Identification of proteins associated with type 2 diabetes risk in diverse racial and ethnic populations.

AIMS/HYPOTHESIS: Several studies have reported associations between specific proteins and type 2 diabetes risk in European populations. To better understand the role played by proteins in type 2 diabetes aetiology across diverse populations, we conducted a large proteome-wide association study using genetic instruments across four racial and ethnic groups: African; Asian; Hispanic/Latino; and European. METHODS: Genome and plasma proteome data from the Multi-Ethnic Study of Atherosclerosis (MESA) study involving 182 African, 69 Asian, 284 Hispanic/Latino and 409 European individuals residing in the USA were used to establish protein prediction models by using potentially associated cis- and trans-SNPs. The models were applied to genome-wide association study summary statistics of 250,127 type 2 diabetes cases and 1,222,941 controls from different racial and ethnic populations. RESULTS: We identified three, 44 and one protein associated with type 2 diabetes risk in Asian, European and Hispanic/Latino populations, respectively. Meta-analysis identified 40 proteins associated with type 2 diabetes risk across the populations, including well-established as well as novel proteins not yet implicated in type 2 diabetes development. CONCLUSIONS/INTERPRETATION: Our study improves our understanding of the aetiology of type 2 diabetes in diverse populations. DATA AVAILABILITY: The summary statistics of multi-ethnic type 2 diabetes GWAS of MVP, DIAMANTE, Biobank Japan and other studies are available from The database of Genotypes and Phenotypes (dbGaP) under accession number phs001672.v3.p1. MESA genetic, proteome and covariate data can be accessed through dbGaP under phs000209.v13.p3. All code is available on GitHub ( https://github.com/Arthur1021/MESA-1K-PWAS ).

Design and rationale of the cardiometabolic health program linked with community health workers and mobile health telemonitoring to reduce health disparities (LINKED-HEARTS) program.

BACKGROUND: Hypertension and diabetes are major risk factors for cardiovascular diseases, stroke, and chronic kidney disease (CKD). Disparities in hypertension control persist among Black and Hispanic adults and persons living in poverty in the United States. The "LINKED-HEARTS Program" (a Cardiometabolic Health Program LINKED with Community Health WorkErs and Mobile HeAlth TelemonitoRing To reduce Health DisparitieS"), is a multi-level intervention that includes home blood pressure (BP) monitoring (HBPM), blood glucose telemonitoring, and team-based care. This study aims to examine the effect of the LINKED-HEARTS Program intervention in improving BP control compared to enhanced usual care (EUC) and to evaluate the reach, adoption, sustainability, and cost-effectiveness of the program. METHODS: Using a hybrid type I effectiveness-implementation design, 428 adults with uncontrolled hypertension (systolic BP ≥ 140 mm Hg) and diabetes or CKD will be recruited from 18 primary care practices, including community health centers, in Maryland. Using a cluster-randomized trial design, practices are randomly assigned to the LINKED-HEARTS intervention arm or EUC arm. Participants in the LINKED-HEARTS intervention arm receive training on HBPM, BP and glucose telemonitoring, and community health worker and pharmacist telehealth visits on lifestyle modification and medication management over 12 months. The primary outcome is the proportion of participants with controlled BP (<140/90 mm Hg) at 12 months. CONCLUSIONS: The study tests a multi-level intervention to control multiple chronic diseases. Findings from the study may be leveraged to reduce disparities in the management and control of chronic diseases and make primary care more responsive to the needs of underserved populations. TRIAL REGISTRATION: ClinicalTrials.gov. Identifier: NCT05321368.

Persistence of significant secondary mitral regurgitation post-cardiac resynchronization therapy and survival: a systematic review and meta-analysis : Mitral regurgitation and mortality post-CRT.

Cardiac resynchronization therapy (CRT) significantly reduces secondary mitral regurgitation (MR) in patients with severe left ventricular systolic dysfunction. However, uncertainty remains as to whether improvement in secondary MR correlates with improvement with mortality seen in CRT. We conducted a meta-analysis to determine the association of persistent unimproved significant secondary MR (defined as moderate or moderate-to-severe or severe MR) compared to improved MR (no MR or mild MR) post-CRT with all-cause mortality, cardiovascular mortality, and heart failure hospitalization. A systematic search of PubMed, EMBASE, and Cochrane Library databases till July 31, 2022 identified studies reporting clinical outcomes by post-CRT secondary MR status. In 12 prospective studies of 4954 patients (weighted mean age 66.8 years, men 77.8%), the median duration of follow-up post-CRT at which patients were re-evaluated for significant secondary MR was 6 months and showed significant relative risk reduction of 30% compared to pre-CRT. The median duration of follow-up post-CRT for ascertainment of main clinical outcomes was 38 months. The random effects pooled hazard ratio (95% confidence interval) of all-cause mortality in patients with unimproved secondary MR compared to improved secondary MR was 2.00 (1.57-2.55); p < 0.001). There was insufficient data to evaluate secondary outcomes in a meta-analysis, but limited data that examined the relationship showed significant association of unimproved secondary MR with increased cardiovascular mortality and heart failure hospitalization. The findings of this meta-analysis suggest that lack of improvement in secondary MR post-CRT is associated with significantly elevated risk of all-cause mortality and possibly cardiovascular mortality and heart failure hospitalization. Future studies may investigate approaches to address persistent secondary MR post-CRT to help improved outcome in this population.

Trends in direct health care costs among US adults with atherosclerotic cardiovascular disease with and without diabetes.

OBJECTIVE: Population-based national data on the trends in expenditures related to coexisting atherosclerotic cardiovascular diseases (ASCVD) and diabetes is scarce. We assessed the trends in direct health care expenditures for ASCVD among individuals with and without diabetes, which can help to better define the burden of the co-occurrence of diabetes and ASCVD. METHODS: We used 12-year data (2008-2019) from the US national Medical Expenditure Panel Survey including 28,144 U.S individuals aged ≥ 18 years. Using a two-part model (adjusting for demographics, comorbidities and time), we estimated mean and adjusted incremental medical expenditures by diabetes status among individuals with ASCVD. The costs were direct total health care expenditures (out-of-pocket payments and payments by private insurance, Medicaid, Medicare, and other sources) from various sources (office-based visits, hospital outpatient, emergency room, inpatient hospital, pharmacy, home health care, and other medical expenditures). RESULTS: The total direct expenditures for individuals with ASCVD increased continuously by 30% from $14,713 (95% confidence interval (CI): $13,808-$15,619) in 2008-2009 to $19,145 (95% CI: $17,988-$20,301) in 2008-2019. Individuals with diabetes had a 1.5-fold higher mean expenditure that those without diabetes. A key driver of the observed increase in direct costs was prescription drug costs, which increased by 37% among all individuals with ASCVD. The increase in prescription drug costs was more pronounced among individuals with ASCVD and diabetes, in whom a 45% increase in costs was observed, from $5184 (95% CI: $4721-$5646) in 2008-2009 to $7501 (95% CI: $6678-$8325) in 2018-2019. Individuals with ASCVD and diabetes had $5563 (95% CI: $4643-$6483) higher direct incremental expenditures compared with those without diabetes, after adjusting for demographics and comorbidities. Among US adults with ASCVD, the estimated adjusted total direct excess medical expenditures were $42 billion per year among those with diabetes vs. those without diabetes. CONCLUSIONS: In the setting of ASCVD, diabetes is associated with significantly increased health care costs, an increase that was driven by marked increase in medication costs.

Associations between hysterectomy and metabolic syndrome: the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Metabolic syndrome is linked to an increased risk of incident cardiovascular disease and all-cause mortality. Notable associations exist between hysterectomy with bilateral salpingo-oophorectomy and metabolic syndrome. However, there is emerging evidence that even with ovarian conservation, hysterectomy may be independently associated with long-term cardiovascular disease risk. OBJECTIVE: To examine the associations between hysterectomy with ovarian preservation and metabolic syndrome risk in a multiethnic cohort. STUDY DESIGN: We studied 3367 female participants in the Multi-Ethnic Study of Atherosclerosis who had data on self-reported history of hysterectomy, oophorectomy, hystero-oophorectomy, and metabolic syndrome at baseline (2000-2002). We used adjusted logistic regression to assess the cross-sectional associations between hysterectomy and or oophorectomy subgroups and prevalent metabolic syndrome at baseline. Furthermore, we investigated 1355 participants free of baseline metabolic syndrome and used adjusted Cox regression models to evaluate incident metabolic syndrome from examinations 2 (2002-2004) to 6 (2016-2018). RESULTS: The mean age was 59.0±9.5 years, with 42% White, 27% Black, 19% Hispanic, and 13% Chinese American participants. 29% and 22% had a history of hysterectomy and oophorectomy, respectively. Over a median follow-up of 10.5 (3.01-17.62) years, there were 750 metabolic syndrome events. Hysterectomy (hazard ratio, 1.32 [95% confidence interval, 1.01-1.73]) and hystero-oophorectomy (hazard ratio, 1.40 [95% confidence interval, 1.13-1.74]) were both associated with incident metabolic syndrome compared with having neither hysterectomy nor oophorectomy. CONCLUSION: Hysterectomy, even with ovarian preservation, may be independently associated with a higher risk of metabolic syndrome. If other studies confirm these findings, screening and preventive strategies focused on females with ovary-sparing hysterectomies and the mechanisms underpinning these associations may be explored.

Associations of Cardiac Biomarkers With Peripheral Artery Disease and Peripheral Neuropathy in US Adults Without Prevalent Cardiovascular Disease.

BACKGROUND: NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity cardiac troponin T (hs-troponin T), and high-sensitivity cardiac troponin I (hs-troponin I) are increasingly being recommended for risk stratification for a variety of cardiovascular outcomes. The aims of our study were to establish the prevalence and associations of elevated NT-proBNP, hs-troponin T, and hs-troponin I with lower extremity disease, including peripheral artery disease (PAD) and peripheral neuropathy (PN), in the US general adult population without known cardiovascular disease. We also assessed whether the combination of PAD or PN and elevated cardiac biomarkers was associated with an increased risk of all-cause and cardiovascular mortality. METHODS: We conducted a cross-sectional analysis of the associations of NT-proBNP, hs-troponin T, and hs-troponin I with PAD (based on ankle-brachial index <0.90) and PN (diagnosed by monofilament testing) in adult participants aged ≥40 years of age without prevalent cardiovascular disease in NHANES (National Health and Nutrition Examination Survey) 1999 to 2004. We calculated the prevalence of elevated cardiac biomarkers among adults with PAD and PN and used multivariable logistic regression to assess the associations of each cardiac biomarker, modeled using clinical cut points, with PAD and PN separately. We used multivariable Cox proportional hazards models to assess the adjusted associations of cross categories of clinical categories of each cardiac biomarker and PAD or PN with all-cause and cardiovascular mortality. RESULTS: In US adults aged ≥40 years, the prevalence (±SE) of PAD was 4.1±0.2% and the prevalence of PN was 12.0±0.5%. The prevalence of elevated NT-proBNP (≥125 ng/L), hs-troponin T (≥6 ng/L), and hs-troponin I (≥6 ng/L for men and ≥4 ng/L for women) was 54.0±3.4%, 73.9±3.5%, and 32.3±3.7%, respectively, among adults with PAD and 32.9±1.9%, 72.8±2.0%, and 22.7±1.9%, respectively, among adults with PN. There was a strong, graded association of higher clinical categories of NT-proBNP with PAD after adjusting for cardiovascular risk factors. Clinical categories of elevated hs-troponin T and hs-troponin I were strongly associated with PN in adjusted models. After a maximum follow-up of 21 years, elevated NT-proBNP, hs-troponin T, and hs-troponin I were each associated with all-cause and cardiovascular mortality, with higher risks of death observed among adults with elevated cardiac biomarkers plus PAD or PN compared with elevated biomarkers alone. CONCLUSIONS: Our study establishes a high burden of subclinical cardiovascular disease defined by cardiac biomarkers in people with PAD or PN. Cardiac biomarkers provided prognostic information for mortality within and across PAD and PN status, supporting the use of these biomarkers for risk stratification among adults without prevalent cardiovascular disease.

Evolution and prognosis of tricuspid and mitral regurgitation following cardiac implantable electronic devices: a systematic review and meta-analysis.

AIMS: Significant changes in tricuspid regurgitation (TR) and mitral regurgitation (MR) post-cardiac implantable electronic devices (CIEDs) are increasingly recognized. However, uncertainty remains as to whether the risk of CIED-associated TR and MR differs with right ventricular pacing (RVP) via CIED with trans-tricuspid RV leads, compared with cardiac resynchronization therapy (CRT), conduction system pacing (CSP), and leadless pacing (LP). The study aims to synthesize extant data on risk and prognosis of significant post-CIED TR and MR across pacing strategies. METHODS AND RESULTS: We searched PubMed, EMBASE, and Cochrane Library databases published until 31 October 2023. Significant post-CIED TR and MR were defined as ≥ moderate. Fifty-seven TR studies (n = 13 723 patients) and 90 MR studies (n = 14 387 patients) were included. For all CIED, the risk of post-CIED TR increased [pooled odds ratio (OR) = 2.46 and 95% CI = 1.88-3.22], while the risk of post-CIED MR reduced (OR = 0.74, 95% CI = 0.58-0.94) after 12 and 6 months of median follow-up, respectively. Right ventricular pacing via CIED with trans-tricuspid RV leads was associated with increased risk of post-CIED TR (OR = 4.54, 95% CI = 3.14-6.57) and post-CIED MR (OR = 2.24, 95% CI = 1.18-4.26). Binarily, CSP did not alter TR risk (OR = 0.37, 95% CI = 0.13-1.02), but significantly reduced MR (OR = 0.15, 95% CI = 0.03-0.62). Cardiac resynchronization therapy did not significantly change TR risk (OR = 1.09, 95% CI = 0.55-2.17), but significantly reduced MR with prevalence pre-CRT of 43%, decreasing post-CRT to 22% (OR = 0.49, 95% CI = 0.40-0.61). There was no significant association of LP with post-CIED TR (OR = 1.15, 95% CI = 0.83-1.59) or MR (OR = 1.31, 95% CI = 0.72-2.39). Cardiac implantable electronic device-associated TR was independently predictive of all-cause mortality [pooled hazard ratio (HR) = 1.64, 95% CI = 1.40-1.90] after median of 53 months. Mitral regurgitation persisting post-CRT independently predicted all-cause mortality (HR = 2.00, 95% CI = 1.57-2.55) after 38 months. CONCLUSION: Our findings suggest that, when possible, adoption of pacing strategies that avoid isolated trans-tricuspid RV leads may be beneficial in preventing incident or deteriorating atrioventricular valvular regurgitation and might reduce mortality.

Associations of N-terminal pro-B-type natriuretic peptide, estimated glomerular filtration rate, and mortality in US adults.

BACKGROUND: NT-proBNP is an important predictor of mortality but is inversely related to estimated glomerular filtration rate (eGFR). Whether the prognostic value of NT-proBNP is similar at different levels of kidney function is unknown. AIMS: We evaluated the association of NT-proBNP with eGFR and its implications for all-cause and cardiovascular mortality risk in the general population. METHODS: We included adults without prior cardiovascular disease from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004. We used linear regression to characterize the cross-sectional associations of NT-proBNP with eGFR. We used Cox regression to assess the prospective associations of NT-proBNP with mortality across categories of eGFR. RESULTS: Among 11,456 participants (mean age 43 years, 48% female, 71% White, 11% Black), there was an inverse association between NT-proBNP and eGFR, which was stronger in those with more impaired kidney function. Per 15-unit decrease in eGFR, NT-proBNP was 4.3-fold higher for eGFR<30; 1.7-fold higher for eGFR 30 to 60, 1.4-fold higher for eGFR 61 to 90, 1.1-fold higher for eGFR 91 to 120 mL/min/1.73 m2. Over a median 17.6 years of follow-up, 2,275 deaths (622 cardiovascular) occurred. Higher NT-proBNP was associated with higher all-cause (HR per doubling of NT-proBNP: 1.20, 95% CI: 1.16-1.25) and cardiovascular mortality (HR: 1.34, 95% CI 1.25-1.44). Associations were similar across eGFR categories (P-interaction >.10). Adults with NT-proBNP≥450 pg/mL and eGFR<60 mL/min/1.73m2 had 3.4-fold higher all-cause mortality and 5.5-fold higher cardiovascular mortality risk, compared to those with NT-proBNP<125 pg/mL and eGFR>90 mL/min/1.73m2. CONCLUSION: Despite its strong inverse association with eGFR, NT-proBNP has robust associations with mortality across the full range of kidney function in the general US adult population.

Performance of the Glucose Management Indicator (GMI) in Type 2 Diabetes.

BACKGROUND: The glucose management indicator (GMI) is an estimated measure of hemoglobin A1c (HbA1c) recommended for the management of persons with diabetes using continuous glucose monitoring (CGM). However, GMI was derived primarily in young adults with type 1 diabetes, and its performance in patients with type 2 diabetes is poorly characterized. METHODS: We conducted a prospective cohort study in 144 adults with obstructive sleep apnea and type 2 diabetes not using insulin (mean age: 59.4 years; 45.1% female). HbA1c was measured at the study screening visit. Participants simultaneously wore 2 CGM sensors (Dexcom G4 and Abbott Libre Pro) for up to 4 weeks (2 weeks at baseline and 2 weeks at the 3-month follow-up visit). GMI was calculated using all available CGM data for each sensor. RESULTS: Median wear time was 27 days (IQR: 23-29) for the Dexcom G4 and 28 days (IQR: 24-29) for the Libre Pro. The mean difference between HbA1c and GMI was small (0.12-0.14 percentage points) (approximately 2 mmol/mol). However, the 2 measures were only moderately correlated (r = 0.68-0.71), and there was substantial variability in GMI at any given value of HbA1c (root mean squared error: 0.66-0.69 percentage points [7 to 8 mmol/mol]). Between 36% and 43% of participants had an absolute difference between HbA1c and GMI ≥0.5 percentage points (≥5 mmol/mol), and 9% to 18% had an absolute difference >1 percentage points (>11 mmol/mol). Discordance was higher in the Libre Pro than the Dexcom G4. CONCLUSIONS: GMI may be an unreliable measure of glycemic control for patients with type 2 diabetes and should be interpreted cautiously in clinical practice.Clinicaltrials.gov Registration Number: NCT02454153.

Body Composition Measures and N-terminal pro-B-type Natriuretic Peptide (NT-pro-BNP) in US Adults.

BACKGROUND: The associations of N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) with dual energy x-ray absorptiometry (DEXA)-derived measures of body mass and composition are largely unknown. METHODS: We included participants aged ≥20 years from the 1999-2004 National Health and Nutrition Examination Survey with NT-pro-BNP and DEXA-derived body composition (fat and lean mass) measures. We used linear and logistic regression to characterize the associations of measures of body mass and composition (body mass index [BMI], waist circumference [WC], fat mass, and lean mass) with NT-pro-BNP, adjusting for cardiovascular risk factors. RESULTS: We conducted sex-specific analyses among 9134 adults without cardiovascular disease (mean age 44.4 years, 50.8% women, and 72% White adults). The adjusted mean NT-proBNP values were lowest in the highest quartiles of BMI, WC, fat mass, and lean mass. There were large adjusted absolute differences in NT-pro-BNP between the highest and lowest quartiles of DEXA-derived lean mass, -6.26 pg/mL (95% confidence interval [CI], -8.99 to -3.52) among men and -22.96 pg/mL (95% CI, -26.83 to -19.09) among women. Lean mass exhibited a strong inverse association with elevated NT-pro-BNP ≥ 81.4 pg/mL (highest quartile) - odds ratio (OR) 0.58 (95% CI, 0.39-0.86) in men and OR 0.59 (95% CI, 0.47-0.73) in women for highest lean mass quartile vs. lowest quartile. Further adjustment for fat mass, BMI, or WC did not appreciably alter the inverse association of lean mass with NT-pro-BNP. CONCLUSIONS: In a national sample of US adults, lean mass was inversely associated with NT-pro-BNP.

Within-Person and Between-Sensor Variability in Continuous Glucose Monitoring Metrics.

BACKGROUND: The within-person and between-sensor variability of metrics from different interstitial continuous glucose monitoring (CGM) sensors in adults with type 2 diabetes not taking insulin is unclear. METHODS: Secondary analysis of data from 172 participants from the Hyperglycemic Profiles in Obstructive Sleep Apnea randomized clinical trial. Participants simultaneously wore Dexcom G4 and Abbott Libre Pro CGM sensors for up to 2 weeks at baseline and again at the 3-month follow-up visit. RESULTS: At baseline (up to 2 weeks of CGM), mean glucose for both the Abbott and Dexcom sensors was approximately 150 mg/dL (8.3 mmol/L) and time in range (70180 mg/dL [3.910.0 mmol/L]) was just below 80. When comparing the same sensor at 2 different time points (two 2-week periods, 3 months apart), the within-person coefficient of variation (CVw) in mean glucose was 17.4 (Abbott) and 14.2 (Dexcom). CVw for percent time in range: 20.1 (Abbott) and 18.6 (Dexcom). At baseline, the Pearson correlation of mean glucose from the 2 sensors worn simultaneously was r 0.86, root mean squared error (RMSE), 13 mg/dL (0.7 mmol/L); for time in range, r 0.88, RMSE, 8 percentage points. CONCLUSIONS: Substantial variation was observed within sensors over time and across 2 different sensors worn simultaneously on the same individuals. Clinicians should be aware of this variability when using CGM technology to make clinical decisions.ClinicalTrials.gov Identifier: NCT02454153.

Ideal Cardiovascular Health and Adipokine Levels: The Multi-Ethnic Study of Atherosclerosis.

OBJECTIVE: To evaluate the association between ideal cardiovascular health (CVH) and adipokine levels. Adipokines are hormones implicated in obesity and its cardiometabolic consequences. The concept of ideal CVH was introduced to promote 7 key health factors and behaviors in the general population. Previous studies have found strong associations between obesity and ideal CVH. However, existing literature on the link between CVH and adipokines is scarce. METHODS: We studied 1842 Multi-Ethnic Study of Atherosclerosis participants free of cardiovascular disease who had 7 CVH metrics (smoking, body mass index, physical activity, diet, total cholesterol, blood pressure, and fasting blood glucose) measured at baseline and serum adipokine levels measured at a median of 2.4 years later. Each CVH metric was assigned a score of 0 (poor), 1 (intermediate), or 2 (ideal), and all scores were summed for a total CVH score (0-14). The total CVH scores of 0 to 8, 9 to 10, and 11 to 14 were considered inadequate, average, and optimal, respectively. We used multivariable linear regression models to assess the nonconcurrent associations between the CVH score and log-transformed adipokine levels. RESULTS: The mean age was 62.1 ± 9.8 years; 50.2% of participants were men. After adjusting for sociodemographic factors, a 1-unit higher CVH score was significantly associated with 4% higher adiponectin and 15% and 1% lower leptin and resistin levels. Individuals with optimal CVH scores had 27% higher adiponectin and 56% lower leptin levels than those with inadequate CVH scores. Similar trends were observed for those with average versus inadequate CVH scores. CONCLUSION: In a multi-ethnic cohort free of cardiovascular disease at baseline, individuals with average and optimal CVH scores had a more favorable adipokine profile than those with inadequate CVH scores.

Diagnosis and Management of Prediabetes: A Review.

Importance: Prediabetes, an intermediate stage between normal glucose regulation and diabetes, affects 1 in 3 adults in the US and approximately 720 million individuals worldwide. Observations: Prediabetes is defined by a fasting glucose level of 100 to 125 mg/dL, a glucose level of 140 to 199 mg/dL measured 2 hours after a 75-g oral glucose load, or glycated hemoglobin level (HbA1C) of 5.7% to 6.4% or 6.0% to 6.4%. In the US, approximately 10% of people with prediabetes progress to having diabetes each year. A meta-analysis found that prediabetes at baseline was associated with increased mortality and increased cardiovascular event rates (excess absolute risk, 7.36 per 10 000 person-years for mortality and 8.75 per 10 000 person-years for cardiovascular disease during 6.6 years). Intensive lifestyle modification, consisting of calorie restriction, increased physical activity (≥150 min/wk), self-monitoring, and motivational support, decreased the incidence of diabetes by 6.2 cases per 100 person-years during a 3-year period. Metformin decreased the risk of diabetes among individuals with prediabetes by 3.2 cases per 100 person-years during 3 years. Metformin is most effective for women with prior gestational diabetes and for individuals younger than 60 years with body mass index of 35 or greater, fasting plasma glucose level of 110 mg/dL or higher, or HbA1c level of 6.0% or higher. Conclusions and Relevance: Prediabetes is associated with increased risk of diabetes, cardiovascular events, and mortality. First-line therapy for prediabetes is lifestyle modification that includes weight loss and exercise or metformin. Lifestyle modification is associated with a larger benefit than metformin.

Diabetes, GDF-15 and incident heart failure: the atherosclerosis risk in communities study.

AIMS/HYPOTHESIS: Elevated circulating growth differentiation factor-15 (GDF-15), a marker of cellular stress, is associated with both heart failure (HF) and diabetes. However, it is unclear to what extent GDF-15 is associated with HF among individuals with and without diabetes. METHODS: We evaluated 10,570 participants free of HF at Visit 3 (1993-1995) of the Atherosclerosis Risk in Communities study. We used Cox regression to evaluate the joint associations of GDF-15 and diabetes with incident HF. Models were adjusted for traditional cardiovascular risk factors. RESULTS: Among a total of 10,570 individuals (mean age of 60.0 years, 54% women, 27% black adults), elevated GDF-15 (≥75th percentile) was more common in people with diabetes compared with those without diabetes (32.8% vs 23.6%, p<0.0001). During 23 years of follow-up, there were 2429 incident HF events. GDF-15 (in quartiles) was independently associated with HF among those with and without diabetes, with a stronger association among individuals with diabetes (p-for-diabetes-GDF-15 interaction = 0.034): HR for highest vs lowest GDF-15 quartile (reference): 1.64 (95% CI 1.41, 1.91) among those without diabetes and 1.72 (95% CI 1.32, 2.23) among those with diabetes. Individuals with diabetes and elevated GDF-15 had the highest risk of incident HF (HR 2.46; 95% CI 1.99, 3.03). After accounting for HF risk factors, GDF-15 provided additional prognostic information among participants with diabetes (ΔC statistic for model with vs model without GDF-15: +0.008, p = 0.001) and among those without diabetes (+0.006, p<0.0001). CONCLUSIONS/INTERPRETATION: In a community-based sample of US adults, GDF-15 provided complementary prognostic information on the HF risk, especially among individuals with diabetes.

Association of Serum Aldosterone and Plasma Renin Activity With Ambulatory Blood Pressure in African Americans: The Jackson Heart Study.

BACKGROUND: The renin-angiotensin-aldosterone system (RAAS) is an important driver of blood pressure (BP), but the association of the RAAS with ambulatory BP (ABP) and ABP monitoring phenotypes among African Americans has not been assessed. METHODS: ABP and ABP monitoring phenotypes were assessed in 912 Jackson Heart Study participants with aldosterone and plasma renin activity (PRA). Multivariable linear and logistic regression analyses were used to analyze the association of aldosterone and PRA with clinic, awake, and asleep systolic BP and diastolic BP (DBP) and ABP monitoring phenotypes, adjusting for important confounders. RESULTS: The mean age of participants was 59±11 years and 69% were female. In fully adjusted models, lower log-PRA was associated with higher clinic, awake, and asleep systolic BP and DBP (all P<0.05). A higher log-aldosterone was associated with higher clinic, awake, and asleep DBP (all P<0.05). A 1-unit higher log-PRA was associated with lower odds of daytime hypertension (odds ratio [OR] 0.59 [95% CI, 0.49-0.71]), nocturnal hypertension (OR, 0.68 [95% CI, 0.58-0.79]), daytime and nocturnal hypertension (OR, 0.59 [95% CI, 0.48-0.71]), sustained hypertension (OR, 0.52 [95% CI, 0.39-0.70]), and masked hypertension (OR 0.75 [95% CI, 0.62-0.90]). A 1-unit higher log-aldosterone was associated with higher odds of nocturnal hypertension (OR, 1.38 [95% CI, 1.05-1.81]). Neither PRA nor aldosterone was associated with percent dipping, nondipping BP pattern, or white-coat hypertension. Patterns for aldosterone:renin ratio were similar to patterns for PRA. CONCLUSIONS: Suppressed renin activity and higher aldosterone:renin ratios were associated with higher systolic BP and DBP in the office and during the awake and asleep periods as evidenced by ABP monitoring. Higher aldosterone levels were associated with higher DBP, but not systolic BP, in the clinic and during the awake and asleep periods. Further clinical investigation of novel and approved medications that target low renin physiology such as epithelial sodium channel inhibitors and mineralocorticoid receptor antagonists may be paramount in improving hypertension control in African Americans.

Diabetic kidney disease and risk of incident stroke among adults with type 2 diabetes.

BACKGROUND: Data on the relations between kidney function abnormalities and stroke in type 2 diabetes are limited. We evaluated the associations of kidney function abnormalities and chronic kidney disease (CKD) stages with incident stroke in a large sample of adults with type 2 diabetes. METHODS: Participants with type 2 diabetes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study without history of stroke at baseline were included. Urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) were assessed at baseline. CKD categories were defined according to the KDIGO (Kidney Disease: Improving Global Outcomes) guidelines. Cox proportional hazards regression models were used to compute hazard ratios (HR) and 95% confidence intervals (CI) for stroke in relation to measures of kidney function and CKD categories. RESULTS: A total of 9170 participants (mean age 62.8 [SD: 6.6] years, 38.2% women, 62.9% white) were included. Over a median follow-up of 4.9 years (interquartile range: 4.0-5.7), 156 participants developed a stroke (incidence rate 3.6/1000 person-years [95% CI 3.0-4.2]). After adjusting for relevant confounders, higher UACR and lower eGFR were each associated with increased risk of stroke. Compared to UACR < 30 mg/g, moderate albuminuria and severe albuminuria were associated with increasing hazards for stroke (HR 1.61 [95% CI 1.12-2.32] and 2.29 [95% CI 1.39-3.80], respectively). Compared to eGFR of ≥ 60 mL/min/1.73 m2, decreased eGFR (eGFR < 60 mL/min/1.73 m2) was associated with higher risk of stroke (HR 1.50, 95% CI 0.98-2.29). Compared to no CKD, worsening CKD stage was associated with an increasing risk of stroke (HRs of 1.76 [95% CI 1.10-2.83] for CKD G1, 1.77 [95% CI 1.13-2.75] for CKD G2, and 2.03 [95% CI 1.27-3.24] for CKD G3). CONCLUSIONS: In a large sample of adults with type 2 diabetes, increasing albuminuria and worsening stages of early CKD were independently associated with higher risk of incident stroke. TRIAL REGISTRATION: ClinicalTrials.gov. Identifier: NCT00000620 .

The need for screening, early diagnosis, and prediction of chronic kidney disease in people with diabetes in low- and middle-income countries-a review of the current literature.

Chronic kidney disease (CKD) in people with diabetes is becoming an increasing major public health concern, disproportionately burdening low- and middle-income countries (LMICs). This rising burden is due to various factors, including the lack of disease awareness that results in late referral and the cost of screening and consequent treatment of the comorbid conditions, as well as other factors endemic to LMICs relating to inadequate management of risk factors. We critically assessed the extant literature, by performing searches of Medline via PubMed, EBSCOhost, Scopus, and Web of Science, for studies pertaining to screening, diagnosis, and prediction of CKD amongst adults with diabetes in LMICs, using relevant key terms. The relevant studies were summarized through key themes derived from the Wilson and Jungner criteria. We found that screening for CKD in people with diabetes is generally infrequent in LMICs. Also, LMICs are ill-equipped to appropriately manage diabetes-associated CKD, especially its late stages, in which supportive care and kidney replacement therapy (KRT) might be required. There are acceptable and relatively simple tools that can aid diabetes-associated CKD screening in these countries; however, these tools come with limitations. Thus, effective implementation of diabetes-associated CKD screening in LMICs remains a challenge, and the cost-effectiveness of such an undertaking largely remains to be explored. In conclusion, for many compelling reasons, screening for CKD in people with diabetes should be a high policy priority in LMICs, as the huge cost associated with higher mortality and morbidity in this group and the cost of KRT offers a compelling economic incentive for improving early detection of diabetes in CKD.

Association of plasma endothelin-1 with blood pressure progression among Blacks: The Jackson Heart Study.

BACKGROUND: Despite pathophysiological links between endothelin (ET)-1 and hypertension in Black adults, there is no population-based data appraising the association of plasma ET-1 with longitudinal blood pressure (BP) changes in Blacks. METHODS: We analyzed data from 1197 Jackson Heart Study participants without hypertension (mean age 47.8 years [SD: 12.0]; 64.2% women), with plasma ET-1 available at the baseline examination (2000-2004). Poisson regression with robust variance was used to generate risk ratios (RRs) and 95% confidence intervals (CIs) of BP progression (an increase by ≥1 BP category based on the 2017 American College of Cardiology/American Heart Association classification) and incident hypertension (BP ≥ 130/80 mm Hg or use of antihypertensive medication) at follow-up (2005-2008 or 2009-2013). RESULTS: Over a median follow-up of 7 years (range: 4-11), 71.2% (n = 854) progressed to a higher BP stage and 64.6% (n = 773) developed hypertension. After adjusting for possible confounders, each unit increment in baseline log (ET-1) was associated with higher risks of BP progression (RR 1.15 [95% CI 1.03-1.29], P = .016) and incident hypertension (RR 1.15 [95% CI 1.01-1.31], P = .032). Compared to those in the lowest ET-1 quartile, participants in the highest quartile had significantly higher risks of BP progression (RR 1.20 [95% CI 1.05-1.37], P = .007) and incident hypertension (RR 1.16 [95% CI 1.00-1.36], P = .052). CONCLUSIONS: In a large, community-based sample of African Americans, higher plasma ET-1 concentrations were associated with higher risks of BP progression and incident hypertension.

Dysglycemia and incident heart failure among blacks: The jackson heart study.

BACKGROUND: We aimed to investigate the associations of glycemic markers (hemoglobin A1C [HbA1C], fasting plasma glucose [FPG] and glycemic status [normoglycemia, prediabetes and diabetes]) with incident heart failure (HF) and its subtypes, among Blacks. METHODS: We included 2,290 community-dwelling Blacks (64% women, mean age 58 years) without prevalent HF from the Jackson Heart Study who attended the second exam (2005 - 2008). The associations between glycemic markers and incident HF (and subtypes including HF with preserved ejection fraction [HFpEF] and reduced ejection fraction [HFrEF]) were evaluated using Cox proportional hazards regression models, adjusting for risk factors and coronary heart disease. RESULTS: There were 119 incident HF events (48 HFpEF, 58 HFrEF, and 13 unclassified HF events) over a median follow-up of 10.5 years. Higher levels of HbA1C (HR per SD increment, 1.30; 95% CI 1.12, 1.51) and FPG (HR per SD increment FPG: 1.32; 95% CI: 1.17, 1.48) were associated with a higher risk of incident HF. Compared to normal glycemia, diabetes status was associated with a higher risk of incident HF (HR: 1.24; 95%CI: 1.02, 2.05). HbA1C was significantly associated with higher risks of HFpEF (HR per SD increment: 1.41, 95% CI: 1.18, 1.69) and HFrEF (HR per SD increment: 1.32; 95% CI: 1.12, 1.56). FPG was significantly associated with higher risk of HFpEF (HR per SD increment: 1.35, 95% CI: 1.14, 1.62) but not HFrEF (HR per SD increment: 1.12; 95% CI: 0.53, 2.35). CONCLUSIONS: Among community-dwelling Blacks, higher levels of glycemic markers were associated with higher risk of HF subtypes.

Diabetes Duration and Subclinical Myocardial Injury: The Atherosclerosis Risk in Communities Study (ARIC).

BACKGROUND: Diabetes exerts adverse effects on the heart, and a longer diabetes duration is associated with greater heart failure risk. We studied diabetes duration and subclinical myocardial injury, as reflected by high-sensitivity cardiac troponin (hs-cTnT). METHODS: We analyzed 9052 participants without heart failure or coronary heart disease (mean age 63 years, 58% female, 21% Black, 15% with diabetes) at The Atherosclerosis Risk in Communities Study (ARIC) Visit 4 (1996 to 1998). Diabetes duration was calculated based on diabetes status at Visits 1 (1987 to 1989) through 4, or using self-reported age of diabetes diagnosis prior to Visit 1. We used multinomial logistic regression to determine the association of diabetes duration with increased (≥14 ng/L) or detectable (≥6 ng/L) Visit 4 hs-cTnT, relative to undetectable hs-cTnT, adjusted for demographics and cardiovascular risk factors. RESULTS: The prevalence of increased Visit 4 hs-cTnT was higher in persons with longer diabetes duration, from 12% for those with diabetes 0 to <5 years up to 31% among those with diabetes for ≥15 years (P for trend <0.0001). New onset diabetes at Visit 4 was associated with 1.92× higher relative risk (95% CI, 1.27-2.91) of increased hs-cTnT than no diabetes. Longer diabetes duration was associated with greater myocardial injury, with duration ≥15 years associated with 9.29× higher risk (95% CI, 5.65-15.29) for increased hs-cTnT and 2.07× (95% CI, 1.24-3.16) for detectable hs-cTnT, compared to no diabetes. CONCLUSIONS: Longer diabetes duration is strongly associated with subclinical myocardial injury. Interventional studies are needed to assess whether the prevention and delay of diabetes onset can mitigate early myocardial damage.