheim GmbH, Merck & Co., Inc., Novo Nordisk Inc.. Research Support; Self; AstraZeneca.
Durability of Combination Therapy with Exenatide and Pioglitazone vs. Basal Bolus Insulin in Poorly Controlled T2DM Patients—Three-Year Follow-Up of the QATAR Study
Authors: ABDUL-GHANI MUHAMMAD , MIGAHID OSAMA , MEGAHED AYMAN , MOHAMMAD MOHAMMAD FAWAZ. , DEFRONZO RALPH A. , JAYYOUSI AMIN
Published: June 2018

Background: We previously demonstrated that addition of exenatide (EXEN) plus pioglitazone (PIO) in poorly controlled T2DM patients on maximal dose of metformin plus sulfonylurea produced a greater A1c reduction at 1 year than basal-bolus insulin. Here we report the 3-year follow-up data.

Methods: 274 poorly controlled T2DM patients (age=56 y; BMI=31; Diabetes duration=11 y, HbA1c=10.1%) on maximal doses of metformin plus SU were randomized to receive: (1) Exenatide once weekly (2 mg) plus pioglitazone (n=142) or (2) basal (glargine)-bolus (aspart) insulin (n=132) to maintain HbA1c below 7%.

Results: In subjects receiving EXEN + PIO, A1c decreased to 6.5% at 6 months, and remained at 6.6% after 36 months. With Insulin Therapy, A1c declined to 7.5% at 6 months and remained 7.3 at 36 months (P<0.001) (Figure 1). More subjects receiving Insulin Therapy failed to achieve the A1c goal <7% (63% vs. 22%, p<0.0001). Despite lower A1c, subjects receiving EXEN + PIO had lower rate of hypoglycemia (P<0.001) compared to subjects receiving Insulin Therapy. Lastly, subjects receiving Insulin Therapy gained 4.1 kg vs. 1.7 kg (p=0.0002) vs. subjects treated with EXEN + PIO.

Conclusion: Addition of EXEN + PIO in poorly controlled T2DM patients on MET/SU produces greater and more durable HbA1c reduction with lower rate of hypoglycemia compared to Insulin Therapy.

Disclosure

M. Abdul-Ghani: None. O. Migahid: None. A. Megahed: None. M.F. Mohammad: None. 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.. A. Jayyousi: None.
Treatment and Clinical Measures after Initiation of Injectable Therapy for Type 2 Diabetes—A Real-World Observational Cohort Study
Authors: REGES ORNA , LEVENTER-ROBERTS MAYA , CURTIS BRADLEY , GOFER ILAN , HE XUANYAO , KARPATI TOMAS , RUBIN GIL , LEIBOWITZ MORTON , STRIZEK ALENA , FELDMAN BECCA S.
Published: June 2018

Background: Injectable therapy is required when patients with type 2 diabetes (T2D) do not achieve glycemic control despite previous dietary and lifestyle modifications combined with oral antidiabetic therapy. While both Glucagon-like peptide-1 receptor agonists (GLP-1-RA) and insulin therapy are prescribed, real world evidence is lacking regarding relative therapeutic benefit. The objective of this study was to examine if there were changes in treatment and clinical measures in individuals who initiated any insulin vs. GLP-1 RA injectable therapy.

Methods: All patients with T2D for at least five years who initiated any insulin or GLP-1 -RA therapy between 2010-2014 were identified in Clalit Health Services electronic medical records. Clinical measures and medication use at the time of therapy initiation (index-date) and one year post index date were examined and changes over the period were analyzed.

Results: A total of 49,807 patients were identified: 41,049 received insulin and 8,758 GLP-1 RA. One year post index date, mean HbA1c (%) levels decreased in both groups (from 9.56 ± 2.22 to 8.24 ± 1.79 among insulin initiators and from 8.92 ± 1.43 to 7.96 ± 1.51 among GLP-1 RA initiators). Furthermore, 24.8% of GLP-1 RA initiators vs. 11.7% insulin initiators achieved >5% decrease in BMI level. There was a similar decrease in the percentage of patients purchasing oral hypoglycemic agents in both groups. No change was demonstrated in systolic and diastolic blood pressure between the 2 groups.

Conclusions: This descriptive assessment found that clinical improvement was achieved in individuals that purchased insulin or GLP-1 RA, with a greater percentage achieving favorable HbA1c and BMI levels among those that initiated GLP-1 RA. Longer term follow-up with adjusted analyses is necessary in order to understand if the differential impact persists between these therapeutic treatments for individuals with T2D.

Disclosure

O. Reges: None. M. Leventer-Roberts: None. B. Curtis: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. I. Gofer: None. X. He: None. T. Karpati: None. G. Rubin: Employee; Self; Eli Lilly and Company. M. Leibowitz: None. A. Strizek: None. B.S. Feldman: None.
Dulaglutide-Combined Conventional Insulin Therapy Contributes to Ideal Glycemic Control in Noncritically Ill Hospitalized Patients
Authors: FUSHIMI NOBUTOSHI , SHIBUYA TAKASHI , YOSHIDA YOHEI , ITO SHUN , HACHIYA HIROKI , MORI AKIHIRO
Published: June 2018

Object: We investigated whether dulaglutide (DU)-combined conventional insulin therapy is beneficial for glycemic control in noncritically ill hospitalized patients with type-2 diabetes.

Method: This study was a prospective, randomized-controlled pilot study. Participants were randomized to either basal-plus (BP) therapy, those receiving basal insulin and corrective doses of regular insulin before meals, or BP+DU therapy, those receiving BP therapy combined with DU. Blood glucose (BG) levels before and after every meal were measured for 7 days after assignment. Because we consider the ideal BG during hospitalization to be within 100-180 mg/dL, we define this range as the hospitalized ideal glucose range (hIGR). We compared the percentage of hIGR with all measured BGs (%hIGR), mean BG, glucose variability (GV), and insulin dose.

Result: Of 54 patients participating in the study, 27 were assigned to the BP group and 27 to the BP+DU group. The %hIGR was significantly higher and percentage of BG >240 and BG <70 was significantly lower in the BP+DU compared with the BP group. The mean BG, SD, coefficient of variation, and total regular insulin dose in the BP+DU group were significantly lower than those in the BP group (Table). No significant side effects were observed.BP groupBP+DU groupn=974, N=27n=899, N=27P valueBaseline characteristicsAge, years70.1±1470.9±130.822Male, N (%)18 (67)15 (56)0.577BMI, kg/m224.6±5.725.1±6.70.904Duration, years10.1±8.88.7±9.40.488HbA1c, %8.0±1.98.2±1.70.401Frequency of the measured BGs in each BG ranges, n (%)BG <7021 (2.3)4 (0.4)<0.001BG 71–9963 (7)99 (10)0.019BG 100–180 (%hIGR)399 (44)545 (56)<0.001BG 181–240232 (26)244 (25)0.748BG >240184 (21)82 (8)<0.001Daily BG profiles, mean±SD mg/dLFasting131±38127±400.254After breakfast244±61196±540.004Before lunch216±65173±56<0.001After lunch195±62182±540.041Before dinner135±47143±440.232After dinner203±62177±54<0.001mean BG after first day183±29162±300.014Glucose variability, mean±SDIndividual glucose SD during study62.5±2145.0±140.001Individual glucose CV during study0.34±0.090.27±0.050.002Hypoglycemic event, N (%)Patients <70 mg/dL9 (33)3 (11)0.099Insulin therapy, mean±SD U/dayTotal insulin17.1±6.616.1±6.40.762Total glargine insulin12.0±5.712.6±4.80.55Total regular insulin5.4±2.53.6±2.80.017n, number of the measured BGs; N, number of the patients

Conclusion: BP+DU therapy reduced the frequency of hyperglycemia and hypoglycemia and resulted in a lower GV.

Disclosure

N. Fushimi: None. T. Shibuya: None. Y. Yoshida: None. S. Ito: None. H. Hachiya: None. A. Mori: None.
Long-Term Use of GLP-1 Receptor Agonists Alter GLP-1 Receptor mRNA Expression in Hindbrain Pathways That Regulate Gastric Motility in Mice
Authors: WANG PEILI , MAMILLAPALLI RAMANAIAH , ZHU WANLING , CHAN OWEN
Published: June 2018

Therapeutic strategies targeting the incretin system are effective in treating type 2 diabetes. GLP-1 receptor agonists (GLP-1RA) reduce post-prandial glucose levels by stimulating insulin and inhibiting glucagon release, but also by reducing gastric motility. Although GLP-1RA reduce gastric motility initially, their ability to sustain this over the long-term is reduced and the mechanism(s) underlying this change is not known. GLP-1R are expressed in neurons of the nucleus of the solitary tract (NTS) which play a fundamental role in regulating metabolism and gastric motility. Here, we examined whether long-term use of GLP-1RA alters GLP-1R expression in the NTS that can influence gastric motility. C57BL6 mice were treated with either saline, lixisenatide, liraglutide or exenatide ER, for 2hrs, 1d, 1wk, 2wks, 4wks or 6wks before their effects on gastric motility and NTS GLP-1R mRNA expression were evaluated. All GLP-1RA effectively slowed gastric emptying in the early stages of treatment, but within 1-2wks, their efficacy waned. By 4-6wks, no significant reduction in gastric motility was observed with any of the agonists. Of note, we observed a decline in GLP-1R mRNA expression in the NTS at 1-2wks of treatment which corresponded to the initial decline in drug efficacy. At 4wks, however, GLP-1R mRNA levels returned to pretreatment levels and suppression of gastric motility was no longer observed. To test whether the decrease in NTS GLP-1R expression contributed to attenuating the suppressive effects on gastric motility, we knocked down GLP-1R expression in the NTS using an adeno-associated viral vector to express a shRNA against the GLP-1R. Reducing NTS GLP-1R expression prevented the suppressive effects of lixisenatide on gastric motility, suggesting in mice, a decrease in NTS GLP-1R expression may contribute to the initial decrease in GLP-1RA efficacy, whereas receptor desensitization may play a more dominant role in the latter stages.

Disclosure

P. Wang: None. R. Mamillapalli: None. W. Zhu: None. O. Chan: None.
Repeat BCG Vaccination Creates Lasting Reductions of HbA1c in Subjects with Long-Term Type 1 Diabetes—Long-Term Clinical Trial Follow-up
Authors: KUHTREIBER WILLEM , TRAN LISA , JANES SOPHIE E. , DEFUSCO AUDREY A. , ZHENG HUI , FAUSTMAN DENISE L.
Published: June 2018

We report on a randomized, placebo-controlled prospective examination of adult subjects with long-term type 1 diabetes who received 2 bacillus Calmette-Guerin (BCG) vaccine doses 4 weeks apart and were studied for up to 5 years. All enrolled subjects had disease >10 years duration without complications. Starting after year 3 of follow-up, only BCG vaccinated subjects had lowered HbA1c for 1 year (Year 05 data: BCG-treated HbA1c 6.18+/-.34 [n=9], placebo 7.07+/-.41 [n=3], reference subjects with type 1 diabetes 7.22+/-.17 [n=34, p=0.02]). Continuing follow-up of 6 subjects who have been followed for a total of 8 years, 4 years after the first documented lowering of HbA1c (Phase 1 trial participants), confirms the ability of repeat BCG vaccination to maintain lowered HbA1c levels without hypoglycemia in long-term disease (BCG-treated HbA1c 6.65+/-.26 vs. placebo 7.22+/-.38, p=0.0002) for a total of 5 continuous years. For all BCG-treated subjects, the stable reductions in HbA1c were not associated with hypoglycemia. BCG-treated subjects had no change in their enrollment use of insulin pumps and none utilized a CGM device. The apparent stable and long-lasting impact of BCG on blood sugars in humans with type 1 diabetes appears to be the result of a novel mechanism, as documented with metabolomics, mRNAseq, and epigenetic methods; namely, a systemic shift in glucose metabolism from oxidative phosphorylation to aerobic glycolysis, a state of high glucose utilization on cellular levels. BCG via epigenetics also resets T-regulatory genes for genetic reprogramming of tolerance. Trials are being designed to confirm the value of BCG for blood sugar control in humans. The identification of a novel mechanism for blood sugar lowering with BCG opens the door for future trials in both type 1 and 2 diabetes with a safe, novel and affordable approach.

Disclosure

W. Kuhtreiber: None. L. Tran: None. S.E. Janes: None. A.A. DeFusco: None. H. Zheng: None. D.L. Faustman: None.
Effects of IDegLira (Insulin Degludec/Liraglutide) in Patients with Poorly Controlled Type 2 Diabetes (T2D) with A1C >9%—Analyses from the DUAL Program
Authors: SUGIMOTO DANNY , FRIAS JUAN P. , GOUET DIDIER , TAKÁCS RÓBERT , JIA TING , ÖRSY PETRA , BAIN STEPHEN C.
Published: June 2018

Despite a variety of treatment options for type 2 diabetes (T2D), more than half of patients do not achieve glycemic control. In a post-hoc analysis of the DUAL I (oral antidiabetic drugs [OADs]), II, V and VII (basal insulin + OADs) trials, we evaluated patients with an A1C >9% at baseline to determine the impact of IDegLira on their glycemic control. Within each DUAL trial, baseline characteristics for patients with A1C >9% were similar for all treatment groups. In DUAL I, II and V, treatment with IDegLira resulted in greater reductions in A1C from baseline, vs. comparators of basal insulin or liraglutide, leading to lower A1C at end of trial (EOT). In DUAL VII, reduction in A1C from baseline and A1C at EOT were comparable for IDegLira and insulin glargine U100 (100 U/mL) + insulin aspart (≤4 times/day). At EOT, the composite endpoint of A1C <7% without hypoglycemia (DUAL I, II and V: unable to self-treat and/or plasma glucose [PG] <56 mg/dL; DUAL VII: unable to self-treat or PG <56 mg/dL with hypoglycemia symptoms) was achieved by a greater proportion of patients treated with IDegLira than with comparators.

In conclusion, even in patients with T2D with A1C >9%, IDegLira treatment achieved glycemic control with a high proportion of patients achieving A1C <7% and clinically important composite endpoints of A1C <7% without hypoglycemia and/or weight gain.

Disclosure

D. Sugimoto: Research Support; Self; Novo Nordisk A/S. J.P. Frias: Research Support; Self; AbbVie Inc., Allergan, Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company. Consultant; Self; CeQur Corporation. Research Support; Self; Cirius Therapeutics, AstraZeneca, Calibra Medical, Elcelyx Therapeutics, Inc.. Consultant; Self; Elcelyx Therapeutics, Inc.. Research Support; Self; Eli Lilly and Company, Genentech, Inc., Ionis Pharmaceuticals, Inc., ICON plc., Janssen Pharmaceuticals, Inc.. Consultant; Self; Johnson & Johnson Diabetes Institute, LLC.. Research Support; Self; Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc.. Consultant; Self; Ligand Pharmaceuticals, Inc.. Research Support; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc., Sanofi. Consultant; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Research Support; Self; Theracos, Inc. D. Gouet: Research Support; Self; Novo Nordisk A/S, Eli Lilly and Company, Boehringer Ingelheim GmbH, Medtronic, Johnson & Johnson Diabetes Institute, LLC., Sanofi. R. Takács: None. T. Jia: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. P. örsy: Employee; Self; Novo Nordisk A/S. S.C. Bain: Research Support; Self; Novo Nordisk Inc., AstraZeneca.
Impact of Type 2 Diabetes (T2D) Duration on Response to iGlarLixi vs. IGlar—A Subanalysis of LixiLan-L
Authors: BLONDE LAWRENCE , BERARD LORI , SAREMI ARAMESH , HUANG YAO , ARODA VANITA , RACCAH DENIS
Published: June 2018

Shorter-acting GLP-1RA like lixisenatide have insulin-independent effects, which may benefit patients (pts) with longer T2D duration and more β-cell dysfunction. We assessed the effects of insulin glargine (iGlar) vs. fixed-ratio iGlar plus lixisenatide (iGlarLixi) by T2D duration in the LixiLan-L trial (N=736). HbA1c, weight, insulin dose change (BL-Wk 30) and hypoglycemia were analyzed in pts divided in quartiles by recorded baseline (BL) T2D duration (<7.3; 7.3-<10.7; 10.7-15.7; >15.7 years). Pts were also grouped by BL insulin dose (may relate inversely to β-cell function). BL HbA1c was higher in long-duration quartiles but similar with iGlarLixi vs. iGlar. iGlarLixi reduced HbA1c more vs. iGlar across duration quartiles (Figure). Difference was greater in pts in the longest duration quartile (LS mean difference [SE] -0.62 [0.13]; p<0.0001). In both treatment groups, pts in the shortest duration quartile had the greatest insulin dose change (BL-Wk 30). Difference in hypoglycemia (iGlarLixi vs. iGlar) was greatest in pts in the longest duration quartile (3.3 vs. 6.9 events/pt-yr; p<0.0001). In pts grouped by T2D duration and insulin dose, those with both long duration (>15.7 years) and high dose (>42 U) showed greatest difference in HbA1c lowering with iGlarLixi vs. iGlar. In LixiLan-L, iGlarLixi lowered HbA1c more vs. iGlar regardless of T2D duration, with greatest difference in those with longest duration.

Disclosure

L. Blonde: Other Relationship; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Other Relationship; Self; Lexicon Pharmaceuticals, Inc.. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Other Relationship; Self; Janssen Scientific Affairs, LLC.. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Merck & Co., Inc., Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Other Relationship; Self; Novo Nordisk Inc., Sanofi. Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; Sanofi US. L. Berard: Other Relationship; Self; Abbott, Becton, Dickinson and Company, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi, Montmed Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., LifeScan Canada. Consultant; Self; Ascensia Diabetes Care. Other Relationship; Self; Novo Nordisk Inc., Merck & Co., Inc. A. Saremi: Employee; Self; Sanofi US. Y. Huang: Consultant; Self; Sanofi. V. Aroda: Consultant; Self; Novo Nordisk Inc.. Research Support; Self; Novo Nordisk Inc., AstraZeneca, Calibra Medical, Eisai Inc., Sanofi. Consultant; Self; Sanofi. Research Support; Self; Theracos, Inc.. Employee; Spouse/Partner; Merck & Co., Inc.. Other Relationship; Self; American Diabetes Association. Consultant; Self; ADOCIA. D. Raccah: Advisory Panel; Self; Novo Nordisk Inc., Lilly, Sanofi, Merck & Co., Inc..
Efpeglenatide, a Long-Acting Glucagon-Like Peptide-1 Receptor Agonist—Immunogenicity Profile Based on Preclinical and Clinical Studies
Authors: PRATO STEFANO DEL , CHOI IN YOUNG , KANG JAHOON , TRAUTMANN MICHAEL E. , YOON KUN-HO , SORLI CHRISTOPHER H.
Published: June 2018

Once-weekly (QW), subcutaneous efpeglenatide (efpeg) is a long-acting glucagon-like peptide 1 receptor agonist, with glucose- and weight-lowering effects, in development for type 2 diabetes (T2D). Efpeg is based on a single amino acid-modified exendin analog coupled to a fragment crystallizable (Fc) fragment of the human immunoglobulin G molecule for slow clearance that permits QW dosing. As immunogenicity may hamper pharmacological effects, the incidence of anti-drug antibodies (ADAs) was assessed in efpeg studies. In a cynomolgus monkey study, no primate developed ADAs (Table). In clinical dose-finding studies (efpeg exposure <3 months), no treatment-emergent ADAs (TE ADAs) or in vitro neutralizing antibodies (nAbs) were detected. Primary and immunogenicity endpoints from efpeg QW clinical studies (>3 months) are shown (Table). In patients with T2D or obesity, efpeg QW led to significant reductions in glycated hemoglobin and body weight, respectively, with low immunogenicity (<20% of patients with TE ADAs) and no nAbs. Analysis of individual patient data suggest that presence of ADAs did not impact efficacy and no serious or severe immunogenicity events were reported. Overall, the modification of exendin and Fc conjugation in efpeg were associated with low development of ADAs, with no apparent immunogenicity effects on pharmacological action.

Disclosure

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. I. Choi: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. J. Kang: Employee; Self; Hanmi Pharmaceutical. M.E. Trautmann: Consultant; Self; ProSciento. Stock/Shareholder; Self; Eli Lilly and Company. Consultant; Self; Hanmi Pharmaceutical, CeQur Corporation, Intarcia Therapeutics, Inc., Servier. K. Yoon: None. C.H. Sorli: Employee; Self; Sanofi.
Hypoglycemia Unawareness in T1DM Is Associated with Altered Brain Default Mode Network Connectivity
Authors: GROSKREUTZ DEREK , HWANG JANICE , SEO DONGJU , LACADIE CHERYL , PARIKH LISA , BELFORT-DEAGUIAR RENATA , SCHEINOST DUSTIN , SINHA RAJITA , CONSTABLE TODD , SHERWIN ROBERT
Published: June 2018

The impact of hypoglycemia awareness (HA) on brain resting state connectivity remains unclear. To examine the impact of HA on the default mode network (DMN), a functional network in the brain that is active during wakeful rest and associated with introspection, 12 T1DM individuals with hypo unawareness (T1DM-UW) (by Clarke score) (7F/5M, age 44±12 years, BMI 26.4±4.2 kg/m2, HbA1c 7.1±0.7) and 15 T1DM-Aware (AW) (10F/5M, age 30±7, BMI 24.5±3.1, HbA1C 7.1±0.9) individuals underwent resting state BOLD fMRI scanning to assess the DMN during a two-step euglycemic (Eu)-hypoglycemic (Hypo) clamp (90-60 mg/dl). T1DM-AW individuals exhibited a hypoglycemia-induced decrease in DMN connectivity (P<0.001). In contrast, T1DM-UW individuals showed no difference in connectivity between conditions. Moreover, the degree of DMN inhibition correlated inversely with plasma cortisol (r=-0.432, p=0.031), norepinephrine (r=-0.40, p=0.038) and positively with hypoglycemia symptom scores (r=0.40, p=0.037). These findings suggest that, unlike T1DM-AW individuals, hypoglycemia fails to elicit changes in the DMN amongst T1DM-UA individuals. Furthermore, the change in DMN connectivity is associated with measures of physiological and interoceptive responses to stress. These findings highlight the need for future studies to investigate whether avoidance of hypoglycemia can restore brain connectivity patterns.

Disclosure

D. Groskreutz: None. J. Hwang: None. D. Seo: None. C. Lacadie: None. L. Parikh: None. R. Belfort-DeAguiar: Research Support; Self; GlaxoSmithKline plc.. D. Scheinost: None. R. Sinha: None. T. Constable: None. R. Sherwin: Other Relationship; Self; QuintilesIMS, MannKind Corporation. Research Support; Self; Regeneron Pharmaceuticals, Inc.. Other Relationship; Self; ICON plc..
Dulaglutide Has Favorable Outcomes in Elderly or Renal Impairment Patients with Type 2 Diabetes
Authors: KANEKO SHIZUKA , UEDA YOUHEI , TAHARA YUMIKO
Published: June 2018

In Japan, society is aging. Additionally, dialysis is performed in one out of 400 people. Safe, effective and convenient therapies for elderly or renal impairment type 2 diabetic patients (T2D) including those undergoing dialysis are needed. We investigated the the long-term efficacy and safety of a new once weekly GLP-1RAg dulaglutide (Dura) on glycemic control in those. We conducted two different retrospective analyses of 2 year efficacy and safety of Dura in T2D according to; 1)subgroups stratified by ages (≤70 years old or >71 years old), 2) renal impairment including those undergoing dialysis. Regarding 1) Of 322 T2D, 214 elderly T2D (109 males, 76.6±6.9 years old, disease duration of 7.6±7.4 years, HbA1c 8.3±1.8%, BMI 24.1±4.1) and 1younger T2D (48 males, 58.4±10.6 years old, disease duration of 5.6±5.6 years, HbA1c 7.9±1.4%, BMI 25.5±4.4) were newly administered Dura weekly. Elderly and younger T2D treated with Dura achieved 7.0±6.9% and 7.2±6.9% in HbA1c after 2 years respectively. 20 elderly T2D were injected under help with care persons due to cognitive impairment. One patient discontinued Dura due to intolerance. Nocturnal hypoglycemia never occurred. 2) 33 patients with renal impairment (69.5±10.2 years old, HbA1c 7.6±1.0%, eGFR 42.3±7.9 mL/min/1.73m2) including 6 patients undergoing dialysis (5 hemodialysis and 1 peritoneal dialysis). The levels of eGFR remained those at the start of Dura therapy. Only one patient with hemodialysis discontinued Dura due to vomiting. Weekly GLP-1RAg provides more effective and safer glycemic control in elderly T2D with/without renal impairment including dialysis. It might be expected to reduce: patient burden due to weekly injections, risk of hypoglycemia, burden on care givers in an aging society. It might also be expected to improve QoL of patients due to a reduced burden when taking medicines daily or hypoglycemia, and due to saving care person’s burden in elderly society which is workforce shortage, result in reduce of medical costs.

Disclosure

S. Kaneko: Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S, Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Sanwa Kagaku Kenkyusho Co., Ltd.. Other Relationship; Self; Elsevier. Speaker's Bureau; Self; Kowa Pharmaceuticals America, Inc., Ono Pharmaceutical Co., Ltd., Astellas Pharma US, Inc., Sanofi, Nippon Boehringer Ingelheim Co. Ltd., AstraZeneca, Sumitomo Dainippon Pharma Co., Ltd.. Speaker's Bureau; Spouse/Partner; Sumitomo Dainippon Pharma Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Otsuka Holdings Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Biogen, Eisai Co., Ltd., Bayer AG, Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Nihon Pharmaceutical Co., Ltd., Fujimoto Pharmaceutical Corporation. Y. Ueda: None. Y. Tahara: None.
Exploring Two Dose Regimens of ITCA 650 to Switch from Stable Liraglutide Therapy in Type 2 Diabetes (T2D)
Authors: RASOULI NEDA , ROSENSTOCK JULIO , NAKHLE SAMER , SCHWARTZ BRIAN , PRABHAKAR PRAKASH , KRUGER SYDNEY L. , HUANG HOLLY , BARON MICHELLE A.
Published: June 2018

ITCA 650 is an investigational titanium osmotic mini pump that is subdermally placed in the abdominal wall during a brief office procedure to continuously deliver exenatide over 3 and 6-month periods and has the potential to improve medication adherence because patients do not self-administer. In this 26 week, open-label phase 3b study, 136 patients with T2D receiving liraglutide (1.2 to 1.8 mg/d) and metformin (≥1000 mg/d) were randomized to either the standard ITCA 650 dose regimen used in phase 3 trials of 20 mcg/d for 13 weeks followed by a 60 mcg/d maintenance dose (for 13 weeks in this study) or starting directly with the maintenance dose of 60 mcg/d for 26 weeks. The last injection of liraglutide occurred 2 days prior to randomization. The primary endpoint compared the incidence of nausea (N) and vomiting (V) between the two dose regimens. Switching from liraglutide to either dose regimen of ITCA 650 had a similar incidence of transient mild to moderate N/V (Table). Of note, 3 sites, which recruited 25% of the study population, accounted for 47% and 68% of the total N/V seen in the study. 4 patients discontinued due to GI AEs. Glycemic control remained stable in both groups. At Week 26, significant weight reduction was observed in both groups (p<0.vs. baseline).

In conclusion, patients on stable liraglutide therapy can be switched to ITCA 650 60 mcg/d without the need for up-titration from a lower dose.

Disclosure

N. Rasouli: Consultant; Self; AstraZeneca, Intarcia Therapeutics, Inc. J. Rosenstock: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; Sanofi. Consultant; Self; Sanofi. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Consultant; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Intarcia Therapeutics, Inc.. Research Support; Self; Merck & Co., Inc., Pfizer Inc., Sanofi, Novo Nordisk Inc., Bristol-Myers Squibb Company, Eli Lilly and Company, Intarcia Therapeutics, Inc., Genentech, Inc.. S. Nakhle: None. B. Schwartz: Employee; Self; Intarcia Therapeutics, Inc.. P. Prabhakar: None. S.L. Kruger: None. H. Huang: None. M.A. Baron: Employee; Self; Intarcia Therapeutics, Inc..
Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonist (GLP-1RA) plus Basal Insulin vs. GLP-1RA in Type 2 Diabetes Mellitus—A Systematic Review and Meta-analysis
Authors: SATTI MUNIZA M. , O'BRIEN TIMOTHY , LIEW AARON
Published: June 2018

Combination therapy with Glucagon-like peptide-1 receptor agonist (GLP-1RA) and basal insulin represents a new therapeutic option for diabetes mellitus. We hypothesized that GLP-1RA plus basal insulin is more efficacious, safer and tolerable than GLP-1RA for patients with type 2 diabetes mellitus (T2DM). Randomized controlled trials (RCTs) comparing GLP-1RA plus basal insulin vs. GLP-1RA were searched using PubMed, Cochrane library and www.ClinicalTrials.gov database. Inclusion criteria were: (1) RCTs; (2) comparison between GLP-1RA plus basal insulin vs. GLP-1RA; (3) duration of treatment between 24-30 weeks; and (4) T2DM. Four RCTs with 2,732 participants were included in this meta-analysis. Compared with GLP-1RA alone, GLP-1RA plus basal insulin was associated with a significant reduction in HbA1c (Mean difference [MD]: -0.79%; 95% CI [confidence interval]: -0.96,-0.61; P<0.001) and fasting plasma glucose (FPG) (MD: -2.03mmol/l; 95% CI: -2.28, -1.77; p<0.001). More participants achieved HbA1c ≤7% in the GLP-1RA plus basal insulin group (Odds ratio [OR]: 4.66; 95% CI: 3.00, 7.23; p<0.001). GLP-1RA plus basal insulin was associated with more symptomatic hypoglycaemia (OR: 7.04; 95% CI: 3.81, 13.00; p<0.001) and weight gain (MD: 2.46kg; 95% CI: 2.08, 2.84; P<0.001). There was no significant difference in treatment emergent adverse effects (OR: 0.80; 95% CI: 0.57, 1.11; p=0.18) and discontinuation due to adverse events (OR: 0.52; 95% CI: 0.26, 1.03; p=0.06) between both groups. GLP-1RA plus basal insulin is more efficacious for HbA1c and FPG reduction when compared with GLP-1RA in patients with T2DM. Symptomatic hypoglycaemia and weight gain were more common with GLP-1RA plus basal insulin, but discontinuation due to adverse events was similar between both groups.

Disclosure

M.M. Satti: None. T. O'Brien: Advisory Panel; Self; Merck Sharp & Dohme Corp., Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca. A. Liew: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk A/S.
Cholesterol 7 Alpha–Hydroxylase (CYP7A1) Activity and 7–Alpha–Hydroxy–4–Cholesten–3–One (C4) Are Not Translatable Biomarkers of Glucagon Receptor (GCGR) Activation
Authors: CAMACHO RAUL , LI WENYU , KIRCHNER THOMAS , ZHANG RUI , BONILLA FANY , JIAN WENYING , GAO BIN , SINHAROY RANABIR , LEONARD JAMES , CONNOLLY THOMAS
Published: June 2018

Glucagon-like peptide 1 receptor/glucagon receptor (GLP–1R/GCGR) dual agonists are being pursued for obesity and type 2 diabetes mellitus (T2DM). A biomarker for GCGR would aid in optimizing receptor balance and in modeling dose selection to avoid potential adverse events from excess GCGR agonism. It has been reported that glucagon treatment decreases CYP7A1 transcription in primary rat and human hepatocytes, whereas GCGR antagonists increase CYP7A1 mRNA in mice and its product, 7–HCO (the precursor of C4), in diabetic patients. We tested glucagon, insulin, dulaglutide, and a GLP–1R/GCGR dual agonist, Cpd. A, in primary human and cynomolgus monkey hepatocytes. All treatments decreased CYP7A1 expression in monkey hepatocytes. C4 was undetectable in the culture media. Lean mice or rats treated with Cpd. A showed no changes in non–fasting C4. Diet–induced obese mice treated with Cpd. A or a GCGR–null analog had decreased non–fasting C4. To test whether GCGR (and/or GLP–1R) agonism affects plasma C4 in higher species, we infused saline or glucagon (at two different rates) on a background of somatostatin infusion in cynomolgus monkeys dosed with dulaglutide the day before. C4 levels did not differ between treatment groups. To determine whether this lack of an effect was specific to pre-clinical species, T2DM patients were dosed once a week for 4 weeks with a placebo or 2 doses of a second GLP-1R/GCGR dual agonist. There were no statistically significant differences in C4 levels between groups. Hence, in contrast to GCGR antagonists, GCGR and/or GLP–1R agonists did not modulate C4 levels in pre–clinical species or in T2DM patients.

Disclosure

R. Camacho: Employee; Self; Janssen Research & Development. W. Li: None. T. Kirchner: None. R. Zhang: Employee; Self; Janssen Research & Development. F. Bonilla: None. W. Jian: None. B. Gao: None. R. SinhaRoy: Employee; Self; Janssen Research & Development. Employee; Spouse/Partner; Bristol–Myers Squibb Company. Stock/'Shareholder; Self; Merck & Co., Inc.. Stock/Shareholder; Spouse/Partner; Merck & Co., Inc. J. Leonard: Employee; Self; Janssen Research & Development. T. Connolly: None.
FTY720 Treatment Rejuvenates ß-Cell Function and Improves Cardiac Function in Diabetic Nonhuman Primates (NHPs)
Authors: WANG YIXIN , LIU YONGQIANG , WEI QIAO , WANG XIAOLI , SUN GAO , XIAO YONG-FU , YU GUOLIANG , MA ZHONGMIN A.
Published: June 2018

Pancreatic β-cell regeneration is considered as a possible therapy for cure of type 2 diabetes (T2D). It has been reported that administration of FTY720, a sphingosine 1-phosphate (S1P) receptor modulator, to db/db mice led to sustained normalization of hyperglycemia by stimulating β-cell in vivo regeneration through PI3K-dependent regulation of cyclin D3 and p57KIP2. To further evaluate the therapeutic potential of FTY720 in the treatment of T2D, we examined the effects of FTY720 on glucose homeostasis in spontaneous diabetic NHP model. NHPs with mean fasting glucose (FG) level of 249 mg/dL were randomly divided into the control (vehicle) and the FTY720-treatment group. FTY720 was orally administered at 5 mg/kg to diabetic NHPs once per day and the FG and HbA1c levels were measured biweekly. Here we show that FTY720 treatment of diabetic NHPs significantly lowered their FG and HbA1c in two weeks. After 10 weeks of treatment, their FG and HbA1c levels remained low and their glucose tolerance was significantly improved. To determine the effect of FTY720 on β-cell function, IVGTT was performed. Following glucose injection, the insulin levels in the control NHPs barely changed. In contrast, the FTY720-treated NHPs secreted large amount of insulin in response to glucose stimulation, consistent with β-cell in vivo regeneration observed in mice. We also evaluated the cardiac function in these NHPs by echocardiography, from which ejection fraction (EF) and fractional shortening (FS) are found abnormally lower in diabetic NHPs (EF=60% and FS=30%) than that in normal NHPs (EF=68% and FS=43%). After 10 weeks of treatment, however, EF in the treatment group was significantly increased from 60% to 70% and FS from 30% to 38% while these values remained abnormally low in the control group. Our data strongly suggest that FTY720 has a great therapeutic promise for the treatment of T2D with benefit to improve the cardiac function in the patients.

Disclosure

Y. Wang: None. Y. Liu: None. Q. Wei: Employee; Self; Crownbio.Inc.. X. Wang: None. G. Sun: None. Y. Xiao: None. G. Yu: None. Z.A. Ma: None.
A Phase 3 Study to Assess the Efficacy and Safety of Ipragliflozin in Russian Patients with Type 2 Diabetes Mellitus Inadequately Controlled by Metformin
Authors: SHESTAKOVA MARINA V. , WILDING JOHN P. , WILPSHAAR WIM , TRETTER REINER N. , ORLOVA VALERIA L. , VERBOVOY ANDREY F.
Published: June 2018

Aim: To assess the efficacy and safety of ipragliflozin as add-on therapy to metformin in Russian patients with T2DM.

Methods: In this double-blind trial conducted in 14 centers in Russia, 165 patients were randomized 2:1 to ipragliflozin (50 mg/day) or placebo for 24 weeks while continuing metformin. Patients who had HbA1c ≥7.0% at Week 12 received open-label ipragliflozin (50 mg/day) in addition to the blinded drug from Week 12-24.

Results: Significant reductions in HbA1c and body weight from baseline to Week 12 in favor of ipragliflozin were observed; the incidence of AEs was similar in both groups (Table). HbA1c and weight improvements were sustained from Week 12-24 in patients who remained on 50 mg ipragliflozin (mean change from Week 12: 0.16% and -0.48 kg, respectively; p>0.05). Uptitration to 100 mg ipragliflozin led to a further reduction in body weight (mean change from Week 12: -0.65 kg, P=0.004) and an additional 13% (9/69) achieving HbA1c <7% at Week 24. Incidence of AEs was similar in 50 mg (23.7%) and 100 mg groups (24.6%). No clinically significant changes in vital signs were noted during the study.

Conclusion: 50 mg Ipragliflozin added to metformin significantly reduced HbA1c and body weight after 12 weeks and showed a comparable safety profile as placebo. Uptitration to 100 mg/day conferred added benefits with no additional safety concerns.

Table. Efficacy and AE results from baseline to Week 12  Baseline Iprag/PlaceboEOT Week 12 Iprag/PlaceboChange Iprag/Placebo*Adjusted mean difference to placebo (95% CI)*P valueEfficacy endpoints (FAS)HbA1c, %8.40 (0.94)/8.46 (0.96)7.38 (0.90)/7.69 (1.11)-1.01 (0.85)/-0.77 (1.10)-0.26 (-0.53, 0.00)0.048Body weight, kg92.88 (16.25)/89.54 (15.60)90.87 (16.42)/88.92 (14.89)-2.01 (2.47)/-0.62 (2.14)-1.34 (-2.06, -0.61)<0.001Safety endpoints (SAF)AEs, n (%)-32 (29.1)/19 (34.5)- - -Drug-related AEs, n (%)-12 (10.9)/4 (7.3)- - -*ANCOVA model with treatment as fixed effect, center as random effect, and baseline value as covariate. Data are presented as mean (SD) unless stated otherwise. Ipragliflozin (FAS = 109; SAF = 110) and placebo (FAS or SAF = 55). AEs, adverse events; EOT, end of treatment; FAS, full analysis set; Iprag, ipragliflozin; SAF, safety analysis set.

Disclosure

M.V. Shestakova: 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. W. Wilpshaar: Employee; Self; Astellas. R.N. Tretter: Employee; Self; Astellas Pharma Europe B.V.. V.L. Orlova: None. A.F. Verbovoy: None.
Oral Semaglutide Does Not Affect the Bioavailability of the Combined Oral Contraceptive Ethinylestradiol/Levonorgestrel
Authors: JORDY ANDREAS BÔRSTING , BREITSCHAFT ASTRID , CHRISTIANSEN ERIK , GRANHALL CHARLOTTE , HANSEN CILIE W. , HOUSHMAND-OREGAARD AZADEH , BAEKDAL TINE A.
Published: June 2018

Semaglutide is a glucagon-like peptide (GLP-1) analog co-formulated with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC), to allow oral administration. The effect of oral semaglutide on the pharmacokinetics (PK) of the combined oral contraceptive (OC) ethinylestradiol (EE; 0.03 mg)/levonorgestrel (LN; 0.15 mg) was assessed in an open-label, one sequence crossover trial. Healthy post-menopausal females (n=25) received 8 days of OC alone and 8 days of OC with oral semaglutide (dose escalated to steady state at week 6: 1 week at 3 mg dose, 1 week at 7 mg dose, 4 weeks at 14 mg dose). Primary endpoints were the areas under the plasma concentration−time curve for EE and LN during a dosing interval (0−24 h) at steady state (AUC0−24h,SS). Secondary endpoints included other PK parameters, safety and tolerability. Total exposure of EE and LN were similar for OC alone vs. OC with oral semaglutide, and oral semaglutide did not affect the maximum plasma exposure (Cmax,SS) of EE or LN. AUC0−24h,SS and Cmax,SS ratios for EE and LN were within the predefined no effect interval (0.8−1.25) (Figure). Adverse events with oral semaglutide were consistent with previous trials and expected GLP-1 receptor agonist class effects. These data indicate that oral semaglutide did not affect the bioavailability of the combined OC.

Disclosure

A. Bôrsting Jordy: Employee; Self; Novo Nordisk A/S. A. Breitschaft: None. E. Christiansen: Stock/Shareholder; Self; Novo Nordisk A/S. Employee; Self; Novo Nordisk A/S. C. Granhall: Employee; Self; Novo Nordisk A/S. C.W. Hansen: Employee; Self; Novo Nordisk A/S. A. Houshmand-Oregaard: Employee; Self; Novo Nordisk A/S. T.A. Baekdal: Stock/Shareholder; Self; Novo Nordisk A/S. Employee; Self; Novo Nordisk A/S.
Duodenal Mucosal Resurfacing Elicits Improvement in Glycemic and Hepatic Parameters in Type 2 Diabetes—One-Year Multicenter Study Results
Authors: VAN BAAR ANNIEKE C.G. , NIEUWDORP MAX , HOLLEMAN FRITS , DEVIERE JACQUES , CRENIER LAURENT , HAIDRY REHAN , BATTERHAM RACHEL L. , HOPKINS DAVID , GRUNERT LEONARDO RODRIGUEZ , NETO MANOEL GALVAO , VIGNOLO PAULINA , COSTAMAGNA GUIDO , BERGMAN JACQUES J.
Published: June 2018

Aims: Duodenal Mucosal Resurfacing (DMR) is a novel endoscopic procedure which has been shown to improve glycemic control at 6 months in type 2 diabetes (T2D). It is thought to exert insulin-sensitizing effects. DMR entails catheter based circumferential mucosal lifting followed by hydrothermal ablation. This study aimed to extend DMR experience, determining efficacy over 12 months in T2D patients on stable oral glucose lowering treatment.

Methods: Single arm, multicenter study. 46 T2D patients on oral glucose lowering medication received a DMR procedure. Impact on glycemic control (HbA1c and fasting plasma glucose), insulin resistance (HOMA-IR) and liver enzymes (AST and ALT) was determined at baseline and 1, 3, 6, 9, 12 mo post DMR. Glucose lowering medication was kept stable 6 mo post DMR and adjusted according to local guidelines thereafter.

Results: See figure 1. At 12 mo: δHbA1c -1.0±0.2% (p ≤ 0.001), δFPG -41±8 mg/dL (p ≤ 0.001), δHOMA-IR -3.6±0.9 (p = 0.005), δ weight -2.7±0.6kg (p = 0.003), δALT -10±2 (p = 0.005) and δAST -6±2 (p=0.002). DMR was well tolerated with no related serious adverse events or unexpected adverse device events reported.

Conclusions: Single DMR treatment elicited significant and clinically relevant reductions in glycemic and hepatic parameters that were sustained at 12 months, suggesting considerable potential of DMR for the treatment of T2D.

Disclosure

A.C.G. van Baar: None. M. Nieuwdorp: None. F. Holleman: Other Relationship; Self; Sanofi-Aventis, Bioton, AstraZeneca. J. Deviere: None. L. Crenier: None. R. Haidry: None. R.L. Batterham: Research Support; Self; Fractyl Laboratories, Inc.. Board Member; Self; Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; National Institute for Health and Clinical Excellence, Nestlé. Speaker's Bureau; Self; Orexigen Therapeutics, Inc., Medtronic. D. Hopkins: Advisory Panel; Self; Novo Nordisk A/S, Sanofi-Aventis, Roche Pharma. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc., AstraZeneca, Eli Lilly and Company, Napp Pharmaceuticals, Ltd., Sunovion Pharmaceuticals Inc.. Other Relationship; Self; Diabetes UK. Speaker's Bureau; Self; Fractyl Laboratories, Inc.. L. Rodriguez Grunert: None. M. Galvao Neto: Consultant; Self; Fractyl Laboratories, Inc., GI Dynamics Inc., GI Windows, Inc., Ethicon US, LLC., Apollo EndoSurgery. P. Vignolo: None. G. Costamagna: None. J.J. Bergman: Research Support; Self; Fractyl Laboratories, Inc..
Safety and Efficacy of Sitagliptin (SITA) Compared with Dapagliflozin (DAPA) in Subjects with T2D, Mild Renal Impairment, and Inadequate Glycemic Control on Metformin (MET) ± a Sulfonylurea (SU)
Authors: SCOTT RUSSELL S. , MORGAN JERRY D. , ZIMMER ZACHARY , LAM RAYMOND L.H. , O'NEILL EDWARD A. , KAUFMAN KEITH D. , ENGEL SAMUEL S. , RAJI ANNASWAMY
Published: June 2018

While choice of AHAs may be modified in patients with T2D and moderate or severe renal insufficiency, this is generally not the case in patients with mild renal insufficiency. Clinical trial data focused on this population, which represents ∼40% of patients with T2D, are lacking.

In a randomized, double-blind, active comparator-controlled clinical trial, the safety and efficacy of adding SITA (100 mg qd) or DAPA (10 mg qd) to treatment of patients with eGFR ≥60 and <90 mL/min/1.73 m2 and A1C ≥7.0% and ≤9.5% while on MET ± SU were assessed. The primary efficacy endpoint was change from baseline A1C at Week 24 (analyzed with a constrained longitudinal data analysis model), with a primary hypothesis of non-inferiority of SITA to DAPA based on the prespecified criterion of the upper bound of the between-treatment difference 95% CI (SITA minus DAPA) <0.3%; if the upper bound was <0.0%, SITA would be declared superior.

Treatment groups were well-balanced at baseline (n = 307 and 306, mean A1C [%] = 7.7 and 7.8, mean eGFR [mL/min/1.73 m2] = 79.4 and 76.9 for SITA and DAPA, respectively). At Week 24, LS mean changes from baseline A1C were -0.51% (SITA) and -0.36% (DAPA); between-group difference = -0.15%, 95% CI (-0.26, -0.04), p=0.006, confirming both non-inferiority and superiority of SITA vs. DAPA. The pre-specified analysis of 2 hour post-prandial glycemic excursion showed no significant difference between groups. The A1C goal of <7% was met by 43% (SITA) and 27% (DAPA) of patients. Treatments were well tolerated; there were significantly fewer patients with drug-related adverse events (AEs) with SITA than with DAPA, but summary AE profiles were otherwise similar.

In summary, SITA treatment over 24 weeks resulted in greater glycemic efficacy and greater % of patients at A1C goal than DAPA in patients with T2D and mild renal impairment who were inadequately controlled on MET ± SU.

Disclosure

R.S. Scott: None. J.D. Morgan: Employee; Self; Merck & Co., Inc. Z. Zimmer: Employee; Self; Merck & Co., Inc. R.L.H. Lam: Employee; Self; Merck & Co., Inc. E.A. O'Neill: Employee; Self; Merck & Co., Inc. K.D. Kaufman: Employee; Self; Merck & Co., Inc. S.S. Engel: Employee; Self; Merck & Co., Inc.. Stock/Shareholder; Self; Merck & Co., Inc. A. Raji: Employee; Self; Merck & Co., Inc..