Associations of Serum Folate and Vitamin B12 Levels With Cardiovascular Disease Mortality Among Patients With Type 2 Diabetes.

Importance: The associations of serum folate and vitamin B12 levels with cardiovascular outcomes among patients with type 2 diabetes (T2D) remain unclear. Objective: To investigate the associations of serum folate and vitamin B12 levels with risk of cardiovascular disease (CVD) mortality among individuals with T2D. Design, Setting, and Participants: This prospective cohort study included 8067 patients with T2D who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 through 2014 and NHANES III (1988-1994). American Diabetes Association criteria were used to define T2D. Data were analyzed between October 1, 2020, and April 1, 2021. Exposures: Serum folate and vitamin B12 levels. Main Outcomes and Measures: Multivariable Cox proportional hazards regression models were used to compute hazard ratios and 95% CIs for the associations of serum folate and vitamin B12 levels with risks of CVD and all-cause mortality. Two multivariable models were constructed. Restricted cubic spline analyses were used to examine the nonlinear association of serum folate levels and vitamin B12 levels with CVD mortality, and nonlinearity was assessed using the likelihood ratio test. Results: This cohort study included data from 7700 participants in the folate analysis (mean [SE] age, 57.8 [0.3] years; 3882 men [weighted, 50.5%]; median serum folate level, 12.1 ng/mL [IQR, 7.1-19.5 ng/mL]) and 4860 participants for the vitamin B12 analysis (mean [SE] age, 57.8 [0.3] years; 2390 men [weighted, 50.7%]; median serum vitamin B12 level, 506.1 pg/mL [IQR, 369.1-703.5 pg/mL]). During 72 031 person-years of follow-up, 799 CVD deaths were documented for the folate analysis, and during 43 855 person-years of follow-up, 467 CVD deaths were reported for the vitamin B12 analysis. Nonlinear associations were observed for serum levels of folate (P = .04 for nonlinearity) and vitamin B12 (P = .04 for nonlinearity) with risk of CVD mortality among patients with T2D. Compared with participants in the second quartile of serum folate levels (7.1-12.1 ng/mL), the hazard ratios for CVD mortality were 1.43 (95% CI, 1.04-1.98) for participants in the lowest serum folate level quartile (<7.1 ng/mL) and 1.03 (95% CI, 0.74-1.44) for participants in the highest quartile (≥19.5 ng/mL). In addition, compared with participants in the second quartile of serum vitamin B12 levels (369.1-506.0 pg/mL), the hazard ratios for CVD mortality were 1.74 (95% CI, 1.20-2.52) for participants in the lowest quartile (<369.1 pg/mL) and 2.32 (95% CI, 1.60-3.35) for participants in the highest quartile (≥703.5 pg/mL). Similar patterns of association were observed for all-cause mortality (nonlinearity: P = .01 for folate and P = .02 for vitamin B12). Conclusions and Relevance: This cohort study found that both low and high serum levels of vitamin B12 as well as low serum levels of folate were significantly associated with higher risk of CVD mortality among individuals with T2D.

Circulating long chain acylcarnitines and outcomes in diabetic heart failure: an HF-ACTION clinical trial substudy.

BACKGROUND: Whether differences in circulating long chain acylcarnitines (LCAC) are seen in heart failure (HF) patients with and without diabetes mellitus (DM), and whether these biomarkers report on exercise capacity and clinical outcomes, remains unknown. The objective of the current study was to use metabolomic profiling to identify biomarkers that report on exercise capacity, clinical outcomes, and differential response to exercise in HF patients with and without DM. METHODS: Targeted mass spectrometry was used to quantify metabolites in plasma from participants in the heart failure: a controlled trial investigating outcomes of exercise training (HF-ACTION) trial. Principal components analysis was used to identify 12 uncorrelated factors. The association between metabolite factors, diabetes status, exercise capacity, and time to the primary clinical outcome of all-cause mortality or all-cause hospitalization was assessed. RESULTS: A total of 664 participants were included: 359 (54%) with DM. LCAC factor levels were associated with baseline exercise capacity as measured by peak oxygen consumption (beta 0.86, p = 2 × 10-7, and were differentially associated in participants with and without DM (beta 1.58, p = 8 × 10-8 vs. 0.67, p = 9 × 10-4, respectively; p value for interaction = 0.012). LCAC levels changed to a lesser extent in participants with DM after exercise (mean ∆ 0.09, p = 0.24) than in those without DM (mean ∆ 0.16, p = 0.08). In univariate and multivariate modeling, LCAC factor levels were associated with time to the primary outcome (multivariate HR 0.80, p = 2.74 × 10-8), and were more strongly linked to outcomes in diabetic participants (HR 0.64, p = 3.21 × 10-9 v. HR 0.90, p = 0.104, p value for interaction = 0.001). When analysis was performed at the level of individual metabolites, C16, C16:1, C18, and C18:1 had the greatest associations with both exercise capacity and outcomes, with higher levels associated with worse outcomes. Similar associations with time to the primary clinical outcome were not found in a control group of patients without HF from the CATHeterization GENetics (CATHGEN) study. CONCLUSIONS: LCAC biomarkers are associated with exercise status and clinical outcomes differentially in HF patients with and without DM. Impaired fatty acid substrate utilization and mitochondrial dysfunction both at the level of the skeletal muscle and the myocardium may explain the decreased exercise capacity, attenuated response to exercise training, and poor clinical outcomes seen in patients with HF and DM. Trial Registration clinicaltrials.gov Identifier: NCT00047437.

Dietary Soy Consumption and Cardiovascular Mortality among Chinese People with Type 2 Diabetes.

Randomized controlled trials showed that soy intervention significantly improved blood lipids in people with diabetes. We sought to prospectively examine the association of soy consumption with the risk of cardiovascular death among individuals with diabetes. A total of 26,139 participants with a history of diabetes were selected from the Chinese Kadoorie Biobank study. Soy food consumption was assessed by a food frequency questionnaire. Causes of death were coded by the 10th International Classification of Diseases. The Cox proportional hazard regression was used to compute the hazard ratios. During a median follow-up of 7.8 years, a total of 1626 deaths from cardiovascular disease (CVD) were recorded. Compared with individuals who never consumed soy foods, the multivariable-adjusted risks (95% confidence intervals) of CVD mortality were 0.92 (0.78, 1.09), 0.89 (0.75, 1.05), and 0.77 (0.62, 0.96) for those who consumed soy foods monthly, 1-3 days/week, and ≥4 days/week, respectively. For cause-specific cardiovascular mortality, significant inverse associations were observed for coronary heart disease and acute myocardial infarction. Higher soy food consumption was associated with a lower risk of cardiovascular death, especially death from coronary heart disease and acute myocardial infarction, in Chinese adults with diabetes.

Skin autofluorescence predicts new cardiovascular disease and mortality in people with type 2 diabetes.

BACKGROUND: Skin autofluorescence (SAF) is a non-invasive marker of tissue accumulation of advanced glycation endproducts (AGE). Recently, we demonstrated in the general population that elevated SAF levels predict the development of type 2 diabetes (T2D), cardiovascular disease (CVD) and mortality. We evaluated whether elevated SAF may predict the development of CVD and mortality in individuals with T2D. METHODS: We included 2349 people with T2D, available baseline SAF measurements (measured with the AGE reader) and follow-up data from the Lifelines Cohort Study. Of them, 2071 had no clinical CVD at baseline. 60% were already diagnosed with diabetes (median duration 5, IQR 2-9 years), while 40% were detected during the baseline examination by elevated fasting blood glucose ≥7.0 mmol/l) and/or HbA1c ≥6.5% (48 mmol/mol). RESULTS: Mean (±SD) age was 57 ± 12 yrs., BMI 30.2 ± 5.4 kg/m2. 11% of participants with known T2D were treated with diet, the others used oral glucose-lowering medication, with or without insulin; 6% was using insulin alone. Participants with known T2D had higher SAF than those with newly-detected T2D (SAF Z-score 0.56 ± 0.99 vs 0.34 ± 0.89 AU, p < 0.001), which reflects a longer duration of hyperglycaemia in the former group. Participants with existing CVD and T2D had the highest SAF Z-score: 0.78 ± 1.25 AU. During a median follow-up of 3.7 yrs., 195 (7.6%) developed an atherosclerotic CVD event, while 137 (5.4%) died. SAF was strongly associated with the combined outcome of a new CVD event or mortality (OR 2.59, 95% CI 2.10-3.20, p < 0.001), as well as incidence of CVD (OR 2.05, 95% CI 1.61-2.61, p < 0.001) and death (OR 2.98, 2.25-3.94, p < 0.001) as a single outcome. In multivariable analysis for the combined endpoint, SAF retained its significance when sex, systolic blood pressure, HbA1c, total cholesterol, eGFR, as well as antihypertensive and statin medication were included. In a similar multivariable model, SAF was independently associated with mortality as a single outcome, but not with incident CVD. CONCLUSIONS: Measuring SAF can assist in prediction of incident cardiovascular disease and mortality in individuals with T2D. SAF showed a stronger association with future CVD events and mortality than cholesterol or blood pressure levels.

Examining the Relationship and Prognostic Implication of Diabetic Status and Extracellular Matrix Expansion by Cardiac Magnetic Resonance.

BACKGROUND: Although not fully understood, diabetes mellitus is thought to be associated with cardiac fibrosis and stiffness due to alteration of myocardial extracellular matrix. Newer cardiac magnetic resonance techniques may be able to identify extracellular matrix expansion by measuring extracellular volume fraction (ECV). We used cardiac magnetic resonance to evaluate the association of alteration in the extracellular matrix with diabetic status and its implications on incident heart failure events and all-cause mortality. METHODS: We studied 442 patients who underwent comprehensive contrast cardiac magnetic resonance to assess cardiac morphology and function, left ventricular replacement fibrosis, and pre-post contrast T1 mapping to quantify ECV. The cohort did not have coexisting pathologies associated with ECV alteration. We categorized our final cohort based on diabetic status using criteria from the American Diabetic Association. Subsequent heart failure hospitalization and all-cause death were ascertained. RESULTS: Our patients were predominantly white with a median age of 57 with 48% being men. Compared with nondiabetes mellitus, diabetes mellitus was significantly associated with elevated ECV after adjusting for clinical and imaging covariates: ß coefficient 1.33 (95% CI, 0.22-2.44); P=0.02. Over a median follow-up of 24.5 (interquartile range, 14.8-33.4) months, 52 deaths and 24 heart failure events occurred. Patients with diabetes mellitus and elevated ECV had the worst outcomes compared with patients with diabetes mellitus and normal ECV or nondiabetics. Elevated ECV remained an independent predictor of outcomes (hazard ratio, 3.31 [95% CI, 1.93-5.67]; P<0.001) after adjusting for covariates. CONCLUSIONS: Elevated ECV is an independent predictor of mortality among patients with diabetes mellitus and may have an additive effect with diabetes mellitus on outcomes. ECV may represent a novel noninvasive biomarker to evaluate severity of diabetic heart disease.

Impact of diabetes mellitus on left ventricular longitudinal function of patients with non-ischemic dilated cardiomyopathy.

BACKGROUND: Left ventricular (LV) longitudinal dysfunction has been identified in type 2 diabetes mellitus (T2DM) patients with preserved LV ejection fraction (LVEF). However, the impact of T2DM on LV longitudinal function or the association of LV longitudinal function with outcome for dilated cardiomyopathy (DCM) remains unclear. METHODS: We retrospectively studied 206 patients with non-ischemic DCM, mean age of 59 ± 17 years and LVEF of 31 ± 8% (all < 45%). All patients underwent a standard echocardiographic examination, and LV longitudinal function was assessed in terms of global longitudinal strain (GLS). Long-term outcomes were assessed, with a median follow-up period of 6.2 years, as primary endpoints of death from or hospitalization for deteriorating heart failure. RESULTS: GLS of DCM patients with T2DM (n = 55) was significantly lower than that in DCM patients without T2DM (n = 151) in spite of similar conventional LV function (7.0 ± 2.0% vs. 7.8 ± 2.2%, p = 0.03). Kaplan-Meier curves indicated that long-term outcomes for DCM patients without T2DM were better than for those with T2DM (log-rank p = 0.001). Subdividing the two groups into four with by using the median value of GLS (7.9%) showed long-term outcome was worst for DCM patients with T2DM and low GLS. Cox proportional hazards analyses demonstrated an independent association of T2DM, GLS and left atrial volume index with long-term outcome. Moreover, multiple regression analysis for the association of GLS showed that T2DM was the independent determinant parameter for GLS as well as for LVEF and left atrial volume index. CONCLUSION: Management of DCM patients with T2DM may be improved by using GLS guidance.

Empagliflozin improves left ventricular diastolic function of db/db mice.

OBJECTIVES: Investigation of the effect of SGLT2 inhibition by empagliflozin on left ventricular function in a model of diabetic cardiomyopathy. BACKGROUND: SGLT2 inhibition is a new strategy to treat diabetes. In the EMPA-REG Outcome trial empagliflozin treatment reduced cardiovascular and overall mortality in patients with diabetes presumably due to beneficial cardiac effects, leading to reduced heart failure hospitalization. The relevant mechanisms remain currently elusive but might be mediated by a shift in cardiac substrate utilization leading to improved energetic supply to the heart. METHODS: We used db/db mice on high-fat western diet with or without empagliflozin treatment as a model of severe diabetes. Left ventricular function was assessed by pressure catheter with or without dobutamine stress. RESULTS: Treatment with empagliflozin significantly increased glycosuria, improved glucose metabolism, ameliorated left ventricular diastolic function and reduced mortality of mice. This was associated with reduced cardiac glucose concentrations and decreased calcium/calmodulin-dependent protein kinase (CaMKII) activation with subsequent less phosphorylation of the ryanodine receptor (RyR). No change of cardiac ketone bodies or branched-chain amino acid (BCAA) metabolites in serum was detected nor was cardiac expression of relevant catabolic enzymes for these substrates affected. CONCLUSIONS: In a murine model of severe diabetes empagliflozin-dependent SGLT2 inhibition improved diastolic function and reduced mortality. Improvement of diastolic function was likely mediated by reduced spontaneous diastolic sarcoplasmic reticulum (SR) calcium release but independent of changes in cardiac ketone and BCAA metabolism.

Comparison of Mortality and Major Cardiovascular Events Among Adults With Type 2 Diabetes Using Human vs Analogue Insulins.

Importance: The comparative cardiovascular safety of analogue and human insulins in adults with type 2 diabetes who initiate insulin therapy in usual care settings has not been carefully evaluated using machine learning and other rigorous analytic methods. Objective: To examine the association of analogue vs human insulin use with mortality and major cardiovascular events. Design, Setting, and Participants: This retrospective cohort study included 127 600 adults aged 21 to 89 years with type 2 diabetes at 4 health care delivery systems who initiated insulin therapy from January 1, 2000, through December 31, 2013. Machine learning and rigorous inference methods with time-varying exposures were used to evaluate associations of continuous exposure to analogue vs human insulins with mortality and major cardiovascular events. Data were analyzed from September 1, 2017, through June 30, 2018. Exposures: On the index date (first insulin dispensing), participants were classified as using analogue insulin with or without human insulin or human insulin only. Main Outcomes and Measures: Overall mortality, mortality due to cardiovascular disease (CVD), myocardial infarction (MI), stroke or cerebrovascular accident (CVA), and hospitalization for congestive heart failure (CHF) were evaluated. Marginal structural modeling (MSM) with inverse probability weighting was used to compare event-free survival in separate per-protocol analyses. Adjusted and unadjusted hazard ratios and cumulative risk differences were based on logistic MSM parameterizations for counterfactual hazards. Propensity scores were estimated using a data-adaptive approach (machine learning) based on 3 nested covariate adjustment sets. Sensitivity analyses were conducted to address potential residual confounding from unmeasured differences in risk factors across delivery systems. Results: The 127 600 participants (mean [SD] age, 59.4 [12.6] years; 68 588 men [53.8%]; mean [SD] body mass index, 32.3 [7.1]) had a median follow-up of 4 quarters (interquartile range, 3-9 quarters) and experienced 5464 deaths overall (4.3%), 1729 MIs (1.4%), 1301 CVAs (1.0%), and 3082 CHF hospitalizations (2.4%). There were no differences in adjusted hazard ratios for continuous analogue vs human insulin exposure during 10 quarters for overall mortality (1.15; 95% CI, 0.97-1.34), CVD mortality (1.26; 95% CI, 0.86-1.66), MI (1.11; 95% CI, 0.77-1.45), CVA (1.30; 95% CI, 0.81-1.78), or CHF hospitalization (0.93; 95% CI, 0.75-1.11). Conclusions and Relevance: Insulin-naive adults with type 2 diabetes who initiate and continue treatment with human vs analogue insulins had similar observed rates of major cardiovascular events, CVD mortality, and overall mortality.

Impact of Cardio-Renal-Metabolic Comorbidities on Cardiovascular Outcomes and Mortality in Type 2 Diabetes Mellitus.

BACKGROUND: We evaluated the incremental contribution of chronic kidney disease (CKD) to the risk of major adverse cardiovascular (CV) events (MACE), heart failure (HF), and all-cause mortality (ACM) in type 2 diabetes mellitus (T2DM) patients and its importance relative to the presence of other cardio-renal-metabolic (CaReMe) comorbidities. METHODS: Patients (≥40 years) were identified at the time of T2DM diagnosis from US (Humedica/Optum) and UK (Clinical Practice Research Datalink) databases. Patients were monitored post-diagnosis for modified MACE (myocardial infarction, stroke, ACM), HF, and ACM. Adjusted hazard ratios were obtained using Cox proportional-hazards regression to evaluate the relative risk of modified MACE, HF, and ACM due to CKD. Patients were stratified by the presence or absence of atherosclerotic CV disease (ASCVD) and age. RESULTS: Between 2011 and 2015, of 227,224 patients identified with incident T2DM, 40,063 (17.64%) had CKD. Regardless of prior ASCVD, CKD was associated with higher risk of modified MACE, HF, and ACM; this excess hazard was more pronounced in older patients with prior ASCVD. In time-to-event analyses in the overall cohort, patients with T2DM + CKD or T2DM + CKD + hypertension + hyperlipidemia had increased risks for modified MACE, HF, and ACM versus patients with T2DM and no CaReMe comorbidities. Patients with CKD had higher risks for and shorter times to modified MACE, HF, and ACM than those without CKD. CONCLUSION: In T2DM patients, CKD presence was associated with higher risk of modified MACE, HF, and ACM. This may have risk-stratification implications for T2DM patients based on background CKD and highlights the potential importance of novel renoprotective strategies.

Trends in Cause-Specific Outcomes Among Individuals With Type 2 Diabetes and Heart Failure in the United Kingdom, 1998-2017.

Importance: The phenotype of individuals with type 2 diabetes and heart failure (HF) is changing. Successful public health interventions for type 2 diabetes mean that patients more frequently present with HF without a prior ischemic event, which is likely to change outcomes, but trends in cause-specific outcomes are unknown. Objective: To investigate cause-specific outcomes and trends associated with type 2 diabetes among individuals with incident HF. Design, Setting, and Participants: This cohort study used UK primary care data, linked to hospital admissions and mortality, for 87 709 patients with incident HF from 1998 to 2017. Patients were 30 years or older and observed to death or July 31, 2017. Data analysis was conducted in March and April 2019. Exposure: Preexisting type 2 diabetes at diagnosis of HF. Individuals with type 1 diabetes were excluded. Main Outcomes and Measures: All-cause, cardiovascular (CVD), and non-CVD unplanned hospitalizations and mortality rates. Results: Of 87 709 patients with HF (43 173 [49.2%] women; 78 211 [89.2%] white), 20 858 (23.8%) had type 2 diabetes (median [interquartile range] age, 78.0 [70.0 to 84.0] years), and 66 851 (76.2%) had no diabetes (median [interquartile range] age, 80.0 [72.0 to 86.0] years). In patients with HF, type 2 diabetes was associated with an increase in the risk of unplanned hospital admission (adjusted incidence rate ratio for CVD hospitalizations: 1.24; 95% CI, 1.19 to 1.30; for non-CVD hospitalizations: 1.26; 95% CI, 1.22 to 1.30) and an increase in the risk of mortality (adjusted hazard ratio for CVD mortality: 1.06; 95% CI, 1.02 to 1.10; for non-CVD mortality: 1.24; 95% CI, 1.19 to 1.29). Age-standardized mortality risk at 1 year was 35.6% (95% CI, 35.1% to 36.1%) in the type 2 diabetes group vs 29.2% (95% CI, 29.0% to 29.5%) in the group with no diabetes. During the study period (ie, 1998 to 2017), associations of type 2 diabetes with hospitalization and mortality rates decreased for CVD outcomes but not for non-CVD outcomes. Age-adjusted hospitalization rates during the first year following HF diagnosis increased similarly for both groups over time (eg, HF with type 2 diabetes, 1998 to 2001: 133.3 per 100 person-years; 95% CI, 102.2 to 105.4 per 100 person-years; 2012 to 2015: 152.5 per 100 person-years; 95% CI, 145.5 to 159.5 per 100 person-years; P for difference in trend = .06), but trends diverged by cause. For example, hospitalizations for HF decreased for patients with type 2 diabetes at approximately the same annual rate (-2.2%; 95% CI, -3.9% to -0.5%) as they increased for those without diabetes (1.7%; 95% CI, 1.1% to 2.3%; P for difference in trend < .001). After 2004, a trend emerged showing a greater increase in non-CVD admissions among patients with HF and type 2 diabetes than among patients with no diabetes (2.3% [95% CI, 0.9% to 3.6%] vs 1.1% [95% CI, 0.8% to 1.4%]). In contrast to hospitalization rates, mortality rates reduced over time in both groups, but the reduction was greater among those with type 2 diabetes than without (-1.4% [95% CI, -1.8% to -0.9%] vs -0.7% [95% CI, -1.2% to -0.2%]; P for difference in trend < .001). Conclusions and Relevance: In this study, the higher risk of all cause-specific outcomes and emerging non-CVD trends associated with patients with type 2 diabetes who experienced HF indicated an urgent need for earlier comorbidity management and patient-centered multimorbidity care.

Association of Diabetes Mellitus on Cardiac Remodeling, Quality of Life, and Clinical Outcomes in Heart Failure With Reduced and Preserved Ejection Fraction.

Background Diabetes mellitus frequently coexists with heart failure (HF), but few studies have compared the associations between diabetes mellitus and cardiac remodeling, quality of life, and clinical outcomes, according to HF phenotype. Methods and Results We compared echocardiographic parameters, quality of life (assessed by the Kansas City Cardiomyopathy Questionnaire), and outcomes (1-year all-cause mortality, cardiovascular mortality, and HF hospitalization) between HF patients with and without type 2 diabetes mellitus in the prospective ASIAN-HF (Asian Sudden Cardiac Death in Heart Failure) Registry, as well as community-based controls without HF. Adjusted Cox proportional hazards models were used to assess the association of diabetes mellitus with clinical outcomes. Among 5028 patients with HF and reduced ejection fraction (HFrEF; EF <40%) and 1139 patients with HF and preserved EF (HFpEF; EF ≥50%), the prevalences of type 2 diabetes mellitus were 40.2% and 45.0%, respectively (P=0.003). In both HFrEF and HFpEF cohorts, diabetes mellitus (versus no diabetes mellitus) was associated with smaller indexed left ventricular diastolic volumes and higher mitral E/e' ratio. There was a predominance of eccentric hypertrophy in HFrEF and concentric hypertrophy in HFpEF. Patients with diabetes mellitus had lower Kansas City Cardiomyopathy Questionnaire scores in both HFpEF and HFrEF, with more prominent differences in HFpEF (Pinteraction<0.05). In both HFpEF and HFrEF, patients with diabetes mellitus had more HF rehospitalizations (adjusted hazard ratio, 1.27; 95% CI, 1.05-1.54; P=0.014) and higher 1-year rates of the composite of all-cause mortality/HF hospitalization (adjusted hazard ratio, 1.22; 95% CI, 1.05-1.41; P=0.011), with no differences between HF phenotypes (Pinteraction>0.05). Conclusions In HFpEF and HFrEF, type 2 diabetes mellitus is associated with smaller left ventricular volumes, higher mitral E/e' ratio, poorer quality of life, and worse outcomes, with several differences noted between HF phenotypes. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01633398.

Markers of Collagen Formation and Degradation Reflect Renal Function and Predict Adverse Outcomes in Patients With Type 1 Diabetes.

OBJECTIVE: Patients with type 1 diabetes (T1D) have a higher risk of developing chronic kidney disease, cardiovascular events (CVEs), and mortality than the general population. We hypothesized that two previously published biomarkers, namely PRO-C6, a biomarker of collagen type VI formation, and C3M, a biomarker of collagen type III degradation, may be associated with impaired renal function and have prognostic value for adverse renal, CVE, and mortality in patients with T1D. RESEARCH DESIGN AND METHODS: PRO-C6 and C3M in serum (sPRO-C6, sC3M) and urine (uPRO-C6, uC3M) were measured by ELISA in 663 patients with T1D ranging from normoalbuminuric to macroalbuminuric. Association of the biomarkers with mortality, CVEs, heart failure, decline in estimated glomerular filtration rate (eGFR) ≥30%, and end-stage renal disease (ESRD) were tested in Cox proportional hazards models after log2 transformation and adjusted for relevant clinical characteristics. Hazard ratios (HRs) were reported per doubling of biomarker levels. RESULTS: High levels of sPRO-C6 were independently associated with a higher risk of all-cause mortality (HR 2.26 [95% CI 1.31-3.87], P < 0.0031). There was an association with higher risk of CVEs (n = 94) and heart failure (n = 28) but not after adjustment (P ≥ 0.58). In relation to renal outcomes, adjusted sPRO-C6 was associated with a higher risk of eGFR decline ≥30% in T1D, with eGFR >45 and >30 mL/min/1.73 m2, and with a higher risk of ESRD (all P ≤ 0.03). Higher uPRO-C6 was associated with a lower risk of decline in eGFR. CONCLUSIONS: In patients with T1D, higher sPRO-C6 was an independent predictor of both decline in eGFR and development of ESRD and of all-cause mortality. Higher uPRO-C6 was also associated with a lower risk of decline in eGFR.

Microvascular Disease in Patients With Diabetes With Heart Failure and Reduced Ejection Versus Preserved Ejection Fraction.

OBJECTIVE: Microvascular complications are common among patients with diabetes mellitus (DM). The presence of heart failure (HF) is presumed to be due to macrovascular disease (typically HF with reduced ejection fraction [HFrEF] following myocardial infarction). We hypothesized that HF with preserved ejection fraction (HFpEF) in patients with DM may be a manifestation of microvascular disease compared with HFrEF. The objective of this study was to examine the prevalence and association with clinical outcome of microvascular complications in patients with HF and DM. RESEARCH DESIGN AND METHODS: We investigated the prevalence, association with clinical outcome, and cardiac structure and function of microvascular (neuropathy, nephropathy, and retinopathy) complications of DM in 2,800 prospectively enrolled participants with HF and DM (561 with HFpEF) from the Asian Sudden Cardiac Death In Heart Failure (ASIAN-HF) registry. RESULTS: A total of 601 (21.5%) participants with DM had microvascular complications. Participants with DM and any (one or more) microvascular complications were more likely to have HFpEF (odds ratio 1.70 [95% CI 1.15-2.50]; P = 0.008). Furthermore, the likelihood of having HFpEF increased with an increasing number of microvascular complications (P trend < 0.001). Microvascular complications were associated with more left ventricular (LV) hypertrophy and a greater reduction in quality of life in HFpEF than HFrEF (P interaction < 0.001 for all). Compared with participants with DM and without microvascular complications, the adjusted hazard ratio for the composite outcome of all-cause death or HF hospitalization was 1.35 (95% CI 1.04-1.76) for participants with DM and microvascular complications regardless of HF type (P interaction = 0.112). CONCLUSIONS: Diabetic microvascular disease is more common, and related to greater LV remodeling, more impairment of quality in life, and similar adverse outcomes, in participants with HFpEF compared with HFrEF. HFpEF may be a clinical manifestation of microvascular disease in DM.

Utility of Plasma Concentration of Trimethylamine N-Oxide in Predicting Cardiovascular and Renal Complications in Individuals With Type 1 Diabetes.

OBJECTIVE: Trimethylamine N-oxide (TMAO) is suggested as an independent gut microbiota-derived risk factor for cardiovascular and renal disease. We investigated associations between plasma TMAO concentrations and cardio-renal outcomes in a prospective study of individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS: Plasma TMAO was measured at baseline in 1,159 individuals with type 1 diabetes (58% male, mean ± SD age 46 ± 13 years). End points were all-cause and cardiovascular mortality, cardiovascular disease (CVD), and renal events tracked from national registries. Associations between TMAO and end points were tested using Cox regression models. RESULTS: After 15.0 (6.7-19.3) (median [interquartile range]) years of follow-up, we recorded all-cause and cardiovascular mortality (n = 363 and 120, respectively), combined CVD (n = 406), coronary outcome (myocardial infarction and coronary intervention) (n = 163), stroke (n = 115), hospitalization for heart failure (n = 81), and end-stage renal disease (n = 144). In univariate analyses, higher TMAO concentrations were associated with all end points (P ≤ 0.005). Except for stroke and heart failure, all end points remained significantly associated with higher TMAO concentrations after adjustment for conventional cardiovascular risk factors (P ≤ 0.003). After further adjustment for baseline estimated glomerular filtration rate (eGFR), results became insignificant for all end points. TMAO was inversely associated with baseline eGFR (R 2 = 0.29; P < 0.001). CONCLUSIONS: In individuals with type 1 diabetes, higher concentrations of plasma TMAO were associated with mortality, CVD events, and poor renal outcome, independent of conventional risk factors. However, the association became insignificant after further adjustment for baseline eGFR. This could reflect TMAO as a renal function marker or a risk factor for micro- and macrovascular complications mediated through impaired renal function.

Mediation analysis of the relationship between type 2 diabetes and cardiovascular events and all-cause mortality: Findings from the SMART cohort.

AIM: To quantify the magnitude and specific contributions of known cardiovascular risk factors leading to higher cardiovascular risk and all-cause mortality caused by type 2 diabetes (T2D). METHODS: Mediation analysis was performed to assess the relative contributions of known classical risk factors for vascular disease in T2D (insulin resistance, systolic blood pressure, renal function, LDL-cholesterol, triglycerides and micro-albuminuria), and what proportion of the effect of T2D on cardiovascular events and all-cause mortality these factors mediate in the Second Manifestations of ARTerial disease (SMART) cohort consisting of 1910 T2D patients. RESULTS: Only 35% (95% CI 15-71%) of the excess cardiovascular risk caused by T2D is mediated by the classical cardiovascular risk factors. The largest mediated effect was through insulin resistance [proportion of mediated effect (PME) 18%, 95% CI 3-37%], followed by elevated triglycerides (PME 8%, 95% CI 4-14%) and micro-albuminuria (PME 7%, 95% CI 3-17%). Only 42% (95% CI 18-73%) of the excess mortality risk was mediated by the classical risk factors considered. The largest mediated effect was by micro-albuminuria (PME 18%, 95% CI 10-29%) followed by insulin resistance (PME 15%, 95% CI 1-33%). CONCLUSION: A substantial amount of the increased cardiovascular risk and all-cause mortality caused by T2D cannot be explained by traditional vascular risk factors. Future research should focus on identifying non-classical pathways that might further explain the increased cardiovascular and mortality risk caused by T2D.

Early cardiovascular risk and all-cause mortality following an incident of severe hypoglycaemia: A population-based cohort study.

AIMS: Severe hypoglycaemia is associated with a high risk of cardiovascular events in patient with diabetes. The aim of this study was to clarify the temporal relationship between hypoglycaemia and cardiovascular events. MATERIALS AND METHODS: This observational cohort study was conducted using Taiwan's Longitudinal Cohort of Diabetes Patients Database, which included 360 000 patients with newly diagnosed diabetes during the period 1999 to 2001. Patients with the first severe hypoglycaemia after 2002 served as the study cohort. Each patient in the study cohort was matched with two control patients without severe hypoglycaemia, based on a propensity score. A joinpoint regression model was used to determine trends in all-cause mortality and incidence of cardiovascular disease (CVD) events in both cohorts. RESULTS: A total of 10 157 patients with severe hypoglycaemia and 20 314 matched controls were recruited. Patients with severe hypoglycaemia had a significantly higher risk of CVD (HR, 7.28; 95% CI, 5.19-10.20) and all-cause mortality (HR, 19.92; 95% CI, 13.42-29.56) during the first month compared with those without. In patients with severe hypoglycaemia, the incidence of CVDs dropped by 17.29% monthly during the first 4 months and slowly decreased (-0.67%) during subsequent months. All-cause mortality decreased by 16.55% and 3.24% monthly during months 0-6 and months 6-17, respectively. CONCLUSIONS: Severe hypoglycaemia is associated with a greater risk of cardiovascular events and death, especially during the first month following a hypoglycaemic episode. Patients prone to severe hypoglycaemia should be made aware of the elevated risk of subsequent cardiovascular events.

Combination of ST2 and B-type natriuretic peptide in diabetic patients with acute heart failure: relation with ventricular stiffness and outcome.

BACKGROUND: Diabetes is a common disease in heart failure and its prevalence ranges from 10 to 30%. ST-2 is a novel biomarker of myocardial fibrosis and remodelling in heart failure and may be involved in the inflammatory process of diabetes mellitus. In this study, we sought: to evaluate levels of ST-2 and B-type natriuretic peptide (BNP) in groups with acute heart failure with and without diabetes; to analyse the prognostic impact of ST-2 over a 6-month follow-up period. METHODS: We performed an echocardiographic examination and measured ST-2 and BNP within 24 h of hospital admission. Patients were classified as heart failure with reduced ejection fraction {HFrEF [left ventricular ejection fraction (LVEF) <50%]} or heart failure with preserved ejection fraction (HFpEF, LVEF ≥50%). We defined diastolic function according to recent guidelines, and we calculated left ventricular stiffness was assessed by the ratio between E/e' (index of left ventricular filling pressure) and left ventricular diastolic diameter (LVEDD) (index of left ventricular volume). The sum of death and rehospitalization due to cardiovascular causes was considered in the composite outcome. RESULTS: Of 121 patients enrolled, 58 experienced diabetes and 63 had normal glucose levels. Sixty patients showed HFrEF and 61 HFpEF. Among patients with diabetes, we observed significantly increased levels of serum ST-2 with respect to patients without diabetes [89 (29-147) 72 ±â€Š42 vs. 48 (29-80) 59 ±â€Š33 ng/ml; P = 0.04]. No differences were found between the two groups in terms of BNP levels, risk factors, renal function and echocardiographic measurements. Conversely, BNP was significantly higher in HFrEF with respect to HFpEF [786 (344-1390) vs. 423 (195-796) pg/ml; P = 0.004]. A significant correlation between ST-2 and BNP in diabetic patients (r = 0.50; P < 0.001) compared with nondiabetic patients (r = 0.40; P = 0.001) was found. ST-2 showed a numerically greater correlation with left ventricular stiffness in patients with diabetes (r = 0.56; P < 0.001) than patients without (r = 0.29; P = 0.04). Moreover, in all patients, ST-2 demonstrated a significant correlation with glycated glycosylated haemoglobin HbA1c (r = 0.40; P < 0.001). Univariate analysis demonstrated that both ST-2 more than 54 ng/ml and BNP more than 567 pg/ml were related to adverse events occurrence within 6 months [hazard ratio (HR): 3.64 (1.90-6.94), P < 0.001; HR: 2.21 (1.20-4.07), P = 0.01, respectively]. After adjustment for potential confounding factors, the multivariable analysis showed that only ST-2 levels greater than 54 ng/ml were associated with poor prognosis [HR: 3.56 (1.66-7.62); P = 0.001]. CONCLUSION: ST-2 confirmed its prognostic power independently of diabetes and LVEF. Patients with diabetes showed higher levels of ST-2. However, the mechanism related to ST-2 increase needs to be better understood, although increased left ventricle stiffness and filling pressure seem to be the most important causative factors. CLINICAL TRIAL REGISTRATION: www.clinicaltrial.gov Diur-HF Trial (Trial ID: NCT01441245).

Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors and the Treatment of Type 2 Diabetes.

Clinical studies evaluating the cardiovascular safety/impact of sodium-glucose cotransporter-2 (SGLT-2) inhibitors demonstrated a reduction in major adverse cardiovascular events driven primarily by a reduced cardiovascular mortality in individuals with type 2 diabetes and previous cardiovascular disease. These somewhat unexpected results are coupled with SGLT-2 inhibitors' known acute effect of improvement in glycemia, reduction in blood pressure, and weight loss. In this review, we summarize the mechanism of action of SGLT-2 inhibitors, the metabolic effects of this class of medication, and the remarkable results of cardiovascular safety trials. In addition, we discuss adverse effects associated with these medications and the current recommendations for the use of these agents in the management of diabetes.

Average Clinician-Measured Blood Pressures and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus and Ischemic Heart Disease in the EXAMINE Trial.

Background Blood pressure ( BP ) treatment goals in patients with diabetes mellitus and increased cardiovascular risk remain controversial. Our study objective was to determine cardiovascular outcomes according to achieved BP s over the average follow-up period in the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care) trial. Methods and Results EXAMINE was a cardiovascular outcomes trial in 5380 patients with type 2 diabetes mellitus and recent acute coronary syndromes. Risks of major adverse cardiac events and cardiovascular death or heart failure were analyzed using a Cox proportional hazards model with adjustment for baseline covariates in 10-mm Hg increments of clinician-measured systolic BP from ≤100 to >160 mm Hg and diastolic BP from ≤60 to >100 mm Hg averaged during the 24 months after randomization. Based on 2015 guidelines from the American College of Cardiology, the American Heart Association and the American Society of Hypertension and 2017 American Diabetes Association guidelines, systolic BP s of 131 to 140 mm Hg and diastolic BP s of 81 to 90 mm Hg were the reference groups. A U-shaped relationship between cardiovascular outcomes and BP s was observed. Importantly, compared with the systolic BP reference group, adjusted hazard ratios for major adverse cardiac events and cardiovascular death or heart failure were significantly higher in patients with systolic BP s <130 mm Hg. Similarly, compared with the diastolic BP reference group, adjusted hazard ratios for major adverse cardiac events and for cardiovascular death or heart failure were significantly higher for diastolic BP s <80 mm Hg. Conclusions In patients with type 2 diabetes mellitus and recent acute coronary syndrome, average BP s <130/80 mm Hg were associated with worsened cardiovascular outcomes. These data suggest that intensive control of BP in patients with type 2 diabetes mellitus and ischemic heart disease should be evaluated in a prospective randomized trial. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 00968708.