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To explore details of the incidence and rates of daytime and nocturnal hypoglycaemia, levels of hypoglycaemia, and relationship to glycated haemoglobin (HbA1c), when comparing iGlarLixi versus premixed biphasic insulin aspart 30 (BIAsp 30) in the SoliMix randomized controlled trial.This exploratory analysis of SoliMix used logistic regression and negative binomial regression analyses to assess between-treatment differences in the incidence and rates of hypoglycaemia by time of day. A negative binomial model was used to derive estimated annualized hypoglycaemia rates as a function of HbA1c.iGlarLixi was associated with lower incidence and rates of American Diabetes Association Level 2 (54 mg/dL [3.0 mmol/L]) hypoglycaemia during both night and day versus BIAsp 30. Incidence and rates of Level 1 (70 to ≥54 mg/dL [3.9 to ≥3.0 mmol/L]) hypoglycaemia were also mostly shown to be reduced with iGlarLixi versus BIAsp 30. Severe (Level 3) events were too few for analysis (n = 3). iGlarLixi was associated with lower modelled event rates of Level 2 and Level 1 hypoglycaemia over a wide range of HbA1c levels versus BIAsp 30.These results show that the lower HbA1c levels and weight benefit seen with iGlarLixi versus premixed BIAsp 30 in people with type 2 diabetes advancing their basal insulin therapy in the SoliMix trial are also accompanied by a lower risk of hypoglycaemia at any time of day and across a broad range of HbA1c levels.

AimsTo explore the modifying effect of glucagon-like peptide-1 receptor agonist (GLP-1RA) use on outcomes with finerenone across a wide spectrum of patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) in the pooled analysis of FIDELIO-DKD and FIGARO-DKD.Materials and methodsPatients with T2D and CKD treated with optimized renin-angiotensin system blockade were randomized to finerenone or placebo. Effects of finerenone on a cardiovascular composite outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and a kidney composite outcome (kidney failure, sustained ≥57% estimated glomerular filtration rate [eGFR] decline, or renal death), change in urine albumin-to-creatinine ratio (UACR), and safety were analysed by GLP-1RA use.ResultsOf 13 026 patients, 944 (7.2%) used GLP-1RAs at baseline. Finerenone reduced the risk of the cardiovascular composite outcome (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.52–1.11 with GLP-1RA; HR 0.87, 95% CI 0.79–0.96 without GLP-1RA; P-interaction = 0.63) and the kidney composite outcome (HR 0.82, 95% CI 0.45–1.48 with GLP-1RA; HR 0.77, 95% CI 0.67–0.89 without GLP-1RA; P-interaction = 0.79) irrespective of baseline GLP-1RA use. Reduction in UACR with finerenone at Month 4 was –38% in patients with baseline GLP-1RA use compared with –31% in those without GLP-1RA use (P-interaction = 0.03). Overall safety and incidence of hyperkalaemia were similar, irrespective of GLP-1RA use.ConclusionsThe cardiorenal benefits of finerenone on composite cardiovascular and kidney outcomes and UACR reduction in patients with CKD and T2D appear to be maintained, regardless of GLP-1RA use. Subsequent studies are needed to investigate any potential benefit of this combination. Aims: To explore the modifying effect of glucagon-like peptide-1 receptor agonist (GLP-1RA) use on outcomes with finerenone across a wide spectrum of patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) in the pooled analysis of FIDELIO-DKD and FIGARO-DKD. Materials and methods: Patients with T2D and CKD treated with optimized renin-angiotensin system blockade were randomized to finerenone or placebo. Effects of finerenone on a cardiovascular composite outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and a kidney composite outcome (kidney failure, sustained ≥57% estimated glomerular filtration rate [eGFR] decline, or renal death), change in urine albumin-to-creatinine ratio (UACR), and safety were analysed by GLP-1RA use. Results: Of 13 026 patients, 944 (7.2%) used GLP-1RAs at baseline. Finerenone reduced the risk of the cardiovascular composite outcome (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.52–1.11 with GLP-1RA; HR 0.87, 95% CI 0.79–0.96 without GLP-1RA; P-interaction = 0.63) and the kidney composite outcome (HR 0.82, 95% CI 0.45–1.48 with GLP-1RA; HR 0.77, 95% CI 0.67–0.89 without GLP-1RA; P-interaction = 0.79) irrespective of baseline GLP-1RA use. Reduction in UACR with finerenone at Month 4 was –38% in patients with baseline GLP-1RA use compared with –31% in those without GLP-1RA use (P-interaction = 0.03). Overall safety and incidence of hyperkalaemia were similar, irrespective of GLP-1RA use. Conclusions: The cardiorenal benefits of finerenone on composite cardiovascular and kidney outcomes and UACR reduction in patients with CKD and T2D appear to be maintained, regardless of GLP-1RA use. Subsequent studies are needed to investigate any potential benefit of this combination.

Introduction Although hyperkalemia and metabolic acidosis often co-occur in patients with chronic kidney disease (CKD), the prevalence of metabolic acidosis among patients with CKD and hyperkalemia is understudied. Therefore, we used medical record data from the Research Action for Health Network to estimate this prevalence. Methods Adult patients with CKD stage 3–5, ≥ 1 outpatient potassium value > 5.0 mEq/l, and ≥ 1 outpatient bicarbonate value available were identified. Patients with end stage kidney disease (ESKD) in the prior year were excluded. The prevalence of metabolic acidosis in each calendar year from 2014 to 2017 among patients with CKD and hyperkalemia was estimated using two definitions of hyperkalemia (potassium > 5.0 mEq/l and > 5.5 mEq/l) and metabolic acidosis (bicarbonate 5.0 mEq/l and ranged from 33 to 39% when hyperkalemia was defined by potassium > 5.5 mEq/l. Conclusion Results demonstrated that prevalence estimates of metabolic acidosis varied based on the definition of hyperkalemia and metabolic acidosis utilized.

OBJECTIVE To prospectively analyze the association of sedentary behavior time with type 2 diabetes (T2D) risk and perform the isotemporal substitution analyses to estimate the effect of substitution of sedentary behaviors by equal time of different types of daily-life physical activities and structured exercise. We also examined modifications by the genetic predisposition to T2D. RESEARCH DESIGN AND METHODS We included 475,502 participants free of T2D in the UK Biobank. Sedentary time was quantified by summing up the time spent on television watching, computer use, and driving. RESULTS During a median follow-up of 11 years, we documented 18,169 incident T2D cases. In comparison of the extreme categories (≥6 vs. CONCLUSIONS Our study indicates that sedentary behavior time is associated with an increased risk of T2D; replacing sedentary behavior with a short duration (30 min/day) of daily-life physical activities or structured exercise is related to a significant reduction in T2D risk. Furthermore, such association was stronger among those with a lower genetic risk of T2D.

Recommended A1C targets for people with type 2 diabetes are between 6.5 and 8%; however, real-world data suggest that an increasing proportion of people with diabetes have suboptimal control, and ∼15% have an A1C level >9%. People with A1C >9% are at increased risk for micro- and macrovascular complications and require treatment intensification to improve glycemic control as early as possible. In a series of short videos now available on the Clinical Diabetes website, the authors discuss the pathophysiological changes that occur during the progression of type 2 diabetes, with particular focus on the key role of declining β-cell function. The authors review clinical characteristics—long diabetes duration and A1C ≥9%—that are indicative of diminishing β-cell function, and they discuss the clinical data that support the use of available treatment options for these individuals, consistent with current diabetes treatment guidelines. This article is intended to briefly summarize those discussions. The videos described below are available in their entirety, along with short biographies of the authors, at https://clinical.diabetesjournals.org/content/combination-injectable-therapy. ### Need for Glycemic Control in Individuals With A1C ≥9% (Video 1) Video 1. Need for Glycemic Control in Individuals With A1C ≥9%. Available from https://bcove.video/3bda5FB. Current treatment guidelines for people with type 2 diabetes from the American Diabetes Association, the American Association of Clinical Endocrinologists, the American College of Endocrinology, and the American College of Physicians recommend A1C targets within the range of 6.5–8% (1–3). However, public health reports suggest that a significant proportion of U.S. adults with diabetes have an A1C >9% (4), which is defined as “poor glycemic control” by the Healthcare Effectiveness Data and Information Set (5). Furthermore, A1C levels >9% can negatively affect reimbursement (e.g., through a decrease in the star ratings used to assess quality and performance) (6). In this video, the authors discuss the deleterious health consequences for patients with high A1C levels, including …

OBJECTIVES Heart disease is the most common cause of death in patients with nonalcoholic fatty liver disease (NAFLD). Emerging data have shown that NAFLD may affect subclinical myocardial remodeling, mainly left ventricular hypertrophy; however, evidence from the prospective studies is still lacking. METHODS Prospective analyses were performed to investigate the association of fatty liver index (FLI) with left ventricular mass (LVM) among 1962 participants from the Bogalusa Heart Study (BHS, 1995-2010) and 1547 participants from the Cardiovascular Risk in Young Finns Study (YFS, 2001-2011) free of cardiovascular diseases (CVD) at baseline. LVM was assessed by two-dimensional guided M-mode echocardiography and indexed (LVMI) to body height (m2.7). Multivariable regression models were applied after adjustment for traditional CVD risk factors. RESULTS In both cohorts, we observed significant and positive associations between FLI and LVM (BHS: β=0.59, P

Management of diabetes requires a multifaceted approach of risk factor reduction; through management of risk factors such as glucose, blood pressure and cholesterol. Goals for these risk factors often vary and guidelines suggest that this is based on patient characteristics and need to be individualized. Evaluating risk is therefore critically important to determine goals and choose appropriate treatments. A risk engine is an analytic tool that collects a large amount of population data allowing the simulation of the progression of diabetes with set equations over a period of time. Recently, a number of data cohorts have become available, leading to the development of newer risk engines that are more dynamic and generalizable. An example is the Building, Relating, Assessing, and Validating Outcomes in (BRAVO) diabetes model which was built on the ACCORD trial database. It is capable of accurately predicting diabetes comorbidities in an international population based on calibration with international clinical trial data. It has potential uses in risk stratification of patients, evaluation of interventions and calculation of their long term cost effectiveness. Recently, it has been used to simulate long term outcomes based on short term data, using difference modelling scenarios.

This study aimed to identify patient characteristics associated with the effectiveness of intensive glucose control (i.e., A1c Disclosure H.Kianmehr: None. J.Guo: None. V.Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. L.Shi: None. H.Shao: Board Member; BRAVO4HEALTH, LLC.

CKD is highly prevalent and costly in individuals with diabetes. Clinicians need to have a tool for early identification and prediction of incident CKD in individuals with diabetes. This study aimed to predict incident CKD among individuals with diabetes. A time-varying Cox model was derived from the ACCORD clinical trial data to predict the risk of incident CKD, defined as eGFR30 mg/g lasting for 3 months. A list of candidate variables was chosen based on literature reviews and experts’ consultation, including demographic characteristics, physical exam, laboratory, medical history, drug use, and healthcare utilization. Predictors were selected from candidate variables using a stepwise algorithm. Data were split into training and validation set. Model performance was evaluated by Brier score (BS) and C statistics. Confidence intervals (CI) was calculated using a bootstrap method. Decomposition analysis was conducted to assess the predictor contribution. External validation was performed on patient-level data of HARMONY Outcome clinical trial. A total of 6,006 diabetes patients free of CKD at baseline were used for model development, with a median follow-up of 3 years and 2,257 new onset CKD events. The CKD risk model identified age at T2D diagnosed, smoking status, BMI, HDL, VLDL, ALT, eGFR, UACR, hypoglycemia event, retinopathy event, CHF event, CHD history, antihyperlipidemic drug use, antihypertensive drug use, and hospitalization. The model demonstrated good discrimination (C-statistics 0.828 [95% CI 0.812-0.845]) and calibration (BS 0.0552 [95% CI 0.0474-0.0593]) performance. UACR, eGFR, and CHF event were the top 3 factors that contributed most to the prediction. A total of 8,221 patients free of CKD was selected from HARMONY Outcome trial with 1,288 CKD events and median follow-up of 2 years. The model demonstrated acceptable discrimination (C-statistics: 0.772 [95% CI 0.767-0.805]) and calibration (BS: 0.0504 [95% CI 0.0477-0.0531]) in external data. A risk prediction of incident CKD among T2D patients was developed and validated for use in decision support of CKD prevention. Disclosure Y. Lin: None. H. Shao: Board Member; BRAVO4HEALTH, LLC. A. H. Anderson: None. V. Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. V. Batuman: None. L. Shi: None.

Time in range (TIR) referres to the percentage of time that blood glucose levels stay within a pre-determined range for patients with diabetes. This study used simulation methods to quantify the long-term health benefit and economic return associated with the improvement of TIR in individuals with T2D. Individuals with self-reported T2D were identified from the 2017-2018 National Health and Nutrition Examination Survey as the target population for the simulation. A Markov model with three states (i.e., diabetes, diabetes with a history of cardiovascular disease (CVD) , death) was developed to calculate the 20-year cost, quality-adjusted life-years (QALY) gained, and cardiovascular disease (CVD) risk reduction under four scenarios: TIR >85%, 71-85%, 51-70%, and ≤50%. The risk of CVD and mortality were extracted from literature. CVD and mortality risk reduction associated with TIR improvement, as well as cost and QALY associated with each health state were all extracted from the literature. Costs were standardized to the 2021 US Dollar, and a 3.0% annual discount rate was used. A willingness-to-pay threshold of $50,000/QALY was used to determine cost-effectiveness. Compared with having a TIR 85% was associated with an increase of 3.QALY and 1.97 life-years, and a 14.89% relative risk reduction in CVD. The annual spending on treatment to improve the TIR from 85% should be lower than $2,592, $3,082, and $4,120 respectively to make the treatment cost-effective. Improving TIR can potentially lead to a substantial health benefit. Our study qualified the maximum medical expenses allocated to improve the TIR while keeping the treatment cost-effective. Disclosure K.Alkhuzam: None. L.Shi: None. V.Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. Y.Zhang: None. J.Guo: None. H.Shao: Board Member; BRAVO4HEALTH, LLC.

Negative or neutral treatment effects reported in many clinical trials reflect average treatment effects in the trial population and may mask heterogeneous treatment effects across patient subgroups. Machine learning (ML) methods are valuable tools to study these treatment heterogeneities. Using ML methods and data collected in the ACCORD trial, we identified patient subgroups that might benefit from intensive glycemic and blood pressure intervention. The ACCORD found that intensive glucose (A1c 55 mg/dL, men >45 mg/dL; relative risk [RR] 0.51, 95% CI: 0.34-0.74%) and those with LDL >100 mg/dL (RR: 0.74, 95% CI: 0.59-0.94) , but had no significant effects in other patient groups. Intensive glycemic control reduced MACE in those with baseline A1c 1mL/min/1.73m2 (i.e., highest quartile; RR: 0.74, 95% CI: 0.55-0.99) ; reductions were not significant in other patient groups. Our findings may assist clinicians in developing a more precise approach to managing persons with type 2 diabetes at high risk of CVD events. Future clinical trials may be needed to confirm these findings. Disclosure H.Kianmehr: None. P.Zhang: None. N.Singh ospina: None. L.Shi: None. V.Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. J.Guo: None. H.Shao: Board Member; BRAVO4HEALTH, LLC.

Aim: Evaluate if cardiovascular (CV) risk factors increase at a greater rate during the prediabetes (preDM) stage rather than the diabetes (DM) stage by sex. Methods: We pooled data from the Atherosclerosis Risk in Communities Study and the Multi-Ethnic Study of Atherosclerosis. The CV risk outcome was the metabolic syndrome (MetS) severity z-score derived from components of waist circumference, HDL, triglycerides, SBP, and fasting glucose accounting for the weight of each component. The score was calculated for participants at visits 1 to 4 (3-year interval between visits) . We used linear mixed regressions to model the MetS z-score over time in men and women by levels of glucose (normal Results: Men and women had a greater rate of change in MetS severity during the preDM than the DM stage. Women had a significantly greater increase of MetS severity than men during the preDM stage, while men had a significantly greater increase in the DM stage than women. Conclusion: A more rapid increase in MetS severity occurred in preDM than in DM. Women exhibited a faster increase in MetS severity compared to men during the preDM stage. Greater attention should be given to CV risk in women with preDM. Disclosure Y.Yoshida: None. Z.Chen: n/a. R.L.Baudier: None. M.Krousel-wood: None. A.H.Anderson: None. V.Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. F.Mauvais-jarvis: Consultant; Mithra Pharmaceutical. Funding NIH K12HD043451

The hemoglobin glycation index (HGI) is the difference between observed HbA1c and predicted HbA1c from FPG using linear regression. HGI is an important biomarker of clinical management/drug treatment outcomes and can identify individuals at high risk for multiple adverse events and outcomes before the appearance of clinical symptoms. Here, we sought to test if variation in HGI has genetic determinants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial using a genome-wide association approach (N = 7913) . We subsequently replicated the top hits (P < 1e-5) in the Atherosclerosis Risk in Communities Study (ARIC; N = 3741) . An intergenic SNP rs73407935 (7q11.22) was associated with HGI (P = 5.8e-10) with the locus replicating in ARIC. Further, multiple variants at suggestive genome-wide significance in discovery (P < 5e-6) replicated in ARIC including variants near or in ASAH1 (P = 2.4e-6) , a region previously associated with risk of CAD in T2D, LRRC4C (P = 2.4e-6) , SHLD1 (P = 3.7e-6) and FAM22B (P = 2.5e-6) . The top 2 replicated SNPs in FAM22B are characterized eQTLs for expression of multiple genes in cells from pancreas, brain, and the immune system, including TRAF4, PROCA1, and RPL23A. Many SNPs associated with HGI were distinct from those associated with FPG or HbA1c. In ACCORD, sex-specific HGI associations with SNPs in or near GALNT11 in females (P = 5e-9) and HECW2 (P = 1.5e-8) in males were observed. Further, analysis of 544 Hispanics revealed associations of a strong eQTL variant near USF1 (rs2516837; P = 1.5e-09) and SNPs near NXNL2/SPIN1 (rs141006133; P = 6.9e-9) with HGI. This work represents the first evaluation of the genetic etiology of HGI. We identified and replicated variants that merit further study in the development of precision medicine for treatment of T2D. The results of the stratified analyses highlight the potential importance of heterogeneity in these efforts. Disclosure J.S.House: None. D.M.Rotroff: Research Support; Novo Nordisk, Stock/Shareholder; Clarified Precision Medicine. V.Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. J.M.Hempe: None. J.Mychaleckyj: None. A.Doria: Research Support; Novo Nordisk Foundation. J.B.Buse: Consultant; Alkahest, Anji, AstraZeneca, Boehringer Ingelheim International GmbH, Cirius Therapeutics, Inc., Eli Lilly and Company, Fortress biotech, GentiBio, Glycadia, Glyscend, Janssen Pharmaceuticals, Inc., Mellitus Health, Moderna, Inc., Pendulum Therapeutics, Praetego, LLC, Stability Health, Valo, Zealand Pharma A/S, Other Relationship; Adocia, AstraZeneca, Eli Lilly and Company, Intarcia Therapeutics, Inc., MannKind Corporation, Novo Nordisk, Sanofi, Senseonics, vTv Therapeutics, Research Support; AstraZeneca, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, vTv Therapeutics, Stock/Shareholder; Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Praetego, LLC, Stability Health. A.Motsinger-reif: None. Funding NHLBI RO1HL110380NIDDK P30DK124723NCATS UL1TR002489

Several hypotheses have been proposed that SGLT2 inhibitors and GLP-1 receptor agonists may have additional mechanisms to further reduce risks of cardiovascular complications unexplained by traditional risk factors control. This study aimed to examine and quantify the magnitude of additional protective effects of these two drugs on cardiovascular outcomes in individuals with type 2 diabetes (T2D) . Patient characteristics were extracted from four cardiovascular outcomes trials (CVOTs) of SGLT2 inhibitors and four CVOTs of GLP-1 receptor agonists completed before Nov 2021. We used the BRAVO simulation model to translate risk factors reductions from the newer drugs into risk reductions in cardiovascular complications, assuming the simulated risk reductions are only driven by traditional risk factors (i.e., A1c, SBP, LDL, and BMI) . We then derived the relative risk (RR) between observed risk reductions and simulated risk-factor-driven risk reductions in study outcomes to determine whether additional cardiovascular benefit of the newer drugs exist that can be explained by improvement of traditional risk factor control. Controlling for effect from traditional risk factors, SGLT2 inhibitor was associated with an additional risk reduction of hospitalization for heart failure (HHF) (RR: 0.74, 95% confidence interval (CI) : 0.59-0.94) , and a meaningful but not significant reduction in all-cause mortality (RR: 0.90, 95% CI: 0.77-1.03) , but an increased risk of stroke (RR: 1.29, 95% CI: 1.03-1.62) . No additional benefit was observed in preventing MI or CVD mortality from SGLT2 inhibitors. No additional benefit in preventing any study outcomes was associated with GLP-1 receptor agonists. Except for the benefit on HHF by SGLT2i, improvement in traditional CVD risk factors largely account for all the benefit associated with GLP-1 and SGLT2i to reduce CVD. Disclosure S.Niu: None. D.Guan: None. N.Singh ospina: None. K.Cusi: Consultant; Altimmune, Arrowhead Pharmaceuticals, Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Fractyl Health, Inc., Genentech, Inc., Hanmi Pharm. Co., Ltd., Intercept Pharmaceuticals, Inc., Novo Nordisk. V.Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. L.Shi: None. H.Shao: Board Member; BRAVO4HEALTH, LLC.

This study aimed to identify patient characteristics associated with the effectiveness of albiglutide in preventing MACE among patients with type 2 diabetes (T2D) in the HARMONY trial. The HARMONY trial was a randomized, double-blind, placebo-controlled trial to examine the effectiveness of albiglutide in reducing the risk of cardiovascular disease in 9,463 individuals with T2D. We used the causal forest (CF) and causal tree (CT) algorithm to identify participant characteristics that modulate the effectiveness of albiglutide in preventing MACE from a list of 16 candidate variables (demographics, disease histories, medications, and biomarkers) at the study baseline. A computer-driven approach identified that study participants with baseline A1c level above 8.0% (absolute risk change (ARC) : -2.77%, 95% confidence interval [-4.21% to -1.28%]; relative risk (RR) : 0.74 [0.62 to 0.87]) , or diabetes duration less than 15 years (ARC: -2.55% [ -3.85% to -1.04%]; RR: 0.70 [0.58 to 0.85]) , or DBP higher than 70 mmHg (ARC: -2.40% [-3.68% to -1.21%]; RR: 0.73 [0.62 to 0.86]) , or heart rate below 70 per hour (ARC: -2.88% [-4.76% to -1.04%]; RR: 0.70 [0.56 to 0.88]) , or ALP level below 70 U/L (ARC: -3.10% [-3.10% to -1.30%]; RR: 0.65 [0.52 to 0.81]) , or serum creatinine level below 90 umol/L (ARC: -1.99% [-3.33% to -0.81%]; RR: 0.74 [0.61 to 0.88]) benefited from albiglutide in reducing the risk of MACE. In contrast, their counterparts who did not have these characteristics did not receive statistically significant MACE risk reduction from albiglutide. Our study identified clinical features that may result in greater benefits of albiglutide on MACE than what would be expected from a population average. Clinicians may consider these individualized characteristics for better-targeted albiglutide treatment. However, future GLP-1 trials may help to confirm this approach to optimize outcomes. Disclosure H.Kianmehr: None. Y.Lin: None. L.Shi: None. V.Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. J.Guo: None. H.Shao: Board Member; BRAVO4HEALTH, LLC.

This study compared the 5-year risk of diabetes complications of tirzepatide (TZP) and semaglutide with insulin glargine in individuals with type 2 diabetes (T2Ds) , using the BRAVO diabetes model, which has been validated to have a high degree of accuracy. We used the BRAVO model to predict 5-year complications among users of TZP (5 mg, mg, or 15 mg) , semaglutide (1 mg) , and insulin glargine, based on short-tern efficacy data from the SURPASS-2 trial and SUSTAIN-4 trial, under two scenarios: the short-term drug efficacy lasted for 5 years (optimistic) , and the drug efficacy diminished in 5 years (conservative) . We found a 5-year risk reduction in major adverse cardiovascular events (MACE) (relative risk [RR] 63.7%, 95% CI: 61.4%-66.2%) with 15 mg TZP under an optimistic scenario, and MACE (RR 87.6%, 95% CI: 86.8%-88.6%) risk reduction with 15 mg TZP under a conservative scenario, when compared with insulin glargine (Figure) . Lower doses of TZP also had similar, albeit slightly smaller, benefits. The long-term use of TZP and semaglutide may lead to a substantial reduction in diabetes-related complications among individuals with T2Ds, compared to insulin. A high dose of TZP was also superior to semaglutide in this respect. Disclosure S.Niu: None. T.Jiao: None. Y.Guo: None. J.Bian: None. L.Shi: None. V.Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. H.Shao: Board Member; BRAVO4HEALTH, LLC.

Background: Women with diabetes are at higher risk of CVDs than men. We investigated the associations between the degree of risk factor control and CVD in women and men with diabetes. Methods: A total of 16,760 diabetes patients from UK Biobank were included. The exposure was the number of optimized risk factors including HbA1c level Results: During a mean follow-up of 8.4 years, 2000 incident CVD were documented, including 1685 IHD and 412 stroke. Number of risk-factor control was inversely associated with the risks of IHD, stroke and total CVD, and such associations were stronger in women than men (P for interaction with sex=0.012, 0.018 and 0.017, respectively) . The two most important risk factors for men were blood pressure and non-HDL-cholesterol, while for women were HbA1c and non-HDL-cholesterol. In addition, as compared with non-diabetic controls, the diabetes-related risk of CVD was theoretically eliminated when 2 or more risk-factors were under control in women, and 3 risk-factors were under control in men. Conclusion: Among diabetes patients, to control the risk factors within the target range benefit more in women than men in preventing subsequent risk of CVD. Our findings highlight the importance of raising awareness of control of risk factors and provide evidence for the sex-specific priority of control strategies. Disclosure X.Wang: None. H.Ma: None. V.Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. L.Qi: None. Funding National Heart, Lung, and Blood Institute (HL071981, HL034594, HL126024) , the National Institute of Diabetes and Digestive and Kidney Diseases (DK115679, DK091718, DK100383, DK078616)

The cost-effectiveness of SGLT2i can be modulated by patients’ characteristics, such as cardiovascular risks. We performed an individualized cost-effectiveness assessment of SGLT2i when added to metformin in people with inadequately controlled T2D to quantify the modulating effect of patients’ characteristics on the cost-effectiveness of SGLT2i. We identified survey participants with T2D receiving metformin monotherapy who had an A1c level above 7.0% from the National Health and Nutrition Examination Survey (2013-2018) . We applied a simulation-based smoothing method to populate the survey sample to its represented national population. We used the BRAVO diabetes model to simulate the lifetime cost and QALYs associated with SGLT2i or sulfonylureas. Treatment escalations were governed by the A1c level at 7% and 8% consequentially. Both costs and QALYs were discounted at 3% annually, and the incremental cost-effectiveness ratio (ICER) threshold was set at $100,000/QALYs. The study sample included 2.89 million individuals. Compared with sulfonylureas, the use of SGLT2i was associated with an average of $9,400 higher medical cost and 0.10 additional QALY, leading to an ICER of $94,000/QALY in the overall population. SGLT2i was cost-effective in people with a history of heart failure (ICER: $67,000/QALY) and myocardial infarction (ICER: $94,000/QALY) , and marginally cost-effective in stroke patients (ICER: $100,000/QALY) . Among individuals without CVD, SGLT2i was cost-effective only in subgroups with HbA1c > 7.5%, age > 60, and diabetes duration > 10 years. Overall, SGLT2i was only cost-effective in individuals with a baseline 10-year CVD risk over 16%, constituting 51.6% of the overall population. Our results align closely with the ADA guideline on the recommended population for SGLT2i use. Out-of-pocket payment subsidy or cost-sharing reduction of SGLT2i should be prioritized in patient subgroups in which SGLT2i has high economic values. Disclosure D. Guan: None. S. Niu: None. V. Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. L. Shi: None. N. Laiteerapong: None. J. Guo: None. H. Shao: Board Member; BRAVO4HEALTH, LLC.

We developed an individual-level discrete-time microsimulation model, namely the Building, Relating, Assessing, and Validating Outcomes (BRAVO) diabetes model. The BRAVO model was externally validated using cohort-level data in people with type 2 diabetes (T2D) . This study further externally validated the BRAVO diabetes model using patient-level data from the Exenatide Study of Cardiovascular Event Lowering Trial (EXSCEL) . Baseline characteristics and trajectories of key biomarkers, including A1c, LDL, SBP, and BMI, were retrospectively extracted from the EXSCEL study database. To protect patients’ private information, variables of age and BMI were masked in ranges from the EXSCEL study (e.g., BMI 35 coded as BMI>30) . To convert the ranges back into specific values to support the simulation, we used the National Health and Nutrition Examination Survey (NHANES) data for the data imputations. We used the median value for each population subgroup from NHANES to replace the ranges. The BRAVO diabetes model was applied to the EXSCEL baseline data to predict the 7-year EXSCEL study outcomes. We assessed the BRAVO model’s discrimination power using C-statistics and calibration using the Brier score. The model demonstrated good discrimination and calibration in predicting the first occurrence of non-fatal myocardial infarction (C-index 0.620 [95% CI 0.590-0.650] and Brier Score (BS) 0.080 [0.074-0.085]) , non-fatal stroke (C-index 0.696 [0.634-0.758] and BS 0.031 [0.028-0.034]) , heart failure (C-index 0.700 [0.666-0.733] and BS 0.037 [0.034-0.041]) , revascularization (C-index 0.664 [0.590-0.738] and BS 0.036 [0.033-0.039]) , and all-cause mortality (C-index 0.746 [0.711-0.781] and BS 0.102 [0.098-0.106]) , respectively. Although the majority of the data obtained from EXSCEL trial was obtained in range instead of specific values, the BRAVO model remained robust in prediction performance in diabetes complications and mortality. Disclosure Y.Shao: None. S.Niu: None. L.Shi: None. V.Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. H.Shao: Board Member; BRAVO4HEALTH, LLC. Funding Astrazeneca

Introduction: Finerenone reduced risk of cardiorenal outcomes in patients with CKD and T2D in the FIDELIO-DKD and FIGARO-DKD studies. In FIDELIO-DKD the effects of finerenone on kidney and CV outcomes were consistent irrespective of glucagon-like peptide-1 receptor agonist (GLP-1RA) use, but analyses were better powered to evaluate change in urine albumin-to-creatinine ratio (UACR) . Here, we extend these analyses to patients in both studies (FIDELITY analysis) , thus encompassing a larger population with broader inclusion criteria. Methods: Patients with T2D and CKD (UACR ≥30- Results: Of 13026 patients, 944 (7.2%) received GLP-1RAs at baseline. Results were consistent irrespective of GLP-1RA use at baseline for the CV composite outcome (hazard ratio [HR] 0.76; 95% CI 0.52-1.with GLP-1RA; HR 0.87, 95% CI 0.79-0.96 without GLP-1RA; p-interaction 0.63) , and the kidney composite outcome (HR 0.82; 95% CI 0.45-1.48 with GLP-1RA; HR 0.77, 95% CI 0.67-0.89 without GLP-1RA; p-interaction 0.79) . A greater reduction in UACR was observed with finerenone in patients taking GLP-1RA at baseline (placebo-corrected change -38% with GLP-1RA and -31% without GLP-1RA use; p-interaction 0.03) . Incidence of hyperkalemia was similarly increased with finerenone irrespective of GLP-1RA use at baseline. Conclusion: The benefits of finerenone on composite CV and kidney outcomes in patients with CKD and T2D are not modified by GLP-1RA use at baseline, with an increased effect observed for UACR reduction, suggesting a different mechanism of reduction in albuminuria. Disclosure P.Rossing: Consultant; Astellas Pharma Inc., AstraZeneca, Bayer AG, Gilead Sciences, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Speaker's Bureau; Eli Lilly and Company. P.Viswanathan: Employee; Bayer AG. R.Lawatscheck: None. A.Joseph: Employee; Bayer AG. G.Bakris: Consultant; Alnylam Pharmaceuticals, Inc., AstraZeneca, DiaMedica Therapeutics, Inc., Horizon Therapeutics plc, Ionis Pharmaceuticals, Merck & Co., Inc., Other Relationship; Novo Nordisk. S.Anker: Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Novartis AG, Novo Nordisk, Vifor Pharma Management Ltd., Research Support; Abbott. G.Filippatos: Other Relationship; Amgen Inc., Amgen Inc., Bayer AG, Boehringer Ingelheim International GmbH, Medtronic, Novartis AG, Servier Laboratories, Vifor Pharma Management Ltd. B.Pitt: Advisory Panel; Merck & Co., Inc., Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Lexicon Pharmaceuticals, Inc., Vifor Pharma Management Ltd. L.M.Ruilope: Consultant; Bayer AG. V.Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. G.E.Umpierrez: Research Support; AstraZeneca, Dexcom, Inc., Novo Nordisk. L.Caramori: Advisory Panel; Bayer AG, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Research Support; Bayer AG, Novartis AG. M.Lambelet: Other Relationship; Bayer AG.

CKD progression among individuals with T2D is associated with poor outcomes and high costs. The risk factors for CKD progression in T2D have not been fully studied. This study aimed to predict CKD progression among individuals with T2D. Using the ACCORD clinical trial, a time-varying Cox model was developed to predict the risk of CKD progression among patients with CKD. CKD progression was defined as a 50% decline, or 25 mL/min/1.73 m2 decline in eGFR from baseline, doubling of the serum creatinine, or onset of ESKD. A list of candidate variables included demographic characteristics, physical exam, laboratory, medical history, drug use, and healthcare utilization. A stepwise algorithm was used for variable selection. Data was separated into training and validation set. Model performance was evaluated by Brier score (BS) and C statistics. Confidence intervals (CI) were calculated by bootstraping. Decomposition analysis was conducted to assess the predictor contribution. Generalizability was assessed on patient-level data of the HARMONY Outcome clinical trial. A total of 6,982 T2D patients with CKD were used for model development, with a median follow-up of 4 years and 3,346 CKD progression events. The predictors for CKD progression included female sex, age at T2D diagnosis, smoking status, BP, HR, HbA1c, ALT, eGFR, UACR, retinopathy event, hospitalization, interaction of SBP and smoking, and SBP and ALT. The model demonstrated good discrimination (C-statistics 0.745 [95% CI 0.723-0.763]) and calibration (BS 0.0923 [95% CI 0.0873-0.0965]) . The most contributing predictors for CKD progression were eGFR, HbA1c, and SBP. There were 2,954 patients with CKD extracted from HARMONY with 640 CKD progression events and median follow-up of 2 years. The model demonstrated acceptable discrimination (C-statistics: 0.742 [95% CI 0.721-0.7645]) and calibration (BS: 0.0988 [95% CI 0.0952-0.1022]) in the external data. For high-risk patients with both diabetes and CKD, the tool as a dynamic risk prediction of CKD progression may help develop novel strategies to lower the risk of CKD progression. Disclosure Y. Lin: None. H. Shao: Board Member; BRAVO4HEALTH, LLC. A. H. Anderson: None. V. Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. V. Batuman: None. L. Shi: None.

Many people with type 2 diabetes mellitus (T2DM) experience suboptimal glycemic control and require therapy advancement. This cost-effectiveness analysis was conducted to compare iGlarLixi (insulin glargine 100 U/mL plus lixisenatide) versus BIAsp 30 (biphasic insulin aspart 30) in people with T2DM suboptimally controlled with basal insulin.The IQVIA Core Diabetes Model was used to estimate lifetime costs and outcomes for people with T2DM from a US healthcare payer perspective. Initial clinical data were based on the phase 3 randomized, open-label, active-controlled SoliMix clinical study, which compared the efficacy and safety of once-daily iGlarLixi with twice-daily BIAsp 30. Lifetime costs (US$) and quality-adjusted life-years (QALYs) were predicted, and the incremental cost-effectiveness ratio (ICER) for iGlarLixi versus BIAsp 30 was estimated; the willingness-to-pay threshold was considered to be $50,000. A subgroup analysis considered people with T2DM aged ≥ 65 years.Estimated QALYs gained were slightly higher with iGlarLixi compared with BIAsp 30 (9.3 vs. 9.2), with lower costs for iGlarLixi ($117,854 vs. $120,109); the ICER for iGlarLixi was therefore considered dominant over BIAsp 30 in the base case. Key drivers for cost savings were the higher dose and twice-daily administration for BIAsp 30 versus once-daily administration for iGlarLixi. The robustness of the base-case results was confirmed by sensitivity and scenario analyses. Results were similar in a subgroup of people with T2DM aged ≥ 65 years.In people with T2DM with suboptimal glycemic control on basal insulin, iGlarLixi confers improved QALYs and reduced costs compared with BIAsp 30.

OBJECTIVE The effects of preventive interventions on cardiovascular autonomic neuropathy (CAN) remain unclear. We examined the effect of intensively treating traditional risk factors for CAN, including hyperglycemia, hypertension, and dyslipidemia, in individuals with type 2 diabetes (T2D) and high cardiovascular risk participating in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. RESEARCH DESIGN AND METHODS CAN was defined as heart rate variability indices below the fifth percentile of the normal distribution. Of 10,251 ACCORD participants, 71% (n = 7,275) had a CAN evaluation at study entry and at least once after randomization. The effects of intensive interventions on CAN were analyzed among these subjects through generalized linear mixed models. RESULTS As compared with standard intervention, intensive glucose treatment reduced CAN risk by 16% (odds ratio [OR] 0.84, 95% CI 0.75–0.94, P = 0.003)—an effect driven by individuals without cardiovascular disease (CVD) at baseline (OR 0.73, 95% CI 0.63–0.85, P < 0.0001) rather than those with CVD (OR 1.10, 95% CI 0.91–1.34, P = 0.34) (Pinteraction = 0.001). Intensive blood pressure (BP) intervention decreased CAN risk by 25% (OR 0.75, 95% CI 0.63–0.89, P = 0.001), especially in patients ≥65 years old (OR 0.66, 95% CI 0.49–0.88, P = 0.005) (Pinteraction = 0.05). Fenofibrate did not have a significant effect on CAN (OR 0.91, 95% CI 0.78–1.07, P = 0.26). CONCLUSIONS These data confirm a beneficial effect of intensive glycemic therapy and demonstrate, for the first time, a similar benefit of intensive BP control on CAN in T2D. A negative CVD history identifies T2D patients who especially benefit from intensive glycemic control for CAN prevention.

Aim To assess the impact of the timing of initiating both basal insulin and glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) on reaching glycaemic control targets over 6 and 12 months in people with type 2 diabetes (T2D) uncontrolled on oral antihyperglycaemic drugs with an HbA1c of 9% or higher. Methods This retrospective cohort study assessed the impact of the timing of initiating both basal insulin and GLP‐1 RA therapies on reaching glycaemic targets (HbA1c

Objective Coronavirus disease 2019 (COVID-19) has disproportionately impacted the African American community. This study aims to identify the risk factors for severe COVID-19 disease in African American patients. Methods This was a retrospective cross-sectional analysis of African American patients with COVID-19 treated between March 12 and April 9, 2020, at a single tertiary center. The primary outcome of interest was severe disease defined as those requiring intensive care unit (ICU) admission. Results The study included 158 consecutive patients. The mean age was 57 years, and 61% were women. The mean (SD) of BMI was 33.2 (8.6) kg/m2 . Overall, patients admitted to the ICU were older (62 vs. 55 years, P = 0.003) and had higher BMI (36.5 kg/m2 vs. 31.9 kg/m2 , P = 0.002). In unadjusted and adjusted analysis, the factors most associated with ICU admission in this sample were age (adjusted odds ratio [aOR]: 1.073; 95% CI: 1.033-1.114), BMI (aOR: 1.115; 95% CI: 1.052-1.182), and lung disease (aOR: 3.097; 95% CI: 1.137-8.437). Conclusions This study identified risk factors for severe disease in COVID-19, specifically in an African American population. Further inclusive research aimed at optimizing clinical care relevant to the African American population is critical to ensure an equitable response to COVID-19.

OBJECTIVE This study evaluated the ability of the Building, Relating, Assessing, and Validating Outcomes (BRAVO) risk engine to accurately project cardiovascular outcomes in three major clinical trials—BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME), Canagliflozin Cardiovascular Assessment Study (CANVAS), and Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction (DECLARE-TIMI 58) trial—on sodium–glucose cotransporter 2 inhibitors (SGLT2is) to treat patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Baseline data from the publications of the three trials were obtained and entered into the BRAVO model to predict cardiovascular outcomes. Projected benefits of reducing risk factors of interest (A1C, systolic blood pressure [SBP], LDL, or BMI) on cardiovascular events were evaluated, and simulated outcomes were compared with those observed in each trial. RESULTS BRAVO achieved the best prediction accuracy when simulating outcomes of the CANVAS and DECLARE-TIMI 58 trials. For EMPA-REG OUTCOME, a mild bias was observed (∼20%) in the prediction of mortality and angina. The effect of risk reduction on outcomes in treatment versus placebo groups predicted by the BRAVO model strongly correlated with the observed effect of risk reduction on the trial outcomes as published. Finally, the BRAVO engine revealed that most of the clinical benefits associated with SGLT2i treatment are through A1C control, although reductions in SBP and BMI explain a proportion of the observed decline in cardiovascular events. CONCLUSIONS The BRAVO risk engine was effective in predicting the benefits of SGLT2is on cardiovascular health through improvements in commonly measured risk factors, including A1C, SBP, and BMI. Since these benefits are individually small, the use of the complex, dynamic BRAVO model is ideal to explain the cardiovascular outcome trial results.

BACKGROUND AND OBJECTIVES: The glucagon-like peptide-1 receptor agonist liraglutide demonstrated cardiovascular and kidney benefits in the LEADER trial, particularly in participants with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This post hoc analysis evaluated the safety of liraglutide treatment in patients with CKD in LEADER. Overall, 9340 patients were randomized to liraglutide or placebo, both in addition to standard of care. Of those, 2158 patients had CKD versus 7182 without CKD (defined as eGFR 300 mg/g and ≥30 to ≤300 mg/g, respectively). At baseline, the mean eGFR in patients with CKD was 46±11 ml/min per 1.73 m(2) versus 91±22 ml/min per 1.73 m(2) in those without CKD. Time to first event within event groups was analyzed using Cox regression with treatment group, baseline eGFR group, or baseline albuminuria group as fixed factors. RESULTS: Overall, serious adverse events were more frequently recorded in patients with CKD compared with those without CKD (59% versus 50%; interaction P=0.11); however, they occurred to the same extent in those on liraglutide versus placebo. Similarly, no interaction of adverse events with randomized therapy was observed in patients with micro- or macro- versus normoalbuminuria (interaction P=0.11). Risk of severe hypoglycemia was significantly reduced with liraglutide versus placebo in patients with CKD or with micro- or macroalbuminuria (hazard ratio, 0.63 [95% CI, 0.43 to 0.91] and 0.57 [95% CI, 0.40 to 0.82], respectively). CONCLUSIONS: In LEADER, the use of liraglutide in those with CKD was safe, with no difference between patients with and without CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov; NCT01179048 (https://clinicaltrials.gov/ct2/show/NCT01179048).

Introduction When and how to intensify treatment in patients with type 2 diabetes (T2D) not achieving glycated hemoglobin (HbA1c) targets with oral antidiabetic drugs (OADs) in clinical practice remains a matter of clinical preference. This pilot study was conducted using the retrospective observational data from such patients to evaluate the impact on HbA1c of three treatment sequences: simultaneous initiation of basal insulin (BI) and a glucagon-like peptide-1 receptor agonist (GLP-1 RA; Cohort 1); BI followed by GLP-1 RA initiation within a 90-day timeframe (Cohort 2); or BI followed by GLP-1 RA initiation beyond 90 days (Cohort 3). Methods Data from the regional US electronic medical records database, Research Action for Health Network (REACHnet), were extracted for all patients with T2D aged ≥ 18 years who had encounter dates between January 2011 and August 2017 and ≥ 1 HbA1c laboratory value(s)

Renal proximal tubular angiotensinogen (AGT) is increased by hyperglycemia (HG) in diabetes mellitus, which augments intrarenal angiotensin II formation, contributing to the development of hypertension and kidney injury. Sodium-glucose cotransporter 2 (SGLT2) is abundantly expressed in proximal tubular cells (PTCs). The present study investigated the effects of canagliflozin (CANA), a SGLT2 inhibitor, on HG-induced AGT elevation in cultured PTCs. Mouse PTCs were treated with 5–25 mM glucose. CANA (0–10 µM) was applied 1 h before glucose treatment. Glucose (10 mM) increased AGT mRNA and protein levels at 12 h (3.06 ± 0.48-fold in protein), and 1 and 10 µM CANA as well as SGLT2 shRNA attenuated the AGT augmentation. CANA did not suppress the elevated AGT levels induced by 25 mM glucose. Increased AGT expression induced by treatment with pyruvate, a glucose metabolite that does not require SGLT2 for uptake, was not attenuated by CANA. In HG-treated PTCs, intracellular reactive oxygen species levels were elevated compared with baseline (4.24 ± 0.23-fold), and these were also inhibited by CANA. Furthermore, tempol, an antioxidant, attenuated AGT upregulation in HG-treated PTCs. HG-induced AGT upregulation was not inhibited by an angiotensin II receptor antagonist, indicating that HG stimulates AGT expression in an angiotensin II-independent manner. These results indicate that enhanced glucose entry via SGLT2 into PTCs elevates intracellular reactive oxygen species generation by stimulation of glycolysis and consequent AGT augmentation. SGLT2 blockade limits HG-induced AGT stimulation, thus reducing the development of kidney injury in diabetes mellitus.

To examine the effects of changes in body size phenotypes between childhood and adulthood on risks of diabetes and left ventricular hypertrophy (LVH) in adulthood.We included 3,351 individuals who participated as both children and adults in the Bogalusa Heart Study.Compared with participants with persistently metabolically healthy normal weight (MHNW) from childhood to adulthood, MHNW children who became metabolically unhealthy in adulthood had increased diabetes burden and LVH risk in adulthood; Metabolically unhealthy normal weight (MUNW) children who became MHNW or metabolically healthy obese (MHO) as adults and individuals with persistent MHO from childhood to adulthood were not at increased risks of diabetes or LVH. The risks were increased if MHO during childhood transitioned to metabolically unhealthy obesity (MUO) by adulthood or MUO stayed from childhood to adulthood. MUO children who became MHO or MHNW as adults had decreased diabetes burden and LVH risk in adulthood.Individuals maintained MHO from childhood to adulthood and MUNW children who became MHO as adults had a diabetes burden and LVH risk similar to individuals with persistent MHNW. Progression to metabolically unhealthy status and maintenance of metabolically unhealthy status, regardless of childhood BMI status, were associated with increased cardiometabolic outcomes.

IntroductionAs of November 2021, COVID-19 has killed more than 5 million people globally, including over 750 000 in the USA. Apart from corticosteroids, most available therapeutic options are at best marginally efficient in reducing disease severity and are extremely expensive. The systematic investigation of clinically approved drugs is a priority to determine what does mitigate disease severity. Oestradiol (E2) and progesterone (P4) produce a state of anti-inflammatory immune responses and immune tolerance, and enhanced antibody production. The goal of this trial is to evaluate the efficacy of a short E2 and P4 therapy, in addition to standard of care (SOC), in mitigating disease severity in COVID-19 hospitalised patients.Methods and analysisPhase 2, randomised, double blind, placebo-controlled, single-centre trial. Patients hospitalised for confirmed COVID-19, with scores 3–5 on the 9-point WHO ordinal scale are randomised between two arms: (1) Oestradiol cypionate intramuscular (IM) and micronised progesterone oral (PO), in addition to SOC, and (2) placebo, in addition to SOC. The primary outcome is the proportion of patients improving to scores 1 or 2 on the WHO scale through day 28. Secondary outcomes include length of hospital stay, duration of mechanical ventilation, cause of death, readmission rates, change in inflammatory biomarkers between admission and occurrence of primary endpoint, and adverse events. Study sample size will be up to 120 participants. The trial is currently recruiting subjects.Ethics and disseminationThe sponsor of this study is the Center of Excellence in Sex-Based Biology & Medicine at Tulane University, New Orleans, Louisiana, USA. Ethical approval was obtained from the Tulane institutional review board on 14 May 2021. The study was reviewed by the US Food and Drug Administration and granted Investigational New Drug #152 499. Results of the study will be submitted for publication in a peer-reviewed journal.Trial registration numberNCT04865029; Pre-results.

OBJECTIVE Early menopause may be associated with higher cardiovascular disease (CVD) risk. Type 2 diabetes mellitus (T2DM), coupled with early menopause, may result in even greater CVD risk in women. We examined CVD risk in women with early compared with normal-age menopause, with and without T2DM overall, and by race/ethnicity. RESEARCH DESIGN AND METHODS We pooled data from the Atherosclerosis Risk in Communities study, the Multi-Ethnic Study of Atherosclerosis, and the Jackson Heart Study. We included women with data on menopausal status, menopausal age, and T2DM, excluding pre- or perimenopausal women and those with prevalent CVD. Outcomes included incident coronary heart disease (CHD), stroke, heart failure (HF), and atherosclerotic cardiovascular disease (ASCVD) (CHD or stroke). We estimated the risk associated with early ( RESULTS We included 9,374 postmenopausal women for a median follow-up of 15 years. We observed 1,068 CHD, 659 stroke, 1,412 HF, and 1,567 ASCVD events. T2DM significantly modified the effect of early menopause on CVD risk. Adjusted hazard ratios for early menopause and the outcomes were greater in women with T2DM versus those without (CHD 1.15 [95% CI 1.00, 1.33] vs. 1.09 [1.03, 1.15]; stroke 1.21 [1.04, 1.40] vs. 1.10 [1.04, 1.16]; ASCVD 1.29 [1.09, 1.51] vs. 1.10 [1.04, 1.17]; HF 1.18 [1.00, 1.39] vs. 1.09 [1.03, 1.16]). The modifying effect of T2DM on the association between early menopause and ASCVD was only statistically significant in Black compared with White women. CONCLUSIONS Early menopause was associated with an increased risk for CVD in postmenopausal women. T2DM may further augment the risk, particularly in Black women.

Introduction The progression of mild hyperkalemia and the predictors of progression have not been well characterized. In this study we aimed to characterize the progression of hyperkalemia and identify the risk factors for hyperkalemia progression. Methods Adults with mild hyperkalemia (at least one serum potassium measure > 5.0 and ≤ 5.5 mEq/L) were identified using electronic medical records from the Research Action for Health Network (2012–2018). Progression to moderate-to-severe and progression to severe hyperkalemia were defined as the first occurrences of a serum potassium measure > 5.5 and > 6.0 mEq/L, respectively. Kaplan–Meier analyses were conducted to estimate progression rates for all patients and by pre-specified patient subgroups. Hazard ratios (HR) of moderate-to-severe and severe hyperkalemia progression were estimated using Cox models. Results Of 35,369 patients with mild hyperkalemia, 16.9% and 8.7% progressed to moderate-to-severe and severe hyperkalemia, respectively. Rates of hyperkalemia progression elevated with the severity of chronic kidney disease (CKD). The highest progression rates were seen in patients with CKD stage 5 (stage 5 vs. no CKD: moderate-to-severe, 50.2% vs. 12.0%; severe, 31.3% vs. 3.9%; p

OBJECTIVE To improve outcomes of patients with adult type 2 diabetes by decreasing HbA1c undertesting, reducing the proportion of patients with poor glycemic control, and lowering mean HbA1c levels using a quality improvement (QI) program. RESEARCH DESIGN AND METHODS Six years of outpatient electronic health record (EHR) data were analyzed for care gaps before and 2 years after implementing a QI initiative in an urban academic medical center. QI strategies included 1) individual provider and departmental outcome reports, 2) patient outreach programs to address timely follow-up care, 3) a patient awareness campaign to improve understanding of achieving clinical goals, 4) improving EHR data capture to improve population monitoring, and 5) professional education. RESULTS Analysis (January 2010 to May 2018) of 7,798 patients from Tulane Medical Center (mean age 61 years, 57% female, 62% black, 97% insured) with 136,004 visits showed target improvements. A Cox proportional hazards model controlling for age, sex, race, and HbA1c level showed a statistically significant reduction in HbA1c undertesting >6 months (hazard ratio 1.20 ± 0.07). Statistical process control charts showed 15.5% relative improvement in the patient proportion with HbA1c >9% (75 mmol/mol) from 13% to 11% (P < 10−6) following QI interventions and a 2.1% improvement of population mean HbA1c from 7.4% (57 mmol/mol) to 7.2% (55 mmol/mol) (P < 10−6). CONCLUSIONS Multidisciplinary QI teams using EHR data to design interventions for providers and patients produced statistically significant improvements in both care process and clinical outcome goals.

Context Intermediate-term glycemic control metrics fulfill a need for measures beyond hemoglobin A1C. Objective Compare glycated albumin (GA), a 14-day blood glucose measure, with other glycemic indices. Design 24-week prospective study of assay performance. Setting 8 US clinics. Participants Subjects with type 1 (n = 73) and type 2 diabetes (n = 77) undergoing changes to improve glycemic control (n = 98) or with stable diabetes therapy (n = 52). Interventions GA, fructosamine, and A1C measured at prespecified intervals. Mean blood glucose (MBG) calculated using weekly self-monitored blood glucose profiles. Main Outcome Measures Primary: Pearson correlation between GA and fructosamine. Secondary: magnitude (Spearman correlation) and direction (Kendall correlation) of change of glycemic indices in the first 3 months after a change in diabetes management. Results GA was more concordant (60.8%) with changes in MBG than fructosamine (55.5%) or A1C (45.5%). Across all subjects and visits, the GA Pearson correlation with fructosamine was 0.920. Pearson correlations with A1C were 0.655 for GA and 0.515 for fructosamine (P < .001) and with MBG were 0.590 and 0.454, respectively (P < .001). At the individual subject level, Pearson correlations with both A1C and MBG were higher for GA than for fructosamine in 56% of subjects; only 4% of subjects had higher fructosamine correlations with A1C and MBG. GA had a higher Pearson correlation with A1C and MBG in 82% and 70% of subjects, respectively. Conclusions Compared with fructosamine, GA correlates significantly better with both short-term MBG and long-term A1C and may be more useful than fructosamine in clinical situations requiring monitoring of intermediate-term glycemic control (NCT02489773).

OBJECTIVE Although emerging evidence indicates that increased variability in cardiovascular risk factors (CVRFs) among populations at midlife or later is a reliable predictor of adverse health outcomes, it is unknown whether intraindividual CVRF variability during childhood or adolescence is an independent predictor of later-life diabetes. We aimed to examine the association of CVRF variability during childhood with diabetes in later life. RESEARCH DESIGN AND METHODS We included 1,718 participants who participated in the Bogalusa Heart Study and had measures at least four times during childhood (aged 4–19 years). The mean follow-up period was 20.5 years. Intraindividual CVRF variabilities during childhood were calculated using SD, coefficient of variation, deviation from age-predicted values, and residual SD based upon four to eight serial measurements in childhood. RESULTS Increased variability in BMI or HDL cholesterol (HDL-C) during childhood, irrespective of the indices used, was significantly positively associated with later-life diabetes risk independent of their respective mean levels in childhood and other possible confounding factors. In combined analysis, the magnitude of the association with diabetes risk was similar for high childhood BMI variability and high childhood HDL-C variability. After adjustments for potential confounding variables, other CVRF variabilities including systolic/diastolic blood pressure, total cholesterol, triglycerides, and LDL cholesterol were not significantly associated with diabetes. CONCLUSIONS Increased BMI and HDL-C variabilities during childhood were significant risk factors for the development of diabetes independently of diverse risk factors, which may offer new insights into the childhood origin of adult-onset diabetes.

Context Studies suggest that menopausal hormone therapy (MHT) prevents type 2 diabetes (T2D). The combination of conjugated estrogens (CE) with the selective estrogen receptor modulator bazedoxifene (BZA) is an MHT that improves obesity and T2D in preclinical models of menopausal metabolic syndrome. The effect of CE/BZA on adiposity and glucose homeostasis in obese postmenopausal women is unknown. Objective To investigate the effect of CE/BZA on body composition, glucose homeostasis, and markers of inflammation in obese postmenopausal women. Research Design, Intervention, and Participants Randomized, double-blind, placebo-controlled pilot trial of 12 obese menopausal women assigned to 12-week treatment with CE 0.45 mg/BZA 20 mg (n = 7) or placebo (n = 5). At baseline and after 12 weeks, we assessed body composition (dual-energy X-ray absorptiometry), glucose homeostasis (IV glucose tolerance test), and inflammation biomarkers. Results Women treated with CE/BZA exhibited increased β cell function using homeostatic model assessment-B [median (interquartile range) CE/BZA vs placebo: 18.5 (−0.9 to 320.6) μU/mM vs −25.5 (−39.9 to −0.1) μU/mM; P = 0.045], and decreased basal glucose concentrations (Gb) [−5.2 (−9.2 to −1.7) mg/dL vs 2.7 (0.9 to 4.9) mg/dL; P = 0.029]. Insulin sensitivity was higher in the placebo arm [1.35 (1.12 to 1.82) (μU/mL) min−1 vs −0.24 (−1.50 to 0.19) (μU/mL) min−1; P = 0.029]. No changes between treatment groups were observed for the acute insulin response to glucose (AIRg), the disposition index (DI), body composition, and inflammatory biomarkers. Conclusions A 12-week treatment of obese postmenopausal women with CEs/BZA improves fasting β cell function and glucose concentrations without change in AIRg, HOMA-IR, DI, body composition, or markers of inflammation.

Rationale: In observational studies, type 2 diabetes mellitus (T2D) has been associated with an increased risk of hypertension, and vice versa; however, the causality between these conditions remains to be determined. Objectives: This population-based prospective cohort study sought to investigate the bidirectional causal relations of T2D with hypertension, systolic and diastolic blood pressure (BP) using Mendelian randomization (MR) analysis. Methods and Results: After exclusion of participants free of a history of heart failure, cardiovascular disease, cardiac procedures, and non-T2D diabetes mellitus, a total of 318 664 unrelated individuals with qualified genotyping data of European descent aged 37 to 73 from UK Biobank were included. The genetically instrumented T2D and hypertension were constructed using 134 and 233 single nucleotide polymorphisms, respectively. Seven complementary MR methods were applied, including inverse-variance weighted method, 2 median-based methods (simple and weighted), MR-Egger, MR-robust adjusted profile scores, MR-Pleiotropy Residual Sum and Outlier, and multivariate MR. The genetically instrumented T2D was associated with risk of hypertension (odds ratio, 1.07 [95% CI, 1.04–1.10], P =3.4×10 −7 ), whereas the genetically determined hypertension showed no relationship with T2D (odds ratio, 0.96 [0.88–1.04], P =0.34). Our MR estimates from T2D to BP showed that the genetically instrumented T2D was associated with a 0.67 mm Hg higher systolic BP (95% CI, 0.41–0.93, P =5.75×10 –7 ) but not with a higher diastolic BP. There was no clear evidence showing a causal effect of elevated systolic BP or diastolic BP on T2D risk. Positive pleiotropic bias was indicated in the hypertension→T2D relation (odds ratio, of MR-Egger intercept 1.010 [1.004–1.016], P =0.001) but not from T2D to hypertension (1.001 [0.998–1.004], P =0.556). Conclusions: T2D may causally affect hypertension, whereas the relationship from hypertension to T2D is unlikely to be causal. These findings suggest the importance of keeping an optimal glycemic profile in general populations, and BP screening and monitoring, especially systolic BP, in patients with T2D.

Abbreviations: A1C = hemoglobin A1C; AACE = American Association of Clinical Endocrinologists; ACCORD = Action to Control Cardiovascular Risk in Diabetes; ACCORD BP = Action to Control Cardiovascular Risk in Diabetes Blood Pressure; ACE = American College of Endocrinology; ACEI = angiotensin-converting enzyme inhibitor; AGI = alpha-glucosidase inhibitor; apo B = apolipoprotein B; ARB = angiotensin II receptor blocker; ASCVD = atherosclerotic cardiovascular disease; BAS = bile acid sequestrant; BMI = body mass index; BP = blood pressure; CCB = calcium channel blocker; CGM = continuous glucose monitoring; CHD = coronary heart disease; CKD = chronic kidney disease; DKA = diabetic ketoacidosis; DPP4 = dipeptidyl peptidase 4; eGFR = estimated glomerular filtration rate; EPA = eicosapentaenoic acid; ER = extended release; FDA = Food and Drug Administration; GLP1 = glucagon-like peptide 1; HDL-C = high-density-lipoprotein cholesterol; HeFH = heterozygous familial hypercholesterolemia; LDL-C = low-density-lipoprotein cholesterol; LDL-P = low-density-lipoprotein particle; Look AHEAD = Look Action for Health in Diabetes; NPH = neutral protamine Hagedorn; OSA = obstructive sleep apnea; PCSK9 = proprotein convertase subtilisin-kexin type 9 serine protease; RCT = randomized controlled trial; SU = sulfonylurea; SGLT2 = sodium-glucose cotransporter 2; SMBG = self-monitoring of blood glucose; T2D = type 2 diabetes; TZD = thiazolidinedione

Background: Hypertension and renal injury are common complications of type 2 diabetes mellitus (T2DM). Hyperglycemia stimulates renal proximal tubular angiotensinogen (AGT) expression via elevated oxidative stress contributing to the development of high blood pressure and diabetic nephropathy. The sodium glucose cotransporter 2 (SGLT2) in proximal tubules is responsible for the majority of glucose reabsorption by renal tubules. We tested the hypothesis that SGLT2 inhibition with canagliflozin (CANA) prevents intrarenal AGT augmentation and ameliorates kidney injury and hypertension in T2DM. Methods: We induced T2DM in New Zealand obese mice with a high fat diet (DM, 30% fat) with control mice receiving regular fat diet (ND, 4% fat). When DM mice exhibited > 350 mg/dL blood glucose levels, both DM- and ND-fed mice were treated with 10 mg/kg/day CANA or vehicle by oral gavage for 6 weeks. We evaluated intrarenal AGT, blood pressure, and the development of kidney injury. Results: Systolic blood pressure in DM mice (133.9 ± 2.0 mm Hg) was normalized by CANA (113.9 ± 4.0 mm Hg). CANA treatment ameliorated hyperglycemia-associated augmentation of renal AGT mRNA (148 ± 21 copies/ng RNA in DM, and 90 ± 16 copies/ng RNA in DM + CANA) and protein levels as well as elevation of urinary 8-isoprostane levels. Tubular fibrosis in DM mice (3.4 ± 0.9-fold, fibrotic score, ratio to ND) was suppressed by CANA (0.9 ± 0.3-fold). Furthermore, CANA attenuated DM associated increased macrophage infiltration and cell proliferation in kidneys of DM mice. Conclusions: CANA prevents intrarenal AGT upregulation and oxidative stress and which may mitigate high blood pressure, renal tubular fibrosis, and renal inflammation in T2DM.

To examine patient characteristics that may modulate the heterogeneous treatment effect of intensive systolic blood pressure control (SBP) and intensive glycemic control on incident heart failure (HF) risk in people with type 2 diabetes.We analyzed 10,251 participants from the ACCORD glucose trial, and 4733 from the SBP sub-trial separately. We applied a robust machine-learning (ML) algorithm, namely the causal forest/causal tree analysis, to each trial to identify participants' characteristics that modulate the effectiveness of each trial intervention.Diastolic blood pressure (DBP) was found to interact with intensive glycemic control and impact outcomes. An increased HF risk associated with intensive glycemic control (absolute risk change (ARC): 2.28 %, 95 % confidence interval (CI): 0.69 % to 3.90 %; relative risk (RR):1.57, 95 % CI: 1.15 to 2.20; P 0.05) was observed in individuals with baseline DBP at the lowest tertile (45-69 mmHg), while no changes in HF risk associated with intensive glycemic control were observed in individuals with baseline DBP at the middle (70-79 mmHg) and the highest tertiles (80-100 mmHg). Liver function was identified as a modulator of intensive BP control, and baseline Alanine transaminase (ALT) level was a sensitive marker for the modulating effect. Only individuals with baseline ALT at the lowest tertile (8-19 mg/dl) benefited from the intensive BP control for HF prevention (ARC: -1.95 %, 95 % CI: -4.06 % to 0.11 %; RR:0.62. 95 % CI: 0.27 to 0.94; P 0.05).Our study is the first to observe and quantify the potential synergistic harmful effect when low DBP was combined with an intensive blood glucose intervention. Recognizing these may help clinicians develop a more precise approach to such treatments, thus increasing the efficiency and outcomes of diabetes treatments.

CMS announced the Medicare Part D SSM to lower out-of-pocket costs for insulin. This study aimed to estimate the impacts of the SSM on clinical and economic outcomes among Medicare insulin users. We used the 2015-2016 National Health and Nutrition Examination Survey to generate a nationally representative simulation sample. We used the Building, Relating, Validating, Assessing, Outcomes (BRAVO™) Diabetes microsimulation model to simulate the impact of the SSM on diabetes-related complications, quality-adjusted life-years (QALYs), and medical costs. We used 30% rebate rate for Medicare insulin payment. 1.29 million insulin users covered by Medicare enhanced health plans are projected to be eligible for SSM in 2021. The SSM associated risk reductions in complications were reported in the Table. Over 5 years, the SSM is projected to increase $2.0 billion medical cost ($1,573/person) with a gain of 7,750 (0.01/person) QALYs (Incremental cost-effectiveness ratio (ICER): $157,300/QALY). In 20 years, the SSM will incur an additional $4.5 billion medical cost ($3474/person) with an increased QALYs of 72,095 (0.06/person, ICER=$57,900/QALY). Because the SSM was projected to increase medical costs for diabetes, this policy would have to be in place for longer than the 5-year period (as currently planned), or further reduce Medicare payment on insulin. Disclosure H. Shao: Research Support; Self; Sanofi. H. Kianmehr: None. L. Shi: Research Support; Self; AstraZeneca, Sanofi. V. Fonseca: Consultant; Self; Abbott Diabetes, Asahi Kasei Corporation, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Intarcia Therapeutics, Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Stock/Shareholder; Self; Amgen Inc., Bravo4health, Mellitus Health. J. D. Brown: None.

Achieving treatment goals could prolong life in people with T2D, but this benefit has not been thoroughly examined. We quantified potential gains in LE from achieving different levels of A1c, systolic blood pressure (SBP), low-density lipoproteins (LDL), and body mass index (BMI). We previously developed and extensively validated the BRAVO diabetes miscrosimulation model. In current tudy, we calibrated the BRAVO diabetes model to a US representative cohort, using the 2011-2012 National Health and Nutrition Examination Survey and its linked mortality records from the National Death Index. We then used the BRAVO model to project LE by level of A1c, SBP, LDL, and BMI. We found that reducing BMI was associated with the largest gain in LE, followed by lowering SBP, and then LDL (Figure). A reduction in A1c from 4th (mean: 9.1%) to 3rd (mean: 7.2%) quartile was associated with a gain of about 2 years, but further A1c reduction was associated with little gains in LE. Our findings can be used to assist communications between clinicians and patients to motivate patients in achieving the recommended treatment goals, and to measure potential health benefits for interventions/programs to improve diabetes care in the US. Disclosure H. Kianmehr: None. P. Zhang: None. M. E. Pavkov: None. K. M. Bullard: None. V. Fonseca: Consultant; Self; Abbott Diabetes, Asahi Kasei Corporation, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Intarcia Therapeutics, Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Stock/Shareholder; Self; Amgen Inc., Bravo4health, Mellitus Health. L. Shi: Research Support; Self; AstraZeneca, Sanofi. H. Shao: Research Support; Self; Sanofi.