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Aims: When administered in early type 2 diabetes (T2DM), the strategy of 'induction' with short-term intensive insulin therapy (IIT) followed by 'maintenance' with metformin thereafter can yield outstanding glycaemic control, with some patients achieving A1c in the normal range of its assay. We thus sought to identify determinants of sustained normalisation of A1c in response to this treatment strategy., Materials and Methods: In this study, adults with T2DM of mean duration 1.7 ± 1.4 years received induction IIT (glargine, lispro) for 3 weeks, followed by metformin maintenance either with or without periodic 2-week courses of IIT every 3 months for 2 years. Sustained glycaemic normalisation was defined by A1c <6.0% at 2 years., Results: Of 101 participants, 26 achieved A1c <6.0% at 2 years. At baseline, these individuals had lower A1c and fasting glucose than the other participants, along with better beta-cell function. During maintenance therapy from 3 weeks to 2 years, they had greater reduction of adiposity (body mass index: p = 0.02; waist circumference: p = 0.02), hepatic insulin resistance (HOMA-IR: p = 0.02) and ALT (p = 0.005), coupled with relative stabilisation of beta-cell function and glycaemia. On logistic regression analyses, significant independent predictors of normalisation of A1c at 2 years were baseline A1c (adjusted odds ratio [aOR] = 0.01 [95% CI 0.001-0.16], p = 0.001) and the changes in waist circumference (aOR = 0.77 [0.63-0.94], p = 0.012) and ALT (aOR = 0.90 [0.82-0.98], p = 0.019) during maintenance therapy from 3 weeks to 2 years., Conclusions: While lower baseline A1c and greater reduction in central adiposity predicted A1c <6.0% at 2 years as anticipated, the emergence of greater reduction in ALT as a concomitant determinant highlights the role of the liver in the achievement of sustained glycaemic normalisation., (© 2024 John Wiley & Sons Ltd.)

Aim: The diagnosis of gestational diabetes (GDM) identifies women who are at future risk of developing type 2 diabetes. However, it is unclear if diagnosing GDM thus motivates women to increase physical activity after pregnancy or if this medicalization has the opposite effect of decreasing activity, possibly reflecting assumption of a sick role. We thus sought to evaluate the impact of diagnosing GDM on changes in maternal physical activity after pregnancy., Methods: In this prospective cohort study, physical activity patterns were assessed by the Baecke questionnaire for the year before pregnancy and the first year postpartum in 405 white women comprising the following three gestational glucose tolerance groups: (a) those who did not have GDM (non-GDM; n = 247), (b) women with undiagnosed GDM (n = 46) and (c) those diagnosed with GDM (n = 112)., Results: In the year before pregnancy, mean adjusted total physical activity progressively decreased from non-GDM to undiagnosed GDM to diagnosed GDM (p = .067). Conversely, at 1 year postpartum, total physical activity was highest in those who had been diagnosed with GDM (p = .02). Compared with non-GDM, diagnosed GDM predicted an increase in total physical activity from pre-pregnancy to 1 year postpartum (t = 2.3, p = .02) whereas undiagnosed GDM predicted a concurrent decrease in leisure-time activity (t = -2.74, p = .006). Accordingly, the mean adjusted increase in body mass index from pre-pregnancy to 1 year postpartum was lowest in those with diagnosed GDM (0.26 ± 0.25 kg/m 2 ), highest in undiagnosed GDM (1.23 ± 0.38 kg/m 2 ) and intermediate in non-GDM (0.89 ± 0.22 kg/m 2 ) (overall p = .04)., Conclusion: Diagnosis of GDM leads to increased physical activity after pregnancy that may partially attenuate postpartum weight retention., (© 2023 John Wiley & Sons Ltd.)

PurposeWe examined the relationship between glycemic control and urinary tract infections in women with type 1 diabetes mellitus.Materials and methodsWomen enrolled in the Epidemiology of Diabetes Interventions and Complications study, the observational followup of the Diabetes Control and Complications Trial, were surveyed to assess the rate of physician diagnosed urinary tract infections in the preceding 12 months. The relationship between glycated hemoglobin levels and number of urinary tract infections in the previous 12 months was assessed using a multivariable Poisson regression model.ResultsA total of 572 women were evaluated at year 17. Mean age was 50.7 ± 7.2 years, mean body mass index was 28.6 ± 5.9 kg/m(2), mean type 1 diabetes duration was 29.8 ± 5.0 years and mean glycated hemoglobin was 8.0% ± 0.9%. Of these women 86 (15.0%) reported at least 1 physician diagnosed urinary tract infection during the last 12 months. Higher glycated hemoglobin levels were significantly associated with number of urinary tract infections such that for every unit increase (1%) in recent glycated hemoglobin level, there was a 21% (p=0.02) increase in urinary tract infection frequency in the previous 12 months after adjusting for race, hysterectomy status, urinary incontinence, sexual activity in the last 12 months, peripheral and autonomic neuropathy, and nephropathy.ConclusionsThe frequency of urinary tract infections increases with poor glycemic control in women with type 1 diabetes. This relationship is independent of other well described predictors of urinary tract infections and suggests that factors directly related to glycemic control may influence the risk of lower urinary tract infections.

We examined whether persistence of epigenetic DNA methylation (DNA-me) alterations at specific loci over two different time points in people with diabetes are associated with metabolic memory, the prolonged beneficial effects of intensive vs. conventional therapy during the Diabetes Control and Complications Trial (DCCT) on the progression of microvascular outcomes in the long-term follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) Study. We compared DNA-me profiles in genomic DNA of whole blood (WB) isolated at EDIC Study baseline from 32 cases (DCCT conventional therapy group subjects showing retinopathy or albuminuria progression by EDIC Study year 10) vs. 31 controls (DCCT intensive therapy group subjects without complication progression by EDIC year 10). DNA-me was also profiled in blood monocytes (Monos) of the same patients obtained during EDIC Study years 16-17. In WB, 153 loci depicted hypomethylation, and 225 depicted hypermethylation, whereas in Monos, 155 hypomethylated loci and 247 hypermethylated loci were found (fold change ≥1.3; P < 0.005; cases vs. controls). Twelve annotated differentially methylated loci were common in both WB and Monos, including thioredoxin-interacting protein (TXNIP), known to be associated with hyperglycemia and related complications. A set of differentially methylated loci depicted similar trends of associations with prior HbA1c in both WB and Monos. In vitro, high glucose induced similar persistent hypomethylation at TXNIP in cultured THP1 Monos. These results show that DNA-me differences during the DCCT persist at certain loci associated with glycemia for several years during the EDIC Study and support an epigenetic explanation for metabolic memory.

Context: Lactation is associated with lower future risk of cardiovascular disease in women but the mechanism(s) underlying this relationship remain unclear., Objective: We sought to characterize the relationship between duration of exclusive breastfeeding and cardiovascular risk factors over the first 5-years postpartum., Design/setting/patients: In this prospective cohort study, 328 women underwent serial cardiometabolic characterization (anthropometry, blood pressure, lipids, fasting glucose, adiponectin, C-reactive protein (CRP)) at 1-year, 3-years, and 5-years postpartum., Outcome: Cardiovascular risk factors in 3 groups defined by duration of exclusive breastfeeding, as follows: <3 months (n=107), 3-6 months (n=101), and ≥6 months (n=120)., Results: The prevalence of metabolic syndrome did not differ between the groups at 3-years but, by 5-years postpartum, was higher in women who had exclusively breastfed <3 months than in those who did so for 3-6 and ≥6 months, respectively (14.0% vs 6.9% vs 4.2%; p=0.02). However, after adjustment for covariates (including BMI), there were no significant differences between groups in blood pressure, glucose, LDL cholesterol, HDL cholesterol, triglycerides or adiponectin. Indeed, the only cardiovascular risk factor difference that persisted after covariate adjustment was that women who had exclusively breastfed <3 months had higher CRP at both 3-years (p=0.04) and 5-years (p=0.01). Moreover, generalized estimating equation analyses with adjustment for covariates (including time-dependent BMI) showed that CRP remained higher over time in these women, as compared to their peers, from 1-year to 3-years to 5-years postpartum (p=0.03)., Conclusion: Sustained reduction of subclinical inflammation may contribute to the cardioprotective effect of lactation in women., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Objective: Alleviation of unrecognized glucotoxicity, with resultant recovery of β-cell function, could amplify the glucose-lowering effect of pharmacotherapy and contribute to the variable therapeutic response observed among patients with type 2 diabetes (T2D). However, clinical evidence supporting this concept is lacking. Short-term intensive insulin therapy (IIT) can ameliorate glucotoxicity and improve β-cell function in early T2D. Thus, for evidence of recovery of glucotoxicity-associated β-cell dysfunction, we sought to determine whether there exists a baseline fasting glucose threshold above which the post-IIT improvement in both β-cell function and glycemia is amplified., Research Design and Methods: IIT (glargine, lispro) was administered for 3 weeks to 108 adults with T2D (mean duration 1.8 ± 1.4 years). Oral glucose tolerance tests before and after IIT enabled assessment of β-cell function by Insulin Secretion-Sensitivity Index-2 and insulinogenic index/HOMA-insulin resistance. For each level of baseline fasting glycemia from 6.0 to 10.5 mmol/L, we modeled the difference in IIT-induced percentage change in β-cell function between those at/above the indicated glucose level and those below it., Results: The relationship between baseline fasting glucose and the differential change in β-cell function was nonlinear. Instead, this relationship was best fit by a cubic regression model with inflection (amplification) at fasting glucose at 9.3 mmol/L. Moreover, baseline fasting glucose at 9.3 mmol/L also identified the inflection point at which nonlinear reductions in fasting glucose and 2-h glucose, respectively, were both amplified., Conclusions: The respective improvements in β-cell function and glycemia in response to short-term IIT are amplified in those in whom baseline fasting glucose exceeds a defined threshold, consistent with reversal of glucotoxicity., (© 2024 by the American Diabetes Association.)

Aims/hypothesis: Excess adiposity, insulin resistance and beta cell dysfunction each contribute to the development of prediabetes (impaired glucose tolerance and/or impaired fasting glucose)/diabetes but their comparative impact in relation to one another remains uncertain. We thus ranked their contributions to incident dysglycaemia over the first 5 years postpartum in women reflecting the full spectrum of gestational glucose tolerance (spanning normoglycaemia to gestational diabetes) and hence a range of future diabetic risk., Methods: In this study, 302 women with normal glucose tolerance (NGT) on OGTT at 3 months postpartum underwent repeat OGTT at 1 year, 3 years and 5 years, enabling serial assessment of glucose tolerance, insulin sensitivity/resistance (Matsuda index, HOMA-IR) and beta cell function (insulin secretion-sensitivity index-2 [ISSI-2], insulinogenic index [IGI]/HOMA-IR). Determinants of prediabetes/diabetes were ranked by change in concordance index (CCI) of Cox proportional hazard regression models., Results: Over 5 years of follow-up, 89 women progressed from NGT to prediabetes/diabetes (progressors). At 3 months postpartum, though all women were normoglycaemic, future progressors had higher fasting glucose (p=0.03) and 2 h glucose (p<0.0001) than non-progressors, coupled with higher BMI (p=0.001), greater insulin resistance (both Matsuda index and HOMA-IR, p≤0.02) and poorer beta cell function (both ISSI-2 and IGI/HOMA-IR, p≤0.006). Unlike their peers, progressors exhibited deteriorating beta cell function from 1 year to 5 years (both p<0.0001). On regression analyses, the dominant determinants of progression to prediabetes/diabetes were time-varying ISSI-2 (change in CCI 25.2%) and IGI/HOMA-IR (13.0%), in contrast to time-varying Matsuda index (2.9%) and HOMA-IR (0.5%). Neither time-varying BMI nor waist were significant predictors after adjustment for beta cell function and insulin sensitivity/resistance., Conclusion/interpretation: Declining beta cell function is the dominant determinant of incident prediabetes/diabetes in young women following pregnancy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: To identify baseline determinants of diabetes remission in response to short-term insulin-based therapy., Methods: In this study, adult patients with type 2 diabetes (T2D) of less than 7 years duration were randomized to 8 weeks of treatment with (a) insulin glargine, (b) glargine + thrice-daily lispro, or (c) glargine + twice-daily exenatide, followed by 12 weeks of washout that enabled assessment of remission (defined as HbA1c < 6.5% after ≥ 3 months without glucose-lowering therapy). At baseline, 8 weeks and washout, beta-cell function was assessed with four measures: Insulin Secretion-Sensitivity Index-2 (ISSI-2), insulinogenic index/Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), ΔC-peptide 0-120 /Δglucose 0-120  × Matsuda and Δinsulin secretion rate (ISR) 0-120 /Δgluc 0-120  × Matsuda., Results: Diabetes remission was achieved in 31 of 90 participants (34.4%). Compared with their peers, those who went on to remission had lower HbA1c (P < .001) and better beta-cell function at baseline (all four measures P ≤ .01). The non-remission and remission groups did not otherwise differ in baseline insulin sensitivity/resistance (Matsuda, HOMA-IR), body mass index, duration of diabetes, pretrial diabetes medications or allocated insulin-based therapy during the trial. On logistic regression analyses, each baseline measure of beta-cell function emerged as a significant predictor of remission (log ISSI-2: adjusted OR 4.41 [95% CI: 1.71-11.34]; log insulinogenic index/HOMA-IR: 2.21 [1.26-3.89]; log ΔC-peptide 0-120 /Δglucose 0-120  × Matsuda: 1.62 [1.00-2.64]; log ΔISR 0-120 /Δgluc 0-120  × Matsuda: 1.87 [1.09-3.23]). Similarly, higher baseline ISSI-2 tertile predicted longer time to glycaemic relapse after cessation of the insulin-based therapy (log-rank P = .029)., Conclusion: Beta-cell function is the dominant baseline pathophysiological determinant of the likelihood of achieving remission of diabetes in response to short-term insulin-based therapy., (© 2023 John Wiley & Sons Ltd.)

Introduction: Mechanisms underlying kidney benefits with sodium-glucose cotransporter-2 (SGLT2) inhibition in heart failure and/or type 2 diabetes (T2D) with established cardiovascular disease are currently unclear., Methods: We evaluated post hoc the factors mediating the effect of empagliflozin on a composite kidney outcome (first sustained estimated glomerular filtration rate ≥40% reduction from baseline, initiation of renal replacement therapy or death due to kidney disease) in EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients). Variables, calculated as change from baseline or updated mean, were evaluated as time-dependent covariates and using a landmark approach (at Week 12) in Cox regression analyses. In multivariable analyses, variables with the greatest mediating effect were added using a step-up procedure., Results: In univariable time-dependent updated mean covariate analyses, the strongest mediator was hematocrit (99.5% mediation). Hemoglobin, uric acid and urine albumin-to-creatinine ratio mediated 79.4%, 33.2% and 31.0%, respectively. Multivariable analyses were not performed due to the very strong mediation effect of hematocrit. In univariable Week 12 landmark change from baseline analyses, the strongest mediators included hematocrit (40.7%), glycated hemoglobin (28.3%), systolic blood pressure (16.8%) and free fatty acids (16.5%), which yielded a combined mediation of 78.9% in multivariable analysis., Conclusions: Changes in hematocrit and hemoglobin were the strongest mediators of empagliflozin's kidney benefits in EMPA-REG OUTCOME participants with T2D and cardiovascular disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Objective: Time-restricted eating (TRE) which consists of restricting the eating window to typically 4-8h (while fasting for the remaining hours of the day) has been proposed as a non-pharmacological strategy with cardio-metabolic benefits but little is known about its metabolic impact in type 2 diabetes (T2DM). We evaluated whether TRE can improve pancreatic beta-cell function and metabolic status in overweight individuals with early T2DM., Research Design and Methods: In a randomized cross-over trial, 39 participants [mean 2.9 years of diabetes duration, baseline glycated hemoglobin (HbA1c) 6.6% ± 0.7% and body mass index (BMI) 32.4 ± 5.7 kg/m2] were randomized to either an initial intervention consisting of 6-weeks of TRE (20h-fasting/4h-eating) or standard lifestyle. The primary outcome of beta-cell function was assessed by Insulin Secretion-Sensitivity Index-2 (ISSI-2) derived from an oral glucose tolerance test. Trial registration: clinicaltrials.gov NCT05717127., Results: As compared to standard lifestyle, TRE induced a 14% increase in ISSI-2 (+14.0 ± 39.2%, p = 0.03) accompanied by 14% reduction of hepatic insulin resistance as evaluated by HOMA-IR [-11.6% (-49.3-21.9), p = 0.03]. Fasting glucose did not differ between interventions, but TRE yielded a significant reduction in HbA1c (-0.32 ± 0.48%, p <0.001). These metabolic improvements were coupled by a reduction of body weight of 3.86% (-3.86 ± 3.1%, p <0.001) and waist circumference of 3.8 cm (-3.8 ± 7.5 cm, p = 0.003)., Conclusion: TRE improved beta-cell function and insulin resistance in overweight patients with early diabetes, accompanied by beneficial effects on adiposity., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Background: The effect of empagliflozin, a sodium-glucose-co-transporter-2 inhibitor, on risk for myocardial infarction has not been fully characterized., Methods: This study comprised prespecified and post-hoc analyses of the EMPA-REG OUTCOME trial in which 7020 people with type 2 diabetes (T2D) and cardiovascular disease [mostly atherosclerotic (ASCVD)] were randomized to empagliflozin or placebo and followed for a median 3.1 years. We assessed the effect of empagliflozin on total (first plus recurrent) events of centrally adjudicated fatal and non-fatal myocardial infarction (MI) using a negative binomial model with robust confidence intervals (CI) that preserves randomization and accounts for the within-patient correlation of multiple events. Post hoc, we analyzed types of MI: type 1 (related to plaque-rupture/thrombus), type 2 (myocardial supply-demand imbalance), type 3 (sudden-death related, i.e. fatal MI), type 4 (percutaneous coronary intervention-related), and type 5 (coronary artery bypass graft-related). MIs could be assigned to > 1 type., Results: There were 421 total MIs (including recurrent); 299, 86, 26, 19, and 1 were classified as type 1, 2, 3, 4, and 5 events, respectively. Overall, empagliflozin reduced the risk of total MI events by 21% [rate ratio for empagliflozin vs. placebo, 0.79 (95% CI, 0.620-0.998), P = 0.0486], largely driven by its effect on type 1 [rate ratio, 0.79 (95% CI, 0.61-1.04)] and type 2 MIs [rate ratio, 0.67 (95% CI, 0.41-1.10)]., Conclusions: In T2D patients with ASCVD, empagliflozin reduced the risk of MIs, with consistent effects across the two most common etiologies, i.e. type 1 and 2., Trail Registration: URL: https://www., Clinicaltrials: gov ; Unique identifier: NCT01131676., (© 2024. The Author(s).)

In EMPA-REG OUTCOME, empagliflozin reduced the composite of total events leading to/prolonging hospitalisation for any cause and all-cause mortality by 24 % versus placebo in patients with T2DM and ASCVD, with 67.7 events prevented/1000 patient-years and a low NNT. Effects were sustained and were consistent regardless of the reason for hospitalisation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SEI has served as a consultant and/or member of clinical trial steering committees for AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novo Nordisk, and Pfizer. He has delivered lectures sponsored by AstraZeneca and Boehringer Ingelheim. CW has served as a consultant and/or member of clinical trial steering committees for AstraZeneca, Bayer, Boehringer Ingelheim and Merck Sharp & Dohme. He has delivered lectures sponsored by AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, and Mitsubishi. DF has received financial support from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck & Co., and Sanofi. BZ has received financial support from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi. SDA has received research support from Abbott Vascular and Vifor International, and personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Cardiac Dimensions, Impulse Dynamics, Novartis, Respicardia, Servier, St Jude Medical, Thermo Fisher Scientific, and Vifor International. SJP reports personal fees from Boehringer Ingelheim during the conduct of the study. MM and SH are employees of Boehringer Ingelheim. SSL is an employee of Boehringer Ingelheim and owns shares in Novo Nordisk and shares in dynamically traded investment funds, which might own stocks from pharmaceutical companies., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The cumulative effect of postpartum weight retention from each pregnancy in a woman's life may contribute to her risk of ultimately developing type 2 diabetes and cardiovascular disease. However, there is limited direct evidence supporting this hypothesis. Thus, we sought to characterize the impact of postpartum weight retention on the trajectories of cardiovascular risk factors over the first 5-years after pregnancy., Methods: In this prospective observational cohort study, 330 women (mean age 35.7 ± 4.3 years, mean pre-pregnancy body mass index 25.2 ± 4.8 kg/m 2 , 50.9% primiparous) underwent serial cardiometabolic characterization (anthropometry, blood pressure, lipids, oral glucose tolerance test, insulin sensitivity/resistance (Matsuda index, HOMA-IR), C-reactive protein (CRP), adiponectin) at 1-year, 3-years, and 5-years postpartum. Based on the magnitude of weight change between pre-pregnancy and 5-years postpartum, they were stratified into the following 3 groups: weight loss (n = 100), weight gain 0-6% (n = 110), and weight gain ≥ 6% (n = 120)., Results: At 1-year postpartum, cardiovascular risk factors did not differ between the groups. However, an adverse risk factor profile progressively emerged in the weight retention groups at 3- and 5-years. Indeed, after covariate adjustment, there was stepwise worsening (from the weight loss group to weight gain 0-6% to weight gain ≥ 6% group) of the following cardiovascular risk factors at 5-years: triglycerides (p = 0.001), HDL (p = 0.02), LDL (p = 0.01), apolipoprotein-B (p = 0.003), Matsuda index (p < 0.0001), HOMA-IR (p < 0.0001), fasting glucose (p = 0.07), and CRP (p = 0.01). Moreover, on logistic regression analyses, weight gain ≥ 6% emerged as an independent predictor of pre-diabetes/diabetes at 5-years (adjusted OR = 3.40, 95%CI: 1.63-7.09)., Conclusion: Postpartum weight retention predicts trajectories of worsening cardiovascular risk factors and glucose intolerance over the first 5-years after delivery, consistent with its postulated contribution to future vascular disease in women., (© 2024. The Author(s).)

Aims: Empagliflozin treatment reduced liver fat in small type 2 diabetes cohorts. This post-hoc study evaluated effects of empagliflozin on risk for non-alcoholic fatty liver disease-related steatosis and fibrosis, as well as the relationship between risk categories and cardiorenal outcomes in the randomized, placebo-controlled EMPA-REG OUTCOME trial., Materials and Methods: EMPA-REG OUTCOME treated 7020 people with type 2 diabetes and cardiovascular disease with 10/25 mg/day empagliflozin or placebo. For this analysis, the Dallas steatosis index, hepatic steatosis index, non-alcoholic fatty liver disease fibrosis score and Fibrosis-4 score were calculated to assess steatosis and fibrosis risk. Changes from baseline in scores were examined by mixed model repeated measures and their associations with cardiorenal outcomes and mortality by Cox regression., Results: At baseline, 73% and 84% of participants had high steatosis risk by Dallas steatosis index and hepatic steatosis index, whereas 23% and 4% had a high risk of advanced fibrosis by non-alcoholic fatty liver disease fibrosis score and Fibrosis-4 score. Percentages of people at high steatosis risk slightly decreased with empagliflozin only, whereas empagliflozin did not improve percentages of individuals at high fibrosis risk over time compared with placebo. The high risk of advanced fibrosis at baseline related to higher risk for cardiovascular events. Effects of empagliflozin on cardiorenal and all-cause mortality outcomes were consistent across all risk groups., Conclusions: Empagliflozin may reduce steatosis but not fibrosis risk in individuals with type 2 diabetes and cardiovascular disease. The improvements in cardiorenal outcomes and mortality associated with empagliflozin therapy appear to be independent of steatosis and fibrosis risk., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: In patients with type 2 diabetes mellitus (T2DM), a history of an ischemic event is associated with increased risk for cardiovascular (CV) disease. Whether patients with T2DM and a recent atherothrombotic diagnosis benefit from early intervention with a sodium-glucose co-transporter 2 inhibitor is unknown., Methods: This study is a secondary analysis of the Empa gliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients- R emoving E xcess G lucose (EMPA-REG OUTCOME), which compared empagliflozin to placebo in adults with T2DM and atherosclerotic CV disease (ASCVD). Participants were categorized based on the time since their last qualifying ASCVD diagnosis (≤ 1 year vs > 1 year). Qualifying ASCVD diagnoses included ischemic or hemorrhagic stroke, myocardial infarction, coronary artery disease, and peripheral artery disease. The primary outcome was a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke., Results: A total of 6796 participants (n = 4547 empagliflozin, n = 2249 placebo) were included. Median time since the last qualifying ASCVD diagnosis was 3.8 years (quartile 1-quartile 3: 1.5-7.6), and most qualifying diagnoses occurred > 1 year before randomization (≤ 1 year, n = 1214; > 1 year, n = 5582). Empagliflozin reduced the incidence of the primary outcome irrespective of the time since the last qualifying ASCVD diagnosis (≤ 1 year: hazard ratio 0.82, 95% confidence interval: 0.57-1.16; vs > 1 year: hazard ratio 0.85, 95% confidence interval: 0.72-1.00; P for interaction = 0.84). Results were similar for the composite of CV death or hospitalization for heart failure., Conclusions: Empagliflozin improved CV outcomes in participants with T2DM, irrespective of the time since the last qualifying ASCVD diagnosis at randomization. Prospective trials are necessary to investigate the use of sodium-glucose co-transporter 2 inhibitors at the time of an acute ASCVD event., Trial Registration: EMPA-REG OUTCOME (Clinicaltrials.gov identifier: NCT01131676)., (© 2024 The Authors.)

Background: Tirzepatide, a once-weekly GIP/GLP-1 receptor agonist, reduces blood glucose and body weight in people with type 2 diabetes. The cardiovascular (CV) safety and efficacy of tirzepatide have not been definitively assessed in a cardiovascular outcomes trial., Methods: Tirzepatide is being studied in a randomized, double-blind, active-controlled CV outcomes trial. People with type 2 diabetes aged ≥40 years, with established atherosclerotic CV disease, HbA1c ≥7% to ≤10.5%, and body mass index ≥25 kg/m 2 were randomized 1:1 to once weekly subcutaneous injection of either tirzepatide up to 15 mg or dulaglutide 1.5 mg. The primary outcome is time to first occurrence of any major adverse cardiovascular event (MACE), defined as CV death, myocardial infarction, or stroke. The trial is event-driven and planned to continue until ≥1,615 participants experience an adjudication-confirmed component of MACE. The primary analysis is noninferiority for time to first MACE of tirzepatide vs dulaglutide by demonstrating an upper confidence limit <1.05, which will also confirm superiority vs a putative placebo, and also to determine whether tirzepatide produces a greater CV benefit than dulaglutide (superiority analysis)., Results: Over 2 years, 13,299 people at 640 sites in 30 countries across all world regions were randomized. The mean age of randomized participants at baseline was 64.1 years, diabetes duration 14.7 years, HbA1c 8.4%, and BMI 32.6 kg/m 2 . Overall, 65.0% had coronary disease, of whom 47.3% reported prior myocardial infarction and 57.4% had prior coronary revascularization. 19.1% of participants had a prior stroke and 25.3% had peripheral artery disease. The trial is fully recruited and ongoing., Conclusion: SURPASS-CVOT will provide definitive evidence as to the CV safety and efficacy of tirzepatide as compared with dulaglutide, a GLP-1 receptor agonist with established CV benefit., Competing Interests: Conflict of interest SJN reports grants or contracts from Amgen, Anthera Pharmaceuticals, AstraZeneca, Cerenis Therapeutics, CSL Behring, Eli Lilly and Company, Esperion Therapeutics, Infraredx, New Amsterdam Pharma, Novartis, Resverlogix, and Sanofi Regeneron; consulting fees from Akcea Therapeutics, Amgen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly and Company, Esperion Therapeutics, Kowa, Merck, Novo Nordisk, Pfizer, Sanofi Regeneron, Takeda, Vaxxinity, Silence Therapeutics, and CSL Sequiris; is a named inventor on a patent planned, issued or pending with Amgen; and is President of Cardiac Society of Australia and New Zealand. DLB reports grants or contracts from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, Cincor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Eli Lilly and Company, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer Inc, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89bio, Otsuka, and Alnylam; royalties from Elsevier; consulting fees from Broadview Ventures, Hims, and McKinsey; payment or honoraria from American College of Cardiology, Baim Institute for Clinical Research, Belvoir Publications, Boston Scientific, Cleveland Clinic, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, Novartis, Population Health Research Institute, Rutgers University, Canadian Medical and Surgical Knowledge Translation Research Group, Cowen and Company, HMP Global, Journal of the American College of Cardiology, K2P, Level Ex, Medtelligence/ReachMD, MJH Life Sciences, Oakstone CME, Piper Sandler, Population Health Research Institute, Slack Publications, WebMD, Wiley, Society of Cardiovascular Patient Care, and CSL Behring; payment for expert testimony from Arnold and Porter law firm; meeting/travel support from American College of Cardiology, Society of Cardiovascular Patient Care, and American Heart Association; a pending patent for Sotagliflozin; participation on data monitoring or advisory boards for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, AngioWave, Baim Institute, Bayer, Boehringer Ingelheim, Boston Scientific, Cardax, CellProthera, Cereno Scientific, Cleveland Clinic, Contego Medical, Duke Clinical Research Institute, Elsevier Practice Update Cardiology, Janssen, Level Ex, Mayo Clinic, Medscape Cardiology, Merck, Mount Sinai School of Medicine, MyoKardia, NirvaMed, Novartis, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, Population Health Research Institute, and Stasys; leadership or fiduciary roles with American College of Cardiology, AngioWave, Boston VA Research Institute, Bristol Myers Squibb, DRS.LINQ, High Enroll, Society of Cardiovascular Patient Care, TobeSoft, and AHA NYC Chapter; stock or stock options in AngioWave, Bristol Myers Squibb, DRS.LINQ, and High Enroll; and other financial or non-financial interests in Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), American Heart Association Quality Oversight Committee (Chair), VA CART Research and Publications Committee (Chair), Contego Medical (Chair, PERFORMANCE 2), conducts unfunded research with FlowCo and Takeda, and is site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Phillips SpectraWAVE, Svelte, and Vascular Solutions. JBB reports grant support from Dexcom, Insulet, MannKind, NovaTarg, Novo Nordisk, Sanofi, Tolerion, and vTv Therapeutics; consulting fees from Novo Nordisk, Alkahest, Altimmune, Anji, AstraZeneca, Bayer, Biomea Fusion Inc, Boehringer Ingelheim, CeQur, Cirius Therapeutics Inc, Corcept Therapeutics, CultHealth, Eli Lilly and Company, embecta, GentiBio, Glycadia, Glyscend, Janssen, Mellitus Health, Metsera, Moderna, Pendulum Therapeutics, Praetego, Sanofi, Stability Health, Tandem, Terns Inc, Valo, and Zealand Pharma; payment for expert testimony from Medtronic; participation on data monitoring or advisory boards for Alkahest, Altimmune, AstraZeneca, and Tandem; a leadership or fiduciary role with Association of Clinical and Translational Science; stock or stock options in Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio, Praetego and Stability Health; and other financial or other non-financial interests in Dasman Diabetes Center, Kuwait City (scientific advisory board), and ReachMD and Mediflix (audiovisual content development). SDP reports consultation for Abbott, Amarin, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Hengrui Pharmaceuticals, Menarini International, MSD, Novo Nordisk, and Sanofi; grant support from AstraZeneca and Boehringer Ingelheim; and speaker fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Laboratori Guidotti, MSD, Novartis, Novo Nordisk, and Sanofi.. SEK reports consulting fees from Anji Pharamceuticals, Eli Lilly and Company, Merck, and Novo Nordisk; and payment or honoraria from Novo Nordisk. AML reports grants or contracts from Eli Lilly and Company; consulting fees from Eli Lilly and Company, Novo Nordisk, and Novartis; and meeting/travel support from Novo Nordisk and Eli Lilly and Company. DKM reports research support for clinical trials leadership from Boehringer Ingelheim, Merck & Co, Pfizer, AstraZeneca, Novo Nordisk, Esperion, Lilly USA, Lexicon, CSL Behring, and New Amsterdam; and honoraria for consultancy from Lilly USA, Boehringer Ingelheim, Merck & Co, Novo Nordisk, Applied Therapeutics, Altimmune, CSL Behring, Bayer, and Intercept. MAN reports grants or contracts from Merck, Sharp & Dohme; consulting fees from Boehringer Ingelheim, Berlin-Chemie/Menarini, Eli Lilly and Company, Medtronic, Merck, Sharp & Dohme, Novo Nordisk, Pfizer, Regor, Structure Therapeutics (Gasherbrum), and Sun Pharma; payment or honoraria from Berlin-Chemie/Menarini, Eli Lilly and Company, Medical Learning Institute, Medscape, Merck, Sharp & Dohme, Novo Nordisk, Sanofi, and Sun Pharma; and participation on a data monitoring or advisory board with Inventiva. SEN reports that the Cleveland Clinic Center for Clinical Research has received funding to perform clinical trials from Abbvie, AstraZeneca, Arrowhead, Amgen, Bristol Myers Squibb, Eli Lilly, Medtronic, MyoKardia, New Amsterdam Pharmaceuticals, Novartis, and Silence Therapeutics. NS reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, and Novartis; a grant from Roche Diagnostics; and personal fees from Abbott Laboratories, Amgen, Eli Lilly and Company, Hanmi Pharmaceuticals, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, and Sanofi. BZ reports consulting fees from Eli Lilly and Company. SZ reports grants or contracts from NHMRC, Australian Government Department of Health and Aged Care, JDRF Centre of Excellence, and MRFF; consulting fees from Eli Lilly Australia, Boehringer-Ingelheim, MSD Australia, Astra Zeneca, Novo Nordisk, and Sanofi; payment or honoraria from Heart Foundation; meeting/travel support from Australian Diabetes Society 2022, International Diabetes Federation 2022, and KDIGO Implementation Summit on Diabetes Management in CKD; and leadership or fiduciary roles with Melanoma and Skin Cancer Trials Ltd., Australian Clinical Trials Alliance, and Victorian Institute of Forensic Medicine. JB reports consulting fees from Eli Lilly and Company, ReCor, and Medtronic; and participation on advisory boards for ReCor, Medtronic, and Eli Lilly and Company. AB, DM, HN, IP, GW, and RJW are employees and shareholders in Eli Lilly and Company. DD reports consulting fees from Eli Lilly and Company, Sun Pharmaceuticals, and Structure Therapeutics; payment or honoraria from University of Chicago, University of Iowa, and Korean Diabetes Association; meeting/travel support from American Diabetes Association; and stock or stock options in MBX Biosciences., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The Developmental Origins of Health and Disease (DOHaD) paradigm emphasizes the significance of early life factors for the prevention of chronic health conditions, like type 2 diabetes (T2DM) and obesity, which disproportionately affect First Nations communities in Canada. Despite increasing DOHaD research related to maternal health during pregnancy, early childhood growth patterns, and infant feeding practices with many populations, data from First Nations communities in Canada are limited. In partnership with Sandy Lake First Nation, the aims of this project were to characterize birthweights and growth patterns of First Nations infants/children over the first 6 years of life and to study the impact of maternal and infant social and behavioral factors on birthweight and growth trajectories., Methods: We recruited 194 families through community announcements and clinic visits. Infant/child length/height and weight were measured at 1 and 2 weeks; 1, 2, 6, 12, and 18 months; and 2, 3, 4, 5 and 6 years. Maternal and infant/child questionnaires captured data about health, nutrition, and social support. Weight-for-Age z-score (WAZ), Height-for-Age z-score (HAZ), and BMI-for-Age z-score (BAZ) were calculated using WHO reference standards and trajectories were analyzed using generalized additive models. Generalized estimating equations and logistic regression were used to determine associations between exposures and outcomes., Results: WAZ and BAZ were above the WHO mean and increased with age until age 6 years. Generalized estimating equations indicated that WAZ was positively associated with age (0.152; 95% CI 0.014, 0.29), HAZ was positively associated with birthweight (0.155; 95% CI 0.035, 0.275), and BAZ was positively associated with caregiver's BMI (0.049; 95% CI 0.004, 0.090). There was an increased odds of rapid weight gain (RWG) with exposure to gestational diabetes (OR: 7.47, 95% CI 1.68, 46.22). Almost 70% of parents initiated breastfeeding, and breastfeeding initiation was modestly associated with lower WAZ (-0.18; 95% CI -0.64, 0.28) and BAZ (-0.23; 95% CI -0.79, 0.34)., Conclusions: This work highlights early life factors that may contribute to T2DM etiology and can be used to support community and Indigenous-led prevention strategies., (© 2023. The Author(s).)

Background: The cardiometabolic implications of postprandial hyperinsulinemia are unclear with recent studies suggesting both adverse and beneficial associations. We aimed to evaluate the longitudinal cardiometabolic implications of the post-challenge insulin secretory response over 4-years follow-up., Methods: In this prospective cohort study, conducted in Toronto (Ontario, Canada), women comprising the full range of antepartum glucose tolerance were recruited in pregnancy (at the time of glucose tolerance screening, late in the second trimester) to undergo cardiometabolic testing in the years thereafter. Participants underwent oral glucose tolerance tests (OGTT) at 1-year, 3-years, and 5-years postpartum, enabling serial assessment of cardiovascular risk factors, glucose tolerance, insulin sensitivity or resistance (Matsuda index, HOMA-IR), and beta-cell function-via Insulin Secretion-Sensitivity Index-2 (ISSI-2) and insulinogenic index/HOMA-IR (IGI/HOMA-IR). Baseline post-challenge insulinemia was assessed with the corrected insulin response (CIR) at 1-year. Cardiometabolic factors were compared between baseline CIR tertiles., Findings: Between Oct 23, 2003 and March 31, 2014, 306 women were enrolled. In this study population, there was progressive worsening of waist circumference (p = 0.016), HDL (p = 0.018), CRP (p = 0.006), and insulin sensitivity (p < 0.001) from the lowest to middle to highest tertile of CIR at 1-year. However, these adverse features were accompanied by progressively better beta-cell function (both p < 0.001), coupled with lower fasting and 2-h glucose on the OGTT (both p < 0.001). On adjusted longitudinal analyses, higher CIR tertile at 1-year was independently associated with (i) higher ISSI-2 and IGI/HOMA-IR and (ii) lower fasting and 2-h glucose at both 3-years and 5-years (all p < 0.001), but was not associated with BMI, waist, lipids, CRP or insulin sensitivity/resistance. The highest CIR tertile at 1-year predicted lower risk of pre-diabetes or diabetes at both 3-years (adjusted OR = 0.19; 95% CI 0.08-0.45) and 5-years (aOR = 0.18; 0.08-0.39), relative to the lowest tertile., Interpretation: A robust post-challenge insulin secretory response does not indicate adverse cardiometabolic health but, rather, portends favourable metabolic function in the years to come. Future long-term study of the implications of the post-challenge insulinemic response is warranted., Funding: Canadian Institutes of Health Research., Competing Interests: We declare no competing interests., (© 2023 The Author(s).)

The evolution of basal insulin therapy over the past 100 years since the discovery of insulin is a testimony to the biomedical bench-to-bedside process, wherein incremental advances in the basic sciences are progressively translated over time into a series of enhancements in clinical care, each building upon the success of its predecessors. The emergence of recombinant DNA technology and the resultant biosynthesis of human insulin in the 1980s provided the critical capacity to bioengineer designer insulin analogues with pharmacokinetic and pharmacodynamic properties that can better mimic, although not fully replicate, the effects of endogenous insulin secretion. Through these efforts, basal insulin therapy has progressed over this time from first-generation analogues (glargine U-100, detemir) to second-generation analogues (glargine U-300, degludec) to ultra-long-acting formulations that are suitable for administration once weekly (icodec). Each iteration in this progression has represented a step closer towards the goal of replicating the continuous secretion of insulin that normally comprises the basal output of the pancreatic beta-cells between meals, during episodes of fasting and overnight. However, it may be that we may have reached the achievable limit in the context of an "open-loop" approach, such that only with the addition of closed loop control will we be able to achieve physiologic basal insulin replacement. In this review, we will examine the evolution of basal insulin therapy over the past 100 years and its implications for patient care and outcomes in current practice and the future., (© 2021 John Wiley & Sons Ltd.)

T2D is a well-established risk factor for development and progression of CKD. KDIGO recommends categorization of risk by likelihood of progression to ESKD. Compared to placebo, empagliflozin decreases likelihood of worsening (OR 0.70, 95 % CI 0.62-0.78) and increases likelihood of improvement (OR 1.56, 95 % CI 1.30-1.86) in KDIGO risk category., Competing Interests: Declaration of competing interest Bernard Zinman has received financial support from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk and Sanofi. Christoph Wanner has served as a consultant and/or member of clinical trial steering committees for AstraZeneca, Bayer, Boehringer Ingelheim and Merck Sharp & Dohme. He has delivered lectures sponsored by AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme and Mitsubishi. Silvio E. Inzucchi has received honoraria for lectures, advisory work and/or clinical trial leadership from AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Merck, Pfizer and Bayer., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: To test the hypothesis that the addition of periodic courses of short-term intensive insulin therapy (IIT) could enhance the effect of metformin (MET) maintenance therapy on preservation of beta-cell function following induction IIT., Methods: In this multicentre, randomized controlled trial, 108 adults with type 2 diabetes (median 1.3 years' duration; HbA1c 6.6% ± 0.6%) were randomized to 3 weeks of induction IIT (glargine, lispro) followed by MET maintenance, either with or without periodic 2-week courses of IIT every 3 months for 2 years. Beta-cell function was assessed by the Insulin Secretion Sensitivity Index-2 (ISSI-2) at an oral glucose tolerance test every 3 months., Results: In both arms, induction IIT increased ISSI-2, improved whole-body insulin sensitivity and reduced hepatic insulin resistance (all P ≤ .0004). The primary outcome of baseline-adjusted ISSI-2 at 2 years was not improved by the addition of intermittent IIT (MET + IIT) and was slightly higher in the MET arm (baseline-adjusted difference -35 [95% CI: -66, -3]), with three additional beta-cell measures showing no significant differences. Baseline-adjusted HbA1c at 2 years did not differ between MET and MET + IIT (6.3% ± 0.1% vs. 6.4% ± 0.1%, P = .46), with 32.6% of participants in each arm maintaining HbA1c of 6.0% or less at 2 years., Conclusion: Although initial induction IIT induces metabolic improvement, subsequent repeat courses of IIT every 3 months do not further enhance the effect of MET maintenance therapy on beta-cell function., (© 2021 John Wiley & Sons Ltd.)

Background: Patients with type 2 diabetes (T2D) and cardiovascular disease are at increased risk for recurrent ischemic events. Cardiovascular risk factor control is vital for secondary prevention, but how this compares among individuals with different T2D macrovascular complications is unknown. We aimed to determine if there might be differences in risk factor control in patients with T2D with previous stroke versus coronary artery disease (CAD)., Methods: Cross-sectional analyses were performed on 12 856 patients with T2D with prior history of stroke with or without CAD from 3 diabetes cardiovascular outcome trials: CARMELINA (The Cardiovascular and Renal Microvascular Outcome Study With Linagliptin), EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), and CAROLINA (The Cardiovascular Outcome Study of Linagliptin vs Glimepiride in Type 2 Diabetes). Risk factors at baseline assessed included dyslipidemia, hypertension, smoking, and current antiplatelet/anticoagulant therapy. Control, respectively, was defined as LDL (low-density lipoprotein)-C <100 mg/dL or statin use, systolic blood pressure <140 and diastolic blood pressure <90 mm Hg, not currently smoking, and use of an antiplatelet/anticoagulant medication. The odds ratio of 3 to 4 (or good) versus 0 to 2 (or suboptimal) risk factors controlled was analyzed by logistic regression models., Results: The odds for good versus suboptimal risk factor control in patients with CAD alone was higher than in those with stroke alone across all 3 trials odds ratios (95% CI): CARMELINA, 2.05 (1.67-2.51), EMPA-REG OUTCOME, 2.50 (2.10-2.99), and CAROLINA, 1.63 (1.21-2.20). The respective odds ratios were lower (and rendered nonsignificant in CAROLINA) when cardiovascular risk factor control in patients with both CAD and stroke were compared with those with stroke alone: CARMELINA, 1.45 (1.13-1.87); EMPA-REG OUTCOME, 1.62 (1.25-2.08); and CAROLINA, 1.16 (0.74-1.83)., Conclusions: In contemporary populations of patients with T2D, there was significant discordance in control of cardiovascular risk factors between patients with stroke versus CAD, with the former having less optimal control. The intermediate results in patients with both CAD and stroke suggest that these differences could be related at least in part to clinician factors., Registration: URL: https://www., Clinicaltrials: gov; Unique identifiers: NCT01243424, NCT01131676, NCT01897532., Competing Interests: Disclosures Dr Sheth reports compensation from Astrocyte for consultant services; service as President for Advanced Innovation in Medicine; grants from Hyperfine; employment by Yale School of Medicine; grants from Biogen; compensation from Cerevasc for consultant services; a patent pending for Stroke wearables licensed to Alva Health; compensation from CSL Behring for consultant services; compensation from Sense for data and safety monitoring services; compensation from Certus for consultant services; grants from Novartis; grants from BARD; compensation from ZOLL Medical Corporation for data and safety monitoring services; and compensation from Rhaeos for consultant services. Dr Rosenstock reports grants from Novo Nordisk; compensation from Intarcia for consultant services; travel support from Novo Nordisk; travel support from Applied Therapeutics; grants from Boehringer Ingelheim; travel support from Boehringer Ingelheim; grants from Pfizer; compensation from Oramed for consultant services; grants from Hanmi Pharmaceutical Co, Ltd; compensation from Boehringer Ingelheim for consultant services; compensation from Zealand for consultant services; compensation from Novo Nordisk for consultant services; grants from Intarcia; travel support from Intarcia; compensation from Eli Lilly and Company for consultant services; travel support from Sanofi US Services, Inc; compensation from Regor Pharmaceuticals, Inc for consultant services; compensation from Applied Therapeutics for consultant services; grants from Sanofi US Services, Inc; compensation from Hanmi Pharmaceutical, Co Ltd, for consultant services; grants from Eli Lilly and Company; grants from Novartis; grants from Applied Therapeutics; compensation from Sanofi US Services, Inc for consultant services; grants from Oramed; and travel support from Oramed. Dr Wanner reports compensation from Astellas Pharma for consultant services; compensation from Sanofi US Services, Inc for consultant services; compensation from Fresenius USA, Inc for consultant services; compensation from Idorsia for consultant services; compensation from Vifor Fresenius Medical Care Renal Pharma, Ltd, for consultant services; compensation from Eli Lilly and Company for consultant services; compensation from Amicus Therapeutics Inc. for consultant services; compensation from Takeda California Inc. for consultant services; compensation from Boehringer Ingelheim for consultant services; compensation from Chiesi Farmaceutici for consultant services; compensation from Amgen for consultant services; compensation from GlaxoSmithKline for consultant services; compensation from Merck for consultant services; compensation from AstraZeneca for consultant services; compensation from Novo Nordisk AS for consultant services; compensation from Bayer for consultant services; compensation from Novartis for consultant services; and compensation from Gilead Sciences for consultant services. Dr Zinman has served as a consultant for Boehringer Ingelheim, Novo Nordisk and Eli Lilly. Dr Ofstad and M. Mattheus are employees of Boehringer Ingelheim. Dr Marx reports compensation from AstraZeneca for other services; compensation from Sanofi Aventis for other services; compensation from Boehringer Ingelheim for other services; compensation from Bristol-Myers Squibb for other services; compensation from Bristol-Myers Squibb for other services; compensation from AstraZeneca for consultant services; compensation from Novo Nordisk for other services; compensation from Kowa Research Institute for consultant services; compensation from Novo Nordisk for other services; compensation from Merck Sharp and Dohme for other services; compensation from Genfit for other services; grants from Boehringer Ingelheim; compensation from Boehringer Ingelheim for other services; compensation from Lilly Deutschland for other services; and compensation from Amgen for other services. Dr Inzucchi has served as a consultant and member of clinical trial steering committees for Boehringer Ingelheim, AstraZeneca, Novo Nordisk, Merck, Pfizer, and Bayer. He has delivered lectures sponsored by Boehringer Ingelheim, AstraZeneca, and Merck. The other authors report no conflicts.

In early type 2 diabetes, the strategy of "induction" with short-term intensive insulin therapy followed by "maintenance" with metformin can stabilize pancreatic beta-cell function in some patients but not others. We thus sought to elucidate determinants of sustained stabilization of beta-cell function. In this secondary analysis of ClinicalTrials.Gov NCT02192424, adults with ≤5-years diabetes duration were randomized to 3-weeks induction insulin therapy (glargine/lispro) followed by metformin maintenance either with or without intermittent 2-week courses of insulin every 3-months for 2-years. Sustained stabilization (higher beta-cell function at 2-years than at baseline) was achieved in 55 of 99 participants. Independent predictors of sustained stabilization were the change in beta-cell function during induction and changes in hepatic insulin resistance and alanine aminotransferase during maintenance. Thus, initial reversibility of beta-cell dysfunction during induction and subsequent preservation of hepatic insulin sensitivity during maintenance are associated with sustained stabilization of beta-cell function following short-term insulin and metformin.ClinicalTrials.Gov NCT02192424., (© 2023. The Author(s).)

Rationale & Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study., Study Design: Secondary analysis of a randomized controlled trial., Setting & Participants: Participants in the CREDENCE trial., Intervention: Participants were randomly assigned to receive canagliflozin 100mg/d or placebo., Outcomes: Primary composite outcome of kidney failure, doubling of serum creatinine concentration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Outcomes were evaluated by age at baseline (<60, 60-69, and≥70 years) and sex in the intention-to-treat population using Cox regression models., Results: The mean age of the cohort was 63.0±9.2 years, and 34% were female. Older age and female sex were independently associated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (a composite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.48-0.82], and 0.89 [0.61-1.29] for ages<60, 60-69, and≥70 years, respectively; P=0.3for interaction) or sexes (HRs, 0.71 [95% CI, 0.54-0.95] and 0.69 [0.56-0.84] in women and men, respectively; P=0.8for interaction). No differences in safety outcomes by age group or sex were observed., Limitations: This was a post hoc analysis with multiple comparisons., Conclusions: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants., Funding: This post hoc analysis of the CREDENCE trial was not funded. The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical., Trial Registration: The original CREDENCE trial was registered at ClinicalTrials.gov with study number NCT02065791., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: REDUCE-IT showed that icosapent ethyl (IPE) improved cardiovascular (CV) outcomes in participants with established CV disease (CVD) or type 2 diabetes (T2D) and at least one additional risk factor plus mild-moderate hypertriglyceridemia and reasonably controlled low-density lipoprotein cholesterol (LDL-C). As the generalizability of REDUCE-IT has not been investigated in a T2D population with established CVD, this post hoc analysis investigated how many participants from EMPA-REG OUTCOME, which tested the effects of empagliflozin versus placebo on CV outcomes in participants with T2D and CVD, would have been eligible for IPE treatment, and whether CV outcomes differed based on eligibility for IPE treatment., Methods: Participants from EMPA-REG OUTCOME were screened for inclusion using both REDUCE-IT-like criteria (baseline statin therapy, triglycerides 135-499 mg/dL and LDL-C 41-100 mg/dL) and slightly amended FDA indication criteria (triglycerides ≥150 mg/dL). Analyses were conducted to characterize the study population and CV outcomes in participants eligible for IPE versus those not eligible for IPE., Results: Of the 7020 participants from EMPA-REG OUTCOME, 1810 (25.8%) fulfilled REDUCE-IT criteria and 3182 (45.3%) fulfilled FDA criteria for IPE treatment. Treatment effects of empagliflozin versus placebo on CV and kidney outcomes and mortality were consistent in participants meeting REDUCE-IT and FDA criteria and those who did not., Conclusions: These results indicate that a sizable proportion of patients with diabetes and established CVD, such as those in EMPA-REG OUTCOME, may be eligible for IPE treatment to lower residual CV risk. Treatment benefit with empagliflozin was consistent, regardless of REDUCE-IT or FDA eligibility criteria., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S.V. declares that he has received research and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, CMS, HLS, Janssen, Merck Novartis, Novo Nordisk, PhaseBio, and Sanofi. He is also the President of the Canadian Medical and Surgical Knowledge Translation Research Group and holds the Tier 1 Canada Research Chair in Cardiovascular Surgery. A.K. declares no conflict of interest. D.L.B. discloses the following relationships - Advisory Board: AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, Stasys; Board of Directors: AngioWave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, TobeSoft; Chair: Inaugural Chair, American Heart Association Quality Oversight Committee; Consultant: Broadview Ventures; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Eli Lilly and Company, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier (Editor, Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Takeda. D.F. has received honoraria from Sanofi, Merck & Co., Amgen, AstraZeneca, Eli Lilly and Company, and Boehringer Ingelheim and has served on the data and safety monitoring board for Novo Nordisk. A.P.O. and M.M. are employees of Boehringer Ingelheim. C.W. reports personal fees from Boehringer Ingelheim during the conduct of the study; personal fees from Akebia, AstraZeneca, Bayer, Eli Lilly and Company, GSK, GILEAD, MSD, Mundipharma, Sanofi-Genzyme and Vifor Fresenius outside the submitted work. B.Z. has received research grants awarded to his institution from Boehringer Ingelheim, AstraZeneca, and Novo Nordisk and honoraria from Janssen, Sanofi, Eli Lilly and Company, Boehringer Ingelheim, Novo Nordisk, and Merck. P.R.L. is supported by a Heart and Stroke Foundation of Canada National New Investigator Award. L.A.L. has received research funding from, has provided CME on behalf of, and/or has acted as an advisor to Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Esperion, HLS, Kowa, Merck, Novartis, Novo Nordisk, Pfizer, Sanofi, and Servier., (© 2023 Published by Elsevier B.V.)

Introduction: Relationships between glycemic-lowering effects of sodium glucose co-transporter 2 inhibitors and impact on kidney and cardiovascular outcomes are uncertain., Research Design and Methods: We analyzed 4395 individuals with prebaseline and postbaseline hemoglobin A1c (HbA1c) randomized to canagliflozin (n=2193) or placebo (n=2202) in The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial. Effects on HbA1c were assessed using mixed models. Mediation of treatment effects by achieved glycemic control was analyzed using proportional hazards regression with and without adjustment for achieved HbA1c. End points included combined kidney or cardiovascular death, end-stage kidney disease or doubling of serum creatinine (primary trial outcome), and individual end point components., Results: HbA1c lowering was modified by baseline estimated glomerular filtration rate (eGFR). For baseline eGFR 60-90, 45-59, and 30-44 mL/min/1.73 m 2 , overall HbA1c (canagliflozin vs placebo) decreased by -0.24%, -0.14%, and -0.08% respectively and likelihood of >0.5% decrease in HbA1c decreased with ORs of 1.47 (95% CI 1.27 to 1.67), 1.12 (0.94 to 1.33) and 0.99 (0.83 to 1.18), respectively. Adjustment for postbaseline HbA1c marginally attenuated canagliflozin effects on primary and kidney composite outcomes: unadjusted HR 0.67 (95% CI 0.57 to 0.80) and 0.66 (95% CI 0.53 to 0.81); adjusted for week 13 HbA1c, HR 0.71 (95% CI 0.060 to 0.84) and 0.68 (95% CI 0.55 to 0.83). Results adjusted for time-varying HbA1c or HbA1c as a cubic spline were similar and consistent with preserved clinical benefits across a range of excellent and poor glycemic control., Conclusions: The glycemic effects of canagliflozin are attenuated at lower eGFR but effects on kidney and cardiac end points are preserved. Non-glycemic effects may be primarily responsible for the kidney and cardioprotective benefits of canagliflozin.22., Competing Interests: Competing interests: DMC has personal fees or fees paid by Janssen Pharmaceuticals to the Baim Institute for work on the CREDENCE trial steering committee. He has received consulting fees from Amgen, CSL Behring, Eli Lilly, Fresenius, Gilead, Medtronic/Covidien, Merck, Novo Nordisk, Zoll, AstraZeneca, GlaxoSmithKline, PLC Medical, and Allena Pharmaceuticals, and has received research support from Medtronic and Amgen. KWM’s financial disclosures can be viewed at http://med.stanford.edu/profiles/kenneth-mahaffey. MJJ is supported by a Medical Research Future Fund Next Generation Clinical Researchers Program Career Development Fellowship; is responsible for research projects that have received unrestricted funding from Amgen, Baxter, CSL, Eli Lilly, Gambro, and MSD; has served on advisory boards sponsored by Akebia, AstraZeneca, Baxter, Bayer, Boehringer Ingelheim (BI), MSD, and Vifor; serves on steering committee for trials sponsored by CSL and Janssen; serves on a steering committee for an investigator-initiated trial with funding support from Dimerix, spoken at scientific meetings sponsored by Janssen, Amgen, Roche, and Vifor; with any consultancy, honoraria, or travel support paid to her institution. CPC reports in calendar years 2020–2022: Research Grants from: Amgen, Better Therapeutics, BI, Bristol-Myers Squibb (BMS), Daiichi Sankyo, Janssen, Merck, Novo Nordisk, Pfizer. Consulting fees from Aegerion/Amryt, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, BI, BMS, Eli Lilly, Janssen, Lexicon, Merck, Pfizer, Rhoshan, Sanofi. He serves on the Data and Safety Monitoring Boards for the Veteran’s Administration, Applied Therapeutics, and Novo Nordisk. BN has received research grants and consulting fees from Janssen, all paid to his institution. HJLH has received honoraria for participation in steering committees or advisory boards from AstraZeneca, BI, Bayer, CSL Behring, Chinook, Gilead, Goldfinch, Janssen, Merck, Mitsubishi Tanabe, Mundipharma; Novartis, Novo Nordisk, and Travere Pharmaceuticals. His institution received research grants from AstraZeneca, AbbVie, Janssen, BI, and Novo Nordisk. RA was a member of the CREDENCE study steering committee and chair of its adjudication committee; is a member of the steering committees of FIDELIO/FIGARO (Bayer); INNOVATE/PROTECT (Akebia); AMBER (Relypsa/Vifor), and chairs a data safety monitoring board (Chinook). He also serves as a consultant for AstraZeneca, Bayer, BI, DiaMedica, Janssen, Merck, Reata, Relypsa, and Sanofi. GLB works for The University of Chicago Medicine. He is a consultant for Merck, Bayer, Vascular Dynamics, KBP Biosciences, Ionis, Alnylam, and AstraZeneca. He has research support and is on the steering committee of trials for Bayer and Vascular Dynamics. He is the editor of the American Journal of Nephrology. DdZ: advisory boards and/or speaker fees for Bayer, BI, Fresenius, Mitsubishi-Tanabe, Travere Pharmaceuticals; steering committees and/or speaker for AbbVie and Janssen; data safety and monitoring committees for Bayer. Honoraria paid to institution and consultant/speaker. AL serves as a scientific advisor to BI, AstraZeneca, and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); is on the data safety and monitoring board for NIDDK, Kidney Precision Medicine, University of Washington Kidney Research Institute Scientific Advisory Committee; and is funded by the Canadian Institute of Health Research and Kidney Foundation of Canada. She has received fees for time as CREDENCE National Coordinator from Janssen, directed to her academic team. CP has received honoraria for serving on advisory boards and as a speaker for Merck Sharp & Dohme, AstraZeneca, and BI/Eli Lilly. HZ has received fees for CREDENCE steering committee roles and travel support from Janssen. BZ has received honoraria for serving on advisory boards for BI, Novo Nordisk, Sanofi, and Eli Lilly. NR had has nothing to disclose. KR is the recipient of research funding from the NHMRC and MRFF and has received honoraria from Elsevier and PLOS for commissioned reviews. JY has nothing to disclose. CA is supported by a NSW Health EMCR Grant and a NHMRC/MRFF Priority Investigator Grant. She is an employee of the George Institute. She has received honoraria from AstraZeneca and Amgen. DCW has an ongoing consultancy contract with AstraZeneca and over the last 2 years has received payments for consultancy, speaking, or educational activities from Amgen, Astellas, Bayer, BI, GlaxoSmithKline, Gilead, Janssen, Merck Sharp & Dohme, Tricida, Vifor, and Zydus., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: The kidney protective effects of renin-angiotensin system inhibitors are greater in people with higher levels of albuminuria at treatment initiation. Whether this applies to sodium-glucose cotransporter 2 (SGLT2) inhibitors is uncertain, particularly in patients with a very high urine albumin-to-creatinine ratio (UACR; ≥3000 mg/g). We examined the association between baseline UACR and the effects of the SGLT2 inhibitor, canagliflozin, on efficacy and safety outcomes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) randomized controlled trial., Design, Setting, Participants, & Measurements: The study enrolled 4401 participants with type 2 diabetes, an eGFR of 30 to <90 ml/min per 1.73 m 2 , and UACR of >300 to 5000 mg/g. Using Cox proportional hazards regression, we examined the relative and absolute effects of canagliflozin on kidney, cardiovascular, and safety outcomes according to a baseline UACR of ≤1000 mg/g ( n =2348), >1000 to <3000 mg/g ( n =1547), and ≥3000 mg/g ( n =506). In addition, we examined the effects of canagliflozin on UACR itself, eGFR slope, and the intermediate outcomes of glycated hemoglobin, body weight, and systolic BP., Results: Overall, higher UACR was associated with higher rates of kidney and cardiovascular events. Canagliflozin reduced efficacy outcomes for all UACR levels, with no evidence that relative benefits varied between levels. For example, canagliflozin reduced the primary composite outcome by 24% (hazard ratio [HR], 0.76; 95% confidence interval [95% CI], 0.56 to 1.04) in the lowest UACR subgroup, 28% (HR, 0.72; 95% CI, 0.56 to 0.93) in the UACR subgroup >1000 to <3000 mg/g, and 37% (HR, 0.63; 95% CI, 0.47 to 0.84) in the highest subgroup ( P heterogeneity =0.55). Absolute risk reductions for kidney outcomes were greater in participants with higher baseline albuminuria; the number of primary composite events prevented across ascending UACR categories were 17 (95% CI, 3 to 38), 45 (95% CI, 9 to 81), and 119 (95% CI, 35 to 202) per 1000 treated participants over 2.6 years ( P heterogeneity =0.02). Rates of kidney-related adverse events were lower with canagliflozin, with a greater relative reduction in higher UACR categories., Conclusions: Canagliflozin safely reduces kidney and cardiovascular events in people with type 2 diabetes and severely increased albuminuria. In this population, the relative kidney benefits were consistent over a range of albuminuria levels, with greatest absolute kidney benefit in those with an UACR ≥3000 mg/g., Clinical Trial Registry Name and Registration Number: ClinicalTrials.gov: CREDENCE, NCT02065791., Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021&#95;02&#95;22&#95;CJN15260920&#95;final.mp3., (Copyright © 2021 by the American Society of Nephrology.)