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Background: We assessed the effect of once-weekly semaglutide and once-daily liraglutide on kidney outcomes in type 2 diabetes., Methods: Pooled (n=12 637) and by-trial data from SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes; n=3297) and LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; n=9340) were assessed for albuminuria change, annual slope of estimated glomerular filtration rate (eGFR) change, and time to persistent eGFR reduction (30%, 40%, 50%, and 57%) from baseline., Results: The median follow-up durations were 2.1 years for SUSTAIN 6 and 3.8 years for LEADER. In the pooled analysis, semaglutide/liraglutide lowered albuminuria from baseline to 2 years after randomization by 24% versus placebo (95% CI, 20%-27%; P <0.001). Significant reductions were also observed in by-trial data analyses ( P <0.001 for all), the largest being with semaglutide 1.0 mg (33% [95% CI, 24%-40%]; P <0.001) at 2 years. With semaglutide 1.0 mg and liraglutide, eGFR slope decline was significantly slowed by 0.87 and 0.26 mL/min/1.73 m 2 /y ( P <0.0001 and P <0.001), respectively, versus placebo. Effects appeared larger in patients with baseline eGFR <60 versus ≥60 mL/min/1.73 m 2 ( P interaction =0.06 and 0.008 for semaglutide 1.0 mg and liraglutide, respectively). Semaglutide/liraglutide significantly lowered risk of persistent 40% and 50% eGFR reductions versus placebo (hazard ratio [HR], 0.86 [95% CI, 0.75-0.99]; P =0.039 and HR, 0.80 [95% CI, 0.66-0.97]; P =0.023, respectively). Similar, nonsignificant, directional results were observed for 30% and 57% eGFR reductions (HR, 0.92 [95% CI, 0.84-1.02]; P =0.10 and HR, 0.89 [95% CI, 0.69-1.13]; P =0.34). In patients with baseline eGFR 30 to <60 mL/min/1.73 m 2 , the likelihood of persistent reduction for all thresholds was increased, ranging from HR 0.71 for 30% reduction (95% CI, 0.59-0.85; P =0.0003, P interaction =0.017) to 0.54 for 57% reduction (95% CI, 0.36-0.81; P =0.003, P interaction =0.035)., Conclusions: In patients with type 2 diabetes, semaglutide/liraglutide offered kidney-protective effects, which appeared more pronounced in patients with preexisting chronic kidney disease.

Objective: Intensive glycemic control reduces the risk of kidney, retinal, and neurologic complications in type 1 diabetes (T1D), but whether it reduces the risk of lower-extremity complications is unknown. We examined whether former intensive versus conventional glycemic control among Diabetes Control and Complications Trial (DCCT) participants with T1D reduced the long-term risk of diabetic foot ulcers (DFUs) and lower-extremity amputations (LEAs) in the subsequent Epidemiology of Diabetes Interventions and Complications (EDIC) study., Research Design and Methods: DCCT participants (n = 1,441) completed 6.5 years on average of intensive versus conventional diabetes treatment, after which 1,408 were enrolled in EDIC and followed annually over 23 years for DFU and LEA occurrences by physical examination. Multivariable Cox proportional hazard regression models estimated associations of DCCT treatment assignment and time-updated exposures with DFU or LEA., Results: Intensive versus conventional glycemic control was associated with a significant risk reduction for all DFUs (hazard ratio 0.77 [95% CI 0.60, 0.97]) and a similar magnitude but nonsignificant risk reduction for first-recorded DFUs (0.78 [0.59, 1.03]) and first LEAs (0.70 [0.36, 1.36]). In adjusted Cox models, clinical neuropathy, lower sural nerve conduction velocity, and cardiovascular autonomic neuropathy were associated with higher DFU risk; estimated glomerular filtration rate <60 mL/min/1.73 m2, albuminuria, and macular edema with higher LEA risk; and any retinopathy and greater time-weighted mean DCCT/EDIC HbA1c with higher risk of both outcomes (P < 0.05)., Conclusions: Early intensive glycemic control decreases long-term DFU risk, the most important antecedent in the causal pathway to LEA., (© 2022 by the American Diabetes Association.)

Aim: To evaluate the effect of empagliflozin on uric acid (UA) levels, antigout medication and gout episodes in the EMPA-REG OUTCOME trial (NCT01131676)., Materials and Methods: A total of 7020 patients with type 2 diabetes (T2D) were randomized to either empagliflozin (10 or 25 mg) or placebo. The effects of empagliflozin versus placebo on UA concentration were assessed using mixed linear models. A composite outcome of new prescription of antigout medication or gout episode was studied with Cox proportional hazards models., Results: Empagliflozin reduced serum UA levels versus placebo: week 52 adjusted mean treatment difference = -0.37 (95% confidence interval [CI] -0.42, -0.31) mg/dL; this was more pronounced in patients with baseline UA ≥ 7.0 mg/dL versus <7.0 mg/dL: week 52 adjusted mean treatment difference = -0.56 (95% CI -0.68, -0.43) and -0.30 (95% CI -0.37, -0.24) mg/dL, respectively. Among 6607 patients not taking antigout medications at baseline, 5.2% had a gout episode or initiated antigout treatment versus 3.6% in the placebo and empagliflozin groups, respectively: hazard ratio 0.67 (95% CI 0.53, 0.85; P = 0.001). Both components of the composite outcome contributed to the reduction with empagliflozin in the composite. Risk reduction was similar with both empagliflozin doses., Conclusions: Empagliflozin reduced UA levels and the composite of gout episodes or prescription of antigout medication. These clinically important findings expand the utility of empagliflozin as a potential antigout treatment in patients with T2D, beyond its well-established cardio-renal benefits., (© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Diabetic kidney disease with nephrotic-range proteinuria (NRP) is commonly associated with rapid kidney function loss, increased cardiovascular risk, and premature mortality. We explored the effect of empagliflozin in patients with type 2 diabetes and cardiovascular disease, complicated by presence of this major risk factor for progressive kidney disease, in a post-hoc analysis of data from the EMPA-REG OUTCOME trial (NCT01131676)., Methods: Cox proportional hazards models were used to investigate the risk of cardiovascular and kidney outcomes in participants with and without NRP, defined by urine albumin-to-creatinine ratio (UACR) ≥2200 mg/g at baseline. Annual loss of eGFR during chronic treatment (eGFR slopes) and hypothetical time to projected end-stage kidney disease (ESKD), conditioning upon linearity of eGFR change over time if a patient did not decease before projected ESKD, were calculated using a random-intercept random-coefficient model. Safety was described based on investigator-reported adverse events., Findings: 112 participants (pooled empagliflozin, n  = 70; placebo, n  = 42; median on-treatment follow-up of 1·9 years on placebo compared with 2·3 years on empagliflozin) presented with NRP at baseline; eGFR and UACR were balanced between treatments. Empagliflozin benefits on cardiovascular death, hospitalisation for heart failure, or kidney outcomes, were consistent in participants with and without NRP (p interaction >0·1). Treatment effects of empagliflozin on adjusted annual mean eGFR slope were more pronounced in participants with NRP versus those without (p interaction 0·005). Empagliflozin was estimated to double the median hypothetical time to projected ESKD in participants with NRP. The overall safety profile of empagliflozin was comparable between participants with and without NRP at baseline., Interpretation: Our data suggests that empagliflozin might slow kidney function loss and delay the estimated onset of projected ESKD in patients with type 2 diabetes and cardiovascular disease complicated by NRP., Competing Interests: PR and GR have no conflicts to report. BJK is an employee of Boehringer Ingelheim, the University Hospital of Würzburg and has received grants from the IZKF (Interdisziplinaeres Zentrum fuer klinische Forschung) of the University of Wuerzburg, and from Boehringer Ingelheim. SI reports consulting fees and honoraria from Intarcia Therapeutics, Daiichi-Sankyo, Lexicon Pharmaceuticals, Janssen, Sanofi, AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. BZ has received grant support from Boehringer Ingelheim, AstraZeneca, and Novo Nordisk; and consulting fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi Aventis. SH, MM, MvE, and AKW are employees of Boehringer Ingelheim. CW reports honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Mitsubishi, and MSD., (© 2021 Published by Elsevier Ltd.)

Aims: In the EMPA-REG OUTCOME trial, empagliflozin reduced risk of death from heart failure (HF) or hospitalization for heart failure (HHF) versus placebo in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular (CV) disease. We evaluated post hoc the degree to which covariates mediated the effects of empagliflozin on HHF or HF death., Methods and Results: A mediator had to fulfil the following criteria: (i) affected by active treatment, (ii) associated with the outcome, and finally (iii) adjustment for it results in a reduced treatment effect compared with unadjusted analysis. Potential mediators were calculated as change from baseline or updated mean and evaluated in univariable analyses as time-dependent covariates in Cox regression of time to HHF or HF death; those with the largest mediating effects were then included in a multivariable analysis. Increases in heart rate, log urine albumin-to-creatinine ratio (UACR), waist circumference, and uric acid were associated with increased risk of HHF or HF death; increases in high-density lipoprotein cholesterol, estimated glomerular filtration rate, haematocrit, haemoglobin, and albumin were associated with reduced risk of HHF or HF death. In univariable analyses, change from baseline in haematocrit, haemoglobin, albumin, uric acid, and logUACR mediated 51%, 54%, 23%, 24%, and 27% of the risk reduction with empagliflozin versus placebo, respectively. Multivariable analysis including haemoglobin, logUACR, and uric acid mediated 85% of risk reduction with similar results when updated means were evaluated., Conclusions: Changes in haematocrit and haemoglobin were the most important mediators of the reduction in HHF and death from HF in patients with T2DM and established CV disease treated with empagliflozin. Albumin, uric acid, and logUACR had smaller mediating effects in this population., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aim: To evaluate the effects of empagliflozin versus placebo on subsequent insulin initiation or dosing changes in a large cardiovascular outcomes trial., Materials and Methods: In EMPA-REG OUTCOME, 7020 patients with type 2 diabetes and cardiovascular disease received empagliflozin 10 mg, 25 mg, or placebo. Median follow-up was 3.1 years. After 12 weeks of treatment, changes in background antihyperglycaemic therapy were permitted. Among insulin-naïve patients, we assessed the effects of pooled empagliflozin arms versus placebo on time to initiation of insulin. Among insulin-treated patients, we assessed effects on time to an increase or decrease in insulin dose of more than 20%., Results: In 3633 (52%) participants not treated with insulin at baseline, empagliflozin reduced new use of insulin versus placebo by 60% (7.1% vs. 16.4%; adjusted HR 0.40 [95% CI 0.32-0.49]; P < .0001). In 3387 (48%) patients using insulin at baseline, empagliflozin reduced the need for a greater than 20% insulin dose increase by 58% (14.4% vs. 29.3%; adjusted HR 0.42 [95% CI 0.36-0.49]; P < .0001) and increased the proportion achieving sustained greater than 20% insulin dose reductions without subsequent increases in HbA1c compared with placebo (9.2% vs. 4.9%; adjusted HR 1.87 [95% CI: 1.39-2.51]; P < .0001). Sensitivity analyses confirmed consistent findings when insulin dose changes of more than 10% or more than 30% were considered., Conclusions: In patients with type 2 diabetes and cardiovascular disease, empagliflozin markedly and durably delays insulin initiation and substantial increases in insulin dose, while facilitating sustained reductions in insulin requirements over time., (© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

The article features Canadian diabetes clinician scientist Bernard Zinman and his works and accomplishments in the management of diabetes. Also cited are a brief family background of Zinman including his marriage to Jean Zucker, his studies at McGill University and McGill Medical School, and his works on endocrinology that are driven by his interests in biochemistry and metabolism.

Background: The metabolic syndrome is associated with increased vascular disease risk. We evaluated two carotid ultrasound measurements, namely intima media thickness and total plaque volume, in a Canadian Oji-Cree population with a high metabolic syndrome prevalence rate. Methods: As part of the Sandy Lake Complications Prevalence and Risk Factor Study, 166 Oji-Cree subjects (baseline metabolic syndrome prevalence, 44.0%, according to the National Cholesterol Education Program Adult Treatment Panel III guidelines) were examined using a highresolution duplex ultrasound scanner. Results: Image analysis showed that mean intima media thickness was elevated in subjects with the metabolic syndrome (818 ± 18 vs 746 ± 20 μm), as was total plaque volume (125 ± 26 vs 77.3 ± 17.0 mm3). However, after adjustment for age and sex, the differences were significant only for intima media thickness (P = 0.039). Furthermore, a significant trend towards increased intima media thickness was observed with increasing numbers of metabolic syndrome components: mean intima media thickness was highest among individuals with all five metabolic syndrome components compared to those with none (866 ± 55 vs 619 ± 23 μm, P = 0.0014). A similar, but non-significant trend was observed for total plaque volume. Conclusion: This is the first study of the relationship between the metabolic syndrome and two distinct carotid ultrasound traits measured in the same individuals. The results suggest that standard intima media thickness measurement shows a more consistent and stronger association with the metabolic syndrome than does total plaque volume. [ABSTRACT FROM AUTHOR]

Background: Recent studies have suggested that gestational diabetes (GDM) is a heterogeneous condition with distinct subtypes determined by whether the predominant metabolic abnormality is impaired insulin sensitivity or deficient insulin secretion. However, it is not known if the elevated future risk of pre-diabetes/diabetes associated with GDM varies according to these subtypes. Thus, we sought to evaluate maternal metabolic function in the 1st year postpartum in relation to GDM subtypes., Methods: In this prospective cohort study conducted in Toronto, Canada, 613 women underwent GDM screening by oral glucose tolerance test (OGTT) in pregnancy, followed by repeat OGTT at both 3-months and 12-months postpartum between 09/2003 and 03/2016. The antepartum OGTT identified 3 groups of women: GDM with predominant sensitivity defect (GDM-sensitivity), GDM with predominant secretion defect (GDM-secretion), and non-GDM., Findings: Antepartum findings persisted after pregnancy, with lower insulin sensitivity in GDM-sensitivity (Matsuda index; HOMA-IR) and lower insulin secretion in GDM-secretion (Stumvoll first-phase; insulinogenic index (IGI)) at both 3-months and 12-months (all p <0.005). Beta-cell compensation (Insulin Secretion-Sensitivity Index-2; IGI/HOMA-IR) was lower in both GDM subtypes compared to non-GDM (all p <0.0005) but did not differ between GDM-sensitivity and GDM-secretion. Similarly, both subtypes exhibited higher post-challenge glycemia on OGTT at 3-months and 12-months than non-GDM (all p <0.0005) but did not differ from one another. The prevalence of pre-diabetes/diabetes was higher in both GDM-sensitivity (30.9%; 95%CI: 21.7-41.2) and GDM-secretion (27.6%; 16.7-40.9) than in non-GDM (10.4%; 7.7-13.6) at 12-months (both p <0.005), with no difference between GDM subtypes ( p  = 0.75)., Interpretation: Beta-cell dysfunction, glycemia and incident pre-diabetes/diabetes do not vary between GDM subtypes in the 1st year postpartum., Funding: Canadian Institutes of Health Research; Diabetes Canada., Competing Interests: RR reports grants from Boehringer Ingelheim, grants and personal fees from Novo Nordisk, personal fees from Sanofi, personal fees from Eli Lilly, outside the submitted work. RR holds the Boehringer Ingelheim Chair in Beta-cell Preservation, Function and Regeneration at Mount Sinai Hospital and his research program is supported by the Sun Life Financial Program to Prevent Diabetes in Women. BZ reports personal fees from Eli Lilly, personal fees from NovoNordisk Advisory Board, personal fees from Merck, personal fees from Boehringer Ingelheim, outside the submitted work. CY, AJH, PWC, and MS have nothing to disclose., (© 2021 The Author(s).)

Aim: To investigate whether the cardiorenal benefits of the sodium-glucose co-transporter-2 inhibitor empagliflozin are affected by body mass index (BMI) in type 2 diabetes patients with established cardiovascular (CV) disease, including Asians., Methods: In this exploratory analysis of the EMPA-REG OUTCOME trial, we used Cox regression to evaluate the effects of empagliflozin on all-cause mortality, hospitalization for heart failure (HHF) or CV death, and incident or worsening nephropathy by baseline BMI category., Results: Of the 7020 participants (1517 Asians [21.6%]), 934 (13.3%), 2465 (35.1%) and 3621 (51.6%) had a BMI of less than 25, 25 to less than 30, and 30 kg/m 2 or higher, respectively. Overall, hazard ratios for empagliflozin versus placebo for all-cause mortality, HHF or CV death, and incident or worsening nephropathy were 0.68 (95% CI 0.57, 0.82), 0.66 (0.55, 0.79) and 0.61 (0.53, 0.70), respectively, and were consistent across BMI categories (P values for interaction between treatment and BMI were .6772, .3087 and .6265, respectively). Results were similar in Asians using these BMI categories and categories of less than 24, 24 to less than 28, and 28 kg/m 2 or higher., Conclusion: Empagliflozin reduced cardiorenal and mortality risk regardless of BMI at baseline, including in Asians with a lower BMI., (© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: In the EMPA-REG OUTCOME trial, in patients with type 2 diabetes and established atherosclerotic cardiovascular (CV) disease, empagliflozin vs. placebo reduced the risk of hospitalization for heart failure (HHF) by 35%, CV death/HHF by 34%, and CV death by 38%, with an early separation of the cumulative incidence curves. We explored at what time point after randomization these benefits became apparent., Methods and Results: We expressed time trajectories for the effect of pooled empagliflozin doses vs. placebo on HHF, CV death/HHF, and CV death based on hazard ratios (95% confidence interval) and calculated the hazard ratio on the day the effect reached significance using Cox proportional hazards models. Overall, 7020 patients aged ≥18 years were treated with empagliflozin 10 mg (N = 2345), empagliflozin 25 mg (N = 2342), or placebo (N = 2333) once daily in addition to standard of care. Mean age (years ± SD) was 63.1 ± 8.6, and 72% were male. The benefit of empagliflozin on CV death first reached statistical significance on Day 59 (HR [95% confidence interval]) (0.28 [0.08, 0.96], P = 0.0424) and was generally sustained throughout the trial (overall 0.62 [0.49, 0.77], P < 0.0001). Risk reduction with empagliflozin on HHF reached statistical significance on Day 17 (0.10 [0.01, 0.87], P = 0.0372) and was sustained throughout the study (overall 0.65 [0.50, 0.85], P = 0.0017). For the composite outcome of CV death or HHF, risk reduction with empagliflozin reached statistical significance on Day 27 (0.28 [0.08, 0.97], P = 0.0445) and was sustained throughout follow-up (overall 0.66 [0.55, 0.79], P < 0.0001)., Conclusions: In EMPA-REG OUTCOME, the benefit of empagliflozin in reducing the risk of HHF, CV death/HHF, and CV death emerged within weeks after treatment initiation. The earliest benefit appears to be on HHF., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objectives: Using latent class analysis (LCA) of EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), this study identified distinct phenotypes in subjects with type 2 diabetes (T2D) and cardiovascular (CV) disease and explored treatment effects across phenotypes., Background: In the EMPA-REG OUTCOME trial, empagliflozin reduced risk of CV death or hospitalization for heart failure (HHF) by 34% in subjects with T2D and CV disease. Among such subjects, there has been limited evaluation of clinical phenotypes., Methods: Overall, 7,020 participants were treated with empagliflozin 25 mg, 10 mg, or placebo. For this post hoc analysis, participants were randomly separated into training (two-thirds of patients) and validation (remaining one-third) sets. LCA identified 3 phenotype groups (n = 6,639 with complete data). The phenotype association with CV death or HHF and empagliflozin treatment effect across groups was explored by Cox regression (in training and validation sets)., Results: In the training set, phenotype group 1 (n = 1,463; 33.1%) included younger patients with shorter T2D duration and the highest estimated glomerular filtration rate (eGFR). Phenotype group 2 (n = 1,172; 26.5%) included more women with non-coronary artery disease. Phenotype group 3 (n = 1,785; 40.4%) included older patients with advanced coronary disease and the lowest eGFR. The risk of CV death varied across phenotypes (group 2 vs. 1: hazard ratio [HR]; 1.83; 95% confidence interval [CI]: 1.23 to 2.71; group 3 vs. 1: HR: 1.86; 95% CI: 1.30 to 2.67) with similar patterns for CV death or HHF. Consistent treatment effects of empagliflozin were seen across phenotypes in the training and validation sets (interaction p > 0.30)., Conclusions: Among participants with T2D, this study identified 3 phenotypes with varying CV risk. The treatment effect across phenotypes reaffirms the robustness of CV death or HHF reduction with empagliflozin. (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients [EMPA-REG OUTCOME]; NCT01131676)., Competing Interests: Funding Support and Author Disclosures The EMPA-REG OUTCOME trial was funded by Boehringer Ingelheim and Eli-Lilly. Dr. Sharma has been supported by Canada Institute for Health Research - (Grant Number: 175095), the Fonds de Recherche Santé Quebec (FRSQ) Junior 1 clinician scholars program, Alberta Innovates Health Solution, European Society of Cardiology young investigator grant, Roche Diagnostics, Boehringer Ingelheim, Novartis, and Takeda. Drs. Ofstad, Zwiener and Hantel are employees of Boehringer Ingelheim. Dr. Ahmad has been a consultant for Amgen and Cytokinetics. Dr. Zinman has received research grants awarded to his institution from Boehringer Ingelheim, AstraZeneca and Novo Nordisk, and has received honoraria from Janssen, Sanofi, Eli Lilly and Company, Boehringer Ingelheim, Novo Nordisk, and Merck Sharp & Dohme. Dr. Wanner has received personal fees from Boehringer Ingelheim; and has received personal fees from Akebia, AstraZeneca, Bayer, Eli Lilly, GlaxoSmithKline, Gilead, Merck Sharpe Dohme, Mundipharma, Sanofi-Genzyme, and Vifor Fresenius outside the submitted work. Dr. George was an employee of Boehringer Ingelheim at the time of the study conduct. Dr. Desai has worked under contract with the Centers for Medicare and Medicaid Services; and has been a consultant for Amgen, Boehringer Ingelheim, Cytokinetics, Relypsa, Novartis, and SC Pharmaceuticals. Dr. Mentz has received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Eli Lilly, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Medtronic, Merck, Novartis, Relypsa, Respicardia, Roche, Sanofi, Vifor, and Windtree Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the association of adipose tissue insulin resistance with longitudinal changes in biomarkers of adipose tissue function, circulating lipids, and dysglycemia., Research Design and Methods: Adults at risk for type 2 diabetes in the Prospective Metabolism and Islet Cell Evaluation (PROMISE) cohort had up to four assessments over 9 years ( n = 468). Adipose tissue insulin resistance was determined using a novel validated index, Adipo-IR, calculated as the product of fasting insulin and nonesterified fatty acids measured at baseline. Fasting serum was used to measure biomarkers of adipose tissue function (adiponectin and soluble CD163 [sCD163]), circulating lipids (total cholesterol, HDL, LDL, triglyceride [TG]), and systemic inflammation (interleukin-6 [IL-6] and tumor necrosis factor-α [TNF-α]). Incident dysglycemia was defined as the onset of impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes at follow-up. Generalized estimating equation (GEE) models were used to assess the relationship of Adipo-IR with longitudinal outcomes., Results: GEE analyses showed that elevated Adipo-IR was longitudinally associated with adipose tissue dysfunction (adiponectin -4.20% [95% CI -6.40 to -1.95]; sCD163 4.36% [1.73-7.06], HDL -3.87% [-5.15 to -2.57], TG 9.26% [5.01-13.69]). Adipo-IR was associated with increased risk of incident dysglycemia (odds ratio 1.59 [95% CI 1.09-2.31] per SD increase). Associations remained significant after adjustment for waist circumference and surrogate indices for insulin resistance. There were no significant longitudinal associations of Adipo-IR with IL-6, TNF-α, total cholesterol, or LDL., Conclusions: Our findings demonstrate that adipose tissue insulin resistance is prospectively associated with adipose tissue function, HDL, TG, and incident dysglycemia., (© 2021 by the American Diabetes Association.)

Objectives: This study sought to evaluate the effects of empagliflozin on extracellular volume (ECV) in individuals with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD)., Background: Empagliflozin has been shown to reduce left ventricular mass index (LVMi) in patients with T2DM and CAD. The effects on myocardial ECV are unknown., Methods: This was a prespecified substudy of the EMPA-HEART (Effects of Empagliflozin on Cardiac Structure in Patients with Type 2 Diabetes) CardioLink-6 trial in which 97 participants were randomized to receive empagliflozin 10 mg daily or placebo for 6 months. Data from 74 participants were included: 39 from the empagliflozin group and 35 from the placebo group. The main outcome was change in left ventricular ECV from baseline to 6 months determined by cardiac magnetic resonance (CMR). Other outcomes included change in LVMi, indexed intracellular compartment volume (iICV) and indexed extracellular compartment volume (iECV), and the fibrosis biomarkers soluble suppressor of tumorgenicity (sST2) and matrix metalloproteinase (MMP)-2., Results: Baseline ECV was elevated in the empagliflozin group (29.6 ± 4.6%) and placebo group (30.6 ± 4.8%). Six months of empagliflozin therapy reduced ECV compared with placebo (adjusted difference: -1.40%; 95% confidence interval [CI]: -2.60 to -0.14%; p = 0.03). Empagliflozin therapy reduced iECV (adjusted difference: -1.5 ml/m 2 ; 95% CI: -2.6 to -0.5 ml/m 2 ; p = 0.006), with a trend toward reduction in iICV (adjusted difference: -1.7 ml/m 2 ; 95% CI: -3.8 to 0.3 ml/m 2 ; p = 0.09). Empagliflozin had no impact on MMP-2 or sST2., Conclusions: In individuals with T2DM and CAD, 6 months of empagliflozin reduced ECV, iECV, and LVMi. No changes in MMP-2 and sST2 were seen. Further investigation into the mechanisms by which empagliflozin causes reverse remodeling is required. (Effects of Empagliflozin on Cardiac Structure in Patients With Type 2 Diabetes [EMPA-HEART]; NCT02998970)., Competing Interests: Funding Support And Author Disclosures This trial was supported by an unrestricted investigator-initiated study grant from Boehringer Ingelheim. The study sponsor was not involved in the study design; data collection, analysis and interpretation; writing of this report or in the decision to submit for publication. Dr. Mason was the recipient of a Boehringer Ingelheim Diabetes and Cardiovascular Disease Scholarship. Dr. Coelho-Filho was partially supported by a National Council for Scientific and Technological Development (CNPq) Productivity in Research award grant (303366/2015-0) and a Young Investigators Grant from The São Paulo Research Foundation (2015/15402-2). Dr. Verma holds a Canada Research Chair in Cardiovascular Surgery. Dr. Gilbert holds a Canada Research Chair in Diabetes Complications. Dr. Jüni holds a Canada Research Chair in Clinical Epidemiology of Chronic Diseases. Dr. Mazer is the recipient of a Merit Award from the University of Toronto Department of Anesthesia. Dr Connelly is supported by a Merit Award from the Department of Medicine, University of Toronto. Dr. Coelho-Filho has received research grants and/or speaking honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Shire, and Pfizer. Dr. Verma has received research grants and/or speaking honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, EOCI Pharmacomm Ltd., HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, Sun Pharmaceuticals, and the Toronto Knowledge Translation Working Group; and is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. Dr. Teoh has received honorarium from Boehringer Ingelheim and writing fees for unrelated manuscripts from Merck. Dr. Gilbert has received institutional research grants from AstraZeneca and Boehringer Ingelheim; served on advisory panels for AstraZeneca, Boehringer Ingelheim, and Janssen; received CME speaker honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, and Janssen; and owns stock in Certa, OccuRx, and Fibrocor Therapeutics. Dr. Leiter has received research grants from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, GlaxoSmithKline, Novo Nordisk, and Sanofi; served on advisory panels for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi; and received CME speaker honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi, and Servier. Dr. Jüni has served as unpaid member of the steering group of trials funded by Abbott Vascular, AstraZeneca, Biotronik, Biosensors, St. Jude Medical, Terumo, and The Medicines Company; received institutional research grants from AstraZeneca, Biotronik, Biosensors International, Eli Lilly, and The Medicines Company; and received institutional honoraria for participation in advisory boards and/or consulting from Amgen, Ava, and Fresenius but has not received personal payments by any pharmaceutical company or device manufacturer. Dr. Zinman has received research grants and/or advisory board honorarium from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi. Dr. Mazer has received honoraria from Amgen, Boehringer Ingelheim, Octapharma, and AstraZeneca. Dr. Yan has received research support from AstraZeneca. Dr. Connelly is listed as an inventor on a patent application by Boehringer Ingelheim on the use of dipeptidyl peptidase-4 inhibitors in heart failure; has received institutional research grants from AstraZeneca, Servier, and Boehringer Ingelheim; has received support for travel to scientific meetings from Boehringer Ingelheim; has received honoraria for speaking engagements and ad hoc participation in advisory boards from Servier, Merck, Eli Lilly, AstraZeneca, Boehringer Ingelheim, Ferring, Novo Nordisk, Novartis, and Janssen; and is supported by a Merit Award from the Department of MEdicine, University of Toronto. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021. Published by Elsevier Inc.)

Aim: To determine the relationship between polyvascular disease and risk of hospitalization for heart failure (HHF) and cardiovascular (CV) death in the EMPA-REG OUTCOME population, and the relationship of kidney dysfunction co-existent with polyvascular disease on CV/heart failure (HF) outcomes., Materials and Methods: Patients with type 2 diabetes and atherosclerotic CV (ASCVD) received empagliflozin 10, 25 mg or placebo. Post hoc, subgroups were analyzed by one versus two or more vascular beds, and the estimated glomerular filtration rate ([eGFR] < vs. ≥60 mL/min/1.73 m 2 ) at baseline. The empagliflozin arms were pooled. Time to CV death, HHF, CV death (excluding fatal stroke) or HHF, all-cause mortality (ACM) and 3-point major adverse CV events (3P-MACE) were assessed using multivariable Cox regression models., Results: Baseline characteristics (N = 6959) within subgroups were balanced between treatment groups. In the placebo group, two or more versus one vascular bed increased HHF risk (1.59 [95% confidence interval 1.02, 2.49]), CV death (2.17 [1.52, 3.09]), CV death/HHF (1.79 [1.32, 2.43]), ACM (1.95 [1.44, 2.64]) and 3P-MACE (1.76 [1.36, 2.27]). Hazard ratios for those with polyvascular disease/kidney dysfunction (vs. 1 vascular bed/eGFR ≥60 mL/min/1.73 m 2 ) were HHF 2.80 (1.46, 5.36), CV death 3.10 (1.87, 5.13), CV death/HHF 2.71 (1.74, 4.23), ACM 2.59 (1.67, 4.02) and 3P-MACE 2.62 (1.82, 3.77). Empagliflozin reduced the risk of all outcomes across subgroups., Conclusions: Polyvascular disease with/without kidney dysfunction markedly increases the risk of HF/CV events. Empagliflozin consistently reduces risk, regardless of vascular bed and kidney function status., (© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

The discovery of insulin in 1921 and the progress achieved in the ensuing century highlight the promise and challenge of biochemically modifying the molecule to achieve optimization of its delivery and therapeutic efficacy. Normal endogenous insulin secretion consists of a highly orchestrated physiologic loop wherein multiple metabolic signals trigger the pancreatic β cells to secrete the precise amount of insulin into the portal system required to maintain euglycemia. Accordingly, in the treatment of diabetes, attempting to replicate this complex physiology with exogenous insulin therapy given subcutaneously presents a clinical challenge. In this context, recombinant DNA-based technology has enabled the development of insulin analogs that have been specifically designed to confer advantageous pharmacodynamic features that can better mimic endogenous insulin secretion. In this review, we discuss the development of the most widely available insulin preparations and provide evidence-based insight into their use in clinical practice., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background Cardio/kidney composite end points are clinically relevant but rarely analyzed in cardiovascular trials. This post hoc analysis of the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial evaluated cardio/kidney composite end points by 2 statistical approaches. Methods and Results A total of 7020 patients with type 2 diabetes mellitus and established cardiovascular disease were treated with empagliflozin 10 or 25 mg (n=4687) or placebo (n=2333) on top of standard care. Cardio/kidney composite end points studied were: (1) cardiac or kidney death, kidney failure, hospitalization for heart failure, sustained decline in estimated glomerular filtration rate ≥40% from baseline, or sustained progression to macroalbuminuria; (2) cardiac or kidney death, kidney failure, hospitalization for heart failure, or sustained estimated glomerular filtration rate decline ≥40% from baseline; and (3) cardiac or kidney death, kidney failure, hospitalization for heart failure, or sustained doubling in serum creatinine from baseline. Cox regression using time-to-first-event analysis and win ratio (WR) using hierarchical order of events were applied. Empagliflozin reduced the risk of all cardio/kidney composites. The results varied only slightly between Cox and WR (eg, composite 1: hazard ratio, 0.56 [95% CI, 0.49-0.64]; WR, 1.76 [95% CI, 1.53-2.02]. WR prioritizes events by clinical importance; in particular, all fatal events are evaluated, whereas Cox regression ignores deaths when preceded by nonfatal events. Of the 285 cardio/kidney deaths in the analysis, 44 to 56 (15%-20%), depending on the composite, occurred after a nonfatal event and were not evaluated in Cox regression but evaluated by the WR. Conclusions By considering the clinical relevance of different event types, the WR represents an appropriate method to complement the traditional time-to-first-event analysis in cardio/kidney outcomes. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01131676.