Maternal but Not Paternal Association of Ambulatory Blood Pressure With Albumin Excretion in Young Offspring With Type 1 Diabetes

OBJECTIVE

Familial predisposition to hypertension has been associated with the development of diabetic nephropathy in adults, but there are limited data in adolescents. Our aim was to assess whether parental ambulatory blood pressure (ABP) was associated with ABP and albumin excretion in young offspring with type 1 diabetes.

RESEARCH DESIGN AND METHODS

Twenty-four-hour ABP monitoring was performed in 509 young offspring (mean ± SD age 15.8 ± 2.3 years) with type 1 diabetes, 311 fathers, and 444 mothers. Systolic (SBP) and diastolic blood pressure (DBP) measurements during 24 h, daytime, and nighttime were calculated. Three early morning urinary albumin-to-creatinine ratios (ACRs), A1C, and anthropometric parameters were available for the offspring.

RESULTS

All paternal ABP parameters, except for nighttime SBP, were independently related to the offspring''s ABP (24-h SBP β = 0.18, 24-h DBP β = 0.22, daytime SBP β = 0.25, daytime DBP β = 0.23, and nighttime DBP β = 0.18; all P < 0.01). Maternal 24-h DBP (β = 0.19, P = 0.004), daytime DBP (β = 0.09, P = 0.04), and nighttime SBP (β = 0.24 P = 0.001) were related to the corresponding ABP parameter in the offspring. Significant associations were found between the offspring''s logACR and maternal ABP. The association with 24-h DBP (β = 0.16, P = 0.02), daytime DBP (β = 0.16 P = 0.02), and nighttime DBP (β = 0.15 P = 0.03) persisted even after adjustment for the offspring''s ABP. Mothers of offspring with microalbuminuria had higher ABP than mothers of offspring without microalbuminuria (all P < 0.05).

CONCLUSIONS

In this cohort, parental ABP significantly influenced offspring blood pressure, therefore confirming familial influences on this trait. In addition, maternal ABP, particularly DBP, was closely related to ACR in the offspring, suggesting a dominant effect of maternal genes or an effect of the intrauterine environment on microalbuminuria risk.Microalbuminuria remains the best predictive marker for the development of overt diabetic nephropathy and represents an independent risk factor for cardiovascular disease (CVD) (1). Evidence indicating that the risk for the development of microalbuminuria and diabetic nephropathy is partly genetic and may relate to the inheritance of genes associated with CVD is accumulating (2). Several studies have shown familial aggregation of renal disease in type 1 diabetes (2,3), and a family history of hypertension, dyslipidemia, insulin resistance, type 2 diabetes, or a cluster of these cardiovascular risk factors has been associated with an increased risk of diabetic nephropathy (2,4).In particular, several lines of evidence have highlighted the fact that predisposition to hypertension might be a risk factor for the development and progression of diabetic nephropathy in individuals with type 1 diabetes (4–8), and, therefore, the inheritance of blood pressure–related genes might also contribute to abnormal albumin excretion and renal damage. Parental hypertension has been associated with changes in renal hemodynamics (9) and with the development of diabetic nephropathy in the offspring with diabetes (5–8). However, the relationship between family history of hypertension and albuminuria has not been confirmed in all studies (10) and in the majority of studies, confirmation has been based on a single blood pressure assessment in the parents (7,8) or on a questionnaire-based history of parental hypertension. In addition, the effect of parental blood pressure, as was that of other heritable factors, has been mainly investigated in adults with diabetes, whereas it has been seldom studied in children and adolescents (11,12).Understanding the role of such a familial/genetic effect of blood pressure on renal disease would be particularly important in adolescents with type 1 diabetes, who represent a vulnerable group at risk of vascular complications (13). In particular, the identification of familial/genetic factors predisposing to diabetic nephropathy and the understanding of their interplay with glycemic control and the hormonal and metabolic changes of puberty could help in identifying subjects at higher risk for diabetes complications, who therefore require more intensive treatment to prevent them. The aim of the present study was to assess whether parental ambulatory blood pressure (ABP) was related to variations in the same trait and in albumin excretion rates in young offspring with childhood-onset type 1 diabetes.     

Patient Race/Ethnicity and Patient-Physician Race/Ethnicity Concordance in the Management of Cardiovascular Disease Risk Factors for Patients With Diabetes

OBJECTIVE

Patient-physician race/ethnicity concordance can improve care for minority patients. However, its effect on cardiovascular disease (CVD) care and prevention is unknown. We examined associations of patient race/ethnicity and patient-physician race/ethnicity concordance on CVD risk factor levels and appropriate modification of treatment in response to high risk factor values (treatment intensification) in a large cohort of diabetic patients.

RESEARCH DESIGN AND METHODS

The study population included 108,555 adult diabetic patients in Kaiser Permanente Northern California in 2005. Probit models assessed the effect of patient race/ethnicity on risk factor control and treatment intensification after adjusting for patient and physician-level characteristics.

RESULTS

African American patients were less likely than whites to have A1C <8.0% (64 vs. 69%, P < 0.0001), LDL cholesterol <100 mg/dl (40 vs. 47%, P < 0.0001), and systolic blood pressure (SBP) <140 mmHg (70 vs. 78%, P < 0.0001). Hispanic patients were less likely than whites to have A1C <8% (62 vs. 69%, P < 0.0001). African American patients were less likely than whites to have A1C treatment intensification (73 vs. 77%, P < 0.0001; odds ratio [OR] 0.8 [95% CI 0.7–0.9]) but more likely to receive treatment intensification for SBP (78 vs. 71%, P < 0.0001; 1.5 [1.3–1.7]). Hispanic patients were more likely to have LDL cholesterol treatment intensification (47 vs. 45%, P < 0.05; 1.1 [1.0–1.2]). Patient-physician race/ethnicity concordance was not significantly associated with risk factor control or treatment intensification.

CONCLUSIONS

Patient race/ethnicity is associated with risk factor control and treatment intensification, but patient-physician race/ethnicity concordance was not. Further research should investigate other potential drivers of disparities in CVD care.There are well-documented racial disparities in diabetes prevalence and mortality. African Americans and Hispanics have higher diabetes prevalence, death rates, and higher rates of serious complications (1). Even after controlling for access to care and socioeconomic status, diabetes disparities in the U.S. persist (1). There are also widely recognized disparities in cardiovascular risk factors associated with diabetes. African American and Hispanic patients with diabetes are less likely to meet glucose, cholesterol, or blood pressure targets (2).The evidence surrounding whether insured patients of color receive worse care for diabetes and cardiovascular disease (CVD) risk factor control is mixed (3–6). Studies have found significant disparities in the likelihood of receipt of medications (7) and medication intensification (8,9). However, several studies have shown that minority patients received equal or better quality processes of care such as screening and medication intensification (4,10–12).Interpersonal barriers resulting from language or cultural differences between patients and physicians may explain a portion of diabetes management disparities (13,14). Physicians engage in less patient-centered communication with patients of color than with white patients (15). Patient race/ethnicity has been associated with physicians'' assessment of patient intelligence, feelings of affiliation toward the patient, and beliefs about the patients'' likelihood of risk behavior and adherence with medical advice (16,17).Patient-physician race/ethnicity concordance (the patient and health care provider having the same race/ethnicity) may help bridge interpersonal barriers in care for minority patients (18). Race/ethnicity concordance is associated with increased patient trust in the physician (19) and health services utilization and satisfaction (20). However, evidence that race/ethnicity concordance is an important factor in the quality of health care is mixed (21). No studies have examined the association among race/ethnicity concordance, cardiovascular disease processes of care, and levels of intermediate outcomes.The purpose of this study was to examine the association of patient race/ethnicity and patient-physician race/ethnicity concordance on CVD risk factor levels and treatment intensification in a large cohort of diabetic patients in an integrated delivery system.     

Sex and Racial/Ethnic Differences in Cardiovascular Disease Risk Factor Treatment and Control Among Individuals With Diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA)

OBJECTIVE

To examine sex and racial/ethnic differences in cardiovascular risk factor treatment and control among individuals with diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA).

RESEARCH DESIGN AND METHODS

This study was an observational study examining mean levels of cardiovascular risk factors and proportion of subjects achieving treatment goals.

RESULTS

The sample included 926 individuals with diabetes. Compared with men, women were 9% less likely to achieve LDL cholesterol <130 mg/dl (adjusted prevalence ratio 0.91 [0.83–0.99]) and systolic blood pressure (SBP) <130 mmHg (adjusted prevalence ratio 0.91 [0.85–0.98]). These differences diminished over time. A lower percentage of women used aspirin (23 vs. 33%; P < 0.001). African American and Hispanic women had higher mean levels of SBP and lower prevalence of aspirin use than non-Hispanic white women.

CONCLUSIONS

Women with diabetes had unfavorable cardiovascular risk factor profiles compared with men. African American and Hispanic women had less favorable profiles than non-Hispanic white women.Population-based health survey data suggest that sex and racial/ethnic disparities are present in diabetes process of care measures and cardiovascular risk factor control (1–9). Available data also indicate that sex-specific race/ethnicity differences are present in cardiovascular risk factor control, but these data are limited to Medicare and Veterans'' Hospital patient populations (5,10–13). We therefore performed analyses of participants with diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA) to examine sex and sex-specific racial/ethnic differences in cardiovascular risk factor treatment and control.     

Pulse pressure predicts incident cardiovascular disease but not diabetic nephropathy in patients with type 1 diabetes (The FinnDiane Study)

OBJECTIVE

Pulse pressure (PP), an estimate of arterial stiffness, has been shown to be associated with incident cardiovascular disease (CVD) in patients with type 1 diabetes (T1D). However, diabetic kidney disease, a strong predictor of CVD, was not previously taken into account. Furthermore, the role of PP as a predictor of diabetic nephropathy is not known. Therefore, we prospectively investigated the associations between PP and these diabetes complications in patients with T1D.

RESEARCH DESIGN AND METHODS

A total of 4,509 patients from the FinnDiane Study participated. Follow-up data on incident CVD events and renal status (median 5.3 years) were available in 69 and 76% of the patients, respectively. Altogether, 269 patients (8.6%) had an incident CVD event and 370 patients (10.8%) progressed to a higher level of albuminuria or to end-stage renal disease.

RESULTS

PP was higher at baseline in patients who experienced a CVD event (66 ± 18 vs. 52 ± 14 mmHg; P < 0.001) or progressed in their renal status (58 ± 18 vs. 54 ± 15 mmHg; P < 0.01) during follow-up. In a Cox regression model, PP was independently associated with a first ever CVD event (hazard ratio per 10 mmHg 1.22 [95% CI 1.10–1.34]) but not progression of renal disease (1.00 [0.89–1.12]) after adjustments for traditional risk factors.

CONCLUSIONS

PP, a marker of arterial stiffness, is a risk factor for cardiovascular complications but not for diabetic nephropathy in patients with T1D.Whereas systolic blood pressure (SBP) increases with age in the western population, diastolic blood pressure (DBP) generally increases during adulthood, peaks at 55–60 years of age, and thereafter starts to decrease as the result of arterial stiffening (1). This results in an increased pulse pressure (PP) that is associated with cardiovascular disease (CVD) (2). We have shown a premature increase in PP in patients with type 1 diabetes (T1D) compared with nondiabetic subjects (3). The results indicated an accelerated arterial aging in patients with T1D that may contribute to a higher risk of CVD.PP has been shown to be a strong predictor of CVD in the general population, especially in elderly subjects aged >65 years (4,5). The EURODIAB Prospective Complications Study extended this finding to patients with T1D because PP was shown to be associated with incident CVD (6). However, diabetic nephropathy, a strong CVD risk factor (7), was not taken into account. Furthermore, Soedamah-Muthu et al. (8) reported that PP predicted all-cause but not cardiovascular mortality in the same cohort.Although PP was shown to be associated with diabetic nephropathy in a cross-sectional study (3), it is not known whether PP could be used as a predictor of progression of diabetic nephropathy. However, blood pressure per se has been shown to predict incipient and overt diabetic nephropathy, although the results have been conflicting (9–11).Therefore, the aim was to explore the role of PP in the development of CVD and progression of diabetic nephropathy in a large, homogeneous and nationwide cohort of patients with T1D.     

Short Sleep Duration Is Associated With a Blood Pressure Nondipping Pattern in Type 1 Diabetes: The DIAPASOM study

OBJECTIVE

To assess whether nocturnal blood pressure dipping status in type 1 diabetes is correlated with specific sleep characteristics and differences in nocturnal glycemic profiles.

RESEARCH DESIGN AND METHODS

Twenty type 1 diabetic adult patients underwent sleep studies with simultaneous 24-h ambulatory blood pressure monitoring and continuous nocturnal glucose monitoring.

RESULTS

Altogether, 55% of patients exhibited blunted blood pressure dipping. They did not differ from the dipper group in age, BMI, or systolic (SBP) and diastolic (DBP) blood pressure. Total sleep period (TSP) was higher in the dipper group (497 ± 30 vs. 407 ± 44 min for dippers and nondippers, respectively, P < 0.001). TSP was correlated with SBP and DBP day-night differences (r = 0.44 and 0.49, respectively). Periods of nocturnal hypoglycemia (i.e., % of TSP with glycemia <70 mg/dl) were longer in the dipper group (8.1 ± 10.7 vs. 0.1 ± 0.4% for dippers and nondippers, respectively, P = 0.02).

CONCLUSIONS

Dipping status in type 1 diabetes was associated with longer sleep duration and with hypoglycemia unawareness.During sleep, ambulatory blood pressure monitoring (ABPM) demonstrates a normal decline of over 10% in blood pressure (BP), corresponding to the so-called dipping status. In type 1 diabetes, nondipping status is more prevalent (1) and is associated with increased risks for sustained hypertension, retinopathy, and nephropathy (1–3). Dipping pattern could be influenced by sleep duration and associated sleep disorders (4). In type 1 diabetes, sleep stability impacts sleep-related hypoglycemia by changing awakening responses to these episodes (5). Our hypothesis was that type 1 diabetic subjects with more stable sleep could exhibit normal BP dip and, because of higher arousal thresholds, could present an increased frequency of nocturnal hypoglycemia.     

Risk factors for metabolic syndrome independently predict arterial stiffness and endothelial dysfunction in patients with chronic kidney disease and minimal comorbidity

OBJECTIVE

Metabolic syndrome (MS) is common in patients with chronic kidney disease (CKD), but its contribution to arterial stiffness and endothelial dysfunction in CKD is not well defined. We hypothesized that risk factors for MS would independently predict arterial stiffness and endothelial dysfunction in CKD patients.

RESEARCH DESIGN AND METHODS

Risk factors for MS, carotid-femoral pulse wave velocity (CF-PWV) and flow-mediated dilation (FMD) as measures of arterial stiffness and endothelial dysfunction, respectively, were assessed in 113 minimally comorbid CKD patients and in 23 matched control subjects.

RESULTS

CF-PWV correlated with systolic blood pressure (SBP), waist circumference, and plasma glucose (r² = 0.25, 0.09, and 0.09; P < 0.01 for all). FMD correlated with SBP (r² = 0.09; P < 0.01) and waist circumference (r² = 0.03; P < 0.05). CF-PWV increased progressively (r² = 0.07; P < 0.01) with increasing number of risk factors for MS. In multiple linear regression, SBP and waist circumference were independent determinants of CF-PWV, whereas only SBP predicted FMD.

CONCLUSIONS

The number of MS risk factors is an important determinant of arterial stiffness in CKD patients irrespective of the degree of renal impairment. Although BP remains the major determinant of arterial stiffness and endothelial dysfunction, waist circumference independently predicts arterial stiffness. MS risk factors, particularly abdominal girth, are potential targets for future interventional studies in patients with CKD.Chronic kidney disease (CKD) is common and associated with an increased risk of cardiovascular disease (CVD) (1). Conventional (Framingham) CVD risk factors, including high blood pressure (BP), hypercholesterolemia, and diabetes, all of which are common in CKD patients, only partly explain the high cardiovascular risk (2). CKD is now regarded as an independent risk factor for CVD (1,3), and we have recently shown that renal dysfunction also contributes to arterial stiffness and endothelial dysfunction in a group of minimally comorbid CKD patients (4).Increased arterial stiffness, as measured by pulse wave velocity (PWV), is a commonly recognized feature of CKD (4), a marker of cardiovascular risk (5,6), and an independent predictor of mortality and survival in dialysis patients (6). The vascular endothelium is an important regulator of arterial stiffness (7), and endothelial dysfunction is also a common feature of CKD (8) and a predictor of CVD (9).Metabolic syndrome (MS) is a clustering of metabolic abnormalities and risk factors for CVD and includes abdominal obesity, hyperglycemia, hypertension, hypertriglyceridemia, and reduced HDL cholesterol (10). As MS is associated with increased risks of diabetes and CVD (11,12), its treatment and prevention have become one of the major public health challenges worldwide. The risk factors for MS, either together or individually, are also associated with arterial stiffness and endothelial dysfunction both in health (13,14) and disease (15,16).MS is widely prevalent in CKD (17) and is itself a risk factor for CKD (18). Although a recent study has suggested that MS and its risk factors contribute to arterial stiffness and endothelial dysfunction in dialysis patients (19), there are no data relating to predialysis CKD. This is clearly important because targeting MS risk factors in early CKD may retard CKD progression, delaying the onset of dialysis and its associated morbidity, as well as reducing the overall risk of CVD.In this current study, we investigated the relationships of MS and its individual components to arterial stiffness and endothelial dysfunction in CKD patients across a wide range of renal function from early CKD to predialysis. Importantly, we planned to recruit patients without diabetes or cardiovascular comorbidity. We hypothesized that the presence of MS, or its components, would be associated with increased arterial stiffness and endothelial dysfunction and that these relationships would be independent of renal function and other well-established risk factors for CVD.     

Blood pressure trajectories prior to death in patients with diabetes

OBJECTIVE

The goals of this study were to examine trajectories of blood pressure (BP) in adults with diabetes and investigate the association of trajectory patterns with mortality.

RESEARCH DESIGN AND METHODS

A nonconcurrent longitudinal design was used to monitor 3,766 Medicare patients with diabetes from 2005 through 2008. Data were extracted from a registry of Medicare beneficiaries, which was developed by a large academic practice that participated in the Physician Group Practice Medicare Demonstration. The relationship between BP trajectories and all-cause mortality was modeled using multilevel mixed-effects linear regression.

RESULTS

During the 4-year study period, 10.7% of the patients died, half of whom were aged ≥75 years. The crude and adjusted models both showed a greater decline in systolic and diastolic BP in patients who died than in those who did not die. In a model adjusted for age, sex, race, medications, and comorbidities, the mean systolic BP decreased by 3.2 mmHg/year (P < 0.001) in the years before death and by 0.7 mmHg/year (P < 0.001) in those who did not die (P < 0.001 for the difference in slopes). Similarly, diastolic BP declined by 1.3 mmHg/year for those who died (P < 0.001) and by 0.6 mmHg/year for those who did not die (P < 0.001); the difference in slopes was significant (P = 0.021).

CONCLUSIONS

Systolic and diastolic BP both declined more rapidly in the 4 years before death than in patients who remained alive.Blood pressure (BP) is usually recorded at every visit to the physician, yet patterns of BP over time in populations are not often published. BP trajectories have been reported in longitudinal studies of children (1,2), but trajectories in adults with diabetes are usually ancillary to treatment trials for hypertension, and the results are explained in terms of the assigned medication (3,4). In healthy adults evaluated longitudinally, systolic BP is relatively stable until approximately age 50, after which there is a steady increase with age (5). Diastolic BP increases longitudinally with age in healthy adult men, but in women, it increases in middle age and declines slightly after age 70 (5). In the Framingham population, systolic BP increased from age 30 through 84 but diastolic BP increased in middle age (40–60 years) and then declined afterward (6). This follows a similar pattern to that reported with cross-sectional data from the National Health and Nutrition Examination Study (7,8). In the Göteberg population, systolic BP increased until age 75 and decreased between 75 and 79 in those without antihypertensive therapy, whereas diastolic BP increased during middle age and then decreased after age 75 (9).Missing from the medical literature are longitudinal BP trajectories in populations with diabetes. In particular, BP trajectories before death have yet to be reported. Therefore, we investigated patterns of BP over time in a longitudinal study of Medicare patients within a diabetes registry.     

Association of high pulse pressure with proteinuria in subjects with diabetes, prediabetes, or normal glucose tolerance in a large Japanese general population sample

OBJECTIVE

To examine whether there is a difference in the association between high pulse pressure and proteinuria, independent of other blood pressure (BP) indices, such as systolic or diastolic BP, among subjects with diabetes, prediabetes, or normal glucose tolerance.

RESEARCH DESIGN AND METHODS

Using a nationwide health checkup database of 228,778 Japanese aged ≥20 years (mean 63.2 years; 39.3% men; none had pre-existing cardiovascular disease), we examined the association between high pulse pressure, defined as the highest quintile of pulse pressure (≥63 mmHg, n = 40,511), and proteinuria (≥1+ on dipstick, n = 12,090) separately in subjects with diabetes (n = 27,913), prediabetes (n = 100,214), and normal glucose tolerance (n = 100,651).

RESULTS

The prevalence of proteinuria was different among subjects with diabetes, prediabetes, and normal glucose tolerance (11.3 vs. 5.0 vs. 3.9%, respectively; P < 0.001). In subjects with diabetes, but not those with prediabetes or normal glucose tolerance, high pulse pressure was associated with proteinuria independently of significant covariates, including systolic BP (odds ratio 1.15 [95% CI 1.04–1.28]) or diastolic or mean BP (all P < 0.01). In patients with diabetes, a +1 SD increase of pulse pressure (+13 mmHg) was associated with proteinuria, even after adjustment for systolic BP (1.07 [1.00–1.13]) or diastolic or mean BP (all P < 0.05).

CONCLUSIONS

Among the Japanese general population, there was a significant difference in the association between high pulse pressure and proteinuria among subjects with diabetes, prediabetes, and normal glucose tolerance. Only in diabetes was high pulse pressure associated with proteinuria independent of systolic, diastolic, or mean BP levels.In the systemic circulation, the kidney has unique features: vascular resistance in the glomerular afferent arterioles is low, and the myogenic response of the glomerular arterioles is insensitive to changes in the other BP indices of systolic blood pressure (BP), including pulse pressure (1–3). These characteristics suggest that pressure pulsatility may contribute to barotrauma-induced renal microvascular injury, and in turn causes glomerular ultrastructural changes (e.g., podocyte loss and glomerular basement membrane thickness) (1–6).In fact, several cross-sectional studies performed in general or hypertensive populations have demonstrated a significant association between pulse pressure and albuminuria (7,8), and some longitudinal studies have underscored the importance of pulse pressure as a risk factor for increased albuminuria in general or hypertensive populations (9,10); however, few studies have directly examined the impact of high pulse pressure on albuminuria with adjustment for other BP components, such as systolic BP, diastolic BP, and/or mean BP levels. Since renal autoregulation is particularly impaired in patients with diabetes (1–3,11–13), we hypothesized that the association between high pulse pressure and albuminuria would be more prominent in patients with diabetes than in subjects without diabetes (14–16); as of yet, however, there have been no studies examining this hypothesis directly in a large database. Furthermore, the association of pulse pressure with albuminuria has never been explored in prediabetics, who are classified as being at an intermediate stage between normal glucose tolerance and diabetes (17), but prediabetics have been shown to have a significantly increased risk of developing not only diabetes but also cardiovascular disease (18).In the current study, therefore, we examined the association of high pulse pressure with proteinuria separately in each of subjects with diabetes, prediabetes, and normal glucose tolerance, using a large nationwide database of subjects recruited from the national health checkup system in Japan.     

The Role of Blood Pressure Variability in the Development of Nephropathy in Type 1 Diabetes

OBJECTIVE

Increases in blood pressure and visit-to-visit variability have both been found to independently increase the likelihood of cardiovascular events in nondiabetic individuals. This study has investigated whether each may also influence the development of microvascular complications in type 1 diabetes by examining data from the Diabetes Control and Complications Trial (DCCT).

RESEARCH DESIGN AND METHODS

Using binary longitudinal multiple logistic regression, mean systolic (SBP) and diastolic (DBP) blood pressure as well as annual visit-to-visit variability (SD.SBP and SD.DBP, respectively) was related to the risk of the development/progression of nephropathy and retinopathy in initially normotensive subjects who did not become pregnant during the DCCT.

RESULTS

Mean SBP and SD.SBP were independently predictive of albuminuria (odds ratio 1.005 [95% CI 1.002–1.008], P < 0.001 and 1.093 [1.069–1.117], P < 0.001, respectively, for 1 mmHg change), although SBP variability did not add to mean SBP in predicting retinopathy (0.999 [0.985–1.013], P = 0.93). DBP variability was also independently predictive of nephropathy (1.102 [1.068–1.137], P < 0.001) and not of retinopathy (0.991 [0.971–1.010], P = 0.37). Mean SBP was poorly related to SD.SBP (r² < 0.01) as was mean DBP with SD. DBP (r² < 0.01).

CONCLUSIONS

Visit-to-visit variability in blood pressure consistently independently added to mean blood pressure in predicting the risk of nephropathy, but not retinopathy, in the DCCT. This observation could have implications for the management and treatment of blood pressure in patients with type 1 diabetes.Hyperglycemia, and the duration of exposure to hyperglycemia, explains only ∼11% of the risk of developing microvascular complications in type 1 diabetes (1). The remaining 89% of risk must be explained by other factors, one of which is the presence of hypertension, which is known to be especially related to development and progression of nephropathy (2–5). Blood pressure lowering using antihypertensive agents has been shown to be successful in slowing the deterioration in renal function of type 1 diabetic patients with established renal impairment or proteinuria (6) but to only have an influence on retinopathy, not nephropathy, at much earlier stages in normotensive patients with normoalbuminuria (7).The role of hypertension in the development of small-vessel disease therefore remains unclear. Certainly, hypertension is related to the presence of microalbuminuria in type 1 diabetes, but it is not known whether it is the hypertension that gives rise to nephropathy or vice versa (8). Hypertension also predicts retinopathy and this frequently coexists with nephropathy, but again it is uncertain whether high blood pressure gives rise to eye disease directly or is more a marker that renal disease is also present.Recently, in two large study meta-analyses (9,10), visit-to-visit variability in systolic blood pressure (SBP) has been found to be a strong predictor of subsequent stroke independent of the mean SBP. We speculated that blood pressure variability may also have an influence on the development of microvascular complications in diabetes. To this end, we have reranalyzed data from the Diabetes Control and Complications Trial (DCCT) to see if blood pressure and its variability influenced the development of nephropathy and retinopathy in its large group of type 1 diabetic patients.     

Long-term and recent progress in blood pressure levels among U.S. adults with diagnosed diabetes, 1988-2008

OBJECTIVE

To examine whether there were long-term (between 1988–1994 and 2001–2008) and recent (between 2001–2004 and 2005–2008) changes in blood pressure (BP) levels among U.S. adults with diagnosed diabetes.

RESEARCH DESIGN AND METHODS

Using data from National Health and Nutrition Examination Surveys (NHANES), we examined changes in BP distributions, mean BPs, and proportion with BP <140/90 mmHg.

RESULTS

Between 1988–1994 and 2001–2008, for adults with diabetes, mean BPs decreased from 135/72 mmHg to 131/69 mmHg (P < 0.01) and the proportion with BP <140/90 mmHg increased from 64 to 69% (P = 0.01). Although hypertension prevalence increased, hypertension awareness, treatment, and control improved. However, there was no evidence of improvement for adults 20–44 years old. Between 2001–2004 and 2005–2008, there were no significant changes in BP levels.

CONCLUSIONS

BP levels among adults with diabetes improved between 1988–1994 and 2001–2008, but the progress stalled between 2001–2004 and 2005–2008. The lack of improvement among young adults is concerning.Hypertension is particularly deleterious for people with diabetes because it confers 2 ∼3 times the risk for cardiovascular morbidity and mortality as for people without diabetes (1,2). Studies demonstrated that blood pressure (BP) control is crucial to reduce vascular complications and improve survival for people with diabetes (3,4). The proportion of people with diabetes with poorly controlled BP declined considerably between the 1970s and the 1990s (5). However, in recent studies using the National Health and Nutrition Examination Surveys (NHANES) data, no improvements in BP levels among adults with diabetes were observed from 1988–1994 to early 2000s (6) or from 1999 to 2006 (7). We updated prior studies with the most recent NHANES 2007–2008 data to examine long-term (between 1988–1994 and 2001–2008) and recent (between 2001–2004 and 2005–2008) changes in BP levels among U.S. adults with diagnosed diabetes.     

Is Prehypertension a Risk Factor for the Development of Type 2 Diabetes?

OBJECTIVE

Prehypertension is associated with cardiovascular disease and insulin resistance. However, whether subjects with prehypertension have more diabetes risk is not known. We examine whether prehypertension is a risk factor for developing type 2 diabetes.

RESEARCH DESIGN AND METHODS

Incident diabetes was examined in nondiabetic normotensive participants in the San Antonio Heart Study (n = 2,767; aged 25–65 years; median follow-up 7.8 years).

RESULTS

Incident diabetes was 12.4% in subjects with prehypertension and 5.6% in subjects with normal blood pressure. The odds of incident diabetes were 2.21 greater for individuals with prehypertension than for those with normal blood pressure (95% CI 1.63–2.98) after adjusting for age, sex, and ethnicity. Prehypertension was not associated with incident diabetes after additional adjustment for BMI, impaired glucose tolerance, insulin resistance and secretion, and family history of diabetes (odds ratio 1.42 [95% CI 0.99–2.02]).

CONCLUSIONS

Subjects with prehypertension are at increased risk of diabetes. Much of this risk is explained by disorders related to the insulin resistance syndrome.Hypertension predicts future cardiovascular disease (1,2) and type 2 diabetes (3). Prehypertension (systolic blood pressure [SBP] 120–139 mmHg and/or diastolic blood pressure [DBP] 80–89 mmHg), a novel blood pressure category of “The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report” (4), is also associated with increased cardiovascular risk (5,6) and insulin resistance (7). Furthermore, results from the Framingham Heart Study indicate that cardiovascular risk may be more relevant in individuals with SBP 130–139 mmHg and/or DBP 85–89 mmHg (8). Therefore, we investigated the relationship between prehypertension and incident type 2 diabetes in the San Antonio Heart Study (SAHS).     

Effect of intensive versus standard blood pressure control on depression and health-related quality of life in type 2 diabetes: the ACCORD trial

OBJECTIVE

We tested the hypothesis that intensive (systolic blood pressure [SBP] <120 mmHg) rather than standard (SBP 130–139 mmHg) blood pressure (BP) control improves health-related quality of life (HRQL) in those with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Subjects were 1,028 ACCORD (Action to Control Cardiovascular Risk in Diabetes) BP trial HRQL substudy participants who completed baseline and one or more 12-, 36-, or 48-month HRQL evaluations. Multivariable linear regression assessed impact of BP treatment assignment on change in HRQL.

RESULTS

Over 4.0 years of follow-up, no significant differences occurred in five of six HRQL measures. Those assigned to intensive (vs. standard) BP control had statistically significant worsening of the Medical Outcomes Study 36-item short-form health survey (SF36) physical component scores (−0.8 vs. −0.2; P = 0.02), but magnitude of change was not clinically significant. Findings persisted across all prespecified subgroups.

CONCLUSIONS

Intensive BP control in the ACCORD trial did not have a clinically significant impact, either positive or negative, on depression or patient-reported HRQL.In those with type 2 diabetes (T2DM), adequate blood pressure (BP) control may enhance control of hypertension (HT)-related symptoms and reduce the risk of major vascular events that impair health-related quality of life (HRQL) (1,2). However, the net impact of BP treatment on HRQL in patients with T2DM is determined by the balance of treatment burden, hypotension-related adverse events, and BP medication side effects on the one hand and potential reductions of cardiovascular disease (CVD) and microvascular events on the other (3).In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, intensive BP control did not reduce the main prespecified, composite macrovascular outcome, or reduce mortality or myocardial infarctions, although intensive BP treatment did reduce the rate of strokes (4,5). In light of mixed clinical results, the impact of BP interventions on HRQL may inform the selection of optimal BP targets by clinicians and patients.     

Nonalcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in patients with type 2 diabetes

OBJECTIVE

Data on cardiac function in patients with nonalcoholic fatty liver disease (NAFLD) are limited and conflicting. We assessed whether NAFLD is associated with abnormalities in cardiac function in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

We studied 50 consecutive type 2 diabetic individuals without a history of ischemic heart disease, hepatic diseases, or excessive alcohol consumption, in whom NAFLD was diagnosed by ultrasonography. A tissue Doppler echocardiography with myocardial strain measurement was performed in all patients.

RESULTS

Thirty-two patients (64%) had NAFLD, and when compared with the other 18 patients, age, sex, BMI, waist circumference, hypertension, smoking, diabetes duration, microvascular complication status, and medication use were not significantly different. In addition, the left ventricular (LV) mass and volumes, ejection fraction, systemic vascular resistance, arterial elasticity, and compliance were also not different. NAFLD patients had lower e′ (8.2 ± 1.5 vs. 9.9 ± 1.9 cm/s, P < 0.005) tissue velocity, higher E-to-e′ ratio (7.90 ± 1.3 vs. 5.59 ± 1.1, P < 0.0001), a higher time constant of isovolumic relaxation (43.1 ± 10.1 vs. 33.2 ± 12.9 ms, P < 0.01), higher LV–end diastolic pressure (EDP) (16.5 ± 1.1 vs. 15.1 ± 1.0 mmHg, P < 0.0001), and higher LV EDP/end diastolic volume (0.20 ± 0.03 vs. 0.18 ± 0.02 mmHg, P < 0.05) than those without steatosis. Among the measurements of LV global longitudinal strain and strain rate, those with NAFLD also had higher E/global longitudinal diastolic strain rate during the early phase of diastole (E/SR_E). All of these differences remained significant after adjustment for hypertension and other cardiometabolic risk factors.

CONCLUSIONS

Our data show that in patients with type 2 diabetes and NAFLD, even if the LV morphology and systolic function are preserved, early features of LV diastolic dysfunction may be detected.The prevalence of obesity and type 2 diabetes has reached epidemic proportions worldwide (1–3). It is known that type 2 diabetes is associated with premature death and is an established risk factor for cardiovascular disease (CVD), particularly for ischemic heart disease and chronic heart failure (2,3). Abnormalities in cardiac structure and function in type 2 diabetic individuals may, however, develop even in the absence of ischemic heart disease or hypertension. These abnormalities are attributed to diabetic cardiomyopathy, in which the basic pathophysiologic mechanisms still remain poorly known (4,5). Diabetic cardiomyopathy may induce changes in cardiac structure such as myocardial hypertrophy, fibrosis, and fat droplet deposition. Early changes in cardiac function are also manifested as abnormal diastolic function that with time can lead to loss of contractile function (4–7).In parallel, it is recognized that nonalcoholic fatty liver disease (NAFLD) is largely prevalent in subjects who are obese or have type 2 diabetes (8–10). Nowadays, growing evidence suggests that NAFLD is linked to increased risk of CVD events in nondiabetic and type 2 diabetic individuals (11). Several investigators have examined the association of NAFLD with markers of subclinical CVD (e.g., carotid artery intima-media thickness) or clinical CVD (11). Conversely, the information regarding abnormalities in cardiac function among NAFLD patients is limited and controversial. It has been shown that nondiabetic, normotensive patients with NAFLD have echocardiographic features of early left ventricular (LV) diastolic dysfunction as measured by tissue Doppler echocardiography (12,13) and impaired LV energy metabolism, as measured by cardiac ³¹P-magnetic resonance spectroscopy (MRS), compared with control subjects without steatosis (14). In a recent study involving type 2 diabetic men, Rijzewijk et al. (15) found that, compared with those with lower intrahepatic fat content, patients with higher intrahepatic fat content, as measured by ¹H-MRS, had impaired myocardial perfusion and lower high-energy phosphates but similar values of LV function and morphology (as detected by cardiac magnetic resonance imaging [MRI]).Since two-dimensional echocardiography using tissue Doppler imaging is the most simple and reliable imaging method to evaluate early, subclinical changes in LV function (4–7), we wanted to apply this technique to test whether subtle cardiac abnormalities could be detected in type 2 diabetic individuals with NAFLD in comparison with those without steatosis.     

Corneal Confocal Microscopy: A novel noninvasive test to diagnose and stratify the severity of human diabetic neuropathy

OBJECTIVE

The accurate quantification of human diabetic neuropathy is important to define at-risk patients, anticipate deterioration, and assess new therapies.

RESEARCH DESIGN AND METHODS

A total of 101 diabetic patients and 17 age-matched control subjects underwent neurological evaluation, neurophysiology tests, quantitative sensory testing, and evaluation of corneal sensation and corneal nerve morphology using corneal confocal microscopy (CCM).

RESULTS

Corneal sensation decreased significantly (P = 0.0001) with increasing neuropathic severity and correlated with the neuropathy disability score (NDS) (r = 0.441, P < 0.0001). Corneal nerve fiber density (NFD) (P < 0.0001), nerve fiber length (NFL), (P < 0.0001), and nerve branch density (NBD) (P < 0.0001) decreased significantly with increasing neuropathic severity and correlated with NDS (NFD r = −0.475, P < 0.0001; NBD r = −0.511, P < 0.0001; and NFL r = −0.581, P < 0.0001). NBD and NFL demonstrated a significant and progressive reduction with worsening heat pain thresholds (P = 0.01). Receiver operating characteristic curve analysis for the diagnosis of neuropathy (NDS >3) defined an NFD of <27.8/mm² with a sensitivity of 0.82 (95% CI 0.68–0.92) and specificity of 0.52 (0.40–0.64) and for detecting patients at risk of foot ulceration (NDS >6) defined a NFD cutoff of <20.8/mm² with a sensitivity of 0.71 (0.42–0.92) and specificity of 0.64 (0.54–0.74).

CONCLUSIONS

CCM is a noninvasive clinical technique that may be used to detect early nerve damage and stratify diabetic patients with increasing neuropathic severity.Established diabetic neuropathy leads to pain and foot ulceration. Detecting neuropathy early may allow intervention with treatments to slow or reverse this condition (1). Recent studies suggested that small unmyelinated C-fibers are damaged early in diabetic neuropathy (2–4) but can only be detected using invasive procedures such as sural nerve biopsy (4,5) or skin-punch biopsy (6–8). Our studies have shown that corneal confocal microscopy (CCM) can identify early small nerve fiber damage and accurately quantify the severity of diabetic neuropathy (9–11). We have also shown that CCM relates to intraepidermal nerve fiber loss (12) and a reduction in corneal sensitivity (13) and detects early nerve fiber regeneration after pancreas transplantation (14). Recently we have also shown that CCM detects nerve fiber damage in patients with Fabry disease (15) and idiopathic small fiber neuropathy (16) when results of electrophysiology tests and quantitative sensory testing (QST) are normal.In this study we assessed corneal sensitivity and corneal nerve morphology using CCM in diabetic patients stratified for the severity of diabetic neuropathy using neurological evaluation, electrophysiology tests, and QST. This enabled us to compare CCM and corneal esthesiometry with established tests of diabetic neuropathy and define their sensitivity and specificity to detect diabetic patients with early neuropathy and those at risk of foot ulceration.     

Lifestyle counseling in routine care and long-term glucose, blood pressure, and cholesterol control in patients with diabetes

OBJECTIVE

In clinical trials, diet, exercise, and weight counseling led to short-term improvements in blood glucose, blood pressure, and cholesterol levels in patients with diabetes. However, little is known about the long-term effects of lifestyle counseling on patients with diabetes in routine clinical settings.

RESEARCH DESIGN AND METHODS

This retrospective cohort study of 30,897 patients with diabetes aimed to determine whether lifestyle counseling is associated with time to A1C, blood pressure, and LDL cholesterol control in patients with diabetes. Patients were included if they had at least 2 years of follow-up with primary care practices affiliated with two teaching hospitals in eastern Massachusetts between 1 January 2000 and 1 January 2010.

RESULTS

Comparing patients with face-to-face counseling rates of once or more per month versus less than once per 6 months, median time to A1C <7.0% was 3.5 versus 22.7 months, time to blood pressure <130/85 mmHg was 3.7 weeks versus 5.6 months, and time to LDL cholesterol <100 mg/dL was 3.5 versus 24.7 months, respectively (P < 0.0001 for all). In multivariable analysis, one additional monthly face-to-face lifestyle counseling episode was associated with hazard ratios of 1.7 for A1C control (P < 0.0001), 1.3 for blood pressure control (P < 0.0001), and 1.4 for LDL cholesterol control (P = 0.0013).

CONCLUSIONS

Lifestyle counseling in the primary care setting is strongly associated with faster achievement of A1C, blood pressure, and LDL cholesterol control. These results confirm that the findings of controlled clinical trials are applicable to the routine care setting and provide evidence to support current treatment guidelines.Diabetes is increasingly common in the U.S. and worldwide (1,2). Elevated blood glucose, blood pressure, and LDL cholesterol are associated with increased risk for micro- and macrovascular complications, and their reduction decreases the risk (3–8). Nevertheless, most patients with diabetes do not have A1C, blood pressure, and LDL cholesterol under control (9,10).American and European guidelines widely recommend diet, exercise, and weight counseling with follow-up for patients with diabetes (11,12). Many short-term randomized clinical trials have shown that intensive lifestyle counseling interventions of up to 1 year in duration can lead to lower blood glucose (13–16) and blood pressure (17–21), but long-term data on the efficacy of lifestyle counseling are lacking (22–24). Furthermore, clinical trials typically involve resource-intensive interventions that may not be feasible in routine care, and the efficacy of lifestyle counseling in everyday clinical practice remains questionable (25–27). Consequently, further evidence is needed to establish that lifestyle counseling as practiced in routine care improves the outcomes of patients with diabetes.We therefore conducted a retrospective study of over 30,000 patients with diabetes and hyperglycemia, hypertension, and/or hyperlipidemia who received care in a primary care setting to test the hypothesis that higher rates of lifestyle counseling in routine care are associated with better diabetes control.     

Serum Levels of the Adipokine Chemerin in Relation to Renal Function

OBJECTIVE

To investigate serum levels of the adipokine chemerin in patients on chronic hemodialysis (CD) as compared with control patients with a glomerular filtration rate (GFR) >50 ml/min.

RESEARCH DESIGN AND METHODS

Chemerin was quantified by ELISA in control patients (n = 60) and CD patients (n = 60) and correlated with clinical and biochemical measures of renal function, glucose, and lipid metabolism, as well as inflammation, in both groups.

RESULTS

Median serum chemerin levels were more than twofold higher in CD patients (542.2 μg/l) compared with subjects with a GFR >50 ml/min (254.3 μg/l) (P < 0.001). Furthermore, GFR, as assessed by the original Modification of Diet in Renal Disease formula, independently predicted circulating chemerin concentrations in multiple regression analyses in both control patients (P < 0.05) and CD patients (P < 0.01).

CONCLUSIONS

We demonstrate that markers of renal function are independently related to circulating chemerin levels.Recently, chemerin has been identified as a novel adipocyte-secreted factor playing a crucial role in adipocyte differentiation and insulin signaling (1–4). Several studies have quantified circulating chemerin in humans. Thus, two reports found an independent association between chemerin and markers of inflammation (5,6). Furthermore, correlations between circulating chemerin and metabolic syndrome–related parameters have been described (6–8). In contrast to other adipokines (9–12), no data have been published so far about the relation of chemerin to renal function.     

Rates and Determinants of Coronary and Abdominal Aortic Artery Calcium Progression in the Veterans Affairs Diabetes Trial (VADT)

OBJECTIVE

To determine the predictors of progression of calcified atherosclerosis and the effect of intensive glycemic control on this process in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

As part of the Risk Factors, Atherosclerosis, and Clinical Events in Diabetes (RACED) substudy of the Veterans Affairs Diabetes Trial (VADT), 197 and 189 individuals with type 2 diabetes received baseline and follow-up computed tomographic scans for measurement of coronary and abdominal artery calcium, respectively. Standard and novel risk factors were assessed at baseline, and progression of calcified atherosclerosis was determined by several methods. Progression was defined both as a categorical (square root increase of volumetric scores ≥2.5 mm³) and continuous variable. In addition, annualized percent change of volume scores was determined.

RESULTS

After an average follow-up of 4.6 years, >75% of individuals demonstrated coronary (CAC) and abdominal artery calcification (AAC) progression. Progression increased with higher baseline calcium categories but was not influenced by standard risk factors. However, the albumin-to-creatinine ratio (ACR) (P = 0.02) and lipoprotein-associated phospholipase A₂ (Lp-PLA₂) (P = 0.01) predicted progression of CAC, and these results were not altered by adjustment for age and other traditional risk factors. Treatment assignment (intensive versus standard) within the VADT did not influence CAC or AAC progression, irrespective of baseline calcium category.

CONCLUSIONS

In patients with long-standing type 2 diabetes, baseline CAC, Lp-PLA₂, and ACR predicted progression of CAC. Intensive glycemic control during the VADT did not reduce progression of calcified atherosclerosis.Atherosclerosis is accelerated in patients with type 2 diabetes and underlies their higher incidence of cardiovascular disease (CVD) events. Noninvasive imaging of atherosclerosis, as measured by coronary (CAC) and abdominal aortic artery calcification (AAC), provides a useful tool to assess coronary and systemic atherosclerosis burden. Although both CAC and AAC scores have been shown to be strong predictors of subsequent cardiovascular morbidity and mortality (1,2), only a few studies have investigated the association of calcium progression with future events (3,4), and there is less certainty about the implications of progression of vascular calcification (5). In a study of asymptomatic subjects, CAC progression ≥15% was a strong predictor of future myocardial infarction (4). In addition, monitoring of CAC and AAC progression has been suggested as a possible method for assessing the treatment efficacy of medicines to reduce CVD risk (6,7). Therefore, an understanding of the determinants of progression of vascular calcium may provide insight into atherogenesis and development and treatment of CVD.Although the relationship of risk factors with extent of vascular calcification is relatively well recognized, determinants of progression, particularly in type 2 diabetes, have been less well studied. The large Multi-Ethnic Study of Atherosclerosis (MESA) reported that most standard cardiovascular risk factors were modestly associated with progression of CAC (8) in individuals without known CVD, and diabetes and the baseline calcium score were strong predictors of CAC progression (8). In patients with diabetes, baseline CAC, blood pressure, central adiposity, urine albumin-to-creatinine ratio (ACR), and suboptimal glycemic control have been reported as predictors of CAC progression (9–11). However, AAC progression has been investigated only in patients with end-stage renal disease (12). In addition, although there are strong correlations between cross-sectional measures of CAC and AAC and they share associations with several standard risk factors, clear differences in association of risk factors with the extent of CAC and AAC exist (13). Whether determinants of CAC and AAC progression differ in those with or without type 2 diabetes is not known, as previous studies have not addressed this question within the same cohort. Moreover, although mounting evidence supports the role of inflammation in atherogenesis, the relationship of subclinical inflammatory markers with the burden and progression of calcified atherosclerosis is still unclear (14). Finally, although the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) showed that intensive glycemic treatment was associated with lower incidence of CVD over time (15), the effect of intensive glycemic control on progression of calcified atherosclerosis in type 2 diabetes has not been directly examined.In this prospective VADT substudy, we characterized the pattern of both CAC and AAC progression in older patients with long-standing type 2 diabetes. In addition, we determined the relationship of both standard and novel inflammatory risk markers (C-reactive protein, interleukin-6 [IL-6], adiponectin, and lipoprotein-associated phospholipase A₂ [Lp-PLA₂]) with CAC and AAC progression. Finally, we provide the first report of the effect of intensive glycemic control on progression of CAC and AAC in patients with type 2 diabetes.     

Prothrombotic State, Cardiovascular, and Metabolic Syndrome Risk Factors in Prepubertal Children Born Large for Gestational Age

OBJECTIVE

To evaluate metabolic syndrome and cardiovascular disease risk factors in prepubertal children born large for gestational age (LGA) to nondiabetic, nonobese mothers.

RESEARCH DESIGN AND METHODS

At 6–7 years of age, the comparison of various factors was made between 31 LGA and 34 appropriate-for-gestational-age (AGA) children: fibrinogen, antithrombin III, protein C and S, fasting insulin, glucose, homeostasis assessment model of insulin resistance (HOMA-IR) index, adiponectin, leptin, visfatin, IGF-1, IGF-binding protein (IGFBP)-1, IGFBP-3, lipids, and the genetic factors V Leiden G1691A mutation, prothrombin 20210A/G polymorphism, and mutation in the enzyme 5,10-methylenetetrahydrofolate-reductase gene (MTHFR-C677T).

RESULTS

LGA children had higher levels of leptin (P < 0.01), fasting insulin (P < 0.01), and HOMA-IR (P < 0.01), but lower IGFBP-3 (P = 0.0001), fibrinogen (P = 0.0001), and lipoprotein(a) (P < 0.001) than AGA children. Significantly more LGA children were homozygous for the MTHFR-C677T mutation (P = 0.0016).

CONCLUSIONS

Being born LGA to nondiabetic, nonobese mothers is associated with diverse effects on cardiometabolic risk factors at prepuberty.Large-for-gestational-age (LGA) infants may be at risk for the development of obesity and insulin resistance (1–4). A relationship between excess birth weight and metabolic syndrome (MetS) and cardiovascular disease (CVD) risk factors (1–4) has not yet been clearly demonstrated.The aim of this study was to evaluate markers of the prothrombotic state and other MetS and CVD risk factors in prepubertal children born LGA to nondiabetic, nonobese mothers.     

initial angiotensin receptor blockade-induced decrease in albuminuria is associated with long-term renal outcome in type 2 diabetic patients with microalbuminuria: a post hoc analysis of the IRMA-2 trial

OBJECTIVE

We aimed to investigate the individual impact of initial responses in urinary albumin excretion (UAE) and systolic blood pressure (SBP) to angiotensin II receptor blocker (ARB) treatment on long-term renal outcome in patients with type 2 diabetes and microalbuminuria.

RESEARCH DESIGN AND METHODS

In a post hoc analysis of the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA)-2 trial we first assessed the individual variability in UAE and SBP response (0–6 months) in 531 subjects. Subsequently, we analyzed the individual effect of both response parameters on renal outcome defined as change in estimated glomerular filtration rate (eGFR) during 2 years of follow-up.

RESULTS

The median reductions in UAE and SBP in the population were −18% and −11 mmHg, respectively. In irbesartan-treated patients, 85 (24.4%) had a robust (>median) reduction in UAE but not in SBP (discordant SBP response) and 67 (19.3%) had a robust (>median) reduction in SBP but not in UAE (discordant UAE response). The degree of reduction in UAE was independently associated with the rate of eGFR decline (P = 0.0037). SBP showed a similar trend (P = 0.087). The relation between a larger UAE reduction and a slower rate of renal function decline was present in both cohorts with a SBP change above and below the median.

CONCLUSIONS

Within an individual, UAE response to ARB therapy may be discordant from SBP response. The initial change in UAE was independently associated with eGFR slope; the more UAE reduction the less eGFR decline, irrespective of the SBP change. These results suggest that in microalbuminuric patients with type 2 diabetes, UAE should be monitored after initiation of therapy and a separate target for renoprotective therapy.Current treatment strategies in diabetes separately target risk factors for micro- and macrovascular complications. HbA_1c is targeted with antidiabetic agents, cholesterol levels with statins, and blood pressure (BP) with antihypertensive agents. Agents blocking the renin-angiotensin-aldosterone system (RAAS) are first choice antihypertensives in patients with diabetes since these agents not only lower BP but also lower urinary albumin excretion (UAE), another important renal risk factor (1,2). Current guidelines recommend dose-titration of RAAS blockade on BP response to achieve a systolic BP (SBP) below 130 mmHg, without taking the response in UAE into account (3).It is known that the initial response in proteinuria during RAAS blockade independently determines renal outcome in patients with diabetes and proteinuria (4). Moreover, recent studies have illustrated that within an individual, the response in BP is not always paralleled by a response in proteinuria or vice versa (5). These so-called discordant responses allow a, albeit retrospective, look at whether the response of BP, proteinuria, or their combination is the driving parameter for renoprotection. Data in patients with proteinuria have demonstrated that long-term renoprotection is mainly achieved in those patients with an initial fall in proteinuria irrespective of the BP response. Accordingly, this suggests that a treatment approach solely focusing on BP reduction may not be the most efficacious way to achieve renoprotection (6–8). Whether responses in albuminuria irrespective of BP relate to long-term renoprotection in patients with microalbuminuria has not been published.We therefore performed a post hoc analysis in the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA-2) trial (9), investigating the variability in initial treatment responses in UAE and SBP in patients with type 2 diabetes and microalbuminuria. Second, we aimed to determine the impact of different UAE and SBP responses on renal outcome. This should provide insight as to whether albuminuria should be considered a target for renoprotective therapies in addition to BP in microalbuminuric patients.