Changes in glycaemic control and risk of coronary artery disease in type 1 diabetes mellitus: findings from the Pittsburgh Epidemiology of Diabetes Complications Study (EDC)

Aims/hypothesis To complete a comparative analysis of studies that have examined the relationship between glycaemia and cardiovascular disease (CVD)/coronary artery disease (CAD) and perform a prospective analysis of the effect of change in glycosylated Hb level on CAD risk in the Pittsburgh Epidemiology of Diabetes Complications Study (EDC) of childhood-onset type 1 diabetes mellitus (n = 469) over 16 years of two yearly follow-up. Methods Measured values for HbA₁ and HbA_1c from the EDC were converted to the DCCT-standard HbA_1c for change analyses and the change in HbA_1c was calculated (final HbA_1c minus baseline HbA_1c). CAD was defined as EDC-diagnosed angina, myocardial infarction, ischaemia, revascularisation or fatal CAD after medical record review. Results The comparative analysis suggested that glycaemia may have a stronger effect on CAD in patients without, than in those with, albuminuria. In EDC, the change in HbA_1c differed significantly between CAD cases (+0.62 ± 1.8%) and non-cases (−0.09 ± 1.9%) and was an independent predictor of CAD. Conclusions/interpretation Discrepant study results regarding the relationship of glycaemia with CVD/CAD may, in part, be related to the prevalence of renal disease. Measures of HbA_1c change over time show a stronger association with CAD than baseline values.     

Mean blood glucose compared with HbA<Subscript>1c</Subscript> in the prediction of cardiovascular disease in patients with type 1 diabetes

Aims/hypothesis It is not known whether mean blood glucose (MBG) predicts the risk of macrovascular complications in diabetes any differently from HbA_1c. In this study we therefore analysed data from the Diabetes Control and Complications Trial (DCCT) to assess the relationship between MBG, HbA_1c and glucose variability with regard to the risk of cardiovascular disease in patients with type 1 diabetes. Methods Pre- and postprandial seven-point glucose profiles were collected quarterly during the DCCT in 1441 individuals. The relationship between time to first cardiovascular event and MBG, HbA_1c and daily SD of blood glucose was assessed by Cox regression after adjusting for the known risk factors of macrovascular disease and the treatment groups of the patients. Results Cox regression showed MBG to be predictive of a cardiovascular event (p = 0.019), but not HbA_1c (p = 0.858). A rise of 1 mmol/l in MBG was associated with an 11% rise in cardiovascular risk. MBG remained highly predictive (p = 0.015) even after adjustment for HbA_1c values and glucose variability. Conclusions/interpretation This study has shown that during the DCCT MBG was a better predictor of the macrovascular complications of type 1 diabetes than HbA_1c. It indicates that the cardiovascular risk associated with hyperglycaemia appeared within the time period of the study and that blood glucose rather than HbA_1c may be the preferred means of assessing this risk.     

Translating HbA<Subscript>1c</Subscript> measurements into estimated average glucose values in pregnant women with diabetes

Aims/hypothesis

This study aimed to examine the relationship between average glucose levels, assessed by continuous glucose monitoring (CGM), and HbA_1c levels in pregnant women with diabetes to determine whether calculations of standard estimated average glucose (eAG) levels from HbA_1c measurements are applicable to pregnant women with diabetes.

Methods

CGM data from 117 pregnant women (89 women with type 1 diabetes; 28 women with type 2 diabetes) were analysed. Average glucose levels were calculated from 5–7 day CGM profiles (mean 1275 glucose values per profile) and paired with a corresponding (±1 week) HbA_1c measure. In total, 688 average glucose–HbA_1c pairs were obtained across pregnancy (mean six pairs per participant). Average glucose level was used as the dependent variable in a regression model. Covariates were gestational week, study centre and HbA_1c.

Results

There was a strong association between HbA_1c and average glucose values in pregnancy (coefficient 0.67 [95% CI 0.57, 0.78]), i.e. a 1% (11 mmol/mol) difference in HbA_1c corresponded to a 0.67 mmol/l difference in average glucose. The random effects model that included gestational week as a curvilinear (quadratic) covariate fitted best, allowing calculation of a pregnancy-specific eAG (PeAG). This showed that an HbA_1c of 8.0% (64 mmol/mol) gave a PeAG of 7.4–7.7 mmol/l (depending on gestational week), compared with a standard eAG of 10.2 mmol/l. The PeAG associated with maintaining an HbA_1c level of 6.0% (42 mmol/mol) during pregnancy was between 6.4 and 6.7 mmol/l, depending on gestational week.

Conclusions/interpretation

The HbA_1c–average glucose relationship is altered by pregnancy. Routinely generated standard eAG values do not account for this difference between pregnant and non-pregnant individuals and, thus, should not be used during pregnancy. Instead, the PeAG values deduced in the current study are recommended for antenatal clinical care.

     

Different behaviour of haemoglobin A1a−c and glycosyl-albumin levels during recovery from diabetic ketoacidosis and non-acidotic coma

Summary Glycosylated haemoglobin (HbA_1a–c) and serum albumin (glycosyl-albumin) have been determined in patients with severe diabetic ketoacidosis and non-acidotic coma. Within one week of therapy the level of glycosyl-albumin decreased from 184 mmol 5-hydroxymethylfurfural (HMF)/mol albumin to 152 mmol HMF/mol albumin (p<0.01) and was gradually lowered by some 40% during a period of 17 days. In contrast, the level of HbA_1a–c remained unchanged. From these observations and findings in a patient with insulinoma, it appears that glycosyl-albumin provides a more acute measure of variation in relative glycaemia than HbA_1a–c, and may prove useful as a measure of medium-term diabetes control.     

Diabetes,glycaemic control and mortality risk in patients on haemodialysis: the Japan Dialysis Outcomes and Practice Pattern Study

Aims/hypothesis There are few data on the target level of glycaemic control among patients with diabetes on haemodialysis. We investigated the impact of glycaemic control on mortality risk among diabetic patients on haemodialysis. Subjects and methods Data were analysed from the Dialysis Outcomes Practice Pattern Study (DOPPS) for randomly selected patients on haemodialysis in Japan. The diagnosis of diabetes at baseline and information on clinical events during follow-up were abstracted from the medical records. A Cox proportional hazards model was used to evaluate the association between presence or absence of diabetes, glycaemic control (HbA_1c quintiles) and mortality risk. Results Data from 1,569 patients with and 3,342 patients without diabetes on haemodialysis were analysed. Among patients on haemodialysis, those with diabetes had a higher mortality risk than those without (multivariable hazard ratio 1.37, 95% CI 1.08–1.74). Compared with those in the bottom quintile of HbA_1c level, the multivariable-adjusted hazard ratio for mortality was not increased in the bottom second to fourth quintiles of HbA_1c (HbA_1c 5.0–5.5% to 6.2–7.2%), but was significantly increased to 2.36 (95% CI 1.02–5.47) in the fifth quintile (HbA_1c ≥ 7.3%). The effect of poor glycaemic control did not statistically correlate with baseline mortality risk (p = 0.27). Conclusions/interpretation Among dialysis patients, poorer glycaemic control in those with diabetes was associated with higher mortality risk. This suggests a strong effect of poor glycaemic control above an HbA_1c level of about 7.3% on mortality risk, and that this effect does not appear to be influenced by baseline comorbidity status.     

Intensive insulin therapy improves endothelial function and microvascular reactivity in young people with type 1 diabetes

Aims/hypothesis Macrovascular disease is an important cause of the increased morbidity and mortality rates associated with type 1 diabetes, and this vascular impairment begins in childhood. The aim of this study was to determine whether introducing intensive diabetes management [intensive insulin therapy (IIT) and ‘Sweet Talk’ text-messaging support] produces measurable improvements in endothelial function. Methods One hundred and twenty-six patients fulfilled the eligibility criteria (type 1 diabetes for >1 year; on conventional insulin therapy (CIT); aged between 8 and 18 years), of whom 92 enrolled. Patients were randomised to group 1, CIT only (n = 28); group 2, CIT and Sweet Talk (n = 33); or group 3, IIT and Sweet Talk (n = 31). Vascular assessments (including measures of endothelial damage, activation, dysfunction and oxidative stress) and HbA_1c were performed at baseline and repeated after 12 months of the study. Results Glycaemic control deteriorated in patients on CIT, but improved significantly in patients allocated to IIT (p = 0.007). IIT was associated with significantly greater improvements in E-selectin (p < 0.0001) than CIT (group 1, p = 0.026 and group 2, p = 0.053). Vascular responses to acetylcholine improved in patients on IIT (p = 0.017), but not in patients receiving CIT. These changes were all independent of HbA_1c level. Conclusions/interpretation IIT appears to be associated with improvements in vascular markers, independently of changes in HbA_1c, suggesting that IIT may confer vascular protection in addition to improving glycaemic control.     

Continuous Glucose Monitors: Use of Waveform Versus Glycemic Values in the Improvements of Glucose Control,Quality of Life,and Fear of Hypoglycemia

How patients are benefitting from continuous glucose monitoring (CGM) remains poorly understood. The focus on numerical glucose values persists, even though access to the glucose waveform and rate of change may contribute more to improved control. This pilot study compared outcomes of patients using CGMs with or without access to the numerical values on their CGM. Ten persons with type 1 diabetes, naïve to CGM use, enrolled in a 12-week study. Subjects were randomly assigned to either unmodified CGM receivers, or to CGM receivers that had their numerical values obscured but otherwise functioned normally. HbA_1c, quality of life (QLI-D), and fear of hypoglycemia (HFS) were assessed, at baseline and at week 12. Baseline HbA_1c for the entire group was 7.46 ± 1.27%. At week 12 the experimental group HbA_1c reduction was 1.5 ± 0.9% (p < .05), the control group’s reduction was 0.06 ± 0.61% (p > .05). Repeated measures testing revealed no significant difference in HbA_1c reduction between groups. Both groups had reductions in HFS; these reductions were statistically significant within groups (p < .05), but not between groups. QLI-D indices demonstrated improvements (p < .05) in QLI-D total and the health and family subscales, but not between groups. The results of this pilot study suggest that benefits of CGM extend beyond reductions in HbA_1c to reductions in fear of hypoglycemia and improvements in quality of life. The display of a numerical glucose value did not improve control when compared to numerically blinded units.     

Epidemiological features of glycated haemoglobin A1c-distribution in a healthy population

Summary HbA_1c was measured in 3240 healthy non-diabetic adult individuals in a working population. There was no difference in HbA_1c between sexes. The distribution of HbA_1c was approximately normal with a slight difference between mean and median values at all ages in both sexes. HbA_1c increased with deterioration of glucose tolerance and with all the known risk factors for diabetes (age, obesity, family history of diabetes, history of a large newborn delivery); age but not body mass index appeared as a factor influencing HbA_1c independently. In women, HbA_1c levels rose particularly at the age of menopause but the use of oral contraceptives or oestrogens made no difference. In both sexes, HbA_1c was higher in smokers than in non-smokers. No consistent seasonal variation was observed. Haematologic factors had a negligible influence on HbA_1c level. HbA_1c was more highly correlated with fasting plasma glucose than with 2 h-plasma/glucose (r=0.20 vs 0.11). In a stepwise multiple regression analysis, age followed by fasting plasma glucose were the only two significant factors associated with the level of HbA_1c. These data indicate that HbA_1c is influenced only by factors closely linked to diabetes.     

Efficacy and safety of sitagliptin monotherapy and combination therapy in Japanese type 2 diabetes patients

(J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00221.x, 2012) Aims/Introduction: To determine the efficacy and safety of sitagliptin monotherapy and combination therapy in Japanese type 2 diabetes patients after 3 months’ therapy. Materials and Methods: A retrospective, observational study of 741 type 2 diabetes patients was carried out; 110 received sitagliptin monotherapy, and 631 received combination therapy with sitagliptin when other oral medications were insufficient. The primary outcome measure was glycated hemoglobin (HbA_1c) measured at 0, 4 and 12 weeks of sitagliptin therapy. Results: In the monotherapy and combination therapy groups, HbA_1c decreased significantly after 12 weeks. Target HbA_1c (<7%) was achieved in 39.1% overall. On logistic regression analysis, baseline HbA_1c was the strongest contributing factor for achieving target HbA_1c; baseline body mass index and duration of diabetes were also significant factors. A total of 82 patients (11%) were unresponsive to sitagliptin. These patients’ baseline body mass index was significantly higher and their baseline HbA_1c was significantly lower than those of patients who responded to sitagliptin. The most commonly co‐administered drugs were sulfonylureas (508 patients). In these patients, the dose of sulfonylurea decreased with time. In 66 patients whose sulfonylurea dosage was reduced when sitagliptin was started, HbA_1c and bodyweight decreased significantly after 12 weeks. A total of 24 patients receiving sulfonylureas had mild hypoglycemia, but none discontinued sitagliptin. Conclusions: Sitagliptin was effective and safe as both monotherapy and combination therapy in Japanese type 2 diabetes patients. When sulfonylureas were ineffective, sitagliptin improved glycemic control. In patients whose sulfonylurea dose was reduced at the start of sitagliptin, blood glucose improved and bodyweight decreased after 12 weeks.     

HbA1c measured in stored erythrocytes and mortality rate among middle-aged and older women

Aims/hypothesis Diabetes is known to increase mortality rate, but the degree to which mild hyperglycaemia may be associated with the risk of death is uncertain. We examined the association between HbA_1c measured in stored erythrocytes and mortality rate in women with and without diabetes. Methods We conducted a cohort study of 27,210 women ≥ 45 years old with no history of cardiovascular disease or cancer who participated in the Women’s Health Study, a randomised trial of vitamin E and aspirin. Results Over a median of 10 years of follow-up, 706 women died. Proportional hazards models adjusted for age, smoking, hypertension, blood lipids, exercise, postmenopausal hormone use, multivitamin use and C-reactive protein were used to estimate the relative risk of mortality. Among women without a diagnosis of diabetes and HbA_1c <5.60%, those in the top quintile (HbA_1c 5.19–5.59%) had a relative risk of mortality of 1.28 (95% CI 0.98–1.69, p value for linear trend = 0.14) compared with those with HbA_1c 2.27–4.79%. Women with HbA_1c 5.60–5.99% and no diagnosis of diabetes had a 54% increased risk of mortality (95% CI 1–136%) compared with those with HbA_1c 2.27–4.79%. HbA_1c was significantly associated with mortality across the range 4.50–7.00% (p value for linear trend = 0.02); a test of deviation from linearity was not statistically significant (p = 0.67). Diabetic women had more than twice the mortality risk of non-diabetic women. Conclusions/interpretation This study provides further evidence that chronic mild hyperglycaemia, even in the absence of diagnosed diabetes, is associated with increased risk of mortality. ClinicalTrials.gov ID no.: NCT00000479     

HbA<Subscript>1c</Subscript> as a risk factor for heart failure in persons with diabetes: the Atherosclerosis Risk in Communities (ARIC) study

Aims/hypothesis  Heart failure (HF) incidence in diabetes in both the presence and absence of CHD is rising. Prospective population-based studies can help describe the relationship between HbA_1c, a measure of glycaemia control, and HF risk. Methods  We studied the incidence of HF hospitalisation or death among 1,827 participants in the Atherosclerosis Risk in Communities (ARIC) study with diabetes and no evidence of HF at baseline. Cox proportional hazard models included age, sex, race, education, health insurance status, alcohol consumption, BMI and WHR, and major CHD risk factors (BP level and medications, LDL- and HDL-cholesterol levels, and smoking). Results  In this population of persons with diabetes, crude HF incidence rates per 1,000 person-years were lower in the absence of CHD (incidence rate 15.5 for CHD-negative vs 56.4 for CHD-positive, p<0.001). The adjusted HR of HF for each 1% higher HbA_1c was 1.17 (95% CI 1.11–1.25) for the non-CHD group and 1.20 (95% CI 1.04–1.40) for the CHD group. When the analysis was limited to HF cases which occurred in the absence of prevalent or incident CHD (during follow-up) the adjusted HR remained 1.20 (95% CI 1.11–1.29). Conclusions/interpretations  These data suggest HbA_1c is an independent risk factor for incident HF in persons with diabetes with and without CHD. Long-term clinical trials of tight glycaemic control should quantify the impact of different treatment regimens on HF risk reduction.     

Genetic Determinants of Variability in Glycated Hemoglobin (HbA<Subscript>1c</Subscript>) in Humans: Review of Recent Progress and Prospects for Use in Diabetes Care

Glycated hemoglobin A_1c (HbA_1c) indicates the percentage of total hemoglobin that is bound by glucose, produced from the nonenzymatic chemical modification by glucose of hemoglobin molecules carried in erythrocytes. HbA_1c represents a surrogate marker of average blood glucose concentration over the previous 8 to 12 weeks, or the average lifespan of the erythrocyte, and thus represents a more stable indicator of glycemic status compared with fasting glucose. HbA_1c levels are genetically determined, with heritability of 47% to 59%. Over the past few years, inroads into understanding genetic predisposition by glycemic and nonglycemic factors have been achieved through genome-wide analyses. Here I review current research aimed at discovering genetic determinants of HbA_1c levels, discussing insights into biologic factors influencing variability in the general and diabetic population, and across different ethnicities. Furthermore, I discuss briefly the relevance of findings for diabetes monitoring and diagnosis.     

Glycated haemoglobin and cardiovascular risk factors in Chinese subjects with normal glucose tolerance

Increased plasma glucose concentration is a predictive factor for mortality in both diabetic and non-diabetic subjects. Although glycated haemoglobin (HbA_1c) is a useful index of mean blood glucose concentrations over the preceding 1 to 3 months, there are few data regarding its relationship to cardiovascular risk. We have examined the relationship between HbA_1c and cardiovascular risk factors in 1280 subjects with normal glucose tolerance. Based on HbA_1c tertiles (tertile 1: n = 427, 262 men and 165 women, HbA_1c level: 2.9–4.7 % in men and 3.2–4.2 % in women; tertile 2: n = 426, 261 men and 165 women, HbA_1c level: 4.7–5.1 % in men and 4.2–4.6 % in women; tertile 3: n = 427, 262 men and 165 women, HbA_1c level: 5.1–6.7 % in men and 4.6–6.9 % in women), increasing HbA_1c was associated with increasing age, blood pressure, waist–hip ratio, fasting and 2-h plasma glucose, 2-h insulin, cholesterol, low-density lipoprotein cholesterol, apolipo- protein B and urate concentrations. When age and sex were included as covariates, increasing HbA_1c remained associated with increasing fasting and 2-h plasma glucose, 2-h insulin, total cholesterol, and low-density lipoprotein cholesterol concentrations. These findings emphasize the importance of hyperglycaemia, as reflected by HbA_1c, as a continuum in the evaluation of cardiovascular risk. Furthermore, these findings support the hypothesis that cardiovascular disease risk commences with rising glucose concentrations before ‘conventionally-defined’ glucose intolerance occurs. © 1998 John Wiley & Sons, Ltd.     

Glycaemia‐independent ethnic differences in HbA1c in subjects with impaired glucose tolerance

Aim To study the ethnic differences in HbA_1c between Whites and South Asians with impaired glucose tolerance. Methods We audited 75g oral glucose tolerance tests (OGTT) performed in Clinical Chemistry, New Cross Hospital, Wolverhampton over 1 year. HbA_1c and glycaemia were compared between Whites and South Asians with impaired glucose intolerance (IGT). Results There were 46 South Asians (22 female) and 88 Whites (41 female). South Asian subjects were younger (59.2 ± 14.31 vs. 67.6 ± 12.63 yrs; P < 0.001) and weighed less (78.1 ± 17.2 vs. 87.47 ± 19.1 kgs; P < 0.001) than White subjects. HbA_1c levels were higher (6.5 ± 0.7 vs. 6.1 ± 0.6%; P < 0.001) in South Asians compared to Whites. Fasting glucose (5.71 ± 0.5 vs. 5.93 ± 0.7; P = 0.039) was lower in South Asians but 2hour glucose (10.5 ± 1.0 vs. 10.40 ± 0.9; P = 0.404) was similar in both ethnic groups. Conclusion South Asians have higher HbA_1c levels than Whites despite lower fasting glucose value on OGTT, indicating ethnic differences in HbA_1c are due to glycaemia‐independent factors     

Additive effects of glycaemia and blood pressure exposure on risk of complications in type 2 diabetes: a prospective observational study (UKPDS 75)

Aims/hypothesis The relative importance of glucose and blood pressure control in type 2 diabetes remains uncertain. We assessed interactive effects of glycaemia and systolic blood pressure (SBP) exposure on the risk of diabetic complications over time.Subjects, materials and methods HbA_1c and SBP, measured annually for a median of 10.4 years in 4,320 newly diagnosed type 2 diabetic patients from the UK Prospective Diabetes Study (UKPDS), were categorised as updated mean values <6.0, 6.0–6.9, 7.0–7.9 or ≥8.0%, and <130, 130–139, 140–149 or ≥150 mmHg, respectively. Clinical outcomes were UKPDS predefined composite endpoints.Results The incidence of the ‘any diabetes-related endpoint’ in the lowest (HbA_1c <6.0%, SBP <130 mmHg) and highest (HbA_1c ≥8%, SBP ≥150 mmHg) category combinations was 15 and 82 per 1,000 person-years, respectively, and 24 and 120 per 1,000 person-years in a Poisson model adjusted to white Caucasian male sex, age 50 to 54 years and diabetes duration of 7.5 to 12.5 years. Updated mean HbA_1c and SBP effects were additive in an adjusted proportional hazards model with risk reductions of 21% per 1% HbA_1c decrement and 11% per 10 mmHg SBP decrement. Endpoint rates obtained in the 887 patients randomised in both the glycaemia and hypertension intervention trial arms were consistent with the observational data. Those allocated to both intensive glucose and tight blood pressure control policies had fewer events than those allocated to either policy alone or to neither (p for trend 0.024).Conclusions/interpretation Risk of complications in type 2 diabetes is associated independently and additively with hyperglycaemia and hypertension. Intensive treatment of both these risk factors is required to minimise the incidence of complications.     

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus

Aims/hypothesis The aim of this study was to assess the efficacy and safety of sitagliptin (MK-0431) as monotherapy in patients with type 2 diabetes mellitus and inadequate glycaemic control (HbA_1c ≥7% and ≤10%) on exercise and diet.Methods A total of 521 patients aged 27–76 years with a mean baseline HbA_1c of 8.1% were randomised in a 1:2:2 ratio to treatment with placebo, sitagliptin 100 mg once daily, or sitagliptin 200 mg once daily, for 18 weeks. The efficacy analysis was based on an all-patients-treated population using an analysis of covariance, excluding data obtained after glycaemic rescue.Results After 18 weeks, HbA_1c was significantly reduced with sitagliptin 100 mg and 200 mg compared with placebo (placebo-subtracted HbA_1c reduction: −0.60% and −0.48%, respectively). Sitagliptin also significantly decreased fasting plasma glucose relative to placebo. Patients with higher baseline HbA_1c (≥9%) experienced greater placebo-subtracted HbA_1c reductions with sitagliptin (−1.20% for 100 mg and −1.04% for 200 mg) than those with HbA_1c <8% (−0.44% and −0.33%, respectively) or ≥8% to 8.9% (−0.61% and −0.39%, respectively). Homeostasis model assessment beta cell function index and fasting proinsulin:insulin ratio, markers of insulin secretion and beta cell function, were significantly improved with sitagliptin. The incidence of hypoglycaemia and gastrointestinal adverse experiences was not significantly different between sitagliptin and placebo. Sitagliptin had a neutral effect on body weight.Conclusions/interpretation Sitagliptin significantly improved glycaemic control and was well tolerated in patients with type 2 diabetes mellitus who had inadequate glycaemic control on exercise and diet. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible to authorised users.For the Sitagliptin Study 023 Group see electronic supplementary material for list of study investigators.     

Multicentre, randomised, controlled study of the impact of continuous sub-cutaneous glucose monitoring (GlucoDay) on glycaemic control in type 1 and type 2 diabetes patients

AimThis randomised study was designed to investigate the impact of continuous glucose monitoring (CGM) for 48 h on glycaemic control with a 3-month follow-up in patients with type 1 (T1D) or type 2 (T2D) diabetes.MethodsA total of 48 patients with poor glycaemic control (HbA_1c: 8–10.5%) underwent CGM for 48 h using the GlucoDay^® system (A. Menarini Diagnostics), after which they were randomly assigned to treatment adjustments based on either their CGM profile (CGM group) or their usual self-monitoring of blood glucose (SMBG group). HbA_1c measurement and 48-h CGM were repeated 3 months later.ResultsAltogether, 34 patients with either T1D (n = 9) or T2D (n = 25) completed the study; seven patients chose to leave the study, and seven patients in the CGM group were excluded because their baseline CGM graphs were not interpretable. HbA_1c levels decreased significantly in the CGM group (n = 14, –0.63 ± 0.27%; P = 0.023), but not in the controls (n = 20, –0.28 ± 0.21%; P = 0.30). In T2D patients, the improvement associated with CGM vs SMBG was due to HbA_1c decreases (mean: –0.63 ± 0.34%; P = 0.05 vs –0.31 ± 0.29%; P = 0.18, respectively). However, HbA_1c did not change significantly with CGM in T1D patients. Comparisons of CGM data at baseline and after 3 months showed no significant changes in glucose control, glucose variability or hypoglycaemia. No major adverse events related to the GlucoDay^® system were reported.ConclusionThis is the first randomised study showing that CGM improves glycaemic control in patients with T2D.     

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     

A 10-s sprint performed prior to moderate-intensity exercise prevents early post-exercise fall in glycaemia in individuals with type 1 diabetes

Aims/hypothesis We investigated whether a 10-s maximal sprint effort performed immediately prior to moderate-intensity exercise provides another means to counter the rapid fall in glycaemia associated with moderate-intensity exercise in individuals with type 1 diabetes. Materials and methods Seven complication-free type 1 diabetic males (21.6 ± 3.6 years; mean±SD) with HbA_1c levels of 7.4 ± 0.7% injected their normal morning insulin dose and ate their usual breakfast. When post-meal glycaemia fell to ∼11 mmol/l, participants were asked to perform a 10-s all-out sprint (sprint trial) or to rest (control trial) immediately before cycling at 40% of peak rate of oxygen consumption for 20 min, with both trials conducted in a random counterbalanced order. Results Sprinting did not affect the rapid fall in glycaemia during the subsequent bout of moderate-intensity exercise (2.9 ± 0.4 mmol/l in 20 min; p = 0.00; mean±SE). However, during the following 45 min of recovery, glycaemia in the control trial decreased by 1.23 ± 0.60 mmol/l (p = 0.04) while remaining stable in the sprint trial, subsequently decreasing in this latter trial at a rate similar to that in the control trial. The large increase in noradrenaline (norepinephrine) (p = 0.005) and lactate levels (p = 0.0005) may have contributed to the early post-exercise stabilisation of glycaemia in the sprint trial. During recovery, adrenaline (epinephrine) and NEFA levels increased marginally in the sprint trial, but other counter-regulatory hormones did not change significantly (p < 0.05). Conclusions/interpretation A 10-s sprint performed immediately prior to moderate-intensity exercise prevents glycaemia from falling during early recovery from moderate-intensity exercise in individuals with type 1 diabetes.     

Near normalisation of blood glucose improves the potentiating effect of GLP-1 on glucose-induced insulin secretion in patients with type 2 diabetes

Aims/hypothesis The ability of glucagon-like peptide-1 (GLP-1) to enhance beta cell responsiveness to i.v. glucose is impaired in patients with type 2 diabetes mellitus compared with healthy individuals. We investigated whether 4 weeks of near normalisation of blood glucose (BG) improves the potentiation of glucose-stimulated insulin secretion by GLP-1. Methods Nine obese patients with type 2 diabetes and inadequate glycaemic control (HbA_1c 8.0 ± 0.4%) were investigated before and after 4 weeks of near normalisation of BG using insulin treatment (mean diurnal blood glucose 6.4 ± 0.3 mmol/l, HbA_1c 6.6 ± 0.3%). Nine matched healthy participants were also studied. Beta cell function was investigated before and after insulin treatment using stepwise glucose infusions and infusion of saline or GLP-1 (1.0 pmol kg⁻¹ min⁻¹), resulting in supraphysiological total GLP-1 concentrations of approximately 200 pmol/l. The responsiveness to glucose or glucose+GLP-1 was expressed as the slope of the linear regression line relating insulin secretion rate (ISR) and plasma glucose concentration (pmol kg⁻¹ min⁻¹ [mmol/l]⁻¹). Results In the diabetic participants, the slopes during glucose+saline infusion did not differ before and after insulin treatment (0.33 ± 0.07 and 0.39 ± 0.04, respectively; p = NS). In contrast, near normalisation of blood glucose improved beta cell sensitivity to glucose during glucose+GLP-1 infusion (1.27 ± 0.2 before vs 1.73 ± 0.31 after; p < 0.01). In the healthy participants, the slopes during the glucose+saline and glucose+GLP-1 infusions were 1.01 ± 0.14 and 4.79 ± 0.53, respectively. Conclusions/interpretation A supraphysiological dose of GLP-1 enhances beta cell responses to glucose in patients with type 2 diabetes, and 4 weeks of near normalisation of blood glucose further improves this effect. ClinicalTrials.gov ID no.: NCT00612625