bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness of Insulin Glargine U300 Used as Part of Basal Bolus Therapy in People with T2DM—Toujeo 6 Months Real-World Data From Hungary
Authors: HIDVEGI TIBOR , STELLA PETER
Published: June 2018

The EDITION program demonstrated similar efficacy with lower risk of hypoglycemia (HG) of insulin glargine U300 (Gla-300) compared to insulin glargine U100 in T2DM. Data prospectively collected on real world use of Gla-300 are still of scarce. This single-arm, non-interventional, observational study aimed to describe the effectiveness of Gla-300 in real world setting in people with advanced T2DM. Data on HbA1c, fasting BG, weight (BMI), insulin doses and HG were collected for 6 months in routine clinical care in Hungary from 229 people with T2DM (age: 60.9 years±10.4, diabetes duration:13.4 years±7.9, being on insulin for: 7.4 years±6.2, HbA1c: 8.9%±1.5, BMI: 32.5kg/m2±5.7 (mean±SD)) previously treated with human basal-bolus (BB) regime (NPH+regular insulin) who were switched to analogue BB with Gla-300 and insulin glulisine. Data on safety and efficacy were available for 217 (95%) and 189 (83%) patients, respectively. Reasons for switching were: uncontrolled diabetes (68%), HG (15%), combination of the two (17%). By Month 6, HbA1c decreased by 1.36% (-1.55; -1.17), (mean+95% CI), fasting BG by 47 mg/dl (-57; -37), (p<0.001 for both), while BMI decreased by 0.28 (-0.68; 0.13, NS). An HbA1c of 8.0%, the glycemic target for long term reimbursement for insulin analogues was achieved in 78% of the patients. Daily basal dose (U) was increased from 34.5 to 41.0, bolus dose remained the same (+0.13, (+0.3%)). From safety perspective, proportion of patients with documented (severe/non-severe) HG (BG≤70mg/dl) decreased from 44.2% to 27.6% (change in HG incidence: patients with HG within the preceding 3 months before switching vs. patients with HG during follow-up). The effectiveness of Gla-300 in routine clinical care was consistent with results from the EDITION program. When used concomitantly with glulisine, Gla-300 provided a clinically significant HbA1c reduction alongside with a decreased risk of hypoglycemia allowing 78% of patients to reach an HbA1c goal ≤8%.

Disclosure

T. Hidvegi: None. P. Stella: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi.
The Challenges and Potential of Digital Therapeutic Solutions for Long-Acting Insulin Management
Authors: KANCHI ARATI , PARKS LINDA , SHENG TONG , SMITH JANE LEA , GREENFIELD MICHAEL
Published: June 2018

Starting on long acting insulin (LAI) can be difficult for people with type 2 diabetes (PWT2D). Delayed treatment initiation, imprecise titration, and poor adherence to therapy can lead to inadequate glycemic control. While emerging digital therapeutic solutions aim to help clinicians and PWT2D achieve optimal individualized LAI regimens, real world use of these solutions remains unknown. In this human factors validation study, we present findings on the Mobile Insulin Dosing System (MIDS), a mobile app module designed to reduce the manual burden of LAI titration. Sixteen PWT2Ds (age: 35-70 years) participated in the study. Participants were introduced to MIDS without training. Six real world use scenarios related to LAI management were presented with simulated data. Participants worked through each task using MIDS without assistance. Task performance was measured. Three out of six tasks had 100% success rates and the remaining three tasks had success rates from 73.3-87.5%. Three participants had 100% success rate despite having no prior experience with insulin therapy. All participants endorsed MIDS to be straightforward, easy to use, and effective for insulin management. Among unsuccessful tasks, the individual’s mental model of LAI adjustment was the common root cause. Some PWT2Ds did not understand that LAI is adjusted based on the fasting blood glucose (BG) only and assumed that non-fasting BG readings should also be included. Confidence in self titration was also a risk factor. Overall, MIDS proved to be simple, effective, and easy to use for PWT2Ds of varying ages, LAI experience, and smartphone use. Observed failure risks were related to poor understanding of diabetes and insulin regimens in general and not with the mobile implementation per se. Minimizing these risks, in addition to those inherent to manual recall and entry of BG readings, can enhance the use of digital therapeutic solutions for LAI therapy management.

Disclosure

A. Kanchi: Employee; Self; Glooko, Inc. L. Parks: Employee; Self; Glooko, Inc. T. Sheng: Employee; Self; Glooko, Inc.. J. Smith: None. M. Greenfield: Stock/Shareholder; Self; Glooko, Inc..
Impact of Insulin Therapy Assistance Program, a Patient Support Program, on 10,426 Indian T2DM Patients to Assess Safety and Efficacy with Biosimilar Insulin
Authors: JABEEN SARAH , PAWAR DILIP , SHIVARAM VS , RAJ PRAVEEN
Published: June 2018

Introduction: Insulin Therapy Assistance Program (iTAP) is a structured Patient Support Program (PSP) designed by Biocon for T2DM patients receiving insulin therapy. The contact program trained the patients on essentials of diabetes, life style management including diet, importance of exercise and general care by trained and certified health care providers.

The aim of this study is to understand efficacy and safety of insulin (Biosimilar) treatment in patients with T2DM with PSP.

Method: A total of 10,426 patients were enrolled over a four-year period. These patients were observed at 3, 6 and 9 months post-initiation. This study presents the improvements in the glycaemic parameters—blood glucose, glycated haemoglobin (HbA1c) and body weight in patients on insulin therapy over 9 months follow-up period. Patients in the PSP received either human insulin (Insugen) or basal insulin (Basalog). The mean blood glucose, glycated haemoglobin and body weight were analysed for any differences with respect to the type of insulin.

Results: The mean (SD) blood glucose (mg%) significantly reduced (p<0.05) with insulin initiation from 183.78 (54.74) at baseline to 145.15 (33.79) at 3 months and 132.80 (29.38) at 6 months and 133.98 (25.13) at 9 months. Similarly, the HbA1c reduced (p<0.05) from 10.10% (1.75) at baseline to 7.85% (1.06) at the end of 9 months. Minimal changes were observed in the bodyweight.

Conclusion: It was observed with iTAP, there was an overall significant improvement in the glycaemic parameters when therapy was aided with a PSP. Insulin therapy in this study proved to be safe and well tolerated in patients with T2DM. The preponderance of evidence that is glycaemic control and low risk of hypoglycaemia suggest a positive impact of PSP on clinical outcomes which aid patients stand to benefit from participation.

Disclosure

S. Jabeen: Employee; Self; Biocon. D. Pawar: Employee; Self; Biocon. S. Vs: Employee; Self; Biocon. P. Raj: Employee; Self; Biocon.
Relative Contribution of Basal and Postprandial Hyperglycemia Stratified by A1C Categories Before and After Treatment Intensification with Dulaglutide
Authors: UMPIERREZ GUILLERMO E , PANTALONE KEVIN M , ATISSO CHARLES , LANDO LAURA FERNANDEZ , PATEL HIREN
Published: June 2018

Dulaglutide (DU) has demonstrated non-inferiority vs. liraglutide (LIR) and superiority vs. exenatide BID (EXE) in A1c reduction. No data are available on how GLP-1RAs affect the relative contribution of basal hyperglycemia (BHG) and post-prandial hyperglycemia (PPHG) to overall hyperglycemia (OHG) across A1c categories. Data from five phase 3 studies (N=673) were pooled to assess the change in relative contributions of BHG and PPHG to diurnal OHG across different A1c categories after 6 months of treatment intensification with DU 1.5 mg as monotherapy or with oral medication(s) in patients with type 2 diabetes. BHG and PPHG were calculated using the area under the curve of the 7-point SMPG profiles. As a secondary objective, overall change in BHG for DU vs. LIR and DU vs. EXE was assessed by individual studies. At baseline, relative contributions of BHG increased and PPHG decreased with increasing A1c levels (Figure). After 6 months of treatment with DU, this pattern was maintained, despite 1.3% overall mean A1c reduction. At 6 months, the relative contribution of BHG and PPHG were similar between LIR and DU, whereas DU had lower BHG but higher PPHG contribution than EXE. The trend of relative contribution of PPHG and BHG across A1c categories is similar before and after DU treatment intensification, implying its effect on both BHG and PPHG to lower A1c.

Disclosure

G.E. Umpierrez: Research Support; Self; Sanofi US, Merck & Co., Inc., Novo Nordisk Inc., AstraZeneca. Advisory Panel; Self; Sanofi, Intarcia Therapeutics, Inc. K.M. Pantalone: Consultant; Self; Merck & Co., Inc.. Speaker's Bureau; Self; Merck & Co., Inc.. Research Support; Self; Merck & Co., Inc.. Speaker's Bureau; Self; AstraZeneca. Consultant; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Sanofi. Speaker's Bureau; Self; Sanofi. C. Atisso: Employee; Self; Eli Lilly and Company. L. Fernandez Lando: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. H. Patel: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.
Achieving Composite Endpoint of A1C <7.0% without Weight Gain or Hypoglycemia with Once-Weekly Dulaglutide in Chinese Patients with Type 2 Diabetes—Post-Hoc Analysis
Authors: XIAO XINHUA , WANG CHANGJIANG , WANG FENG , LI PENGFEI , GU LIQUN
Published: June 2018

This post-hoc analysis of 2 randomized trials of the once weekly glucagon-like peptide-1 receptor agonist dulaglutide (DU) assessed the proportion of Chinese patients with type 2 diabetes (T2D) achieving a composite endpoint of glycated hemoglobin (A1C) <7.0%, no weight gain (≤0 kg), and no hypoglycemia (confirmed glucose ≤3.9 mmol/L or report of severe hypoglycemia) after 26 or 52 weeks of treatment with DU 1.5 mg or 0.75 mg vs. glimepiride (GLIM) or insulin glargine (GLAR). Patients in the DU vs. GLIM study (n = 556) were treatment-naive or discontinued from oral monotherapy; those in the DU vs. GLAR study (n = 591) continued on metformin and/or sulfonylurea. Analyses in each trial were on modified intent—to-treat population; missing values were imputed using last observation carried forward. Significantly (p<.001, Fisher’s exact test) more patients achieved the composite endpoint with DU 1.5 mg or 0.75 mg vs. GLIM after 26 weeks (47.8% and 39.2% vs. 19.9%), as well as vs. GLAR after 26 weeks (39.5% and 30.1% vs. 14.9%) and after 52 weeks (26.0% and 23.0% vs. 6.7%). Similar results were observed for composite endpoints of A1C <7.0% and no weight gain, and A1C <7.0% and no hypoglycemia. Dulaglutide is an effective treatment option for Chinese patients with T2D, resulting in a large proportion of patients reaching A1C targets without weight gain or hypoglycemia.

Disclosure

X. Xiao: None. C. Wang: None. F. Wang: None. P. Li: Employee; Self; Eli Lilly and Company. L. Gu: Employee; Self; Eli Lilly and Company.
ZGN-1061 Improves Metabolic Parameters and Hepatic Pathology in an Obese Mouse Model of Diet-Induced and Biopsy-Confirmed Nonalcoholic Steatohepatitis
Authors: BURKEY BRYAN F. , ILLEMANN MARTIN , VEIDAL SANNE , FEIGH MICHAEL , VATH JAMES , HUGHES THOMAS E.
Published: June 2018

ZGN-1061 (1061) is a methionine aminopeptidase 2 (MetAP2) inhibitor being developed to improve glycemic control in type 2 diabetes. In diet-induced obese mice, 1061 reduces fat mass and improves glycemic control, lipid metabolism, and other metabolic parameters. This study investigated 8 weeks of treatment with 1061 (0.3 mg/kg, SC, N=11) or vehicle (N=10) on metabolic parameters, hepatic pathology, and nonalcoholic fatty liver disease (NAFLD) activity score (NAS; composite measure of steatosis, inflammation, and ballooning degeneration; range 0-8) in male mice with diet-induced and biopsy-confirmed nonalcoholic steatohepatitis (DIO-NASH). At week 8, there was a vehicle corrected weight loss of 13.1% with 1061 (p<0.001). 1061-treated mice had reduced liver weight (mean±SE: 2.6±0.4 g) vs. vehicle (3.8±0.8 g, p<0.001) and 21% reduction of liver triglyceride (p<0.05). There was no change in food intake. NAS was unchanged in vehicle-treated mice (BL 6.2±0.1, Wk8 6.4±0.2, ns). 1061-treated mice had reduced NAS (BL 6.2±0.2, Wk8 5.0±0.3, p=0.002). Two of the NAS component measures improved: steatosis in vehicle-treated mice was unchanged (BL 3.0±0.0, Wk8 3.0±0.0, ns), whereas ZGN-1061 reduced steatosis (BL 2.9±0.1, Wk8 2.5±0.2, p=0.02), and hepatocellular ballooning was unaffected in vehicle-treated mice (BL 0.7±0.2, Wk8 0.6±0.2, ns), whereas 1061 significantly reduced ballooning severity (BL 0.6 ± 0.2, Wk8 0.0 ± 0.0, p=0.006). There was no treatment effect on fibrosis stage or liver collagen 1A. However, liver galectin-3 was reduced with 1061 vs. vehicle. 1061 produced a reduction in terminal plasma ALT and AST vs. vehicle. In DIO-NASH mice, 1061 markedly reduced body weight in conjunction with liver weight and triglyceride content. Importantly, 1061 improved liver function, steatohepatitis and NAS composite score. These findings introduce 1061 as a promising therapy for obesity-related NASH.

Disclosure

B.F. Burkey: Employee; Self; Zafgen. M. Illemann: None. S. Veidal: None. M. Feigh: None. J. Vath: Employee; Self; Zafgen. Stock/Shareholder; Self; Zafgen. T.E. Hughes: Board Member; Self; Zafgen. Employee; Self; Zafgen. Stock/Shareholder; Self; Zafgen.
MEDI0382, a GLP-1/Glucagon Receptor Dual Agonist, in Patients with Type 2 Diabetes—A Multiple-Ascending-Dose Study
Authors: ROBERTSON DARREN , STUMVOLL MICHAEL W , POSCH MAXIMILIAN G , HEISE TIM , PLUM-MOERSCHEL LEONA , KLEIN GERNOT , TSAI LAN-FENG , PETRONE MARCELLA , HIRSHBERG BOAZ , RONDINONE CRISTINA , PARKER VICTORIA E , JERMUTUS LUTZ , AMBERY PHILIP
Published: June 2018

MEDI0382 is a GLP-1/glucagon receptor dual agonist under development for the treatment of type 2 diabetes mellitus (T2DM). This double-blind study (NCT02548585) evaluated MEDI0382 in T2DM patients with BMI 27-40 kg/m2. Subjects (n = 61) were randomized to once-daily subcutaneous MEDI0382 or placebo (PBO) at different dosing levels and uptitration schedules (100 μg [C1], 150 μg [C2], 200 μg [C3], and 300 μg (2 uptitration schedules, C4 and C5). Marked reduction in fasting and postprandial glucose was achieved with a ∼40% decrease in glucose AUC0-4h after mixed-meal testing across all cohorts (P ≤ 0.0102) (Figure 1A). Weight loss was observed at all dose levels and reached statistical significance (P = 0.024) at 300 μg (C4) (Figure 1B). Ambulatory systolic blood pressure decreased nonsignificantly from baseline in the 300-μg cohort (C4, -4.9 vs. -6.5 mmHg; C5, -9.1 vs. -5.0 mmHg). Similar to other marketed GLP-1 analogs, MEDI0382 increased pulse rate vs. PBO (C4, 8.4 vs. -2.4 BPM, P = 0.0039; C5, 5.8 vs. 0.2 BPM, P = 0.0796). Treatment-related adverse events occurred more often with MEDI0382 vs. PBO (86% [36/42] vs. 47% [9/19]); most events were mild or moderate in severity.

In conclusion, MEDI0382 administered for up to 22 days showed a marked reduction in both fasting and postprandial glucose with weight reduction and an acceptable tolerability profile.

Disclosure

D. Robertson: Employee; Self; MedImmune. Employee; Spouse/Partner; GlaxoSmithKline plc. M.W. Stumvoll: Speaker's Bureau; Self; Novartis Pharmaceuticals Corporation. Advisory Panel; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; Merck Foundation. M.G. Posch: None. T. Heise: Research Support; Self; ADOCIA, Boehringer Ingelheim GmbH, Dance Biopharm, Eli Lilly and Company, Janssen Research & Development, MedImmune, Merck Sharp & Dohme Corp., Mylan, Nordic Bioscience, Novo Nordisk A/S, Poxel SA, Roche Diagnostics Corporation, Saniona, Sanofi, Senseonics, Zealand Pharma A/S. Advisory Panel; Self; Novo Nordisk A/S, Mylan. Speaker's Bureau; Self; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk A/S, Sanofi. L. Plum-Moerschel: None. G. Klein: None. L. Tsai: Employee; Self; MedImmune. M. Petrone: Employee; Self; MedImmune. Stock/Shareholder; Self; MedImmune. B. Hirshberg: Employee; Self; AstraZeneca, MedImmune. C. Rondinone: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca, F. Hoffmann-La Roche Ltd., Abbott, AbbVie Inc. V.E. Parker: Employee; Self; MedImmune. Stock/Shareholder; Self; Accenture. Employee; Self; AstraZeneca. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. P. Ambery: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca.
Short Duration of Diabetes Should Be Associated with More Prominent Effect of Liraglutide—Titrated from Insulin Degludec plus Liraglutide Combination Therapy
Authors: KASHIMA KOJI , SHIMIZU HIROYUKI , YAMADA MASANOBU
Published: June 2018

Objective: In management of type 2 diabetes (T2DM), controlling HbA1c <7% is required. We examined effectiveness of insulin degludec (DEG) plus liraglutide (LIRA) combination therapy in Japanese T2DM patients.

Methods: Hospitalized hyperglycemic 55 patients with T2DM who started this therapy were randomly recruited. Changes of HbA1c, Insulin doses, and ADRR in patients who did self-blood glucose monitoring (SMBG) were evaluated for a year after discharge. Since preserved β-cell function might influence the effect, effectiveness was compared by duration of T2DM ≤ 5 year (n=27) or ≥ 6 year (n=28).

Results: 1) Baseline characteristics: Patients with short duration (SHORT) were younger (62±9.5 vs. 69.9±11.8 years old: p<0.05), had shorter duration (0.44±1.3 vs. 17.1±9.3 year:p<0.01), higher urinary C-peptide (91.1±4.6 vs. 47.0±30μg/day: p<0.01), higher HbA1c (12.4±2.5 vs. 11.0±2.3%: p<0.05), and lower final dose of liraglutide (0.68±0.18 vs. 0.78±0.17mg/day: p<0.05) compared with long duration (LONG) group. 2) Mean HbA1c in 55 patients have reached the target from 3rd month to 12th month. 3) Although daily glucose excursions at discharge and mean body weight were identical throughout a year in 2 groups, HbA1c in SHORT group dramatically improved after discharge. The average of HbA1c was maintained ≤ 6.0% from 4th month to 12th month. 4) Patients with HbA1c ≤ 6.0% using SMBG showed lower ADRR scores (1∼9). 5) The combined use of DEG and its dose gradually decreased in SHORT group, one third of patients could quit DEG at 6th month and over half at 12th month, but none in LONG group. 6) Although Long group had higher rates of chronic kidney disease (CKD) 46.4% and ischemic heart disease (IHD) 28.5%, SHORT group still had high rates of CKD 22.2% and IHD 18.5%.

Conclusion: Since T2DM is a complex metabolic disorder, prominent effect of LIRA in the patients with short duration is supportive for GLP-1 receptor agonists as a first-line therapy.

Disclosure

K. Kashima: None. H. Shimizu: Speaker's Bureau; Self; Eli Lilly and Company, MSD K.K., Daiichi Sankyo Company, Limited, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Inc.. M. Yamada: None.
Medication Compliance on Glycemic Control in Patients with Elevated HbA1c
Authors: ELHASSAN AHMED , ABREU MARCONI , TUMYAN ANNA , PAPACOSTEA OLIVIA , PEICHER KATHERINE , DIMACHKIE PERIHAN , SIDDIQUI MUHAMMAD S. , ADAMS-HUET BEVERLEY , LI XILONG , POP LAURENTIU , LINGVAY ILDIKO
Published: June 2018

The SIMPLE study was a randomized trial comparing two treatment strategies [basal insulin (BI) + GLP-1 RA vs. basal-bolus insulin (BBI)] in patients with T2DM and very elevated HbA1c (>10%). The glucose lowering agents were provided free of charge for the 6-month study. This post-hoc analysis evaluates compliance with the assigned glucose lowering agents, and the effect of compliance on glycemic control. Compliance was assessed by inventory of the returned medication. Optimal compliance was defined as >80% use of the respective agent over the entire duration of the study. Mixed model repeated measures analysis with compliance as a covariate was used to evaluate the treatment effect on HbA1c.

The 120 randomized patients had a mean (SD) age 47.4 (9.5) years, BMI 37.2 (10.3) kg/m2, and baseline HbA1c 12.1 (1.4)%. The proportion of patients with optimal compliance with basal insulin was numerically higher in the BI+GLP-1 RA vs. BBI group (p=0.16); optimal compliance with GLP-1 RA was higher compared to bolus insulin (p=0.04) (Table). Compliance was an independent predictor for glycemic improvement (P = 0.008); treatment with BI+GLP-1 RA was superior at lowering HbA1c after adjustment for compliance (P = 0.01).

Optimal compliance was low in this patient population. While compliance was a significant contributor to glycemic control, treatment with BI+GLP-1 RA improved HbA1c more than BBI independent of medication compliance.Table. Patients with optimal compliance with glucose lowering agents (>80% over the 6-month study duration) in the two treatment groups (basal insulin + GLP1 RA compared with basal-bolus insulin) and the effect of compliance on glycemic control.Basal-Bolus Insulin Group(BBI, n=56a)Basal Insulin + GLP1 RA Group (BI+GLP1 RA, n=54a)Patients with optimal compliance:Basal Insulin8 (14.3)14 (25.9)Bolus Insulin6 (10.7)NAGLP1 RANA14 (25.9)Change in HbA1c:Adjusted for compliance- 3.1 (-4.0,-2.2)- 4.5 (-5.2,-3.8)Optimal Compliance subgroup-3.2 (-4.8,-1.6)-5.4 (-6.6, -4.2)Low Compliance subgroup-3.0 (-3.7,-2.3)-3.6 (-4.4,-2.8)Data are Least squares means (95%CI) or N (%); NA - Not applicable. acompliance data available for n=110 (intention-to-treat analysis sample).

Disclosure

A. Elhassan: None. M. Abreu: None. A. Tumyan: None. O. Papacostea: None. K. Peicher: None. P. Dimachkie: None. M.S. Siddiqui: None. B. Adams-Huet: None. X. Li: None. L. Pop: None. I. Lingvay: Advisory Panel; Self; Novo Nordisk A/S, Eli Lilly and Company, AstraZeneca, Intarcia Therapeutics, Inc., Sanofi-Aventis. Research Support; Self; Novo Nordisk A/S, Merck Sharp & Dohme Corp., Pfizer Inc., GI Dynamics Inc., Novartis AG. Other Relationship; Self; Sanofi, AstraZeneca, Boehringer Ingelheim GmbH, Novo Nordisk A/S.
ZGN-1061, a Novel MetAP2 Inhibitor, and Liraglutide Combine to Improve Glycemic Control and Reduce Body Weight in a Rat Model of Diet-Induced Obesity
Authors: BURKEY BRYAN F. , PEDERSEN PHILIP J. , PEDERSEN TANJA X. , FEIGH MICHAEL , VATH JAMES , HUGHES THOMAS E.
Published: June 2018

ZGN-1061 (1061) is a methionine aminopeptidase 2 (MetAP2) inhibitor being developed to improve glycemic control in T2D. This study investigated 5 weeks (weeks) of once-daily SC treatment with a submaximal 0.3 mg/kg dose of 1061, a maximal 0.4 mg/kg dose of liraglutide (lira), 1061+lira, or vehicle (N=10/group) on body weight (BW), food intake/preference, and glycemic control in the Gubra diet-induced obese (DIO) rat model (ad libitum fed chow and highly palatable high-fat, high-sugar [HFHS] diet). Fasting (4 hour) blood glucose (FBG) was collected weekly and a semifasted (16 hour access to 50% of daily energy requirement) OGTT was performed at week 4. At week 5 (day 33), BW changed by +1.7% with vehicle vs. -6.0% with 1061, -9.1% with lira, and -16.9% with 1061+lira (all p<0.001). BW loss occurred earlier with lira (day 1) than 1061 (day 5). Starting at day 6, intake of the HFHS diet was modestly reduced (15-30%) with 1061 vs. vehicle. In contrast, lira and 1061+lira induced rapid and sustained 40-50% and 50-80% reductions in intake of the HFHS diet, respectively, over the first 8-9 days. Cumulative (day 0-35) HFHS diet intake was reduced vs. vehicle by 1061 (13.4%, p=0.07), lira (17.8%, p<0.01), and 1061+lira (38.2%, p<0.001). Cumulative chow intake was increased by 1061 and 1061+lira but not lira alone. There was a modest reduction in FBG (mean week 1-5) with 1061 vs. vehicle (p=0.08), a significant reduction with lira, and 1061+lira produced the largest reduction (both p<0.001) that was significantly lower than either agent alone (both p<0.01). In the OGTT, 1061 reduced the glucose AUC vs. vehicle by 37% (p=0.07), lira by 60% (p<0.001), and 1061+lira by 80% (p<0.001), achieving an AUC that was no different from lean rats. In this DIO rat model, 1061 and lira had complementary effects on reducing BW and normalizing glycemic control. Combination treatment with 1061 and liraglutide may yield greater weight loss and glycemic control than either agent alone in patients with T2D.

Disclosure

B.F. Burkey: Employee; Self; Zafgen. P.J. Pedersen: None. T.X. Pedersen: Employee; Self; Gubra. M. Feigh: None. J. Vath: Employee; Self; Zafgen. Stock/Shareholder; Self; Zafgen. T.E. Hughes: Board Member; Self; Zafgen. Employee; Self; Zafgen. Stock/Shareholder; Self; Zafgen.
LIRA-PRIME Trial Design and Baseline Data—Efficacy in Controlling Glycemia with Liraglutide in a Primary Care Setting
Authors: UNGER JEFF , LOWE DEREK , MURPHY GERRI , PANDA JAYANT KUMAR , SARGIN MEHMET , KALTOFT MARGIT , TREPPENDAHL MARIANNE , ZOGHBI MAROUAN
Published: June 2018

Despite the majority of patients with type 2 diabetes (T2D) being treated in primary care, clinical evidence to guide treatment decisions is still scarce in this setting.

LIRA-PRIME (NCT02730377), a 104-week, randomized (1:1), open-label, active-controlled trial in primary care, compares the efficacy of liraglutide vs. oral antidiabetic drugs (chosen by the investigator) in controlling glycemia in patients with T2D inadequately controlled with metformin alone. Besides an A1C of 7.5-9.0% within 90 days prior to screening, the pragmatic approach of the trial includes few inclusion and exclusion criteria, treatment according to local labels, quarterly visits after week 26, and trial product dispensing by retail pharmacy. Primary endpoint is time to inadequate glycemic control, defined as A1C >7.0% at two scheduled consecutive visits after the first 26 weeks of treatment.

The trial randomized 1997 patients from 9 countries. The broad distribution of baseline characteristics, e.g., age range of 19.0-89.0 years, reflects the study design and heterogeneity of patients treated in primary care (Table).

LIRA-PRIME will provide data-currently lacking-from primary care regarding the efficacy of liraglutide in controlling glycemia in patients with T2D inadequately controlled with metformin alone. A population with such broad baseline characteristics is well suited for this investigation.

Disclosure

J. Unger: Advisory Panel; Self; Novo Nordisk A/S, Abbott. Consultant; Self; Novo Nordisk A/S, Abbott. Research Support; Self; Novo Nordisk A/S, Janssen Pharmaceuticals, Inc., Sanofi-Aventis, Merck & Co., Inc., Abbott, Mylan. Speaker's Bureau; Self; Novo Nordisk A/S, Janssen Pharmaceuticals, Inc.. Stock/Shareholder; Self; Novo Nordisk A/S. D. Lowe: Consultant; Self; Novo Nordisk A/S. G. Murphy: None. J. Panda: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim GmbH, Sanofi, Eli Lilly Ltd.. Employee; Self; Department of Health & Family Welfare, Govt. of Odisha, India. Research Support; Self; Novo Nordisk India Ltd. M. Sargin: Speaker's Bureau; Self; Novo Nordisk A/S, AstraZeneca. M. Kaltoft: Employee; Self; Novo Nordisk A/S. M. Treppendahl: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. M. Zoghbi: Advisory Panel; Self; Novo Nordisk A/S. Research Support; Self; Pharmaline. Speaker's Bureau; Self; Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, AstraZeneca, Novo Nordisk A/S. Advisory Panel; Spouse/Partner; AbbVie Inc., NewBridge.
Distinct Patterns of Daily Glucose Variation by Pubertal Stage in Youth with Type 1 Diabetes (T1D)
Authors: ZHU JIA , VOLKENING LISA , KATZ MICHELLE , LAFFEL LORI M.
Published: June 2018

Background: Glucose variability is an emerging risk factor for diabetes complications. As basal insulin requirements vary in youth with T1D by age and time of day, we analyzed daily patterns of glucose variation by pubertal stage in youth with T1D.

Methods: Glucose patterns were assessed using 4 weeks of continuous glucose monitoring (CGM) data from 107 youth ages 8-17 years with T1D for >1 year. Glucose values per hour were expressed as percentages relative to the mean glucose over a 24-hour period. Glucose patterns were compared by pubertal stage (pre-pubertal: Tanner (T) 1, pubertal: T2-4, post-pubertal: T5).

Results: The sample had a mean (±SD) age of 13.1±2.6 years, T1D duration of 6.3±3.5 years, A1c of 7.8±0.8; 88% were pump-treated. Pre-pubertal youth had greater mean standard deviation (86.4±12.0, p=.008) and coefficient of variation (0.43±.05, p=.04) compared to pubertal (79.8±13.4; 0.41±.05) and post-pubertal youth (75.8±13.3; 0.40±.05). There was no difference in mean glucose or A1c by pubertal stage (p >.4). Patterns of glucose variation appear in Figure.

Conclusion: Pre-pubertal compared with pubertal and post-pubertal youth appear to have greater glucose variability independent of A1c, with a notable dawn-dusk pattern. Thus, A1c alone does not seem to capture the full range of glycemic parameters in youth with T1D, highlighting the added value of CGM data when determining optimal insulin doses.

Disclosure

J. Zhu: None. L. Volkening: None. M. Katz: None. L.M. Laffel: Consultant; Self; Eli Lilly and Company, Novo Nordisk Inc., Sanofi US, MannKind Corporation, Roche Diagnostics Corporation, Dexcom, Inc., Insulet Corporation, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Johnson & Johnson Diabetes Institute, LLC..
Effect of Biased GLP-1/Glucagon Receptor Co-agonists on Insulin Secretion
Authors: FAROOQ GALA , JONES BEN , MINNION JAMES S. , BLOOM STEPHEN R.
Published: June 2018

Introduction: The effect of dual GLP-1 and glucagon analogues on insulin secretion remains unclear. Here, we investigated the effect of novel GLP-1 / glucagon receptor (GLP-1R/GCGR) co-agonists on beta cell lines, finding augmented insulin release compared to reference agonist Exendin-4. This effect was related to signalling bias at the GLP-1R.

Methods: GLP-1R/GCGR co-agonists were designed, based on the sequence of oxyntomodulin. INS-1 832/3 beta cells and MIN6B1 beta cells were used to perform 24 hour insulin secretion assays. Ligand-directed signal bias was determined from cyclic adenosine monophosphate (cAMP) and β arrestin-1/2 responses measured by enzyme fragment complementation in CHO-K1 cells expressing GLP-1R or GCGR.

Results: Several co-agonists show enhanced maximal insulin release compared to Exendin-4 (representative co-agonist Peptide A vs. Exendin-4 fold insulin release, normalized to 11mM glucose: INS-1 823/3 cells 4.45 ± 0.24 vs. 2.55 ± 0.22, p = 0.0002; MIN6B1 cells 2.28 ± 0.22 vs. 1.57 ± 0.08, p = 0.002). At the GLP-1 receptor, co-agonists were biased towards cAMP generation, compared to the β arrestin-2 pathway (delta log (τ/KA) -0.70 ± 0.11 [Peptide A], vs. 0.29 ± 0.11 [Exendin-4], p= <0.0001). At the GCGR, no significant change in bias was seen relative to native glucagon.

Conclusion: GLP-1R/GCGR co-agonists show enhanced insulin release in vitro compared to exendin-4. As canonical effects of β arrestin recruitment include desensitisation and loss of cell surface receptors via endocytosis, the observed signal bias with these peptides may be linked to their insulinotropic effect. These findings may inform the design of more potent insulinotropic compounds for therapeutic use in type 2 diabetes.

Disclosure

G. Farooq: None. B. Jones: None. J.S. Minnion: None. S.R. Bloom: None.
Exploring the Efficacy of Efpeglenatide, a Weekly Glucagon–Like Peptide–1 Receptor Agonist (GLP–1RA)–Evidence from Preclinical, Modeling, and Clinical Studies
Authors: ROSENSTOCK JULIO , TRAUTMANN MICHAEL E. , HOMPESCH MARCUS , CHOI IN YOUNG , KANG JAHOON , YOON KUN-HO , SORLI CHRISTOPHER H.
Published: June 2018

Once-weekly (QW), subcutaneous efpeglenatide (efpeg) is a long-acting GLP–1 RA in development for type 2 diabetes (T2D). In vitro studies have shown that efpeg is a superagonist: an agent that can achieve a greater maximal effect than that of the endogenous ligand. Exploratory analyses of preclinical, modeling, and clinical data investigated the effects of efpeg on glycated hemoglobin (HbA1c) and body weight (BW) vs. dulaglutide (dula), liraglutide (lira), and semaglutide (sema) (Table). In preclinical studies, efpeg significantly reduced the increment of HbA1c vs. lira and dula in db/db mice, and reduced BW vs. dula in diet-induced obesity mice. Predictive treatment effects of GLP–1 RAs over 30 weeks (based on modeled data) suggest that efpeg 6 mg QW has a high probability of superiority vs. dula on HbA1c and BW, and similar effects on HbA1c vs. sema; 4 mg QW has a high probability of non-inferiority and superiority vs. dula on HbA1c and BW endpoints, respectively. Analyses of the EXCEED 203 dose-ranging study in T2D suggest that efpeg 4 mg QW is at least non-inferior to lira on HbA1c reduction; safety profiles and effects on BW were comparable.

In conclusion, the efficacy of efpeg in reducing HbA1c and BW is supported by preclinical, modeling, and clinical studies, providing the basis for long-term randomized trials to compare these effects vs. other GLP-1 RAs.

Disclosure

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. M.E. Trautmann: Consultant; Self; ProSciento. Stock/Shareholder; Self; Eli Lilly and Company. Consultant; Self; Hanmi Pharmaceutical, CeQur Corporation, Intarcia Therapeutics, Inc., Servier. M. Hompesch: Other Relationship; Self; Hanmi Pharmaceutical. I. Choi: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. J. Kang: Employee; Self; Hanmi Pharmaceutical. K. Yoon: None. C.H. Sorli: Employee; Self; Sanofi.
Health State Utilities Associated with Attributes of Weekly Injection Devices and Subdermal Implant for Treatment of Type 2 Diabetes
Authors: RENTZ ANNE M. , CUTTS KATELYN , WASHINGTON KELLIE , BEILLAT MAUD , YU-ISENBERG KRISTINA
Published: June 2018

Cost-utility analyses include health utilities to compare medical treatments. Health utilities, ranging from 0 to 1, represent the strength of a patient’s preference for a drug profile or health-related outcome. Recently glucagon-like peptide-1 (GLP-1) receptor agonists have been used for management of glycemic control in type 2 diabetes (T2DM). Many GLP-1 drugs have similar modes of administration. In contrast, ITCA 650 is an investigational product which is an implantable device that, following subdermal placement, provides continuous delivery of exenatide for 3 or 6 months. The study’s purpose was to estimate health utilities associated with treatment processes of GLP-1s for use in economic models. During a UK-based pilot study, 19 general population (general population) participants completed time trade-off (TTO) interviews to value health states (often called vignettes or scenarios) which were based on literature review, instructions for use, and clinician interviews. A follow-up pilot study was conducted in both general population and T2DM participants to value modified health states. Participants were recruited to ensure equal distribution across gender and education levels. A total of 20 general population and 18 T2DM patients completed face-to-face interviews (general population mean age= 50.7; T2DM mean age = 56.2). Mean utilities (SD) for ITCA-650 were 0.93 (0.06) for T2DM patients and 0.91 (0.11) for the general population. Mean utility scores for injection health states ranged from 0.83-0.92 for T2DM and 0.82-0.91 for general population. Results are higher than others found in the literature for diabetes treatment processes (range: 0.85 to 0.88). A main study with 200 participants will be conducted in early 2018. Results may be useful in cost-utility models comparing the value of treatment processes for patients with T2DM. Findings suggest the TTO method may be used to quantify preferences among different treatment processes.

Disclosure

A.M. Rentz: Other Relationship; Self; Intarcia Therapeutics, Inc., Servier. K. Cutts: None. K. Washington: None. M. Beillat: None. K. Yu-Isenberg: Employee; Self; Intarcia Therapeutics, Inc..
An Allosteric Glucagon Receptor Antagonist, LGD-6972, Displays Biased Receptor Signaling
Authors: VAJDA ERIC G. , ZHI LIN , MARSCHKE KEITH
Published: June 2018

Glucagon receptor antagonists (GRA) are novel molecules in development for the treatment of type 1 and type 2 (T2DM) diabetes. LGD-6972 recently demonstrated robust efficacy in a 12-week, Phase 2 study in T2DM, reducing HbA1c by 1.2% from baseline, with a safety profile more favorable than other GRAs at this stage of development. LGD-6972 is structurally distinct from other small molecule GRAs, containing a sulphonic acid tail (SAT) rather than a carboxylic acid tail (CAT), potentially explaining this finding. We performed computational modeling of LGD-6972 bound to the glucagon receptor (GCGR) and compared it to x-ray crystallography data with receptor bound MK-0893. The SAT of LGD-6972 creates a larger pocket between helix 6 and 7 in the GCGR transmembrane domain, and alters the orientation of helix 8. Activity of LGD-6972, MK-0893 and other SAT and CAT GRAs were examined in cellular models of glucagon-stimulated cAMP accumulation, β-arrestin recruitment, and receptor internalization. All tested GRAs were full (>95%) antagonists of cAMP accumulation. CAT GRAs were full antagonists of β-arrestin (≥96%) and receptor internalization (≥94%). In contrast, SAT GRAs had reduced antagonism of β-arrestin (58-87%) and receptor internalization (6-52%). The relative potency was also altered with greater potency for CAT GRAs on β-arrestin vs. cAMP, whereas the opposite was true for SAT GRAs. Furthermore, a LGD-6972 analog with a CAT and a MK-0893 analog with a SAT displayed CAT- and SAT-like activity, respectively, indicating a clear structure-activity relationship exists, with LGD-6972 displaying receptor-biased signaling. To further investigate the potential differences among compounds, primary human hepatocytes were treated with glucagon or glucagon with MK-0893 or LGD-6972 and gene expression was analyzed by microarray. Broad differences between glucagon and the GRAs were observed and future studies will investigate the effects of SAT and CAT compounds.

Disclosure

E.G. Vajda: Employee; Self; Ligand Pharmaceuticals, Inc. L. Zhi: Employee; Self; Ligand Pharmaceuticals, Inc. K. Marschke: Employee; Self; Ligand Pharmaceuticals, Inc..
OWL833, an Orally Active Nonpeptide GLP-1 Receptor Agonist, Improves Glucose Tolerance by Increasing Insulin Secretion and Reduces Food Intake of Cynomolgus Monkeys
Authors: KAWAI TAKAHIRO , TANINO FUMIHITO , FUKAZAWA MASANORI , OGAWA KOTARO , NAGAO SHUNSUKE , YOSHINO HITOSHI , KOMATSU SHUN-ICHIRO , SUZUKI YOSHIYUKI , KAWABE YOSHIKI
Published: June 2018

Activation of glucagon-like peptide-1 receptors (GLP-1R) is a promising approach for the treatment of type 2 diabetes mellitus (T2D), and several peptide analogues of GLP-1 have been successfully developed. Here we identified a new orally active non-peptide GLP-1R agonist, OWL833, and examined its efficacy in cynomolgus monkeys. The agonistic activity of OWL833 was evaluated by measuring cAMP accumulation in cells expressing mammal GLP-1Rs and other glucagon family receptors. In the cells expressing human or cynomolgus monkey GLP-1R, OWL833 promoted cAMP accumulation to the same level achieved by GLP-1, and its EC50 values for human and cynomolgus monkey GLP-1Rs were the same at 1.1 nmol/L. In contrast, OWL833 showed no stimulatory activity on human glucagon, GIP, and GLP-2 receptors. The predicted bioavailability and T1/2 of OWL833 in human based on rodent and non-rodent experimental data are 30% and ∼18 hour, respectively. After OWL833 followed by glucose was intravenously injected in cynomolgus monkeys, OWL833 decreased the blood glucose level via insulin secretion to the same extent as effective concentrations of exenatide, a GLP-1 peptide mimetic, in clinic. Doses of 0.and 0.1 mg/kg OWL833 given orally to cynomolgus monkeys reduced their food intake by 25% and 45%, respectively, as compared with vehicle group, and the effect on food intake was equal to that of 0.3 and 0.6 µg/kg subcutaneous injections of exenatide. No critical finding was observed in the subchronic toxicity studies in rats and cynomolgus monkeys. These findings demonstrate that OWL833 has full agonistic activity on human and cynomolgus GLP-1R and improves glucose tolerance by stimulating insulin secretion, and that it exhibits an anti-feeding activity similar to exenatide.

In conclusion, OWL833 has potential as a once-daily, orally active, non-peptide GLP-1 receptor agonist.

Disclosure

T. Kawai: Employee; Self; Chugai Pharmaceutical Co., Ltd. F. Tanino: Employee; Self; Chugai Pharmaceutical Co., Ltd. M. Fukazawa: Employee; Self; Chugai Pharmaceutical Co., Ltd. K. Ogawa: Employee; Self; Chugai Pharmaceutical Co., Ltd. S. Nagao: Employee; Self; Chugai Pharmaceutical Co., Ltd. H. Yoshino: Employee; Self; Chugai Pharmaceutical Co., Ltd. S. Komatsu: Employee; Self; Chugai Pharmaceutical Co., Ltd. Y. Suzuki: Employee; Self; Chugai Pharmaceutical Co., Ltd. Y. Kawabe: Employee; Self; Chugai Pharmaceutical Co., Ltd..
Alteration of Gut Microbiota Induced by DPP-4i Treatment Improves Glucose Homeostasis
Authors: LIAO XIAOYU , ZHENG HONGTING
Published: June 2018

Background and Aims: Emerging evidence indicates that the gut microbiota contributes to the occurrence and development of metabolic diseases. While, little is known about the effect of antidiabetic agents on the gut microbiota. In the current study, we investigated the role of DPP-4i and acarbose in modulating the gut microbial community.

Methods: 16S rRNA sequencing was performed to analysis the effect of DPP-4i and acarbose on the gut microbiota in HFD mice. Fecal microbiota transplantation (FMT) from DPP-4i, acarbose, or placebo- treated T2D patients to germ-free (GF) mice was performed to investigate the contribution of the altered microbiota to the antidiabetic effect. Fecal metabolomics were analyzed by untargeted and targeted GC-MS system.

Results: DPP-4i and acarbose changed the gut microbial composition, and the DPP-4i- altered microbiome improved the glucose tolerance, while acarbose- altered microbiome did not. Moreover, DPP-4i primarily reduced the ratio of Firmicutes to Bacteroidetes, and changed the pattern of metabolites in HFD mice, especially the increase of succinate.

Conclusions: Our findings demonstrated that the alterations of the gut microbial composition and metabolites might be a previously unsuspected hypoglycemic mechanism of DPP-4i. It might provide a potential strategy for modulating glucose homeostasis in the future.

Disclosure

X. Liao: None. H. Zheng: None.
Cumulative Delays in Treatment Intensification over Three Typical Stages of Antihyperglycemic Treatment
Authors: VUPPUTURI SUMA
Published: June 2018

Although delays in treatment intensification (TI) have been documented for anti-hyperglycemic medications, cumulative delays over the life course of diabetes treatment have not been reported. We combined 2005-2016 data from the Northwest and Mid-Atlantic regions of Kaiser Permanente to identify 248 patients who: (1) initiated metformin (MET); (2) then added a sulfonylurea (SU) to existing MET; and (3) initiated insulin (INS) after MET or SU. We used the date of the initiation of each stage of therapy to calculate time between A1C ≥7% and TI, pre-TI A1C, post-TI A1C, and achievement of A1C goal ≤7% within one year of TI. We also measured time to intensification within 6 months prior to TI. Mean or median cumulative measures were summed across the three TI stages. Among patients who experienced each stage of MET, SU, and INS intensification, the mean A1C percentage points outside of goal summed to 5.9 (Table). These patients accrued a median of 191 days of TI delays in the 3 6-month periods preceding TI. Although A1C was lowered after each stage of TI, a minority of patients achieved A1C goals of ≤7% resulting in accumulation of a mean of 3.3 excess A1C percentage points over the 3 one year periods after TI of MET, SU, and INS. TI delays occur at every stage of diabetes therapy. Glycemic burden accumulates over the life course of diabetes and may result in differential complication risks. However, further study is needed.

Cumulative TI ExposuresMET initiationSU add-onINS add-onCumulativeMean distance from goal measured during 1 year after TI1.7%1.7%2.5%5.9 %Median days to intensification measured during 6 months prior to TI27.967.795.3190.9Mean Pre-TI A1c8.7%8.7%9.5%--Mean Post-TI A1c7.7%8.5%8.1%--Post-A1c minus A1c goal measured during 1 year after TI0.7%1.5%1.1%3.3%Achieved A1C goal ≤7%35.1%16.9%26.6%--

Disclosure

S. Vupputuri: Research Support; Self; Sanofi US.
The Comparative Cardiovascular Effectiveness of Six Antidiabetic Medications among Insured Adults with Type 2 Diabetes
Authors: O'BRIEN MATTHEW , KARAM SUSAN L. , WALLIA AMISHA , KANG RAYMOND , COOPER ANDREW J. , LANCKI NICOLA , MORAN MARGARET R. , LISS DAVID T. , PROSPECT THEODORE A. , ACKERMANN RONALD T.
Published: June 2018

This retrospective cohort study compared the effectiveness of six antidiabetic medication (ADM) classes on major adverse cardiovascular events. Using nationwide U.S. administrative claims data from 2011-2015, we studied 132,737 insured adults with type 2 diabetes who started one of six ADM after taking metformin alone or no prior ADM. The key exposure was the new ADM class, which was filled ≥2 times. The composite primary outcome included hospitalization for one of the following conditions: heart failure, stroke, ischemic heart disease, and peripheral artery disease. Eligibility criteria and outcomes were ascertained using claims data. We used Cox regression to model the association between new ADM class and composite cardiovascular events, adjusting for baseline characteristics of patients, including prior use of metformin and cardiovascular medications, as well as prescribers and health plans. DPP-4 inhibitors (DPP-4) were the comparator given evidence of their cardiovascular neutrality. Overall, 5.5% of patients had a history of prior cardiovascular disease. There were 3,603 cardiovascular events during a mean follow-up of 1.3 years. Compared to DPP-4, the adjusted hazard ratios for each ADM class were: [sulfonylureas (SFU): HR 1.36, 95% CI: 1.23-1.49; basal insulin: HR 2.03, 1.81-2.27; thiazolidinediones (TZD): HR 0.89, 0.73-1.08; SGLT2 inhibitors (SGLT2): HR 0.80, 0.56-1.14; and GLP-1 receptor agonists (GLP-1): HR 0.78, 0.63-0.96]. The GLP-1 benefit was not robust across alternate modeling approaches. Among low-risk patients with type 2 diabetes, we found higher cardiovascular risk associated with SFU and basal insulin compared to newer ADM classes. Cardiovascular outcomes associated with DPP-4, GLP-1, and SGLT2 were similar in this population. Providers may consider prescribing these newer drugs routinely after metformin. Future clinical trials and data describing total costs of care will further inform providers’ choice of second-line ADM.

Disclosure

M. O'Brien: None. S.L. Karam: Research Support; Self; United Healthcare Services. A. Wallia: Research Support; Self; UnitedHealth Group. Consultant; Self; Glytec Systems, Lexicon Pharmaceuticals, Inc.. Research Support; Self; Eli Lilly and Company. R. Kang: Research Support; Self; UnitedHealth Group. A.J. Cooper: Research Support; Self; UnitedHealth Group. N. Lancki: Research Support; Self; United Healthcare Services. M.R. Moran: Research Support; Self; United Healthcare Services. D.T. Liss: Research Support; Self; United Healthcare Services. T.A. Prospect: Employee; Self; UnitedHealth Group. R.T. Ackermann: Consultant; Self; UnitedHealth Group.