No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
ABC goal achievement predicts microvascular but not macrovascular complications over 6-years in adults with type 1 diabetes: The Coronary Artery Calcification in Type 1 Diabetes Study
Abstract
Hypothesis
Vascular complications of type 1 diabetes are thought to cluster. We examined the prevalence and incidence of vascular complications and American Diabetes Association’s ABC goal achievements in a prospective cohort of adults with type 1 diabetes. We hypothesized that ABC achievement at baseline would predict both micro- and macrovascular complications over 6-years.
Methods
Participants (N = 652) were 19-56 year old at baseline and re-examined6-years later. Microvascular complications included diabetic nephropathy (DN), defined as incident albuminuria (AER ≥ 20 μg/min) or rapid GFR decline (> 3.3%/year) by CKD-EPI cystatin C and proliferative diabetic retinopathy (PDR), defined as laser eye-therapy. Macrovascular complications were defined as coronary artery calcium progression (CACp), measured by electron-beam computed-tomography. ABC goals were defined as HbA1c < 7.0%, BP < 130/80 mmHg, LDL-C < 100 mg/dL.
Results
ABC control was suboptimal with only 6% meeting all goals. Meeting no ABC goals at baseline compared to meeting all goals was associated with increased odds of developing microvascular complications (OR: 8.5, 2.3-31.5, p = 0.001), but did not reach significance for CACp (OR: 1.7, 0.8-3.9, p = 0.19).
Conclusion
ABC achievement at baseline strongly predicted microvascular but not macrovascular complications over 6-years in adults with type 1 diabetes, suggesting a need for novel therapeutic targets to complement conventional risk factors in treating macrovascular complications.
... In fact, most youth with type 1 diabetes in the T1D Exchange Clinic Registry did not meet the American Diabetes Association (ADA) and International Society for Pediatric and Adolescent Diabetes (ISPAD) targets for HbA1c, systolic and diastolic blood pressure (SBP/DBP), LDL-cholesterol (LDL-C), triglycerides (TG) and body mass index (BMI) (10). In adults with type 1 diabetes, suboptimal achievement of the ADA's ABC goals (HbA1c <7%, SBP/DBP <130/80 mmHg, LDL-C <100mg/dL) is strongly associated with microvascular complications, but not with macrovascular complications to the same degree (11,12). ...
... Contemporary cohorts of adolescents and adults with type 1 diabetes demonstrate suboptimal ADA and ADA/ISPAD goal achievements respectively (11,12). The ISPAD and ADA target achievements in our cohort is similar to what was reported in the T1D Exchange study for their [13][14][15][16][17][18][19][20] year age group with 21% of their participants meeting the HbA1c target, 78% meeting the BP target, 62% meeting the LDL-target, 94% meeting the HDL-C target, 89% meeting the TG target and 69% meeting the BMI target (10). ...
... Moreover, the benefits of intensive therapy persisted in the former adolescent cohort during the Epidemiology of Diabetes Interventions and Complications (EDIC) study: the previously intensively managed group had 48% less microalbuminuria and 85% less albuminuria (38). We have also previously reported an association between ABC control and vascular complications in adults with type 1 diabetes (12), but this is the first time it has been shown that attaining optimal targets for BP, lipids, BMI and HbA1c is associated with improved cardiorenal health both crosssectionally and longitudinally in adolescents. In addition, no studies to date have examined the associations between ISPAD/ADA target attainment and PWV, AIx and BrachD in adolescents with type 1 diabetes. ...
Objective:
Most youth with type 1 diabetes do not meet the American Diabetes Association (ADA) and International Society for Pediatric and Adolescent Diabetes (ISPAD) targets for hemoglobin A1c (HbA1c), blood pressure (BP), lipids, and body mass index (BMI). We hypothesized that ISPAD/ADA goal achievement at baseline would be associated with cardiorenal risk factors at baseline and 2 yr follow-up in adolescents with type 1 diabetes.
Methods:
We assessed the cross-sectional and longitudinal relationships between ISPAD/ADA goal achievement at baseline and cardiorenal health at baseline and 2-yr follow-up (n = 297; 15.4 ± 2.1 yr at baseline) in adolescents with type 1 diabetes. Goal achievement was defined as HbA1c < 7.5%, BP < 90th percentile for age, sex, and height, low density lipoprotein-cholesterol (LDL-C) <100 mg/dL, high density lipoprotein-cholesterol (HDL-C) >35 mg/dL, triglycerides (TG) <150 mg/dL and BMI <85th percentile for age and sex. Cardiorenal outcomes included pulse-wave velocity (PWV), brachial distensibility (BrachD), augmentation index (AIx), and epidermal growth factor receptor (eGFR) continuously and categorically as hyperfiltration (eGFR ≥ 135 mL/min/1.73 m(2)).
Results:
Adolescents with type 1 diabetes who met 1-3 goals, had significantly greater (P < 0.05) baseline PWV (5.1 ± 0.1 vs. 5.4 ± 0.1 m/s), follow-up PWV (5.5 ± 0.1 vs. 5.7 ± 0.1 m/s), greater follow-up eGFR (104 ± 2 vs. 116 ± 3 mL/min/1.73 m(2)), and greater odds of renal hyperfiltration at follow-up (odds ratio (OR): 20.0, 95% confidence interval (CI): 3.8-105.2) compared to those who met 4-6 goals after adjusting for Tanner stage, sex, age, and diabetes duration. No statistically significant differences in the cardiorenal outcomes were observed between adolescents with type 1 diabetes who met 4-6 goals and non-diabetic controls (n = 96).
Conclusions:
In adolescents with type 1 diabetes, baseline ADA/ISPAD goal achievement was associated with cardiorenal protection at baseline and 2-yr follow-up.
... Attainment of ≥ 3 treatment goals rather than structured care reduced end-stage renal disease and death. In the Coronary Artery Calcification in Type 1 Diabetes Study [25], 652 participants were 19 -56 years old at baseline and reexamined 6-years later. Microvascular complications included incident albuminuria or rapid GFR decline (> 3.3%/year) and laser eye-therapy. ...
... Macrovascular complications were defined as coronary artery calcium progression, measured by electronbeam computed-tomography. ABC achievement at baseline strongly predicted microvascular but not macrovascular complications over 6 years [25]. In the present study on type 2 diabetes patients with preserved kidney function, ABC achievement at baseline predicted deterioration of albuminuria and GFR stages over 6 years in a real-life situation. ...
Background:
We investigated cross-sectional and prospective associations of ABC (hemoglobin A1c (HbA1c), blood pressure and low-density lipoprotein cholesterol) goal attainment with chronic kidney disease. Cross-sectional association with carotid intima-media thickness (IMT) was evaluated as well.
Methods:
Prevalence of low estimated glomerular filtration rate (eGFR < 60 mL/min/1.73 m2) and albuminuria (urinary albumin-to-creatinine ratio (ACR) ≥ 30 mg/g) were assessed at baseline and after a median follow-up of 6.0 years in 168 patients with type 2 diabetes with preserved kidney function (aged 62.3 years, 53.6% men). Carotid IMT was measured at baseline only.
Results:
At baseline, 47 (28.0%), 45 (26.8%), 63 (37.5%) and 13 (7.7%) patients achieved triple-goal, dual-goal, single-goal and no-goal, respectively. Achieving more ABC targets was associated with lower log ACR (P < 0.01), lower percentage of albuminuria (P = 0.02), and lower carotid IMT (P < 0.01) at baseline. Over 6.0 years, eGFR decreased from 76 ± 16 to 67 ± 18 mL/min/1.73 m2 (P < 0.01) whereas ACR levels did not change. There were 32 patients with incident reduced eGFR, eight with GFR stage progression, 15 with progression of albuminuric stages and five with doubling of ACR within the microalbuminuric range. Achieving more ABC targets decreased the percentage of deterioration of GFR stages (30.8%, 28.6%, 24.4% and 14.9%, respectively, P = 0.01). Achieving two or more (8.9% and 8.5%, respectively) compared with one or less ABC targets (15.4% and 15.9%, respectively) was associated with less deterioration of albuminuria (P < 0.001). Although achieving more ABC targets was associated with lower annual decline in eGFR, the difference was not significant.
Conclusions:
ABC goal achievement has shown cross-sectional and prospective associations with deterioration of chronic kidney disease in type 2 diabetic patients with preserved kidney function. Cross-sectional association with carotid IMT has been demonstrated as well. Reaching more ABC treatment targets may be important for preventing adverse renal outcomes.
... For example, in the Diabetes Control and Complications Trial, intensive glycemic control was associated with a reduction in the risk of developing diabetic kidney disease (DKD), which is detected through routine monitoring of albumin excretion and estimated glomerular filtration rate (eGFR) annually [7][8][9]. Observational studies also support the link between glycemic control and microvascular complications, including DKD in T1D [10][11][12][13]. Unfortunately, DKD remains common in the setting of T1D, and increases the risk of cardiovascular disease (CVD) and end stage kidney disease [14][15][16]. ...
Objectives: Diabetic kidney disease (DKD) is an independent predictor of cardiovascular morbidity and mortality in type 1 diabetes (T1D). We aimed to explore clinical and biochemical factors, including the achievement of American Diabetes Association (ADA) recommended targets associated with DKD in people living with T1D for ≥50 years.
Methods: This was a post hoc analysis of a cross-sectional study of 75 participants enrolled in the Canadian Study of Longevity in T1D. We explored diabetes-related complications, including neuropathy, retinopathy, cardiovascular disease, and DKD. Study participants were dichotomized based on the achievement of ADA recommended targets as the low-target group (achieving ≤4 targets, n = 31) and high-target group (achieving >4 targets, n = 44). The outcome of interest was DKD defined by estimated glomerular filtration rate (eGFR) values <60/mL/min/1.73 m² and/or 24-h albumin excretion >30 mg. Multivariable logistic regression models were employed to estimate odds ratios (ORs) for DKD with 95% confidence intervals (CIs).
Results: Of the 75 participants with prolonged T1D duration (45% male, mean age 66 years), 25 participants had DKD and 50 did not. There was no statistical difference between the high- and low-target groups in terms of age and body mass index. eGFR was significantly higher and the prevalence of diabetic retinopathy was significantly lower in the high-target group. Older age at diagnosis of T1D and lower frequency component to high-frequency component ratio increased the odds of having DKD.
Conclusions: In adults with prolonged T1D duration, older age at diagnosis and lower heart rate variability may be associated with DKD.
... TEMD study also provided the first representative data about the triple metabolic control rates of patients with Type 1 diabetes in Turkey. To our knowledge, only one report from North America mentioned a 6% achievement rate of triple targets, which is very similar to the findings of the present survey [30]. ...
... The American Diabetes Association recommends that most adults with T1D should achieve an HbA1C b 7.0% (b53 mmol/mol), BP b130/ 80 mm Hg, and LDL-C b 100 mg/dL (Anonymous, 2016). We have previously reported that only 6% of adults with T1D in CACTI achieved all three ABC goals (Bjornstad, Maahs, Rewers, Johnson, & Snell-Bergeon, 2014), and not a single subject met the American Heart Association's 7 metrics for ideal cardiovascular health (ICH) (Alman, Maahs, Rewers, & Snell-Bergeon, 2014). The suboptimal ABC and ICH control may be reflective of unattainable goals for subjects with T1D or the lack of sufficiently effective strategies to achieve these goals. ...
Objective:
Reduced insulin sensitivity (IS) is well documented in type 1 diabetes (T1D) and may contribute to vascular complications. We examined the association of estimated IS (eIS) with incident macro- and microvascular complications in adults with T1D in the prospective CACTI study.
Methods:
Participants (N=652) were 19-56 years old at baseline and re-examined 6.2±0.6years later. Urinary albumin excretion was measured, and categorized as microalbuminuria or greater. Diabetic retinopathy (DR) was based on self-reported history, proliferative DR (PDR) as history of laser eye therapy and coronary artery calcium (CAC) was measured using electron-beam CT. Progression of CAC was defined as a change in the square root transformed CAC volume score of ≥2.5. IS was estimated (eIS) by an equation derived from clamp studies. Predictors of each complication were examined using stepwise logistic regression and subjects with complications at baseline excluded. Age, T1D duration, sex, HbA1c, SBP, LDL-C, and eIS were considered for inclusion.
Results:
Greater eIS at baseline predicted lower odds of developing albuminuria (OR: 0.67, 95% CI 0.51-0.88), DR (OR 0.79, 0.64-0.97), PDR (OR: 0.76, 0.57-0.99) and CACp (OR: 0.71, 0.60-0.85) in multivariable models.
Conclusions:
Greater eIS conferred protection from the development of vascular complications over 6-years in T1D.
Aims
To determine the degree patients with diabetic foot ulcers, Charcot neuroarthropathy and neuropathic fractures and dislocations fear complications (death, dialysis, heart attack, stroke, blindness, diabetic foot infection, minor and major lower extremity amputation [LEA]) that can occur and to assess if there is a difference between fears of patients with diabetic foot ulcers, Charcot neuroarthropathy and neuropathic fractures and dislocations and diabetic patients without these complications.
Methods
478 patients completed an eight question Likert scale survey. The study group was defined as non-infected foot ulcers, neuropathic fractures and Charcot neuroarthropathy.
Results
Of the 478 patients, 121 (25.3 %) had diabetic foot ulcers, Charcot neuroarthropathy or neuropathic fractures and dislocations and 357 (74.7 %) did not. The study group had significantly higher odds of reporting extreme fear of foot infection (OR 2.8, 95 % CI 1.8–4.5), major LEA (OR 2.8, 95 % CI 1.8–4.4), minor LEA (OR 2.3, 95 % CI 1.5–3.5), blindness (OR 2.0, 95 % CI 1.3–3.2), dialysis (OR 2.0, 95 % CI 1.1–3.3), and death (OR 2.4, 95 % CI 1.4–4.2). In the study group highest rated fear measures were foot infection (3.71, SD 1.23), minor amputation (3.67, SD 1.45) and major amputation (3.63, SD 1.52). There were no significant differences in the mean fear of infection, minor amputation or major amputation.
Conclusion
Patients with diabetic foot ulcers, Charcot neuroarthropathy or neuropathic fractures and dislocations reported higher fear ratings of diabetes-related complications compared to those without these complications.
Background and aim:
To study the association between achievement of guideline-defined treatment targets on HbA1c, low-density lipoproteins (LDL-C), and blood pressure with the progression of diabetic complications in patients with type 1 diabetes (T1D).
Methods:
The study included 355 patients at baseline and 114 patients with follow-up data after 3-5 years. Outcome variables were the progression of diabetic kidney disease, retinopathy, or cardiovascular disease (CVD). We used logistic regression and other machine learning algorithms (MLA) to model the association of achievement of treatment targets and probability of progression of complications.
Results:
Achievement of the target blood pressure was associated with 96% lower odds of a new CVD event (0.04 (95% CI 0.00, 0.53), p = 0.016), and 72% lower odds of progression of any complication (0.28 (95% CI 0.09, 0.89), p = 0.027. Achievement of HbA1c target was associated with lower odds of composite complication progression by 82% (0.18 (95% CI 0.04, 0.88), p = 0.034.) None of the patients who achieved HbA1c target progressed in CVD. MLA demonstrated good accuracy for the prediction of progression of CVD (AUC 0.824), and lower accuracy for other complications.
Conclusion:
The achievement of blood pressure and HbA1c treatment targets is associated with lower odds of vascular complication of T1D in a real life study.
Aims/hypothesis
We aimed to evaluate the effect of NAFLD on the risk of incident cardiovascular disease (CVD) and estimated glomerular filtration rate (eGFR)-based chronic kidney disease (CKD), and further test the joint effects and interactions between NAFLD status and individual metabolic element, as well as the total ‘ABCs’ metabolic goal achievement, on the CVD and CKD risk among 101,296 patients with prediabetes or diabetes from a prospective cohort study.
Methods
We conducted the study based on the China Cardiometabolic Disease and Cancer Cohort (4C) study, a large-scale, population-based prospective cohort. After excluding alcohol abuse and other cause of hepatic diseases, we used fatty liver index (FLI) ≥ 60 as a proxy of NAFLD and stratified the probability of fibrosis by aspartate transaminase / alanine transaminase ratio (AAR) with cut-offs of 0.8 and 1.4. ‘ABCs’ metabolic goal was defined as subjects who had HbA1c < 6.5% (A), SBP/DBP < 130/80 mmHg (B), and LDL-C < 100 mg/dL (C). During 3.8 years follow-up, we validated 2,340 CVD events based on medical records and identified 1,943 participants developed CKD based on centrally tested eGFR.
Results
The multivariable adjusted hazard ratios (HRs) were 1.15 (95% confidence interval (CI), 1.05-1.27) for CVD events and 1.33 (95% CI, 1.20-1.48) for CKD among NAFLD patients, compared with participants without NAFLD. Of NAFLD patients, relative to individuals with low AAR (< 0.8), those with high AAR (≥ 1.4) were more likely to experience CVD events [1.62 (1.21-2.18)] and CKD [1.63 (1.17-2.28)]. Participants with NAFLD and comorbid poorly controlled metabolic risk factors had higher risk of CVD events or CKD than having either alone, with a significant interaction between poor glycemic control and NAFLD on the risk of vascular complications.
Conclusions
NAFLD was associated with incident CVD and CKD among patients with prediabetes or diabetes. Such associations were substantially modified by the comprehensive achievement of metabolic goal.
The purpose of this study was to identify positive experiences associated with diabetes from the perspective of adults diagnosed with type 1 or type 2 diabetes. We conducted in-depth face-to-face and telephone interviews with adults with diabetes. Participants focused on positive and supportive experiences with their peers and community, improved health behaviors, personal growth, and engagement in diabetes advocacy. Communicating positive experiences about diabetes may help clinicians and educators reframe the negative messages commonly shared with people with diabetes.
Objective:
Most youth with type 1 diabetes do not meet the American Diabetes Association (ADA) and International Society for Pediatric and Adolescent Diabetes (ISPAD) targets for hemoglobin A1c (HbA1c), blood pressure (BP), lipids, and body mass index (BMI). We hypothesized that ISPAD/ADA goal achievement would be associated with better insulin sensitivity (IS) and cardiopulmonary fitness.
Methods:
IS was quantified as glucose infusion rate (GIR) from a hyperinsulinemic-euglycemic clamp in youth with type 1 diabetes from the RESistance to InSulin in Type 1 ANd Type 2 diabetes (RESISTANT) (n = 86) and Effects of MEtformin on CardiovasculaR Function in AdoLescents with Type 1 Diabetes (EMERALD) (n = 41) cohorts (n = 127; age 15.7 ± 2.2 years, 52% girls). Cardiopulmonary fitness was measured as peak oxygen consumption (VO2 peak/kg) during upright (RESISTANT) or supine (EMERALD) cycle ergometry and were stratified by cycle type. Goal achievement was defined as HbA1c < 7.5%, BP < 90th percentile, LDL-cholesterol < 100 mg/dL, HDL-cholesterol > 35 mg/dL, triglycerides < 150 mg/dL and BMI < 85th percentile. Participants were stratified into 3 groups: achieving 0-3 goals (n = 52), 4 goals (n = 48), and 5-6 goals (n = 27). Differences between groups were examined with generalized linear models.
Results:
IS was lower in youth who met 0-3 goals (5.2 ± 3.4 mg/kg/min) vs those who met 4 goals (7.4 ± 4.1 mg/kg/min, P = .04) and those who met 5-6 goals (8.5 ± 4.3 mg/kg/min, P = .003), and remained significant after adjustments for sex and diabetes duration. Upright VO2 peak was lower in youth who met 0-3 goals (25.8 ± 4.6 mL/kg/min) vs those who met 4 goals (33.0 ± 7.8 mL/kg/min, P = .01) and those who met 5-6 goals (33.2 ± 4.4 mL/kg/min, P = .004). Similar and significant relationships were observed in EMERALD participants for supine VO2 peak.
Conclusions:
ADA/ISPAD goal achievement was associated with greater IS and cardiopulmonary fitness.
Aims:
The aim was to systematically review published articles that reported the incidence of chronic kidney disease among people with diabetes.
Methods:
A systematic literature search was performed using MEDLINE, Embase and CINAHL databases. The titles and abstracts of all publications identified by the search were reviewed and 10 047 studies were retrieved.
Results:
A total of 71 studies from 30 different countries with sample sizes ranging from 505 to 211 132 met the inclusion criteria. The annual incidence of microalbuminuria and albuminuria ranged from 1.3% to 3.8% for Type 1 diabetes. For Type 2 diabetes and studies combining both diabetes types, the range was from 3.8% to 12.7%, with four of six studies reporting annual rates between 7.4% and 8.6%. In studies reporting the incidence of eGFR < 60 ml/min/1.73 m(2) using the Modification of Diet on Renal Disease (MDRD) equation, apart from one study which reported an annual incidence of 8.9%, the annual incidence ranged from 1.9% to 4.3%. The annual incidence of end-stage renal disease ranged from 0.04% to 1.8%.
Conclusions:
The annual incidence of microalbuminuria and albuminuria is ~ 2-3% in Type 1 diabetes, and ~ 8% in Type 2 diabetes or mixed diabetes type. The incidence of developing eGFR < 60 ml/min/1.73 m(2) is ~ 2-4% per year. Despite the wide variation in methods and study design, within a particular category of kidney disease, there was only modest variation in incidence rates. These findings may be useful in clinical settings to help understand the risk of developing kidney disease among those with diabetes. This article is protected by copyright. All rights reserved.
OBJECTIVE Diabetic nephropathy and cardiovascular disease are strongly related in adults with type 1 diabetes, yet little is known about this relationship in adolescents prior to the onset of detectable clinical disease. We hypothesized that cardiopulmonary fitness would be directly associated with albumin-to-creatinine ratio (ACR) and inversely related to estimated glomerular filtration rate (eGFR) in adolescents with type 1 diabetes.
RESEARCH DESIGN AND METHODS Sixty-nine adolescents with type 1 diabetes and 13 nondiabetic control subjects of similar pubertal stage and BMI had insulin sensitivity (glucose infusion rate [GIR]), measured by hyperinsulinemic-euglycemic clamp, and lean body mass, measured by DEXA. Cardiopulmonary fitness was measured by cycle ergometry to obtain peak volume of oxygen (VO2peak), and renal function was measured by eGFR using the Bouvet equation (measuring creatinine and cystatin C levels) and ACR.
RESULTS Adolescents (15.5 ± 2.2 years of age) with type 1 diabetes (6.3 ± 3.8 years diabetes duration) had reduced VO2peak (31.5 ± 6.3 vs. 36.2 ± 7.9 mL/kg ⋅ min, P = 0.046) and VO2peak/lean kg (43.7 ± 7.0 vs. 51.0 ± 8.6 mL/lean kg ⋅ min, P = 0.007) compared with nondiabetic control subjects. eGFR was inversely associated with VO2peak and VO2peak/lean kg after adjusting for sex, Tanner stage, GIR, HbA1c level, systolic blood pressure, and LDL cholesterol level (β ± SE, VO2peak: −0.19 ± 0.07, P = 0.02; VO2peak/lean kg: −0.19 ± 0.09, P = 0.048). Moreover, participants in the highest tertile for eGFR had significantly lower sex- and Tanner-adjusted VO2peak and VO2peak/lean kg compared with participants in the lowest tertile.
CONCLUSIONS Adolescents with type 1 diabetes had reduced exercise capacity, which was strongly associated with renal health, independent of insulin sensitivity. Future studies should examine the underlying interrelated pathophysiology in order to identify probable targets for treatment to reduce cardiovascular and renal complications.
Epidemiologic evidence supports a link between serum uric acid (SUA) and vascular complications in diabetes, but it remains unclear whether SUA improves the ability of conventional risk factor to predict complications. We hypothesized that SUA at baseline would independently predict the development of vascular complications over 6 years and that the addition of SUA to American Diabetes Association’s ABC risk factors (HbA1c, BP, LDL-C) would improve vascular complication prediction over 6 years in adults with type 1 diabetes. Study participants (N = 652) were 19–56 year old at baseline and re-examined 6 years later. Diabetic nephropathy was defined as incident albuminuria or rapid GFR decline (>3.3 %/year) estimated by the CKD-EPI cystatin C. Diabetic retinopathy (DR) was based on self-reported history, and proliferative diabetic retinopathy (PDR) was defined as laser eye therapy; coronary artery calcium (CAC) was measured using electron-beam computed tomography. Progression of CAC (CACp) was defined as a change in the square-root-transformed CAC volume ≥2.5. Predictors of each complication were examined in stepwise logistic regression with subjects with complications at baseline excluded from analyses. C-statistics, integrated discrimination indices and net-reclassification improvement were utilized for prediction performance analyses. SUA independently predicted development of incident albuminuria (OR 1.8, 95 % CI 1.2–2.7), rapid GFR decline (1.9, 1.1–3.3), DR (1.4, 1.1–1.9), PDR (2.1, 1.4–3.0) and CACp (1.5, 1.1–1.9). SUA improved the discrimination and net-classification risk of vascular complications over 6 years. SUA independently predicted the development of vascular complications in type 1 diabetes and also improved the reclassification of vascular complications.
Objective:
Diabetic nephropathy (DN) remains the most common cause of end-stage renal disease and is a major cause of mortality in type 2 diabetes. Insulin sensitivity is an important determinant of renal health in adults with type 2 diabetes, but limited data exist in adolescents. We hypothesized that measured insulin sensitivity (glucose infusion rate [GIR]) would be associated with early markers of DN reflected by estimated glomerular filtration rate (eGFR) and albumin-creatinine ratio (ACR) in adolescents with type 2 diabetes.
Research design and methods:
Type 2 diabetic (n = 46), obese (n = 29), and lean (n = 19) adolescents (15.1 ± 2.2 years) had GIR measured by hyperinsulinemic-euglycemic clamps. ACR was measured and GFR was estimated by the Bouvet equation (combined creatinine and cystatin C).
Results:
Adolescents with type 2 diabetes had significantly lower GIR, and higher eGFR and ACR than obese or lean adolescents. Moreover, 34% of type 2 diabetic adolescents had albuminuria (ACR ≥30 mg/g), and 24% had hyperfiltration (≥135 mL/min/1.73 m2). Stratifying ACR and eGFR into tertiles, adolescents with type 2 diabetes in the highest tertiles of ACR and eGFR had respectively lower GIR than those in the mid and low tertiles, after adjusting for age, sex, Tanner stage, BMI, and HbA1c (P = 0.02 and P = 0.04). GIR, but not HbA1c, LDL, or systolic blood pressure, was also associated with eGFR after adjusting for sex and Tanner stage (β ± SE: -2.23 ± 0.87; P = 0.02).
Conclusions:
A significant proportion of adolescents with type 2 diabetes showed evidence of early DN, and insulin sensitivity, rather than HbA1c, blood pressure, or lipid control, was the strongest determinant of renal health.
Objective
In 2010, the American Heart Association defined 7 metrics (smoking, body mass index, physical activity, diet, total cholesterol, blood pressure, and fasting plasma glucose) for ideal cardiovascular health (ICH). Subsequent studies have shown that the prevalence of achieving these metrics is very low in the general population. Adults with type 1 diabetes are at increased risk of cardiovascular disease, but no studies to date have been published on the prevalence of ICH in this population.Research Design and Methods
Data for this analysis were collected as part of the prospective Coronary Artery Calcification in Type 1 Diabetes (CACTI) Study. This analysis involved 546 subjects with type 1 diabetes and 631 subjects without diabetes who had complete information for calculating the ICH metrics.ResultsOverall, the prevalence of ICH was low in this population, with none meeting the ideal criteria for all 7 metrics. The prevalence of ideal physical activity (10.0%) and diet (1.1%) were particularly low. ICH was significantly associated with both decreased prevalence (OR 0.70; 95% CI 0.62-0.80) and progression (OR 0.77; 95% CI 0.66-0.90) of coronary artery calcification.ConclusionsICH is significantly associated with decreased prevalence and progression of coronary artery calcification, however, prevalence of ICH metrics was low in both adults with and without type 1 diabetes. Efforts to increase the prevalence of ICH could have a significant impact on reducing the burden of cardiovascular disease.
OBJECTIVE
Diabetic nephropathy (DN) is a major cause of mortality in type 1 diabetes. Reduced insulin sensitivity is a well-documented component of type 1 diabetes. We hypothesized that baseline insulin sensitivity would predict development of DN over 6 years.RESEARCH DESIGN AND METHODS
We assessed the relationship between insulin sensitivity at baseline and development of early phenotypes of DN-microalbuminuria (albumin-creatinine ratio [ACR] ≥30 mg/g) and rapid renal function decline (glomerular filtration rate [GFR] loss >3 mL/min/1.73 m(2) per year)-with three Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations over 6 years. Subjects with diabetes (n = 449) and without diabetes (n = 565) in the Coronary Artery Calcification in Type 1 Diabetes study had an estimated insulin sensitivity index (ISI) at baseline and 6-year follow-up.RESULTSThe ISI was lower in subjects with diabetes than in those without diabetes (P < 0.0001). A higher ISI at baseline predicted a lower odds of developing an ACR ≥30 mg/g (odds ratio 0.65 [95% CI 0.49-0.85], P = 0.003) univariately and after adjusting for HbA1c (0.69 [0.51-0.93], P = 0.01). A higher ISI at baseline conferred protection from a rapid decline of GFR as assessed by CKD-EPI cystatin C (0.77 [0.64-0.92], P = 0.004) and remained significant after adjusting for HbA1c and age (0.80 [0.67-0.97], P = 0.02). We found no relation between ISI and rapid GFR decline estimated by CKD-EPI creatinine (P = 0.38) or CKD-EPI combined cystatin C and creatinine (P = 0.50).CONCLUSIONS
Over 6 years, a higher ISI independently predicts a lower odds of developing microalbuminuria and rapid GFR decline as estimated with cystatin C, suggesting a relationship between insulin sensitivity and early phenotypes of DN.
OBJECTIVE
Progressive decrease in the glomerular filtration rate (GFR), or renal decline, in type 1 diabetes (T1D) is seen in patients with macroalbuminuria. However, it is unknown whether this decline begins during microalbuminuria (MA) or normoalbuminuria (NA).METHODS
The study group (2(nd) Joslin Kidney Study) comprises patients with T1D and NA (n=286) or MA (n=248) who were followed for 4-12 years (median 8 years). Serial measurements (median 6, range 3 to 16) of serum creatinine and cystatin C were used jointly to estimate GFR (eGFRcr-cys) and assess its trajectories during follow-up.RESULTSRenal decline (progressive eGFRcr-cys loss at least -3.3% per year) occurred in 10% of the NA and in 35% of the MA (p<0.001). In both groups, the strongest determinants of renal decline were baseline serum concentrations of uric acid (p<0.001) and a tumor necrosis factor receptor (TNFR1 or 2, p<0.001). Other significant risk factors included baseline HbA1c, age/diabetes duration and systolic blood pressure. Relative impacts of these determinants were similar in NA and MA. Renal decline was not associated with sex or baseline serum concentration of TNFa, IL-6, IL-8, IP-10, MCP-1, VCAM, ICAM, Fas or FasL.CONCLUSIONS
Renal decline in T1D begins during NA and it is determined by multiple factors, similar to MA. Thus, this early decline is the primary disease process leading to impaired renal function in T1D. Changes in AER, such as the onset of MA, or its progression to macroalbuminuria, are either caused by or develop in parallel to the early renal decline.
OBJECTIVE
To determine whether baseline estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR) independently predict coronary artery calcification (CAC) progression, and to determine how eGFR changes over 6 years in adults with type 1 diabetes compared with nondiabetic adults.RESEARCH DESIGN AND METHODS
The Coronary Artery Calcification in Type 1 Diabetes study participants (n = 1,066) with complete data for eGFR assessment at baseline and 6 years were included. Three Chronic Kidney Disease Epidemiology Collaboration equations (serum creatinine, cystatin C, and both) were used to estimate eGFR. The association of baseline ACR and eGFR with CAC progression was analyzed using multiple logistic regression.RESULTSIncreasing categorical baseline ACR (<10, 10-30, and >30 µg/mg) predicted CAC progression in participants with type 1 diabetes (odds ratio [OR], 2.15; 95% CI, 1.50-3.09; 7.19 [3.90-13.26]; and 18.09 [8.48-38.62]), respectively, compared with nondiabetic subjects. Baseline eGFR <60 mL/min/1.73 m(2) also predicted CAC progression (OR, 5-7, compared with nondiabetic participants). ORs for CAC progression were higher in women than in men when using the cystatin C-based Chronic Kidney Disease Epidemiology Collaboration equations. Participants with type 1 diabetes had greater eGFR decreases over 6 years than nondiabetic participants using cystatin C-based equations.CONCLUSIONS
Although increasing ACR or decreasing eGFR predicts CAC progression, coronary atherosclerosis progresses faster in people with type 1 diabetes even in the absence of diabetic kidney disease. These findings emphasize the interaction between kidney disease and cardiovascular disease in type 1 diabetes and highlight the public health importance of lowering cardiorenal risk in people with type 1 diabetes.
Aim/hypothesis:
Arginine vasopressin (AVP), the hormone important for maintaining fluid balance, has been shown to cause kidney damage in rodent models of diabetes. We investigated the potential role of AVP in the natural course of kidney function decline in diabetes in an epidemiological study.
Methods:
Plasma copeptin, a surrogate for AVP, was measured in baseline samples from patients with type 2 diabetes treated in primary care and included in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) cohort.
Results:
Samples from 1,328 patients were available; 349 were analysed separately because they used renin-angiotensin-aldosterone system inhibition (RAASi), which influences albumin/creatinine ratio (ACR) and estimated (e)GFR. In the other 979 patients (46% men, age 68 years [58-75], ACR 1.8 mg/mmol [0.9-5.7], eGFR 67 ± 14 ml min(-1) 1.73 m(-2)) baseline copeptin (5.3 pmol/l [3.2-9.5]) was significantly associated with log e [ACR] and eGFR, even after adjustment for sex, age and risk factors for kidney function decline (standardised [std] β 0.13, p < 0.001, std β -0.20, p < 0.001 respectively). Follow-up data were available for 756 patients (6.5 years [4.1-9.6]). Baseline copeptin was associated with increase in ACR (std β 0.09, p = 0.02), but lost significance after adjustment (std β 0.07, p = 0.08). Copeptin was associated with a decrease in eGFR after adjustment (std β -0.09, p = 0.03). The strength of the association of copeptin with change in eGFR was stronger than that of established risk factors for kidney function decline (e.g. BMI, HbA1c). In patients who used RAASi there was a significant association between baseline copeptin and ACR and eGFR, but not with change in ACR and eGFR.
Conclusions/interpretation:
In patients with diabetes not using RAASi a higher baseline copeptin concentration is significantly associated with higher baseline ACR and lower eGFR values and with a decline in eGFR during follow-up. This last association is independent of, and stronger than, most traditional risk factors for kidney function decline.
Context
Microalbuminuria is a risk factor for cardiovascular (CV) events. The
relationship between the degree of albuminuria and CV risk is unclear.Objectives
To estimate the risk of CV events in high-risk individuals with diabetes
mellitus (DM) and without DM who have microalbuminuria and to determine whether
levels of albuminuria below the microalbuminuria threshold increase CV risk.Design
The Heart Outcomes Prevention Evaluation study, a cohort study conducted
between 1994 and 1999 with a median 4.5 years of follow-up.Setting
Community and academic practices in North and South America and Europe.Participants
Individuals aged 55 years or more with a history of CV disease (n =
5545) or DM and at least 1 CV risk factor (n = 3498) and a baseline urine
albumin/creatinine ratio (ACR) measurement.Main Outcome Measures
Cardiovascular events (myocardial infarction, stroke, or CV death);
all-cause death; and hospitalization for congestive heart failure.Results
Microalbuminuria was detected in 1140 (32.6%) of those with DM and 823
(14.8%) of those without DM at baseline. Microalbuminuria increased the adjusted
relative risk (RR) of major CV events (RR, 1.83; 95% confidence interval [CI],
1.64-2.05), all-cause death (RR, 2.09; 95% CI, 1.84-2.38), and hospitalization
for congestive heart failure (RR, 3.23; 95% CI, 2.54-4.10). Similar RRs were
seen for participants with or without DM, even after adjusting for other CV
risk factors (eg, the adjusted RR of the primary aggregate end point was 1.97
[95% CI, 1.68-2.31] in those with DM and 1.61 [95% CI, 1.36-1.90] in those
without DM).Compared with the lowest quartile of ACR (<0.22 mg/mmol), the
RRs of the primary aggregate end point in the second quartile (ie, ACR range,
0.22-0.57 mg/mmol) was 1.11 (95% CI, 0.95-1.30); third quartile, 1.38 (95%
CI, 1.19-1.60; ACR range, 0.58-1.62 mg/mmol); and fourth quartile, 1.97 (95%
CI, 1.73-2.25; ACR range, >1.62 mg/mmol) (P for trend
<.001, even after excluding those with microalbuminuria). For every 0.4-mg/mmol
increase in ACR level, the adjusted hazard of major CV events increased by
5.9% (95% CI, 4.9%-7.0%).Conclusions
Our results indicate that any degree of albuminuria is a risk factor
for CV events in individuals with or without DM; the risk increases with the
ACR, starting well below the microalbuminuria cutoff. Screening for albuminuria
identifies people at high risk for CV events.
Figures in this Article
Diabetes mellitus (DM) is a strong risk factor for cardiovascular (CV)
disease.1 Compared with those who do not have
DM, people with DM have a 2- to 4-fold increased risk of subsequent CV disease.2- 4 Risk factors that independently
increase CV risk in people with DM include smoking, hypertension, dyslipidemia,3 renal dysfunction,5
and hyperglycemia.6- 10
Recently, data from several studies have established microalbuminuria (MA),
or dipstick-negative albuminuria, as another CV risk factor. Microalbuminuria
is reported in approximately 30% of middle-aged patients with either type
1 or type 2 DM and in approximately 10% to 15% of middle-aged individuals
who do not have DM.11- 13
Although MA is associated with other risk factors in those with or without
DM,11,13- 14 it is
also an independent predictor of future strokes, death, and myocardial infarction
(MI).15- 19
Moreover, MA may also predict future congestive heart failure (CHF). However,
at present, there are few prospective data regarding this association.20- 23
Despite being increasingly recognized as a CV risk factor, the definition
of MA was based on its ability to predict diabetic nephropathy (ie, macroalbuminuria
or clinical proteinuria). Whether individuals with albumin excretion rates
below the MA threshold are also at risk for CV disease or whether there is
a progressive graded relationship between different degrees of albuminuria
and CV events is unclear.
Our study examines the relationship between baseline albuminuria levels
and future CV events using data collected from individuals with or without
DM enrolled in the Heart Outcomes Prevention Evaluation (HOPE) Study. Participants
were followed-up for a median of 4.5 years
OBJECTIVE
To determine the prevalence of people with diabetes who meet hemoglobin A(1c) (A1C), blood pressure (BP), and LDL cholesterol (ABC) recommendations, and their current statin use, factors associated with goal achievement, and changes in the proportion achieving goals between 1988 and 2010.RESEARCH AND DESIGN METHODS
Data were cross-sectional from the National Health and Nutrition Examination Surveys (NHANES) from 1988-1994, 1999-2002, 2003-2006, and 2007-2010. Participants were 4,926 adults aged ≥20 years who self-reported a previous diagnosis of diabetes and completed the household interview and physical examination (n = 1,558 for valid LDL levels). Main outcome measures were A1C, BP, and LDL cholesterol, in accordance with the American Diabetes Association recommendations, and current use of statins.RESULTSIn 2007-2010, 52.5% of people with diabetes achieved A1C <7.0% (<53 mmol/mol), 51.1% achieved BP <130/80 mmHg, 56.2% achieved LDL <100 mg/dL, and 18.8% achieved all three ABCs. These levels of control were significant improvements from 1988 to 1994 (all P < 0.05). Statin use significantly increased between 1988-1994 (4.2%) and 2007-2010 (51.4%, P < 0.01). Compared with non-Hispanic whites, Mexican Americans were less likely to meet A1C and LDL goals (P < 0.03), and non-Hispanic blacks were less likely to meet BP and LDL goals (P < 0.02). Compared with non-Hispanic blacks, Mexican Americans were less likely to meet A1C goals (P < 0.01). Younger individuals were less likely to meet A1C and LDL goals.CONCLUSIONS
Despite significant improvement during the past decade, achieving the ABC goals remains suboptimal among adults with diabetes, particularly in some minority groups. Substantial opportunity exists to further improve diabetes control and, thus, to reduce diabetes-related morbidity and mortality.
We aimed to describe the prevalence of retinopathy in an aged cohort of Icelanders with and without diabetes mellitus.
The study population consisted of 4,994 persons aged ≥ 67 years, who participated in the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-R). Type 2 diabetes mellitus was defined as HbA(1c) ≥ 6.5% (>48 mmol/mol). Retinopathy was assessed by grading fundus photographs using the modified Airlie House adaptation of the Early Treatment Diabetic Retinopathy Study protocol. Associations between retinopathy and risk factors were estimated using odds ratios obtained from multivariate analyses.
The overall prevalence of retinopathy in AGES-R was 12.4%. Diabetes mellitus was present in 516 persons (10.3%), for 512 of whom gradable fundus photos were available, including 138 persons (27.0%, 95% CI 23.2, 31.0) with any retinopathy. Five persons (1.0%, 95% CI 0.3, 2.3) had proliferative retinopathy. Clinically significant macular oedema was present in five persons (1.0%, 95% CI 0.3, 2.3). Independent risk factors for retinopathy in diabetic patients in a multivariate model included HbA(1c), insulin use and use of oral hypoglycaemic agents, the last two being indicators of longer disease duration. In 4478 participants without diabetes mellitus, gradable fundus photos were available for 4,453 participants, with retinopathy present in 476 (10.7%, 95% CI 9.8, 11.6) and clinically significant macular oedema in three persons. Independent risk factors included increasing age and microalbuminuria.
Over three-quarters (78%) of retinopathy cases were found in persons without diabetes and a strong association between microalbuminuria and non-diabetic retinopathy was found. These results may have implications for patient management of the aged.
Cystatin C is used increasingly as a biomarker of renal function; however, cystatin C assays are not standardized. Our objective was to compare cystatin C results within the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study over time and in repeated measures to evaluate for assay drift.
Serum samples were obtained at baseline (visit 1 [V1], 2000 to 2002) and follow-up (visit 2 [V2], 2003 to 2005; visit 3 [V3], 2006 to 2008) and were assayed in 2006 (V1), 2007 to 2008 (V2), and 2010 (V3) in the same laboratory.
Mean cystatin C levels measured using the Dade-Behring assay decreased over time in subjects, with measures at all three visits (V1: 0.80 ± 0.19 [0.42 to 3.41], V2: 0.75 ± 0.22 [0.39 to 3.77], and V3: 0.69 ± 0.22 [0.39 to 3.79]). Cystatin C values were lower in V1 and V2 samples remeasured in 2010 (mean differences -0.13 ± 0.04 and -0.08 ± 0.04, P < 0.0001 for both). Correlations for original and re-run values were strong for V1 (r = 0.99) and V2 (r = 0.99). Deming regression equations and Bland-Altman plots suggest a systematic shift in the values over time.
Systematic shifts in cystatin C levels, which can be corrected by regression adjustment, occurred in our laboratory in samples measured in 2006 and 2007 to 2008 as compared with 2010. Assay standardization and measurement reliability for cystatin C must be addressed.
Soft-tissue calcification is a prominent feature in both chronic kidney disease (CKD) and experimental Klotho deficiency, but whether Klotho deficiency is responsible for the calcification in CKD is unknown. Here, wild-type mice with CKD had very low renal, plasma, and urinary levels of Klotho. In humans, we observed a graded reduction in urinary Klotho starting at an early stage of CKD and progressing with loss of renal function. Despite induction of CKD, transgenic mice that overexpressed Klotho had preserved levels of Klotho, enhanced phosphaturia, better renal function, and much less calcification compared with wild-type mice with CKD. Conversely, Klotho-haploinsufficient mice with CKD had undetectable levels of Klotho, worse renal function, and severe calcification. The beneficial effect of Klotho on vascular calcification was a result of more than its effect on renal function and phosphatemia, suggesting a direct effect of Klotho on the vasculature. In vitro, Klotho suppressed Na(+)-dependent uptake of phosphate and mineralization induced by high phosphate and preserved differentiation in vascular smooth muscle cells. In summary, Klotho is an early biomarker for CKD, and Klotho deficiency contributes to soft-tissue calcification in CKD. Klotho ameliorates vascular calcification by enhancing phosphaturia, preserving glomerular filtration, and directly inhibiting phosphate uptake by vascular smooth muscle. Replacement of Klotho may have therapeutic potential for CKD.
To assess insulin action on peripheral glucose utilization and nonesterified fatty acid (NEFA) suppression as a predictor of coronary artery calcification (CAC) in patients with type 1 diabetes and nondiabetic controls.
Insulin action was measured by a three-stage hyperinsulinemic-euglycemic clamp (4, 8, and 40 mU/m²/min) in 87 subjects from the Coronary Artery Calcification in Type 1 Diabetes cohort (40 diabetic, 47 nondiabetic; mean age 45 ± 8 years; 55% female).
Peripheral glucose utilization was lower in subjects with type 1 diabetes compared with nondiabetic controls: glucose infusion rate (mg/kg FFM/min) = 6.19 ± 0.72 vs. 12.71 ± 0.66, mean ± SE, P < 0.0001, after adjustment for age, sex, BMI, fasting glucose, and final clamp glucose and insulin. Insulin-induced NEFA suppression was also lower in type 1 diabetic compared with nondiabetic subjects: NEFA levels (μM) during 8 mU/m²/min insulin infusion = 370 ± 27 vs. 185 ± 25, P < 0.0001, after adjustment for age, sex, BMI, fasting glucose, and time point insulin. Lower glucose utilization and higher NEFA levels, correlated with CAC volume (r = -0.42, P < 0.0001 and r = 0.41, P < 0.0001, respectively) and predicted the presence of CAC (odds ratio [OR] = 0.45, 95% CI = 0.22-0.93, P = 0.03; OR = 2.4, 95% CI = 1.08-5.32, P = 0.032, respectively). Insulin resistance did not correlate with GHb or continuous glucose monitoring parameters.
Type 1 diabetic patients are insulin resistant compared with nondiabetic subjects, and the degree of resistance is not related to current glycemic control. Insulin resistance predicts the extent of coronary artery calcification and may contribute to the increased risk of cardiovascular disease in patients with type 1 diabetes as well as subjects without diabetes.
The FinnDiane Study has reported that mortality in type 1 diabetes is not increased over a 7 year follow-up in the absence of renal disease (RD). Using the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study population (n = 658) of childhood-onset type 1 diabetes (age <17 years), the present study sought to replicate and expand these findings to a 20 year follow-up (as of 1 January 2008) and examine cause of death by renal status.
At baseline (1986-1988), mean age and duration of diabetes were 28 and 19 years, respectively. RD was defined as an albumin excretion rate ≥20 μg/min from multiple samples and grouped as microalbuminuria (MA; 20-200 μg/min), overt nephropathy (ON; >200 μg/min), or end stage renal disease (ESRD; dialysis or renal transplantation).
At baseline, 311 (47.3%) individuals had RD (MA 21.3%, ON 22.2% and ESRD 3.8%). During a median 20 year follow-up, there were 152 deaths (23.1%). Mortality was 6.2 (95% CI 5.2-7.2) times higher than expected, with standardised mortality ratios of 2.0 (1.2-2.8) for normoalbuminuria (NA); 6.4 (4.4-8.4) for MA; 12.5 (9.5-15.4) for ON; and 29.8 (16.8-42.9) for ESRD. Excluding those (n = 64) with NA who later progressed to RD, no significant excess mortality was observed in the remaining NA group (1.2, 0.5-1.9), whose deaths were largely unrelated to diabetes.
These data confirm the importance of RD, including persistent microalbuminuria, as a marker of mortality risk and suggest that type 1 diabetes patients without renal disease achieve long-term survival comparable to the general population.
The purpose of this study was to examine prospectively whether renal hyperfiltration is associated with the development of microalbuminuria in patients with type 1 diabetes, after taking into account known risk factors.
The study group comprised 426 participants with normoalbuminuria from the First Joslin Kidney Study, followed for 15 years. Glomerular filtration rate was estimated by serum cystatin C, and hyperfiltration was defined as exceeding the 97.5th percentile of the sex-specific distribution of a similarly aged, nondiabetic population (134 and 149 ml/min per 1.73 m(2) for men and women, respectively). The outcome was time to microalbuminuria development (multiple albumin excretion rate >30 microg/min). Hazard ratios (HRs) for microalbuminuria were calculated at 5, 10, and 15 years.
Renal hyperfiltration was present in 24% of the study group and did not increase the risk of developing microalbuminuria. The unadjusted HR for microalbuminuria comparing those with and without hyperfiltration at baseline was 0.8 (95% CI 0.4-1.7) during the first 5 years, 1.0 (0.6-1.7) during the first 10 years, and 0.8 (0.5-1.4) during 15 years of follow-up. The model adjusted for baseline known risk factors including A1C, age at diagnosis of diabetes, diabetes duration, and cigarette smoking resulted in similar HRs. In addition, incorporating changes in hyperfiltration status during follow-up had minimal impact on the HRs for microalbuminuria.
Renal hyperfiltration does not have an impact on the development of microalbuminuria in type 1 diabetes during 5, 10, or 15 years of follow-up.
Microalbuminuria is a risk factor for cardiovascular (CV) events. The relationship between the degree of albuminuria and CV risk is unclear.
To estimate the risk of CV events in high-risk individuals with diabetes mellitus (DM) and without DM who have microalbuminuria and to determine whether levels of albuminuria below the microalbuminuria threshold increase CV risk.
The Heart Outcomes Prevention Evaluation study, a cohort study conducted between 1994 and 1999 with a median 4.5 years of follow-up.
Community and academic practices in North and South America and Europe.
Individuals aged 55 years or more with a history of CV disease (n = 5545) or DM and at least 1 CV risk factor (n = 3498) and a baseline urine albumin/creatinine ratio (ACR) measurement.
Cardiovascular events (myocardial infarction, stroke, or CV death); all-cause death; and hospitalization for congestive heart failure.
Microalbuminuria was detected in 1140 (32.6%) of those with DM and 823 (14.8%) of those without DM at baseline. Microalbuminuria increased the adjusted relative risk (RR) of major CV events (RR, 1.83; 95% confidence interval [CI], 1.64-2.05), all-cause death (RR, 2.09; 95% CI, 1.84-2.38), and hospitalization for congestive heart failure (RR, 3.23; 95% CI, 2.54-4.10). Similar RRs were seen for participants with or without DM, even after adjusting for other CV risk factors (eg, the adjusted RR of the primary aggregate end point was 1.97 [95% CI, 1.68-2.31] in those with DM and 1.61 [95% CI, 1.36-1.90] in those without DM). Compared with the lowest quartile of ACR (<0.22 mg/mmol), the RRs of the primary aggregate end point in the second quartile (ie, ACR range, 0.22-0.57 mg/mmol) was 1.11 (95% CI, 0.95-1.30); third quartile, 1.38 (95% CI, 1.19-1.60; ACR range, 0.58-1.62 mg/mmol); and fourth quartile, 1.97 (95% CI, 1.73-2.25; ACR range, >1.62 mg/mmol) (P for trend <.001, even after excluding those with microalbuminuria). For every 0.4-mg/mmol increase in ACR level, the adjusted hazard of major CV events increased by 5.9% (95% CI, 4.9%-7.0%).
Our results indicate that any degree of albuminuria is a risk factor for CV events in individuals with or without DM; the risk increases with the ACR, starting well below the microalbuminuria cutoff. Screening for albuminuria identifies people at high risk for CV events.
To describe the association of retinopathy with atherosclerosis and atherosclerotic risk factors in people with diabetes.
296 of the 558 people classified as having diabetes by the American Diabetes Association criteria, from a population based cohort of adults (ranging in age from 69 to 102 years) living in four United States communities (Allegheny County, Pennsylvania; Forsyth County, North Carolina; Sacramento County, California; and Washington County, Maryland) were studied from 1997 to 1998. Lesions typical of diabetic retinopathy were determined by grading a 45 degrees colour fundus photograph of one eye of each participant, using a modification of the Airlie House classification system.
Retinopathy was present in 20% of the diabetic cohort, with the lowest prevalence (16%), in those 80 years of age or older. Retinopathy was detected in 20.3% of the 296 people with diabetes; 2.7% of the 296 had signs of proliferative retinopathy and 2.1% had signs of macular oedema. The prevalence of diabetic retinopathy was higher in black people (35.4%) than white (16.0%). Controlling for age, sex, and blood glucose, retinopathy was more frequent in black people than white (odds ratio (OR) 2.26, 95% confidence interval (CI) 1.01, 5.05), in those with longer duration of diabetes (OR (per 5 years of diabetes) 1.42, 95% CI 1.18, 1.70), in those with subclinical cardiovascular disease (OR 1.49, 95% CI 0.51, 4.31), or coronary heart disease or stroke (OR 3.23, 95% CI 1.09, 9.56) than those without those diseases, in those with higher plasma low density lipoprotein (LDL) cholesterol (OR (per 10 mg/dl of LDL cholesterol) 1.12, 95% CI 1.02, 1.23), and in those with gross proteinuria (OR 4.76, 95% CI 1.53, 14.86).
Data from this population based study suggest a higher prevalence of retinopathy in black people than white people with diabetes and the association of cardiovascular disease, elevated plasma LDL cholesterol, and gross proteinuria with diabetic retinopathy. However, any conclusions or explanations regarding associations described here must be made with caution because only about one half of those with diabetes mellitus were evaluated.
To develop risk-adjusted multivariable models that included risk factors and coronary calcium scores determined with electron-beam computed tomography (CT) in asymptomatic patients for the prediction of all-cause mortality.
We followed up a cohort of 10,377 asymptomatic individuals undergoing cardiac risk factor evaluation and coronary calcium screening with electron-beam CT. Multivariable Cox proportional hazards models were developed to predict all-cause mortality. Risk-adjusted models incorporated traditional risk factors for coronary disease and coronary calcium scores.
Cardiac risk factors such as family history of coronary disease (69%), hypercholesterolemia (62%), hypertension (44%), smoking (40%), and diabetes (9%) were prevalent. The frequency of coronary calcium scores was 57%, 20%, 14%, 6%, and 3% for scores of 10 or less, 11-100, 101-400, 401-1,000, and greater than 1,000, respectively. During a mean follow-up of 5.0 years +/- 0.0086 (standard error of the mean), the death rate was 2.4%. In a risk-adjusted model (model chi2 = 388.2, P <.001), coronary calcium was an independent predictor of mortality (P <.001). Risk-adjusted relative risk values for coronary calcium were 1.64, 1.74, 2.54, and 4.03 for scores of 11-100, 101-400, 401-1,000, and greater than 1,000, respectively (P <.001 for all values), as compared with that for a score of 10 or less. Five-year risk-adjusted survival was 99.0% for a calcium score of 10 or less and 95.0% for a score of greater than 1,000 (P <.001). With a receiver operating characteristic curve, the concordance index increased from 0.72 for cardiac risk factors alone to 0.78 (P <.001) when the calcium score was added to a multivariable model for prediction of death.
This large observational data series shows that coronary calcium provides independent incremental information in addition to traditional risk factors in the prediction of all-cause mortality.
Coronary artery disease (CAD) occurs earlier in life and is more often fatal in people with type 1 diabetes. This excess risk seems to be higher than in those with type 2 diabetes and is poorly explained by conventional risk factors. The role of glycemic control is controversial and has not been previously addressed in a prospective manner using a reliable marker for subclinical CAD, such as coronary artery calcification (CAC), measured by electron beam computed tomography (EBCT).
We measured CAC twice during an interval of 2.7 years in 109 men and women with type 1 diabetes (aged 22-50 years). Progression of CAC was found in 21 patients, based on change in the square root-transformed volume score.
In multiple logistic regression, CAC progression was associated with baseline hyperglycemia (odds ratio [OR] 7.11, 95% CI 1.38-36.6, P = 0.02), adjusted for the presence of CAC at baseline (P = 0.01), duration of diabetes (P = 0.02), sex (P = 0.09), and age (P = 0.27). There was also a significant interactive effect of higher insulin dose and higher BMI (P = 0.03).
In conclusion, in this young cohort with type 1 diabetes, suboptimal glycemic control (HbA(1c) >7.5%) was a strong risk factor for progression of CAC. Insulin resistance may also play a role.
To compare the prevalence, awareness, treatment, and control of hypertension in a population-representative sample of adults with type 1 diabetes and comparable nondiabetic control subjects.
In 2000-2002, the Coronary Artery Calcification in Type 1 Diabetes Study enrolled 1,416 individuals aged 19-56 years with no known history of coronary artery disease: 652 type 1 diabetic patients (46% male, mean age 37 years) and 764 nondiabetic control subjects (50% male, mean age 39 years). Subjects were asked if they had been told by a physician that they had hypertension or were on a blood pressure medication. Blood pressure was measured using standardized Joint National Committee (JNC) protocol.
Type 1 diabetic subjects, compared with nondiabetic subjects, had higher rates of hypertension prevalence (43 vs. 15%, P < 0.001), awareness (53 vs. 45%, P = 0.11), treatment (87 vs. 47%, P < 0.001), and control (55 vs. 32%, P < 0.001) for the JNC 6 goal (130/85 mmHg). Only 42% of all type 1 diabetic hypertensive subjects met the new JNC 7 goal (130/80 mmHg). Type 1 diabetic subjects had better blood pressure control (72 vs. 32%, P < 0.0001), using 140/90 mmHg as a common measure. The majority of treated subjects were on a single antihypertensive agent (75 vs. 64%).
Subjects with type 1 diabetes have higher rates of hypertension prevalence, treatment, and control than nondiabetic subjects. However, hypertension remains largely uncontrolled, even if treated in high-risk populations, such as type 1 diabetic subjects and undiagnosed individuals in the general population. Achieving more stringent blood pressure goals will require increased attention and may necessitate the use of multiple antihypertensive agents.
To study the relationship of nonproliferative and proliferative retinopathy with all-cause mortality and cardiovascular disease (CVD) incidence in type 1 diabetic patients and, additionally, the role of cardiovascular risk factors in these associations.
This prospective study included 2,237 type 1 diabetic patients from 31 centers in 16 European countries at baseline, aged 15-60 years, who were examined for retinopathy by taking two-field 45 degrees fundus photographs, which were centrally graded. Mortality and cardiovascular morbidity follow-up was assessed 6-8 years after baseline examination according to a standardized protocol.
After 7.9 years of follow-up, 64 patients had died and 128 patients had incident CVD. The age- and sex-adjusted hazard ratios (HRs) of all-cause mortality were 1.45 (95% CI 0.71-2.96) and 4.16 (1.96-8.84) in patients with nonproliferative and proliferative retinopathy at baseline, respectively. Adjustments for cardiovascular risk factors completely obliterated the association with nonproliferative retinopathy, whereas the association with proliferative retinopathy remained twofold increased, although nonsignificant. The age- and sex-adjusted HRs of incident CVD were 1.73 (1.15-2.60) and 2.05 (1.22-3.45) in patients with nonproliferative and proliferative retinopathy, respectively. After adjustments for cardiovascular risk factors, both associations were attenuated and lost statistical significance.
This study shows that type 1 diabetic patients with nonproliferative or proliferative retinopathy have an increased risk for all-cause mortality and incident CVD. The presence of cardiovascular risk factors explained the associations to a large extent, except for the associations with proliferative retinopathy, which suggests that other shared mechanisms may be involved.
AimTo test the hypothesis that greater baseline insulin sensitivity would predict regression of albuminuria over 6 years in adults with Type 1 diabetes.Method
We enrolled 81 people aged 30–48 years with albuminuria at baseline in the present study and re-examined them 6 years later. Urinary albumin excretion rate was measured and albuminuria was defined as urinary albumin excretion rate ≥20 μg/min. Regression of albuminuria was defined as normoalbuminuria (urinary albumin excretion rate <20μg/min) at follow-up. Predictors of regression of albuminuria were examined in stepwise logistic regression. The variables age, diabetes duration, sex, serum uric acid, HbA1c, systolic blood pressure, LDL cholesterol, HDL cholesterol, BMI, baseline albumin excretion rate, estimated insulin sensitivity at baseline, change in estimated insulin sensitivity from baseline to follow-up and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were considered for inclusion in the model.ResultsEstimated insulin sensitivity was significantly higher at both baseline (4.6±1.2 vs 3.4±1.7; P=0.002) and follow-up (5.2±1.9 vs. 3.5±1.7; P<0.0001) in people who had regression of albuminuria vs those who did not. HbA1c (odds ratio 0.4, 95% CI 0.2–0.8; P=0.006), estimated insulin sensitivity (odds ratio 2.5, 95% CI 1.3–4.9; P=0.006) at baseline and change in estimated insulin sensitivity from baseline to follow-up (odds ratio 2.7, 95% CI 1.4–5.3; P=0.003) were independently associated with regression of albuminuria in a multivariable stepwise model.Conclusions
In conclusion, over 6 years, higher baseline estimated insulin sensitivity and change in estimated insulin sensitivity independently predicted regression of albuminuria. Improving insulin sensitivity in people with Type 1 diabetes is a potential therapeutic target to increase rates of regression of albuminuria.This article is protected by copyright. All rights reserved.
Purpose of review:
Despite improvements in glycemic and blood pressure control in patients with type 1 diabetes, diabetic nephropathy remains the most common cause of chronic kidney disease worldwide. A major challenge in preventing diabetic nephropathy is the inability to identify high-risk patients at an early stage, emphasizing the importance of discovering new therapeutic targets and implementation of clinical trials to reduce diabetic nephropathy risk.
Recent findings:
Limitations of managing patients with diabetic nephropathy with renin-angiotensin-aldosterone system blockade have been identified in recent clinical trials, including the failure of primary prevention studies in T1D and the demonstration of harm with dual renin-angiotensin-aldosterone system blockade. Fortunately, several new targets, including serum uric acid, insulin sensitivity, vasopressin, and sodium-glucose cotransporter-2 inhibition, are promising in the prevention and treatment of diabetic nephropathy.
Summary:
Diabetic nephropathy is characterized by a long clinically silent period without signs or symptoms of disease. There is an urgent need for improved methods of detecting early mediators of renal injury, to ultimately prevent the initiation and progression of diabetic nephropathy. In this review, we will focus on early diabetic nephropathy and summarize potential new therapeutic targets.
Epidemiologic evidence supports a link between serum uric acid (SUA) and vascular complications in diabetes, but it remains unclear whether SUA improves the ability of conventional risk factor to predict complications. We hypothesized that SUA at baseline would independently predict the development of vascular complications over 6 years and that the addition of SUA to American Diabetes Association’s ABC risk factors (HbA1c, BP, LDL-C) would improve vascular complication prediction over 6 years in adults with type 1 diabetes. Study participants (N = 652) were 19–56 year old at baseline and re-examined 6 years later. Diabetic nephropathy was defined as incident albuminuria or rapid GFR decline (>3.3 %/year) estimated by the CKD-EPI cystatin C. Diabetic retinopathy (DR) was based on self-reported history, and proliferative diabetic retinopathy (PDR) was defined as laser eye therapy; coronary artery calcium (CAC) was measured using electron-beam computed tomography. Progression of CAC (CACp) was defined as a change in the square-root-transformed CAC volume ≥2.5. Predictors of each complication were examined in stepwise logistic regression with subjects with complications at baseline excluded from analyses. C-statistics, integrated discrimination indices and net-reclassification improvement were utilized for prediction performance analyses. SUA independently predicted development of incident albuminuria (OR 1.8, 95 % CI 1.2–2.7), rapid GFR decline (1.9, 1.1–3.3), DR (1.4, 1.1–1.9), PDR (2.1, 1.4–3.0) and CACp (1.5, 1.1–1.9). SUA improved the discrimination and net-classification risk of vascular complications over 6 years. SUA independently predicted the development of vascular complications in type 1 diabetes and also improved the reclassification of vascular complications.
Cardiovascular disease (CVD) is the primary cause of mortality in patients with type 1 diabetes (T1D). Despite advances in the management of microvascular complications of T1D, there is a lack of similar progress in reduction of macrovascular complications. Dyslipidemia is one of the major contributory factors for macrovascular complications in T1D, but the literature suggests significant under-treatment of this risk factor in children and adolescents with diabetes. Statins have shown to be both effective and safe in young people with familial hypercholesterolemia and adults with diabetes mellitus, but the role for statins in children and adolescent with T1D remains unclear and controversial. In this review, we will summarize the risks and benefits of statin use in young people with T1D.
Hypothesis
Decreased insulin sensitivity (IS) exists in type 1 diabetes. Serum uric acid (SUA), whose concentration is related to renal clearance, predicts vascular complications in type 1 diabetes. SUA is also inversely associated with IS in non-diabetics, but has not been examined in type 1 diabetes. We hypothesized SUA would be associated with reduced IS in adolescents and adults with type 1 diabetes.
Methods
The cross-sectional and longitudinal associations of SUA with IS was investigated in 254 adolescents with type 1 diabetes and 70 without in the Determinants of Macrovascular Disease in Adolescents with Type 1 Diabetes Study, and in 471 adults with type 1 diabetes and 571 without in the Coronary Artery Calcification in Type 1 diabetes (CACTI) study.
Results
SUA was lower in subjects with type 1 diabetes (p < 0.0001), but still remained inversely associated with IS after multivariable adjustments- in adolescents (β ± SE:-1.99 ± 0.62, p = 0.001, R2 = 2%) and adults (β ± SE:-0.91 ± 0.33, p = 0.006, R2 = 6%) with type 1 diabetes, though less strongly than in non-diabetic controls (adolescents: β ± SE:-2.70 ± 1.19, p = 0.03, R2 = 15%, adults: β ± SE:-5.99 ± 0.75, p < 0.0001, R2 = 39%).
Conclusion
We demonstrated a significantly weaker relationship between SUA and reduced IS in subjects with type 1 diabetes than non-diabetic controls.
Purpose
This study sought to determine the validity of self-report of prior panretinal photocoagulation (PRP) and focal photocoagulation (FP) compared with fundus photography.
Design
Prospective cohort study.
Participants
One thousand three hundred sixty-three type 1 diabetic subjects from the Epidemiology of Diabetes Interventions and Complications (EDIC) study, a subset of the 1441 subjects originally enrolled in the multicenter Diabetes Control and Complications Trial.
Methods
At each annual visit, subjects were asked by EDIC staff whether they had undergone PRP, FP, or both since the last completed annual clinic visit. Fundus photographs were collected from one quarter of the cohort each year and from the entire cohort at EDIC years 4 and 10. Photographs were graded for the presence and extent of PRP and FP. Seventeen years of subject reporting and photograph grading of PRP and FP were compared in EDIC subjects.
Main Outcome Measures
The κ, sensitivity, specificity, and positive and negative predictive values were calculated for subject-reported PRP and FP. Factors influencing subject misreporting were investigated.
Results
For subject reporting, 1244 (96%) of 1296 subjects with gradable photographs accurately reported whether they had a history of PRP in one or both eyes, and 1259 (97.5%) of 1291 with valid photographs correctly reported their history of FP. For PRP and FP, sensitivities were 90.4% and 74.0%, respectively; specificities were 96.0% and 98.8%, respectively; positive predictive values were 75.9% and 80.3%, respectively; negative predictive values were 98.9% and 98.4%, respectively; and κ values were 0.80 and 0.76, respectively. Risk factors associated with misreporting included prior laser for diabetic retinopathy and prior ocular surgery (each P<0.04).
Conclusions
For subjects with type 1 diabetes, in the absence of a clinical examination or fundus photographs, subject self-report could be a reliable tool in a well-monitored study for assessing laser treatment type in diabetic retinopathy.
Financial Disclosure(s)
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Risk factors are clinical measurements that predict the subsequent development of an adverse health outcome. Whether a risk factor is causal is irrelevant with respect to its value as a target for intervention. The key point is whether changing the level or removing the risk factor consistently reduces the incidence of the outcome; that is, whether the risk factor is a modifiable and responsive risk factor. The value of albuminuria as a strong risk factor for cardiovascular disease has been established. It is used in this article to illustrate concepts related to risk and its measurement in clinical research.
Estimates of glomerular filtration rate (GFR) that are based on serum creatinine are routinely used; however, they are imprecise, potentially leading to the overdiagnosis of chronic kidney disease. Cystatin C is an alternative filtration marker for estimating GFR.
Using cross-sectional analyses, we developed estimating equations based on cystatin C alone and in combination with creatinine in diverse populations totaling 5352 participants from 13 studies. These equations were then validated in 1119 participants from 5 different studies in which GFR had been measured. Cystatin and creatinine assays were traceable to primary reference materials.
Mean measured GFRs were 68 and 70 ml per minute per 1.73 m(2) of body-surface area in the development and validation data sets, respectively. In the validation data set, the creatinine-cystatin C equation performed better than equations that used creatinine or cystatin C alone. Bias was similar among the three equations, with a median difference between measured and estimated GFR of 3.9 ml per minute per 1.73 m(2) with the combined equation, as compared with 3.7 and 3.4 ml per minute per 1.73 m(2) with the creatinine equation and the cystatin C equation (P=0.07 and P=0.05), respectively. Precision was improved with the combined equation (interquartile range of the difference, 13.4 vs. 15.4 and 16.4 ml per minute per 1.73 m(2), respectively [P=0.001 and P<0.001]), and the results were more accurate (percentage of estimates that were >30% of measured GFR, 8.5 vs. 12.8 and 14.1, respectively [P<0.001 for both comparisons]). In participants whose estimated GFR based on creatinine was 45 to 74 ml per minute per 1.73 m(2), the combined equation improved the classification of measured GFR as either less than 60 ml per minute per 1.73 m(2) or greater than or equal to 60 ml per minute per 1.73 m(2) (net reclassification index, 19.4% [P<0.001]) and correctly reclassified 16.9% of those with an estimated GFR of 45 to 59 ml per minute per 1.73 m(2) as having a GFR of 60 ml or higher per minute per 1.73 m(2).
The combined creatinine-cystatin C equation performed better than equations based on either of these markers alone and may be useful as a confirmatory test for chronic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).
Klotho is known to function as a cofactor for the phosphatonin, fibroblast growth factor (FGF)-23 at the kidney. FGF-23 levels rise in chronic kidney disease (CKD) despite progression of accelerated vascular calcification. There are currently conflicting data on whether FGF-23 may exhibit direct vasculoprotective effects in CKD.
In this study, we describe for the first time endogenous Klotho expression in human arteries and human aortic smooth muscle cells. We show that CKD is a state of vascular Klotho deficiency promoted by chronic circulating stress factors, including proinflammatory, uremic, and disordered metabolic conditions. Mechanistic studies demonstrated that Klotho knockdown potentiated the development of accelerated calcification through a Runx2 and myocardin-serum response factor-dependent pathway. Klotho knockdown studies further revealed that vascular cells are a Klotho-dependent target tissue for FGF-23. FGF-23 mediated cellular activation of p-ERK, p-AKT, and cellular proliferative effects, which were abrogated following Klotho knockdown. We next showed that vascular Klotho deficiency driven by procalcific stressors could be restored by vitamin D receptor activators, in vitro and further confirmed using human arterial organ cultures from CKD patients, in vivo. Furthermore, restoration of suppressed Klotho expression by vitamin D receptor activators conferred human aortic smooth muscle cells responsive to FGF-23 signaling and unmasked potential anticalcific effects.
Chronic metabolic stress factors found in CKD promote vascular Klotho deficiency. Mechanistic studies revealed a bifunctional role for local vascular Klotho, first, as an endogenous inhibitor of vascular calcification and, second, as a cofactor required for vascular FGF-23 signaling. Furthermore, vitamin D receptor activators can restore Klotho expression and unmask FGF-23 anticalcific effects.
Type 1 diabetes (T1D) is an autoimmune disorder which affects millions around the world. The incidence of T1D in children is increasing worldwide at a rate that cannot be explained by genetics alone. This review explores the recent research regarding possible causes of this epidemic.
Investigation into T1D epidemiology has recently focused on several hypotheses. These theories include the role of infections, early childhood diet, vitamin D exposure, environmental pollutants, increased height velocity, obesity, and insulin resistance in the risk for T1D. Over the past year, the evidence has strengthened for early childhood infections, dietary proteins, and insulin resistance as risk factors for T1D, but not for vitamin D exposure or environmental pollutants.
Investigation into the source of the current epidemic of T1D has shed light on several possible causes, but has not provided definitive answers, yet.
In ESRD, the neurohormone arginine vasopressin (AVP) may act primarily through V1a and V1b receptors, which promote vasoconstriction, myocardial hypertrophy, and release of adrenocorticotropic hormone. The preanalytical instability of AVP limits the investigation of whether this hormone associates with cardiovascular events, but the stable glycopeptide copeptin may serve as a surrogate because it is co-secreted with AVP from the posterior pituitary. Here, we studied whether copeptin predicts cardiovascular risk and mortality in ESRD. We measured copeptin at baseline in 1241 hemodialysis patients with type 2 diabetes participating in the German Diabetes and Dialysis Study. The median copeptin level was 81 pmol/L (interquartile range, 81 to 122 pmol/L). In Cox regression analyses, compared with patients with copeptin levels in the lowest quartile (≤51 pmol/L), patients with copeptin levels in the highest quartile (>122 pmol/L) had a 3.5-fold increased risk for stroke (HR, 3.48; 95% CI: 1.71 to 7.09), a 73% higher risk for sudden death (HR, 1.73; 95% CI: 1.01 to 2.95), a 42% higher risk for combined cardiovascular events (HR, 1.42; 95% CI: 1.06 to 1.90), and a 48% higher risk for all-cause mortality (HR, 1.48; 95% CI: 1.15 to 1.90). In contrast, we did not detect significant associations between copeptin levels and risks for myocardial infarction or death caused by congestive heart failure. In conclusion, copeptin levels strongly associate with stroke, sudden death, combined cardiovascular events, and mortality in hemodialysis patients with type 2 diabetes. Whether vasopressin receptor antagonists will improve these outcomes requires further studies.
Presence of microvascular obstruction (MVO) following primary percutaneous coronary intervention (pPCI) for ST-elevation myocardial infarction (STEMI) confers higher risk of left-ventricular remodelling and dysfunction. Measurement of cardiac troponin I (cTnI) after STEMI reflects the extent of myocardial destruction. We aimed to explore whether cTnI values were associated with presence of MVO independently of infarct size in STEMI patients receiving pPCI.
175 patients with STEMI were included. cTnI was sampled at 24 and 48 h. MVO and infarct size was determined by delayed enhancement with cardiac magnetic resonance at five to seven days post index event.
The presence of MVO following STEMI was associated with larger infarct size and higher values of cTnI at 24 and 48 h. For any given infarct size or cTnI value, there was a greater risk of MVO development in non-anterior infarctions. cTnI was strongly associated with MVO in both anterior and non-anterior infarctions (P < 0.01) after adjustment for covariates (including infarct size); and was reasonably effective in predicting MVO in individual patients (area-under-the-curve ≥0.81).
Presence of MVO is reflected in levels of cTnI sampled at an early time-point following STEMI and this association persists after adjustment for infarct size.
Routine blood pressure lowering with the fixed combination of perindopril and indapamide in 11,140 patients with type 2 diabetes was very well tolerated and produced substantial benefits in reducing all-cause and cardiovascular mortality, the primary combined outcome of macro- or microvascular events, total coronary events, and total renal events, as reported previously. We present here a wealth of evidence, most of it previously published either in journal articles or in recent abstract form, that the relative risk reductions conferred by the combination of perindopril and indapamide are broadly consistent across subgroups defined by a wide range of baseline characteristics, including blood pressure at entry, age from below 65 to above 75 years, total cardiovascular risk defined according to the European guidelines, stage of chronic disease, and cognitive function. Furthermore, we report that the absolute risk reductions are significantly greater in those with increased cardiovascular risk, with more advanced nephropathy and in older subjects. We confirm that the effects of blood pressure lowering with perindopril-indapamide and of intensive glucose control with the gliclazide modified release (MR)-based regimen are independent and produce substantial additional benefits when combined. We also discuss these results in the context of other major trials and demonstrate how they extend the evidence on the benefits of blood pressure lowering in patients with diabetes. Finally, we present evidence that the results of The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE trial) are broadly generalizable to patients with type 2 diabetes in community practice, and that if the joint benefits from routine blood pressure lowering with perindopril-indapamide and more intensive control with the gliclazide-MR-based regimen were applied worldwide, close to 2 million lives would be saved over the next 5 years.
To determine whether patient self-report of prior laser treatment can be used as a reliable tool for assessing the presence of severe diabetic retinopathy.
This was a retrospective study on two groups of diabetic subjects.
One hundred patients with diabetes were recruited from the general eye and retina clinics at the University of Chicago Hospitals. The patients were asked, "Have you ever received laser treatment for your diabetic eye disease (DED)?" A chart review was then conducted noting if the patient had received either focal laser treatment for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy. Data from the Wisconsin Epidemiological Study of Diabetic Retinopathy (WESDR) were also analyzed. Participant responses to the question "Have you had laser photocoagulation treatment for your eyes?" were analyzed with documentation of photocoagulation scars determined by grading seven-standard field color fundus photographs.
In the University of Chicago group, 96 of 100 (96%) of patients were accurate in reporting whether they had received previous laser treatment for DED (sensitivity 95.8%, specificity 96.1%, and positive predictive value 88.5%). In the WESDR analysis, 2,329 of 2,348 (99%) of participants were accurate in reporting whether they had prior laser treatment for DED (sensitivity 96.0%, specificity 99.5%, and positive predictive value 95.6%).
The high sensitivity and specificity of our results validate the use of patient self-report as a useful tool in assessing past laser treatment for severe diabetic retinopathy. Patient self-report may be a useful surrogate to clinical examination or medical record review to determine the presence of severe diabetic retinopathy.
The term complication as employed in reference to a chronic disease is commonly used to refer to an associated disease as well as to a condition more directly the result, per se, of the primary condition.
In diabetes, a vascular complication, or associated vascular disease, is considered, as to degree at least, to be the direct result of the disturbed metabolic state, or greatly aggravated by it in both tempo and time.
Many pathologic conditions observed in the diabetic person are most favorably influenced through our ability to control the diabetes. Thus, for example, the person with controlled diabetes is less susceptible to infection and acidosis than the one with uncontrolled diabetes. Surgical procedures, acute and elective, trauma, neoplastic disease and even pregnancy—this latter if especially approached—do not present to the surgeon and internist a more formidable problem in the diabetic person than in the nondiabetic.
Premature vascular disease, with
The risk of premature coronary artery disease (CAD) and its determinants were investigated in a cohort of 292 patients with juvenile-onset, insulin-dependent diabetes mellitus (IDDM) who were followed for 20 to 40 years. Although patients with juvenile-onset IDDM had an extremely high risk of premature CAD, the earliest deaths due to CAD did not occur until late in the third decade of life. After age 30 years, the mortality rate due to CAD increased rapidly, equally in men and women, and particularly among persons with renal complications. By age 55 years the cumulative mortality rate due to CAD was 35 +/- 5%. This was far higher than the corresponding rate for nondiabetic persons in the Framingham Heart Study, 8% for men and 4% for women. Angina and acute nonfatal myocardial infarction followed a similar pattern, as did asymptomatic CAD detected by stress test, so that their combined prevalence rate was 33% among survivors aged 45 to 59 years. Age at onset of IDDM and the presence of eye complications did not contribute to risk of premature CAD. This pattern suggests that juvenile-onset diabetes and its renal complications are modifiers of the natural history of atherosclerosis in that although they profoundly accelerate progression of early atherosclerotic lesions to very severe CAD, they may not contribute to initiation of atherosclerosis.
This study sought to assess the differences in coronary flow reserve in patients with and without diabetic retinopathy.
Microvascular abnormalities throughout the body and impairment of coronary flow reserve have been described in patients with diabetes mellitus. However, the relation between diabetic retinopathy and coronary microvascular disease has not been investigated.
The study included 29 patients with diabetes mellitus (18 with and 11 without diabetic retinopathy) and 15 control patients with chest pain and normal coronary arteries. Diabetic retinopathy was nonproliferative in all 18 patients with this disorder (8 had background, 10 preproliferative retinopathy). Five minutes after injection of 3 mg of isosorbide dinitrate, phasic flow velocities were recorded in the proximal segment of the angiographically normal left anterior descending coronary artery at rest and during hyperemia (0.14 mg/kg body weight per min of adenosine infused intravenously) using a 0.014-in. 15-MHz Doppler guide wire. Coronary blood flow was calculated, and coronary flow reserve was obtained from the hyperemic/baseline flow ratio.
Coronary blood flow was significantly lower during hyperemia ([mean +/- SD] 107 +/- 23 and 116 +/- 18 vs. 136 +/- 17 ml/min, respectively) and higher at baseline (58 +/- 16 and 45 +/- 12 vs. 37 +/- 10 ml/min, respectively) in diabetic patients with and without retinopathy than in control subjects (p < 0.05 for both diabetic groups). As a result, coronary flow reserve in both groups of diabetic patients was significantly lower than in control patients (1.9 +/- 0.4 and 2.8 +/- 0.3 vs. 3.3 +/- 0.4, respectively, p < 0.01 for both diabetic groups), and its reduction was greater in patients with than without retinopathy (p < 0.01). Furthermore, in patients with diabetic retinopathy, maximal hyperemic coronary flow (102 +/- 11 vs. 114 +/- 16 ml/min, p < 0.05) and flow reserve (1.6 +/- 0.2 vs. 2.3 +/- 0.2, p < 0.01) were significantly lower in those with preproliferative than background retinopathy.
Coronary flow reserve is significantly restricted in patients with diabetes mellitus, and its reduction is more marked in those with diabetic retinopathy, especially in advanced retinopathy. Thus, diabetic retinopathy should identify marked restriction of coronary flow reserve in patients with diabetes mellitus.
Much of the practice of modern medicine deals with prevention of the consequences of chronic conditions, including diabetes, hypertension, obesity, asthma, chronic bronchitis, and inflammatory bowel diseases. To achieve this end, identifying people at risk for these consequences and then initiating the appropriate, evidence-based preventive therapies are key. Characterization and study of risk factors are at the core of this effort and represent the only way that high-risk individuals can be identified. These risk factors can be any imagined variable, ranging from a genetic mutation to a blood result, a previous disease, exposure to an infectious agent or toxin, a socioeconomic state, ethnicity, birth weight, or country of origin. All causal factors for an outcome are risk factors for that outcome; reducing these risk factors almost certainly reduces the outcome. The converse is usually not true, however: identification of a risk factor reveals little about its causal connection to the outcome in question, and reducing this risk factor may or may not reduce the outcome. Once high-risk individuals are identified on the basis of their risk factor profile, the relevant clinical question relates to which therapies have been identified clearly that will reduce the risk or the outcome. If modification of the level of the risk factor is considered therapeutically, the question of whether the risk factor is also a good surrogate outcome must be answered. Information regarding whether the risk factor causes the disease is highly desirable; however, it is often unavailable and is not required before making therapeutic decisions.
In the present study, we aimed to determine the frequency of a significant reduction in urinary albumin excretion and factors affecting such reduction in patients with type 1 diabetes and microalbuminuria.
The study included 386 patients with persistent microalbuminuria, indicated by repeated measurements of urinary albumin excretion (estimated on the basis of albumin-to-creatinine ratios) in the range of 30 to 299 microg per minute during an initial two-year evaluation period. Subsequent measurements during the next six years were grouped into two-year periods, averaged, and analyzed for regression of microalbuminuria, which was defined as a 50 percent reduction in urinary albumin excretion from one two-year period to the next.
Regression of microalbuminuria was frequent, with a six-year cumulative incidence of 58 percent (95 percent confidence interval, 52 to 64 percent). The use of angiotensin-converting-enzyme inhibitors was not associated with the regression of microalbuminuria. However, microalbuminuria of short duration, salutary levels of glycosylated hemoglobin (less than 8 percent), low systolic blood pressure (less than 115 mm Hg), and low levels of both cholesterol and triglycerides (less than 198 mg per deciliter [5.12 mmol per liter] and 145 mg per deciliter [1.64 mmol per liter], respectively) were independently associated with the regression of microalbuminuria. Patients with salutary levels of all modifiable factors had a hazard ratio for regression of 3.0 (95 percent confidence interval, 1.5 to 6.0), as compared with patients with no salutary levels of any modifiable factor.
Frequent regression of microalbuminuria in patients with type 1 diabetes indicates that elevated urinary albumin excretion does not imply inexorably progressive nephropathy. Identification of the multiple determinants of the regression of microalbuminuria has implications for current theories about the mechanisms of early diabetic nephropathy.
Coronary calcium measured by electron beam CT is associated with coronary disease and can be used to predict coronary disease events. Studies investigating changes in coronary calcium need to address interscan variability as it relates to the overall coronary calcium score in defining progression or regression of coronary calcium over time. SUBJECTS AND METHODS. Electron beam CT was performed on 1,074 participants. Coronary calcium volume scores were repeated 5 min apart. Interscan variability was examined using Bland-Altman plots and homogeneity tests. Transformations of the Box-Cox family (including power, roots, and logarithm) were applied to calcium volume scores. The transformation that stabilized the variation in calcium volume scores was applied to progression of calcium volume scores in 109 subjects with diabetes.
The variability in calcium volume score increased as the level of coronary calcium increased (rho = 0.67, p < 0.001 for the relation between the absolute difference and the mean value of calcium volume scores). This heterogeneity was removed using the square root transformation of the calcium volume score (rho = 0.09, p < 0.15 for the relation between the absolute difference in the square root of the calcium volume score and the mean square root of the calcium volume score). This transformation was applied to calcium volume scores taken a mean of 2.7 years apart in 109 subjects with diabetes. A significant change in calcium volume score was defined as a difference between the square root-transformed to calcium volume scores greater than or equal to 2.5 mm(3) (> 99th percentile of interscan variability). Significant progression was observed in 10% of the subjects. The square root of the calcium volume score corrected for the bias in progression of calcium volume because of the level of coronary calcium.
Using the square root of the calcium volume score stabilized interscan variability across the range of coronary calcium. Defining change in coronary calcium as greater than or equal to 2.5 mm(3) of the difference in the square root-transformed calcium volume scores provided an estimate that was unbiased with respect to baseline coronary calcium. This analytic technique may facilitate investigations of the relevance of changes in coronary calcium to clinical outcomes and the use of changes in coronary calcium as a measure of the therapeutic impact on subclinical disease in clinical trials.
Cardiovascular disease ( CVD) constitutes the major cause of mortality and morbidity in both type 1 ( T1D) and type 2 ( T2D) diabetes patients. Although the microvascular complications of T1D are well studied, macrovascular CVD, its treatment, and link to diabetes have been investigated primarily in T2D patients. On April 27 and 28, 2003, the National Heart, Lung, and Blood Institute ( NHLBI) and the National Institute of Diabetes and Digestive and Kidney Diseases ( NIDDK) sponsored a meeting to identify ways to close gaps in our knowledge about CVD in T1D to improve prevention and treatment. Participants were asked to: ( 1) Evaluate opportunities for studying the pathogenesis of CVD in T1D patients. Risk factors unique to these patients were of particular interest, as well as studies of the cause of CVD in T1D with respect to existing databases or cohorts and involving partnerships between basic and clinical investigators. ( 2) Evaluate opportunities for intervention studies to treat or prevent CVD in T1D. Because of practical obstacles ( recruitment, duration, and cost of interventional studies with hard clinical end points), identification of reliable methods and markers that enable efficient intervention were a high priority. The meeting included 3 sessions: ( 1) current understanding of T1D and CVD; ( 2) opportunities to expand our understanding of the pathogenesis and clinical course of CVD in T1D; and ( 3) opportunities for intervention studies to reduce cardiovascular complications in T1D. This report summarizes the presentations made and concludes with recommendations drawn from the presentations and discussion among the participants.
Retinopathy in old persons with and without diabetes mellitus: the Age
- E Gunnlaugsdottir
- S Halldorsdottir
- R Klein
Gunnlaugsdottir E, Halldorsdottir S, Klein R, et al. Retinopathy in old persons with and without
diabetes mellitus: the Age, Gene/Environment Susceptibility--Reykjavik Study (AGES-R).
Standards of medical care in diabetes--2013
Standards of medical care in diabetes--2013. Diabetes Care. 2013; 36(Suppl 1):S11–66. [PubMed:
23264422]
The epidemic of type 1 diabetes: what is it telling us? Current opinion in endocrinology, diabetes, and obesity
- G P Forlenza
- M Rewers
Forlenza GP, Rewers M. The epidemic of type 1 diabetes: what is it telling us? Current opinion in
endocrinology, diabetes, and obesity. 2011; 18:248-251.