The rise and fall of HbA1c as a risk marker for diabetes complications

It is still unclear whether short-term, within-day, variability in glycaemic control is contributory to the development of diabetes micro- or macrovascular complications. However, consistent and compelling data are emerging that longer term fluctuations in glucose, as evidenced by increases in HbA_1c variability, do indeed add to the mean HbA_1c value in predicting the risk of microvascular disease. Until now, studies have found this to be the case mainly in type 1 diabetes, but in this issue of Diabetologia (DOI: ) an analysis of the Tsukuba Kawai Diabetes Registry in Japan has found that HbA_1c variability also predicts the risk of nephropathy in type 2 diabetic patients. These observations raise the possibility that reducing rises and falls in HbA_1c may help avoid hyperglycaemia-related vascular disease without running the same risk of hypoglycaemia that a strategy focusing purely on lower HbA_1c might incur.     

Nutrition-related cardiovascular risk factors in older people: results from the Third National Health and Nutrition Examination Survey

SETTING: In view of the recognized potential benefits of nutritional therapy in older persons, Congress is evaluating the coverage of nutritional services for Medicare beneficiaries. OBJECTIVE: To estimate the number of older persons in the US who have one or more cardiovascular risk factors (hypertension, increased low density lipoprotein (LDL) cholesterol, and diabetes mellitus), for which nutritional therapy is recommended. DESIGN: Cross-sectional analysis of adults, aged > or = 65, participating in the Third National Health and Nutrition Examination Survey (NHANES III). MAIN OUTCOMES: The authors estimated the proportion of adults, aged > or = 65, with diabetes mellitus, increased LDL cholesterol, and/or hypertension. Efforts were made to assess whether obesity status, gender, race, and/or socioeconomic factors were associated with the prevalence of any or all three conditions. RESULTS: Approximately 86% (20 million persons) in the US, aged > or = 65, have at least one of the index conditions. Whereas a higher body mass index (BMI) increased the likelihood of having any or all three conditions, 81% of persons of average body weight (BMI <25 kg/m2) had at least one condition. After adjusting for age, gender, BMI, marital status, and poverty index, blacks were more likely than whites to have any one condition (odds ratio (OR) = 3.0, P < .01) or all three conditions (OR = 2.3, P = .05). CONCLUSIONS: Almost 90% of Americans aged > or = 65 have one or more nutrition-related cardiovascular risk factors. Improved nutritional interventions may be valuable especially for blacks, who have a higher prevalence of conditions requiring nutritional therapy.     

Hemoglobin A1c predicts diabetes but not cardiovascular disease in nondiabetic women

Background

Hemoglobin A1c (HbA1c) is a marker of cumulative glycemic exposure over the preceding 2- to 3-month period. Whether mild elevations of this biomarker provide prognostic information for development of clinically evident type 2 diabetes and cardiovascular disease among individuals at usual risk for these disorders is uncertain.

Methods

We examined baseline HbA1c levels as a predictor of incident clinical diabetes and cardiovascular disease (nonfatal myocardial infarction, coronary revascularization procedure, ischemic stroke, or death from cardiovascular causes) in a prospective cohort study beginning in 1992 of 26,563 US female health professionals aged 45 years or more without diagnosed diabetes or vascular disease (median follow-up 10.1 years).

Results

During follow-up, 1238 cases of diabetes and 684 cardiovascular events occurred. In age-adjusted analyses using quintiles of HbA1c, a risk gradient was observed for both incident diabetes and cardiovascular disease. After multivariable adjustment, HbA1c remained a strong predictor of diabetes but was no longer significantly associated with incident cardiovascular disease. In analyses of threshold effects, adjusted relative risks for incident diabetes in HbA1c categories of less than 5.0%, 5.0% to 5.4%, 5.5% to 5.9%, 6.0% to 6.4%, 6.5% to 6.9%, and 7.0% or more were 1.0, 2.9, 12.1, 29.3, 28.2, and 81.2, respectively. Risk associations persisted after additional adjustment for C-reactive protein and after excluding individuals developing diabetes within 2 and 5 years of follow-up.

Conclusions

These prospective findings suggest that HbA1c levels are elevated well in advance of the clinical development of type 2 diabetes, supporting recent recommendations for lowering of diagnostic thresholds for glucose metabolic disorders. In contrast, the association of HbA1c with incident cardiovascular events is modest and largely attributable to coexistent traditional risk factors.     

Hemoglobin A1c and diagnosis of diabetes

The prevalence of diabetes is increasing markedly worldwide, especially in China. Hemoglobin A1c is an indicator of mean blood glucose concentrations and plays an important role in the assessment of glucose control and cardiovascular risk. In 2010, the American Diabetes Association included HbA1c ≥6.5% into the revised criteria for the diagnosis of diabetes. However, the debate as to whether HbA1c should be used to diagnose diabetes is far from being settled and there are still unanswered questions regarding the cut‐off value of HbA1c for diabetes diagnosis in different populations and ethnicities. This review briefly introduces the history of HbA1c from discovery to diabetes diagnosis, key steps towards using HbA1c to diagnose diabetes, such as standardization of HbA1c measurements and controversies regarding HbA1c cut‐off points, and the performance of HbA1c compared with glucose measurements in the diagnosis of diabetes.     

Abdominal volume index trajectories and risk of diabetes mellitus: Results from the China Health and Nutrition Survey

Aims/IntroductionAbdominal obesity is a risk factor for developing diabetes mellitus, but trajectories of abdominal obesity over time and incident diabetes mellitus have not been considered. We derived trajectories of abdominal volume index (AVI) over 16 years of follow up, and examined the associations between AVI trajectories and risk of diabetes mellitus.Materials and MethodsData were used from the China Health and Nutrition Survey, and 5,267 participants were enrolled to fit the trajectory of AVI by using latent class growth models. Multivariate logistic regression models explored the relationship between different AVI trajectories and risk of diabetes mellitus. In addition, we examined the slope of the AVI trajectories in relation to age to identify appropriate life course intervention opportunities for the prevention of diabetes mellitus.ResultsThree trajectories were derived reflecting graded categories in the speed and slope of increase in AVI over time: slow, intermediate and fast increase group, respectively. After multivariate adjustment, the odds ratios for diabetes mellitus among those in the intermediate and fast increase groups were 1.81 (95% confidence interval 1.37–2.38, P < 0.001) and 2.80 (95% confidence interval 1.85–4.24, P < 0.001) respectively, relative to the slow increase group. The distribution of AVI slope in the slow increase group showed an inverted "U" shape, whereas the fast increase group presented a "U" shape.ConclusionsAVI trajectory is associated with an increased risk of diabetes mellitus. These results provide new insights on the relationship between abdominal adiposity and diabetes mellitus, which in turn can help improve clinical and public health intervention for diabetes mellitus prevention.     

Dietary sodium and potassium and risk of diabetes: A prospective study using data from the China Health and Nutrition Survey

AimsDietary sodium and potassium intakes are well-known risk factors for cardiovascular outcomes. However, the associations between dietary sodium and potassium and diabetes are still controversial. Our study aimed to examine whether dietary sodium, potassium and the sodium–potassium ratio are associated with the risk of diabetes, based on a large sample of Chinese adults.MethodsThe study data were from the 2004–2009 China Health and Nutrition Survey (CHNS), and 5867 participants were eligible for analysis. Sodium and potassium intakes were estimated based on three consecutive 24-h recalls at an individual level combined with a food inventory at a household level performed over the same 3-day period. Diabetes was defined as fasting glucose ≥ 7.0 mmol/L (≥ 126 mg/dL), HbA_1c ≥ 6.5% or use of antidiabetic drugs.ResultsOver a mean follow-up of 4.7 years, there were 611 (10.4%) incident cases of diabetes. Participants in the higher quartiles (Q3 and Q4) of sodium intake had significantly higher risks of diabetes than those with the lowest sodium intake [Q3, RR: 1.41, 95% CI: 1.06–1.86 and Q4, RR: 1.35, 95% CI: 1.02–1.80; P < 0.001 for trend]. In addition, high sodium intakes were significantly associated with levels of fasting glucose and HbA_1c (P < 0.05 for trend), with similar associations also found with sodium–potassium ratios (P < 0.05 for trend), but not for potassium intakes.ConclusionThis study found that higher sodium intakes and sodium–potassium ratios were significantly associated with a higher risk of diabetes. Further clinical research is now necessary to confirm these results.     

The expanding burden of cardiometabolic risk in China: the China Health and Nutrition Survey

China faces a major increase in cardiovascular disease, yet there is limited population‐based data on risk factors, particularly in children. Fasting blood samples, anthropometry and blood pressure were collected on 9,244 children and adults aged ≥7 years in late 2009 as part of the national China Health and Nutrition Survey. Prevalent overweight, elevated blood pressure, and cardiometabolic risk factors: glucose, HbA1c, triglycerides (TG), total cholesterol (TC), high‐ and low‐density lipoprotein cholesterol (HDL‐C and LDL‐C), and C‐reactive protein (CRP) are presented. We found that 11% of Chinese children and 30% of Chinese adults are overweight. Rates of diabetes, dyslipidaemia, hypertension and inflammation are high and increased with age and were associated with urbanization. Approximately 42% of children have at least one of the following: pre‐diabetes or diabetes, hypertension, high TC, LDL‐C, TG, and CRP and low HDL‐C, as do 70% men and 60% women aged 18–40 years and >90% of men and women ≥60 years. In sum, the HbA1c findings suggest that as many as 27.7 million Chinese children and 334 million Chinese adults may be pre‐diabetic or diabetic. The high prevalence in less urban areas and across all income levels suggests that cardiometabolic risk is pervasive across rural and urban China.     

Hemoglobin A1c levels in a diabetes detection program.

Hemoglobin A1c concentration (HbA1c) was compared to the plasma glucose responses at 1 and 2 h of an oral glucose tolerance test (OGTT) in 63 subjects preselected because of postprandial hyperglycemia. HbA1c concentrations were correlated with 1- and 2-hour plasma glucose responses during the OGTT (r = 0.776 and 0.8602, respectively). The OGTT responses were diabetic-like in 21, indeterminate in 15, and normal in 27 subjects. HbA1c values were within normal limits in all subjects who had a normal or indeterminate OGTT response and in 10 out of 21 with a diabetic OGTT. The 2-h OGTT response among the 10 diabetic responders with normal HbA1c was 200 +/- 31 mg/100 ml (mean +/- SD), while that of the 11 diabetic responders with elevated HbA1c was 352 +/- 122 mg/100 ml. All subjects with an elevated HbA1c had a 2-h plasma glucose above 228 mg/100 ml, whereas only 7% of subjects with a normal HbA1c had a 2-h glucose above this value. It is concluded that only about half of the patients currently diagnosed as having mild or chemical diabetes by OGTT have elevated HbA1c and that an elevated HbA1c is usually associated with 2-h OGTT levels above 228 mg/100 mg.     

Microalbuminuria as a marker of cardiovascular risk in patients with type 2 diabetes

Diabetes is a major risk factor for coronary artery disease and most patients with diabetes die of cardiovascular complications. Reduction of cardiovascular risk is therefore a high priority in the management of patients with diabetes. Microalbuminuria is an important predictor of cardiovascular events and forms one of the components of the insulin resistance/metabolic syndrome, which confers a particularly high risk of cardiovascular death. The currently available glucose-lowering agents vary considerably in their ability to reduce microalbuminuria. The sulfonylureas and metformin appear to have little effect on microalbuminuria expressed as urinary albumin/creatinine ratio, while the thiazolidinediones have unique effects on this risk factor, in parallel with their effects on insulin resistance. In two 1-year European multicenter, randomized, double-blind monotherapy trials (n=2444), pioglitazone produced similar reductions in urinary albumin/creatinine ratio to gliclazide and greater reductions than metformin (P<0.001). Similarly, two further 1-year European multicenter, randomized, double-blind trials assessed the effects of add-on therapy (n=1269) on urinary albumin/creatinine ratio. In the first study, urinary albumin/creatinine ratio was reduced by pioglitazone add-on to sulfonylurea (-15%), but was largely unaffected by metformin add-on to sulfonylurea (2%; P<0.05). In the second, urinary albumin/creatinine ratio was also reduced by pioglitazone add-on to metformin (-10%), but increased by gliclazide add-on to metformin (6%, P<0.05). The results of these studies indicated that compared with metformin or gliclazide, pioglitazone may provide therapeutic benefits, over and above those due to improved glycemic control. These include significant reductions in urinary albumin/creatinine ratio, a known cardiovascular risk marker.     

Hemoglobin A1c level and future cardiovascular events among women

BACKGROUND: Available data suggest that hemoglobin A(1c) (A(1c)), also known as glycosylated hemoglobin, levels may be related to cardiovascular risk in the general population without diabetes mellitus. We sought to test this hypothesis prospectively in a cohort of women without overt cardiovascular disease. METHODS: We conducted a nested case-control study of the Women's Health Study cohort. We identified 464 case patients with incident myocardial infarction, stroke, or coronary revascularization and 928 unmatched control subjects who remained free of cardiovascular events at case diagnosis. The mean follow-up was 7 years. RESULTS: Of the overall study population, 136 had a history of diabetes mellitus or an overtly elevated baseline A(1c) level (>6.4%) and were excluded from the primary analyses. Among women without diabetes mellitus or an elevated baseline A(1c) level, mean +/- SD baseline levels of A(1c) were significantly higher among future cases than controls (5.47% +/- 0.27% vs 5.37% +/- 0.22%; P<.001). The crude relative risks (RRs) of incident cardiovascular events for increasing quartiles of A(1c) were 1.00, 0.98, 1.33, and 2.25 (95% confidence interval [CI] for the highest vs the lowest quartile, 1.59-3.18). The A(1c) levels correlated with several other traditional cardiovascular risk factors, and in fully adjusted models, the predictive effect of A(1c) was attenuated and not significant (RR for the highest vs the lowest quartile, 1.00; 95% CI, 0.65-1.54). In contrast, in the population including women with diabetes mellitus at enrollment, diabetes mellitus (RR, 4.97; 95% CI, 2.81-8.77) remained a strong independent determinant of cardiovascular risk in fully adjusted analyses, while A(1c) levels did not (RR for the highest vs the lowest quartile, 1.11; 95% CI, 0.73-1.71). CONCLUSIONS: The A(1c) level is associated with future cardiovascular risk among women without diabetes mellitus, but this relationship is largely attributable to a strong correlation with other cardiovascular risk factors. In contrast, diabetes mellitus is a strong independent determinant of cardiovascular risk, even after adjustment for A(1c) levels.     

Fasting plasma glucose and HbA1c as risk factors for Type 2 diabetes

Aims We examined the value of combining fasting plasma glucose (FPG) and glycated haemoglobin (HbA_1c) as a predictor of diabetes, using the new American Diabetes Association (ADA) criteria of FPG and lower cut‐off point of HbA_1c. Methods A retrospective cohort study was conducted from 1998 to 2006, inclusive, in 10 042 persons (55 884 person‐years), with a mean age of 53.0 years at baseline. The cumulative incidence of diabetes (defined either as an FPG ≥ 7.0 mmol/l or as clinically diagnosed diabetes) was measured. Results The cumulative incidence and incidence density of diabetes were 3.7% (368 cases) and 6.6/1000 person‐years over a mean follow‐up period of 5.5 years. The cumulative incidence of diabetes in subjects with impaired fasting glucose (IFG) and HbA_1c 5.5–6.4% was 24.8% (172/694 persons) compared with 0.4% (25/6698 persons), 2.5% (15/605 persons), 7.6% (156/2045 persons) in those with normal fasting glucose (NFG) and HbA_1c < 5.5%, NFG and HbA_1c 5.5–6.4% and IFG and HbA_1c < 5.5%, respectively. The hazard ratio for diabetes, adjusted for possible confounders, was 7.4 (95% confidence interval, 4.70 to 11.74) for those with NFG and HbA_1c 5.5–6.4%, 14.4 (11.93 to 27.79) for those with IFG and HbA_1c < 5.5% and 38.4 (24.63 to 59.88) for those with IFG and HbA_1c 5.5–6.4%. Conclusions The combination of FPG and HbA_1c identifies individuals who are at risk of progression to Type 2 diabetes at the new ADA criteria of FPG and a lower cut‐off point of HbA_1c than previous studies.     

Trends in the control of risk factors for cardiovascular disease among adults with diagnosed diabetes: Findings from the National Health and Nutrition Examination Survey 1999–2008*

Background: The aim of the present study was to examine trends in the control of key risk factors for cardiovascular disease among adults with diagnosed diabetes in the US from 1999 to 2008. Methods: Data for up to 2623 adults aged ≥20 years with diagnosed diabetes who participated in 2‐year cycles of the National Health and Nutrition Examination Surveys from 1999 to 2008 were examined. Results: Significant improvements were seen in the control of HbA1c (37.0%–55.2%), blood pressure (35.2%–51.0%), and low‐density lipoprotein–cholesterol (LDL‐C; 32.5%–52.9%). Both men and women experienced significant improvement in HbA1c and LDL‐C. Whites showed significant improvement in glycemic control, LDL‐C control, and the control of all three risk factors. African Americans showed significant improvement in glycemic control and blood pressure control, and Mexican Americans showed significant improvement in glycemic control and the control of all three risk factors. Compared with Whites, African Americans (prevalence ratio [PR] = 0.84; 95% confidence interval [CI] 0.74–0.96) and Mexican Americans (PR = 0.82; 95% CI 0.72–0.92) had worse glycemic control, and Mexican Americans had worse control of LDL‐C (PR = 0.70; 95% CI 0.57–0.87) and of all three risk factors (PR = 0.46; 95% CI 0.23–0.90). There was little change in the prevalence of not currently smoking, having C‐reactive protein <3 g/L, and having a urinary albumin:creatinine ratio <30 mg/g. The prevalence of body mass index <30 kg/m² decreased from 45.4% to 37.6% (P_{linear trend} = 0.045). Conclusions: Significant improvements in recommended levels of HbA1c, blood pressure, and LDL‐C occurred in diabetic adults in the US between 1999 and 2008.     

Menstrual cycle irregularity as a marker of cardiovascular risk factors at postmenopausal years

To evaluate the association between cardiovascular risk factors (CVRF) during postmenopausal years and previous menstrual irregularity during reproductive years, we performed a case-control study in 414 postmenopausal women (mean age 60.4 +/- 5.5 years; BMI 25.3 +/- 4.7 kg/m(2)). The variables assessed were: menstrual cycle characteristics at age 2035y (independent) and records of arterial hypertension, dyslipidemia, diabetes mellitus, and coronary heart disease (dependent). Statistical analysis used the chi-square test and logistic regression, adjusting for potential confounders for cardiovascular risk, with significance set at 5%. Women reporting previous menstrual irregularity were associated with increased risk for some CVRF [adjusted odds ratio (OR) 2.14; CI-95%=1,024.48], when compared with those reporting regular menstrual cycles. Stratified analysis demonstrated significant associations of previous menstrual irregularity with: arterial hypertension (OR= 2.74; CI-95%=1,395.41), hypercholesterolemia (OR= 2.32; CI-95%=1,174.59)), hypertriglyceridemia (OR= 2.09; CI-95%=1,104.33), and coronary angioplasty (OR= 6.82; CI-95%=1,4432.18). These data suggest that a prior history of menstrual irregularity, as indicative of polycystic ovary syndrome, may be related to increased risk for CVD during postmenopausal years.     

Hemoglobin A1c and diabetes control (author's transl)]

Hemoglobin A1c (HbA1c) is a minor component of human hemoglobin resulting from a non enzymatic linkage of glucose with the NH2-terminal amino acid of the beta chain of hemoglobin. Under normal conditions, HbA1c represent about 5% of total hemoglobin. The HbA1c blood concentration increases in direct proportion of the duration and degree of hyperglycemia. Available procedures for measuring HbA1c include column chromatography, high pressure liquid chromatography, a colorimetric procedure based on the formation of 5-hydroxymethylfurfural and isoelectrofocusing. In a group of 138 patients, we have confirmed that HbA1c provides a useful means of evaluating the degree of diabetic control: the highest values have been recorded in cases of poor control, the lowest in cases of excellent control. In the latter case, the HbA1c values recorded were not statistically different from those obtained in a control group of 92 non-diabetic subjects. The interest of evaluating this parameter in diabetes is briefly analyzed.     

Short sleep duration as a risk factor for hypertension: analyses of the first National Health and Nutrition Examination Survey

Depriving healthy subjects of sleep has been shown to acutely increase blood pressure and sympathetic nervous system activity. Prolonged short sleep durations could lead to hypertension through extended exposure to raised 24-hour blood pressure and heart rate, elevated sympathetic nervous system activity, and increased salt retention. Such forces could lead to structural adaptations and the entrainment of the cardiovascular system to operate at an elevated pressure equilibrium. Sleep disorders are associated with cardiovascular disease, but we are not aware of any published prospective population studies that have shown a link between short sleep duration and the incidence of hypertension in subjects without apparent sleep disorders. We assessed whether short sleep duration would increase the risk for hypertension incidence by conducting longitudinal analyses of the first National Health and Nutrition Examination Survey (n=4810) using Cox proportional hazards models and controlling for covariates. Hypertension incidence (n=647) was determined by physician diagnosis, hospital record, or cause of death over the 8- to 10-year follow-up period between 1982 and 1992. Sleep durations of < or =5 hours per night were associated with a significantly increased risk of hypertension (hazard ratio, 2.10; 95% CI, 1.58 to 2.79) in subjects between the ages of 32 and 59 years, and controlling for the potential confounding variables only partially attenuated this relationship. The increased risk continued to be significant after controlling for obesity and diabetes, which was consistent with the hypothesis that these variables would act as partial mediators. Short sleep duration could, therefore, be a significant risk factor for hypertension.     

Microvascular changes in the retina as a risk marker for cardiovascular disease

The retinal vasculature can be viewed directly and noninvasively, offering an easily accessible window through which to study the human microcirculation in vivo and, therefore, early processes and pathways in cardiovascular disease (CVD) development. Recent advances in digital retinal photography and image analysis have allowed reliable and objective evaluation of retinal vascular pathologies (eg, retinopathy signs) as well as quantitative assessment of other topographic retinal vascular parameters, including retinal vascular caliber. An expanding series of clinical and epidemiologic studies now show that retinal vascular changes are associated with cardiovascular and metabolic diseases, including hypertension, diabetes, obesity, stroke, coronary heart disease, and heart failure. These data indicate that structural alterations in the retinal vasculature may mirror pathologic processes occurring in the systemic circulation and may represent novel biomarkers for CVD risk. This review summarizes the systemic cardiovascular associations of retinal vascular changes and discusses their clinical and research implications.