bluuebunny/crossref_metadata_2025 huggingface dataset:
1072-P: Activation of Heat Shock Response Ameliorates Nonalcoholic Fatty Liver Disease Biomarkers
Authors: KONDO TATSUYA , KITANO SAYAKA , MIYAKAWA NOBUKAZU , WATANABE TAKURO , GOTO RIEKO , SAKAGUCHI MASAJI , IGATA MOTOYUKI , KAWASHIMA JUNJI , MOTOSHIMA HIROYUKI , MATSUMURA TAKESHI , ARAKI EIICHI
Published: June 2020

Background: Nonalcoholic fatty liver disease (NAFLD) often accompanies with metabolic disorders, such as metabolic syndrome (Mets) and type 2 diabetes (T2D). Effective treatment strategy to control NAFLD is not fully established yet. Cellular stress adaptation is one of the most important homeostatic ability, but this response can be deteriorated by metabolic insults. Heat shock (HS) with appropriate mild electrical stimulation (MES) activates stress adaptive heat shock response and improves metabolic abnormalities such as insulin resistance, hyperglycemia and inflammation in Mets and T2D.

Methods: Retrospective analysis of the effects of MES+HS treatment on NAFLD biomarkers was performed in the subject with healthy men (n=10), Mets (n=40) and the patient with T2D (n=100).

Results: In healthy males, there were no alterations in NAFLD steatosis or fibrosis biomarkers. In subjects with Mets, many of the NAFLD steatosis markers, such as AST/ALT ratio (from 0.80 to 0.94. p<0.01), fatty liver index (FLI: from 62.3 to 57.3. p<0.01), NAFLD-liver fat score (NAFLD-LFS: from 0.002 to - 0.276. p<0.01), liver/spleen (L/S) ratio (from 0.994 to 1.098. p<0.01) and hepatic steatosis index (HSI: from 37.2 to 36.0. p<0.01) were ameliorated upon MES+HS treatment, but NAFLD fibrosis markers were not. In patients with T2D, all those investigated NAFLD steatosis markers including AST/ALT ratio (from 0.94 to 1.08. p<0.05), FLI (from 64.0 to 59.6. p<0.01), LFS (from 1.40 to 0.90. p<0.05), L/S ratio (from 0.987 to 1.096. p<0.01) and HSI (from 40.2 to 39.4. p<0.01), visceral adiposity index (VAI: from 219.4 to 197.2. p<0.01) and triglyceride × fasting glucose index (TyG: from 4.05 to 3.95. p<0.01) were improved and NAFLD fibrosis markers such as Fib4 index (from 1.72 to 1.62. p<0.05) and NAFLD-fibrosis score (from - 0.23 to - 0.18. p<0.05) were ameliorated upon MES+HS treatment.

Conclusions: Thus MES+HS, a physical interventional medicine may become a novel treatment strategy for NAFLD as well as metabolic disorders.

Disclosure

T. Kondo: None. S. Kitano: None. N. Miyakawa: None. T. Watanabe: None. R. Goto: None. M. Sakaguchi: None. M. Igata: None. J. Kawashima: None. H. Motoshima: None. T. Matsumura: None. E. Araki: Advisory Panel; Self; Abbott. Speaker’s Bureau; Self; ARKRAY, Astellas Pharma Inc., AstraZeneca, Eli Lilly Japan K.K., Merck & Co., Inc., Novo Nordisk Inc., WebMD LLC. Other Relationship; Self; Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited.

Funding

Japan Ministry of Economy, Trade and Industry (24-065)
1081-P: Metabolic Effects of Praliciguat, Empagliflozin, and Their Combination in Rats with Programmed Hypertension and Early Exposure to High-Fat Diet
Authors: SCHWARTZKOPF CHAD , RIBÓ VIRGINIA REVERTE , RODRIGUEZ FRANCISCA , OLTRA LIDIA , MORENO AYUSO JUAN MANUEL , LLINÁS M. TERESA , NICOLAS ALEJANDRO S. , SHEA COURTNEY , CURRIE MARK , JONES JULI E. , BUYS EMMANUEL S. , MASFERRER JAIME , APARICIO FRANCISCO JAVIER SALAZAR
Published: June 2020

Background: The soluble guanylate cyclase (sGC) stimulator praliciguat (PRL) lowers blood pressure and improves metabolism in preclinical models. PRL is under development for diabetic nephropathy and therefore combination with antidiabetic agents such as empagliflozin (EMPA), a sodium glucose cotransporter 2 (SGLT2) inhibitor, is of interest. Here, we assessed the metabolic effects of PRL, EMPA, and their combination in SD rats with programmed hypertension and early exposure to high fat diet (HT-HF), a model with several features of metabolic syndrome - hypertension, glucose intolerance and increased adiposity.

Methods: Mean arterial pressure (MAP) and abdominal fat (AF) were determined at 12 weeks of age in 4 groups of HT-HF rats that were subsequently treated for 6 weeks with vehicle control (HT-HF), PRL (10 mg/kg/day), EMPA (7.5 mg/kg/day), or PRL+EMPA. A normotensive, non-disease group on normal diet was also included. At Week 6 of treatment, an intraperitoneal glucose tolerance test (GTT) was performed, and MAP, AF, plasma leptin, and adipocyte area (AA) were measured.

Results: See table.

Conclusion: The sGC stimulator praliciguat in combination with the SGLT2 inhibitor empagliflozin has additive pharmacological effects in a rat programmed hypertension model.

Disclosure

C. Schwartzkopf: None. V. Reverte Ribó: Research Support; Self; Cyclerion. F. Rodriguez: Research Support; Self; CYCLERION. L. Oltra: Research Support; Self; Cyclerion. J. Moreno Ayuso: Research Support; Self; Cyclerion. M. Llinás: Research Support; Self; Cyclerion. A.S. Nicolas: None. C. Shea: None. M. Currie: Employee; Self; Cyclerion Therapeutics. Stock/Shareholder; Self; Cyclerion Therapeutics. J.E. Jones: None. E.S. Buys: Employee; Self; Cyclerion. Stock/Shareholder; Self; Cyclerion. J. Masferrer: None. F. Salazar aparicio: Research Support; Self; Cyclerion.
1086-P: GLP-1 Promotes Osteogenic Differentiation of Human ADSCs via Wnt/GSK-3ß/ß-Catenin Pathway
Authors: LI YUN , FU HUIRONG , LUO SHUNKUI , WANG LINGLING , CHEN JIANDI , LU HONGYUN
Published: June 2020

Background: Glucagon-like peptide-1(GLP-1) analogue, which act as endogenous intestinal hormone and promising antidiabetic drugs, have shown beneficial effects on bone metabolism in some clinical studies, but the molecular mechanism remains unclear. The aim of our study was to investigate whether GLP-1 could affect the “intestines-fat- bone axis” via Wnt/GSK-3β/β-catenin pathway.

Methods: Human ADSCs (hADSCs) were cultured and induced to osteogenic and adipogenic differentiation under high glucose condition. The cells was cultured with different dose of GLP-1, and treated with Wnt pathway agonist (LiCL) or inhibitor (DKK-1) respectively. In order to further explore the mechanisms, we use lentivirus to knockdown the core molecule (GSK-3β and DKK-1) of Wnt pathway. The Oil red O staining, Alizarin red staining, quantitative RT-PCR and Western blotting were also used.

Results: GLP-1 repressed induction of adipocyte differentiation biomarkers, and reduced endogenous lipoid deposits in cells. In addition, GLP-1 enhanced the expression of osteoblastogenic biomarkers such as OCN, Runx2 as well as Collagen I, which promoted osteoblastic mineralization. These impacts were substantially suppressed by the inhibitor of Wnt. The above results could be reversed when GSK-3β were silenced. It provide that GLP-1 promotes osteogenic differentiation of hADSCs via Wnt/GSK-3β/β-catenin pathway.

Disclosure

Y. Li: None. H. Fu: None. S. Luo: None. L. Wang: None. J. Chen: None. H. Lu: None.

Funding

Sun Yat-sen University (17YKZD23); National Natural Science Foundation of China (81670815); Natural Science Foundation of Guangdong Province (2016A030313279)
1098-P: Biomarkers of Tubular Injury and Effects of Canagliflozin in the CANVAS Trial
Authors: SEN TAHA , LI JINGWEI , NEAL BRUCE , NEUEN BRENDON L. , JARDINE MEG J. , IX JOACHIM , SHLIPAK MICHAEL G. , PERKOVIC VLADO , YAVIN YSHAI , ROSENTHAL NORM , HANSEN MICHAEL K. , HEERSPINK HIDDO L.
Published: June 2020

Introduction: Canagliflozin (CANA) slows progression of kidney disease, which may be at least partly mediated by improvements in tubular function. To test this hypothesis, we assessed effects of CANA on markers of tubular function and injury in the CANVAS trial.

Methods: Urine biomarkers of tubule function (β2-microglobulin [B2M], cystatin C, and uromodulin), tubular injury (interleukin-18 [IL-18], kidney injury molecule-1 [KIM-1], neutrophil gelatinase associated lipocalin [NGAL], and osteopontin), and inflammation (monocyte chemotactic protein-1 [MCP-1]) were measured at baseline and after 12 months. Biomarker concentrations were standardized for urine creatinine concentration. Differences between CANA and placebo treatment were assessed using ANCOVA models.

Results: We included 3723 CANVAS participants with available urine samples (eGFR 77.1 ml/min/1.73 m2 and median UACR 11.7 mg/g). Clinical characteristics and biomarker levels were well balanced between treatment groups at baseline. CANA compared to placebo significantly reduced urinary KIM-1, uromodulin, cystatin C, and osteopontin. It did not change NGAL or MCP-1 and increased IL-18 and B2M. Results were consistent in subgroups by baseline UACR except MCP-1, which decreased in patients with UACR ≥30 mg/g (Table).

Conclusion: CANA had variable effects on markers of tubule cell injury and function, decreasing 4, while 2 remained stable and 2 increased.

Disclosure

T. Sen: None. J. Li: Employee; Self; George Institute. B. Neal: Research Support; Self; Janssen Research & Development, LLC, Merck Schering Plough, Roche Pharma, Servier, Zydus Pharmaceuticals, Inc. Other Relationship; Self; Abbott, Janssen, Novartis, Pfizer, Roche, and Servier. B.L. Neuen: Research Support; Self; Australian National Health and Medical Research Council Postgraduate Scholarship, Oxford Australia Clarendon Scholarship from the University of Oxford, University Postgraduate Award from UNSW Sydney. Other Relationship; Self; Janssen Research & Development, LLC. M.J. Jardine: Other Relationship; Self; See Other Relationship field. J. Ix: Research Support; Self; Baxter. M.G. Shlipak: Advisory Panel; Self; Cricket Health, Tai Diagnostics. V. Perkovic: Other Relationship; Self; See Other Relationshipfield. Y. Yavin: Employee; Self; Janssen Research & Development, LLC. N. Rosenthal: None. M.K. Hansen: Employee; Self; Janssen Research & Development, LLC. H.L. Heerspink: Consultant; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mundipharma International, Retrophin, Inc.

Funding

Janssen Research & Development, LLC
11-OR: Youth Empowerment Skills (YES): A Novel Psychosocial Behavioural Intervention for Adolescents with Type 1 Diabetes
Authors: KARIYAWASAM DULMINI , SAQI KHULAT A. , DEHZAD FARANAZ , PENDER SIOBHAN , JONES MARIE , YEMANE NARDOS , GRIFFITHS REBECCA H. , SOUKUP TAYANA , SINGHAM STEPHANIE M. , FORBES ANGUS
Published: June 2020

Background: The transition from adolescence to young adulthood can be challenging for young people with type 1 diabetes. During this period many young people become disengaged from their health care and can experience increases in adverse diabetes events and diabetes distress.

Study Aim: To deliver a novel psychoeducational programme called Youth Empowerment Skills (YES), using simulation based experiential learning and peer learning to increase diabetes knowledge and social confidence in young people with type 1 diabetes.

Method: The YES programme was delivered in community settings with a youth worker supporting engagement. HbA1c and admission data were collected 12-months pre and post intervention. Follow-up qualitative questionnaires and semi-structured interviews were conducted 6 weeks post-intervention to elicit participant views of the programme. The study was conducted in a South London boroughs with high levels of socioeconomic disadvantage and ethnic diversity.

Results: Data were collected from all participants (n=41), mean age 17.3±2.3 years. Mean HbA1c 12 month prior to attending the programme was (DDCT%) 10.4%±4.8%. There was a reduction of mean HbA1c at 12-months post-intervention to 9.7%± 4.6%m (Δ 0.7%) (p< 0.01). DKA admissions reduced by 55.6% (n=15) over the 12 month follow-up; saving £78,000 in admission avoidance. The programme successfully engaged young people from ethnic minorities (53%) and with high social deprivation (65%). Qualitative data showed perceived improvements in clinical knowledge and psychosocial health. Feedback highlighted active learning sessions and peer support as strengths of the programme.

Conclusion: The study showed that the YES programme was beneficial in improving glycaemic control and reducing diabetes related admissions in adolescents with type 1 diabetes; and encouraged a more positive and accepting attitude towards living with diabetes.

Disclosure

D. Kariyawasam: None. K.A. Saqi: None. F. Dehzad: None. S. Pender: None. M. Jones: None. N. Yemane: None. R.H. Griffiths: None. T. Soukup: None. S.M. Singham: None. A. Forbes: None.
111-OR: MODY3 Diagnosis from Deidentified Pancreatic Tissue Leads to Variant Identification in Living Relatives
Authors: SPARLING DAVID , HALIYUR RACHANA , LINDNER JILL , WEBER LINDA , RAMIREZ ANDREA , BRISSOVA MARCELA , POWERS ALVIN C.
Published: June 2020

As part of studies to understand human pancreatic islet pathophysiology in type 1 diabetes (T1D), we discovered normal β cell mass in a 33-year-old deceased organ donor with T1D for 17 years. Further analysis revealed the donor’s diabetes resulted from a causative variant in hepatic nuclear factor 1-alpha (HNF1A), associated with Maturity-onset Diabetes of the Young-3 (MODY3) (J Clin Invest 129:246, 2019), which can be treated with sulfonylureas. Review of the donor’s redacted medical chart suggested a family history of diabetes consistent with the known autosomal dominant pattern of inheritance of MODY3. With this clinically-actionable information, we desired to inform the donor’s family. However, de-identified samples are not considered “human subject” research by Institutional Review Boards (IRB), so the family’s identity was unknown with no defined pathway for communicating these findings. Working with a Human Tissue and Organ Research Resource and an organ procurement organization, we developed a new, IRB-approved communication path between those involved in tissue collection, scientific investigation, and the donor’s family and physician. This allowed targeted genetic testing of potentially affected family members, which revealed five living relatives of the donor who carried the HNF1A variant: three adults diagnosed with diabetes before the age of 25 currently treated with insulin and two children (ages 6 months and 3 years) who did not have clinical diabetes. Since none of the identified individuals were known to have MODY3, they will likely benefit from appropriate clinical care and surveillance. This experience demonstrates the need for the scientific community to develop guidelines to address handling, reporting, and use of research findings from de-identified tissue collected for research. Defining ethical avenues for donor family-investigator communications will benefit for both organ donor families and scientific research.

Disclosure

D. Sparling: None. R. Haliyur: None. J. Lindner: None. L. Weber: None. A. Ramirez: None. M. Brissova: None. A.C. Powers: None.
1114-P: Comparison of Remogliflozin and Canagliflozin as Add-On Therapy in Indian Uncontrolled T2DM Subject
Authors: SHANKAR ANAND
Published: June 2020

Aim: Remogliflozin is a new SGLT2i for the treatment of type 2 diabetes mellitus approved in India. The primary objective of this study was to compare remogliflozin to canagliflozin in patient populations with inadequately controlled (HbA1c>8%) and already treated with either diet/exercise, metformin plus a DPP-4i.

Method: 120 uncontrolled T2DM subjects (HbA1c>8%) who were on optimum tolerable dose of metformin plus a DPP-4i, were selected for this real world observational trial. Primary end point was change from baseline in HbA1C at 12 weeks. Secondary end points included change in fasting plasma glucose (FPG) and post prandial plasma glucose (PPPG), and percent change in body weight. Safety was assessed based on adverse event (AE) like hypoglycemia reports.

Result: A comparable reduction in HbA1c were observed from baseline at the end of 12 weeks in both groups, remogliflozin 100 mg (N=60) (1.96%) (p>0.001)and canagliflozin 300 mg (N=60) (1.67%)(p>0.001), but inter group p value was non-significant(p=0.023). A similar significant reduction was demonstrated in both FPG (47.98% vs. 41.23%) and PPPG (49.81% vs. 42.89%) in remogliflozin group compared to canagliflozin group respectively. The proportion of patients who achieved an HbA1C < 7% at 12 weeks was 51% in the remogliflozin group and 43% in the canagliflozin group. Statistically significant more weight loss was observed in remogliflozin arm compared to canagliflozin arm (-1.38 kg vs. -0.88 kg)(p>0.001). The overall incidence of hypoglycemia (minor) was higher in patients treated with canagliflozin as compared to the patients treated with remogliflozin. The two groups differ in their cost effect, as treatment with canagliflozin group was 4.3 fold costlier than with remogliflozin till 3 months of treatment.

Conclusion: Effectiveness of remogliflozin is as comparable with canagliflozin as GLA. In country like India where cost is matter for compliance remogliflozin can be substitute of canagliflozin.

Disclosure

A. Shankar: None.
1119-P: Alleviating Carbohydrate Counting Burden in Type 1 Diabetes (T1D) with the Artificial Pancreas and Empagliflozin (EMPA)
Authors: HAIDAR AHMAD , YALE JEAN-FRANÇOIS , LOVBLOM LEIF ERIK , CARDINEZ NANCY , ORSZAG ANDREJ , FALAPPA CESAR M. , GOUCHIE-PROVENCHER NIKITA , FATHI ANAS EL , ELDELEKLI DEVRIM , SCARR DANIEL , PERKINS BRUCE A.
Published: June 2020

We aimed to assess whether adding Empa to the artificial pancreas can alleviate the burden of carbohydrate counting without degrading glucose control. We conducted a randomized, open-label, crossover, non-inferiority trial in 30 adults with T1D (age 40±15 years, A1c 7.6±0.7%). Each participant used the artificial pancreas on 5 non-consecutive days at home (9-14 hours/day) with: Empa 25mg and (i) carbohydrate counting, (ii) simple meal announcements (pressing a button, no carbohydrate counting), and (iii) no meal announcements (fully automated), and with: no Empa and (iv) carbohydrate counting (control arm) and (v) simple meal announcements. The fully automated artificial pancreas with Empa was inferior to the artificial pancreas with carbohydrate counting without Empa (mean glucose 10.0±1.6 vs. 8.5±1.5 mmol/L, p<0.001), but the artificial pancreas with simple meal announcement and Empa was non-inferior (8.5±1.4 mmol/L, non-inferiority p-value with a pre-specified margin of 0.75 mmol/L = 0.003). Time spent below 3.9 mmol/L was minimal in all interventions. No diabetic ketoacidosis was observed; mean ketones levels were 0.22±0.18 and 0.13±0.11 mmol/L, with and without Empa, respectively (p<0.001). We conclude that SGLT2 inhibition added to the artificial pancreas may alleviate the need for carbohydrate counting but does not allow a fully closed-loop system.

Disclosure

A. Haidar: Consultant; Self; Eli Lilly and Company. Research Support; Self; Dexcom, Inc., Eli Lilly and Company. J. Yale: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Board Member; Self; Diagnos. Research Support; Self; Bayer Inc., Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Medtronic, Novo Nordisk A/S, Sanofi. L. Lovblom: None. N. Cardinez: None. A. Orszag: None. C.M. Falappa: None. N. Gouchie-Provencher: None. A. El Fathi: None. D. Eldelekli: None. D. Scarr: None. B.A. Perkins: Consultant; Self; Abbott, Boehringer Ingelheim International GmbH, Insulet Corporation. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Other Relationship; Self; Medtronic.

Funding

Diabetes Canada
1123-P: Stress Cardiac Biomarkers and Adverse Cardiac Outcomes in the CANagliflozin CardioVascular Assessment Study (CANVAS)
Authors: SATTAR NAVEED , XU JIALIN , BUTLER JAVED , MAHAFFEY KENNETH W. , SHAW WAYNE , ROSENTHAL NORM , GUTSTEIN DAVID E. , HANSEN MICHAEL K. , JANUZZI JAMES
Published: June 2020

SGLT2 inhibitors reduce risk of major adverse cardiovascular events (MACE) and hospitalization for heart failure (HHF) in patients with type 2 diabetes (T2D), but mechanisms remain unclear. We examined effects of canagliflozin vs. placebo on 3 prognostic biomarkers in CANVAS, as well as their predictive ability for outcomes of interest.

High sensitivity cardiac troponin T (hs-cTnT; Roche Diagnostics), soluble (s)ST2 (Critical Diagnostics), and insulin-like growth factor binding protein 7 (IGFBP7; Roche Diagnostics) were measured in up to 3680 participants at baseline, 1 y, and for hs-cTnT and sST2, 6 y. Conventional statistical methods adjusting relevant covariates were used to relate biomarkers to risk for incident MACE or HHF.

Higher concentration of all 3 biomarkers was associated with higher adjusted risk for incident MACE or HHF, with C-index improvements beyond covariates for MACE or HHF (Table). In terms of treatment effect, no biomarkers were differentially altered by 1 y but where data existed, both hs-cTnT (n=915; treatment coefficient [95% CI]: -0.064 [-0.121, -0.007]; p=0.027) and sST2 (n=828, treatment coefficient [95% CI]: -0.129 [-0.248, -0.010]; p=0.033) were reduced significantly at 6 y.

Among patients with T2D, concentrations of hs-cTnT, sST2, and IGFBP7 were associated with risk for MACE and HHF. Canagliflozin slowed longer term (6 y) increases in hs-cTnT and sST2.

Disclosure

N. Sattar: Advisory Panel; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Pfizer Inc., Sanofi. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. J. Xu: Employee; Self; Janssen Research & Development, LLC. J. Butler: Consultant; Self; Amgen, Array BioPharma, AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb, CVRx, G3 Pharmaceuticals, Innolife Co., Ltd., Janssen Pharmaceuticals, Inc., Luitpold Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Relypsa, Inc., VIfor. K.W. Mahaffey: Consultant; Self; Medscape, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, SmartMedics, Springer Publishing, UCSF. Research Support; Self; Afferent, Amgen, Apple, Inc, AstraZeneca, Cardiva Medical, Inc, Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St. Jude, Tenax. W. Shaw: Employee; Self; Janssen Pharmaceuticals, Inc. N. Rosenthal: None. D.E. Gutstein: Employee; Self; Janssen Research & Development, LLC. M.K. Hansen: Employee; Self; Janssen Research & Development, LLC. J. Januzzi: Consultant; Self; Roche Diagnostic USA. Research Support; Self; Janssen Pharmaceuticals, Inc.

Funding

Janssen Research & Development, LLC
1131-P: Clinical, Demographic, Provider, and Formulary Characteristics Associated with Initiation of a SGLT2i or GLP-1RA among Medicare Beneficiaries with Type 2 Diabetes on Prior Oral Agents: A Cohort Study
Authors: LUO JING , HERNANDEZ INMACULADA , GABRIEL NICO , GELLAD WALID F.
Published: June 2020

Using 2014-2016 claims data from a random 5% sample of Medicare beneficiaries, we sought to describe characteristics associated with initiation of a SLT2i or GLP-1RA, focusing on measures of plan generosity (e.g., the number of drugs covered with no or minimal copays). Our cohort included beneficiaries with type 2 diabetes who had at least 1 prescription claim for an oral diabetes medication in the 180 days before the start of follow-up (1/1/2015). To identify new initiators of these agents, we excluded beneficiaries who filled any insulin, SGLT2i or GLP-1RA prior to the index date or who died before 12/31/16. We developed multivariable logistic regression models controlling a priori for age, race, region, prior medication use, claims-based measures of diabetes severity and clinical comorbidities, provider specialty and measures of formulary generosity. Of 103,112 eligible beneficiaries (mean age 73, 57% female), 5,076 (4.9%) initiated a SGLT2i or GLP-1RA between 1/1/15-12/31/16. After adjusting for all baseline characteristics, beneficiaries in plans covering 2 or more target drugs in preferred tiers (i.e., 1-3) were more likely (adjusted odds ratio [aOR] 1.18 [95% CI, 1.05 to 1.32]) to initiate one of these medications than patients enrolled in plans covering 0 drugs. Other characteristics associated with higher odds included: age<65 (aOR 1.78 [95% CI, 1.64 to 1.92]), diabetic retinopathy (aOR 1.19 [95% CI, 1.08 to 1.31], obesity (aOR 1.49 [95% CI, 1.38 to 1.62) and having baseline medications prescribed by an endocrinologist (aOR 1.68 [95% CI, 1.49 to 1.89]. Black race (aOR 0.66 [95% CI, 0.60 to 0.73]) and CKD (aOR 0.84 [95% CI, 0.76 to 0.92]) were associated with lower risk of initiation. After controlling for a large number of prespecified covariates, Medicare beneficiaries with type 2 diabetes with more generous prescription drug coverage were more likely to initiate a SGLT2i or GLP-1RA.

Disclosure

J. Luo: Consultant; Self; Alosa Health. I. Hernandez: None. N. Gabriel: None. W.F. Gellad: None.

Funding

National Center for Advancing Translational Sciences (KL2TR001856)
1137-P: Anti–Skeletal Muscle Atrophy Effect of Luseogliflozin via Lipidome Modification in db/db Mice
Authors: BAMBA RYP
Published: June 2020

It has been controversial that the sodium glucose cotransporter-2 inhibitor (SGLT2i) have a protective effect for muscle atrophy. We previously reported that muscle atrophy in Db/Db mice were improved by luseogliflozin via upregulation of foxo1 expression. Here we show that systemic or local lipidome were altered in Db/Db mice, which were modified by luseogliflozin. Additionally, we investigated the underling molecular mechanisms between altered lipidome and gene expressions in the atrophic soleus muscle. Eight-week-old mice were fed a standard diet or the standard diet with added luseogliflozin (0.01% w/w in chow) for 8 weeks. The mice were divided into the following three genotype/dietary groups: Db/m mice without (w/o) SGLT2i, Db/Db w/o SGLT2i, and Db/Db with SGLT2i. Concentration of stearate acids in blood in Db/Db mice with SGLT2i decreased compared to that without. The expression of scd1 or foxo1 increased in Db/Db mice w/o SGLT2i and decreased in Db/Db mice with SGLT2i. Stearate acids in blood increased in Db/Db mice, which increased stearate acids in skeletal muscle. Increased stearate acid concentration in skeletal muscle stimulates the expression of scd1, on the other hand, the administration of luseogliflozin decreased stearate acids in blood and skeletal muscle, which decreased the expression of scd1 in skeletal muscle.

Disclosure

R. Bamba: Research Support; Spouse/Partner; Taisho Pharmaceutical Co., Ltd.
1141-P: Effects of SGLT2 Inhibitors on Nighttime Sympathetic Nerve Activity, Heart Rate, Blood Pressure Variability, and Glycemic Variability in Type 2 Diabetic Patients
Authors: ONISHI TETSUROU , SHIODA YOSHINOBU , MORI YUTAKA
Published: June 2020

Objective: SGLT2 inhibitors (SGLT2i) were examined for their effects on nighttime sympathetic nerve activity in type 2 diabetic patients.

Methods: A total of 15 type 2 diabetic outpatients with poor glycemic and body weight control despite conventional antidiabetic therapy (HbA1c, 7.7 ± 1.1%; BMI, 27.6 ± 3.8 kg/m2) were given dapagliflozin (Dapa) 5 mg/day for 3 months. Patients were compared before and 3 months after Dapa treatment for Low frequency/High frequency (LF/HF) ratios at 5-minute intervals as index of sympathetic verve activity through spectrum analysis of heart rate variability, blood pressure (BP) variability at 30-minute intervals, glucose variability at 5-minute intervals using concurrent Holter electrocardiogram, ambulatory blood pressure monitoring, and continuous glucose monitoring. Blood samples were drawn from these patients after 30 minutes of bed rest before and 3 months after Dapa treatment to measure their plasma catecholamine values. Outcome measures of the study included the area under the curve for LF/HF ratios (AUC-LF/HF ratio), mean BP values during sleep, extent of nighttime BP dip, and mean glucose/SD of glucose values during sleep.

Results: HbA1c and body weight were significantly decreased with Dapa. Again, the nighttime AUC-LF/HF ratio and plasma noradrenalin values, as well as the heart rate, systolic BP (SBP) and diastolic BP (DBP) values during the same hours, were significantly decreased, and the extent of nighttime BP dip was also significantly increased, in those achieving weight reductions with Dapa. In contrast, these findings were not observed in 3 patients failing to achieve weight reductions with Dapa.

Conclusions: Study results suggest that reductions in sympathetic nerve activity associated with the SGLT2i treatment may be closely associated with SGLT2i-mediated weight reductions.

Disclosure

T. Onishi: None. Y. Shioda: None. Y. Mori: None.
1142-P: Comparison of Hospitalization for Heart Failure (HHF) among Patients with Type 2 Diabetes Mellitus (T2DM) and Macroalbuminuria Initiated on Canagliflozin (CANA) or a DPP-4
Authors: PILON DOMINIC , DURKIN MICHAEL , MANCEUR AMEUR , GHELERTER ISABELLE , LAFEUILLE MARIE-HÉL , LEFEBVRE PATRICK
Published: June 2020

This study compared the risk of HHF in T2DM patients with macroalbuminuria initiated on CANA or DPP-4 using real-world insurance claims data.

Adults with a T2DM diagnosis and a urine albumin-to-creatinine ratio >300 mg/g or albumin excretion rate >300 mg/day, initiated on CANA or DPP-4 after 03/29/2013, with at least 6 months of pre-initiation insurance eligibility were selected from Optum’s ClinformaticsTM Data Mart database (03/2012-03/2019). Patients were excluded if they notably had a diagnosis for T1DM, acute kidney injury, or stage 5 chronic kidney disease at baseline. The observation period was censored at the earliest of the index drug discontinuation, a claim for a drug from the alternate index cohort (DPP-4 or CANA), or the end of eligibility or data. Inverse probability of treatment weighting (IPTW) accounted for differences in baseline demographics, clinical characteristics, and healthcare costs. HHF events were defined as inpatient stays with a diagnosis of heart failure (ICD-9: 428.x; ICD-10: I50.x). Rates of HHF events per 100 patient-years (PY) were calculated and weighted Cox proportional hazards model accounting for repeated measurement was used to estimate the hazard ratio (HR), 95% confidence interval (CI), and p-value.

A total of 759 patients were initiated on CANA and 1,892 on a DPP-4. After IPTW balanced baseline characteristics, mean age was ∼64 years old, ∼40% were female, and mean HbA1c was ∼9.0%. Among CANA and DPP-4 patients, respectively, the mean observation period was 5.4 and 6.6 months and the rate of HHF events per 100 PY was 0.57 and 3.73. At 12 months, the hazard for HHF was 74% lower among patients initiated on CANA relative to patients initiated on DPP-4 (HR [95%CI]: 0.26 [0.07-0.91]; p=0.0343).

In this real-world analysis of patients with T2DM and macroalbuminuria during the initial months on therapy, patients on CANA had a significantly lower risk of HHF events compared to patients on DPP-4.

Disclosure

D. Pilon: Consultant; Self; Janssen Scientific Affairs, LLC. M. Durkin: Employee; Self; Janssen Scientific Affairs, LLC. A. Manceur: Employee; Self; Analysis Group, Inc. I. Ghelerter: Employee; Self; Analysis Group, Inc. M. Lafeuille: Other Relationship; Self; Janssen Scientific Affairs, LLC. P. Lefebvre: Consultant; Self; Janssen Scientific Affairs, LLC.

Funding

Janssen Scientific Affairs, LLC
1149-P: Effect of SGLT2 on Cardiovascular Events in Type 2 Diabetic Patients with Atrial Fibrillation
Authors: ZHANG YUAN , CHEN YIXIN , DENG JUNHAO , HU PENGWEI , TANG ZEFANG , MEI JING , LI SHOACHUN
Published: June 2020

Background: Previous studies have suggested that Sodium Glucose Cotransporter-2(SGLT2) inhibitor may play cardio-protective role in type 2 diabetes mellitus (T2DM) patients. However, its effects on cardiovascular events for T2DM patients with atrial fibrillation (AF) have less been addressed. Therefore, we performed a large-scale multi-center retrospective study to explore the potential value of SGLT2 in the treatment of T2DM patients with AF.

Method: We thoroughly searched the IBM Explorys database for T2DM patients with AF from January 2010 to January 2015. The patients were included or excluded with strict criteria. Primary outcomes were cardiovascular disease (CVD) events including myocardial infarction (MI) and stroke happened in 5 years after T2DM diagnose. Cox proportional hazards models with propensity-score-matching were adopted to assess the effect of SGLT2 inhibitor use and CVD events.

Result: Among 1,573,330 T2DM patients, 44048(7.3%) patients were once treated with SGLT2 drugs. A total of 88,096 propensity score-matched T2DM patients were included in the analysis according to a thorough including criteria. After adjusting for age, gender, disease history, other antidiabetic drugs and anti-coagulate drugs, the use of SGLT2 inhibitor was associated with a 11% decreased risk of MI [Hazard Ratio(HR): 0.90 (95% confidence interval(CI):0.84, 0.94), p = 0.002] compare to non-SGLT2 user. However, no significant protective effect was found in stroke risk (HR: 0.94 (95% CI: 0.86, 1.03), p = 0.194). Besides, insulin was associated with increased risk of developing MI (HR: 1.09 (95% CI: 1.01, 1.18)).

Conclusion: In conclusion, our study suggests that SGLT2 inhibitor has positive effects on the control of MI for T2DM patients with AF. However, no significant effect was found for stroke risk in this multi-center cohort. More high-quality randomized controlled trials are required to confirm cardio-protective roles of SGLT2 for T2DM patients with AF in the future.

Disclosure

Y. Zhang: None. Y. Chen: None. J. Deng: None. P. Hu: None. Z. Tang: None. J. Mei: None. S. Li: None.
1152-P: Effect of Initiating Empagliflozin vs. Glucagon-Like Peptide-1 Receptor Agonists on Health-Care Costs among Patients with Type 2 Diabetes
Authors: PIMPLE PRATIK , RAJU ADITYA , STAFKEY-MAILEY DANA , SHETTY SHARASH
Published: June 2020

The 2019 ADA’s Standards of Medical Care in Diabetes recommends use of SGLT2 inhibitor (SGLT2i) or GLP-1 receptor agonist (GLP-1RA) as one of the six drug classes after metformin (MET) in T2D patients, and is recommended as the treatment of choice among patients with cardiovascular disease (CVD; empagliflozin [EMPA] and liraglutide showing stronger evidence). To understand the economic impact of these recommendations, we evaluated the effect of EMPA vs. GLP-1 RA initiation on all-cause (AC) healthcare costs in patients with T2D. This retrospective cohort study utilized an U.S. commercial claims database to identify patients with T2D who newly initiated EMPA or a GLP-1RA between 08/2014 - 12/2016. First prescription date (index date) for EMPA or a GLP-1RA was used to classify patients into respective cohorts. T2D diagnosis and baseline covariates were assessed during 1-year pre-index period. During a post-index period of up to 1 year, AC costs were computed on a per patient per month (PPPM) basis; and evaluated using generalized linear models that controlled for pre-index covariates. Compared to the GLP-1RA cohort (N = 13,216), patients in the EMPA cohort (N= 3,857) were younger, more likely to be male, and had lower rates of obesity in the 1-year baseline period; all other measured pre-index covariates were similar. After covariate adjustment, the adjusted total AC PPPM cost difference ($1,137 vs. $1,370; difference (Δ) = -$233 PPPM) remained significantly lower for the EMPA cohort (P<0.001), as compared to GLP-1 RA cohort. Both medical (Δ = -$26 PPPM, p=0.06), and pharmacy (Δ = -$197 PPPM, p<0.001) costs were lower in EMPA cohort, as compared to GLP-1 RA cohort. Use of empagliflozin vs. GLP-1 RA in T2D patients was associated with lower all-cause healthcare costs. Together with ADA guidelines, these findings can aid health care stakeholders in treatment decisions and optimizing clinical and economic outcomes for patients with T2D.

Disclosure

P. Pimple: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Employee; Spouse/Partner; CVS Caremark. A. Raju: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb. D. Stafkey-Mailey: None. S. Shetty: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc.
1155-P: Durable vs. Disposable Insulin Pumps for Type 1 Diabetes: Health Care Costs and Utilization
Authors: SHAH MONA , ZHU CYRUS
Published: June 2020

Objectives: To compare the economic impact of using a durable versus disposable insulin pump over a 4-year period (i.e., the typical warranty period) in individuals with type 1 diabetes (T1D).

Methods: This population-based, longitudinal analysis used a large repository of healthcare claims data were used to compare healthcare costs (in 2017 U.S. dollars) and utilization in individuals with T1D using durable pumps (N=2,013) to those using disposable pumps (N=642), before and after pump adoption. T-test was used to examine the between-group difference in pump-related costs, and a generalized linear model regression was used to estimate the difference-in-difference effect of pump type on other outcomes.

Results: Mean pump-related costs over the 4-year period were $6,606 less for durable pump users versus disposable pump users (Figure; p<0.0001). Mean out-of-pocket pump-related costs for the same time period were $1,037 less for durable pump versus disposable pump users (p<0.0001). There were no statistically significant differences between durable and disposable pump users for any other variables studied (continuous glucose monitoring costs, insulin costs, inpatient costs, emergency room costs, outpatient costs, hospital admissions, or emergency room visits).

Conclusions: Use of a durable versus disposable insulin pump is associated with significantly lower pump-related costs.

Disclosure

M. Shah: Employee; Self; Medtronic. C. Zhu: Employee; Self; Medtronic.
1157-P: Out-of-Pocket and Health Plan Spending on Diabetes Drugs, 2006-2018
Authors: LIPSKA KASIA J. , MCCOY ROZALINA G. , HOUTEN HOLLY VAN , YAO XIAOXI , ROSS JOSEPH , ALTAN AYLIN E. , SHAH NILAY
Published: June 2020

The rising cost of managing diabetes is of major concern.

To examine trends in expenditures on diabetes drugs, we used OptumLabs Data Warehouse to identify commercially insured and Medicare Advantage enrollees with type 2 diabetes who filled ≥1 diabetes drug between 2006 and 2018. In each year, we examined mean health plan and patient out of pocket (OOP) spending, stratified by health plan (commercial vs. Medicare Advantage), for generic vs. brand, and for insulin vs. non-insulin drugs. We assessed trends using logistic regression. All costs were adjusted to 2018 U.S. dollars. 1,592,663 unique type 2 diabetes patients were included (commercially-insured: 698,725, Medicare Advantage: 893,938). Total mean diabetes drug expenditures increased among all patients (Figure). Among commercially insured patients, OOP spending increased for brand drugs and insulin but decreased for generics (p for trends <0.001). Health plan spending also increased for brand drugs and insulin (p<0.001) but did not change for generics (p=0.32). Among Medicare Advantage enrollees, OOP spending for brand drugs and insulin did not change (p=0.69 and 0.41, respectively), but decreased for generics (p<0.001). Health plan spending increased for brand drugs and insulin (p<0.001) but decreased for generics (p=0.02). Health plan and OOP spending on diabetes drugs increased 2006-2018, particularly among commercially insured patients, those using brand drugs and insulin.

Disclosure

K.J. Lipska: None. R.G. McCoy: None. H. Van Houten: None. X. Yao: None. J. Ross: Research Support; Self; Centers for Medicare and Medicaid Services, Janssen Pharmaceuticals, Inc., U.S. Food and Drug Administration. A.E. Altan: None. N. Shah: None.
1164-P: Trends in Diagnosed Diabetes among Medicare Beneficiaries in 2006-2015
Authors: SOHN MIN-WOONG , KIM SOYOUN , KANG HYOJUNG , MCMURRY TIMOTHY L. , LOBO JENNIFER M.
Published: June 2020

Objective: As the U.S. population ages, there have been projections that the number of people living with diabetes would double in the next two decades. Our objective is to track how diabetes prevalence rates have changed over time before and after the Affordable Care Act (ACA) among Medicare beneficiaries residing in the Diabetes Belt compared to those residing outside.

Methods: We used complete Medicare Beneficiary Summary Files for 2006 - 2015 (A/B/C/D and Chronic Conditions segments) to compute prevalence rates of diabetes as identified in the CMS Chronic Conditions Warehouse. The Diabetes Belt in this study was defined as 644 counties across southeastern counties in the U.S. that had diabetes prevalence ≥ 11% in 2008 (Barker et al. 2012).

Results: Overall diabetes prevalence increased from 24.4% in 2006 to 27.2% in 2011 and slightly decreased to 26.7% in 2015. In the Diabetes Belt, the prevalence rates were 29.1% in 2006, reaching 32.0% in 2012. The prevalence rates were 5.2% higher in absolute percentages in the Belt than outside in 2006. This difference steadily increased to 5.6% in 2015. After adjusting for age, sex, race, rurality, health professional shortage area designation, and economic level in counties, individuals in the Diabetes Belt experienced 8.1% higher risk (OR = 1.081; 95% CI = 1.078, 1.083) of having diabetes compared to those outside the Belt in 2015.

Discussion: Diabetes prevalence was stable among Medicare beneficiaries in 2011-2015, but the gap between the Diabetes Belt and the non-Belt counties widened throughout the study period. The ACA and the concerted efforts at diabetes prevention have succeeded in “bending the curve” on the projected increased in the number of persons with diabetes, but growing disparities in diabetes prevalence between the Diabetes Belt and other regions is a concern that requires more policy attention.

Disclosure

M. Sohn: None. S. Kim: None. H. Kang: None. T.L. McMurry: None. J.M. Lobo: None.

Funding

National Institutes of Health (R01DK113295)
1165-P: Costs of Diabetes Complications: Hospital-Based Care and Production Loss for 392,200 People with Type 2 Diabetes and Matched Controls
Authors: ANDERSSON EMELIE , PERSSON SOFIE , HALLÉN NINO , ERICSSON ÅSA , THIELKE DESIRÉE , LINDGREN PETER , CARLSSON KATARINA STEEN , JENDLE JOHAN H.
Published: June 2020

Background: The prevalence of type 2 diabetes (T2D) has increased rapidly over the last decades. The risks of complications and the medical consequences are well known, where hospital costs have been identified as a key driver of total costs. Less evidence has been generated on the impact of individual diabetic complications on the overall societal burden.

Objective: To analyse costs of hospital-based health care and of work absence related to individual microvascular and macrovascular complications of T2D in Sweden in 2016.

Method: The study used data from a Swedish retrospective observational database cross-linking 20 years of individual-level data (1997-2016) from national population-based health, social insurance and socio-economic registers for 392,200 people with T2D and matched controls (5:1). T2D status and presence of complications were derived from years 1997-2016 while the costs of hospital-based care and of production loss due to diabetes complications were estimated for 2016. Regression analysis was used for comparison to controls, to attribute production loss to individual complications, and to account for joint presence of complications.

Results: Hospital-based care costs were U.S. $622/person and production loss costs directly attributed to diabetes complications were U.S. $1,958/person in 2016. Additional costs were U.S. $523/person for early mortality in working ages and USD 377/person for medications in risk-factor treatment. Costs linked to angina pectoris and heart failure were key drivers of costs of macrovascular complications, and retinopathy and kidney disease of microvascular complications.

Conclusion: This study shows that the burden of complications in T2D is substantial. Costs of productivity loss were found to be greater than hospital-based care highlighting the need for considering outcomes beyond the health sector in treatment development and policy.

Disclosure

E. Andersson: Research Support; Self; Novo Nordisk A/S. S. Persson: Research Support; Self; Novo Nordisk A/S. N. Hallén: Employee; Self; Novo Nordisk A/S. Å. Ericsson: Employee; Self; Novo Nordisk Scandinavia AB. D. Thielke: Employee; Self; Novo Nordisk A/S. P. Lindgren: Research Support; Self; Novo Nordisk A/S. K. Steen Carlsson: Research Support; Self; Novo Nordisk A/S. J.H. Jendle: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Novo Nordisk A/S, Sanofi. Research Support; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Sanofi.

Funding

Novo Nordisk A/S
1166-P: Cost Analysis of a Flash Glucose Monitoring System in Type 2 Diabetes Receiving ≥2 Insulin Doses a Day in Spain
Authors: GOMEZ-PERALTA FERNANDO , OYAGÜEZ ITZIAR , ARTOLA SARA , CARRASCO FRANCISCO JAVIER , GOMEZ JUANA CARRETERO , GARCIA-SOIDAN FRANCISCO JAVIER , GOMEZ-HUELGAS RICARDO , MERINO TORRES JUAN FRANCISCO , PÉREZ ANTONIO
Published: June 2020

FreeStyle Libre2 system is a sensor-based flash monitoring (FM) system, which assesses interstitial fluid glucose. The study aimed to estimate the cost associated with the use of FM compared to self-monitoring of blood glucose (SMBG) in type 2 diabetes mellitus (T2DM) population from the Spanish National Health System perspective. The cost for glucose monitoring in T2DM patients treated with ≥2 insulin doses a day was modelled. The cost estimation considered the annual resource consumption for glucose monitoring (strips, lancets and FM sensors) and clinical management of hypoglycemia episodes. Severe hypoglycemia episodes (SHE) and non-severe hypoglycemia episodes (NSHE) published event rates (2.5 and 17.0 episodes/patient/year) were considered. Event reductions associated to FM system use were applied (48.8% [SHE]; 27.7% [NSHE]), derived from REPLACE trial findings. Based on published evidence, hospital attendance was required in 20.5% of SHEs (further hospitalization in 16.0%). Daily strip and lancet-consumption in T2DM patients was fixed at 4.81 for SMBG users, and 0.2 for FM system users according the REPLACE findings. FM sensor annual consumption per patient was 26. Unitary costs (€,2019 excluding VAT) derived from national databases and literature were: €0.28/strip; €0.09/lancet; €3.09/daily FM sensor; €3,774/hospitalized SHE; €1,779/hospital-attended non-admitted SHE; €385/community attended SHE and €15/NSHE. Yearly cost was €2,779 and €2,295 per patient using SMBG or FM system, respectively. For a cohort of 1,000 T2DM patients using ≥2 insulin doses a day; 1,221 SHEs (48 hospitalizations for SHE) and 4,715 NSHEs, yearly could be avoided with FM use. The use of the FM system in 1,000 patients could generate annual cost-savings up to €483,031 compared to SMBG (-17.4% of cost reduction).

In conclusion, FM system is a potential cost-saving strategy in T2DM patients treated with ≥2 insulin doses a day, in Spain.

Disclosure

F. Gomez-Peralta: Advisory Panel; Self; Abbott, Menarini Group, Novartis AG, Sanofi. Speaker’s Bureau; Self; Abbott, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novartis AG, Novo Nordisk A/S, Sanofi. I. Oyagüez: None. S. Artola: None. F. Carrasco: None. J. Carretero Gomez: None. F. Garcia-Soidan: None. R. Gomez-Huelgas: None. J. Merino Torres: None. A. Pérez: None.

Funding

Abbott Diabetes Care