Screening for diabetes in Indigenous populations using glycated haemoglobin: sensitivity, specificity, post-test likelihood and risk of disease.

AIMS: Screening for diabetes using glycated haemoglobin (HbA1c) offers potential advantages over fasting glucose or oral glucose tolerance testing. Current recommendations advise against the use of HbA1c for screening but test properties may vary systematically across populations, according to the diabetes prevalence and risk. We aimed to: (i) characterize the properties of test cut-offs of HbA1c for diagnosis of diabetes relative to a diagnosis based on a fasting plasma glucose concentration of 7.0 mmol/l for high-risk Indigenous populations; and (ii) examine test properties across a range of diabetes prevalence from 5 to 30%. METHODS: Data were collected from Aboriginal and Torres Strait Islander communities in Australia and a Canadian First Nations community (diabetes prevalence 12-22%) in the course of diabetes diagnostic and risk factor screening programmes (n = 431). Screening test properties were analyzed for the range of HbA1c observed (3-12.9%). RESULTS: In separate and pooled analyses, a HbA1c cut point of 7.0% proved the optimal limit for classifying diabetes, with summary analysis results of sensitivity = 73 (56-86)%, specificity = 98 (96-99)%, overall agreement (Youden's index) = 0.71, and positive predictive value (for an overall prevalence of 18%) = 88%. For diabetes prevalence from 5 to 30% the post-test likelihood of having diabetes given HbA1c = 7.0% (positive predictive value) ranged from 62.7 to 93.2%; for HbA1c < 7.0%, the post-test likelihood of having diabetes ranged from 4.5 to 27.7%. CONCLUSIONS: The results converge with research on the likelihood of diabetes complications in supporting a HbA1c cut-off of 7.0% in screening for diabetes in epidemiological research. Glycated haemoglobin has potential utility in screening for diabetes in high-risk populations.     

Association between glycated haemoglobin and the risk of chronic obstructive pulmonary disease: A prospective cohort study in UK biobank

Aims

To investigate the association between glycated haemoglobin (HbA1c) levels and chronic obstructive pulmonary disease (COPD) incidents in the general population, and the association between HbA1c levels and mortality in patients with COPD.

Materials and Methods

We investigated the association of HbA1c levels with COPD risk in the general population in the UK Biobank, using data from 420 065 participants. Survival analysis was conducted for 18 854 patients with COPD. We used restricted cubic spline analysis to assess the dose-response relationship between HbA1c levels and COPD risk and survival. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs).

Results

During a median follow-up of 12.3 years, 11 556 COPD cases were recorded. HbA1c had a non-linear relationship with COPD risk (p for non-linearity < .05). Compared with the quintile 2 (32.2-<34.3 mmol/mol), those with HbA1c levels above 38.7 mmol/mol (quintile 5) had a 22% (HR, 1.22, 95% CI: 1.15-1.30) higher risk of COPD. Compared with the HbA1c decile 2 (30.5-<32.2 mmol/mol), the HRs (95% CI) of COPD risk were 1.16 (1.03-1.30) and 1.36 (1.24-1.50) in the lowest HbA1c decile (<30.5 mmol/mol) and highest decile (≥41.0 mmol/mol), respectively. The increased COPD risk associated with HbA1c was more pronounced in younger, current smokers, passive smokers, and participants with a higher Townsend deprivation index (all p for interaction < .05). Among patients with COPD, 4569 COPD cases died (488 because of COPD) during a median follow-up of 5.4 years. Regarding COPD survival, HbA1c had a non-linear relationship with all-cause death (p for non-linearity < .05). Those with HbA1c quintile 5 (≥38.7 mmol/mol) had a 23% (HR, 1.23, 95% CI: 1.10-1.37) higher risk of all-cause death compared with the quintile 2 (32.2-<34.3 mmol/mol). Compared with the HbA1c decile 4 (33.3-<34.3 mmol/mol), those in the lowest HbA1c decile (<30.5 mmol/mol) and highest HbA1c decile (≥41.0 mmol/mol) had 22% (HR, 1.22; 95% CI: 1.01-1.47) and 28% (HR, 1.28; 95% CI: 1.11-1.48) higher risk for overall death. However, no significant association was observed between HbA1c levels and the risk of COPD-specific death.

Conclusions

Our findings indicated that lower and higher HbA1c levels were associated with a higher risk of COPD. In COPD cases, lower and higher HbA1c levels were associated with a higher COPD all-cause death risk.     

Comparison of fructosamine and glycated haemoglobin in children with Type 1 (insulin-dependent) diabetes mellitus

Summary In six children (age: mean 8.4 years, range 2.2–12.6 years) with newly diagnosed Type 1 (insulin-dependent) diabetes mellitus, plasma fructosamine and glycated haemoglobin (HbA₁) were compared in respect to their disappearance during the first month after diagnosis during well controlled glycaemia. The disappearance of the surplus plasma fructosamine and HbA₁ was calculated applying exponential equations. The estimated half-lives of fructosamine (mean 57.2 days, range 40.7–77 days) and HbA₁ (mean 59.7 days, range 43.3–82 days) were not significantly different, a finding which is left unexplained.     

Near patient testing for glycated haemoglobin in people with Type 2 diabetes mellitus managed in primary care: acceptability and satisfaction.

AIMS: To assess the acceptability of and satisfaction with near patient testing for glycated haemoglobin in primary care in patients and health professionals. METHODS: A questionnaire survey and qualitative study were nested within a randomized controlled trial conducted in eight general practices in Leicester-shire, UK. Satisfaction with diabetes care was compared in the intervention group (near patient test) and in the control subjects (usual laboratory test), using the Diabetes Clinic Satisfaction Questionnaire. Semistructured interviews were conducted with a purposive sample of patients and healthcare professionals and analysed using thematic coding and framework charting. RESULTS: Questionnaire data for 344 patients were analysed and interviews were conducted with 15 patients and 11 health professionals. Interviews indicated that the near patient test was highly acceptable to patients and staff and confirmed that there may be potential benefits such as time saving, reduced anxiety and impact on patient management and job satisfaction. However, both the survey and the interviews identified high pre-existing levels of satisfaction with diabetes care in both intervention and control group patients and survey results failed to confirm increased patient satisfaction as a result of rapid testing. Limited patient understanding of glycated haemoglobin testing was noted. CONCLUSIONS: We were unable to confirm actual rather than potential advantages of the near patient test. Widespread adoption in primary care cannot be recommended without further evidence of benefit.     

Diabetes control and complications: the role of glycated haemoglobin, 25 years on.

The long-term complications of diabetes have major consequences for individual subjects and growing healthcare delivery and cost implications for society. Evidence for the benefits of good glycaemic control, as monitored by glycated haemoglobin measurements, has been developed in the 25 years since they were introduced to the point where HbA(1c) assays play central roles in patient management, clinical guidance and audit, and clinical trial design. In this review this evidence is examined and three classes of uncertainty identified that diminish confidence in the effectiveness of these roles for HbA(1c). 1 Analytical variability between different methods for HbA(1c) has restricted the application of clinical targets and this problem has recently been addressed by reference method standardization. There are two approaches to this which result in different HbA(1c) values and this discrepancy needs to be resolved. 2 Biological variability in HbA(1c) values between individuals also restricts its predictive role when applied to populations. The correlations between HbA(1c) measurements and various components of glycaemia (overall, fasting, postprandial) are still uncertain and differences in protein glycation and de-glycation are greater between subjects than often thought. The influence of variability in erythrocyte life span is an area where research is needed, especially in diabetic subjects. 3 Clinical variability is the most important and complex area of uncertainty. A predictive link between HbA(1c) and clinical outcomes is not as clear-cut as often stated. The correlation with the development of microvascular disease is well established in Type 1 diabetes, but in Type 2 subjects (90% of those with diabetes) the evidence that HbA(1c) monitoring is of value in predicting or preventing macrovascular disease is not strong, although it is the major cause of morbidity and early death in this group. It is recommended that, as a matter of urgency, these issues be examined, particularly within the context of self-care in diabetes.     

The relationship between birth weight and maternal glycated haemoglobin (HbA1c) concentration in pregnancies complicated by Type 1 diabetes.

AIM: To examine the relationships between maternal HbA1c concentration at different time points and birth weight in pregnancies complicated by pre-existing Type 1 diabetes. METHODS: A comprehensive audit dataset was collected prospectively on all deliveries in Scotland to women with pre-existing Type 1 diabetes occurring between 1 April 1998 and 31 March 1999. Data items included HbA1c concentrations prior to conception and in each of the three trimesters of pregnancy, and birth weight. Relationships between standardized birth weight and HbA1c concentrations at each of the four time points were examined using correlation analysis. RESULTS: Standardized birth weight (Z scores) could be calculated for 203 of 208 singleton liveborn infants. HbA1c concentrations, standardized to correct for assay differences among hospitals, at different time points were available for between 134 (pre-pregnancy) and 192 (third trimester) cases. Standardized birth weight, relative to a reference population, showed a unimodal distribution, shifted to the right (mean, +1.57 sd). There was a significant negative correlation between pre-pregnancy HbA1c and birth weight (Spearman's R, -0.208; P = 0.016). There were no statistically significant correlations for other time points. CONCLUSIONS: Standardized birth weight scores of the infants of diabetic mothers are higher than those of a reference population. There is no simple relationship between maternal glycaemic status and birth weight, but there appears to be a paradoxical inverse relationship between pre-pregnancy glycaemic control and standardized birth weight.     

Diabetes risk in British adults in mid life: a national prevalence study of glycated haemoglobin.

AIMS: Information on the population at risk of developing Type 2 diabetes in the UK is scarce. We used data from the 1958 British birth cohort to estimate geographical and socio-economic variations in HbA(1c) in mid life. METHODS: Participants (n = 7799) born in England, Scotland and Wales and currently living in the UK. Individuals were classified according to the presence of Type 2 diabetes and by thresholds of HbA(1c). HbA(1c)> or = 5.5 was used as an indicator for possible subclinical alterations in glucose metabolism. RESULTS: The majority of the population had HbA(1c) < 5.5% (79.3%); 16.7% had HbA(1c) 5.5-5.9%, 2.0% 6.0-6.9% and 0.6% had HbA(1c)> or = 7.0%. Individuals from manual socio-economic groups and those living in the East of England and Scotland had a higher prevalence of HbA(1c) at or above the upper normal range (5.5%). CONCLUSIONS: Estimates from this nationwide sample suggest that a proportion of Britons are likely to have subclinical alterations in glucose metabolism by their mid 40s, and this proportion is greater in some socio-economic groups and geographical regions than in others.     

Maternal HBsAg carriers and adverse pregnancy outcomes: A hospital‐based prospective cohort analysis

It is not clear whether chronic hepatitis B virus (HBV) infection during pregnancy can increase the risk of adverse pregnancy outcomes for both mothers and neonates. We conducted a hospital‐based prospective cohort study on pregnant women (PW) and used an analysis strategy that was guided by directed acyclic graphs (DAGs). Maternal characteristics and major adverse pregnancy outcomes were collected both from questionnaires and hospital‐based electronic medical records. Serum hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) status were determined. In total, 3329 of the 3416 pregnant women who received routine antenatal care in a hospital setting at baseline, including 346 HBsAg carriers, were available for analysis. Maternal HBsAg carrier status was associated with an increased risk of intrahepatic cholestasis pregnancy [aOR (adjusting odds ratio) = 1.70; 95% CI (confidence interval) = 1.16‐2.49], premature rupture of the membranes (aOR = 1.38; 95% CI = 1.00‐1.89) and large for gestational age birth aOR = 1.67; 95% CI = 1.17‐2.39). The risk of intrahepatic cholestasis remained in pregnant women with either HBeAg‐positive (aOR = 2.96; 95% CI = 1.33‐6.62) or HBeAg‐negative (aOR = 1.52; 95% CI =1.00‐2.32)] status; notably, only maternal HBeAg‐negative status was associated with a higher risk of large for gestational age birth (aOR = 1.91; 95% CI = 1.33‐2.76). Our results implied that chronic HBV infection during pregnancy may increase the risk of intrahepatic cholestasis of pregnancy, premature rupture of membranes and large for gestational age pregnancies.     

Methadone and perinatal outcomes: a prospective cohort study

Aims Methadone use in pregnancy has been associated with adverse perinatal outcomes and neonatal abstinence syndrome (NAS). This study aimed to examine perinatal outcomes and NAS in relation to (i) concomitant drug use and (ii) methadone dose. Design Prospective cohort study. Setting Two tertiary care maternity hospitals. Participants A total of 117 pregnant women on methadone maintenance treatment recruited between July 2009 and July 2010. Measurements Information on concomitant drug use was recorded with the Addiction Severity Index. Perinatal outcomes included pre‐term birth (<37 weeks' gestation), small‐for‐gestational‐age (<10th centile) and neonatal unit admission. NAS outcomes included: incidence of medically treated NAS, peak Finnegan score, cumulative dose of NAS treatment and duration of hospitalization. Findings Of the 114 liveborn infants 11 (9.6%) were born pre‐term, 49 (42.9%) were small‐for‐gestational‐age, 56 (49.1%) had a neonatal unit admission and 29 (25.4%) were treated medically for NAS. Neonates exposed to methadone‐only had a shorter hospitalization than those exposed to methadone and concomitant drugs (median 5.0 days versus 6.0 days, P = 0.03). Neonates exposed to methadone doses ≥80 mg required higher cumulative doses of morphine treatment for NAS (median 13.2 mg versus 19.3 mg, P = 0.03). The incidence and duration of NAS did not differ between the two dosage groups. Conclusions The incidence and duration of the neonatal abstinence syndrome is not associated with maternal methadone dose, but maternal opiate, benzodiazepine or cocaine use is associated with longer neonatal hospitalization.     

Parental age at delivery, birth order, birth weight and gestational age are associated with the risk of childhood Type 1 diabetes: a UK regional retrospective cohort study.

AIMS: To investigate perinatal risk factors for childhood Type 1 diabetes in a UK population cohort. METHODS: Perinatal data have been routinely recorded in Northern Ireland for all births in the period 1971-86 (n = 447 663). Diabetes status at the age of 15 years was ascertained in this cohort by identifying 991 children from 1079 registered with Type 1 diabetes diagnosed from 1971 to 2001 and date of birth in the period 1971-86. RESULTS: Increased Type 1 diabetes risk was associated with higher maternal age, paternal age, birth weight and birth weight for gestational and lower gestational age. After adjustment for maternal age, the association between Type 1 diabetes and paternal age remained significant [relative risk (RR) = 1.52 (1.10, 2.09) comparing father's age 35 years or more to less than 25 years] but not vice versa [RR = 1.11 (0.80, 1.54) comparing mother's age 35 years or more to less than 25 years]. Increased birth order was associated with a significant decrease in the risk of Type 1 diabetes [adjusted RR = 0.75 (0.62, 0.90) comparing birth order three or more with firstborn], but this only became apparent when adjustment was made for maternal age. Furthermore this association with birth order was significant only for diabetes diagnosed under the age of 5 years. CONCLUSIONS: Our analysis demonstrates, for the first time in a UK regional cohort setting, that maternal age and paternal age at delivery, birth order, birth weight and gestational age are significantly associated with Type 1 diabetes risk.     

Birthweight and other pregnancy outcomes in a cohort of women with pre-gestational insulin-treated diabetes mellitus, Scotland, 1979-95.

AIMS: To assess pregnancy outcomes, in particular birthweight, in a large population-based cohort of women in Scotland with pre-gestational insulin-treated diabetes mellitus. METHODS: Data about diabetes from the Diabetes UK cohort were linked to data on births from the Scottish Hospital In-Patient Record System. This identified 1112 eligible singleton deliveries during 1979-95 to 706 insulin-treated women. RESULTS: One thousand and eighty-four (97.5%) deliveries resulted in a live-born infant and 28 (2.5%) in a stillbirth. There were 13 (1.2%) neonatal deaths. The mean birthweight of the live-born infants was 3421 g, 1.06 standard deviations greater than that of infants in the Scottish general population after correcting for sex and gestational age. Forty-three per cent of live-born babies in the study were large (> Scottish 90th percentile) and 4% small (< 10th percentile) for their sex and gestational age. Macrosomia, defined as birthweight > or = 4000 g, occurred in 23% live-born babies and its prevalence was significantly inversely related to duration of maternal diabetes. However, the mean birthweight of infants born to mothers with diabetes for 20 or more years was still 0.90 standard deviations greater than in the general population. Prevalence of macrosomia increased with increasing number of previous pregnancies, but was not associated with maternal height or smoking habits. Stillbirth and neonatal death rates were, respectively, 4.7 (95% confidence interval = 3.3, 6.8) and 2.4 (1.4, 4.1), times higher than those in the general population. CONCLUSIONS: The frequency of adverse pregnancy outcomes in women with pre-existing insulin-treated diabetes was much higher than in the Scottish general population, and changed little during the study period. A detailed quantification of the independent effect of duration of mother's diabetes on birthweight revealed a continuous inverse correlation between these two variables.     

Pregnancy-associated plasma protein A in a large cohort of Type 1 diabetic patients with and without diabetic nephropathy-a prospective follow--up study.

AIM: Pregnancy-associated plasma protein A (PAPP-A) has been implicated in the aetiology of acute coronary syndromes and carotid and peripheral artherosclerosis. Diabetic nephropathy is characterized by increased cardiovascular risk. We investigated the prognostic value of PAPP-A in a large cohort of Type 1 diabetic patients. METHODS: In a prospective observational follow-up study, 197 Type 1 diabetic patients with diabetic nephropathy and a matched group of 178 patients with normoalbuminuria were followed for 10.1 (0-10.3) years. PAPP-A was determined at baseline. RESULTS: In patients with diabetic nephropathy, plasma PAPP-A was elevated 3.6 (0.4-51.1) mIU/l [median (range)] vs. 2.1 (0.4-46.6) mIU/l in normoalbuminuric patients, P < 0.0001. For acute coronary syndromes, a PAPP-A threshold of 10 mIU/l has been suggested. Thirty-seven patients were above the threshold and of these 13 patients (35%) died, compared with 60 of 338 patients (18%) below the threshold; log rank test P = 0.007. PAPP-A significantly predicted mortality after adjustment for presence of nephropathy; hazard ratio for dying when PAPP-A was above the threshold 2.1 (95% CI 1.13-3.9); P = 0.019. After adjusting for traditional risk factors, the results were attenuated. When only patients with nephropathy were analysed, PAPP-A was significantly predictive of all-cause mortality [P = 0.008; 2.43 (1.26-4.67)] in unadjusted analysis. After adjustment, the predictive value of PAPP-A for all-cause mortality was attenuated (P = 0.064). CONCLUSION: We find PAPP-A to be associated with increased mortality in Type 1 diabetic patients with nephropathy in unadjusted analysis. After adjustment for traditional risk factors, the prognostic value of PAPP-A was no longer significant.