Longitudinal Plasma Kallikrein Levels and their Association with the Risk of Cardiovascular Disease Outcomes in Type 1 Diabetes in DCCT/EDIC

10.2337/figshare.12801350 ◽

2020 ◽

Author(s):

Ada Admin ◽

Miran A Jaffa ◽

Ionut Bebu ◽

Deirdre Luttrell ◽

Barbara H Braffett ◽

...

Keyword(s):

Cardiovascular Disease ◽

Type 1 Diabetes ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Major Adverse Cardiovascular Events ◽

Plasma Kallikrein ◽

Cvd Risk ◽

20 Nm ◽

Adjusted Model

We determined the relationship between plasma kallikrein and cardiovascular disease (CVD) outcomes as well as major adverse cardiovascular events (MACE) in the DCCT/EDIC-cohort of type 1 diabetes (T1D). Plasma kallikrein levels were measured longitudinally in 693 subjects at DCCT baseline (1983-1989), mid-point of DCCT (1988-1991), end of DCCT (1993), and EDIC years 4-6 (1997-1999), 8-10 (2001-2003), and 11-13 (2004-2006). Cox proportional hazards regression models assessed the association between plasma kallikrein levels and the risk of CVD. In unadjusted models, higher plasma kallikrein levels were associated with higher risk of any CVD during DCCT/EDIC (HR=1.16 per 20 nM higher levels of plasma kallikrein; p=0.0177) as well as over the EDIC-only period (HR=1.22; p=0.0024). The association between plasma kallikrein levels and the risk of any CVD remained significant during the EDIC follow-up after adjustment for age and mean HbA1c (HR=1.20; p=0.0082) and in the fully adjusted model for other CVD risk factors (HR=1.17; p=0.0330). For MACE, higher plasma kallikrein levels were associated with higher risk in unadjusted (HR=1.25; p=0.0145), minimally adjusted (HR=1.23; p=0.0417, and fully adjusted (HR=1.27; p=0.0328) models during EDIC-only. These novel findings indicate that plasma kallikrein level associates with the risk of any CVD and MACE in T1D individuals.

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Genetic Risk Factors for CVD in Type 1 Diabetes: the DCCT/EDIC Study

10.2337/figshare.14182715 ◽

2021 ◽

Author(s):

Ionut Bebu ◽

Sareh Keshavarzi ◽

Xiaoyu Gao ◽

Barbara H. Braffett ◽

Angelo J. Canty ◽

...

Keyword(s):

Risk Factors ◽

Blood Pressure ◽

Cardiovascular Disease ◽

Type 1 Diabetes ◽

Genetic Factors ◽

Risk Scores ◽

Major Adverse Cardiovascular Events ◽

Cvd Risk ◽

Individual Snps

Background The role of genetic factors on the risk of cardiovascular disease (CVD) risk in type 1 diabetes remains unknown. We therefore examined whether previously identified genetic factors for coronary artery disease (CAD) are associated with the risk of CVD above and beyond established demographic and clinical factors in The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study. Methods Polygenic risk scores (PRS) and individual genetic variants identified in previous studies were obtained from genome-wide genotyping performed in 1371 DCCT/EDIC participants. Two composite CVD outcomes were considered: major adverse cardiovascular events (MACE) (CVD death or non-fatal myocardial infarction or stroke) and any-CVD (MACE plus confirmed angina, silent MI, revascularization, or congestive heart failure). Cox proportional hazards models assessed the association between the genetic factors and the risk of CVD when adjusted for other factors (including age, lipids, blood pressure and glycemia). Results CAD PRS was strongly associated with the subsequent risk of any-CVD (42% and 38% higher risk per 1 standard deviation (SD) increase in unadjusted and fully adjusted models, respectively, p<0.0001), and with the risk of MACE (50% and 40% higher risk per 1SD increase in unadjusted and fully adjusted models, respectively, p<0.0001). Several individual SNPs were also nominally associated with the risk of any-CVD and MACE. Conclusions Genetic factors are associated with the risk of subsequent cardiovascular disease in individuals with type 1 diabetes, above and beyond the effect of established risk factors such as age, lipids, blood pressure and glycemia.

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Genetic Risk Factors for CVD in Type 1 Diabetes: the DCCT/EDIC Study

10.2337/figshare.14182715.v1 ◽

2021 ◽

Author(s):

Ionut Bebu ◽

Sareh Keshavarzi ◽

Xiaoyu Gao ◽

Barbara H. Braffett ◽

Angelo J. Canty ◽

...

Keyword(s):

Risk Factors ◽

Blood Pressure ◽

Cardiovascular Disease ◽

Type 1 Diabetes ◽

Genetic Factors ◽

Risk Scores ◽

Major Adverse Cardiovascular Events ◽

Cvd Risk ◽

Individual Snps

Background The role of genetic factors on the risk of cardiovascular disease (CVD) risk in type 1 diabetes remains unknown. We therefore examined whether previously identified genetic factors for coronary artery disease (CAD) are associated with the risk of CVD above and beyond established demographic and clinical factors in The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study. Methods Polygenic risk scores (PRS) and individual genetic variants identified in previous studies were obtained from genome-wide genotyping performed in 1371 DCCT/EDIC participants. Two composite CVD outcomes were considered: major adverse cardiovascular events (MACE) (CVD death or non-fatal myocardial infarction or stroke) and any-CVD (MACE plus confirmed angina, silent MI, revascularization, or congestive heart failure). Cox proportional hazards models assessed the association between the genetic factors and the risk of CVD when adjusted for other factors (including age, lipids, blood pressure and glycemia). Results CAD PRS was strongly associated with the subsequent risk of any-CVD (42% and 38% higher risk per 1 standard deviation (SD) increase in unadjusted and fully adjusted models, respectively, p<0.0001), and with the risk of MACE (50% and 40% higher risk per 1SD increase in unadjusted and fully adjusted models, respectively, p<0.0001). Several individual SNPs were also nominally associated with the risk of any-CVD and MACE. Conclusions Genetic factors are associated with the risk of subsequent cardiovascular disease in individuals with type 1 diabetes, above and beyond the effect of established risk factors such as age, lipids, blood pressure and glycemia.

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664-P: What Do Youth with Type 1 Diabetes (T1DM) and Caregivers Know about Cardiovascular Disease (CVD) Risk and Reduction?

Diabetes ◽

10.2337/db19-664-p ◽

2019 ◽

Vol 68 (Supplement 1) ◽

pp. 664-P

Author(s):

JODI KRALL ◽

KRISTINE RUPPERT ◽

ANA M. DIAZ ◽

JESSICA FINNEY ◽

LINDA M. SIMINERIO ◽

...

Keyword(s):

Cardiovascular Disease ◽

Type 1 Diabetes ◽

Cvd Risk

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Added value of cardiovascular calcifications for prediction of recurrent cardiovascular events and cardiovascular interventions in patients with established cardiovascular disease

The International Journal of Cardiovascular Imaging ◽

10.1007/s10554-021-02164-9 ◽

2021 ◽

Author(s):

Cilie C. van ’t Klooster ◽

◽

Yolanda van der Graaf ◽

Hendrik M. Nathoe ◽

Michiel L. Bots ◽

...

Keyword(s):

Cardiovascular Disease ◽

Heart Valve ◽

Cardiovascular Events ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Added Value ◽

Cvd Risk ◽

Major Cardiovascular Events ◽

Cox Proportional Hazards Models ◽

Cardiovascular Interventions

AbstractThe purpose is to investigate the added prognostic value of coronary artery calcium (CAC), thoracic aortic calcium (TAC), and heart valve calcium scores for prediction of a combined endpoint of recurrent major cardiovascular events and cardiovascular interventions (MACE +) in patients with established cardiovascular disease (CVD). In total, 567 patients with established CVD enrolled in a substudy of the UCC-SMART cohort, entailing cardiovascular CT imaging and calcium scoring, were studied. Five Cox proportional hazards models for prediction of 4-year risk of MACE + were developed; traditional CVD risk predictors only (model I), with addition of CAC (model II), TAC (model III), heart valve calcium (model IV), and all calcium scores (model V). Bootstrapping was performed to account for optimism. During a median follow-up of 3.43 years (IQR 2.28–4.74) 77 events occurred (MACE+). Calibration of predicted versus observed 4-year risk for model I without calcium scores was good, and the c-statistic was 0.65 (95%CI 0.59–0.72). Calibration for models II–V was similar to model I, and c-statistics were 0.67, 0.65, 0.65, and 0.68 for model II, III, IV, and V, respectively. NRIs showed improvement in risk classification by model II (NRI 15.24% (95%CI 0.59–29.39)) and model V (NRI 20.00% (95%CI 5.59–34.92)), but no improvement for models III and IV. In patients with established CVD, addition of the CAC score improved performance of a risk prediction model with classical risk factors for the prediction of the combined endpoint MACE+ . Addition of the TAC or heart valve score did not improve risk predictions.

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Risk and Timing of Cardiovascular Disease After Androgen-Deprivation Therapy in Men With Prostate Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2014.59.1792 ◽

2015 ◽

Vol 33 (11) ◽

pp. 1243-1251 ◽

Cited By ~ 121

Author(s):

Sean O'Farrell ◽

Hans Garmo ◽

Lars Holmberg ◽

Jan Adolfsson ◽

Pär Stattin ◽

...

Keyword(s):

Prostate Cancer ◽

Cardiovascular Disease ◽

Androgen Deprivation Therapy ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Androgen Deprivation ◽

Gnrh Agonists ◽

Cvd Risk ◽

Comparison Cohort ◽

Using Data

Purpose Findings on the association between risk of cardiovascular disease (CVD) and the duration and type of androgen-deprivation therapy (ADT) in men with prostate cancer (PCa) are inconsistent. Methods By using data on filled drug prescriptions in Swedish national health care registers, we investigated the risk of CVD in a cohort of 41,362 men with PCa on ADT compared with an age-matched, PCa-free comparison cohort (n = 187,785) by use of multivariable Cox proportional hazards regression models. Results From 2006 to 2012, 10,656 men were on antiandrogens (AA), 26,959 were on gonadotropin-releasing hormone (GnRH) agonists, and 3,747 underwent surgical orchiectomy. CVD risk was increased in men on GnRH agonists compared with the comparison cohort (hazard ratio [HR] of incident CVD, 1.21; 95% CI, 1.18 to 1.25; and orchiectomy: HR, 1.16; 95% CI, 1.08 to 1.25). Men with PCa on AA were at decreased risk (HR of incident CVD, 0.87; 95% CI, 0.82 to 0.91). CVD risk was highest during the first 6 months of ADT in men who experienced two or more cardiovascular events before therapy, with an HR of CVD during the first 6 months of GnRH agonist therapy of 1.91 (95% CI, 1.66 to 2.20), an HR of CVD with AA of 1.60 (95% CI, 1.24 to 2.06), and an HR of CVD with orchiectomy of 1.79 (95% CI, 1.16 to 2.76) versus the comparison cohort. Conclusion Our results support that there should be a solid indication for ADT in men with PCa so that benefit outweighs potential harm; this is of particular importance among men with a recent history of CVD.

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30-Year Cardiovascular Disease in Type 1 Diabetes: Risk and Risk Factors Differ by Long-Term Patterns of Glycemic Control

10.2337/figshare.16775965 ◽

2021 ◽

Author(s):

Rachel G. Miller ◽

Trevor J. Orchard ◽

Tina Costacou

Keyword(s):

Risk Factors ◽

Cardiovascular Disease ◽

Type 1 Diabetes ◽

Glycemic Control ◽

Latent Class ◽

Diabetes Duration ◽

Cvd Risk ◽

High Hba1c

Objective: We hypothesized that there is heterogeneity in long-term patterns of glycemic control with respect to cardiovascular disease (CVD) development in type 1 diabetes and that risk factors for CVD differ by glycemic control pattern. Thus, we estimated associations between data-derived latent HbA1c trajectories and 30-year CVD risk in the Pittsburgh Epidemiology of Diabetes Complications (EDC) study of childhood-onset (<17 years old) type 1 diabetes. Research Design and Methods: Participants (n=536 with ≥2 HbA1c measurements [median 6] and CVD-free at baseline; mean age 27 and diabetes duration 18 years) were followed from 1986-88 to 2016-18 to ascertain CVD incidence (CVD death, myocardial infarction, stroke, coronary revascularization or blockage ≥50%, ischemic ECG, or angina). Latent HbA1c trajectories and their association with time-to-CVD incidence were simultaneously assessed using Joint Latent Class Mixed Models. Results: Two HbA1c trajectories with respect to differential CVD risk were identified: Low (HbA1c ~8% [64 mmol/mol] and improving over follow-up, 76% of cohort) and High (HbA1c ~10% [86 mmol/mol] and stable, 24%). Overall, 30-year CVD incidence was 47.4% (n=253); MACE incidence 31.0% (n=176). High HbA1c was associated with 3-fold increased CVD risk versus Low HbA1c. Both groups had similar age and diabetes duration. Non-HDLc and estimated glomerular filtration rate were associated with CVD risk only in Low HbA1c; albumin excretion rate was associated with CVD risk only in High HbA1c. Conclusions: These risk factor differences suggest that pathways to CVD may differ by glycemic control, potentially resulting in important implications for prognosis in type 1 diabetes.

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Abstract 17: Association of Race and Sex with Cardiovascular Disease and Non-Cardiovascular Disease Mortality: The REasons for Geographic and Racial Differences in Stroke study

Circulation ◽

10.1161/circ.135.suppl_1.17 ◽

2017 ◽

Vol 135 (suppl_1) ◽

Author(s):

Gabriel S Tajeu ◽

Monika M Safford ◽

George Howard ◽

Rikki M Tanner ◽

Paul Muntner

Keyword(s):

Risk Factors ◽

Cardiovascular Disease ◽

Racial Differences ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Hazard Ratio ◽

Cvd Risk ◽

Hazard Ratios ◽

Stroke Study ◽

Cvd Mortality

Introduction: Black Americans have higher rates of cardiovascular disease (CVD) mortality compared with whites. Differences in sociodemographic, psychosocial, CVD, and other risk factors may explain increased mortality risk. Methods: We analyzed data from 29,015 REasons for Geographic and Racial Differences in Stroke study participants to determine factors that may explain the higher hazard ratio for CVD and non-CVD mortality in blacks compared with whites. Cause of death was adjudicated by trained investigators. Within age-sex sub-groups, we used Cox proportional hazards regression with progressive adjustment to estimate black:white hazard ratios. Results: Overall, 41.0% of participants were black, and 54.9% were women. Over a mean follow-up of 7.1 years (maximum 12.3 years), 5,299 participants died (1,797 CVD and 3,502 non-CVD deaths). Among participants < 65 years of age, the age and region adjusted black:white hazard ratio for CVD mortality was 2.28 (95% CI: 1.68-3.10) and 2.32 (95% CI: 1.80-3.00) for women and men, respectively, and for participants ≥ 65 was 1.54 (95% CI: 1.30-1.82) and 1.35 (95% CI: 1.16-1.57) for women and men, respectively ( Table ). The higher black:white hazard ratios for CVD mortality were no longer statistically significant after multivariable adjustment, with the largest attenuation occurring with sociodemographic and CVD risk factor adjustment. Among participants < 65 years of age, the age and region adjusted black:white hazard ratios for non-CVD mortality were 1.51 (95% CI: 1.24-1.85) and 1.76 (95% CI: 1.46-2.13) for women and men, respectively, and for participants ≥ 65 was 1.12 (95% CI: 1.00-1.26) and 1.34 (95% CI: 1.20-1.49) for women and men, respectively. The higher black:white hazard ratios for non-CVD mortality were attenuated after adjustment for sociodemographics. Conclusions: Black:white differences are larger for CVD than non-CVD causes of death. The increased CVD mortality for blacks compared with whites is primarily explained by sociodemographic and CVD risk factors.

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Early Glomerular Hyperfiltration and Long-Term Kidney Outcomes in Type 1 Diabetes

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.14831218 ◽

2019 ◽

Vol 14 (6) ◽

pp. 854-861 ◽

Cited By ~ 10

Author(s):

Mark E. Molitch ◽

Xiaoyu Gao ◽

Ionut Bebu ◽

Ian H. de Boer ◽

John Lachin ◽

...

Keyword(s):

Type 1 Diabetes ◽

Confidence Interval ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Glomerular Hyperfiltration ◽

Iothalamate Clearance ◽

Subsequent Risk

Background and objectivesGlomerular hyperfiltration has been considered to be a contributing factor to the development of diabetic kidney disease (DKD). To address this issue, we analyzed GFR follow-up data on participants with type 1 diabetes undergoing 125I-iothalamate clearance on entry into the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications study.Design, setting, participants, & measurementsThis was a cohort study of DCCT participants with type 1 diabetes who underwent an 125I-iothalamate clearance (iGFR) at DCCT baseline. Presence of hyperfiltration was defined as iGFR levels ≥140 ml/min per 1.73 m2, with secondary thresholds of 130 or 150 ml/min per 1.73 m2. Cox proportional hazards models assessed the association between the baseline hyperfiltration status and the subsequent risk of reaching an eGFR <60 ml/min per 1.73 m2.ResultsOf the 446 participants, 106 (24%) had hyperfiltration (iGFR levels ≥140 ml/min per 1.73 m2) at baseline. Over a median follow-up of 28 (interquartile range, 23, 33) years, 53 developed an eGFR <60 ml/min per 1.73 m2. The cumulative incidence of eGFR <60 ml/min per 1.73 m2 at 28 years of follow-up was 11.0% among participants with hyperfiltration at baseline, compared with 12.8% among participants with baseline GFR <140 ml/min per 1.73 m2. Hyperfiltration was not significantly associated with subsequent risk of developing an eGFR <60 ml/min per 1.73 m2 in an unadjusted Cox proportional hazards model (hazard ratio, 0.83; 95% confidence interval, 0.43 to 1.62) nor in an adjusted model (hazard ratio, 0.77; 95% confidence interval, 0.38 to 1.54). Application of alternate thresholds to define hyperfiltration (130 or 150 ml/min per 1.73 m2) showed similar findings.ConclusionsEarly hyperfiltration in patients with type 1 diabetes was not associated with a higher long-term risk of decreased GFR. Although glomerular hypertension may be a mechanism of kidney injury in DKD, higher total GFR does not appear to be a risk factor for advanced DKD.

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Traumatic brain injury associated with dementia risk among people with type 1 diabetes

Neurology ◽

10.1212/wnl.0000000000006391 ◽

2018 ◽

Vol 91 (17) ◽

pp. e1611-e1618 ◽

Cited By ~ 3

Author(s):

Paola Gilsanz ◽

Kathleen Albers ◽

Michal Schnaider Beeri ◽

Andrew J. Karter ◽

Charles P. Quesenberry ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Type 1 Diabetes ◽

Brain Injury ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Competing Risk ◽

Middle Aged ◽

Risk Of Death ◽

Dementia Risk

ObjectiveTo examine the association between traumatic brain injury (TBI) and dementia risk among a cohort of middle-aged and elderly individuals with type 1 diabetes (T1D).MethodsWe evaluated 4,049 members of an integrated health care system with T1D ≥50 years old between January 1, 1996, and September 30, 2015. Dementia and TBI diagnoses throughout the study period were abstracted from medical records. Cox proportional hazards models estimated associations between time-dependent TBI and dementia adjusting for demographics, HbA1c, nephropathy, neuropathy, stroke, peripheral artery disease, depression, and dysglycemic events. Fine and Gray regression models evaluated the association between baseline TBI and dementia risk accounting for competing risk of death.ResultsA total of 178 individuals (4.4%) experienced a TBI and 212 (5.2%) developed dementia. In fully adjusted models, TBI was associated with 3.6 times the dementia risk (hazard ratio [HR] 3.64; 95% confidence interval [CI] 2.34, 5.68). When accounting for the competing risk of death, TBI was associated with almost 3 times the risk of dementia (HR 2.91; 95% CI 1.29, 5.68).ConclusionThis study demonstrates a marked increase in risk of dementia associated with TBI among middle-aged and elderly people with T1D. Given the complexity of self-care for individuals with T1D, and the comorbidities that predispose them to trauma and falls, future work is needed on interventions protecting brain health in this vulnerable population, which is now living to old age.

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