bluuebunny/crossref_metadata_2025_split 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&lt;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&lt;0.001) (Figure 1). More subjects receiving Insulin Therapy failed to achieve the A1c goal &lt;7% (63% vs. 22%, p&lt;0.0001). Despite lower A1c, subjects receiving EXEN + PIO had lower rate of hypoglycemia (P&lt;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 &gt;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 &gt;240 and BG &lt;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 &lt;7021 (2.3)4 (0.4)&lt;0.001BG 71–9963 (7)99 (10)0.019BG 100–180 (%hIGR)399 (44)545 (56)&lt;0.001BG 181–240232 (26)244 (25)0.748BG &gt;240184 (21)82 (8)&lt;0.001Daily BG profiles, mean±SD mg/dLFasting131±38127±400.254After breakfast244±61196±540.004Before lunch216±65173±56&lt;0.001After lunch195±62182±540.041Before dinner135±47143±440.232After dinner203±62177±54&lt;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 &lt;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 &gt;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 &gt;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 &gt;9% at baseline to determine the impact of IDegLira on their glycemic control. Within each DUAL trial, baseline characteristics for patients with A1C &gt;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 &lt;7% without hypoglycemia (DUAL I, II and V: unable to self-treat and/or plasma glucose [PG] &lt;56 mg/dL; DUAL VII: unable to self-treat or PG &lt;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 &gt;9%, IDegLira treatment achieved glycemic control with a high proportion of patients achieving A1C &lt;7% and clinically important composite endpoints of A1C &lt;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 (&lt;7.3; 7.3-&lt;10.7; 10.7-15.7; &gt;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&lt;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&lt;0.0001). In pts grouped by T2D duration and insulin dose, those with both long duration (&gt;15.7 years) and high dose (&gt;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 &lt;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 (&gt;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 (&lt;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.