Blood pressure and cardiovascular disease risk in the Veterans Affairs Diabetes Trial

OBJECTIVE

Blood pressure ranges associated with cardiovascular disease (CVD) events in advanced type 2 diabetes are not clear. Our objective was to determine whether baseline and follow-up (On-Study) systolic blood pressure (SBP), diastolic blood pressure (DBP), and SBP combined with DBP predict CVD events in the Veterans Affairs Diabetes Trial (VADT).

RESEARCH DESIGN AND METHODS

Participants in the VADT (n = 1,791) with hypertension received stepped treatment to maintain blood pressure below the target of 130/80 mmHg in standard and intensive glycemic treatment groups. Blood pressure levels of all subjects at baseline and On-Study were analyzed to detect associations with CVD risk. The primary outcome was the time from randomization to the first occurrence of myocardial infarction, stroke, congestive heart failure, surgery for vascular disease, inoperable coronary disease, amputation for ischemic gangrene, or CVD death.

RESULTS

Separated SBP ≥140 mmHg had significant risk at baseline (hazards ratio [HR] 1.508, P < 0.001) and On-Study (HR 1.469, P = 0.002). DBP <70 mmHg increased CVD events at baseline (HR 1.482, P < 0.001) and On-Study (HR 1.491, P < 0.001). Combined blood pressure categories indicated high risk for CVD events for SBP ≥140 with DBP <70 mmHg at baseline (HR 1.785, P = 0.03) and On-Study (HR 2.042, P = 0.003) and nearly all SBP with DBP <70 mmHg.

CONCLUSIONS

Increased risk of CVD events with SBP ≥140 mmHg emphasizes the urgency for treatment of systolic hypertension. Increased risk with DBP <70 mmHg, even when combined with SBP in guideline-recommended target ranges, supports a new finding in patients with type 2 diabetes. The results emphasize that DBP <70 mmHg in these patients was associated with elevated CVD risk and may best be avoided.Based on results of recent interventional trials (1–3), the question of whether or not intensive glucose control significantly reduces the risk of cardiovascular disease (CVD) in all patients with type 2 diabetes remains controversial. It may be beneficial in subgroups of these patients when severe hypoglycemia is avoided. Blood pressure (BP) control is consistently correlated with CVD events in studies of risk factors in type 2 diabetes. In the UK Prospective Diabetes Study, BP control was twice as effective as glucose control in preventing any diabetes end points (4,5). The Hypertension Optimal Treatment (HOT) study and the Appropriate Blood Pressure Control in Diabetes (ABCD) trial support improved BP control as a significant CVD event preventive factor in patients with diabetes (6–8). Both the American Diabetes Association (ADA) and the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) recommend treatment of BP in patients with diabetes to a target of <130/<80 mmHg (9,10). Current evidence supports a systolic blood pressure (SBP) level of <140 mmHg, but there is sparse information to guide physicians as to how far the SBP and diastolic blood pressure (DBP) can be lowered safely and whether lower BP levels might be associated with increased risk. We analyzed the BP data collected during the Veterans Affairs Diabetes Trial (VADT) to learn whether specific levels of BP in patients with type 2 diabetes predict CVD events.The VADT is a 20-center 1,791-patient prospective study of intensive versus standard glucose treatment in patients with suboptimal responses to maximum oral agents or insulin. The main objective was to assess the benefit of intensive glucose control for up to 7 years on CVD events in patients with advanced type 2 diabetes. Other objectives included the assessment of the effects on microvascular and neurological complications, cognitive function, quality of life, and cost-effectiveness. BP, lipids, diet, and lifestyle were treated identically in both arms. By improving BP control in an identical manner in both glucose arms, VADT excluded the effect of BP differences in CVD events between treatment arms and reduced the overall risk of macrovascular complications during the trial. The initial results were published recently (1).     

Observation on renal outcomes in the Veterans Affairs Diabetes Trial

OBJECTIVE

The Veterans Affairs Diabetes Trial (VADT) was a randomized, prospective, controlled trial of 1,791 patients with type 2 diabetes to determine whether intensive glycemic control would reduce cardiovascular events compared with standard control. The effect of intensive glycemic control and selected baseline variables on renal outcomes is reported.

RESEARCH DESIGN AND METHODS

Baseline mean age was 60.4 years, mean duration of diabetes was 11.5 years, HbA_1c was 9.4%, and blood pressure was 132/76 mmHg. The renal exclusion was serum creatinine >1.6 mg/dL. Renal outcomes were sustained worsening of the urine albumin-to-creatinine ratio (ACR) and sustained worsening by one or more stages in the estimated glomerular filtration rate (eGFR).

RESULTS

Intensive glycemic control did not independently reduce ACR progression but was associated with a significant attenuation in the progression of ACR in those who had baseline photocoagulation, cataract surgery, or both. The beneficial effect of intensive glycemic control increased with increasing BMI and with decreasing diastolic blood pressure (DBP). Intensive glycemic control was associated with less worsening of eGFR with increasing baseline ACR and insulin use. Baseline systolic blood pressure, triglycerides, and photocoagulation were associated with worsening of eGFR.

CONCLUSIONS

Intensive glycemic control had no significant effect on the progression of renal disease in the whole cohort but was associated with some protection against increasing ACR in those with more advanced microvascular disease, lower baseline DBP, or higher baseline BMI and on worsening of eGFR in those with high baseline ACR.We explored the available data from the Veterans Affairs Diabetes Trial (VADT) to determine which of the selected baseline characteristics predicted worsening of nephropathy and to assess any variables that have interactions with intensive (INT group) versus standard (STD group) glycemic treatment. The primary goal of the VADT was to compare the effects of intensive and standard glucose control on cardiovascular events (1). Final median glycated hemoglobin levels were 8.4% in the STD group and 6.9% in the INT group. Secondary outcomes included microvascular complications, such as retinopathy, nephropathy, and neuropathy. Nephropathy is a major microvascular complication of diabetes that is characterized by persistent albuminuria, a rise in arterial blood pressure, and a decline in glomerular filtration rate leading to chronic kidney disease (CKD) and end-stage renal failure. The main VADT showed that intensive glucose control had minimal effects on the incidence of renal failure, but there was a significant reduction (P = 0.01) in any worsening of the urine albumin-to-creatinine ratio (ACR) in the INT group (1). This article will further explore the relationship of risk factors and treatment on renal outcomes and help generate hypotheses for future testing.     

Aggressive Blood Pressure Control Increases Coronary Heart Disease Risk Among Diabetic Patients

OBJECTIVE

Blood pressure control can reduce the risk of coronary heart disease (CHD) among diabetic patients; however, it is not known whether the lowest risk of CHD is among diabetic patients with the lowest blood pressure level.

RESEARCH DESIGN AND METHODS

We performed a prospective cohort study (2000–2009) on diabetic patients including 17,536 African Americans and 12,618 whites. Cox proportional hazards regression models were used to estimate the association of blood pressure with CHD risk.

RESULTS

During a mean follow-up of 6.0 years, 7,260 CHD incident cases were identified. The multivariable-adjusted hazard ratios of CHD associated with different levels of systolic/diastolic blood pressure at baseline (<110/65, 110–119/65–69, 120–129/70–80, and 130–139/80–90 mmHg [reference group]; 140–159/90–100; and ≥160/100 mmHg) were 1.73, 1.16, 1.04, 1.00, 1.06, and 1.11 (P trend <0.001), respectively, for African American diabetic patients, and 1.60, 1.27, 1.08, 1.00, 0.95, and 0.99 (P trend<0.001) for white diabetic patients, respectively. A U-shaped association of isolated systolic and diastolic blood pressure at baseline as well as blood pressure during follow-up with CHD risk was observed among both African American and white diabetic patients (all Ptrend <0.001). The U-shaped association was present in the younger age-group (30–49 years), and this U-shaped association changed to an inverse association in the older age-group (≥60 years).

CONCLUSIONS

Our study suggests that there is a U-shaped or inverse association between blood pressure and the risk of CHD, and aggressive blood pressure control (blood pressure <120/70 mmHg) is associated with an increased risk of CHD among both African American and white patients with diabetes.Hypertension and diabetes are two important public health problems in the U.S. Hypertension is a prevalent condition affecting ~65 million Americans (1), and diabetes is considered ‘‘the epidemic of the 21st century,’’ affecting ~24 million Americans (2). As many as 70% of people aged >40 years who have diabetes are also affected by hypertension, with black and Hispanic individuals affected disproportionately compared with the rest of the population (3,4). All guidelines recommend that blood pressure goals should be more aggressive (<130/80 mmHg) in diabetic patients than in people without diabetes (<140/90 mmHg) (5–7). In the aggressive control of hypertension, the mantra of “lower is better” was mostly based on the landmark randomized clinical trials (RCTs) published in the 1990s (8–10) that established clear benefit with regard to cardiovascular risk reduction when blood pressure was lowered intensively in patients with diabetes.Aggressive targets for blood pressure treatment in type 2 diabetes guidelines have recently been questioned. Data from more contemporary populations with hypertension and diabetes do not confirm the benefit to coronary heart disease (CHD) of intensive blood pressure control (11,12). Specifically, a relationship between adverse cardiovascular outcomes and low blood pressure has been observed in some studies (13,14). However, most studies only use a single baseline measurement of blood pressure to predict CHD risk, which may produce potential bias. Moreover, very few studies have assessed the race-specific association of blood pressure with CHD risk. The aim of the current study is to examine the race-specific association between blood pressure and the risk of CHD among African American and white diabetic patients in the Louisiana State University Hospital–Based Longitudinal Study (LSUHLS).     

Diabetes and Vascular Disease in Different Arterial Territories

OBJECTIVE

The aim of this study was to investigate the relationship between diabetes and different phenotypes of peripheral vascular disease (lower extremity peripheral artery disease [PAD], carotid artery stenosis [CAS], and abdominal aortic aneurysm [AAA]).

RESEARCH DESIGN AND METHODS

Prevalence of vascular disease was evaluated in 3,696,778 participants of the Life Line Screening survey between 2003 and 2008. PAD was defined as ankle-brachial pressure index <0.90 or prior revascularization, CAS as ≥50% stenosis or prior revascularization, and AAA as infrarenal aortic diameter ≥3 cm or prior repair. Odds ratios (ORs) and 95% CIs were assessed using logistic regression modeling.

RESULTS

Diabetes mellitus was present in 10.8% of participants (n = 399,884). Prevalence of PAD, CAS, and AAA was significantly higher (P < 0.0001) in participants with compared with those without diabetes. After multivariate adjustment for baseline demographics and clinical risk factors, a significant interaction existed between diabetes and vascular disease phenotype (P < 0.0001). Diabetes was associated with increased odds of PAD (OR 1.42 [95% CI 1.41–1.4]; P < 0.0001) and CAS (1.45 [1.43–1.47]; P < 0.0001) but decreased odds of AAA (0.86 [0.84–0.88]; P < 0.0001). The strength of association increased with increasing severity of disease in each vascular phenotype, and this association persisted in the population with asymptomatic vascular disease.

CONCLUSIONS

In a large population-based study, the association between diabetes and vascular disease differed according to vascular phenotype. Future studies exploring the mechanism for these vascular-specific differences are needed.     

Higher Levels of Urinary Albumin Excretion Within the Normal Range Predict Faster Decline in Glomerular Filtration Rate in Diabetic Patients

OBJECTIVE

To assess the relationship between albuminuria, including elevation within the normal range, and decline in glomerular filtration rate (GFR) in diabetic patients.

RESEARCH DESIGN AND METHODS

A total of 5,449 Japanese diabetic patients were categorized according to sex and urinary albumin-to-creatinine ratio (ACR; <5, 5–9, 10–29, 30–99, 100–299, 300–999, 1,000–2,999, and ≥3,000 mg/g) and followed for at least 5 years. The rate of change in estimated GFR (eGFR) adjusted for age and baseline eGFR was compared among ACR categories.

RESULTS

A higher baseline ACR predicted a faster decline in eGFR for both sexes. Even within the normal range (<30 mg/g), ACR ≥10 mg/g in women and ≥5 mg/g in men was associated with a significantly greater rate of decline in eGFR relative to subjects with ACR <5 mg/g.

CONCLUSIONS

Elevated ACR, even within the normal range, is associated with a faster decline in eGFR in diabetic patients.Albuminuria and proteinuria are associated with subsequent progression of diabetic kidney disease (1–3). Recent studies suggest that elevated urinary albumin excretion, even within the normal range, is also associated with a greater risk of cardiovascular disease (4–6). Because normal urinary albumin excretion is defined using an arbitrary cutoff value (albumin-to-creatinine ratio [ACR] <30 mg/g [(7)]), we sought to determine whether diabetic patients with high-normal–range ACR have a faster decline in glomerular filtration rate (GFR).     

Incidence of Bladder Cancer in Patients With Type 2 Diabetes Treated With Metformin or Sulfonylureas

OBJECTIVE

Previous studies evaluating the effect of metformin on cancer risk have been impacted by time-related biases. To avoid these biases, we examined the incidence of bladder cancer in new users of metformin and sulfonylureas (SUs).

RESEARCH DESIGN AND METHODS

This cohort study included 87,600 patients with type 2 diabetes in The Health Improvement Network database. Use of metformin or an SU was treated as a time-dependent variable. Cox regression–generated hazard ratios (HRs) compared metformin use with SU use, adjusted for age, sex, smoking, obesity, and HbA_1c level.

RESULTS

We identified 196 incident bladder cancers in the metformin cohort and 66 cancers in the SU cohort. Use of metformin was not associated with decreased bladder cancer risk (HR 0.81 [95% CI 0.60–1.09]). This association did not differ by sex (P for interaction = 0.20). We observed no association with duration of metformin relative to SU use (3 to <4 years of use: 0.57 [0.25–1.34]; 4 to <5 years of use: 0.93 [0.30–2.85; ≥5 years of use: 1.18 [0.44–3.19]; P for trend = 0.26).

CONCLUSIONS

Use of metformin is not associated with a decreased incidence of bladder cancer. Similar methods should be used to study other cancers that have previously been identified as potentially preventable with metformin.     

Insulin Sensitivity Is an Important Determinant of Renal Health in Adolescents With Type 2 Diabetes

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 HbA_1c (P = 0.02 and P = 0.04). GIR, but not HbA_1c, 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 HbA_1c, blood pressure, or lipid control, was the strongest determinant of renal health.     

Prepregnancy SHBG Concentrations and Risk for Subsequently Developing Gestational Diabetes Mellitus

OBJECTIVE

Lower levels of sex hormone–binding globulin (SHBG) have been associated with increased risk of diabetes among postmenopausal women; however, it is unclear whether they are associated with glucose intolerance in younger women. We examined whether SHBG concentrations, measured before pregnancy, are associated with risk of gestational diabetes mellitus (GDM).

RESEARCH DESIGN AND METHODS

This was a nested case-control study among women who participated in the Kaiser Permanente Northern California Multiphasic Health Check-up examination (1984–1996) and had a subsequent pregnancy (1984–2009). Eligible women were free of recognized diabetes. Case patients were 256 women in whom GDM developed. Two control subjects were selected for each case patient and were matched for year of blood draw, age at examination, age at pregnancy, and number of intervening pregnancies.

RESULTS

Compared with the highest quartile of SHBG concentrations, the odds of GDM increased with decreasing quartile (odds ratio 1.06 [95% CI 0.44–2.52]; 2.33 [1.07–5.09]; 4.06 [1.90–8.65]; P for trend < 0.001), after adjusting for family history of diabetes, prepregnancy BMI, race/ethnicity, alcohol use, prepregnancy weight changes, and homeostasis model assessment of insulin resistance. Having SHBG levels below the median (<64.5 nmol/L) and a BMI ≥25.0 kg/m² was associated with fivefold increased odds of GDM compared with normal-weight women with SHBG levels at or above the median (5.34 [3.00–9.49]).

CONCLUSIONS

Low prepregnancy SHBG concentrations were associated with increased risk of GDM and might be useful in identifying women at risk for GDM for early prevention strategies.     

Impaired Renal Function Further Increases Odds of 6-Year Coronary Artery Calcification Progression in Adults With Type 1 Diabetes: The CACTI study

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.

RESULTS

Increasing 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 m² 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.Diabetic kidney disease is an important mediator of accelerated cardiovascular disease (CVD) and continues to be a major cause of morbidity and mortality in patients with type 1 diabetes (1–4). The FinnDiane study (5) and the Pittsburgh Epidemiology of Diabetes Complications (EDC) study (6) recently reported no excess mortality, compared with the general population, among adults with type 1 diabetes and free of kidney disease. Both studies, however, reported stepwise increases in mortality with increasing severity of kidney disease. Less is known about the association of diabetic kidney disease with subclinical atherosclerosis, i.e., whether these processes develop sequentially or in parallel.Although effective treatment exists to prevent or slow decline in renal function, improved early diagnostic (7,8) and treatment (9) methods are needed. Currently, clinical screening for kidney disease is performed by measuring albumin-to-creatinine ratio (ACR) or by measuring estimated glomerular filtration rate (eGFR). The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) recently published three updated glomerular filtration rate (GFR) estimating equations based on serum creatinine, cystatin C, or a combination of these markers (10). Both ACR and eGFR predict CVD and mortality (11,12).The Coronary Artery Calcification in Type 1 Diabetes (CACTI) study is a longitudinal cohort study designed to investigate the determinants of early and accelerated atherosclerosis in people with and without type 1 diabetes. Our objectives were to determine if ACR and eGFR predicted coronary artery calcification (CAC) progression over a 6-year follow-up, whether differences existed by sex, and how eGFR changed over 6 years in people with and without type 1 diabetes.     

Carotid-Femoral Pulse Wave Velocity Is Associated With Cerebral White Matter Lesions in Type 2 Diabetes

OBJECTIVE

Patients with type 2 diabetes have a high incidence of cardiovascular events including stroke. Increased arterial stiffness (AS) predicts cardiovascular events in the general population. Cerebral white matter lesions (WMLs) are associated with an increased risk of stroke. It is unknown whether AS in patients with type 2 diabetes is associated with WMLs.

RESEARCH DESIGN AND METHODS

We examined 89 patients recently diagnosed with type 2 diabetes (<5 years) and 89 sex- and age-matched controls. AS was assessed with carotid-femoral pulse wave velocity (PWV). WMLs were identified using magnetic resonance imaging and graded qualitatively with the Breteler scale (no/slight changes = 0, moderate changes = 1, severe changes = 2) and semiquantitatively.

RESULTS

The diabetic population had excellent glycemic control (HbA_1c, 6.5% [6.2–6.8]; median [interquartile range {IQR}]) and had, compared with the controls, lower office blood pressure (BP) (127 ± 12/79 ± 8 vs. 132 ± 14/84 ± 10 mmHg) and total cholesterol (4.3[3.9–4.7] vs. 5.6 [5.1–6.4]; mmol/L; median [IQR]), (P < 0.01 for all). Despite this, PWV was higher in the patients with diabetes compared with controls (9.3 ± 2.0 vs. 8.0 ± 1.6 m/s; P < 0.0001). PWV was associated with Breteler score (OR 1.36 [95% CI 1.17–1.58]; P < 0.001) and WML volume (OR 1.32 [95% CI 1.16–1.51]; P < 0.001) per 1 m/s increase in PWV. These associations remained significant when adjusted for age, sex, diabetes, 24-h mean arterial BP, BMI, heart rate, and use of antihypertensives and statins (Breteler score: OR 1.28 [95% CI 1.03–1.60]; P < 0.05 and WML volume: OR 1.30 [95% CI 1.06–1.58]; P < 0.05).

CONCLUSIONS

PWV was higher among patients with well-controlled type 2 diabetes compared with controls and was independently associated with WMLs. PWV may represent a clinically relevant parameter in the evaluation of cerebrovascular disease risk in type 2 diabetes.Despite intensified treatment, patients with type 2 diabetes have a significantly higher incidence of cardiovascular events, including stroke, compared with patients without diabetes (1–3). Identifying new risk factors for incident cardiovascular disease, which add prognostic information to established risk factors, is important to improve risk stratification and enable timely initiation of individually tailored preventive measures in this high-risk population (4). Increased arterial stiffness, as indicated by increased pulse wave velocity (PWV), is an independent predictor of cardiovascular morbidity and mortality and total mortality in various nondiabetic populations (5–11). In patients with diabetes, PWV independently predicts cardiovascular and total mortality (12). Several studies have found cerebral white matter lesions (WMLs) to be associated with the risk of stroke (13). Nevertheless, it remains unknown whether PWV in patients with type 2 diabetes is associated with the severity of WMLs. In this study of a sample of patients with recently diagnosed type 2 diabetes and a sex- and age-matched control group, our aims were to 1) compare PWV and established cardiovascular risk factors and 2) study the association between PWV and WMLs.     

A Randomized Trial of a Home System to Reduce Nocturnal Hypoglycemia in Type 1 Diabetes

OBJECTIVE

Overnight hypoglycemia occurs frequently in individuals with type 1 diabetes and can result in loss of consciousness, seizure, or even death. We conducted an in-home randomized trial to determine whether nocturnal hypoglycemia could be safely reduced by temporarily suspending pump insulin delivery when hypoglycemia was predicted by an algorithm based on continuous glucose monitoring (CGM) glucose levels.

RESEARCH DESIGN AND METHODS

Following an initial run-in phase, a 42-night trial was conducted in 45 individuals aged 15–45 years with type 1 diabetes in which each night was assigned randomly to either having the predictive low-glucose suspend system active (intervention night) or inactive (control night). The primary outcome was the proportion of nights in which ≥1 CGM glucose values ≤60 mg/dL occurred.

RESULTS

Overnight hypoglycemia with at least one CGM value ≤60 mg/dL occurred on 196 of 942 (21%) intervention nights versus 322 of 970 (33%) control nights (odds ratio 0.52 [95% CI 0.43–0.64]; P < 0.001). Median hypoglycemia area under the curve was reduced by 81%, and hypoglycemia lasting >2 h was reduced by 74%. Overnight sensor glucose was >180 mg/dL during 57% of control nights and 59% of intervention nights (P = 0.17), while morning blood glucose was >180 mg/dL following 21% and 27% of nights, respectively (P < 0.001), and >250 mg/dL following 6% and 6%, respectively. Morning ketosis was present <1% of the time in each arm.

CONCLUSIONS

Use of a nocturnal low-glucose suspend system can substantially reduce overnight hypoglycemia without an increase in morning ketosis.     

The Prevalence of Meeting A1C,Blood Pressure,and LDL Goals Among People With Diabetes, 1988–2010

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 DESIGN AND 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.

RESULTS

In 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.During the past 2 decades, the prevalence of diagnosed diabetes in the U.S. has more than doubled, from 3.8% in 1988 to 8.7% in 2010 (1), foreboding future growth in premature death, morbidity, and economic costs, largely associated with its complications (1,2). However, that a reduction in hemoglobin A_1c (A1C) and blood pressure (BP) levels significantly reduces microvascular complications has been well established (2). In addition, BP and lipid control substantially reduce cardiovascular disease (CVD), the major cause of death for individuals with diabetes (2). On the basis of this research, the American Diabetes Association (ADA) recommends that most adults with diabetes achieve an A1C <7.0% (<53 mmol/mol), BP <130/80 mmHg, and LDL cholesterol <100 mg/dL (ABCs) (3). The ADA also recommends statin therapy for diabetic individuals with overt CVD, for those aged >40 years with one or more other CVD risk factors, and for lower-risk patients if LDL remains >100 mg/dL.The National Diabetes Education Program (NDEP) was initiated in 1997 to disseminate evidence-based information on diabetes management, including the importance of meeting the ABC goals (4). Although the percentage of people with diabetes who achieve the ABC goals has increased since NDEP was initiated, the most recent estimates indicate that control remains suboptimal. National Health and Nutrition Examination Survey (NHANES) data indicate that the prevalence of achieving an A1C <7.0% (<53 mmol/mol) increased from 44% in 1988–1994 to 57% in 2003–2006; achieving a BP <130/80 mmHg increased from 29 to 46% during the same interval (5,6). In addition, LDL cholesterol improved: in 1999–2002, 36% had LDL <100 mg/dL compared with 46% in 2003–2006. Only 7% of people with diabetes in 1999–2002 and 12% in 2003–2006 met all three ABC goals (5). Evidence for the value of LDL cholesterol control comes from trials of statin therapy, and, importantly, the use of statins increased over the last decade (7). Knowledge of current estimates and trends in achieving the ABCs and the use of statin medication is important for health care providers and public health officials.This study updates national estimates on the percentage of people with diabetes who meet ABC goals and assesses changes over time in achievement from 1988 to 2010 using national data from the NHANES.     

Mismatch of Sleep and Work Timing and Risk of Type 2 Diabetes

OBJECTIVE

To examine whether a mismatch between chronotype (i.e., preferred sleep timing) and work schedule is associated with type 2 diabetes risk.

RESEARCH DESIGN AND METHODS

In the Nurses’ Health Study 2, we followed 64,615 women from 2005 to 2011. Newly developed type 2 diabetes was the outcome measure (n = 1,452). A question on diurnal preference ascertained chronotype in 2009; rotating night shift work exposure was assessed regularly since 1989.

RESULTS

Compared with intermediate chronotypes, early chronotypes had a slightly decreased diabetes risk after multivariable adjustment (odds ratio 0.87 [95% CI 0.77–0.98]), whereas no significant association was observed for late chronotypes (1.04 [0.89–1.21]). Among early chronotypes, risk of type 2 diabetes was modestly reduced when working daytime schedules (0.81 [0.63–1.04]) and remained similarly reduced in women working <10 years of rotating night shifts (0.84 [0.72–0.98]). After ≥10 years of shift work exposure, early chronotypes had a nonsignificant elevated diabetes risk (1.15 [0.81–1.63], P_trend = 0.014). By contrast, among late chronotypes, the significantly increased diabetes risk observed among day workers (1.51 [1.13–2.02]) appeared largely attenuated if their work schedules included night shifts (<10 years: 0.93 [0.76–1.13]; ≥10 years: 0.87 [0.56–1.34]; P_trend = 0.14). The interaction between chronotype and shift work exposure was significant (P_interaction = 0.0004). Analyses restricting to incident cases revealed similar patterns.

CONCLUSIONS

In early chronotypes, type 2 diabetes risk increased with increasing duration of shift work exposure, whereas late types had the highest diabetes risk working daytime schedules. These data add to the growing body of evidence that workers could benefit from shift schedules minimizing interference with chronotype-dependent sleep timing.     

Association of Race/Ethnicity,Inflammation, and Albuminuria in Patients With Diabetes and Early Chronic Kidney Disease

OBJECTIVE

African Americans (AAs) and Hispanics have higher diabetes and end-stage renal disease but similar or lower early chronic kidney disease (CKD) compared with whites. Inflammation plays a critical role in the pathogenesis of diabetes-related CKD. We postulated that in contrast to the general population, AAs and Hispanics have a higher prevalence of early diabetic CKD and systemic inflammatory markers compared with whites.

RESEARCH DESIGN AND METHODS

We analyzed the National Health and Nutrition Examination Survey 1999–2008 of 2,310 diabetic patients aged ≥20 years with fasting plasma glucose (FPG) ≥126 mg/dL. We performed multiple linear regression among patients with early CKD (urinary albumin excretion [UAE] ≥30 μg/mL and estimated glomerular filtration rate ≥60 mL/min/1.73 m²) to test the relationship between UAE and C-reactive protein (CRP) by race/ethnicity, adjusting for demographics, diabetes duration, FPG, hemoglobin A_1c, uric acid, white blood cell count, medication use, cardiovascular disease, and related parameters.

RESULTS

In patients with diabetes, the prevalence of early CKD was greater among Hispanics and AAs than whites (P < 0.0001). AAs had higher adjusted odds ratio (AOR) for CRP ≥0.2 mg/dL (AOR 1.81 [95% CI 1.19–2.78]), and Hispanics had higher AOR for UAE ≥30 μg/mL (AOR 1.65 [1.07–2.54]). In a regression model adjusted for confounding variables, there was a significant association between UAE and CRP in the mid-CRP tertile (CRP 0.20–0.56 mg/dL, P = 0.001) and highest CRP tertile (CRP ≥0.57 mg/dL, P = 0.01) for Hispanics, but only in the mid-CRP tertile (P = 0.04) for AAs, compared with whites.

CONCLUSIONS

AAs and Hispanics with diabetes have a higher prevalence of early CKD compared with whites, which is significantly associated with UAE and/or CRP.     

Restoring Insulin Secretion (RISE): Design of Studies of β-Cell Preservation in Prediabetes and Early Type 2 Diabetes Across the Life Span

OBJECTIVE

The Restoring Insulin Secretion (RISE) Consortium is testing interventions designed to preserve or improve β-cell function in prediabetes or early type 2 diabetes.

RESEARCH DESIGN AND METHODS

β-Cell function is measured using hyperglycemic clamps and oral glucose tolerance tests (OGTTs). The adult medication protocol randomizes participants to 12 months of placebo, metformin alone, liraglutide plus metformin, or insulin (3 months) followed by metformin (9 months). The pediatric medication protocol randomizes participants to metformin or insulin followed by metformin. The adult surgical protocol randomizes participants to gastric banding or metformin (24 months). Adult medication protocol inclusion criteria include fasting plasma glucose 95–125 mg/dL (5.3–6.9 mmol/L), OGTT 2-h glucose ≥140 mg/dL (≥7.8 mmol/L), HbA_1c 5.8–7.0% (40–53 mmol/mol), and BMI 25–40 kg/m². Adult surgical protocol criteria are similar, except for fasting plasma glucose ≥90 mg/dL (≥5.0 mmol/L), BMI 30–40 kg/m², HbA_1c <7.0% (<53 mmol/mol), and diabetes duration <12 months. Pediatric inclusion criteria include fasting plasma glucose ≥90 mg/dL (≥5.0 mmol/L), 2-h glucose ≥140 mg/dL (≥7.8 mmol/L), HbA_1c ≤8.0% (≤64 mmol/mol), BMI >85th percentile and ≤50 kg/m², 10–19 years of age, and diabetes <6 months.

RESULTS

Primary outcomes are clamp-derived glucose-stimulated C-peptide secretion and maximal C-peptide response to arginine during hyperglycemia. Measurements are made at baseline, after 12 months on treatment, and 3 months after treatment withdrawal (medication protocols) or 24 months postintervention (surgery protocol). OGTT-derived measures are also obtained at these time points.

CONCLUSIONS

RISE is determining whether medication or surgical intervention strategies can mitigate progressive β-cell dysfunction in adults and youth with prediabetes or early type 2 diabetes.     

Genetic Risk Score Associations With Cardiovascular Disease and Mortality in the Diabetes Heart Study

OBJECTIVE

Given the high rates of cardiovascular disease (CVD) and associated mortality in individuals with type 2 diabetes, identifying and understanding predictors of CVD events and mortality could help inform clinical management in this high-risk group. Recent large-scale genetic studies may provide additional tools in this regard.

RESEARCH DESIGN AND METHODS

Genetic risk scores (GRSs) were constructed in 1,175 self-identified European American (EA) individuals comprising the family-based Diabetes Heart Study based on 1) 13 single nucleotide polymorphisms (SNPs) and 2) 30 SNPs with previously documented associations with CVD in genome-wide association studies. Associations between each GRS and a self-reported history of CVD, coronary artery calcified plaque (CAC) determined by noncontrast computed tomography scan, all-cause mortality, and CVD mortality were examined using marginal models with generalized estimating equations and Cox proportional hazards models.

RESULTS

The weighted 13-SNP GRS was associated with prior CVD (odds ratio [OR] 1.51 [95% CI 1.22–1.86]; P = 0.0002), CAC (β-coefficient [β] 0.22 [0.02–0.43]; P = 0.04) and CVD mortality (hazard ratio [HR] 1.35 [1.10–1.81]; P = 0.04) when adjusting for the other known CVD risk factors: age, sex, type 2 diabetes affection status, BMI, current smoking status, hypertension, and dyslipidemia. The weighted 30-SNP GRS was also associated with prior CVD (OR 1.33 [1.08–1.65]; P = 0.008), CAC (β 0.29 [0.08–0.50]; P = 0.006), all-cause mortality (HR 1.28 [1.05–1.56]; P = 0.01), and CVD mortality (HR 1.46 [1.08–1.96]; P = 0.01).

CONCLUSIONS

These findings support the utility of two simple GRSs in examining genetic associations for adverse outcomes in EAs with type 2 diabetes.     

Maternal Hyperglycemia During Pregnancy Predicts Adiposity of the Offspring

OBJECTIVE

To investigate associations between maternal pregnancy hyperglycemia, gestational diabetes mellitus (GDM), and offspring adiposity.

RESEARCH DESIGN AND METHODS

We evaluated these associations in a longitudinal study of 421 mother-daughter pairs at Kaiser Permanente Northern California. Maternal pregnancy glucose values were obtained from maternal medical records. Outcomes included three measures of girls’ adiposity, measured annually: 1) ≥85th age-specific percentile for BMI; 2) percent body fat (%BF); and 3) waist-to-height ratio (WHR).

RESULTS

Adjusting for maternal age at delivery, race/ethnicity, pregravid BMI, girl’s age, and girl’s age at onset of puberty, having a mother with GDM increased a girl’s risk of having a BMI ≥85th percentile or having %BF or WHR in the highest quartile (Q4), compared with those in the lowest quintile of blood glucose (odds ratio [OR] 3.56 [95% CI 1.28–9.92]; OR 3.13 [95% CI 1.08–9.09]; and OR 2.80 [95% CI 1.00–7.84], respectively). There was a significant interaction between the presence of GDM and pregravid BMI; girls whose mothers had both risk factors had the highest odds of having a BMI ≥85th percentile (OR 5.56 [95%CI 1.70–18.2]; Q4 %BF, OR 6.04 [95%CI 1.76–20.7]; and Q4 WHR, OR 3.60 [95%CI 1.35–9.58]). Similar, although weaker, associations were found in the association between hyperglycemia and offspring adiposity.

CONCLUSIONS

Girls who were exposed to maternal GDM or hyperglycemia in utero are at higher risk of childhood adiposity; risk increases if the mother is overweight or obese. Screening and intervention for this high-risk group is warranted to slow the intergenerational transmission of obesity and its sequelae.     

Discrepancy of blood pressure between the brachial artery and radial artery

BACKGROUND:

In this study, we attempted to find the relations between blood pressure (BP) measured on the brachial artery (bBP) and BP assessed on the radial artery (rBP) in the right arm.

METHODS:

Three hundred and fifteen patients were enrolled in this study. Those who had peripheral vascular disease, wounds of arm skin or subcutaneous tissue infection were excluded. After a 15-minute equilibration and stabilization period after inducation of anesthesia, three bBP and rBP records were obtained sequentially using an oscillometric device with an adult cuff and infant cuff, respectively. Order for each BP was randomized.

RESULTS:

The bBP was significantly lower than the rBP (P<0.05). The difference between the two values varied from 13 to 18 mmHg in systolic BP (SBP), diastolic BP (DBP) and mean blood pressure (MAP) respectively. And the rBP was positively correlated with the bBP (r=0.872, 0.754, 0.765; P<0.001, <0.001, <0.001; SBP, DBP, MAP, respectively).

CONCLUSION:

The bBP value can be evaluated by the noninvasive measurements of rBP using an appropriate cuff in clinical practice.KEY WORDS: Blood pressure, Brachial artery, Radial artery, Correlation, Linear regression     

The Effect of Intensive Glucose Lowering on Lipoprotein Particle Profiles and Inflammatory Markers in the Veterans Affairs Diabetes Trial (VADT)

OBJECTIVE

Intensive glucose-lowering therapy (INT) did not reduce macrovascular events in the recent randomized trials, possibly because it did not improve or worsen other traditional or novel cardiovascular risk factors.

RESEARCH DESIGN AND METHODS

Standard plasma lipids, cholesterol content of lipoprotein subfractions, and plasma inflammatory and prothrombotic markers were determined in a subgroup of the Veterans Affairs Diabetes Trial (VADT) participants (n = 266) at baseline and after 9 months of INT or standard therapy.

RESULTS

INT lowered glycated hemoglobin (by a median of 2% vs. a median of 0.7% by standard treatment; P < 0.0001); increased BMI (4 vs. 1%; P < 0.001), total HDL (9 vs. 4%; P < 0.05), HDL2 (14 vs. 0%; P = 0.009), LDL2 (36 vs. 1%; P < 0.0001), and plasma adiponectin (130 vs. 80%; P < 0.01); and reduced triglycerides (−13 vs. −4%; P = 0.02) and small, dense LDL4 (−39 vs. −13%; P < 0.001), but had no effect on levels of plasma apolipoproteins B-100 and B-48, C-reactive protein, interleukin-6, lipoprotein-associated phospholipase A2, myeloperoxidase, fibrinogen, and plasminogen activator inhibitor 1. Incident macrovascular events were associated with baseline interleukin-6 (hazard ratio per each quartile increase 1.33 [95% CI 1.06–1.66]), total LDL (1.25 [1.01–1.55]), apolipoprotein B-100 (1.29 [1.01–1.65]), and fibrinogen (1.26 [1.01–1.57]) but not changes in any cardiovascular risk factors at 9 months.

CONCLUSIONS

INT was associated with improved adiponectin, lipid levels, and a favorable shift in LDL and HDL subfractions after 9 months. These data suggest that the failure of INT to lower cardiovascular outcomes occurred despite generally favorable changes in standard and novel risk factors early in the study.Increased concentrations of small, dense lipoprotein particles, elevated levels of prothrombotic factors, and chronic low-grade inflammation are associated with insulin resistance and hyperglycemia and may contribute to increased risk of atherosclerosis and clinical macrovascular events (1–8). In several recent large randomized trials, intensive glucose-lowering therapy (INT) did not significantly decrease cardiovascular outcomes in type 2 diabetes, suggesting that targeting glycemic control alone is insufficient (9–11). One possible explanation is that intensive glucose lowering did not improve, or perhaps worsened, other relevant cardiovascular risk factors (10,12).This study evaluated the effect of intensive glucose lowering on lipoprotein classes and subclasses, apolipoproteins B-100 and B-48, and concentrations of inflammatory and prothrombotic markers in the Risk Factors, Atherosclerosis and Clinical Events in Diabetes (RACED) substudy of the Veterans Affairs Diabetes Trial (VADT) (13). The VADT was a randomized trial comparing the effects of intensive and standard glucose lowering on new clinical macrovascular events in 1,791 military veterans who had a suboptimal response to therapy for type 2 diabetes (10). A 9-month follow-up interval was chosen for collection of blood for analysis of novel risk factors. This allowed us to capture changes in risk factors after glycemic control had stabilized (approximately 6 months into the VADT) and provided the opportunity to assess the prospective association between changes in traditional and novel cardiovascular risk factors and subsequent cardiovascular events (10).     

Evolution of Abnormal Plasma Glucagon Responses to Mixed-Meal Feedings in Youth With Type 1 Diabetes During the First 2 Years After Diagnosis

OBJECTIVE

To examine the evolution of the dysregulated glucagon responses to mixed-meal tolerance tests (MMTTs) in youth with recent-onset type 1 diabetes (T1D).

RESEARCH DESIGN AND METHODS

MMTTs were performed in 25 youth (9–18 years of age) with 1.5–12 months disease duration (year 1); 22 subjects were restudied 1 year later (year 2). Twenty nondiabetic (ND) control children were also studied.

RESULTS

In T1D children, MMTT-stimulated increases in glucagon were significantly greater than that in ND children (median increments: year 1, 21 pg/mL [16–30]; year 2, 25 pg/mL [16–30]; ND, 9 pg/mL [5–16]; P = 0.001 and P < 0.001, respectively).

CONCLUSIONS

In comparison with ND control children, exaggerated plasma glucagon responses to mixed-meal feedings are observed in youth with T1D within the first 2 years of diagnosis. Further studies to determine whether suppression of these abnormal responses may help to improve glycemic control are warranted.