bluuebunny/crossref_metadata_2025 huggingface dataset:
2284-PUB: Food Insecurity and Autonomic Dysfunction among Latinos with Type 2 Diabetes
Authors: SENG KAGNICA , FEINN RICHARD , BERMUDEZ-MILLAN ANGELA , PEREZ-ESCAMILLA RAFAEL , WAGNER JULIE
Published: June 2019

Aims: Food insecurity (FI) is higher among Latinos than non-Hispanic Whites and associated with risk for type 2 diabetes (T2D). Autonomic nervous system (ANS) dysfunction increases mortality in diabetes. We examined FI and ANS function among Low-income Latinos with T2D enrolled in a parent stress management trial.

Methods: Inclusion: age > 18 years, Latino or Hispanic, Spanish speaking, ambulatory status, T2D > 6 months, A1c>7.0%. Exclusion: medical or psychiatric instability; pain or dysfunction in hands precluding handgrip testing.

Measures: FI was assessed with the 6-item U.S. household food security survey module; affirmative responses to >=1 question was coded as FI. Six autonomic measures were scored 0=normal or 1=abnormal based on published cutoffs and then summed for a total ANS dysfunction index. ANS measures and their normal cutoffs were: 1) metanephrine <350 ug/day; 2) normetanephrine <600 ug/day; 3) cortisol 50-190 ug/day, all from 24-hour urine specimens; 4) 24-hour heart rate variability as reflected in standard deviation of the normal-to-normal (SDNN) heart rate acquired with 3-channel, 7-lead ambulatory electrocardiogram (holter) monitors, 149 +/-39; 5) difference between the highest diastolic blood pressure (DBP) during sustained handgrip and the average DBP at rest, >15 mmHg; and, 6) difference between baseline supine and the minimal BP after standing up, normal = decline in SBP <= 20 mmHg and DBP <= 10 mmHg.

Results: N=35 participated, n=23 (65.7%) were women, age M=61.6 (SD=11.2) years, A1c M=8.5% (SD=1.6) and n=20 (57.1%) used insulin. N=22 (62.9%) reported FI and n=25 (71.4%) had at least one abnormal ANS measure. In t-tests, participants with FI had a higher ANS dysfunction index (M=1.5, SD=0.9) than patients who were food secure (M=0.7, SD=0.8), p=0.02. Total ANS index was not related to A1c or insulin use.

Discussion: In this Latino sample with T2D, FI was associated with greater ANS dysfunction. Increasing food security may confer autonomic benefits.

Disclosure

K. Seng: None. R. Feinn: None. A. Bermudez-Millan: None. R. Perez-Escamilla: None. J. Wagner: None.

Funding

American Diabetes Association (7-13-TS-31 to J.W.); National Institute on Minority Health and Health Disparities (R01MD005879)
23-LB: Lipoprotein Subfractions Are Associated with Diabetic Cardiovascular Disease and Death among 9,795 Patients in the FIELD Trial
Authors: JONES STEVEN R. , JENKINS ALICIA J. , JANUSZEWSKI ANDRZEJ S. , OCONNELL RACHEL L. , LI LIPING , SULLIVAN DAVID , TASKINEN MARJA-RIITTA , SCOTT RUSSELL , FRANCIS WATTS GERALD , BARTER PHILIP J. , SIMES R. JOHN , TOTH PETER P. , KEECH ANTHONY C.
Published: June 2019

Background: The FIELD study, a 5-year randomized double-blind placebo-controlled trial of fenofibrate vs. placebo in 9,795 adults with type 2 diabetes (T2D), was designed to evaluate effects on coronary and cardiovascular (CV) events. In this analysis we explored associations between lipoprotein subfractions and on-study CV events and death.

Methods: We performed ultracentrifugation using the vertical auto profile (VAP, Atherotech) on plasma at baseline and after 6 weeks of fenofibrate (active run-in) exposure. Analyses were performed using Cox proportional hazards and logistic regression analysis. Results were adjusted for gender, with log transformation as necessary.

Results: Total CVD and CV death correlated negatively with HDL-C and its subfractions, as well as apoA1 and apoA2. In addition to LDL-C, small, dense LDL (LDL4-C), non-HDL-C, apo B, triglycerides, and apoC3 increased risk for total CVD. For CVD death, HDL-C and its subfractions were protective, while apo B, triglycerides, apo C3, and various VLDL-C species were associated with increased risk.

Conclusions: Detailed lipoprotein analysis identifies multiple lipoprotein subclasses and apolipoproteins and their ratios associated with acute cardiovascular events and death. Serum levels of a number of these lipoprotein and apoprotein species were improved by fenofibrate therapy.

Disclosure

S.R. Jones: None. A.J. Jenkins: Advisory Panel; Self; Abbott, Australian Diabetes Society, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Mylan. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc. A.S. Januszewski: None. R.L. OConnell: None. L. Li: None. D. Sullivan: None. M. Taskinen: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Akcea Therapeutics, Chiesi USA, Inc. Research Support; Self; Amgen Inc., Novo Nordisk A/S. Speaker’s Bureau; Self; Amgen Inc. R. Scott: None. G.F. Watts: None. P.J. Barter: Advisory Panel; Self; Merck & Co., Inc., Pfizer Inc. R. Simes: None. P.P. Toth: Consultant; Self; Amarin Corporation, Amgen Inc., AstraZeneca, Kowa Pharmaceutical Europe Co. Ltd., Novo Nordisk Inc. Speaker’s Bureau; Self; Amarin Corporation, Amgen Inc., Merck & Co., Inc., Novo Nordisk Inc., Regeneron Pharmaceuticals, Sanofi US. A.C. Keech: None.
230-OR: Intramuscular Triglyceride Subcellular Localization Is Related to Insulin Sensitivity in Humans
Authors: KAHN DARCY E. , ZARINI SIMONA , PERREAULT LEIGH , NEWSOM SEAN A. , HARRISON KATHLEEN A. , BERGMAN BRYAN C.
Published: June 2019

Intramuscular triglyceride (IMTG) content is linked to insulin resistance in humans. Similar to bioactive lipids, IMTG is localized in different compartments of skeletal muscle which may influence the impact on insulin sensitivity. Subsarcolemmal and intermyofibrillar localization of IMTG is known to alter the relationship to insulin sensitivity. However, more detailed subcellular localization of IMTG species has yet to be described. We evaluated subcellular localization of IMTG in lean (n=15), endurance trained athletes (n=16), obese (n=15), and type 2 diabetic (n=12) men and women. Muscle biopsies were fractionated into sarcolemmal, cytosolic, mitochondrial/endoplasmic reticulum, and nuclear compartments. IMTG were measured using LC/MS/MS, and insulin sensitivity using insulin clamps. Insulin sensitivity was significantly different between groups, with athletes>lean>obese>T2D (p<0.001). Most sarcolemmal IMTG species were significantly greater in obese and T2D compared to lean and athletes, but IMTG with only saturated acyl chains (C48:0, C50:0, C52:0) were significantly increased only in T2D. Sarcolemmal IMTG were inversely related to insulin sensitivity (p=0.009), and positively related to fasting insulin (p=0.004). Nuclear IMTG were significantly greater in T2D compared to lean and athletes. While there was not a significant difference in total cytosolic IMTG, saturated cytosolic IMTG species were significantly increased in T2D compared to lean and athletes, and saturated cytosolic IMTG were inversely correlated to insulin sensitivity (p=0.001). There were no significant differences between groups for IMTG concentration in the mitochondrial/ER compartment. Combined these data reveal previously unknown differences in subcellular IMTG localization, indicate the importance of sarcolemmal and nuclear IMTG to insulin sensitivity, and suggest saturated IMTG may be uniquely deleterious for muscle insulin sensitivity.

Disclosure

D.E. Kahn: None. S. Zarini: None. L. Perreault: Advisory Panel; Self; Novo Nordisk A/S, Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. S.A. Newsom: None. K.A. Harrison: None. B.C. Bergman: Advisory Panel; Spouse/Partner; AstraZeneca, Merck & Co., Inc., Novo Nordisk Inc.

Funding

National Institutes of Health (R01DK089170, RR-00036, P30DK048520)
2301-PUB: Efficacy of HbA1c Changes, Weight Changes, and Blood Pressure Changes in GLP-1RA Daily Treatment or GLP-1RA Weekly Treatment in Type 2 Diabetes
Authors: CAI XIAOLING , YANG WENJIA , ZHANG SIMIN , JI LINONG
Published: June 2019

Aims: To evaluate the efficacy of GLP-1 receptor agonist daily treatment or GLP-1 receptor weekly treatment in type 2 diabetes.

Methods: A systematic search of MEDLINE, Embase and Cochrane Central Register of Controlled Trials was made from the beginning date to December 2018.

Results: A total of 111 studies were included in the meta-analysis. Compared with placebo, treatment with GLP-1RA daily led to significant decrease in HbA1c from baseline (WMD, -0.78%, P<0.01), significant decrease in weight (WMD, -0.97kg, P<0.01), significant decrease in SBP (WMD, -2.41mmHg, P<0.01). Compared with placebo, treatment with GLP-1RA weekly resulted in significant decrease in HbA1c from baseline (WMD, -1.00%, P<0.01), significant decrease in weight (WMD, -1.33kg, P<0.01), significant decrease in SBP (WMD, -1.41mmHg, P<0.01) (Table 1).

Conclusion: Compared with placebo, in type 2 diabetes patients, treatment with GLP-1 receptor agonist daily and weekly, both resulted in significant decrease in HbA1c, weight and SBP from baseline.

Disclosure

X. Cai: None. W. Yang: None. S. Zhang: None. L. Ji: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck KGaA, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi, Takeda Pharmaceutical Company Limited. Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Roche Pharma, Sanofi.
231-OR: ADA Presidents' Select Abstract: Pyruvate Kinase M2 Overexpression in Podocytes Ameliorates Nephropathy in Diabetic Mice
Authors: SHINJO TAKANORI , ST-LOUIS RONALD , FU JIALIN , PARK KYOUNGMIN , LI QIAN , YOKOMIZO HISASHI , YU MARC GREGORY , WANG HAIYAN , KANNT AIMO , SADOWSKI THORSTEN , KING GEORGE L.
Published: June 2019

Elevated expression of pyruvate kinase isoform M2 (PKM2) in the renal glomeruli of people with diabetes is associated with protection from nephropathy even with hyperglycemia. Furthermore, systemic use of PKM2 activators (TEPP46) can prevent or reverse glomerular pathology in diabetic mice. To determine specifically the role of PKM2 in the development or progression of diabetic glomerulopathy, we generated transgenic mice overexpressing PKM2 specific targeted to the podocytes (PPKM2Tg mice) driven by the podocin promoter. Analysis of the glomeruli from these mice showed 1.5-fold increases in mRNA and protein levels without changes in PKM1, compared to wild type (WT) littermates (p<0.05). Pyruvate kinase (PK) activity in the glomeruli of the PPKM2Tg mice was increased by 40% compared to those in WT mice (p<0.05). Diabetes was induced in eight-week-old WT and PPKM2Tg mice by streptozotocin (STZ) and maintained with sustained glucose levels >400mg/dL for 7 months. Diabetic PPKM2Tg mice showed significantly lower urinary albumin-creatinine ratio (ACR) and kidney weight-body weight ratios (p<0.05) compared to diabetic WT mice even with similar hyperglycemia. PK activity was lowered in the glomeruli of diabetic WT mice by 30%, whereas levels in diabetic PPKM2Tg mice were comparable to nondiabetic WT mice. For renal pathology, diabetic PPKM2Tg mice exhibited smaller glomeruli compared to diabetic WT mice. Similarly, expressions of inflammatory genes including TNFα and MCP-1, and fibrotic genes including fibronectin and TGF-β1 were downregulated in the glomeruli of diabetic PPKM2Tg mice compared to diabetic WT mice. In contrast, mitochondrial genes such as PGC-1α, Opa1, and cytochrome b in the glomeruli of diabetic PPKM2Tg mice were significantly upregulated as compared to diabetic WT mice. These findings strongly suggest that upregulation or activation of PKM2 and glycolysis may improve mitochondrial function in podocytes and prevent the progression of diabetic nephropathy.

Disclosure

T. Shinjo: None. R. St-Louis: None. J. Fu: None. K. Park: None. Q. Li: None. H. Yokomizo: None. M. Yu: None. H. Wang: None. A. Kannt: Employee; Self; Sanofi. T. Sadowski: Employee; Self; Sanofi-Aventis Deutschland GmbH. G.L. King: Research Support; Self; Sanofi.

Funding

National Institutes of Health; Sanofi
2313-PUB: Efficacy by Baseline BMI with Once Weekly Dulaglutide in Chinese T2DM Patients
Authors: SHI YONGQUAN , ZHANG BIN , WU HAIYA
Published: June 2019

Objective: To evaluate the efficacy of dulaglutide (1.5mg, 0.75mg) in Chinese T2DM patients with baseline BMI <25 kg/m2 or ≥25 kg/m2, a post hoc analysis was conducted on two randomized trials at week 26.

Methods: Patients in the dulaglutide versus glimepiride study (AWARD-CHN1, NCT01644500; n=555) were treatment-naive or discontinued from oral monotherapy; those in the dulaglutide versus glargine study (AWARD-CHN2, NCT01648582; n=591) continued on metformin and/or sulfonylurea. Analyses were conducted based on mixed-model repeated measures using modified intent-to-treat analysis set with only Chinese population. HbA1change from baseline was analyzed by individual study.

Results: Overall, 45.6% of patients in AWARD-CHN1 and 42.8% in AWARD-CHN2 had a baseline BMI <25 kg/m2. In patients with BMI<25 kg/m2 or ≥25 kg/m2 of AWARD-CHN1, both doses of dulaglutide were superior to glimepiride for HbA1c reduction from baseline with a least squares mean difference of -0.55% or -0.53% for dulaglutide 1.5mg (both P<0.001) and -0.32% or -0.35% for dulaglutide 0.75mg (both P<0.05). In AWARD-CHN2, dulaglutide 1.5mg was superior to glargine for HbA1c reduction from baseline with a least squares mean difference of -0.58% or -0.55% in patients with BMI<25 kg/m2 or ≥25 kg/m2 of (both P<0.001), while dulaglutide 0.75mg was superior to glargine for HbA1c reduction from baseline with that difference of -0.29% in patients with BMI<25 kg/m2 (P<0.05), but non-inferior to glargine for HbA1c reduction from baseline with that difference of -0.16% in patients with BMI ≥25 kg/m2.

Conclusions: Irrespective of baseline BMI, Dulaglutide showed effective HbA1c reduction in Chinese T2DM patients compared with glimepiride and glargine. For higher BMI patients treated with oral anti-hyperglycemia medicine, dulaglutide 1.5mg could be a better clinical choice.

Disclosure

Y. Shi: None. B. Zhang: Employee; Self; Eli Lilly and Company. H. Wu: Employee; Self; Eli Lilly and Company.
2315-PUB: A Priori Classification of Type 2 Diabetes Patients to Determine the Needed Therapy Option
Authors: TKACHENKO PAVLO , REITERER FLORIAN , CHRISTENSEN MERETE B. , NØRGAARD KIRSTEN , RE LUIGI DEL
Published: June 2019

Introduction: T2D patients represent the majority of diabetes patients, and a large and increasing proportion is on insulin, with a huge impact on health care costs. For some a certain degree of automation of insulin dosing and/or regimen adjustment is required. The aim here is to define a priori the automation level required and beneficial for the individual patient.

Methods: Data from an outpatient study of 14 T2D patients currently unsuccessfully using MDI therapy were used as a baseline and different optimized insulin therapy options were tested in simulation. Among them 9 were able to reach their therapeutic goals (defined here as HbA1c < 7% and time in hypoglycemia < 2%) with CSII therapy, while 5 needed an Artificial Pancreas (AP) system. In a next step it was attempted to correlate the simulation outcomes with patient features to check whether it is possible to define the preferred therapy option before implementation by classifying those patients into AP or CSII group based on features that could be available beforehand.

Results: Coefficient of variation (CV) computed from 14 days of CGM data at baseline MDI therapy and HbA1c have been found to be suitable features for an a priori classification via Naïve Bayes or Classification Tree (CT) algorithm which results in a perfect separation of classes.

Conclusion: It was found that it seems possible to predict which subgroup of T2D patients has an additional benefit of using an AP.

Disclosure

P. Tkachenko: None. F. Reiterer: None. M.B. Christensen: None. K. Nørgaard: Advisory Panel; Self; Abbott, Medtronic, Novo Nordisk A/S. Speaker's Bureau; Self; Bayer US, Medtronic, Roche Diabetes Care, Rubin Medical, Sanofi, Zealand Pharma A/S. Stock/Shareholder; Self; Novo Nordisk A/S. L. del Re: None.
2319-PUB: Glycemic Control with XeriSol Regular Insulin and Lispro Insulin: Comparative PK-PD with Humalog and Humulin in STZ Diabetic Rats
Authors: THOHAN SANJEEV , DONOVAN MARTIN J. , HU WENDY T. , CHOI MONICA S. , HESTER DENNIS M. , PRESTRELSKI STEVEN J.
Published: June 2019

Insulin therapy is the primary treatment option for patients with type 1 and 2 diabetes. Despite considerable advances in insulin chemistry, delivery, and pharmacology, only a small percentage of diabetic patients achieve near normal glycemic levels. Xeris has developed novel room temperature stable insulin formulations that may offer duration of efficacy advantages over commercially available options.

Streptozotocin (65 mg/kg) treated SD rats were given co-formulations of PRAM and Regular Insulin (RI) or Lispro Insulin (LISPRO) as a single injection and compared with dual injection of commercial Symlin, Humulin, or Humalog. Blood samples were evaluated for plasma glucose and PK. A sparse sampling PK scheme resulted in ∼30% CV for glucose values. Mean glucose profiles with reductions in glucose AUC by treatment (efficacy).

XeriSol™ insulins showed comparable efficacy and pharmacokinetic profiles commercial products with up to 4 hours of glycemic control. Xerisol formulations of Insulin and Lispro showed trends for lower sustained means (30-240 min) for glucose levels and slightly longer half-lives than comparative doses of commercial Humulin and Humalog.

Disclosure

S. Thohan: None. M.J. Donovan: None. W.T. Hu: None. M.S. Choi: None. D.M. Hester: None. S.J. Prestrelski: Employee; Self; Xeris Pharmaceuticals, Inc.
2322-PUB: Consistency and Predictability of Control of Glycemic Variability with U200 (Concentrated r-DNA Human Insulin Premix 30/70 - 200 IU/mL) in Type 2 Diabetes Mellitus Patients
Authors: THACKER HEMANT , KESAVADEV JOTHYDEV , INGOLE SHAHU ASHOK , SHAH AGAM , JAIN RISHI
Published: June 2019

Introduction: In type 2 diabetes mellitus (T2DM) patients, U200 (concentrated r-DNA Human Insulin Premix 30/70 - 200IU/mL) provides good control of glycemic variability with minimal glycemic excursions and substantial time spent in euglycemia. Objective of this subgroup analysis was to assess consistency and predictability of control of glycemic variability with U200 by gender, body mass index (BMI) and daily insulin dose.

Methods: Sixty adult patients with T2DM on treatment with human insulin (regular/NPH/Premix) on stable insulin dose were treated with U200 for 7 days. Variability in 24-hour blood glucose profile measured by CGMS device was compared between various subgroups.

Results: There was no statistically significant difference between male and female, patients with BMI <25 kg/m2 vs. ≥ 25 kg/m2 and with daily insulin dose < 20 IU vs. ≥ 20 IU for mean blood glucose, mean number and duration of hyperglycemic episodes (>150 mg/dL), mean number and duration of hypoglycemic episodes (<70 mg/dL), and % of time spent in euglycemic range (70 - 150 mg/dL).

Conclusion: Mean blood glucose, frequency-duration of excursions and time spent in euglycemic range with U200 were unaffected by gender, BMI and daily insulin dose thereby emphasizing consistency and predictability of control of glycemic variability across a wide range of patients.

Disclosure

H. Thacker: None. J. Kesavadev: None. S.A. Ingole: Employee; Self; Wockhardt. A. Shah: Employee; Self; Wockhardt. R. Jain: Employee; Self; Wockhardt.

Funding

Wockhardt Pharmaceuticals Ltd.
2325-PUB: Estimation Formula for the Long-Term Glycemic Remission in Patients with Newly Diagnosed Type 2 Diabetes Receiving Short-Term Intensive Insulin Therapy
Authors: XU LIJUAN , LIU LIEHUA , WAN XUESI , HUANG ZHIMIN , LI YANBING
Published: June 2019

Aims: Half of the patients with newly diagnosed type 2 diabetes who received short-term continuous subcutaneous insulin infusion (CSII) were able to achieve a long-term drug-free glycemic remission. It is meaningful to develop an estimation formula to predict the glycemic remission.

Methods: We collected data from three prospective trials conducted from 2002 to 2015. A 2∼3 weeks of CSII was provided for the patients with newly diagnosed diabetes to achieve and maintain normal glucose. The one-year drug-free remission rate was observed. Differences between patients with remission and those without remission were evaluated. Estimation formula was developed by using the logistic regression models. The receiver operating characteristic (ROC) curve was used to determine the sensitivity and specificity of the estimation formula at different score cutoffs.

Results: Data of 244 patients were analyzed. After comparisons, age, gender, body mass index (BMI), high-density lipoprotein cholesterol (HDL-C), red cell distribution width (RDW), ratio of fasting plasma glucose to HbA1c (FPG/HbA1c) at baseline, FPG, postprandial plasma glucose (PPG) and the homeostasis model assessment of insulin resistance (HOMA-IR) after short-term CSII treatment were analyzed. We developed a formula as follows: R=11.936-1.626*HDL-1.56*FPG/HbA1c-0.14*RDW-0.496*FPG’ (FPG’ means FPG after short-term CSII). When R is greater than 0.5, it indicates a possible glycemic remission. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value were 82.8%, 62.2%, 73.7%, 73.3% and 74.2%, respectively.

Conclusions: We provide a prediction formula for long-term glycemic remission. For those who is predicted glycemic non-remission, sequential treatment after CSII secession may be beneficial for the long-term glucose control.

Disclosure

L. Xu: None. L. Liu: None. X. Wan: None. Z. Huang: None. Y. Li: None.
233-OR: Chronic Kidney Disease (CKD) Outcomes with Dulaglutide (DU) vs. Insulin Glargine (IG) in Type 2 Diabetes (T2D) and Moderate-to-Severe CKD by Albuminuria Status: AWARD-7
Authors: TUTTLE KATHERINE R. , RAYNER BRIAN L. , LAKSHMANAN MARK , WOODWARD BRAD , KWAN ANITA , KONIG MANIGE , BOTROS FADY T.
Published: June 2019

In the AWARD-7 study, conducted in T2D and moderate-to-severe CKD, DU treatment was associated with slower decline in estimated glomerular filtration rate (eGFR) compared to IG. One-year treatment with DU 1.5 mg weekly was associated with a lower rate of CKD outcomes, including eGFR decline ≥40% or end-stage renal disease (ESRD), compared to IG at similar levels of glycemic control and blood pressure. The aim of this post hoc analysis was to determine risk of these CKD outcomes between treatments in albuminuria subgroups. Participants with T2D and CKD stages 3-4 were randomized (1:1:1) to DU 0.75 mg or 1.5 mg weekly versus titrated IG daily, added-on to titrated insulin lispro, for one year. The occurrence of the composite outcome of eGFR decline ≥40% or ESRD was compared between treatments using a Cox proportional hazards model time-to-first event analysis. At baseline, treatment groups had similar eGFR by albuminuria subgroups (Table). The majority of events occurred in patients with macroalbuminuria (Table). Compared to IG, the incidence rate of the composite endpoint was significantly lower for DU 1.5 mg in the overall study population and in those with macroalbuminuria.

In conclusion, the risk of ≥40% eGFR decline or ESRD outcomes was reduced by more than half for DU 1.5 mg compared to IG, particularly in the macroalbuminuric subgroup.

Disclosure

K.R. Tuttle: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Goldfinch Bio. Research Support; Self; Eli Lilly and Company. B.L. Rayner: Advisory Panel; Self; AstraZeneca, Servier. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Cipla Medpro, Novartis AG. M. Lakshmanan: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. B. Woodward: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. A. Kwan: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. M. Konig: Employee; Self; Eli Lilly and Company, Eli Lilly and Company. F.T. Botros: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.

Funding

Eli Lilly and Company
2332-PUB: The Effectiveness of Basal Plus Compared with Premixed Insulin in Insulin-Naïve Type 2 Diabetes Patients
Authors: RAGHAVAN ARUN , NANDITHA ARUN , SATHEESH KRISHNAMOORTHY , SNEHALATHA CHAMUKUTTAN , SEELI ABRAHAM CATHERIN , SIMON MARY , SUSAIRAJ PRISCILLA , RAMACHANDRAN AMBADY
Published: June 2019

Aim: To compare the efficacy and safety of initiating Glargine U100 + Glulisine to Premixed insulin in insulin naïve Asian Indian type 2 diabetes (T2D) patients.

Method: We randomized 101 patients into Glargine U100 + Glulisine (Group 1) and 99 in premixed insulin (Group 2) from 7 different hospitals in Southern India and followed for 24 weeks. Randomized patients were insulin naïve T2D patients on oral antidiabetic drugs.

Results: In both the groups > 80% of patients needed an additional dose of insulin (Glulisine in Group 1 and premixed in group 2). There was a significant reduction in all glycemic levels in both groups (p < 0.05), except for a non-significant reduction in HbA1c in group 2 (Figure 1). The dose at the end of the study was 92 units in Group 1 and 50 units in group 2. There was no clinically significant change in body mass index in both groups. The number of episodes of hypoglycemia was significantly more in premixed insulin BD group compared to Glargine U100 + Glulisine BD group (χ2 - 6.1, p = 0.01).

Conclusion: Marginally better (non-significant) reduction in HbA1c was noted with Glargine U100 + Glulisine compared to premixed insulin. However, the dose required was higher in group 1 than group 2. The overall episodes of symptomatic hypoglycemia were significantly less in Glargine U100 + Glulisine when compared with the premixed insulin. There was no clinically significant change in body weight in both groups.

Disclosure

A. Raghavan: None. A. Nanditha: None. K. Satheesh: None. C. Snehalatha: None. A. Catherin Seeli: None. M. Simon: None. P. Susairaj: None. A. Ramachandran: None.

Funding

Sanofi India Limited
2336-PUB: Treatment Effectiveness of Glimepiride Alone and in Combination with Other Oral Hypoglycemic Agents: Outcomes from Real Clinical Practice
Authors: SESHADRI KRISHNA G. , DWARAKANATH C.S. , MANIKANDAN R.M. , AYYAGARI USHA , BOOCHANDRAN T.S. , DAS SAMBIT , NARAYANAN N.K. , JAGANMOHAN BALAJI , REDDY HARINI , JAYAPRAKASHSAI JANA , TIPPISETTY SUREKHA , KOLUKULA VAMSI KRISHNA ,   APOLLO SUGAR RESEARCH GROUP
Published: June 2019

Aim: To assess the treatment effect of glimepiride monotherapy and combination with metformin, DPP-4 inhibitors (DPP-4i) and SGLT2 inhibitor (SGLT2i) in patients with type 2 diabetes mellitus (T2DM).

Methods: A retrospective cross-sectional data analysis of T2DM patients of Apollo Sugar Clinics, Pan India. An eligible glimepiride prescriptions with a diagnosis of T2DM from Jan 2016 to September 2018 were included in this analysis to assess the role of glimepiride as monotherapy and in combination therapy with metformin, DPP-4i and SGLT2i on glycemic variables- glycated haemoglobin (HbA1c), and fasting blood glucose (FBG), and on weight (Wt) and body mass index (BMI). Descriptive statistics were applied to analyze the data and paired t-test was used to identify the significant difference in the glycemic variable within groups.

Results: Total 7059 T2DM patients were included in the analysis. Mean age was 52.9 year, 62.6% were males and 37.4% were females. At initiation the mean (SD) HbA1c was 8.1(1.7)%, FBG 158(55) mg/dL, Wt 69.3(12.5) kgs, and BMI was 26.6(4.7)kg/m2. Of the total, a majority of the patients were on glimepiride and metformin combination (86.3%) followed by glimepiride monotherapy (8.3%), glimepiride and DPP-4i (5%) and glimepiride and SGLT2i (0.4%). The analysis shows significant reduction in HbA1c (0.4%; p <0.001) and FBG (17mg/dL; p <0.001) in glimepiride and metformin combination treatment only compared to other combinations. Further, there was a considerable reduction in BMI in glimepiride and SGLT2i combination.

Conclusions: Our current study shows glimepiride and metformin combination therapy is highly prescribed and is effective in glycemic control compared to monotherapy and other glimepiride combinations.

Disclosure

K.G. Seshadri: None. D. C.s.: None. M. R.m.: None. U. Ayyagari: None. B. T.s.: None. S. Das: None. N. N.k.: None. B. Jaganmohan: None. H. Reddy: None. J. Jayaprakashsai: None. S. Tippisetty: None. V.K. Kolukula: None.
2345-PUB: Exploring Patient Factors Contributing to Enhanced Efficacy of Incretin-Related Drugs with Add-On SGLT2 Inhibitor Therapy in Reducing Glycemic Variability (GV)
Authors: ONISHI TETSUROU , SHIODA YOSHINOBU , MORI YUTAKA
Published: June 2019

Objective: We investigated the relationship between enhanced efficacy of incretin-related drugs with add-on SGLT2 inhibitor therapy in type 2 diabetic patients and their background characteristics.

Patients and Methods: 1) Add-on SGLT2i therapy was given to a total of 15 type 2 diabetic patients with insufficient glycemic control despite conventional therapy including DPP-4i for 2 months in an outpatient setting. 2) Likewise, add-on SGLT2i therapy was given to a total of 17 type 2 diabetic patients with insufficient glycemic control despite conventional therapy including GLP-1RA for 3 months in an outpatient setting. In both groups, the glycemic variability (GV) was compared before and after add-on SGLT2i therapy by using CGM. GV indices evaluated included the difference before and after SGLT2i therapy in SD of 24-hour glucose values (ΔSD), the 24-hour total GV area (ΔSQ), and MAGE (ΔMAGE). Both groups were further divided according to the GV results by over 50th %tile and under 50th %tile into high-responders (n = 8 and 9) and low-responders (n = 7 and 8).

Results: 1) Effect of add-on SGLT2i therapy on reductions in GV in those receiving DPP-4i: High-responders were shown to be associated with significantly higher mean glucose values, SD, SQ and MAGE than low-responders at baseline (P < 0.05). 2) Effect of add-on SGLT2i therapy on reductions in GV in those receiving GLP-1RA: high-responders were shown to be associated with significantly lower BMI, as well as significantly higher SD and SQ than low-responders at baseline (P < 0.05).

Conclusions: With 2-month SGLT2i therapy as add-on to DPP-4i, reductions were seen in GV among patients with higher mean glucose and greater GV at baseline, suggesting a role for add-on SGLT2i therapy particularly in those with poor glycemic control. In contrast, with 3-month SGLT2i therapy as add-on to GLP-1RA, reductions were seen in GV among those with less severe obesity and greater GV at baseline.

Disclosure

T. Onishi: None. Y. Shioda: None. Y. Mori: None.
235-LB: Time Course of Pancreatic Alpha-Cell Function in Fulminant Type 1 Diabetes
Authors: ZHANG LINGYU , SHI YUWEN , WANG JING , WANG XING , QIN YAO , ZHANG MEI
Published: June 2019

Aim: We aim to investigate the time course of changes in pancreatic alpha-cells function in patients with newly-onset fulminant type 1 diabetes (FT1D).

Methods: Glucagon and C-peptide concentrations were determined in response to 100g steamed bread meal tests (SBMT) in 6 patients with newly-onset FT1D. SBMT were taken every 3 months thereafter until 6 months for 1 FT1D patient and 12 months later for 2 FT1D patients. The area under curve of C-peptide (tAUCc-peptide) and the incremental area under curve of glucagon (iAUCglucagon) were calculated with 0min glucagon as baseline during SBMT.

Results: (1) At the onset of disease, tAUCc-peptide in FT1D patients was significantly lower than that of typical autoimmune type 1 diabetes [(217.04 ± 67.47) vs. (1762.00 ± 255.84) pmol/L*h, P<0.0001]. The iAUCglucagon of 4 FT1D patients were higher than patients with typical autoimmune type 1 diabetes [(21.55±8.88) pmol/L*h vs. (6.72±2.92) pmol/L*h, P=0.006], while iAUCglucagon of 2 FT1D patients were lower [1.09, 3.11 pmol/L*h respectively]. And iAUCglucagon of age-matched healthy control [ -(13.16±7.68) pmol/L*h] was much lower. (2) Glucagon secretion in FT1D patients conversely decreased after 12 months of diagnosis, even as early as 6 months. After 6 months of diagnosis, tAUCc-peptide of the FT1D patient did not decrease (456 vs. 692.1 pmol/L*h), while iAUCglucagon drop from 1.09 to (-4.11) pmol/L*h. After 12 months of diagnosis, with islet beta-cells function completely absent, the iAUCglucagon of 2 FT1D patients were 13.64 vs. 12.34 pmol/L*h, 16.52 vs. (-19.42) pmol/L*h at the onset of diabetes and 12 months later respectively.

Conclusions: The opposing directions of abnormal glucagon and C-peptide secretion support the dysregulated alpha-cells function in newly-onset FT1D patients. The impaired alpha-cells function may recover in the time course of disease.

Disclosure

L. Zhang: None. Y. Shi: None. J. Wang: None. X. Wang: None. Y. Qin: None. M. Zhang: None.

Funding

National Natural Science Foundation of China
2352-PUB: Level of Glycemic Control in Type 2 Diabetes (T2D) Patients with Established Cardiovascular Disease (eCVD) or Chronic Kidney Disease (CKD) Prescribed an SGLT2i
Authors: IGLAY KRISTY , BANSAL NEHA , GULATI TANIA , HANNACHI HAKIMA , FERNANDES GAIL , RAJPATHAK SWAPNIL
Published: June 2019

The recent ADA/EASD consensus statement for management of hyperglycemia preferentially recommends the use of SGLT2i in patients with eCVD or CKD. However, no specific data exist on the level of glycemic control in this high-risk population currently receiving SGLT2i. Our study assessed glycemic control among adult T2D patients with eCVD/CKD on dual therapy (metformin+SGLT2i) at 3 different HbA1c targets (≥7%, ≥7.5%, ≥8%) using the GE Centricity Electronic Medical Record database (June 2015-June 2018). The index date was the most recent encounter for metformin+SGLT2i users. Patients were required to have ≥1 HbA1c measure in the 12 months prior to the index date and ≥1 year of medical history available. ECVD/CKD included patients with CVD only, CKD only, or both CVD and CKD. Results were examined in the overall study cohort and by subgroups of age, gender, and race. Of the 987 included study patients, 40% were female, median age was 62 years, and median A1c was 7.5%. Table 1 shows the level of glycemic control among the study population. 68%, 52% and 36% of patients had HbA1c ≥7%, ≥7.5%, and ≥8%, respectively.

In conclusion, many patients with eCVD/CKD on dual therapy of metformin and SGLT2i were observed to have inadequate glycemic control and should be evaluated for medication adherence and further pharmacological intensification if appropriate.

Disclosure

K. Iglay: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. N. Bansal: Consultant; Self; Merck & Co., Inc. T. Gulati: Consultant; Self; Merck & Co., Inc. H. Hannachi: Employee; Self; Merck & Co., Inc. G. Fernandes: None. S. Rajpathak: None.
2353-PUB: Efficacy and Safety of Ertugliflozin in Hispanic/Latino Patients (Pts) with Type 2 Diabetes Mellitus (T2DM)
Authors: LIU JIE , TARASENKO LISA , ELLISON MISOO C. , PONG ANNPEY , HUYCK SUSAN , MANCUSO JAMES P. , TERRA STEVEN G. , GANTZ IRA
Published: June 2019

Ertugliflozin (ERTU), a SGLT2 inhibitor, improves glycemic control in adults with T2DM. T2DM is prevalent among adults of Hispanic ethnicity in the U.S. Here we report a post hoc analysis of ERTU efficacy and safety in Hispanic/Latino pts in the ERTU Phase 3 program. A1C, body weight (BW), and systolic blood pressure (SBP) were evaluated with ERTU 5 and 15 mg (vs. placebo [PBO] or glimepiride [GLIM]) and ERTU with sitagliptin 100 mg (ERTU 5 or 15 mg/SITA vs. PBO or SITA). Adverse events (AEs) were evaluated.

Among 4855 pts, baseline characteristics were generally similar across treatment groups and between the group of pts self-reported as Hispanic/Latino (n=1178, 24.3%) and the non-Hispanic/Latino group. No meaningful differences were observed between these ethnic groups in A1C reductions with ERTU 5 and 15 mg at week 26 in a pooled analysis of PBO-controlled studies, at week 52 in a GLIM-controlled study, or with ERTU 5 mg/SITA and ERTU 15 mg/SITA groups at week 26 in PBO- and SITA-controlled studies (Figure). Similarly, no meaningful differences between ethnic groups were observed in BW and SBP reductions with ERTU 5 and 15 mg across the program. ERTU was generally well tolerated. The incidence of AEs was similar between ethnic groups. ERTU efficacy and safety were similar between Hispanic/Latino and non-Hispanic/Latino groups. NCTs: 01958671, 02033889, 02036515, 01999218, 02226003, 02099110, 01986855.

Disclosure

J. Liu: Employee; Self; Merck & Co., Inc. L. Tarasenko: Employee; Self; Pfizer Inc. M.C. Ellison: Employee; Self; Merck & Co., Inc. A. Pong: None. S. Huyck: Employee; Self; Merck & Co., Inc. J.P. Mancuso: Employee; Self; Pfizer Inc. Employee; Spouse/Partner; Pfizer Inc. Stock/Shareholder; Spouse/Partner; Pfizer Inc. Stock/Shareholder; Self; Pfizer Inc. S.G. Terra: Employee; Self; Pfizer Inc. I. Gantz: Employee; Self; Merck & Co., Inc.

Funding

Merck Sharp & Dohme Corp; Pfizer Inc.
2367-PUB: Metabolic Abnormalities after Coronary Angiogram in Patients Taking Sodium-Glucose Cotransporter 2 Inhibitors
Authors: SHAHID MARWAH , PICKETT STEPHEN , JIA XIAOMING , ALAM MAHBOOB , BIRNBAUM YOCHAI
Published: June 2019

Background: Some evidence suggests an association of SGLT2 inhibitors (SGLT2i) with an increased risk of euglycemic DKA (euDKA). The incidence and possible procedure-related triggers of metabolic abnormalities in patients taking SGLT2i after coronary angiography has not been well established.

Methods: All patients with diabetes mellitus on a SGLT2i undergoing coronary angiography at a single center from November 2017 to November 2018 were reviewed for periprocedural characteristics and post-procedural metabolic abnormalities. Metabolic abnormalities were defined as: euDKA, DKA with hyperglycemia, or elevated urine ketones without confirmed acidosis.

Results: A total of 44 patients with diabetes mellitus on a SGLT2i undergoing coronary angiogram were identified. There was one case of euDKA after angiography and one of hyperglycemic DKA. There was an additional two cases of patients with elevated urine ketones for whom DKA labs were not available. Baseline characteristics including age (p=0.71), type of SGLT2i (p=.20) and hemoglobin A1c (p=.49) were similar between the cases with metabolic abnormalities and those without. Similarly, procedural variables including indication for angiography (p=0.26), amount of contrast used (p=0.47), angiography outcome (p=0.87) and complications (p=0.40) were not statistically different between the groups.

Conclusions: With a rare incidence and subtle clinical presentation, cases of euDKA may be missed after angiography, especially if acidosis is attributed to the preceding procedure without further workup. Continued case identification may help determine if specific procedural variables contribute to the development of euDKA. As the fasting state and stress of angiography can be triggers for ketosis, protocols should be developed for post-procedural screening and management in this population.

Disclosure

M. Shahid: None. S. Pickett: None. X. Jia: None. M. Alam: None. Y. Birnbaum: Other Relationship; Self; AstraZeneca. Other Relationship; Spouse/Partner; AstraZeneca, Boehringer Ingelheim International GmbH.
238-OR: Long-Term Effects of Intensive Lifestyle Intervention on Cardiovascular Risk Factors in Patients with Diabetes in Real-World Clinical Practice: A 10-Year Longitudinal Study
Authors: ZHANG HONGXIA , TOMAH SHAHEEN , MOTTALIB ADHAM , ASHRAFZADEH SAHAR , HAMDY OSAMA
Published: June 2019

We previously reported that maintenance of significant weight loss for up to 5 years was attainable in real-world clinical practice among patients with diabetes and obesity and had a positive impact on cardiovascular risk factors. This was predicted by the ability to achieve ≥7% weight loss at 1 year through intensive lifestyle intervention (ILI). In this longitudinal study of the same cohort, we report the 10-year follow-up results. The study included 129 patients with diabetes and obesity enrolled in a 12-week ILI program designed for real-world clinical practice. At 1 year, we divided participants into group A, who maintained <7% weight loss (61 patients, 47.3%), and group B, who maintained ≥7% weight loss (68 patients, 52.7%). We prospectively followed them for 10 years. The total cohort lost on average 10.8±4.6 Kg (-9.7%) at 12 weeks and maintained an average weight loss of 7.7±10 Kg (-6.9%) at 10 years. Group A maintained 4.3±9.5 Kg (-4.3%) and group B maintained 10.8±9.3 Kg (-9.3%) of weight loss at 10 years (P<0.001). In group A, A1C decreased from 7.5±1.3% to 6.7±0.9% at 12 weeks but rebounded to 7.7±1.4% at one year and 8.0±1.9% at 10 years. In group B, A1C decreased from 7.4±1.2% to 6.4±0.9% at 12 weeks and rose to 6.8±1.2% at one year and 7.3±1.5% at 10 years (P<0.05 between groups). Despite weight regain, group A maintained significant improvements in LDL and HDL cholesterol, had no change in BP, but significant worsening of serum triglycerides (TG) at 10 years. Group B maintained similar improvements in lipid profile, had a non-significant increase in serum TG at 10 years, but lower BP for the initial 18 months.

In conclusion, significant weight reduction in patients with diabetes can be maintained for up to 10 years in real-world clinical practice. A1C and TG worsened with weight regain, while other lipid improvements were maintained. Sustained weight loss is associated with significantly better A1C at 10 years.

Disclosure

H. Zhang: None. S. Tomah: Stock/Shareholder; Self; Amarin Corporation. A. Mottalib: None. S. Ashrafzadeh: None. O. Hamdy: Advisory Panel; Self; AstraZeneca, Sanofi-Aventis. Consultant; Self; Abbott, Merck & Co., Inc. Research Support; Self; National Dairy Council. Stock/Shareholder; Self; Healthimation, LLC.
2386-PUB: Implications of Lymphoma and Diabetes Mellitus on Patient Outcomes and Care
Authors: KARLIN NINA , VERONA PATRICIA M. , AMIN SHAILJA , BURAS MATTHEW R. , KOSIOREK HEIDI E. , COOK CURTISS
Published: June 2019

Background: We examined the impact of diabetes mellitus (DM) on survival in patients with lymphoma and the impact of lymphoma on glycemic control.

Methods: Patients with newly diagnosed lymphoma with DM (n=91) were identified from the Institutional Cancer Registry and matched to 91 lymphoma patients without DM according to age, gender and year of cancer diagnosis (2005-2016). The file was linked to the electronic medical record to obtain information on DM and lymphoma therapies and laboratory results. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan-Meier method and compared by Cox regression analysis using stratification for matched pairs. Mixed models were used to compare hemoglobin A1c (HbA1c), glucose and lactate dehydrogenase (LDH) during the year following cancer diagnosis.

Results: Mean age of the entire cohort at diagnosis was 73 (range 41-95) years, most (96%) were white. B cell lymphoma accounted for 86% of patients and T cell lymphoma 14%. No differences in race/ethnicity, marital status, alcohol or tobacco use were detected between patients with and without DM. Mean BMI was significantly different between DM and non-DM patients (30.2 (6.5) versus 26.9 (5.6); p=0.003). Among those with DM, mean HbA1c during the year following cancer diagnosis was 6.7%. Mean glucose was significantly different between DM and non-DM pts (140.1 (36.1) versus 107.7 (14.5); p<0.001). Of the DM patients, 51/91 did not have good glycemic control. There was no difference in lactate dehydrogenase (LDH) values between groups. Five-year OS was estimated at 67% (95% CI 56-78%) for DM patients versus 64% (95% CI 53-76%) in non-DM pts. Hazard ratio was 0.64 (95% CI: 0.35 - 1.16; p=0.14). Five-year PFS was estimated at 64% for DM patients versus 57% for non-DM patients. Hazard ratio was 0.60 (95% CI: 0.33-1.08; p=0.09).

Conclusions: Lymphoma and its treatment did not affect glycemic control. DM did not adversely impact survival in patients with lymphoma.

Disclosure

N. Karlin: None. P.M. Verona: None. S. Amin: None. M.R. Buras: None. H.E. Kosiorek: None. C. Cook: None.
240-LB: Angiotensin-Converting Enzyme and Type 2 Diabetes Risk: A Mendelian Randomization Study
Authors: PIGEYRE MARIE , SJAARDA JENNIFER , CHONG MICHAEL , HESS SIBYLLE , BOSCH JACKIE , YUSUF SALIM , GERSTEIN HERTZEL , PARE GUILLAUME
Published: June 2019

The causal relationship between angiotensin-converting enzyme (ACE) inhibition and protection from type 2 diabetes (T2D) remains uncertain. While three large randomized control trials (RCTs) suggested a protective effect of ACE inhibitors compared to placebo, three other RCTs failed to observe an effect, including the only trial dedicated to this question. We hypothesized that ACE concentration-lowering genetic variants could be used to infer the pharmacological effect of ACE inhibitors on T2D risk using a Mendelian Randomization (MR) approach. We first assessed the association between T2D prevalence and ACE serum level in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial (N=8,197). We next investigated whether genetically lowered ACE level was causally linked to the risk of T2D using (i) a two-sample MR analysis applied to the DIAbetes Genetics Replication And Meta-analysis consortium (n=26,676 T2D cases; 132,532 controls), and (ii) an ACE concentration-lowering genetic risk score in the UK Biobank cohort (N=341,872). We then compared the genetically determined effect of lower ACE level on T2D risk to the pharmacological inhibition of ACE vs. placebo, which was evaluated through a meta-analysis of six RCTs (N=31,200). Lower ACE serum level was associated with reduced T2D prevalence (OR, 0.89; 95% CI, 0.82-0.96; P=3.50x10-3) in the ORIGIN trial. Through MR analyses, a 1 SD lower genetically determined ACE level predicted a lower risk of T2D (OR, 0.92; 95% CI, 0.89-0.95; P=1.79x10-7). This result was replicated in the UK Biobank (OR, 0.97; 95% CI, 0.96-0.99, P=8.73x10-4). RCT meta-analysis showed a reduction in T2D incidence on ACE inhibitors vs. placebo (OR, 0.76; 95% CI, 0.60-0.97; P=2.59x10-2), which was consistent with the findings from MR analyses (P for comparison=0.95). Our results support a protective effect of long-term ACE inhibition on T2D risk and suggest to consider patient's risk for T2D when prescribing blood-pressure lowering drugs.

Disclosure

M. Pigeyre: None. J. Sjaarda: None. M. Chong: None. S. Hess: None. J. Bosch: Advisory Panel; Self; Bayer AG. S. Yusuf: None. H. Gerstein: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Sanofi. G. Pare: Consultant; Self; Amgen Inc., Bristol-Myers Squibb Company, Lexicomp, Sanofi. Research Support; Self; Canada Research Chair in Genetic and Molecular Epidemiology, CISCO Professorship in Integrated Health Biosystems, Sanofi.

Funding

Sanofi; Canadian Institutes of Health Research