A retrospective observational study of people with Type 1 diabetes with self‐reported severe hypoglycaemia reveals high level of ambulance attendance but low levels of therapy change and specialist intervention

Aim

To evaluate the impact of severe hypoglycaemia on NHS resources and overall glycaemic control in adults with Type 1 diabetes.

Methods

An observational, retrospective study of adults (aged ≥ 18 years) with Type 1 diabetes reporting one or more episodes of severe hypoglycaemia during the preceding 24 months in 10 NHS hospital diabetes centres in England and Wales. The primary outcome was healthcare resource utilization associated with severe hypoglycaemia. Secondary outcomes included demographic and clinical characteristics, diabetes control and pathway of care.

Results

Some 140 episodes of severe hypoglycaemia were reported by 85 people during the 2‐year observation period. Ambulances were called in 99 of 140 (71%) episodes and Accident and Emergency attendance occurred in 26 of 140 (19%) episodes, whereas 29 of 140 (21%) episode required no immediate help from healthcare providers. Participants attended a median of 5 (range 0–58) diabetes clinic consultations during the observation period; 13% (70 of 552) of all consultations were severe hypoglycaemia‐related. Of the HbA_1c measurements recorded closest prior to severe hypoglycaemia (n = 119), only 7 of 119 measurements were < 48 mmol/mol (< 6.5%) and mean HbA_1c was 70 (sd 19) mmol/mol (8.5%, sd 1.7%). Some 119 changes to diabetes treatment were recorded during the observation period (median/person 0;, range 0–11), of which 52 of 119 changes (44%) followed severe hypoglycaemic events.

Conclusions

We observed a high level of ambulance service intervention but surprisingly low levels of hypoglycaemia follow‐up, therapy change and specialist intervention in people self‐reporting severe hypoglycaemia. These results suggest there may be important gaps in care pathways for people with Type 1 diabetes self‐reporting severe hypoglycaemia.     

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.     

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)     

Improved glycaemic control and treatment satisfaction with a simple wearable 3‐day insulin delivery device among people with Type 2 diabetes

Aim

To evaluate the PAQ^® (CeQur SA, Horw, Switzerland), a wearable 3‐day insulin delivery device that provides set basal rates and bolus insulin on demand, in people with Type 2 diabetes.

Method

Adults with Type 2 diabetes with HbA_1c concentrations ≥53 and ≤97 mmol/mol (7.0 and 11.0%) while treated with ≥2 insulin injections/day were enrolled in two single‐arm studies comprising three periods: a baseline (insulin injections), a transition and a PAQ treatment period (12 weeks). Endpoints included HbA_1c, seven‐point self‐monitored blood glucose, total daily dose of insulin and body weight. Safety was assessed according to examination, hypoglycaemic episodes and adverse device effects.

Results

A total of 28 adults were enrolled (age 63 ± 7 years, 86% men, BMI 32.3 ± 4.3kg/m², Type 2 diabetes duration 17 ± 8 years, HbA_1c 70 ± 12 mmol/mol (8.6 ± 1.1%), total daily insulin dose 58.7 ± 20.7 U), of whom 24 completed the studies. When transitioned to PAQ, 75% of participants continued on the first basal rate selected. After 12 weeks of PAQ wear, significant improvements from baseline were seen [HbA_1c –16 ± 9 mmol/mol (95% CI –20, –12) or –1.5 ± 0.9% (95% CI –1.8, –1.1) P<0.0001], and at all seven self‐monitored blood glucose readings time points (P ≤0.03). Total daily insulin dose increased by 12.1 ± 19.5 U (95% CI 3.9, 20.4; P=0.0058), the number of meal time boluses increased by 0.9 ± 1.5/day (95% CI 0.3, 1.5; P=0.0081) and body weight remained stable. Six participants had mild to moderate catheter site reactions and one mild skin irritation occurred. No participant experienced severe hypoglycaemia.

Conclusions

Adults with Type 2 diabetes were safely transitioned from insulin injections to the PAQ and had significantly improved glycaemic control and treatment satisfaction with insulin therapy. (ClinicalTrials.gov identifiers: NCT02158078 & NCT02419859)     

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.     

Intermittent fasting in Type 2 diabetes mellitus and the risk of hypoglycaemia: a randomized controlled trial

Aims

To establish whether the risk of hypoglycaemia is greater with 2 consecutive days of very‐low‐calorie diet compared with 2 non‐consecutive days of very‐low‐calorie diet in people with Type 2 diabetes.

Methods

This was a non‐blinded randomized parallel group interventional trial of intermittent fasting in adults. The participants had a BMI of 30–45 kg/m², Type 2 diabetes treated with metformin and/or hypoglycaemic medications and an HbA_1c concentration of 50–86 mmol/mol (6.7–10%). The participants followed a 2092–2510‐kJ diet on 2 days per week for 12 weeks. A total of 41 participants were randomized 1:1 to consecutive (n=19) or non‐consecutive (n=22) day fasts, of whom 37 (n=18 and n=19, respectively) were included in the final analysis. The primary outcome was difference in the rate of hypoglycaemia between the two study arms. Secondary outcomes included change in diet, quality of life, weight, lipid, glucose and HbA_1c levels, and liver function.

Results

The mean hypoglycaemia rate was 1.4 events over 12 weeks. Fasting increased the rate of hypoglycaemia despite medication reduction (RR 2.05, 95% CI 1.17 to 3.52). There was no difference between fasting on consecutive days and fasting on non‐consecutive days (RR 1.54, 95% CI 0.35 to 6.11). Improvements in weight, HbA_1c, fasting glucose and quality of life were experienced by participants in both arms.

Conclusions

In individuals with Type 2 diabetes on hypoglycaemic medications, fasting of any type increased the rate of hypoglycaemia. With education and medication reduction, fewer than expected hypoglycaemic events occurred. Although it was not possible to determine whether fasting on consecutive days increased the risk of hypoglycaemia, an acceptable rate was observed in both arms.     

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.     

Long-term outcome of insulin pump therapy in children with type 1 diabetes assessed in a large population-based case–control study

Aims/hypothesis

We determined the impact of insulin pump therapy on long-term glycaemic control, BMI, rate of severe hypoglycaemia and diabetic ketoacidosis (DKA) in children.

Methods

Patients on pump therapy at a single paediatric tertiary hospital were matched to patients treated by injections on the basis of age, duration of diabetes and HbA_1c at the time of pump start. HbA_1c, anthropometric data, episodes of severe hypoglycaemia and rates of hospitalisation for DKA were collected prospectively.

Results

A total of 345 patients on pump therapy were matched to controls on injections. The mean age, duration of diabetes at pump start and length of follow-up were 11.4 (±?3.5), 4.1 (±?3.0) and 3.5 (±?2.5) years, respectively. The mean HbA_1c reduction in the pump cohort was 0.6% (6.6 mmol/mol). This improved HbA_1c remained significant throughout the 7 years of follow-up. Pump therapy reduced severe hypoglycaemia from 14.7 to 7.2 events per 100 patient-years (p?<?0.001). In contrast, severe hypoglycaemia increased in the non-pump cohort over the same period from 6.8 to 10.2 events per 100 patient-years. The rate of hospitalisation for DKA was lower in the pump cohort (2.3 vs 4.7 per 100 patient-years, p?=?0.003) over the 1,160 patient-years of follow-up.

Conclusions/interpretation

This is the longest and largest study of insulin pump use in children and demonstrates that pump therapy provides a sustained improvement in glycaemic control, and reductions of severe hypoglycaemia and hospitalisation for DKA compared with a matched cohort using injections.     

Primary‐care observational database study of the efficacy of GLP‐1 receptor agonists and insulin in the UK

Aims

We investigated use and efficacy of glucagon‐like peptide‐1 (GLP‐1) receptor agonists in UK practice.

Methods

People starting a GLP‐1 receptor agonist (exenatide, liraglutide) or insulin (glargine, detemir, NPH) after a regimen of two or three oral glucose‐lowering agents were identified from The Health Information Network observational primary care database (2007–2011). Mean change in HbA_1c and body weight were compared at 1 year between cohorts, adjusting for baseline characteristics.

Results

Baseline characteristics of GLP‐1 receptor agonist (n = 1123) vs. insulin (n = 1842) users were HbA_1c 78 vs. 84 mmol/mol (9.3 vs. 9.8%) and BMI 38.2 vs. 30.9 kg/m². The GLP‐1 receptor agonist cohort was younger, had shorter diabetes duration and follow‐up, less microvascular disease and heart failure, higher estimated glomerular filtration rate and more use of oral glucose‐lowering agents. Lower HbA_1c reduction on GLP‐1 receptor agonist [7 vs. 13 mmol/mol (0.6 vs. 1.2%) (n = 366 vs. 892)] was not statistically significant [adjusted mean difference ?1.4 (95% CI ?4.1, 1.2) mmol/mol], except in the highest HbA_1c quintile [>96 mmol/mol (>10.9%); adjusted mean difference ?17.8 (?28.6, ?7.0) mmol/mol]. GLP‐1 receptor agonist users lost weight [?4.5 vs. +1.5 kg; adjusted mean difference 4.7 (3.7, 5.8) kg; n = 335 vs. 634]. A UK 6‐month target reduction for GLP‐1 receptor agonists of 11 mmol/mol (1.0%) HbA_1c and 3% weight was reached by 24.9% of those continuing treatment.

Conclusions

Those starting GLP‐1 receptor agonists are heavier with better glycaemic control than those starting basal insulin. Subsequently, they have improved weight change, with similar HbA_1c reduction unless baseline HbA_1c is very high. The UK 6‐month GLP‐1 receptor agonist target is usually not reached.

     

Insulin pump use in pregnancy is associated with lower HbA1c without increasing the rate of severe hypoglycaemia or diabetic ketoacidosis in women with type 1 diabetes

Aims/hypothesis

The aim of this study was to compare glycaemic control and maternal–fetal outcomes in women with type 1 diabetes managed on insulin pumps compared with multiple daily injections of insulin (MDI).

Methods

In a retrospective study, glycaemic control and outcomes of 387 consecutive pregnancies in women with type 1 diabetes who attended specialised clinics at three centres 2006–2010 were assessed.

Results

Women using insulin pumps (129/387) were older and had a longer duration of diabetes, more retinopathy, smoked less in pregnancy, and had more preconception care (p?<?0.01 for each). Among 113 pregnancies >20 weeks’ gestation in women on insulin pumps and 218 in women on MDI, there was a significant difference in HbA_1c in the first trimester (mean HbA_1c 6.90?±?0.71% (52?±?7.8 mmol/mol) vs 7.60?±?1.38% (60?±?15.1 mmol/mol), p?<?0.001), which persisted until the third trimester (mean HbA_1c 6.49?±?0.52% (47?±?5.7 mmol/mol) vs 6.81?±?0.85% (51?±?9.3 mmol/mol), p?=?0.002). Rates of diabetic ketoacidosis were similar in women on insulin pumps vs MDI (1.8% vs 3.0%, p?=?0.72). Despite lower HbA_1c, women on insulin pumps did not have an increased incidence of severe hypoglycaemia (8.0% vs 7.6%, p?=?0.90) or more weight gain (16.3?±?8.7 vs 15.2?±?6.2 kg, p?=?0.18). More large-for-gestational-age infants in the pump group (55.0% vs 39.2%, p?=?0.007) may have resulted from confounding by parity.

Conclusions/interpretation

In this large multicentre study, women using insulin pumps in pregnancy had lower HbA_1c without increased risk of severe hypoglycaemia or diabetic ketoacidosis but no improvement in other pregnancy outcomes. This information can help inform care providers and patients about the glycaemic effectiveness and safety of insulin pumps in pregnancy.     

A population-based study of risk factors for severe hypoglycaemia in a contemporary cohort of childhood-onset type 1 diabetes

Aims/hypothesis

Severe hypoglycaemia is a major barrier to optimising glycaemic control. Recent changes in therapy, however, may have altered the epidemiology of severe hypoglycaemia and its associated risk factors. The aim of this study was to examine the incidence rates and risk factors associated with severe hypoglycaemia in a contemporary cohort of children and adolescents with type 1 diabetes.

Methods

Subjects were identified from a population-based register containing data on >99% of patients (<16 years of age) who were being treated for type 1 diabetes in Western Australia. Patients attend the clinic approximately every 3 months, where data pertaining to diabetes management, demographics and complications including hypoglycaemia are prospectively recorded. A severe hypoglycaemic event was defined as an episode of coma or convulsion associated with hypoglycaemia. Risk factors assessed included age, duration of diabetes, glycaemic control, sex, insulin therapy, socioeconomic status and calendar year.

Results

Clinical visit data from 1,770 patients, providing 8,214 patient-years of data between 2000 and 2011 were analysed. During follow-up, 841 episodes of severe hypoglycaemia were observed. No difference in risk of severe hypoglycaemia was observed between age groups. Good glycaemic control (HbA_1c <7% [53 mmol/mol]) compared with the cohort average (HbA_1c 8–9% [64–75 mmol/mol]) was not associated with an increased risk of severe hypoglycaemia. When compared with patients on injection regimens, subjects aged 12–18 years on pump therapy were at reduced risk of severe hypoglycaemia (incidence risk ratio 0.6; 95% CI 0.4, 0.9).

Conclusions/interpretation

In this population-based sample of children and adolescents with type 1 diabetes, contemporary therapy is associated with a changed pattern and incidence of severe hypoglycaemia.     

Relationship between mean blood glucose and glycated haemoglobin in Type 2 diabetic patients

Aims To correlate the values of MBG to HbA_1c in Greek patients with Type 2 diabetes and/or metabolic syndrome. Methods We followed up 140 Greek adult patients: 92 patients with Type 2 diabetes treated with insulin or oral glucose‐lowering medication, and 48 patients with newly diagnosed Type 2 diabetes or metabolic syndrome not receiving any treatment. MBG was calculated for each patient from self‐measurements of blood glucose using a portable glucometer, made six times a day (before eating and 2 h after a meal), three times a week for 1 month. HbA_1c was determined by HPLC at 0 and 12 weeks. Results HbA_1c at 0 (x) and 12 weeks (y) correlated strongly (y = 0.790x + 1.115, r = 0.92), confirming that the patient's glycaemic status remained stable during the whole period of follow‐up. Linear regression was performed on MBG values; HbA_1c at 12 weeks, sex, age, body mass index (BMI) and patient status (Type 2 diabetes treated or not) were used as independent variables. None of the independent variables reached statistical significance in the model, with the exception of HbA_1c at 12 weeks. The final model was: MBG (mg/dl) = (34.74 × HbA_1c) – 79.21, r = 0.93; or MBG (mmol/l) = 1.91 × HbA_1c – 4.36, r = 0.93. Conclusions Our results establish for the first time a strong correlation between MBG and HbA_1c in Type 2 diabetic patients and support the idea of expressing HbA_1c results as MBG. This will help patients to gain a clearer interpretation of the result, with less confusion. This simplification will allow every person with diabetes using home glucose‐monitoring to understand his or her own target level.     

Taspoglutide,a once‐weekly glucagon‐like peptide 1 analogue,vs. insulin glargine titrated to target in patients with Type 2 diabetes: an open‐label randomized trial

Aims To compare the efficacy and safety of once‐weekly taspoglutide with insulin glargine in patients with advanced Type 2 diabetes failing metformin and sulphonylurea combination therapy. Methods This open‐label, parallel‐group, multi‐centre trial randomized 1049 patients continuing metformin 1:1:1 to taspoglutide 10 mg once weekly, taspoglutide 20 mg once weekly or insulin glargine once daily with forced titration to fasting plasma glucose ≤ 6.1 mmol/l. Sulphonylureas were discontinued before randomization. The primary endpoint was change in HbA_1c after 24 weeks. Results After 24 weeks, least‐square mean changes from baseline in HbA_1c in patients receiving taspoglutide 10 mg [?8 mmol/mol (se 1)] [?0.77% (se 0.05)] or taspoglutide 20 mg [?11 mmol/mol (se 1)] [?0.98% (se 0.05)] were non‐inferior to insulin glargine [?9 mmol/mol (se 1)] [?0.84% (se 0.05)]; treatment difference of 0.07% (95% CI ?0.06 to 0.21) and ?0.14% (95% CI ?0.28 to ?0.01), for taspoglutide 10 and 20 mg, respectively, vs. insulin glargine. Taspoglutide was associated with more adverse events (mainly gastrointestinal) and significantly less hypoglycaemia than insulin glargine. Conclusions Compared with insulin glargine, taspoglutide provided non‐inferior HbA_1c reductions associated with less hypoglycaemia, but more gastrointestinal adverse events.     

Nocturnal hypoglycaemia in Type 1 diabetic patients,assessed with continuous glucose monitoring: frequency,duration and associations

Aims We quantified the occurrence and duration of nocturnal hypoglycaemia in individuals with Type 1 diabetes treated with continuous subcutaneous insulin infusion (CSII) or multiple‐injection therapy (MIT) using a continuous subcutaneous glucose sensor. Methods A microdialysis sensor was worn at home by 24 patients on CSII (mean HbA_1c 7.8 ± 0.9%) and 33 patients on MIT (HbA_1c 8.7 ± 1.3%) for 48 h. Occurrence and duration of nocturnal hypoglycaemia were assessed and using multivariate regression analysis, the association between HbA_1c, diabetes duration, treatment type (CSII vs. MIT), fasting and bedtime blood glucose values, total daily insulin dose and mean nocturnal glucose concentrations, and hypoglycaemia occurrence and duration was investigated. Results Nocturnal hypoglycaemia ≤ 3.9 mmol/l occurred in 33.3% of both the CSII‐ (8/24) and MIT‐treated patients (11/33). Mean (± sd ; median, interquartile range) duration of hypoglycaemia ≤ 3.9 mmol/l was 78 (± 76; 57, 23–120) min per night for the CSII‐ and 98 (± 80; 81, 32–158) min per night for the MIT‐treated group. Multivariate regression analysis showed that bedtime glucose value had the strongest association with the occurrence (P = 0.026) and duration (P = 0.032) of nocturnal hypoglycaemia. Conclusions Microdialysis continuous glucose monitoring has enabled more precise quantification of nocturnal hypoglycaemia occurrence and duration in Type 1 diabetic patients. Occurrence and duration of nocturnal hypoglycaemia were mainly associated with bedtime glucose value.     

The use and efficacy of continuous glucose monitoring in type 1 diabetes treated with insulin pump therapy: a randomised controlled trial

Aims/hypothesis

The aim of this multicentre, randomised, controlled crossover study was to determine the efficacy of adding continuous glucose monitoring (CGM) to insulin pump therapy (CSII) in type 1 diabetes.

Methods

Children and adults (n?=?153) on CSII with HbA_1c 7.5–9.5% (58.5–80.3?mmol/mol) were randomised to (CGM) a Sensor On or Sensor Off arm for 6?months. After 4?months’ washout, participants crossed over to the other arm for 6?months. Paediatric and adult participants were separately electronically randomised through the case report form according to a predefined randomisation sequence in eight secondary and tertiary centres. The primary outcome was the difference in HbA_1c levels between arms after 6?months.

Results

Seventy-seven participants were randomised to the On/Off sequence and 76 to the Off/On sequence; all were included in the primary analysis. The mean difference in HbA_1c was –0.43% (–4.74?mmol/mol) in favour of the Sensor On arm (8.04% [64.34?mmol/mol] vs 8.47% [69.08?mmol/mol]; 95% CI ?0.32%, ?0.55% [?3.50, ?6.01?mmol/mol]; p?<?0.001). Following cessation of glucose sensing, HbA_1c reverted to baseline levels. Less time was spent with sensor glucose <3.9?mmol/l during the Sensor On arm than in the Sensor Off arm (19 vs 31?min/day; p?=?0.009). The mean number of daily boluses increased in the Sensor On arm (6.8?±?2.5 vs 5.8?±?1.9, p?<?0.0001), together with the frequency of use of the temporary basal rate (0.75?±?1.11 vs 0.26?±?0.47, p?<?0.0001) and manual insulin suspend (0.91?±?1.25 vs 0.70?±?0.75, p?<?0.018) functions. Four vs two events of severe hypoglycaemia occurred in the Sensor On and Sensor Off arm, respectively (p?=?0.40).

Conclusions/interpretation

Continuous glucose monitoring was associated with decreased HbA_1c levels and time spent in hypoglycaemia in individuals with type 1 diabetes using CSII. More frequent self-adjustments of insulin therapy may have contributed to these effects.

Trial registration

ClinicalTrials.gov registration no. NCT00598663.

Funding

The study was funded by Medtronic International Trading Sarl Switzerland.     

Short-term impact of HbA1c on morbidity and all-cause mortality in people with type 2 diabetes: a Danish population-based observational study

Aims/hypothesis  

In a population-based setting, we investigated whether diabetes-related morbidity and all-cause mortality within 2 years of HbA_1c measurement were associated with that HbA_1c level in individuals with type 2 diabetes. The main objective was to compare outcomes in those with HbA_1c ≥ and <7% (53 mmol/mol).     

A UK nationwide prospective study of treatment change in MODY: genetic subtype and clinical characteristics predict optimal glycaemic control after discontinuing insulin and metformin

Aims/hypothesis

Treatment change following a genetic diagnosis of MODY is frequently indicated, but little is known about the factors predicting future treatment success. We therefore conducted the first prospective study to determine the impact of a genetic diagnosis on individuals with GCK-, HNF1A- or HNF4A-MODY in the UK, and to identify clinical characteristics predicting treatment success (i.e. HbA_1c ≤58 mmol/mol [≤7.5%]) with the recommended treatment at 2 years.

Methods

This was an observational, prospective, non-selective study of individuals referred to the Exeter Molecular Genetic Laboratory for genetic testing from December 2010 to December 2012. Individuals from the UK with GCK- or HNF1A/HNF4A-MODY who were not on recommended treatment at the time of genetic diagnosis, and who were diagnosed below the age of 30 years and were currently aged less than 50 years, were eligible to participate.

Results

A total of 44 of 58 individuals (75.9%) changed treatment following their genetic diagnosis. Eight individuals diagnosed with GCK-MODY stopped all diabetes medication without experiencing any change in HbA_1c (49.5 mmol/mol [6.6%] both before the genetic diagnosis and at a median of 1.25 years’ follow-up without treatment, p?=?0.88). A total of 36 of 49 individuals (73.5%) diagnosed with HNF1A/HNF4A-MODY changed treatment; however, of the 21 of these individuals who were being managed with diet or sulfonylurea alone at 2 years, only 13 (36.1% of the population that changed treatment) had an HbA_1c ≤58 mmol/mol (≤7.5%). These individuals had a shorter diabetes duration (median 4.6 vs 18.1 years), lower HbA_1c (58 vs 73 mmol/mol [7.5% vs 8.8%]) and lower BMI (median 24.2 vs 26.0 kg/m²) at the time of genetic diagnosis, compared with individuals (n?=?23/36) with an HbA_1c >58 mmol/mol (>7.5%) (or <58 mmol/mol [<7.5%] on additional treatment) at the 2 year follow-up. Overall, 64% (7/11) individuals with a diabetes duration of ≤11 years and an HbA_1c of ≤69 mmol/mol (≤8.5%) at time of the genetic test achieved good glycaemic control (HbA_1c ≤58 mmol/mol [≤7.5%]) with diet or sulfonylurea alone at 2 years, compared with no participants with a diabetes duration of >11 years and an HbA_1c of >69 mmol/mol (>8.5%) at the time of genetic diagnosis.

Conclusions/interpretation

In participants with GCK-MODY, treatment cessation was universally successful, with no change in HbA_1c at follow-up. In those with HNF1A/HNF4A-MODY, a shorter diabetes duration, lower HbA_1c and lower BMI at genetic diagnosis predicted successful treatment with sulfonylurea/diet alone, supporting the need for early genetic diagnosis and treatment change. Our study suggests that, in individuals with HNF1A/HNF4A-MODY with a longer duration of diabetes (>11 years) at time of genetic test, rather than ceasing current treatment, a sulfonylurea should be added to existing therapy, particularly in those who are overweight or obese and have a high HbA_1c.

     

Changes in HbA1c and frequency of measuring HbA1c and adjusting glucose-lowering medications in the 10 years following diagnosis of type 2 diabetes: a population-based study in the UK

Aims/hypothesis

The aim of this work was to study levels of HbA_1c and patterns of adjusting glucose-lowering drugs in patients with impaired glycaemic control over 10 years after diagnosis of type 2 diabetes.

Methods

We studied 4,529 individuals in The Health Improvement Network Database newly diagnosed with type 2 diabetes in the year 2000.

Results

From 6 months to 10 years after diagnosis, the HbA_1c increased from 7.04% (53.4 mmol/mol) to 7.49% (58.3 mmol/mol) (average annual change: 0.047% [0.51 mmol/mol]). The greatest annual change occurred between 6 months and 2 years (0.21% [2.30 mmol/mol] increase per year, p?<?0.001), followed by the 2–5 year time period (0.033% [0.36 mmol/mol] increase per year, p?<?0.001). No significant increase in HbA_1c occurred between 5 and 10 years (p?=?0.20). In multivariable analyses, patients who were younger (p?<?0.001), with higher BMI (p?=?0.033) and who were current insulin users (p?=?0.024) at diagnosis had greater increases in HbA_1c between 6 months and 2 years. For individuals with HbA_1c above 7.0% (53 mmol/mol) the mean time to next measurement of HbA_1c was 0.53 years and increase in doses or changes to other glucose-lowering medications were performed in 26% of cases.

Conclusions/interpretation

HbA_1c increases by approximately 0.5% (5 mmol/mol) over 10 years after diagnosis of type 2 diabetes, with the main increase appearing in the first years after diagnosis. More frequent monitoring of HbA_1c and adjustments of glucose-lowering drugs may be essential to prevent the decline.     

Age at type 2 diabetes onset and glycaemic control: results from the National Health and Nutrition Examination Survey (NHANES) 2005–2010

Aims/hypothesis

We tested the hypothesis that age younger than 65 years at type 2 diabetes diagnosis is associated with worse subsequent glycaemic control.

Methods

A cross-sectional analysis of data from participants in the 2005–2010 National Health and Nutrition Examination Survey was performed. For adults with self-reported diabetes, we dichotomised age at diabetes diagnosis as younger (<65 years) vs older (≥65 years). The primary outcome of interest was HbA_1c >9.0% (75 mmol/mol). Secondary outcomes were HbA_1c >8.0% (64 mmol/mol) and >7.0% (53 mmol/mol). We used multivariable logistic regression for analysis.

Results

Among 1,438 adults with diabetes, a higher proportion of those <65 years at diagnosis compared with those ≥65 at diagnosis had an HbA_1c >9.0% (14.4% vs 2.5%, p?<?0.001). After adjustment for sex, race/ethnicity, education, income, insurance, usual source of care, hyperglycaemia medication, duration of diabetes, family history, BMI and waist circumference, age <65 years at diagnosis remained significantly associated with greater odds of HbA_1c >9.0% (OR 3.22, 95% CI 1.54, 6.72), HbA_1c >8.0% (OR 2.72, 95% CI 1.43, 5.16) and HbA_1c >7.0% (OR 1.92, 95% CI 1.18, 3.11). The younger group reported fewer comorbidities, but were less likely to report good health (OR 0.54, 95% CI 0.36, 0.83).

Conclusions/interpretation

Younger age at type 2 diabetes diagnosis is significantly associated with worse subsequent glycaemic control. Because patients who are younger at diagnosis have fewer competing comorbidities and complications, safe, aggressive, individualised treatment could benefit this higher-risk group.     

Impact of type 1 diabetes on maternal long-term risk of hospitalisation and mortality: a nationwide combined clinical and register-based cohort study (The EPICOM study)

Aims/hypothesis

The aims of this study were to examine long-term mortality and morbidity rates in mothers with type 1 diabetes, both overall and according to the level of albuminuria prior to pregnancy, the presence of hypertension, pre-eclampsia and periconceptional HbA_1c.

Methods

This study was a part of the EPICOM (Environmental Versus Genetic and Epigenetic Influences on Growth, Metabolism and Cognitive Function in Offspring of Mothers with Type 1 Diabetes) study, which is a prospective follow-up study focusing on pregnancies complicated by maternal type 1 diabetes. We carried out a nationwide combined clinical and register-based cohort study of mortality rates and hospital admissions in mothers with diabetes (n?=?986) who gave birth between 1992 and 2000. Control mothers (n?=?91,441) were women from the background population, matched according to age and year of childbirth. Age at follow-up was 32–66 years.

Results

Mortality rate was increased threefold in mothers with diabetes compared with control mothers (HR 3.41 [95% CI 2.42, 4.81]; p?<?0.0001), and was also increased with pre-gestational kidney dysfunction (normoalbuminuria, HR 2.17 [95% CI 1.28, 3.68]; microalbuminuria, HR 3.36 [95% CI 0.82, 13.8]; macroalbuminuria, HR 12.9 [95% CI 5.45, 30.7]). Moreover, the presence of hypertension prior to or at any time during pregnancy and of pre-eclampsia also increased mortality rate (hypertension, HR 4.34 [95% CI 2.13, 8.84]; pre-eclampsia, HR 5.55 [95% CI 2.71, 11.4]). Mortality rate also increased with higher levels of HbA_1c in early pregnancy (HbA_1c ≤75 mmol/mol [≤9%], HR 2.15 [95% CI 1.31, 3.53]; HbA_1c >75 mmol/mol [>9%], HR 6.10 [95% CI 2.67, 14.0]). However, in mothers with diabetes and HbA_1c <64 mmol/mol (<8%) in the first trimester and normal pre-gestational urinary albumin excretion rate (n?=?517), mortality rate was comparable with that of control mothers. Among mothers with diabetes, mortality rate was associated with HbA_1c level: per 11 mmol/mol (1 percentage point) increase in HbA_1c, HR was 1.52 (95% CI 1.19, 1.94; p?=?0.001). In mothers with diabetes, the overall incidence of hospital admissions was more than double (incidence rate ratio [IRR] 2.69 [95% CI 2.59, 2.80]; p?<?0.0001) that of control mothers, as were admissions with various diagnoses from 14 out of 19 ICD-10 chapters. Among mothers with diabetes, the IRR for hospital admissions increased with the level of HbA_1c: per 11 mmol/mol (1 percentage point) increase in HbA_1c, HR was 1.07 (95% CI 1.04, 1.10; p?<?0.0001).

Conclusions/interpretation

Overall, mothers with type 1 diabetes have a two- to threefold increase in mortality and morbidity rates. HbA_1c levels, level of albuminuria around the time of conception, and the presence of hypertension and pre-eclampsia are important risk factors for mortality/morbidity in this cohort. However, it is reassuring that mothers with type 1 diabetes without kidney complications and with HbA_1c <64 mmol/mol (<8%) in early pregnancy have a similar survival potential during the period where they are raising their children to that of control mothers from the background population.