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.     

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.     

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.     

Day-to-day fasting glycaemic variability in DEVOTE: associations with severe hypoglycaemia and cardiovascular outcomes (DEVOTE 2)

Aims/hypothesis

The Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) was a double-blind, randomised, event-driven, treat-to-target prospective trial comparing the cardiovascular safety of insulin degludec with that of insulin glargine U100 (100 units/ml) in patients with type 2 diabetes at high risk of cardiovascular events. This paper reports a secondary analysis investigating associations of day-to-day fasting glycaemic variability (pre-breakfast self-measured blood glucose [SMBG]) with severe hypoglycaemia and cardiovascular outcomes.

Methods

In DEVOTE, patients with type 2 diabetes were randomised to receive insulin degludec or insulin glargine U100 once daily. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In this article, day-to-day fasting glycaemic variability was based on the standard deviation of the pre-breakfast SMBG measurements. The variability measure was calculated as follows. Each month, only the three pre-breakfast SMBG measurements recorded before contact with the site were used to determine a day-to-day fasting glycaemic variability measure for each patient. For each patient, the variance of the three log-transformed pre-breakfast SMBG measurements each month was determined. The standard deviation was determined as the square root of the mean of these monthly variances and was defined as day-to-day fasting glycaemic variability. The associations between day-to-day fasting glycaemic variability and severe hypoglycaemia, MACE and all-cause mortality were analysed for the pooled trial population with Cox proportional hazards models. Several sensitivity analyses were conducted, including adjustments for baseline characteristics and most recent HbA_1c.

Results

Day-to-day fasting glycaemic variability was significantly associated with severe hypoglycaemia (HR 4.11, 95% CI 3.15, 5.35), MACE (HR 1.36, 95% CI 1.12, 1.65) and all-cause mortality (HR 1.58, 95% CI 1.23, 2.03) before adjustments. The increased risks of severe hypoglycaemia, MACE and all-cause mortality translate into 2.7-, 1.2- and 1.4-fold risk, respectively, when a patient’s day-to-day fasting glycaemic variability measure is doubled. The significant relationships of day-to-day fasting glycaemic variability with severe hypoglycaemia and all-cause mortality were maintained after adjustments. However, the significant association with MACE was not maintained following adjustment for baseline characteristics with either baseline HbA_1c (HR 1.19, 95% CI 0.96, 1.47) or the most recent HbA_1c measurement throughout the trial (HR 1.21, 95% CI 0.98, 1.49).

Conclusions/interpretation

Higher day-to-day fasting glycaemic variability is associated with increased risks of severe hypoglycaemia and all-cause mortality.

Trial registration

ClinicalTrials.gov NCT01959529

     

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.     

Clinical perspectives from the BEGIN and EDITION programmes: Trial-level meta-analyses outcomes with either degludec or glargine 300 U/mL vs glargine 100 U/mL in T2DM

Aims

To explore comparative glycaemic control and hypoglycaemia incidence with insulin degludec 100 U/mL (IDeg) or insulin glargine 300 U/mL (Gla-300) versus glargine 100 U/mL (Gla-100) in trial-level meta-analyses of phase 3a clinical trials including people with type-2 diabetes.

Volume of supervised exercise training impacts glycaemic control in patients with type 2 diabetes: a systematic review with meta-regression analysis

Aims/hypothesis

Supervised exercise programmes improve glycaemic control in type 2 diabetes, but training characteristics associated with reduction in HbA_1c remain unclear. We conducted a systematic review with meta-regression analysis of randomised clinical trials (RCTs) assessing the association between intensity and volume of exercise training (aerobic, resistance or combined) and HbA_1c changes in patients with type 2 diabetes.

Methods

Five electronic databases were searched (1980–2012) to retrieve RCTs of at least 12 weeks' duration, consisting of supervised exercise training vs no intervention, that reported HbA_1c changes and exercise characteristics. Two independent reviewers conducted study selection and data extraction.

Results

Twenty-six RCTs (2,253 patients) met the inclusion criteria. In multivariate analysis, baseline HbA_1c and exercise frequency explained nearly 58% of between-study variance. Baseline HbA_1c was inversely correlated with HbA_1c reductions after the three types of exercise training. In aerobic training, exercise volume (represented by frequency of sessions) was associated with changes in HbA_1c (weighted r?=??0.64), while no variables were correlated with glycaemic control induced by resistance training. In combined training, weekly volume of resistance exercise explained heterogeneity in multivariate analysis and was associated with changes in HbA_1c levels (weighted r?=??0.70).

Conclusions/interpretation

Reduction in HbA_1c is associated with exercise frequency in supervised aerobic training, and with weekly volume of resistance exercise in supervised combined training. Therefore, exercise volume is a major determinant of glycaemic control in patients with type 2 diabetes.     

HbA<Subscript>1c</Subscript> is associated with altered expression in blood of cell cycle- and immune response-related genes

Aims/hypothesis

Individuals with type 2 diabetes are heterogeneous in their glycaemic control as tracked by blood HbA_1c levels. Here, we investigated the extent to which gene expression levels in blood reflect current and future HbA_1c levels.

Methods

HbA_1c levels at baseline and 1 and 2 year follow-up were compared with gene expression levels in 391 individuals with type 2 diabetes from the Hoorn Diabetes Care System Cohort (15,564 genes, RNA sequencing). The functions of associated baseline genes were investigated further using pathway enrichment analysis. Using publicly available data, we investigated whether the genes identified are also associated with HbA_1c in the target tissues, muscle and pancreas.

Results

At baseline, 220 genes (1.4%) were associated with baseline HbA_1c. Identified genes were enriched for cell cycle and complement system activation pathways. The association of 15 genes extended to the target tissues, muscle (n = 113) and pancreatic islets (n = 115). At follow-up, expression of 25 genes (0.16%) associated with 1 year HbA_1c and nine genes (0.06%) with 2 year HbA_1c. Five genes overlapped across all time points, and 18 additional genes between baseline and 1 year follow-up. After adjustment for baseline HbA_1c, the number of significant genes at 1 and 2 years markedly decreased, suggesting that gene expression levels in whole blood reflect the current glycaemic state and but not necessarily the future glycaemic state.

Conclusions/interpretation

HbA_1c levels in individuals with type 2 diabetes are associated with expression levels of genes that link to the cell cycle and complement system activation.

     

Statins and glycaemic control in individuals with diabetes: a systematic review and meta-analysis

Aims/hypotheses

Current evidence indicates that statins increase the risk of incident diabetes; however, the relationship between statins and glycaemic control in people with established diabetes has not been well characterised. To address this question, we conducted a meta-analysis of randomised controlled trials (RCTs) of statins in patients with diabetes for whom there was available data on glycaemic control.

Methods

We identified studies published between January 1970 and November 2013 by searching electronic databases and reference lists. We included RCTs in which the intervention group received statins and the control group received placebo or standard treatment, with >200 participants enrolled, with the intervention lasting >12 weeks and with pre- and post-intervention HbA_1c reported. We combined study-specific estimates using random-effects model meta-analysis.

Results

In a pooled analysis of nine trials involving 9,696 participants (4,980 statin, 4,716 control) and an average follow-up of 3.6 years, the mean HbA_1c of participants randomised to statins was higher than those randomised to the control group: mean difference (95% CI) was 0.12% (0.04, 0.20) or 1.3 mmol/mol (0.4, 2.2); p?=?0.003. There was moderate heterogeneity across the studies (I ²?=?54%, p?=?0.014) not explained by available study-level characteristics. This review was limited by the small number of studies, available data on only three statins and sparse reporting on changes in use of glucose-lowering medications.

Conclusions/interpretation

Statin treatment is associated with a modest increase in HbA_1c in patients with diabetes.     

Worse glycaemic control in LADA patients than in those with type 2 diabetes, despite a longer time on insulin therapy

Aims/hypothesis

Our aim was to study whether glycaemic control differs between individuals with latent autoimmune diabetes in adults (LADA) and patients with type 2 diabetes, and whether it is influenced by time on insulin therapy.

Methods

We performed a retrospective study of 372 patients with LADA (205 men and 167 women; median age 54 years, range 35–80 years) from Swedish cohorts from Skåne (n?=?272) and Västerbotten (n?=?100). Age- and sex-matched patients with type 2 diabetes were included as controls. Data on the use of oral hypoglycaemic agents (OHAs), insulin and insulin–OHA combination therapy was retrieved from the medical records. Poor glycaemic control was defined as HbA_1c ≥7.0% (≥53 mmol/mol) at follow-up.

Results

The individuals with LADA and with type 2 diabetes were followed for an average of 107 months. LADA patients were leaner than type 2 diabetes patients at diagnosis (BMI 27.7 vs 31.0 kg/m²; p?<?0.001) and follow-up (BMI 27.9 vs 30.2 kg/m²; p?<?0.001). Patients with LADA had been treated with insulin for longer than those with type 2 diabetes (53.3 vs 28.8 months; p?<?0.001). There was no significant difference between the patient groups with regard to poor glycaemic control at diagnosis, but more patients with LADA (67.8%) than type 2 diabetes patients (53.0%; p?<?0.001) had poor glycaemic control at follow-up. Patients with LADA had worse glycaemic control at follow-up compared with participants with type 2 diabetes (OR?=?1.8, 95% CI 1.2, 2.7), adjusted for age at diagnosis, HbA_1c, BMI at diagnosis, follow-up time and duration of insulin treatment.

Conclusions/interpretation

Individuals with LADA have worse glycaemic control than patients with type 2 diabetes despite a longer time on insulin therapy.     

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     

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.     

Liraglutide reverses pronounced insulin-associated weight gain,improves glycaemic control and decreases insulin dose in patients with type 2 diabetes: a 26 week,randomised clinical trial (ELEGANT)

Aims/hypothesis

The best treatment strategy for a patient with type 2 diabetes who shows pronounced weight gain after the introduction of insulin treatment is unclear. We determined whether addition of a glucagon-like peptide-1 (GLP-1) analogue could reverse pronounced insulin-associated weight gain while maintaining glycaemic control, and compared this with the most practised strategy, continuation and intensification of standard insulin therapy.

Methods

In a 26-week, randomised controlled trial (ELEGANT), conducted in the outpatient departments of one academic and one large non-academic teaching hospital in the Netherlands, adult patients with type 2 diabetes with ≥4% weight gain during short-term (≤16 months) insulin therapy received either open-label addition of liraglutide 1.8 mg/day (n?=?26) or continued standard therapy (n?=?24). A computer-generated random number list was used to allocate treatments. Participants were evaluated every 4–6 weeks for weight, glycaemic control and adverse events. The primary endpoint was between-group weight difference after 26 weeks of treatment (intention to treat).

Results

Of 50 randomised patients (mean age 58 years, BMI 33 kg/m², HbA_1c 7.4% [57 mmol/mol]), 47 (94%) completed the study; all patients were analysed. Body weight decreased by 4.5 kg with liraglutide and increased by 0.9 kg with standard therapy (mean difference ?5.2 kg [95% CI ?6.7, ?3.6 kg]; p?1c were ?0.77% (?8.4 mmol/mol) and +0.01% (+0.1 mmol/mol) (difference ?0.74% [?8.1 mmol/mol]) ([95% CI ?1.08%, ?0.41%] [?11.8, ?4.5 mmol/mol]; p?p?Conclusions/interpretation In patients with pronounced insulin-associated weight gain, addition of liraglutide to their treatment regimen reverses weight, decreases insulin dose and improves glycaemic control, and hence seems a valuable therapeutic option compared with continuation of standard insulin treatment. Trial registration ClinicalTrials.gov NCT01392898 Funding The study was funded by Novo Nordisk.     

DEVOTE 3: temporal relationships between severe hypoglycaemia,cardiovascular outcomes and mortality

Aims/hypothesis

The double-blind Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) assessed the cardiovascular safety of insulin degludec. The incidence and rates of adjudicated severe hypoglycaemia, and all-cause mortality were also determined. This paper reports a secondary analysis investigating associations of severe hypoglycaemia with cardiovascular outcomes and mortality.

Methods

In DEVOTE, patients with type 2 diabetes were randomised to receive either insulin degludec or insulin glargine U100 (100 units/ml) once daily (between dinner and bedtime) in an event-driven, double-blind, treat-to-target cardiovascular outcomes trial. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE; cardiovascular death, non-fatal myocardial infarction or non-fatal stroke). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In the present analysis, the associations of severe hypoglycaemia with both MACE and all-cause mortality was evaluated in the pooled trial population using time-to-event analyses, with severe hypoglycaemia as a time-dependent variable and randomised treatment as a fixed factor. An investigation with interaction terms indicated that the effect of severe hypoglycaemia on the risk of MACE and all-cause mortality were the same for both treatment arms, and so the temporal association for severe hypoglycaemia with subsequent MACE and all-cause mortality is reported for the pooled population.

Results

There was a non-significant difference in the risk of MACE for individuals who had vs those who had not experienced severe hypoglycaemia during the trial (HR 1.38, 95% CI 0.96, 1.96; p = 0.080) and therefore there was no temporal relationship between severe hypoglycaemia and MACE. There was a significantly higher risk of all-cause mortality for patients who had vs those who had not experienced severe hypoglycaemia during the trial (HR 2.51, 95% CI 1.79, 3.50; p < 0.001). There was a higher risk of all-cause mortality 15, 30, 60, 90, 180 and 365 days after experiencing severe hypoglycaemia compared with not experiencing severe hypoglycaemia in the same time interval. The association between severe hypoglycaemia and all-cause mortality was maintained after adjustment for the following baseline characteristics: age, sex, HbA_1c, BMI, diabetes duration, insulin regimen, hepatic impairment, renal status and cardiovascular risk group.

Conclusions/interpretation

The results from these analyses demonstrate an association between severe hypoglycaemia and all-cause mortality. Furthermore, they indicate that patients who experienced severe hypoglycaemia were particularly at greater risk of death in the short term after the hypoglycaemic episode. These findings indicate that severe hypoglycaemia is associated with higher subsequent mortality; however, they cannot answer the question as to whether severe hypoglycaemia serves as a risk marker for adverse outcomes or whether there is a direct causal effect.

Trial registration

ClinicalTrials.gov NCT01959529

     

Estimating the effect of sulfonylurea on HbA1c in diabetes: a systematic review and meta-analysis

Aims/hypothesis

Sulfonylureas are widely prescribed glucose-lowering medications for diabetes, but the extent to which they improve glycaemia is poorly documented. This systematic review evaluates how sulfonylurea treatment affects glycaemic control.

Methods

Medline, EMBASE, the Cochrane Library and clinical trials registries were searched to identify double-blinded randomised controlled trials of fixed-dose sulfonylurea monotherapy or sulfonylurea added on to other glucose-lowering treatments. The primary outcome assessed was change in HbA_1c, and secondary outcomes were adverse events, insulin dose and change in body weight.

Results

Thirty-one trials with a median duration of 16 weeks were included in the meta-analysis. Sulfonylurea monotherapy (nine trials) lowered HbA_1c by 1.51% (17 mmol/mol) more than placebo (95% CI, 1.25, 1.78). Sulfonylureas added to oral diabetes treatment (four trials) lowered HbA_1c by 1.62% (18 mmol/mol; 95% CI 1.0, 2.24) compared with the other treatment, and sulfonylurea added to insulin (17 trials) lowered HbA_1c by 0.46% (6 mmol/mol; 95% CI 0.24, 0.69) and lowered insulin dose. Higher sulfonylurea doses did not reduce HbA_1c more than lower doses. Sulfonylurea treatment resulted in more hypoglycaemic events (RR 2.41, 95% CI 1.41, 4.10) but did not significantly affect the number of other adverse events. Trial length, sulfonylurea type and duration of diabetes contributed to heterogeneity.

Conclusions/interpretation

Sulfonylurea monotherapy lowered HbA_1c level more than previously reported, and we found no evidence that increasing sulfonylurea doses resulted in lower HbA_1c. HbA_1c is a surrogate endpoint, and we were unable to examine long-term endpoints in these predominately short-term trials, but sulfonylureas appear to be associated with an increased risk of hypoglycaemic events.     

Rates of glycaemic deterioration in a real-world population with type 2 diabetes

Aims/hypothesis

There is considerable variability in how diabetes progresses after diagnosis. Progression modelling has largely focused on ‘time to failure’ methods, yet determining a ‘coefficient of failure’ has many advantages. We derived a rate of glycaemic deterioration in type 2 diabetes, using a large real-world cohort, and aimed to investigate the clinical, biochemical, pharmacological and immunological variables associated with fast and slow rates of glycaemic deterioration.

Methods

An observational cohort study was performed using the electronic medical records from participants in the Genetics of Diabetes Audit and Research in Tayside Study (GoDARTS). A model was derived based on an individual’s observed HbA_1c measures from the first eligible HbA_1c after the diagnosis of diabetes through to the study end (defined as insulin initiation, death, leaving the area or end of follow-up). Each HbA_1c measure was time-dependently adjusted for the effects of non-insulin glucose-lowering drugs, changes in BMI and corticosteroid use. GAD antibody (GADA) positivity was defined as GAD titres above the 97.5th centile of the population distribution.

Results

The mean (95% CI) glycaemic deterioration for type 2 diabetes and GADA-positive individuals was 1.4 (1.3, 1.4) and 2.8 (2.4, 3.3) mmol/mol HbA_1c per year, respectively. A younger age of diagnosis, lower HDL-cholesterol concentration, higher BMI and earlier calendar year of diabetes diagnosis were independently associated with higher rates of glycaemic deterioration in individuals with type 2 diabetes. The rate of deterioration in those diagnosed at over 70 years of age was very low, with 66% having a rate of deterioration of less than 1.1 mmol/mol HbA_1c per year, and only 1.5% progressing more rapidly than 4.4 mmol/mol HbA_1c per year.

Conclusions/interpretation

We have developed a novel approach for modelling the progression of diabetes in observational data across multiple drug combinations. This approach highlights how glycaemic deterioration in those diagnosed at over 70 years of age is minimal, supporting a stratified approach to diabetes management.

     

Size and shape of the associations of glucose,HbA<Subscript>1c</Subscript>, insulin and HOMA-IR with incident type 2 diabetes: the Hoorn Study

Aims/hypothesis

Glycaemic markers and fasting insulin are frequently measured outcomes of intervention studies. To extrapolate accurately the impact of interventions on the risk of diabetes incidence, we investigated the size and shape of the associations of fasting plasma glucose (FPG), 2 h post-load glucose (2hPG), HbA_1c, fasting insulin and HOMA-IR with incident type 2 diabetes mellitus.

Methods

The study population included 1349 participants aged 50–75 years without diabetes at baseline (1989) from a population-based cohort in Hoorn, the Netherlands. Incident type 2 diabetes was defined by the WHO 2011 criteria or known diabetes at follow-up. Logistic regression models were used to determine the associations of the glycaemic markers, fasting insulin and HOMA-IR with incident type 2 diabetes. Restricted cubic spline logistic regressions were conducted to investigate the shape of the associations.

Results

After a mean follow-up duration of 6.4 (SD 0.5) years, 152 participants developed diabetes (11.3%); the majority were screen detected by high FPG. In multivariate adjusted models, ORs (95% CI) for incident type 2 diabetes for the highest quintile in comparison with the lowest quintile were 9.0 (4.4, 18.5) for FPG, 6.1 (2.9, 12.7) for 2hPG, 3.8 (2.0, 7.2) for HbA_1c, 1.9 (0.9, 3.6) for fasting insulin and 2.8 (1.4, 5.6) for HOMA-IR. The associations of FPG and HbA_1c with incident diabetes were non-linear, rising more steeply at higher values.

Conclusions/interpretation

FPG was most strongly associated with incident diabetes, followed by 2hPG, HbA_1c, HOMA-IR and fasting insulin. The strong association with FPG is probably because FPG is the most frequent marker for diabetes diagnosis. Non-linearity of associations between glycaemic markers and incident type 2 diabetes should be taken into account when estimating future risk of type 2 diabetes based on glycaemic markers.

     

HbA1c variability is associated with an increased risk of retinopathy requiring laser treatment in type 1 diabetes

Aims/hypothesis

This study aimed to investigate whether variation in long-term glycaemia in type 1 diabetes as measured by HbA_1c variability is associated with the cumulative incidence and risk of retinopathy requiring laser treatment.

Methods

The effect of HbA_1c variability was assessed in 2,019 Finnish Diabetic Nephropathy (FinnDiane) study patients. The patients were studied in two partially overlapping subcohorts with either verified first laser treatment (n?=?1,459) or retinopathy severity graded from ophthalmic records with the Early Treatment of Diabetic Retinopathy Study (ETDRS) scale (n?=?1,346). The ratio of intrapersonal SD and mean of serially measured HbA_1c was considered an estimate of HbA_1c variability.

Results

A subcohort of 1,459 patients did not have laser treatment prior to the first FinnDiane visit and 174 of these patients were treated during a mean follow-up period of 5.2?±?2.2 years. The 5 year cumulative incidence of laser treatment was 19% (95% CI 15, 24) in the highest quartile of HbA_1c variability and 10% (95% CI 7, 12) in the lowest quartile (p?<?0.001, Gray’s test) with a corresponding HR of 1.6 (95% CI 1.1, 2.5; p?=?0.02) adjusted for renal status, diabetes duration, mean HbA_1c, blood pressure, sex and number of HbA_1c measurements. In a subcohort of 1,346 patients, 434 patients had proliferative diabetic retinopathy (PDR). Patients in the highest quartile of HbA_1c variability had an increased risk of PDR compared with the lowest quartile (HR 1.7 [95% CI 1.3, 2.2]; p?<?0.001]).

Conclusions/interpretation

HbA_1c variability was associated with an increased cumulative incidence and risk of retinopathy requiring laser treatment in type 1 diabetes.     

Sex differences in the risk of stroke and HbA1c among diabetic patients

Aims/hypothesis

Sex differences in macrovascular disease, especially in stroke, are observed across studies of epidemiology. We studied a large sample of patients with type 2 diabetes to better understand the relationship between glycaemic control and stroke risk.

Methods

We prospectively investigated the sex-specific association between different levels of HbA_1c and incident stroke risk among 10,876 male and 19,278 female patients with type 2 diabetes.

Results

During a mean follow-up of 6.7 years, 2,949 incident cases of stroke were identified. The multivariable-adjusted HRs of stroke associated with different levels of HbA_1c at baseline (HbA_1c <6.0% [<42 mmol/mol], 6.0–6.9% [42–52 mmol/mol] [reference group], 7.0–7.9% [53–63 mmol/mol], 8.0–8.9% [64–74 mmol/mol], 9.0–9.9% [75–85 mmol/mol] and ≥10.0% [≥86 mmol/mol]) were 0.96 (95% CI 0.80, 1.14), 1.00, 1.04 (0.85, 1.28), 1.11 (0.89, 1.39), 1.10 (0.86, 1.41) and 1.22 (0.92, 1.35) (p for trend?=?0.66) for men, and 1.03 (0.90, 1.18), 1.00, 1.09 (0.94, 1.26), 1.19 (1.00, 1.42), 1.32 (1.09, 1.59) and 1.42 (1.23, 1.65) (p for trend <0.001) for women, respectively. The graded association between HbA_1c during follow-up and stroke risk was observed among women (p for trend?=?0.066). When stratified by race, whether with or without glucose-lowering agents, this graded association of HbA_1c with stroke was still present among women. When stratified by age, the adjusted HRs were significantly higher in women older than 55 years compared with younger women.

Conclusions/interpretation

The current study suggests a graded association between HbA_1c and the risk of stroke among women with type 2 diabetes. Poor control of blood sugar has a stronger effect in diabetic women older than 55 years.     

A randomised,controlled trial of self-monitoring of blood glucose in patients with type 2 diabetes receiving conventional insulin treatment

Aims/hypothesis

We evaluated whether self-monitoring of blood glucose (SMBG) leads to better glycaemic control (HbA_1c) in patients with type 2 diabetes on conventional insulin regimens.

Methods

Patients with type 2 diabetes on a conventional insulin regimen (basal or premixed insulin with or without additional oral glucose-lowering agents) were recruited at study centres led by members of the German Diabetes Association. In a randomised, prospective, open 2?×?2 factorial design, the once-weekly performance of four-point glucose profiles (SMBG +; n?=?151 patients) was compared with no SMBG (SMBG ?; n?=?149), and the measuring and transmitting of HbA_1c results to the study centres (HbA_1c +; n?=?158, of these 82 SMBG ? and 76 SMBG +) was compared with HbA_1c measurement without disclosure of results (HbA_1c ?; n?=?142, of these 67 SMBG ? and 75 SMBG +). Randomised allocation was carried out by a central office, using sequentially numbered, sealed envelopes. The primary endpoint was the reduction of HbA_1c compared with baseline after 12 months. Secondary analyses were of therapy intensification in response to higher blood or urinary glucose or HbA_1c. Participants and caregivers were not blinded as to the allocation of interventions, whereas the laboratory determining HbA_1c remained blinded.

Results

Patient characteristics were balanced across groups. A total of 56 patients dropped out. In completers, HbA_1c was reduced in the SMBG + group from 7.3% to 7.0%, i.e. by 0.3% (0.1%, 0.5%) vs SMBG ? from 7.3% to 7.0% and 0.3% (0.2%, 0.5%), respectively, the difference being 0.0% (?0.2%, 0.2%) (p?=?0.93). The disclosure of HbA_1c results had no significant influence, with a difference of 0.1% (?0.1%, 0.4%) (p?=?0.28). Values above are mean (95% CI). The ORs for therapy intensification significantly rose as the following increased: proportions of urine samples testing positive for glucose, HbA_1c concentrations, and fasting or postprandial glucose concentrations. No important adverse events were associated with the interventions.

Conclusions/interpretation

SMBG profiles once weekly or the disclosure of HbA_1c results did not improve glycaemic control in patients with type 2 diabetes on conventional insulin treatment, although indicators of hyperglycaemia increased the likelihood of therapy intensification. Greater intensification may be necessary to impact on glycaemic control.

Trial registration:

www.clinicaltrials.gov (registration code NCT00688363)

Funding:

Deutsche Diabetes-Gesellschaft, Deutsche Diabetes-Stiftung, Bayer Vital GmbH