An exploratory analysis of the cost-effectiveness of insulin glargine 300 units/mL versus insulin glargine 100 units/mL over a lifetime horizon using the BRAVO diabetes model.

BACKGROUND: This analysis assessed the cost-effectiveness of insulin glargine 300 units/mL (Gla-300) versus insulin glargine 100 units/mL (Gla-100) in insulin-naïve adults with type 2 diabetes (T2D) inadequately controlled with oral antidiabetic drugs (OADs). METHODS: Costs and outcomes for Gla-300 versus Gla-100 from a US healthcare payer perspective were assessed using the BRAVO diabetes model. Baseline clinical data were derived from EDITION-3, a 12-month randomized controlled trial comparing Gla-300 with Gla-100 in insulin-naïve adults with inadequately controlled T2D on OADs. Treatment costs were calculated based on doses observed in EDITION-3 and 2020 US net prices, while costs for complications were based on published literature. Lifetime costs ($US) and quality-adjusted life-years (QALYs) were predicted and used to calculate incremental cost-effectiveness ratio (ICER) estimates; extensive scenario and sensitivity analyses were conducted. RESULTS: Lifetime medical costs were estimated to be $353,441 and $352,858 for individuals receiving Gla-300 and Gla-100 respectively; insulin costs were $52,613 and $50,818. Gla-300 was associated with a gain of 8.97 QALYs and 21.12 life-years, while Gla-100 was associated with a gain of 8.89 QALYs and 21.07 life-years. This resulted in an ICER of $7522/QALY gained for Gla-300 versus Gla-100. Thus, Gla-300 was cost-effective versus Gla-100 based on a willingness-to-pay threshold of $50,000/QALY. Compared with Gla-100, Gla-300 provided a net monetary benefit of $3290. Scenario and sensitivity analyses confirmed the robustness of the base case. CONCLUSION: Gla-300 may be a cost-effective treatment option versus Gla-100 over a lifetime horizon for insulin-naïve people in the United States with T2D inadequately controlled on OADs.

Degree of joint risk factor control and hazard of mortality in diabetes patients: a matched cohort study in UK Biobank.

BACKGROUND: Diabetes patients are at higher risk for mortality than the general population; however, little is known about whether the excess mortality risk associated with diabetes could be mitigated or nullified via controlling for risk factors. METHODS: We included 18,535 diabetes patients and 91,745 matched individuals without diabetes without baseline cancer or cardiovascular disease (CVD), followed up from 2006 to 2021. The main exposure was the number of optimized risk factors including glycated hemoglobin < 53 mmol/mole, systolic blood pressure < 140 mmHg and diastolic blood pressure < 90 mmHg, no albuminuria, non-current smoking and low-density lipoprotein cholesterol (LDL-C) < 2.5 mmol/L. We used Cox proportional hazards models to explore the association of the degree of risk factor control with all-cause mortality, cancer mortality, CVD mortality and other mortality. RESULTS: Each additional risk factor control was associated with a 16, 10, 21 and 15% lower risk of all-cause mortality, cancer mortality, CVD mortality and other mortality, respectively. Optimal risk factors control (controlling 5 risk factors) was associated with a 50% (HR 0.50, 95% CI 0.41-0.62), 74% (HR 0.26, 95% CI 0.16-0.43) and 38% (HR 0.62, 95% CI 0.44-0.87) lower risk of all-cause mortality, CVD mortality and other mortality, respectively. Diabetes patients with 4, 3 and 5 or more controlled risk factors, respectively, showed no excess risk of all-cause mortality, cancer mortality and CVD mortality compared to matched non-diabetes patients. CONCLUSIONS: The results from this study indicate that optimal risk factor control may eliminate diabetes-related excess risk of all-cause mortality, CVD mortality and other mortality.

Some patients with type 2 diabetes may benefit from intensive glycaemic and blood pressure control: A post-hoc machine learning analysis of ACCORD trial data.

AIM: The action to control cardiovascular risk in diabetes (ACCORD) trial showed a neutral average treatment effect of intensive blood glucose and blood pressure (BP) controls in preventing major adverse cardiovascular events (MACE) in individuals with type 2 diabetes. Yet, treatment effects across patient subgroups have not been well understood. We aimed to identify patient subgroups that might benefit from intensive glucose or BP controls for preventing MACE. MATERIALS AND METHODS: As a post-hoc analysis of the ACCORD trial, we included 10 251 individuals with type 2 diabetes. We applied causal forest and causal tree models to identify participant characteristics that modify the efficacy of intensive glucose or BP controls from 68 candidate variables (demographics, comorbidities, medications and biomarkers) at the baseline. The exposure was (a) intensive versus standard glucose control [glycated haemoglobin (HbA1c) <6.0% vs. 7.0%-7.9%], and (b) intensive versus standard BP control (systolic BP <120 vs. <140 mmHg). The primary outcome was MACE. RESULTS: Compared with standard glucose control, intensive one reduced MACE in those with baseline HbA1c <8.5% [relative risk (RR): 0.79, 95% confidence interval (CI): 0.67-0.93] and those with estimated glomerular filtration rate ≥106 ml/min/1.73 m2 (RR: 0.74, 95% CI: 0.55-0.99). Intensive BP control reduced MACE in those with normal high-density lipoprotein levels (women >55 mg/dl, men >45 mg/dl; RR: 0.51, 95% CI: 0.34-0.74). Risk reductions were not significant in other patient subgroups. CONCLUSIONS: Our findings suggest heterogeneous treatment effects of intensive glucose and BP control and could provide biomarkers for future clinical trials to identify more precise HbA1c and BP treatment goals for individualized medicine.

Effects of Non-Face-to-Face Chronic Care Management on Service Utilization and Outcomes Among US Medicare Beneficiaries with Diabetes.

BACKGROUND: Type 2 diabetes mellitus (T2DM) results in heavy economic and disease burdens in Louisiana. The Centers for Medicare and Medicaid Services has reimbursed non-face-to-face chronic care management (NFFCCM) for patients with two or more chronic conditions since 2015. OBJECTIVE: To assess the impacts of NFFCCM on healthcare utilization and health outcomes. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included Medicare fee-for-service beneficiaries with T2DM and at least one additional chronic disease between 2014 and 2018. EXPOSURES: At least one record of NFFCCM Current Procedural Terminology codes. MAIN MEASURES: The health outcomes in the study included major adverse cardiovascular events (MACE), all-cause mortality, and heart failure. The monthly service utilization and continuity of care index for primary care were also included. The propensity score method was used to balance the baseline differences between the two groups. Weighted multivariate regression models were developed using propensity score weights to assess the impacts of NFFCCM on outcomes. KEY RESULTS: During the 5 years of study period, 8415 patients among the 118,643 Medicare beneficiaries received at least one NFFCCM. Patients receiving any NFFCCM had reduced healthcare utilization compared with patients not receiving NFFCCM, including 0.012 (95% CI - 0.014 to - 0.011; p < 0.001) fewer monthly hospital admissions, 0.017 (95% CI - 0.019 to - 0.016; p < 0.001) fewer monthly ED visits, and 0.399 (95% CI 0.375 to 0.423; p < 0.001) more monthly outpatient encounters. Patients receiving NFFCCM services had lower MACE event rates of 7.4% (95% CI 7.1 to 7.8%; p < 0.001), all-cause mortality rate of 7.8% (95% CI 7.4 to 8.1%; p < 0.001), and heart failure rate of 0.3% (95% CI 0.2 to 0.5%; p < 0.001), respectively. CONCLUSIONS AND RELEVANCE: These findings suggest that reimbursement for NFFCCM was associated with the shifting high-cost utilization to lower-cost primary health care settings among patients with diabetes in Louisiana.

Risk factor control and incident cardiovascular disease in patients with diabetes: Sex-specific relations.

AIM: Women with diabetes are at higher risk of cardiovascular diseases (CVD) than men with diabetes; however, the sex difference in the association between the degree of risk factor control and the risk of CVD in patients with diabetes is unclear. METHODS: In total, 17 260 participants diagnosed with diabetes from the UK Biobank were included and matched with 86 300 non-diabetes controls based on age, sex and assessment centre. The main exposure was the number of risk factors within the target range, including glycated haemoglobin level <53 mol/mol (7%), blood pressure <140/90 mm/Hg, low-density lipoprotein cholesterol <100 mg/dl, non-current smoking and absence of microalbuminuria. RESULTS: During a median follow-up of 13.3 years, a total of 3338 incident CVD cases, including 2807 ischaemic heart disease and 793 strokes, were documented. A more stringent control of risk factors was significantly associated with a lower risk of incident CVD, and such an association was significantly stronger in women than men. Compared with non-diabetes participants, the diabetes-related risk of CVD appeared to be eliminated if more than three risk factors were well controlled among women and men with diabetes. Moreover, clinical biomarkers (e.g. glycated haemoglobin and blood pressure) showed greater relative importance than other factors in women, whereas socio-economic and psychological factors (e.g. education and depression) exhibited similar relative importance to clinical biomarkers in men with diabetes. CONCLUSION: Our findings highlighted the importance of raising awareness of sex differences in the management of CVD risk factors among patients with diabetes.

Acute severe hypoglycemia alters mouse brain microvascular proteome.

Hypoglycemia increases the risk related to stroke and neurodegenerative diseases, however, the underlying mechanisms are unclear. For the first time, we studied the effect of a single episode (acute) of severe (ASH) and mild (AMH) hypoglycemia on mouse brain microvascular proteome. After four-hour fasting, insulin was administered (i.p) to lower mean blood glucose in mice and induce ∼30 minutes of ASH (∼30 mg/dL) or AMH (∼75 mg/dL), whereas a similar volume of saline was given to control mice (∼130 mg/dL). Blood glucose was allowed to recover over 60 minutes either spontaneously or by 20% dextrose administration (i.p). Twenty-four hours later, the brain microvessels (BMVs) were isolated, and tandem mass tag (TMT)-based quantitative proteomics was performed using liquid chromatography-mass spectrometry (LC/MS). When compared to control, ASH significantly downregulated 13 proteins (p ≤ 0.05) whereas 23 proteins showed a strong trend toward decrease (p ≤ 0.10). When compared to AMH, ASH significantly induced the expression of 35 proteins with 13 proteins showing an increasing trend. AMH downregulated only 3 proteins. ASH-induced downregulated proteins are involved in actin cytoskeleton maintenance needed for cell shape and migration which are critical for blood-brain barrier maintenance and angiogenesis. In contrast, ASH-induced upregulated proteins are RNA-binding proteins involved in RNA splicing, transport, and stability. Thus, ASH alters BMV proteomics to impair cytoskeletal integrity and RNA processing which are critical for cerebrovascular function.

5-Year simulation of diabetes-related complications in people treated with tirzepatide or semaglutide versus insulin glargine.

AIM: This study compared the 5-year incidence rate of macrovascular and microvascular complications for tirzepatide, semaglutide and insulin glargine in individuals with type 2 diabetes, using the Building, Relating, Assessing, and Validating Outcomes (BRAVO) diabetes simulation model. RESEARCH DESIGN AND METHODS: This study was a 5-year SURPASS-2 trial extrapolation, with an insulin glargine arm added as an additional comparator. The 1-year treatment effects of tirzepatide (5, 10 or 15 mg), semaglutide (1 mg) and insulin glargine on glycated haemoglobin, systolic blood pressure, low-density lipoprotein and body weights were obtained from the SUSTAIN-4 and SURPASS-2 trials. We used the BRAVO model to predict 5-year complications for each study arm under two scenarios: the 1-year treatment effects persisted (optimistic) or diminished to none in 5 years (conservative). RESULTS: When compared with insulin glargine, we projected a 5-year risk reduction in cardiovascular adverse events [rate ratio (RR) 0.64, 95% confidence interval (CI) 0.61-0.67] and microvascular composite (RR 0.67, 95% CI 0.64-0.70) with 15 mg tirzepatide, and 5-year risk reduction in cardiovascular adverse events (RR 0.75, 95% CI 0.72-0.79) and microvascular composite (RR 0.79, 95% CI 0.76-0.82) with semaglutide (1 mg) under an optimistic scenario. Lower doses of tirzepatide also had similar, albeit smaller benefits. Treatment effects for tirzepatide and semaglutide were smaller but still significantly higher than insulin glargine under a conservative scenario. The 5-year risk reduction in diabetes-related complication events and mortality for the 15 mg tirzepatide compared with insulin glargine ranged from 49% to 10% under an optimistic scenario, which was reduced by 17%-33% when a conservative scenario was assumed. CONCLUSION: With the use of the BRAVO diabetes model, tirzepatide and semaglutide exhibited potential to reduce the risk of macrovascular and microvascular complications among individuals with type 2 diabetes, compared with insulin glargine in a 5-year window. Based on the current modelling assumptions, tirzepatide (15 mg) may potentially outperform semaglutide (1 mg). While the BRAVO model offered insights, the long-term cardiovascular benefit of tirzepatide should be further validated in a prospective clinical trial.

Outcomes With Finerenone in Patients With Chronic Kidney Disease and Type 2 Diabetes by Baseline Insulin Resistance.

OBJECTIVE: To explore whether insulin resistance, assessed by estimated glucose disposal rate (eGDR), is associated with cardiorenal risk and whether it modifies finerenone efficacy. RESEARCH DESIGN AND METHODS: In FIDELITY (N = 13,026), patients with type 2 diabetes, either 1) urine albumin-to-creatinine ratio (UACR) of ≥30 to <300 mg/g and estimated glomerular filtration rate (eGFR) of ≥25 to ≤90 mL/min/1.73 m2 or 2) UACR of ≥300 to ≤5,000 mg/g and eGFR of ≥25 mL/min/1.73 m2, who also received optimized renin-angiotensin system blockade, were randomized to finerenone or placebo. Outcomes included cardiovascular (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and kidney (kidney failure, sustained decrease of ≥57% in eGFR from baseline, or renal death) composites. eGDR was calculated using waist circumference, hypertension status, and glycated hemoglobin for 12,964 patients. RESULTS: Median eGDR was 4.1 mg/kg/min. eGDR

Ethnic disparities of vascular complications in pre-diabetes, undiagnosed diabetes, and newly diagnosed diabetes.

In the U.S., ethnic minorities with pre-diabetes, undiagnosed type 2 diabetes (T2D), and newly diagnosed T2D had a higher prevalence of microvascular complications than non-Hispanic Whites and exhibited distinct risk factors, whereas Whites had a higher rate of cardiovascular disease.

Vasoactive mediators of hypertension in obesity.

Obesity is associated with hypertension. However, the mechanisms involved are not fully understood. Therefore, we investigated the relationship between obesity and vasoactive mediators. In this cross-sectional study, blood pressure (BP) and vasoactive mediators of hypertension are compared among 135 adults in the nonobese, obese, and morbidly obese body mass index (BMI) ranges (BMI ≤27, 30-40, and >40 kg/m2, respectively). Angiotensinogen, angiotensin II, renin, aldosterone, endothelin-1 (ET-1), neprilysin, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), cyclic guanosine monophosphate (cGMP), and cyclic adenosine monophosphate (cAMP) levels were measured and their relationship to BP, BMI, race, and gender were investigated. Systolic and diastolic BP (SBP and DSP) were significantly higher in subjects with obesity and morbid obesity compared with nonobese. Angiotensin II, ET-1, and neprilysin were significantly higher in subjects with morbid obesity while BNP was lower. Levels of angiotensinogen, renin, aldosterone, ANP, cGMP, and cAMP did not differ between the groups. BMI was positively related to SBP, DBP, angiotensin II, ET-1, and neprilysin, and inversely related to cGMP and BNP. Age, male gender, and African-American race were associated with higher SBP. SBP was positively related to angiotensin II and ET-1 and inversely related to aldosterone, renin, and cGMP. On multivariate analyses, age, BMI, gender, and race were the main determinants of SBP, and excluding these variables, angiotensin II, aldosterone, renin, and ET-1 accounted for 21.1% ability to predict SBP. Obesity, especially morbid obesity, is associated with higher BP, higher angiotensin II and ET-1 (vasoconstrictors), and lower levels BNP and cGMP (vasodilators). SBP variability can be partly explained by angiotensin II, aldosterone, renin, and ET-1.NEW & NOTEWORTHY Our data show that obesity, especially morbid obesity, is associated with higher blood pressure levels and increases angiotensin II and endotherlin-1 (ET-1) (vasoconstrictors) and lower levels BNP and cGMP (vasodilators) and that systolic blood pressure variability can be partly explained by levels of angiotensin II, aldosterone, renin, and ET-1. The effect of these mediators on blood pressure is in addition to the effects of other known factors related to age, male gender, and AA race.

Dietary intake during a pragmatic cluster-randomized weight loss trial in an underserved population in primary care.

BACKGROUND: Currently there are limited data as to whether dietary intake can be improved during pragmatic weight loss interventions in primary care in underserved individuals. METHODS: Patients with obesity were recruited into the PROPEL trial, which randomized 18 clinics to either an intensive lifestyle intervention (ILI) or usual care (UC). At baseline and months 6, 12, and 24, fruit and vegetable (F/V) intake and fat intake was determined. Outcomes were analyzed by repeated-measures linear mixed-effects multilevel models and regression models, which included random cluster (clinic) effects. Secondary analyses examined the effects of race, sex, age, and food security status. RESULTS: A total of 803 patients were recruited. 84.4% were female, 67.2% African American, 26.1% received Medicaid, and 65.5% made less than $40,000. No differences in F/V intake were seen between the ILI and UC groups at months 6, 12, or 24. The ILI group reduced percent fat at months 6, 12, and 24 compared to UC. Change in F/V intake was negatively correlated with weight change at month 6 whereas change in fat intake was positively associated with weight change at months 6, 12, and 24 for the ILI group. CONCLUSIONS: The pragmatic weight loss intervention in primary care did not increase F/V intake but did reduce fat intake in an underserved population with obesity. F/V intake was negatively associated with weight loss at month 6 whereas percent fat was positively correlated with weight loss throughout the intervention. Future efforts better targeting both increasing F/V intake and reducing fat intake may promote greater weight loss in similar populations. TRIAL REGISTRATION: NCT Registration: NCT02561221.

Initial weight loss and early intervention adherence predict long-term weight loss during the Promoting Successful Weight Loss in Primary Care in Louisiana lifestyle intervention.

OBJECTIVE: This study tested whether initial weight change (WC), self-weighing, and adherence to the expected WC trajectory predict longer-term WC in an underserved primary-care population with obesity. METHODS: Data from the intervention group (n = 452; 88% women; 74% Black; BMI 37.3 kg/m2 [SD: 4.6]) of the Promoting Successful Weight Loss in Primary Care in Louisiana trial were analyzed. Initial (2-, 4-, and 8-week) percentage WC was calculated from baseline clinic weights and daily at-home weights. Weights were considered adherent if they were on the expected WC trajectory (10% at 6 months with lower [7.5%] and upper [12.5%] bounds). Linear mixed-effects models tested whether initial WC and the number of daily and adherent weights predicted WC at 6, 12, and 24 months. RESULTS: Percentage WC during the initial 2, 4, and 8 weeks predicted percentage WC at 6 (R2 = 0.15, R2 = 0.28, and R2 = 0.50), 12 (R2 = 0.11, R2 = 0.19, and R2 = 0.32), and 24 (R2 = 0.09, R2 = 0.11, and R2 = 0.16) months (all p < 0.01). Initial daily and adherent weights were significantly associated with WC as individual predictors, but they only marginally improved predictions beyond initial weight loss alone in multivariable models. CONCLUSIONS: These results highlight the importance of initial WC for predicting long-term WC and show that self-weighing and adherence to the expected WC trajectory can improve WC prediction.

External Validation of the BRAVO Diabetes Model Using the EXSCEL Clinical Trial Data.

INTRODUCTION: We have developed the Building, Relating, Assessing, and Validating Outcomes (BRAVO) diabetes model, an individual-level, discrete-time microsimulation model specifically designed for type 2 diabetes (T2D) management. This study aims to validate the model's performance when populated exclusively with a fully de-identified dataset to ensure its applicability in secure settings. METHODS: Patient-level data from the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial were fully de-identified by removing all identifiable information and masking numerical values (e.g., age, body mass index) within ranges to minimize the risk of re-identification. To populate the simulation, we imputed the masked numerical values using data from the National Health and Nutrition Examination Survey (NHANES). We applied the BRAVO model to the baseline data to predict 7-year study outcomes for the EXSCEL trial and assessed its discrimination power and calibration using C-statistics and Brier scores. RESULTS: The model demonstrated acceptable discrimination and calibration in predicting the first occurrence of non-fatal myocardial infarction, non-fatal stroke, heart failure, revascularization, and all-cause mortality. Even with the fully deidentified data from the EXSCEL trial primarily presented in ranges rather than specific values, the BRAVO model exhibited robust prediction performance for diabetes complications and mortality. CONCLUSIONS: This study demonstrates the feasibility of using the BRAVO model in settings where only fully de-identified patient-level data are available.

Sex differences in cardiometabolic biomarkers during the pre-diabetes stage.

Using two large prospective epidemiological studies in the U.S., we examined biomarkers that reflect sex-specific pathophysiological pathways to cardiovascular complications among people with pre-diabetes. Women with pre-diabetes exhibited higher levels of adipokines, while men had lower eGFR. Sex differences in lipoproteins and vascular inflammatory markers during pre-diabetes indicate sex-specific lipoprotein and inflammatory mechanisms to cardiovascular complications.

Glycated Albumin Correlates With Time-in-Range Better Than HbA1c or Fructosamine.

CONTEXT: Intermediate-term glycemic control metrics may represent a viable alternative to continuous glucose monitoring (CGM) in patients without access to CGM. OBJECTIVE: This work aimed to compare the relationship between CGM parameters and glycated albumin (GA), glycated hemoglobin A1c (HbA1c), and fructosamine for 24 weeks. METHODS: We conducted exploratory comparative analyses of CGM subgroup data from a previously published 24-week prospective study of assay performance in 8 US clinics. Participants included 34 individuals with type 1 (n = 18) and type 2 diabetes (n = 16) undergoing changes to improve glycemic control (n = 22; group 1) or with stable diabetes therapy (n = 12; group 2). Main outcome measures included Pearson correlations between CGM and glycemic indices and receiver operating characteristic (ROC) analysis of glycemic index values predictive of time in range (TIR) greater than 70%. RESULTS: At weeks 4 and 8, GA correlations with TIR were higher than HbA1c correlations in group 1. In group 2, GA correlations with TIR were statistically significant, whereas HbA1c correlations were not. In both groups over the first 12 weeks, GA correlations with TIR were higher than fructosamine-TIR correlations. In the ROC analysis, GA predicted a TIR greater than 70% during weeks 2 to 24 (area under the curve >0.80); HbA1c was predictive during weeks 12 to 24. Cutoff values for TIR greater than 70% were 17.5% (sensitivity and specificity, 0.88) for GA and 7.3% (0.86) for HbA1c. CONCLUSION: GA is the most accurate predictor of TIR over 8 weeks compared with other glycemic indices, which may assist in clinical evaluation of changes in treatment where CGM is not possible and it is too early to use HbA1c (NCT02489773).

A prediction model on incident chronic kidney disease among individuals with type 2 diabetes in the United States.

AIM: Early identification of incident chronic kidney disease (CKD) in individuals with diabetes may help improve patients' clinical outcomes. This study aimed to develop a prediction equation for incident CKD among people with type 2 diabetes (T2D). MATERIALS AND METHODS: A time-varying Cox model was applied to data from the ACCORD trial to predict the risk of incident CKD. A list of candidate variables was chosen based on literature reviews and experts' consultations, including demographic characteristics, vitals, laboratory results, medical history, drug use and health care utilization. Model performance was evaluated. Decomposition analysis was conducted, and external validation was performed. RESULTS: In total, 6006 patients with diabetes free of CKD were included, with a median follow-up of 3 years and 2257 events. The risk model included age at T2D diagnosed, smoking status, body mass index, high-density lipoprotein, very-low-density lipoprotein, alanine aminotransferase, estimated glomerular filtration rate, urine albumin-creatinine ratio, hypoglycaemia, retinopathy, congestive heart failure, coronary heart disease history, antihyperlipidaemic drug use, antihypertensive drug use and hospitalization. The urine albumin-creatinine ratio, estimated glomerular filtration rate and congestive heart failure were the top three factors that contributed most to the incident CKD prediction. The model showed acceptable discrimination [C-statistic: 0.772 (95% CI 0.767-0.805)] and calibration [Brier Score: 0.0504 (95% CI 0.0477-0.0531)] in the Harmony Outcomes Trial. CONCLUSION: Incident CKD prediction among individuals with T2D was developed and validated for use in decision support of CKD prevention.

Joint association of loneliness and traditional risk factor control and incident cardiovascular disease in diabetes patients.

AIMS: To investigate the prospective associations of the loneliness and social isolation scales with cardiovascular disease (CVD) risk in diabetes patients and compare the relative importance of loneliness and social isolation with traditional risk factors. Also, the interactions of loneliness or isolation with the degree of risk factor control in relation to CVD risk were evaluated. METHODS AND RESULTS: A total of 18 509 participants diagnosed with diabetes from the UK Biobank were included. A two-item scale and a three-item scale were used to assess loneliness and isolation levels, respectively. The degree of risk factor control was defined as numbers of glycated hemoglobin (HbA1c), blood pressure (BP), low-density lipoprotein cholesterol (LDL-C), smoking, and kidney condition controlled within the target range. During a mean follow-up of 10.7 years, 3247 total CVD incidents were documented, including 2771 coronary heart disease and 701 strokes. In the fully adjusted model, compared with participants with the lowest loneliness score (zero), hazard ratios (95% confidence interval) for CVD were 1.11 (1.02 and 1.20) and 1.26 (1.11 and 1.42) for participants with a loneliness scale of 1 and 2, respectively (P-trend < 0.001). No significant associations were observed for social isolation. Loneliness ranked higher in relative strength for predicting CVD than the lifestyle risk factors in diabetes patients. A significant additive interaction between loneliness and the degree of risk factor control on the risk of CVD was observed (P for additive interaction = 0.005). CONCLUSION: Among diabetes patients, loneliness, but not social isolation scale, is associated with a higher risk of CVD and shows an additive interaction with the degree of risk factor control.

Sex Differences in Cardiovascular Risk Associated With Prediabetes and Undiagnosed Diabetes.

INTRODUCTION: Women with Type 2 diabetes (T2D) face up to 50% higher risk of cardiovascular disease than men. This study evaluated the extent to which prediabetes and undiagnosed T2D are associated with a greater excess risk of cardiovascular disease in women versus in men. METHODS: Data were pooled from 18,745 cardiovascular disease-free individuals from the Atherosclerosis Risk in Communities Study, the Multi-Ethnic Study of Atherosclerosis, and the Jackson Heart Study. The risk of coronary heart disease, ischemic stroke, and atherosclerotic cardiovascular disease (coronary heart disease or stroke) associated with prediabetes or undiagnosed T2D was estimated using Cox models adjusting for sociodemographic factors, concomitant risk factors, medication use, and menopausal status. Data were collected in 2022, and the analysis was performed in 2023. RESULTS: During a median follow-up of 18.6 years, the associations between prediabetes and risk of atherosclerotic cardiovascular disease were only significant in women (hazard ratio=1.18, 95% CI=1.01, 1.34, p=0.03) but not in men (hazard ratio=1.08, 95% CI=1.00, 1.28, p=0.06) (p-interaction=0.18). The associations between undiagnosed T2D and cardiovascular disease outcomes were significant in both sexes, but the effect was more pronounced in women (coronary heart disease: hazard ratio=1.83, 95% CI=1.4, 2.41, p<0.0001 in women vs hazard ratio=1.6, 95% CI=1.38, 2.07, p=0.007 in men; stroke: hazard ratio=1.99, 95% CI=1.39, 2.72, p<0.0001 vs hazard ratio=1.81, 95% CI=1.36, 2.6, p<0.0001; atherosclerotic cardiovascular disease: hazard ratio=1.86, 95% CI=1.5, 2.28, p<0.0001 vs hazard ratio=1.65, 95% CI=1.4, 1.98, p<0.0001) (all p-interactions≤0.2). Both White and Black patients exhibit similar sex differences. CONCLUSIONS: Prediabetes or undiagnosed T2D was associated with a greater excess risk of cardiovascular disease in women than in men. The sex differential in cardiovascular disease risk among those without the T2D diagnosis suggests the need for sex-specific guidelines in T2D screening and treatment.

Pax4 in Health and Diabetes.

Paired box 4 (Pax4) is a key transcription factor involved in the embryonic development of the pancreatic islets of Langerhans. Consisting of a conserved paired box domain and a homeodomain, this transcription factor plays an essential role in early endocrine progenitor cells, where it is necessary for cell-fate commitment towards the insulin-secreting ß cell lineage. Knockout of Pax4 in animal models leads to the absence of ß cells, which is accompanied by a significant increase in glucagon-producing α cells, and typically results in lethality within days after birth. Mutations in Pax4 that cause an impaired Pax4 function are associated with diabetes pathogenesis in humans. In adulthood, Pax4 expression is limited to a distinct subset of ß cells that possess the ability to proliferate in response to heightened metabolic needs. Upregulation of Pax4 expression is known to promote ß cell survival and proliferation. Additionally, ectopic expression of Pax4 in pancreatic islet α cells or δ cells has been found to generate functional ß-like cells that can improve blood glucose regulation in experimental diabetes models. Therefore, Pax4 represents a promising therapeutic target for the protection and regeneration of ß cells in the treatment of diabetes. The purpose of this review is to provide a thorough and up-to-date overview of the role of Pax4 in pancreatic ß cells and its potential as a therapeutic target for diabetes.