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Mediation of the Effect of Glycemia on the Risk of CVD Outcomes in Type 1 Diabetes: The DCCT/EDIC Study.

ABSTRACT: OBJECTIVE:The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study has demonstrated the major role of hyperglycemia as a risk factor for clinical cardiovascular outcomes in type 1 diabetes (T1D). We assessed whether and to what extent the effect of glycemia is mediated by other established cardiovascular disease (CVD) risk factors. RESEARCH DESIGN AND METHODS:In the DCCT, 1,441 participants were randomized to receive either intensive or conventional diabetes therapy. The EDIC observational follow-up study enrolled 96% of the surviving DCCT cohort with 94% of the survivors still actively participating after more than 27 years of follow-up. Mediation of the effect of glycemia, as captured by HbA1c, on the subsequent CVD risk was quantified using the relative change in the CVD risk associated with HbA1c between models without and with the potential mediator. RESULTS:Adjusted for age, only a few factors (e.g., pulse, triglycerides, albumin excretion rate) explained more than 10% of the effect of glycemia on CVD risk when considered individually. In multivariable models, these traditional risk factors together mediated up to ?50% of the effect of glycemia on the risk of CVD. However, the association between HbA1c and the risk of CVD remained highly significant even after adjustment for these risk factors. CONCLUSIONS:While HbA1c is associated with many traditional CVD risk factors, its association with these factors alone cannot explain its effects on risk of CVD. Consequently, aggressive management of traditional nonglycemic CVD risk factors, coupled with aggressive glycemic management, is indicated for individuals with type 1 diabetes.

SUBMITTER: Bebu I

PROVIDER: S-EPMC6609964 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Mediation of the Effect of Glycemia on the Risk of CVD Outcomes in Type 1 Diabetes: The DCCT/EDIC Study.

Bebu Ionut I Braffett Barbara H BH Orchard Trevor J TJ Lorenzi Gayle M GM Lachin John M JM

Diabetes care 20190320 7

<h4>Objective</h4>The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study has demonstrated the major role of hyperglycemia as a risk factor for clinical cardiovascular outcomes in type 1 diabetes (T1D). We assessed whether and to what extent the effect of glycemia is mediated by other established cardiovascular disease (CVD) risk factors.<h4>Research design and methods</h4>In the DCCT, 1,441 participants were randomized to receive ...[more]

PMID: 30894365

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Project description:BackgroundHyperglycemia leading to increased oxidative stress is implicated in the increased risk for the development of macrovascular and microvascular complications in patients with type 1 diabetes mellitus.Methods and ResultsA random subcohort of 349 participants was selected from the DCCT/EDIC (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications) cohort. This included 320 controls and 29 cardiovascular disease cases that were augmented with 98 additional known cases to yield a case cohort of 447 participants (320 controls, 127 cases). Biosamples from DCCT baseline, year 1, and closeout of DCCT, and 1 to 2 years post‐DCCT (EDIC years 1 and 2) were measured for markers of oxidative stress, including plasma myeloperoxidase, paraoxonase activity, urinary F isoprostanes, and its metabolite, 2,3 dinor‐8 prostaglandin F. Following adjustment for glycated hemoblobin and weighting the observations inversely proportional to the sampling selection probabilities, higher paraoxonase activity, reflective of antioxidant activity, and 2,3 dinor‐8 prostaglandin F, an oxidative marker, were significantly associated with lower risk of cardiovascular disease (−4.5% risk for 10% higher paraoxonase, <0.003; −5.3% risk for 10% higher 2,3 dinor‐8 prostaglandin F, =0.0092). In contrast, the oxidative markers myeloperoxidase and F isoprostanes were not significantly associated with cardiovascular disease after adjustment for glycated hemoblobin. There were no significant differences between DCCT intensive and conventional treatment groups in the change in all biomarkers across time segments.ConclusionsHeightened antioxidant activity (rather than diminished oxidative stress markers) is associated with lower cardiovascular disease risk in type 1 diabetes mellitus, but these biomarkers did not change over time with intensification of glycemic control.Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifiers: NCT00360815 and NCT00360893.

Project description:Background and objectivesIn trials of people with type 2 diabetes, albuminuria reduction with renin-angiotensin system inhibitors is associated with lower risks of cardiovascular events and CKD progression. We tested whether progression or remission of microalbuminuria is associated with cardiovascular and renal risk in a well characterized cohort of type 1 diabetes.Design, setting, participants, & measurementsWe studied 1441 participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study. Albumin excretion rate (AER) was quantified annually or biennially for up to 30 years. For each participant, albuminuria status was defined over time as normoalbuminuria (AER continuously <30 mg/d), sustained microalbuminuria (AER, 30-299 mg/d on two consecutive visits), macroalbuminuria (AER≥300 mg/d), or remitted microalbuminuria (transition from sustained microalbuminuria to AER<30 mg/d on two consecutive visits). We tested associations of time-updated albuminuria status with adjudicated clinical cardiovascular events, the development of reduced GFR (<60 ml/min per 1.73 m2 on two consecutive visits), and subclinical cardiovascular disease.ResultsAt least one cardiovascular event occurred in 184 participants, and 98 participants developed reduced eGFR. Compared with normoalbuminuria, sustained microalbuminuria, remitted microalbuminuria, and macroalbuminuria were each associated with higher risk of cardiovascular events (adjusted hazard ratios [HRs] and 95% confidence intervals [95% CIs]: 1.79 [1.13 to 2.85], 2.62 [1.68 to 4.07], and 2.65 [1.68 to 4.19], respectively) and reduced eGFR (adjusted HRs [95% CIs], 5.26 [2.43 to 11.41], 4.36 [1.80 to 10.57], and 54.35 [30.79 to 95.94], respectively). Compared with sustained microalbuminuria, remission to normoalbuminuria was not associated with reduced risk of cardiovascular events (adjusted HR, 1.33; 95% CI, 0.68 to 2.59) or reduced eGFR (adjusted HR, 1.75; 95% CI, 0.56 to 5.49). Compared with normoalbuminuria, sustained microalbuminuria, remitted microalbuminuria, and macroalbuminuria were associated with greater carotid intima-media thickness, and macroalbuminuria was associated with a greater degree of coronary artery calcification.ConclusionsIn type 1 diabetes, microalbuminuria and macroalbuminuria are associated with higher risks of cardiovascular disease and reduced eGFR, but achieving a remission of established microalbuminuria to normoalbuminuria does not appear to improve outcomes.

Project description:BACKGROUND AND OBJECTIVES:Glomerular 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, & MEASUREMENTS:This 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. RESULTS:Of 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. CONCLUSIONS:Early 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.

Dataset Information

Mediation of the Effect of Glycemia on the Risk of CVD Outcomes in Type 1 Diabetes: The DCCT/EDIC Study.

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Mediation of the Effect of Glycemia on the Risk of CVD Outcomes in Type 1 Diabetes: The DCCT/EDIC Study.

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