bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Endogenous Insulin Adjustment Methods on the Assessment of Insulin Pharmacokinetics and Pharmacodynamics
Authors: CHUNG SANG M. , PENZENSTADLER JUSTIN A. , KHURANA MANOJ , SAHAJWALLA CHANDRAHAS
Published: June 2018

Assessing reliable insulin pharmacokinetics (PK) and pharmacodynamics (PD) following an exogenous insulin administration is a scientific challenge due to the circulating endogenous insulin. Effect of exogenous insulin on the endogenous insulin through the sensitive glucose homeostatic system in the body could further confound the PK/PD data. We compared results of PK/PD parameters of methods in literature for the estimation of insulin PK and PD, namely total method without adjustment (method 1), a simple baseline method (method 2), elimination rate constant method (method 3), empirical C-peptide correction method (method 4), and conventional PK/PD modeling method (method 5). We also developed new PK/PD modeling method reflecting the effect of glucose on endogenous insulin release based on C-peptide (method 6). Subject-level time-matching insulin and glucose concentrations without external glucose administration were collected from clinical trials with regular human insulin administration to healthy subjects under fasting conditions (n=23). Primary insulin PK parameters (i.e., the maximum concentration (Cmax) and area under the concentration-time profile (AUC)) were estimated using subjects’ insulin, glucose and C-peptide level data. Our results indicate that insulin AUC and Cmax differ by up to 32 and 17%, respectively, among different methods. Further, the contribution of endogenous insulin to total insulin AUC is estimated to be approximately 55% but varies depending upon estimation methods. Insulin PD parameters are apparently similar among different methods (e.g., area under the glucose concentration-time profile; 8121.4 and 8293.3 mg/dL*min for method 1-5 and method 6, respectively).

The results call for a careful selection of the method for the assessment of insulin PK and PD parameters depending upon the objectives of study as the relationship between PK and PD could vary among methods and may lead to misinterpretation of data.

Disclosure

S.M. Chung: None. J.A. Penzenstadler: None. M. Khurana: None. C. Sahajwalla: None.
Electron Microscopic Findings of Insulin-Induced Local Amyloidosis
Authors: SENDUR SULEYMAN , KATIPOGLU KUBRA , KOCKARA OZGE , GÖKÖZ ÖZAY , KAYMAZ FIGEN , DAGDELEN SELCUK
Published: June 2018

Introduction: Insulin-induced local amyloidosis (ILA) was firstly described in 1983, but still underdiagnosed. Here we describe clinicopathological and electron microscopic findings of a case with ILA. Case: A 52-year-old male with type 2 diabetes mellitus for 14 years, on basal-bolus insulin (i.e., insulin lispro and glargine), had noticed 2x2 cm mass at injection site. MRI showed a fibrous mass at the subcutaneous tissue. Punch biopsy of the lesion revealed amyloid deposition surrounded by giant cells. Immunohistochemistry studies proved that amyloid material is insulin. Electron microscopic evaluation (EM) revealed both extra-, and intracellular amyloid fibrils (Figure 1A,B). Discussion: Local amyloid deposition due to insulin injection could be seen in both types of diabetes. Despite earlier reports were associated with porcine insulin, subsequent publications linked also with human insulin and recombinant insulin analogues. High doses of insulin and inappropriate insulin injections are the major risk factors. Extracellular amyloid deposits in ILA arises primarily from exogenous insulin, but the precise mechanism of pathogenicity remains to be established. There are only few case reports of ILA with EM. To the best of our knowledge, here in this case we have firstly showed intracellular accumulation of those amyloid fibrils as well as extracellular compartment, which might have further clinical implications.

Disclosure

S. Sendur: None. K. Katipoglu: None. O. Kockara: None. Ö. Gököz: None. F. Kaymaz: None. S. Dagdelen: None.
Identification of Subpopulations Exhibiting the Greatest Cardiovascular Benefit from Long-Acting Glucagon-Like Peptide-1 Receptor Agonists—A Combined Analysis of Large Cardiovascular Outcome Trials
Authors: KANG YU MI , CHO YUN KYUNG , CHOI JONG HAN , WOO CHANGYUN , LEE WOO JE , PARK JOONG-YEOL , JUNG CHANG HEE
Published: June 2018

Background: By combining the results of three large cardiovascular outcome trials (CVOTs) of glucagon-like peptide 1 receptor agonists (GLP-1 RAs), we aimed to investigate the overall effect of GLP-1 RAs on major cardiovascular events (MACE) and identify subpopulations exhibiting the greatest cardiovascular (CV) benefit.

Methods: Three multicenter, randomized, double-blind, placebo-controlled CVOTs of long-acting GLP-1 RAs were included: LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results), SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) and EXSCEL (Exenatide Study of Cardiovascular Event Lowering). The primary endpoint was three-point MACE (i.e., CV death, non-fatal myocardial infarction, and non-fatal stroke). Overall effect estimates were calculated as hazard ratios (HRs) and 95% confidence intervals (CIs) using the random-effects model; pre-defined subgroup analyses were performed.

Results: Overall, significant risk reductions in MACE (relative risk [RR]: 0.88 [95% CI: 0.81-0.97]) and CV death (RR: 0.85 [95% CI: 0.75-0.95]) were observed. Subgroup analysis indicated significant racial differences in this CV benefit (P for test of difference < 0.001). Risk reductions were observed in subjects of black race (RR: 0.78 [95% CI: 0.60-0.99]) and Asians (RR: 0.35 [95% CI: 0.09-1.32]). However, post-hoc analysis using Bonferroni correction revealed that only Asians exhibited a significantly greater CV benefit from treatment, compared with subjects of white race (P < 0.0001).

Conclusions: Long-acting GLP-1 RAs reduced risks of MACE and CV deaths in diabetic study populations, and racial difference in the CV benefit was observed. The existence of extra CV benefit in Asians and the underlying mechanisms should be investigated in the future.

Disclosure

Y. Kang: None. Y. Cho: None. J. Choi: None. C. Woo: None. W. Lee: None. J. Park: None. C. Jung: None.
Lesser eGFR Decline with Dulaglutide Regardless of Weight Changes in People with Type 2 Diabetes and Moderate to Severe Chronic Kidney Disease (AWARD-7)
Authors: TUTTLE KATHERINE R. , LAKSHMANAN MARK , RAYNER BRIAN L. , BUSCH ROBERT S. , ZIMMERMANN ALAN G. , WOODWARD BRAD , BOTROS FADY T.
Published: June 2018

Body weight (BW) changes may affect muscle mass and thus creatinine (Cr) levels. Estimating glomerular filtration rate (eGFR) by Cr-based equations may not accurately reflect changes in kidney function when BW changes. Dulaglutide (DU) treatment was associated with BW loss and lesser eGFR (Cr-CKD-EPI) decline in people with T2D and moderate to severe CKD compared to insulin glargine (IG) (Table). The aim was to evaluate if the lesser eGFR decline observed with DU is related to BW loss. eGFR was evaluated with Cr-based equations (MDRD, CKD-EPI) compared to cystatin C-CKD-EPI equation. Cystatin C is not affected by muscle mass changes. CrCL was evaluated with the Cockcroft-Gault equation. BL characteristics were similar between treatments ([mean±SD] eGFR (Cr-CKD-EPI): 38.3±12.8 mL/min/1.73m2, A1c: 8.6±1.0%, age: 64.6±8.6 y, T2D duration: 18.1±8.7 y). All equations consistently show that eGFR remained stable with DU, but significantly decreased with IG regardless of BW loss in DU or gain in IG (Table). Since BW is a factor in CrCL calculations, compared to eGFR equations, BW loss in DU led to bias toward greater reductions in CrCL. This bias disappeared when using lean BW (Table).

In conclusion, compared to IG, DU was associated with lesser eGFR decline in people with T2D and moderate to severe CKD regardless of BW changes.

Disclosure

K.R. Tuttle: Consultant; Self; Eli Lilly and Company, Boehringer Ingelheim GmbH, AstraZeneca, Gilead Sciences, Inc. M. Lakshmanan: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. B.L. Rayner: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; Novartis AG, Servier. Advisory Panel; Self; AstraZeneca. R.S. Busch: Speaker's Bureau; Self; AbbVie Inc., AstraZeneca. Research Support; Self; Bayer AG, Intarcia Therapeutics, Inc.. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Speaker's Bureau; Self; Amgen Inc.. Research Support; Self; Sanofi US. Speaker's Bureau; Self; Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc.. Research Support; Self; Amarin Corporation. A.G. Zimmermann: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. B. Woodward: Employee; Self; Eli Lilly and Company. F.T. Botros: Employee; Self; Eli Lilly and Company.
Robust Glucose Control and Weight Loss after Six Weeks of Treatment with MEDI0382, a Balanced GLP-1/Glucagon Receptor Dual Agonist, in Patients with Type 2 Diabetes
Authors: AMBERY PHILIP , STUMVOLL MICHAEL W. , POSCH MAXIMILIAN G. , HEISE TIM , PLUM-MOERSCHEL LEONA , TSAI LAN-FENG , ROBERTSON DARREN , PETRONE MARCELLA , RONDINONE CRISTINA , PARKER VICTORIA E. , HIRSHBERG BOAZ , JERMUTUS LUTZ
Published: June 2018

MEDI0382 is under development for the treatment of type 2 diabetes mellitus (T2DM). In a double-blind study (NCT02548585), 51 T2DM patients with BMI 27-40 kg/m2 were randomized (1:1) to daily SC MEDI0382 200 μg or placebo (PBO). Based on ANCOVA with treatment and baseline (BL) values as covariates, MEDI0382 markedly reduced fasting glucose (change from BL at day 41, -49.9 vs. -19.2 mg/dL; P < 0.0001) and postprandial glucose in a mixed-meal tolerance test (percent change from BL in glucose AUC0-4h, -32.8 vs. -10.2; P < 0.0001) (Figure 1) with no increase in hypoglycemia. HbA1c levels decreased -0.9% with MEDI0382 and -0.6% with PBO (P = 0.0004). Weight loss was 3.8 kg vs. BL (1.7 kg vs. PBO; P = 0.0008); 92% of MEDI0382 patients lost >2 kg. Mean reduction in ambulatory systolic BP was -4.2 for MEDI0382 vs. -1.5 mmHg for PBO (P = ns). As with marketed GLP-1 analogs, a mean pulse increase of 6.8 BPM for MEDI0382 vs. a fall of 2.0 BPM for PBO was seen (P < 0.0001). Treatment-related AEs such as decreased appetite, vomiting, and headache were seen in more patients on MEDI0382 (20 vs. 15); 0 were grade >3 severity, 3 led to study discontinuation for MEDI0382 vs. 1 for PBO, and 1 SAE in the PBO arm. Overall, MEDI0382 normalized fasting and postprandial blood glucose, significantly reduced body weight, and had an acceptable safety profile over 41 days of dosing in obese/overweight T2DM patients.

Disclosure

P. Ambery: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. 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. L. Tsai: Employee; Self; MedImmune. D. Robertson: Employee; Self; MedImmune. Employee; Spouse/Partner; GlaxoSmithKline plc. M. Petrone: Employee; Self; MedImmune. Stock/Shareholder; Self; 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. B. Hirshberg: Employee; Self; AstraZeneca, MedImmune. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca.
Semaglutide Treatment and Renal Function in the SUSTAIN 6 Trial
Authors: VILSBØLL TINA , GUMPRECHT JANUSZ , SILVER ROBERT J. , HANSEN THOMAS , PETTERSSON JONAS , WILDING JOHN P.
Published: June 2018

Semaglutide is a new GLP-1 analog for the once-weekly treatment of T2D. This post-hoc analysis assessed the effect of semaglutide on renal function by baseline eGFR in the SUSTAIN 6 trial.

Overall, mean eGFR decreased from baseline to week 104 across all treatment groups and subgroups, with the largest decreases in subjects with normal renal function or mild renal impairment (Figure). Urine albumin-to-creatinine ratio decreased with increasing renal impairment for semaglutide 1.0 mg, but not other treatment groups (Table). AEs related to acute renal failure were generally higher with increasing baseline renal impairment, except with semaglutide 1.0 mg vs. placebo. New or worsening nephropathy was lower with both doses of semaglutide vs. placebo (Table).

No renal-related safety issues were observed with semaglutide regardless of baseline renal function in SUSTAIN 6.

Disclosure

T. Vilsbøll: Advisory Panel; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Consultant; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Speaker's Bureau; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Research Support; Self; Eli Lilly and Company, Novo Nordisk A/S. J. Gumprecht: Speaker's Bureau; Self; AstraZeneca. Consultant; Self; Bayer AG. Speaker's Bureau; Self; Bioton, Berlin-Chemie AG, Eli Lilly and Company, Merck Sharp & Dohme Corp., Boehringer Ingelheim GmbH, Novo Nordisk A/S, Polfa Tarchomin S.A., Polpharma. R.J. Silver: Consultant; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc., Eli Lilly and Company, AstraZeneca. T. Hansen: None. J. Pettersson: Employee; Self; Novo Nordisk A/S. 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..
Glucagon-Like Peptide-1 Receptor Agonists and Pancreatic Cancer—A Meta-analysis with Trial Sequential Analysis
Authors: PINTO LANA C. , RADOS DIMITRIS V. , FALCETTA MARIANA R. , LEITAO CRISTIANE B.
Published: June 2018

Background: Glucagon-like peptide-1 (GLP-1) receptors were identified in both acinar and ductal cells of pancreas. Animal studies suggested an association of GLP-1 agonists use and pancreatic premalignant changes. Randomized controlled trials (RCT) in humans did not report this association, but it may be due to lack of sample power of individual studies.

Aim: To access if GLP-1 agonists are associated with pancreatic cancer.

Methods: Systematic review and meta-analysis of randomized trials with GLP-1 agonists as intervention. Trials that lasted more than 48 weeks were included. Trial sequential analysis (TSA) was performed to access if available information is enough to discard this association.

Results: Twelve trials met study criteria, including 36, 397 patients. GLP-1 analogs did not increase the risk for pancreatic cancer when compared to other treatments (OR 1.14; 95% CI 0.68 to 1.92; I2 0%)(Figure 1). TSA confirmed that enough patients were randomized to exclude this association, and a number needed to harm (NNH) higher than 1000 was reached (Figure 2).

Conclusion: There is enough information to discard the concern regarding GLP-1 agonists and pancreatic cancer.

Disclosure

L.C. Pinto: None. D.V. Rados: None. M.R. Falcetta: None. C.B. Leitao: None.
Investigations into Tissue Distribution and Inhibition of Food Consumption with Efpeglenatide
Authors: PARK YOUNG JIN , CHOI IN YOUNG , TRAUTMANN MICHAEL E. , HOMPESCH MARCUS , SORLI CHRISTOPHER H.
Published: June 2018

Efpeglenatide (efpeg), a long-acting glucagon-like peptide-1 receptor agonist in development for type 2 diabetes, induces weight loss through satiety and reduced food intake. Studies in Sprague Dawley rats investigated how peripheral and central mechanisms contribute to the anorectic effects of efpeg. Tissue distribution of efpeg was assessed by whole-body autoradioluminography with 14C-efpeg. The contribution of vagal nerve signaling to food intake control was assessed in vagotomized rats treated with exenatide (0.15 or 0.45 nmol/kg twice daily) or efpeg (0.71 or 2.1 nmol/kg every 2 days). Pharmacokinetic parameters and mean radioactivity of 14C-efpeg in selected organs/tissues are shown in Figure. Peak concentration (Cmax) of 14C-efpeg was highest in the kidney cortex; Cmax at all other sites was similar to/lower than in blood, relatively high in the intestine and pituitary, with below-quantifiable levels in the cerebellum/cerebrum. Inhibition of food intake was not attenuated in vagotomized vs. sham-operated rats at higher doses of efpeg (3-day cumulative intake: 47.4 vs. 49.4 g) or exenatide (54.9 vs. 60.7 g), suggesting a non-vagal mechanism for these anorectic effects. These findings suggest that central mechanisms are involved in the anorectic effects of efpeg in this animal model; potential cell-signaling effects of efpeg in the intestine and pituitary need to be investigated further.

Disclosure

Y. Park: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. I. Choi: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; 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. M. Hompesch: Other Relationship; Self; Hanmi Pharmaceutical. C.H. Sorli: Employee; Self; Sanofi.
iGlarLixi Effectively Reduces Residual Hyperglycemia in Patients with Type 2 Diabetes on Basal Insulin—A Post-Hoc Analysis from the LixiLan-L Study
Authors: GIORGINO FRANCESCO , RETNAKARAN RAVI , VIDAL JOSEP , ARODA VANITA , SAREMI ARAMESH , LIU MINZHI
Published: June 2018

Residual hyperglycemia (glycated hemoglobin [HbA1c] over target despite fasting plasma glucose [FPG] at target) presents an obstacle in achieving glycemic control in T2D. GLP-1 receptor agonist (RA) therapy can target excessive postprandial glycemia (PPG) and thereby address residual hyperglycemia. This analysis investigated the effect of iGlarLixi, a fixed-ratio combination of insulin glargine (iGlar) U100 and the GLP-1 RA lixisenatide (Lixi), on the proportion of patients with T2D with discordant HbA1c/FPG (HbA1c ≥7% and FPG <140 mg/dL) in the LixiLan-L trial. Patients who had suboptimal glycemic control despite basal insulin ± oral antidiabetes drugs (OADs) stopped all OADs but metformin and, after 6 weeks of iGlar run-in, were randomized to iGlarLixi or iGlar for 30 weeks (N=736). At baseline (post-run-in), proportions with discordant HbA1c/FPG were similar in the two arms. After 12-week randomized treatment, proportions with discordant HbA1c/FPG were 32.1% (iGlarLixi) and 49.9% (iGlar; p<0.0001; Figure). After 30 weeks, the prevalence of discordant HbA1c/FPG was further reduced with iGlarLixi vs. iGlar (22.7% vs. 45.9%; p<0.0001).

In conclusion, iGlarLixi reduces the proportion of T2D patients with discordant HbA1c/FPG levels more than iGlar does, reflecting its capacity to address residual hyperglycemia by targeting both FPG and PPG.

Disclosure

F. Giorgino: Consultant; Self; Abbott, AstraZeneca, Boehringer Ingelheim GmbH. Research Support; Self; Eli Lilly and Company, Johnson & Johnson Services, Inc.. Consultant; Self; MedImmune, Merck Sharp & Dohme Corp., Roche Diabetes Care Health and Digital Solutions, Sanofi. Research Support; Self; Takeda Development Centre Europe Ltd. R. Retnakaran: Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc.. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Sanofi, Eli Lilly and Company. J. Vidal: None. 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. A. Saremi: Employee; Self; Sanofi US. M. Liu: Employee; Self; Sanofi.
Preclinical Effects of Efpeglenatide, a Long-Acting Glucagon-Like Peptide-1 Receptor Agonist, Compared with Liraglutide and Dulaglutide
Authors: TRAUTMANN MICHAEL E. , CHOI IN YOUNG , KIM JUNG KUK , SORLI CHRISTOPHER H.
Published: June 2018

Efpeglenatide (efpeg) is a long-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA) in development for type 2 diabetes. The effects of efpeg vs. those of liraglutide (lira) and dulaglutide (dula) on glucodynamics and weight/lipid profiles were studied over 4 weeks in mouse models of diabetes (db/db) and obesity (diet-induced obesity [DIO]), respectively; doses tested wereefpeg 1.45, 2.89, or 4.35 nmol/kg once every 2 days (Q2D); twice-daily lira 30 nmol/kg (db/db study) or 50 nmol/kg (DIO study); dula 0.98 or 1.96 nmol/kg Q2D (equivalent human doses/key results in Table). At the highest doses tested, efpeg was significantly more effective at lowering blood glucose (vs. lira and dula) and reducing the increase in glycated hemoglobin (HbA1c) from Day 0 (vs. lira) in db/db mice. Efpeg also improved insulin sensitivity (vs. lira and dula) and postprandial glucose control (vs. dula). In DIO mice, efpeg significantly reduced body weight and mesenteric fat mass (vs. dula), and cholesterol (vs. lira and dula; at highest doses). Overall, efpeg showed greater reductions in blood glucose, HbA1c increase, weight, and cholesterol vs. other GLP-1 RAs in mice. These effects may be due to the distinct receptor binding properties of efpeg, which enhance intracellular signaling and insulin release in β-cells. Further studies are needed to assess the clinical relevance of these findings.

Disclosure

M.E. Trautmann: Consultant; Self; ProSciento. Stock/Shareholder; Self; Eli Lilly and Company. Consultant; Self; Hanmi Pharmaceutical, CeQur Corporation, Intarcia Therapeutics, Inc., Servier. I. Choi: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. J. Kim: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. C.H. Sorli: Employee; Self; Sanofi.
Efficacy and Safety of ITCA 650, an Injection-Free GLP-1RA, in T2D Patients—A Pooled Analysis of Phase 3 Studies
Authors: KJEMS LISE L. , PRABHAKAR PRAKASH , SCHWARTZ BRIAN , HUANG HOLLY , BARON MICHELLE A.
Published: June 2018

ITCA 650 consists of a small titanium osmotic mini-pump that is subdermally placed in the abdominal wall during a brief office procedure. As an investigational product for the treatment of type 2 diabetes (T2D), ITCA 650 provides a continuous subcutaneous infusion of exenatide over 3 or 6 months. An integrated analysis of efficacy and safety was conducted from 2 double-blind, randomized, Phase 3 studies, which evaluated pooled data with ITCA 650 20/60 mcg/d vs. placebo or sitagliptin for the treatment of patients with T2D, inadequately controlled on antidiabetic drugs. The efficacy endpoints were mean change from baseline at Week 39 for HbA1c, body weight, composite endpoints of HbA1c and weight loss, and proportion achieving HbA1c <7%. The incidence of treatment-emergent adverse events (TEAEs) was also reported. Significant and clinically meaningful improvements at 39 weeks were observed with ITCA 650 20/60 mcg/d for all these endpoints. The higher incidence of TEAEs with ITCA 650 vs. comparators was explained by the higher incidence of GI TEAEs. Similar proportions of patients in each group discontinued for TEAEs. The results are consistent with results observed from individual Phase 3 studies, which demonstrated that ITCA 650 is effective for lowering HbA1c and weight, for achieving a composite of HbA1c/weight reduction and target HbA1c <7%, and is well tolerated.

Disclosure

L.L. Kjems: Employee; Self; Intarcia Therapeutics, Inc.. Stock/Shareholder; Self; Intarcia Therapeutics, Inc.. P. Prabhakar: None. B. Schwartz: Employee; Self; Intarcia Therapeutics, Inc.. H. Huang: None. M.A. Baron: Employee; Self; Intarcia Therapeutics, Inc..
Effect of a Novel Long-Acting GLP-1/GIP/Glucagon Triple Agonist (HM15211) in a NASH and Fibrosis Animal Model
Authors: CHOI IN YOUNG , KIM JUNG KUK , LEE JONG SUK , PARK EUNJIN , KIM YOUNG HOON , JUNG SUNG YOUB , KIM SUN JIN
Published: June 2018

Nonalcoholic steatohepatitis (NASH), a potential consequence of NAFLD, may lead to end stage liver disease including cirrhosis and hepatocellular carcinoma. Despite its severity and prevalence, NASH currently lacks effective treatment. In this respect, we developed a novel long-acting, GLP-1/GIP/Glucagon triple agonist, HM15211. With a unique activity profile, HM15211 could provide synergistic benefits on body weight loss and lipid profile improvement while avoiding hyperglycemic risk. Previously, we showed that HM15211 exerts potent reductions in body weight and hepatic TG (triglycerides) in DIO mice, and showed a liver preferential distribution, suggesting HM15211 as a potential treatment for NASH. Here, we evaluated the effect of HM15211 in NASH and fibrosis using MCD-diet mice with various disease induction periods. In MCD-diet mice (6 weeks induction), HM15211 treatment led to significant decrease in hepatic TG (-82.6% vs. vehicle) and TBARS (oxidative stress marker, -60.7% vs. vehicle), which coincided with significant reduction in ALT and bilirubin. Time course MRI/MRS imaging further confirmed the progressive steatosis resolution by HM15211. Furthermore, histopathological analysis indicated that HM15211 significantly reduced hepatic inflammatory gene expression and NAFLD activity score (1.3 for HM15211, 3.4 for liraglutide, and 2.7 for vehicle). To further evaluate the therapeutic potential in fibrosis, MCD-diet mice was used for an extended period (10 weeks induction) to achieve overt liver fibrosis. In line with NASH improvement, HM15211 successfully resolved liver fibrosis as demonstrated in histological evaluation. Histological improvements were accompanied by a remarkable decrease in disease biomarkers including hepatic hydroxyproline. Based on these observations, HM15211 may offer a therapeutic potential for NASH and fibrosis as well as obesity.

Disclosure

I. Choi: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. J. Kim: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. E. Park: Employee; Self; Hanmi Pharmaceutical. Y. Kim: Employee; Self; Hanmi Pharmaceutical. S. Jung: None. S. Kim: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical.
Improvement of Type 2 Diabetes (T2DM) and Reduction of Major Adverse Cardiovascular Events and Mortality in Hypogonadal Men Receiving Long-Term Treatment with Injectable Testosterone Undecanoate (TU)—Real-Life Evidence from a Urological Registry Study
Authors: SAAD FARID , HAIDER KARIM S. , HAIDER AHMAD
Published: June 2018

Background: Hypogonadism is highly prevalent in men with T2DM.

Methods: Of 805 hypogonadal men in a urological registry, 311 men (39%) had T2DM diagnosed and treated elsewhere. 141 received TU 1000 mg/12 weeks (T-group), 170 opted against treatment (CTRL). Mean changes over time between groups were compared by mixed effects model. Changes were adjusted for age, weight, waist circumference, HbA1c, blood pressure (BP), lipids to account for baseline differences between the two groups.

Results: Mean follow-up 7.5 years for 2.319 patient-years. Age: 62.8±5.1 years. T-group: HbA1c progressively decreased from 9.0±1.2 to 5.9±0.3% at 10 years (p<0.0001) with statistical significance vs. previous year for the first 7 years. CTRL: HbA1c increased from 7.8±0.7 to 10.6±1.7% (p<0.0001). Estimated adjusted difference between groups; -6.2% (p<0.0001). T-group: fasting insulin decreased from 29.6±4.1 to 13.5±5 µU/mL (p<0.0001) with statistical significance vs. previous year for the first 6 years. CTRL: fasting insulin increased from 26.1±2.7 to 36.7±2 µU/mL (p<0.0001). Estimated adjusted difference between groups: -28 µU/mL (p<0.0001). T-group: HOMA-IR decreased from 10.2±2.1 to 3.3±1.2 after 10 years (p<0.0001). The decrease was statistically significant vs. previous year for the first 6 years. CTRL: HOMA-IR increased from 7.5±1.3 to 17.1±6.3 (p<0.0001). Estimated adjusted difference between groups: -14.8 (p<0.0001). Since injections were administered in the doctor’s office and no patient dropped out, there was a 100% adherence to TTh. 8 patients (5.7%) in T-group died. In CTRL, 47 myocardial infarctions (27.6%), 37 strokes (21.8%), and 41 deaths (24.1%) occurred.

Conclusions: Long-term TTh with TU in hypogonadal men with T2DM improved diabetic measures and reduced MACE compared to untreated controls.

Disclosure

F. Saad: Employee; Self; Bayer AG. Stock/Shareholder; Self; Bayer AG, Novo Nordisk A/S. K.S. Haider: Other Relationship; Self; Bayer AG. A. Haider: Research Support; Self; Bayer AG.
Outcomes of Split Thickness Skin Grafting on Lower Extremity Wounds in Diabetics
Authors: WALTERS ELLIOT , STIMAC GREG , RAJPAL NEHA , NAZ IRAM , ELMARSAFI TAMMER , STEINBERG JOHN , EVANS KAREN , ATTINGER CHRISTOPHER , KIM PAUL
Published: June 2018

Background: Split thickness skin grafting is a widely used surgical technique for wound coverage. Despite the popularity of this procedure, outcomes data has been poorly reported.

Methods: Under IRB approval we reviewed the records of all patients receiving split thickness skin grafting for lower extremity wounds from 2014 to 2016. We have defined success as wound healing of ≥99.5%.

Results: 180 diabetic patients were included in this study. 103 (95%) had hypertension, 75 (69%) had hyperlipidemia, 29 (27%) had congestive heart failure, and 22 (20%) had venous stasis. Complete epithelialization was obtained for 29 (22%) patients at 30d, 48 (36%) patients at 60d, 63 (48%) patients at 90d, and 77 (58%) patients at 365d of follow-up. At last available follow-up 79 (60%) wounds obtained complete healing (≥99.5% coverage). Venous stasis led to inadequate healing at 30d (p<0.0371), 90d (p<0.0006), and 365d (p<0.0005) and trended toward significance at 60d (p<0.0809). Congestive heart failure led to inadequate healing at 60d (p<0.0334), and 90d (p<0.0015). The presence of bacteria on wound bed cultures did not show a significant effect on wound healing. The most common bacteria were coagulase negative Staphylococcus, MRSA, and Enterococcus faecalis. Only enterococcus faecalis showed significance at 30d if present following the initial debridement.

Conclusion: The data suggests that split thickness skin grafting can be a successful coverage technique for diabetic patients with chronic lower extremity wounds. The bacterial milieu of chronic wounds in diabetics is diverse but with excisional debridement these bacteria have little impact on wound healing after split-thickness skin grafting. However, comorbidities (i.e., congestive heart failure and venous stasis) can significantly impact the healing of skin grafts and should be taken into consideration when contemplating split thickness skin grafting in a diabetic patient.

Disclosure

E. Walters: None. G. Stimac: None. N. Rajpal: None. I. Naz: None. T. Elmarsafi: None. J. Steinberg: Consultant; Self; Acelity, Integra LifeSciences. K. Evans: None. C. Attinger: Consultant; Self; Acelity, Integra LifeSciences. P. Kim: Consultant; Self; Acelity, Integra LifeSciences.
Mortality Risk of Noninsulin Glucose-Lowering Drugs in Type 2 Diabetes—A Network Meta-analysis of Observational Trials
Authors: BONGAERTS BRENDA , LINDNER LENA M. , HOYER ANNIKA , KUSS OLIVER , HERDER CHRISTIAN , AL-HASANI HADI , MÜSSIG KARSTEN , RODEN MICHAEL , RATHMANN WOLFGANG
Published: June 2018

Given the short-comings of randomized controlled trials, such as low numbers of patients and events, we aimed to perform a network meta-analysis of observational trials on the effects of non-insulin glucose-lowering drugs on all-cause and cardiovascular mortality in type 2 diabetes.

We searched MEDLINE and EMBASE through August 2017. From the 38 eligible studies, we extracted patient characteristics, exposure, outcome, confounder-adjusted effect measures, and risk of bias. All-cause and cardiovascular mortality risk were assessed with random-effects network meta-analysis.

In 32 studies reporting on all-cause mortality (1,661,945 persons) and in 11 studies on cardiovascular mortality (358,784 persons), 119,591 (7.2%) and 9,221 (2.6%) persons, respectively, died during follow-up. Compared to metformin, sulfonylurea drugs (SU) increased all-cause mortality risk (HR: 1.42 (95% CI: 1.29-1.56)). Dipeptidyl peptidase-4 inhibitors (DDP4i) added to metformin significantly decreased all-cause mortality risk compared to metformin monotherapy (HR: 0.76 (0.63-0.93)), any other drug class as monotherapy, and SU + metformin dual therapy (HR: 0.69 (0.60-0.79)). DPP-4i + metformin dual therapy was associated with even larger reductions in risk of cardiovascular mortality; HR: 0.40 (0.21-0.79) when compared to metformin monotherapy, and HR: 0.41 (0.23-0.74) when compared to SU + metformin dual therapy. Glucagon-like-peptide-1 receptor agonists + metformin dual therapy tended to, but did not significantly, decrease mortality risk when compared to metformin monotherapy (all-cause mortality, HR: 0.88 (0.53-1.47); cardiovascular mortality, HR: 0.74 (0.30-1.82)).

In conclusion, this large network meta-analysis evidently confirmed that SU, compared to metformin, increased all-cause mortality risk. DPP-4i + metformin dual therapy, compared to other treatments, resulted in a consistent risk reduction of both all-cause and cardiovascular mortality.

Disclosure

B. Bongaerts: None. L.M. Lindner: None. A. Hoyer: None. O. Kuss: None. C. Herder: Other Relationship; Self; Sanofi, Eli Lilly and Company. H. Al-Hasani: None. K. Müssig: None. M. Roden: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi. W. Rathmann: Advisory Panel; Self; AstraZeneca. Research Support; Self; Novo Nordisk A/S.
Accuracy of Daily Foot Temperature Monitoring for Patients with Recently Healed Diabetic Foot Ulcers or History of Amputation
Authors: GORDON IAN L. , NOUVONG AKSONE , NAJAFI BIJAN , ROTHENBERG GARY M. , PETERSEN BRIAN , BLOOM JONATHAN D. , FRYKBERG ROBERT
Published: June 2018

Diabetic foot ulcers (DFU) result in significant morbidity, mortality, and healthcare costs. Fortunately, recent data suggest as many as 75% of DFU and 60% of lower extremity amputations (LEA) may be preventable. Clinical practice guidelines recommend evidence-based foot temperature monitoring (thermometry) for preventing DFU and its complications in high-risk patients. Despite this, several authors have noted that thermometry is not commonly practiced. This is potentially due to lack of evidence on the accuracy of thermometry in some of the highest-risk cohorts, including those with a recently-healed DFU or with history of LEA. The former may present with ipsilateral inflammation as part of normal healing, while the latter may lack the anatomy required for direct contralateral comparison of temperatures. Whether these concerns affect the accuracy of thermometry needs to be assessed. A recent study suggests that a novel thermometric mat may address some barriers to adoption. The mat was found to predict as many as 97% of non-traumatic plantar DFU with an average lead time of five weeks in a cohort with history of DFU. In the current investigation, we hypothesized no difference in the predictive accuracy of thermometry in two subgroups: those who healed from a DFU fewer than three months before enrolling, and those with a history of partial LEA (Syme amputation or more distal). Of the 129 subjects studied, 31% had recently-healed DFU and 56% had history of LEA. Although no difference in DFU incidence was found in the LEA subgroup, we found significantly higher incidence in those with recently-healed DFU (0.88 vs. 0.63 DFU/subject/year). Importantly, we found no differences in accuracy or lead time in either cohort. These data suggest thermometry is appropriate for monitoring both recently-healed DFU or partial LEA patients. Utilization of thermometry in these high-risk patients may significantly reduce morbidity, mortality, and resource utilization.

Disclosure

I.L. Gordon: None. A. Nouvong: None. B. Najafi: None. G.M. Rothenberg: Consultant; Self; Podimetrics. B. Petersen: Employee; Self; Podimetrics, Inc.. Stock/Shareholder; Self; Podimetrics, Inc. J.D. Bloom: Employee; Self; Podimetrics, Inc. Board Member; Self; Podimetrics, Inc. Stock/Shareholder; Self; Podimetrics, Inc. R. Frykberg: None.
A Pooled Analysis of the Efficacy and Safety of Ertugliflozin as Add-On Therapy to Metformin
Authors: CALLE ROBERTO A. , LIU JIE , HUYCK SUSAN , WU LARRY , PONG ANNPEY , MANCUSO JAMES P. , TERRA STEVEN , LAURING BRETT
Published: June 2018

Ertugliflozin (ERTU) is a highly selective sodium-glucose cotransporter 2 inhibitor in development for treatment of patients with type 2 diabetes mellitus (T2DM). This pooled analysis characterized the efficacy and safety of ERTU when used as add-on therapy to metformin (MET).

Pooled data from 2 randomized, double-blind, placebo-controlled Phase 3 studies with similar design and patient population (NCT02033889 [VERTIS MET], NCT02036515 [VERTIS SITA2]) were analyzed. Adult patients with T2DM inadequately controlled on MET (± sitagliptin) with A1C ≥7.0 to ≤10.5% were randomized to placebo (PBO), ERTU 5 mg or 15 mg for 26 weeks.

Mean baseline (BL) characteristics of patients (N=1083) were similar across pooled treatment groups (age 57.7 years; T2DM duration 8.6 years; A1C 8.1%; body weight [BW] 85.7 kg; systolic blood pressure [SBP] 130.6 mmHg; estimated glomerular filtration rate 89.4 mL/min/1.73 m2). Changes in A1C, BW and SBP after 26 weeks are shown in the Table. Relative to PBO, more patients receiving ERTU had A1C <7.0%, BW reduction of ≥5%, or SBP <130 mmHg (among patients with BL SBP ≥130 mmHg) at Week 26. ERTU had an overall similar safety profile to PBO, except for a higher incidence of adverse events (AEs) of genital mycotic infections and of AEs related to osmotic diuresis.

Addition of ERTU to MET (± sitagliptin) provides reductions in A1C, BW and SBP, resulting in more patients achieving metabolic treatment goals.Table. Changes from baseline in A1C, BW and SBP at Week 26Placebo (n=362)Ertugliflozin 5 mg (n=363)Ertugliflozin 15 mg (n=358)Least squares mean change from baseline in A1C at Week 26 (95% CI), % Placebo-adjusted difference–0.1 (–0.2, 0.0) ––0.8 (–0.8, –0.7) –0.7 (–0.8, –0.6)–0.9 (–1.0, –0.8) –0.8 (–1.0, –0.7)Patients with A1C <7.0% at Week 26, n (%)59 (16.3)123 (33.9)143 (39.9)Least squares mean change from baseline in BW at Week 26 (95% CI), kg Placebo-adjusted difference–1.3 (–1.6, –1.0) ––3.2 (–3.4, –2.9) –1.8 (–2.3, –1.4)–3.0 (–3.3, –2.7) –1.7 (–2.1, –1.2)Patients with BW reduction ≥5% at Week 26, n (%)39 (10.8)115 (31.7)103 (28.8)Least squares mean change from baseline in SBP at Week 26 (95% CI), mmHg Placebo-adjusted difference–0.8 (–2.0, 0.5) ––4.1 (–5.3, –2.9) –3.4 (–5.1, –1.7)–4.9 (–6.1, –3.7) –4.1 (–5.8, –2.4)Patients with baseline SBP ≥130 mmHg (N) and with SBP <130 mmHg (n) at Week 26, n/N (%)32/171 (18.7)70/192 (36.5)71/189 (40.7)

Disclosure

R.A. Calle: Employee; Self; Pfizer Inc.. J. Liu: None. S. Huyck: Employee; Self; Merck & Co., Inc.. L. Wu: None. A. Pong: None. J.P. Mancuso: Employee; Self; Pfizer Inc.. Stock/Shareholder; Self; Pfizer Inc.. Employee; Spouse/Partner; Pfizer Inc.. Stock/Shareholder; Spouse/Partner; Pfizer Inc. S. Terra: Employee; Self; Pfizer Inc. B. Lauring: Employee; Self; Merck & Co., Inc..
Increased Rates of Readmission, Reoperation, and Mortality following Open Reduction and Internal Fixation of Ankle Fractures Are Associated with Diabetes Mellitus
Authors: LIU JENNIFER , AHN JUNHO , RASPOVIC KATHERINE M. , WUKICH DANE
Published: June 2018

The purpose of this large-scale retrospective study was to calculate the increased risk for postoperative unplanned readmission, unplanned reoperation, and mortality after ankle fracture ORIF in patients with diabetes mellitus (DM). Patients who underwent ORIF for ankle fractures from 20to 2015 were identified in ACS-NSQIP database. Patient demographics and 30-day postoperative readmission, reoperation, and mortality rates were compared in 2,044 patients with DM and 15,420 patients without DM. Adjusted odds ratios controlling for age differences were calculated for each parameter with a 95% confidence interval. Patient factors and pre-operative laboratory statistics are summarized in Figure D, and the distribution of ankle fractures for each group are shown in Figure A and B. Comparing patients with DM vs. without DM, the rate of readmission was 4.35% vs. 1.50%, rate of reoperation was 2.30% vs. 0.75%, and rate of mortality was 0.73% vs. 0.21%. As shown in Figure C, patients with DM had a 2.66 times increased risk of readmission, a 2.76 increased risk of reoperation, and a 2.34 increased risk of mortality. Interestingly, we also found a 22.increased risk of amputation, though the rate of amputation in both groups was very small. Ankle fractures requiring ORIF in patients with DM are serious events and associated with substantial morbidity.

Disclosure

J. Liu: None. J. Ahn: None. K.M. Raspovic: None. D. Wukich: None.
Tofogliflozin and Pemafibrate Combination Therapy Prevents Nonalcoholic Steatohepatitis (NASH) Development of Novel Metabolic Syndrome–Related NASH Model Mice
Authors: SASAKI YUSUKE , ASAHIYAMA MASATO , KAMIYA WAKANA , SAKAI JURO , KODAMA TATSUHIKO , TANAKA TOSHIYA
Published: June 2018

Nonalcoholic steatohepatitis (NASH) is closely associated with metabolic syndrome and widely defined by the presence of steatosis with inflammation and progressive fibrosis that causes to the liver transplantation and hepatocellular carcinoma (HCC). Here, we developed a novel NASH/HCC model represented metabolic syndrome like phenotypes (obesity, hyperglycemia, and glucose intolerance), and evaluated the therapeutic potential of Tofogliflozin and Pemafibrate combination therapy on NASH development. Male C57BL/6J mice were injected multiple low dose STZ (40 mg/kg) for 5 days and fed high-fat diet (HFD). These mice revealed hyperglycemia and higher body weight gain, and glucose intolerance compared with wild type mice. In addition, novel NASH/HCC model shows sequential histological changes from fatty liver to NASH (20 weeks), and all mice developed hepatocellular carcinoma after 52-week HFD feeding. Using our NASH/HCC model, we conducted the prevention study of Tofogliflozin and Pemafibrate (mono-therapy or combination therapy) against NASH development. The combination therapy has significantly prevented body weight gain from 3 weeks after treatment and this effect was persisted throughout study. While Tofogliflozin or Pemafibrate treatment markedly decreased blood glucose and triglyceride levels, the combination therapy showed the synergistic effect compared to mono-therapy groups. Histological analysis revealed Tofogliflozin or combination therapy group markedly suppressed ER-TR7 (fibroblast) and ballooning degeneration. Furthermore, these treatment groups significantly improved NAS score (NAFLD activity score). These results suggested that Tofogliflozin/Pemafibrate combination therapy would be a beneficial for NASH/NAFLD treatment.

Disclosure

Y. Sasaki: Employee; Self; Kowa Company, Ltd. M. Asahiyama: Employee; Self; Kowa Company, Ltd.. Employee; Spouse/Partner; Kowa Company, Ltd.. W. Kamiya: None. J. Sakai: None. T. Kodama: Consultant; Self; Kowa Company, Ltd. T. Tanaka: Research Support; Self; Kowa Company, Ltd..
SGLT2i Dual Therapy with Metformin (Met) for Type 2 Diabetes Mellitus (T2DM)—Systematic Literature Review and Network Meta-analysis (NMA)
Authors: MCNEILL ANN MARIE , DAVIES GLENN M. , KRUGER ELIZA , REASON TIMOTHY , EJZYKOWICZ FLAVIA , HANNACHI HAKIMA , CATER NILO B. , MCLEOD EUAN
Published: June 2018

Objective: Indirectly compare the efficacy and safety of ertugliflozin (ertu) from the VERTIS MET and FACTORIAL trials to other SGLT2i as an add-on to MET.

Methods: Pubmed, EMBASE and Cochrane databases were searched through to end 2016 for RCTs of 24-26 weeks duration in T2DM patients with uncontrolled A1C on MET. Comparators to ertu 5mg and 15mg were low and high doses of SGLT2i licensed in Europe and USA: canagliflozin (cana), dapagliflozin (dapa) and empagliflozin (empa). Included outcomes vs. placebo at 24-26 weeks were change in A1C, weight, systolic blood pressure (SBP), A1C <7% and safety outcomes (urinary tract infections [UTIs], genital mycotic infections [GMIs], hypoglycemic events and patients with ≥1 adverse event [AE]). Evidence synthesis used both fixed effect (FE) and random effects (RE) Bayesian NMA, with model selection informed by guidelines. Credible intervals (CrI), analogous to 95% confidence intervals, were used to determine significance.

Results: The NMA included 7 RCTs. Ertu was significantly more effective in reducing A1C than dapa doses (ertu 5mg vs. dapa 5mg mean difference (MD): -0.22%, CrI -0.42, -0.02; ertu 15mg vs. dapa 10mg MD:-0.26%, CrI -0.46, -0.06) and ertu 15mg was superior to empa 25mg (MD: -0.23%, CrI -0.44, -0.03). There were no further significant differences between ertu and other SGLT2i for change in A1C, SBP, weight, A1C <7%, UTIs or ≥1 AEs. Limited number of hypoglycemic and GMI events in placebo comparators resulted in non-convergence for these networks. The impact of heterogeneity was tested, but potential confounding due to differences in factors such as study design and patient population may remain.

Conclusions: Although reliant upon indirect comparison rather than head to head RCTs, ertu 5 and 15mg were superior to dapa 5 and 10mg, respectively, and ertu 15mg was superior to empa 25mg. Across remaining outcomes, both ertu doses added to MET were comparable to other SGLT2i.

Disclosure

A. McNeill: Employee; Self; Merck & Co., Inc.. Stock/Shareholder; Self; Merck & Co., Inc. G.M. Davies: Employee; Self; Merck & Co., Inc. E. Kruger: Employee; Self; QuintilesIMS. T. Reason: None. F. Ejzykowicz: Employee; Self; Merck Sharp & Dohme Corp. H. Hannachi: Employee; Self; Merck & Co., Inc. N.B. Cater: Employee; Self; Peter Sheehan Diabetes Care Foundation, Inc. E. McLeod: Employee; Self; Pfizer Inc..