Associations of HbA1c and educational level with risk of cardiovascular events in 32 871 drug‐treated patients with Type 2 diabetes: a cohort study in primary care

Aims

To explore the association of HbA_1c and educational level with risk of cardiovascular events and mortality in patients with Type 2 diabetes.

Methods

A cohort of 32 871 patients with Type 2 diabetes aged 35 years and older identified by extracting data from electronic patient records for all patients who had a diagnosis of Type 2 diabetes and had glucose‐lowering agents prescribed between 1999 and 2009 at 84 primary care centres in Sweden. Associations of mean HbA_1c levels and educational level with risks of cardiovascular events and all‐cause mortality were analysed.

Results

The associations of HbA_1c with risk of all‐cause and cardiovascular mortality were J‐shaped, with the lowest risk observed for cardiovascular mortality at an HbA_1c level of 51 mmol/mol (6.8%) for subjects on oral agents and 56 mmol/mol (7.3%) in insulin‐treated patients. The lowest risk observed for all‐cause mortality was at an HbA_1c level of 51 mmol/mol (6.8%) for subjects on oral agents and 56 mmol/mol (7.3%) in insulin‐treated patients. There was an increased risk for cardiovascular death [hazard ratio 1.6 (1.2–2.1), P = 0.0008] at the lowest HbA_1c decile for subjects in the low education category. For subjects with higher education there was no evident J curve for cardiovascular death [hazard ratio 1.2 (0.8–1.6), P = 0.3873].

Conclusions

Our results lend support to the recent American Diabetes Association/ European Association for the Study of Diabetes position statement that emphasizes the importance of additional factors, including the propensity for hypoglycaemia, which should influence HbA_1c targets and treatment choices for individual patients. (Clinical Trials Registry No; NCT 01121315)     

Modelling incremental benefits on complications rates when targeting lower HbA1c levels in people with Type 2 diabetes and cardiovascular disease

Aim

Glucose‐lowering interventions in Type 2 diabetes mellitus have demonstrated reductions in microvascular complications and modest reductions in macrovascular complications. However, the degree to which targeting different HbA_1c reductions might reduce risk is unclear.

Methods

Participant‐level data for Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) participants with established cardiovascular disease were used in a Type 2 diabetes‐specific simulation model to quantify the likely impact of different HbA_1c decrements on complication rates. Ten‐year micro‐ and macrovascular rates were estimated with HbA_1c levels fixed at 86, 75, 64, 53 and 42 mmol/mol (10%, 9%, 8%, 7% and 6%) while holding other risk factors constant at their baseline levels. Cumulative relative risk reductions for each outcome were derived for each HbA_1c decrement.

Results

Of 5717 participants studied, 72.0% were men and 74.2% White European, with a mean (sd ) age of 66.2 (7.9) years, systolic blood pressure 134 (16.9) mmHg, LDL‐cholesterol 2.3 (0.9) mmol/l, HDL‐cholesterol 1.13 (0.3) mmol/l and median Type 2 diabetes duration 9.6 (5.1–15.6) years. Ten‐year cumulative relative risk reductions for modelled HbA_1c values of 75, 64, 53 and 42 mmol/mol, relative to 86 mmol/mol, were 4.6%, 9.3%, 15.1% and 20.2% for myocardial infarction; 6.0%, 12.8%, 19.6% and 25.8% for stroke; 14.4%, 26.6%, 37.1% and 46.4% for diabetes‐related ulcer; 21.5%, 39.0%, 52.3% and 63.1% for amputation; and 13.6%, 25.4%, 36.0% and 44.7 for single‐eye blindness.

Conclusions

These simulated complication rates might help inform the degree to which complications might be reduced by targeting particular HbA_1c reductions in Type 2 diabetes.     

Sex differences in glucose levels: a consequence of physiology or methodological convenience? The Inter99 study

Aims/hypothesis  

We aimed to examine whether sex differences in fasting plasma glucose (FPG), 2 h post-OGTT plasma glucose (2hPG) and HbA_1c could be explained by differences in body size and/or body composition between men and women in a general non-diabetic Danish population. Moreover, we aimed to study to what degree the newly suggested high-risk HbA_1c criteria overlapped with the current OGTT-based criteria of glucose intolerance.     

Assessing the economic value of maintained improvements in Type 1 diabetes management,in terms of HbA1c,weight and hypoglycaemic event incidence

Aims

Insulin therapy is indicated for people with Type 1 diabetes mellitus; however, treatment‐related weight gain and hypoglycaemia represent barriers to optimal glycaemic management. This study assessed the health economic value of maintained reductions in HbA_1c, BMI and hypoglycaemia incidence among the UK Type 1 diabetes population.

Methods

The Cardiff Type 1 Diabetes Model was used to estimate lifetime costs, life‐years and quality‐adjusted life‐years (QALYs) for individuals with Type 1 diabetes at different baseline HbA_1c, BMI and hypoglycaemic event rates. Results were discounted at 3.5%, and the net monetary benefit associated with improving Type 1 diabetes management was derived at £20 000/QALY gained. Per‐person outputs were inflated to national levels using UK Type 1 diabetes prevalence estimates.

Results

Modelled subjects with an HbA_1c of 86 mmol/mol (10.0%) were associated with discounted lifetime per‐person costs of £23 795; £12 649 of which may be avoided by maintaining an HbA_1c of 42 mmol/mol (6.0%). Combined with estimated QALY gains of 2.80, an HbA_1c of 42 mmol/mol (6.0%) vs. 86 mmol/mol (10.0%) was associated with a £68 621 per‐person net monetary benefit. Over 1 year, unit reductions in BMI produced £120 per‐person net monetary benefit, and up to £197 for the avoidance of one non‐severe hypoglyceamic event.

Conclusions

Maintained reductions in HbA_1c significantly alleviate the burden associated with Type 1 diabetes in the UK. Given the influence of weight and hypoglycaemia on health economic outcomes, they must also be key considerations when assessing the value of Type 1 diabetes technologies in clinical practice.     

The shape of the metabolic memory of HbA1c: re-analysing the DCCT with respect to time-dependent effects

Aims/hypothesis  

We determined the shape of the metabolic memory of HbA_1c and its contribution to retinopathy, as well as the importance of reducing HbA_1c to prevent progression of retinopathy.     

Associations between physical fitness and HbA<Subscript>1c</Subscript> in type 2 diabetes mellitus

Aim/hypothesis  

In people with type 2 diabetes, exercise improves glucose control (as reflected in HbA_1c) and physical fitness, but it is not clear to what extent these exercise-induced improvements are correlated with one another. We hypothesised that reductions in HbA_1c would be related: (1) to increases in aerobic fitness and strength respectively in patients performing aerobic training or resistance training; and (2) to changes in strength and aerobic fitness in patients performing aerobic and resistance training.     

HbA<Subscript>1c</Subscript> levels in schoolchildren with type 1 diabetes are seasonally variable and dependent on weather conditions

Aims/hypothesis  

We evaluated seasonal HbA_1c changes in children with type 1 diabetes and its relation with measures of weather conditions.     

Glycaemic control is improved by 7 days of aerobic exercise training in patients with type 2 diabetes

Aims/hypothesis  

Cardiovascular events and death are better predicted by postprandial glucose (PPG) than by fasting blood glucose or HbA_1c. While chronic exercise reduces HbA_1c in patients with type 2 diabetes, short-term exercise improves measures of insulin sensitivity but does not consistently alter responses to the OGTT. The purpose of this study was to determine whether short-term exercise training improves PPG and glycaemic control in free-living patients with type 2 diabetes, independently of the changes in fitness, adiposity and energy balance often associated with chronic exercise training.     

Ageing and associations of fasting plasma glucose and 2 h plasma glucose with HbA(1C) in apparently healthy population. "FIN-D2D" study

Objective

In this FIN-D2D cross-sectional survey the relationship of age with HbA_1c and fasting and 2 h glucose in the oral glucose tolerance test (OGTT) was explored in apparently randomly selected healthy population.

Patients and methods

The glycaemic parameters were measured in 1344 men and 1482 women (aged 45–74 years), and among them we excluded all subjects with known diabetes, hypertension or dyslipidaemia. The final analyses for HbA_1c and the ratios of fasting glucose/HbA_1c and 2 h glucose/HbA_1c included 649 men and 804 women.

Results

Mean age was 57 years and BMI 26.1 kg/m² for both genders. HbA_1c increased in both genders with age (p < 0.001). For a particular fasting glucose level HbA_1c level was higher in older age groups (p < 0.001 for linearity). By contrast, a particular 2 h plasma glucose value in OGTT implied significantly lower HbA_1c in the elderly (p < 0.001 for linearity).

Conclusion

In apparently healthy population, screened with OGTT, in older individuals compared with younger ones a particular HbA_1c value implies slightly lower fasting glucose, but relatively higher 2 h glucose. These results need to be verified in different populations. The effects of age on relation between HbA_1c and plasma glucose should be taken into account in classifying people into different dysglycaemia categories.     

Effects of home‐based exercise and branched‐chain amino acid supplementation on aerobic capacity and glycemic control in patients with cirrhosis

Aim

The aim of the current study is to examine whether home‐based step exercise at anaerobic threshold (AT) and branched‐chain amino acid (BCAA) supplementation improve aerobic capacity, ectopic fat in liver and muscle, and glycemic control in patients with liver cirrhosis.

Methods

Six female patients with compensated liver cirrhosis received oral BCAA and were instructed to undertake bench step exercises at an intensity that corresponded to AT, with a goal of performing 140 min of exercise per week at home for 12 months. Fat deposition in liver (liver to spleen ratio) and intramuscular adipose tissue content were assessed at baseline and after 6 and 12 months by computed tomography. Glycemic control indices (homeostasis model assessment of insulin resistance, hemoglobin A_1c [HbA_1c], glycated albumin [GA] and chronic liver disease [CLD]‐HbA_1c [average of HbA_1c and GA/3]) were also measured.

Results

Twelve months of moderate training significantly increased AT, which is an index of aerobic capacity, but no changes were observed in body weight, liver to spleen ratio, or intramuscular adipose tissue content. Glycated albumin significantly decreased (P < 0.05) and there tended to be a similar decrease in CLD‐HbA_1c (P < 0.1) after the exercise. The baseline serum triglyceride level correlated with changes in GA (P < 0.01) and CLD‐HbA_1c (P < 0.1).

Conclusion

The current results suggest that the combination of home‐based step exercise at AT and BCAA supplementation enhances aerobic capacity and potentially improves glycemic control in patients with cirrhosis without changes in body weight. The baseline serum serum triglyceride may partially explain the degree of improvement in glycemic control with exercise and BCAA intervention.

     

The impact of metabolic control and QTc prolongation on all-cause mortality in patients with type 2 diabetes and foot ulcers

Aims/hypothesis

The increased all-cause mortality in patients with chronic diabetic foot ulcers cannot fully be explained by traditional cardiovascular risk factors. The significance of heart-rate-corrected QT (QTc) prolongation, a finding often seen in these patients, is unknown. Recently, the importance of metabolic control and hypoglycaemia has been discussed. The aim of this study was to evaluate the impact of different HbA_1c levels and QTc prolongation on all-cause mortality in the high-risk population of patients with type 2 diabetes mellitus and foot ulcers.

Methods

All patients with type 2 diabetes, younger than 80 years, visiting our diabetes foot unit, with a foot ulcer duration >4 weeks, were screened for participation. Patients on dialysis were excluded. Patients were grouped according to HbA_1c level and QTc time ≤ or >?440 ms.

Results

Patients (n?=?214, median age 69.1 years) were grouped according to HbA_1c level (HbA_1c?<?7.5% [<58 mmol/mol] n?=?81, 7.5–8.9% [58–74 mmol/mol] n?=?70, >8.9% [>74 mmol/mol] n?=?63). Baseline characteristics, including use of potential hypoglycaemic drugs, were similar between groups. During the 8 years of follow-up 151 patients died (70.6%) and HbA_1c?<?7.5% (<58 mmol/mol) was strongly associated with increased mortality. The highest mortality was seen in patients with a combination of HbA_1c?<?7.5% (<58 mmol/mol) and QTc prolongation, with an 8 year mortality of 92.1% as compared with 48.8% in those with HbA_1c?<?7.5% (<58 mmol/mol) but without QTc prolongation.

Conclusion/interpretations

HbA_1c?<?7.5% (<58 mmol/mol) in a high-risk population of patients with type 2 diabetes and foot ulcers is associated with a significantly higher mortality, particularly in patients with QTc prolongation.     

HbA<Subscript>1c</Subscript> and cardiovascular risk score identify people who may benefit from preventive interventions: a 7 year follow-up of a high-risk screening programme for diabetes in primary care (ADDITION), Denmark

Aims/hypothesis  

The measurement of HbA_1c is suggested as a diagnostic test for diabetes. Screening for diabetes also identifies individuals with elevated cardiovascular risk but who are free of diabetes. This study aims to assess whether screening by HbA_1c or glucose measures alone, or in combination with a cardiovascular risk assessment, identifies people who may benefit from preventive interventions, i.e. people with screen detected diabetes and people belonging to groups with excess mortality, during a median follow-up of 7 years.     

HbA1c variability and the development of microalbuminuria in type 2 diabetes: Tsukuba Kawai Diabetes Registry 2

Aims/hypothesis  

The aim of this study was to examine the association between HbA_1c variability and the development of microalbuminuria as defined by an albumin/creatinine ratio ≥3.4 mg/mmol (≥30 mg/g) in at least two of three consecutive urine samples in Japanese patients with type 2 diabetes.     

Hemoglobin A(1c) proportion, mortality rate, and risk factors for death in diabetic patients with severe hypoglycemia: a multicenter retrospective survey over ten years

Objective

To investigate the HbA_1c proportion and mortality rate across diabetic patients with severe hypoglycemia and the risk factors for death.

Methods

All the diabetic patients with severe hypoglycemia were divided into HbA_1c < 6.5% group and HbA_1c ≥ 6.5% group. The proportion of HbA_1c, mortality rate and the risk factors for death were analyzed. Common causes for severe hypoglycemia were also analyzed.

Results

The percentages of HbA_1c in the HbA_1c < 6.5% and HbA_1c ≥ 6.5% groups were 51.2% and 48.8%, respectively. The mortality rates were not significantly different between the 2 groups (5.3% vs. 5.1%, χ² = 0.01, p = 0.17). Binary logistic regression analysis revealed that in both groups, creatinine, aspartate aminotransferase, and uric acid levels were the risk factors for death. In the HbA_1c < 6.5% and HbA_1c ≥ 6.5% groups, 65.0% and 64.2% showed common causes of severe hypoglycemia, respectively.

Conclusions

With respect to severe hypoglycemia, equal attention should be paid to patients with an HbA_1c level of ≥6.5% and those with an HbA_1c level of <6.5%. The mortality rate is approximately 5% in severe hypoglycemia no matter how the HbA_1c level is. Creatinine, aspartate aminotransferase, and uric acid are the main risk factors in both groups. Two-thirds of severe hypoglycemia cases could be prevented.     

HbA1c variability is associated with microalbuminuria development in type 2 diabetes: a 7-year prospective cohort study

Aims/hypothesis

HbA_1c variability has been shown to be an independent risk factor for nephropathy in patients with type 1 diabetes. In this study, we aimed to explore the association between HbA_1c variability and microalbuminuria development in patients with type 2 diabetes. We also intended to test the applicability of serially measured HbA_1c over 2?years for this risk assessment.

Methods

Between 2003 and 2005, we recruited 821 middle-aged normoalbuminuric individuals with type 2 diabetes and followed them through to the end of 2010. The average follow-up time was 6.2?years. We defined microalbuminuria as a urine albumin to creatinine ratio of 30?mg/g (3.4?mg/mmol) or higher. HbA_1c variability was calculated by the SD of serially measured HbA_1c. The Cox proportional hazards model was used to evaluate the association between HbA_1c SD quartile and development of microalbuminuria.

Results

The incidence of microalbuminuria for the overall population was 58.4, 58.6, 60.8 and 91.9 per 1,000 person-years for Q1- to Q4-adjusted HbA_1c SD, respectively (p for trend?=?0.042). Compared with patients in Q1, those in Q4 were about 37% more likely to develop microalbuminuria. The HR derived from a series of 2?year HbA_1c measurements was similar to that from data collection for longer than 4?years.

Conclusions/interpretation

In addition to mean HbA_1c values, HbA_1c variability, even measured as early as 2?years, is independently associated with the development of microalbuminuria in patients with type 2 diabetes.     

Durable change in glycaemic control following intensive management of type 2 diabetes in the ACCORD clinical trial

Aims/hypothesis

We aimed to determine the persistence of glycaemic control 1 year after a limited period of intensive glycaemic management of type 2 diabetes.

Methods

4119 ACCORD Trial participants randomised to target HbA_1c <6.0% (42 mmol/mol) for 4.0?±?1.2 years were systematically transitioned to target HbA_1c 7.0–7.9% (53–63 mmol/mol) and followed for an additional 1.1?±?0.2 years. Characteristics of participants with HbA_1c <6.5% (48 mmol/mol) or ≥6.5% at transition were compared. Changes in BMI and glucose-lowering medications were compared between those ending with HbA_1c <6.5% vs ≥6.5%. Poisson models were used to assess the independent effect of attaining HbA_1c <6.5% before transition on ending with HbA_1c <6.5%.

Results

Participants with pre-transition HbA_1c <6.5% were older with shorter duration diabetes and took less insulin but more non-insulin glucose-lowering agents than those with higher HbA_1c. A total of 823 participants achieved a final HbA_1c <6.5%, and had greater post-transition reductions in BMI, insulin dose and secretagogue and acarbose use than those with higher HbA_1c (p?1c <6.5% at transition predicted final HbA_1c <6.5% (crude RR 4.9 [95% CI 4.0, 5.9]; RR 3.9 [95% CI 3.2, 4.8] adjusted for demographics, co-interventions, pre-intervention HbA_1c, BMI and glucose-lowering medication, and post-transition change in both BMI and glucose-lowering medication). Progressively lower pre-transition HbA_1c levels were associated with a greater likelihood of maintaining a final HbA_1c of <6.5%. Follow-up duration was not associated with post-transition rise in HbA_1c.

Conclusions/interpretation

Time-limited intensive glycaemic management using a combination of agents that achieves HbA_1c levels below 6.5% in established diabetes is associated with glycaemic control more than 1 year after therapy is relaxed.     

Basal insulin glargine and microvascular outcomes in dysglycaemic individuals: results of the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial

Aims/hypothesis

As glycaemia and the incidence of microvascular diabetes complications follow a log-linear relationship, it becomes increasingly difficult to demonstrate a microvascular benefit of glucose-lowering when the HbA_1c level is close to normal.

Methods

The Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial randomised 12,537 people with diabetes, impaired glucose tolerance or impaired fasting glucose to receive standard glycaemic care or standard care with the addition of basal insulin glargine (A21Gly,B31Arg,B32Arg human insulin), targeting a fasting plasma glucose level ≤5.3 mmol/l. Microvascular outcomes during a median follow-up of 6.2 years were examined in participants whose baseline HbA_1c was above or below the median of 6.4% (46.4 mmol/mol).

Results

Allocation to the insulin glargine group reduced the incidence of the primary microvascular composite outcome of kidney and eye disease in participants whose baseline HbA_1c level was ≥6.4% (46.4 mmol/mol; HR 0.90 [95% CI 0.81, 0.99]) but not in participants with a lower baseline HbA_1c (HR 1.07 [95% CI 0.95, 1.20]; p value for interaction 0.031). In people whose baseline HbA_1c level was ≥6.4% (46.4 mmol/mol), the median post-randomisation change in HbA_1c was ?0.65% (interquartile range ?0.16, ?0.91%) after allocation to insulin glargine and ?0.33% (?0.83, 0.13%) after allocation to standard care (median HbA_1c difference 0.33%; p?<?0.0001). A smaller median difference of 0.22% was noted in people whose baseline HbA_1c was <6.4% (p?<?0.0001).

Conclusions/interpretation

In patients with dysglycaemia, intervention targeting normal fasting glucose levels reduced HbA_1c and attenuated the risk of microvascular outcomes in participants with a baseline HbA_1c level ≥6.4% (46.4 mmol/mol). A neutral effect was seen in those with a lower baseline HbA_1c level.

Trial registration:

ClinicalTrials.gov NCT00069784     

Glycated haemoglobin and cognitive decline: the Atherosclerosis Risk in Communities (ARIC) study

Aims/hypothesis  

This study aimed to examine the association between diabetes and hyperglycaemia—assessed by HbA_1c—and change in cognitive function in persons with and without diabetes.     

Recent population changes in HbA1c and fasting insulin concentrations among US adults with preserved glucose homeostasis

Aims/hypothesis  

Although diagnosed type 2 diabetes has increased in the past decade, little is known about accompanying changes in fasting plasma glucose (FPG), HbA_1c and fasting serum insulin (FI) levels in the non-diabetic population.     

Haemoglobin A<Subscript>1c</Subscript> levels and subsequent cardiovascular disease in persons without diabetes: a meta-analysis of prospective cohorts

Aims/hypothesis  

The aim of this meta-analysis was to determine the relationship between HbA_1c levels and subsequent cardiovascular outcomes in individuals without diabetes.