HARMONY 4: randomised clinical trial comparing once-weekly albiglutide and insulin glargine in patients with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea

Aims/hypothesis

The aim of this study was to compare the efficacy and safety of once-weekly albiglutide with once-daily insulin glargine (A21Gly,B31Arg,B32Arg human insulin) in patients with type 2 diabetes inadequately controlled on metformin with or without sulfonylurea.

Methods

This was a randomised, open-label, multicentre (n?=?222), parallel-group, non-inferiority out-patient clinical trial, with 779 patients enrolled in the study. The study was conducted in 222 centres located in four countries. Patients aged ≥18 years with type 2 diabetes treated with metformin (±sulfonylurea) for at least 3 months with a baseline HbA_1c 7.0–10.0% (53.0–85.8 mmol/mol) were randomly assigned (2:1) via a computer-generated randomisation sequence with a voice response system to receive albiglutide (30 mg once a week, n?=?504) or insulin glargine (10 U once a day, n?=?241) added to current therapy. Participants and investigators were not masked to treatment assignment. Doses of each medication were adjusted on the basis of the glycaemic response. The primary endpoint was change from baseline in HbA_1c at week 52.

Results

In the albiglutide group, HbA_1c declined from 8.28?±?0.90% (67.0?±?9.8 mmol/mol) (mean?±?SD) at baseline to 7.62?±?1.12% (59.8?±?12.2 mmol/mol) at week 52. A similar reduction occurred in the insulin glargine group (8.36?±?0.95% to 7.55?±?1.04% [67.9?±?10.4 to 59.0?±?11.4 mmol/mol]). The model-adjusted treatment difference of 0.11% (95% CI ?0.04%, 0.27%) (1.2 mmol/mol [95% CI ?0.4, 3.0 mmol/mol]) indicated non-inferiority of albiglutide to insulin glargine based on the pre-specified non-inferiority margin of 0.3% (3.3 mmol/mol, p?=?0.0086). Body weight increased in the insulin glargine group and decreased in the albiglutide group, with a mean treatment difference of ?2.61 kg (95% CI ?3.20, ?2.02; p?p?=?0.0377).

Conclusions/interpretation

Albiglutide was non-inferior to insulin glargine at reducing HbA_1c at week 52, with modest weight loss and less hypoglycaemia. Both drugs were well tolerated. Albiglutide may be considered an alternative to insulin glargine in this patient population. Trial registration: ClinicalTrials.gov NCT00838916 (completed) Funding: This study was planned and conducted by GlaxoSmithKline.     

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.     

Effects of 12 weeks’ treatment with a proton pump inhibitor on insulin secretion, glucose metabolism and markers of cardiovascular risk in patients with type 2 diabetes: a randomised double-blind prospective placebo-controlled study

Aims/hypothesis

Recent studies suggest that proton pump inhibitor treatment may increase insulin secretion and improve glucose metabolism in type 2 diabetes. In a randomised double-blind prospective placebo-controlled 2 × 2 factorial study, we examined the effect of esomeprazole on insulin secretion, HbA_1c and cardiovascular risk factors in type 2 diabetes.

Methods

Forty-one patients with type 2 diabetes using dietary control or oral glucose-lowering treatment were randomised to receive add-on esomeprazole 40 mg (n?=?20) or placebo (n?=?21) for 12 weeks. Randomisation was carried out prior to inclusion on the basis of a computer-generated random-number list. The allocation sequence was concealed in sealed envelopes from the researcher enrolling and assessing participants. The study was undertaken at Steno Diabetes Center, Gentofte, Denmark. The primary outcome was change in AUC for insulin levels during a meal test. Secondary outcomes were the levels of HbA_1c and biochemical markers of cardiovascular risk, including lipids, coagulation factors, inflammation markers, markers of endothelial function and 24 h ambulatory BP measurements.

Results

Forty-one participants were analysed. In the esomeprazole-treated group the AUC for insulin did not change (before vs after treatment: 28,049?±?17,659 vs 27,270?±?32,004 pmol/l × min (p?=?0.838). In the placebo group AUC for insulin decreased from 27,392?±?14,348 pmol/l × min to 22,938?±?11,936 pmol/l × min (p?=?0.002). Esomeprazole treatment (n?=?20) caused a ninefold increase in the AUC for gastrin. HbA_1c increased from 7.0?±?0.6% (53?±?5 mmol/mol) to 7.3?±?0.8% (56?±?6 mmol/mol) in the esomeprazole-treated group and from 7.0?±?0.6% (53?±?5 mmol/mol) to 7.4?±?0.8% (57?±?6 mmol/mol) in the placebo group (n?=?21) (p for difference in change >0.05). Except for BP, there were no differences between the groups in the markers of cardiovascular risk (p?>?0.05). Monitoring of 24 h ambulatory BP showed a significant decrease in daytime systolic BP, daytime diastolic BP and 24 h diastolic BP in the placebo group (p?<?0.05). No change in BP was seen in the patients treated with esomeprazole.

Conclusions/interpretation

Treatment with esomeprazole over 12 weeks did not improve insulin secretion, glycaemic control or cardiovascular disease biomarkers in patients with type 2 diabetes.

Trial registration

ClinicalTrials.gov NCT00699426

Funding

The study was funded by Novo Nordisk A/S and Christian Hansen A/S.     

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.     

Intensified insulin treatment is associated with improvement in skin microcirculation and ischaemic foot ulcer in patients with type 1 diabetes mellitus: a long-term follow-up study

Aims/hypothesis

We investigated skin microcirculation and its association with HbA_1c and the incidence of ischaemic foot ulcer in patients with type 1 diabetes formerly randomised (1982–1984) to intensified conventional treatment (ICT) or standard treatment (ST) with insulin for a mean of 7.5 years.

Methods

We re-determined the skin microcirculation of 72 patients (ICT 35 vs ST 37) from the original Stockholm Diabetes Intervention Study with iontophoresis topically applied with the following vasoactive stimuli: acetylcholine (ACh) (endothelial-dependent vasodilatation), sodium nitroprusside (SNP) (endothelial-independent vasodilatation), and capsaicin (C-nociceptive-dependent vasodilatation). HbA_1c levels (mean of 14 values/patient) were prospectively collected between 1990 and 1995 and tested for association with skin microcirculation. The patients were followed until first hospitalisation for an ischaemic foot ulcer or until 2011.

Results

During the median 28 years of follow-up, three patients developed ischaemic foot ulcers in the ICT group compared with ten in the ST group (logrank, p?=?0.035). At the time of iontophoresis, HbA_1c was lower in the ICT group (median 57 mmol/mol [minimum–maximum 40–79 mmol/mol]) compared with the ST group (68 mmol/mol [41–96 mmol/mol], p?<?0.01) (DCCT: ICT 7.4% [5.8–9.4%] vs ST 8.4% [5.9–10.9%]). Stimulated blood flow was higher in the ICT vs ST group with significantly increased perfusion units (PU) for: ACh (8.1 PU [4.6–24.7 PU] vs 5.3 PU [1.7–21.4 PU], p?<?0.01); SNP (8.1 PU [2.2–20.1 PU] vs 5.6 PU [2.3–19.2 PU], p?=?0.03); and capsaicin (5.0 PU [1.7–22.9 PU] vs 3.4 PU [1.5–8.4 PU], p?<?0.01). HbA_1c was associated with vasodilatation induced by ACh (b?=??0.02, p?<?0.01) and capsaicin (b?=??0.02, p?=?0.03). HbA_1c was independently associated with ACh (b?=??1.48, p?<?0.01) and capsaicin-induced vasodilatation (b?=??1.45, p?<?0.01).

Conclusions/interpretation

Improved glycaemic control in patients with type 1 diabetes is associated with an improvement in skin microcirculation and with a lower incidence of ischaemic foot ulcers. Trial registration: ClinicalTrials.gov NCT01957930     

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.     

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.     

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     

‘Exercise snacks’ before meals: a novel strategy to improve glycaemic control in individuals with insulin resistance

Aims/hypothesis

The aim of this study was to investigate whether small doses of intense exercise before each main meal (‘exercise snacks’) would result in better blood glucose control than a single bout of prolonged, continuous, moderate-intensity exercise in individuals with insulin resistance.

Methods

Nine individuals completed three exercise interventions in randomised order. Measures were recorded across 3 days with exercise performed on the middle day, as either: (1) traditional continuous exercise (CONT), comprising 30 min moderate-intensity (60% of maximal heart rate [HR_max]) incline walking before dinner; (2) exercise snacking (ES), consisting of 6?×?1 min intense (90% HR_max) incline walking intervals 30 min before each meal; or (3) composite exercise snacking (CES), encompassing 6?×?1 min intervals alternating between walking and resistance-based exercise, 30 min before meals. Meal timing and composition were controlled within participants for exercise interventions.

Results

ES attenuated mean 3 h postprandial glucose concentration following breakfast (by 1.4?±?1.5 mmol/l, p?=?0.02) but not lunch (0.4?±?1.0 mmol/l, p?=?0.22), and was more effective than CONT following dinner (0.7?±?1.5 mmol/l below CONT; p?=?0.04). ES also reduced 24 h mean glucose concentration by 0.7?±?0.6 mmol/l (p?=?0.01) and this reduction persisted for the subsequent 24 h (lower by 0.6?±?0.4 mmol/l vs CONT, relative to their baselines; p?=?0.01). CES was just as effective as ES (p?>?0.05 for all glycaemic variables) at improving glycaemic control.

Conclusions/interpretation

Dosing exercise as brief, intense ‘exercise snacks’ before main meals is a time-efficient and effective approach to improve glycaemic control in individuals with insulin resistance.     

The impact of restricted gestational weight gain by dietary intervention on fetal growth in women with gestational diabetes mellitus

Aims/hypothesis

We aimed to investigate the impact of maternal gestational weight gain (GWG) during dietary treatment on fetal growth in pregnancies complicated by gestational diabetes (GDM).

Methods

This was a retrospective cohort study of 382 women consecutively diagnosed with GDM before 34 weeks’ gestation with live singleton births in our centre (Center for Pregnant Women with Diabetes, Rigshospitalet, Copenhagen, Denmark) between 2011 and 2017. The women were stratified into three groups according to restricted (53%), appropriate (16%) and excessive (31%) weekly GWG during dietary treatment (using the Institute of Medicine guidelines) to estimate compliance with an energy-restricted ‘diabetes diet’ (6000 kJ/day [1434 kcal/day], with approximately 50% of energy intake coming from carbohydrates with a low glycaemic index, and a carbohydrate intake of 175 g/day). Insulin therapy was initiated if necessary, according to local clinical guidelines.

Results

Glucose tolerance, HbA_1c, weekly GWG before dietary treatment (difference between weight at GDM diagnosis and pre-pregnancy weight, divided by the number of weeks) and SD score for fetal abdominal circumference were comparable across the three groups at diagnosis of GDM at 27⁶?±?5¹ weeks (gestation time is given as weeks^days). The women were followed for 10⁰?±?5¹ weeks, during which 54% received supplementary insulin therapy and the average (mean) GWG during dietary treatment was 0 kg, 3 kg and 5 kg in the three groups, respectively. Excessive weekly GWG during dietary treatment, reflecting poor dietary adherence was associated with increasing HbA_1c (p?=?0.014) from diagnosis of GDM to late pregnancy and infants with a birthweight-SD score of 0.59?±?1.6. In contrast, restricted weekly GWG during dietary treatment, reflecting strict dietary adherence, was associated with decreasing HbA_1c (p?=?0.001) from diagnosis of GDM to late pregnancy and infants with a birthweight-SD score of 0.15?±?1.1, without increased prevalence of infants born small for gestational age. Excessive GWG during dietary treatment and late-pregnancy HbA_1c were identified as potentially modifiable clinical predictors of infant birthweight-SD score (p?=?0.02 for both variables) after correction for confounders.

Conclusions/interpretation

Restricted GWG during dietary treatment was associated with healthier fetal growth in women with GDM. GWG during dietary treatment and late-pregnancy HbA_1c were identified as potentially modifiable clinical predictors of infant birthweight-SD score.

     

Diabetic ketoacidosis at the onset of type 1 diabetes is associated with future HbA1c levels

Aims/hypothesis

We investigated the long-term impact of diabetic ketoacidosis (DKA) at onset on metabolic regulation and residual beta cell function in a Danish population with type 1 diabetes.

Methods

The study is based on data from DanDiabKids, a Danish national diabetes register for children. The register provides clinical and biochemical data on patients with type 1 diabetes diagnosed in 1996–2009 and then followed-up until 1 January 2012. Repeated-measurement models were used as statistical methods.

Results

The study population comprised 2,964 children <18 years. The prevalence of DKA at diagnosis was 17.9%. Of the total subjects, 8.3% had mild, 7.9% had moderate and 1.7% had severe DKA. DKA (moderate and severe) was associated with increased HbA_1c (%) levels (0.24; 95% CI 0.11, 0.36; p?=?0.0003) and increased insulin dose-adjusted HbA_1c (IDAA_1c, 0.51; 95% CI 0.31, 0.70; p?<?0.0001) during follow-up, after adjustment for covariates. Children without a family history of diabetes were more likely to present with DKA (19.2% vs 8.8%, p?<?0.0001); however, these children had a lower HbA_1c (%) level over time (?0.35; 95% CI ?0.46, ?0.24; p?<?0.0001). Continuous subcutaneous insulin infusion (CSII) was associated with a long-term reduction in HbA_1c, changing the effect of DKA, after adjustment for covariates (p?<?0.0001).

Conclusions/interpretation

DKA at diagnosis was associated with poor long-term metabolic regulation and residual beta cell function as assessed by HbA_1c and IDAA_1c, respectively; however, CSII treatment was associated with improvement in glycaemic regulation and residual beta cell function, changing the effect of DKA at onset in our population.     

Glucagon responses to increasing oral loads of glucose and corresponding isoglycaemic intravenous glucose infusions in patients with type 2 diabetes and healthy individuals

Aims/hypothesis

Type 2 diabetes is associated with hypersecretion of glucagon during an OGTT, whereas i.v. glucose suppresses glucagon levels. This suggests that type 2 diabetic hyperglucagonaemia may result from glucose stimulation of the gastrointestinal tract. We evaluated glucagon responses to increasing amounts of glucose given orally and corresponding isoglycaemic i.v. glucose infusions (IIGIs) in patients with type 2 diabetes and in healthy controls.

Methods

Plasma glucagon responses were measured during three 4 h OGTTs with increasing loads of glucose (25 g, 75 g and 125 g) and three corresponding IIGIs in eight patients with type 2 diabetes (age [mean?±?SEM] 57?±?4 years; BMI 29.5?±?1.0 kg/m²; HbA_1c 7.0?±?0.3% [53?±?2 mmol/mol]) and eight healthy individuals (age 57?±?4 years; BMI 28.9?±?0.7 kg/m²; HbA_1c 5.4?±?0.1% [36?±?1 mmol/mol]).

Results

In healthy controls no difference in glucagon suppression during the first 45 min of the 25 g OGTT and the corresponding IIGI (?153?±?35 vs ?133?±?24 min?×?pmol/l; p?=?NS) was observed, whereas patients with type 2 diabetes only exhibited significant glucagon suppression following IIGI (29?±?27 vs ?144?±?20 min?×?pmol/l; p?=?0.005). At higher oral glucose loads this difference increased and also became evident in healthy controls.

Conclusions/interpretation

In patients with type 2 diabetes increasing amounts of oral glucose elicit hypersecretion of glucagon, whereas corresponding IIGIs result in significant glucagon suppression; a phenomenon that is also observed in healthy individuals when larger glucose loads are ingested orally. This suggests that the hyperglucagonaemic response to oral glucose in type 2 diabetes may represent a pathological version of a gut-derived physiological phenomenon. Trial registration: ClinicalTrials.gov NCT00529048     

Effects of calcium–vitamin D co-supplementation on metabolic profiles in vitamin D insufficient people with type 2 diabetes: a randomised controlled clinical trial

Aims/hypothesis

This study was performed to assess the effects of vitamin D and calcium supplementation on the metabolic profiles of vitamin D insufficient persons with type 2 diabetes.

Methods

In a parallel designed randomised placebo-controlled clinical trial, a total of 118 non-smoker individuals with type 2 diabetes and insufficient 25-hydroxyvitamin D, aged >30 years, were recruited from the Isfahan Endocrine and Metabolism Research Centre. Participants were randomly assigned to four groups receiving: (1) 50,000 U/week vitamin D + calcium placebo; (2) 1,000 mg/day calcium + vitamin D placebo; (3) 50,000 U/week vitamin D + 1,000 mg/day calcium; or (4) vitamin D placebo + calcium placebo for 8 weeks. A study technician carried out the random allocations using a random numbers table. All investigators, participants and laboratory technicians were blinded to the random assignments. All participants provided 3 days of dietary records and 3 days of physical activity records throughout the intervention. Blood samples were taken to quantify glycaemic and lipid profiles at study baseline and after 8 weeks of intervention.

Results

30 participants were randomised in each group. During the intervention, one participant from the calcium group and one from the vitamin D group were excluded because of personal problems. Calcium–vitamin D co-supplementation resulted in reduced serum insulin (changes from baseline: ?14.8?±?3.9 pmol/l, p?=?0.01), HbA_1c [?0.70?±?0.19% (?8.0?±?0.4 mmol/mol), p?=?0.02], HOMA-IR (?0.46?±?0.20, p?=?0.001), LDL-cholesterol (?10.36?±?0.10 mmol/l, p?=?0.04) and total/HDL-cholesterol levels (?0.91?±?0.16, p?=?0.03) compared with other groups. We found a significant increase in QUICKI (0.025?±?0.01, p?=?0.004), HOMA of beta cell function (HOMA-B; 11.8?±?12.17, p?=?0.001) and HDL-cholesterol (0.46?±?0.05 mmol/l, p?=?0.03) in the calcium–vitamin D group compared with others.

Conclusions/interpretation

Joint calcium and vitamin D supplementation might improve the glycaemic status and lipid profiles of vitamin D insufficient people with type 2 diabetes. Trial registration: ClinicalTrials.gov NCT01662193 Funding: Clinical Research Council, Isfahan University of Medical Sciences, Isfahan, Iran     

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.     

Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial

Aims/hypothesis

The aim of this work was to evaluate the efficacy and safety of canagliflozin vs placebo and sitagliptin in patients with type 2 diabetes who were being treated with background metformin.

Methods

This randomised, double-blind, four-arm, parallel-group, Phase 3 study was conducted at 169 centres in 22 countries between April 2010 and August 2012. Participants (N?=?1,284) with type 2 diabetes aged ≥18 and ≤80 years who had inadequate glycaemic control (HbA_1c ≥7.0% [53 mmol/mol] and ≤10.5% [91 mmol/mol]) on metformin therapy received canagliflozin 100 mg or 300 mg, sitagliptin 100 mg, or placebo (n?=?368, 367, 366, 183, respectively) for a 26 week, placebo- and active-controlled period followed by a 26 week, active-controlled period (placebo group switched to sitagliptin [placebo/sitagliptin]) and were included in the modified intent-to-treat analysis set. Randomisation was performed using a computer-generated schedule; participants, study centres and the sponsor were blinded to group assignment. The primary endpoint was change from baseline in HbA_1c at week 26; secondary endpoints included changes in HbA_1c (week 52) and fasting plasma glucose (FPG), body weight, and systolic blood pressure (BP; weeks 26 and 52). Adverse events (AEs) were recorded throughout the study.

Results

At week 26, canagliflozin 100 mg and 300 mg reduced HbA_1c vs placebo (?0.79%, –0.94%, –0.17%, respectively; p?<?0.001). At week 52, canagliflozin 100 mg and 300 mg demonstrated non-inferiority, and canagliflozin 300 mg demonstrated statistical superiority, to sitagliptin in lowering HbA_1c (?0.73%, –0.88%,–0.73%, respectively); differences (95% CI) vs sitagliptin were 0% (?0.12, 0.12) and ?0.15% (?0.27, –0.03), respectively. Canagliflozin 100 mg and 300 mg reduced body weight vs placebo (week 26: –3.7%, –4.2%, –1.2%, respectively; p?<?0.001) and sitagliptin (week 52: –3.8%, –4.2%, –1.3%, respectively; p?<?0.001). Both canagliflozin doses reduced FPG and systolic BP vs placebo (week 26) and sitagliptin (week 52) (p?<?0.001). Overall AE and AE-related discontinuation rates were generally similar across groups, but higher with canagliflozin 100 mg. Genital mycotic infection and osmotic diuresis-related AE rates were higher with canagliflozin; few led to discontinuations. Hypoglycaemia incidence was higher with canagliflozin.

Conclusions/interpretation

Canagliflozin improved glycaemia and reduced body weight vs placebo (week 26) and sitagliptin (week 52) and was generally well tolerated in patients with type 2 diabetes on metformin.

Clinical trial registry

ClinicalTrials.gov NCT01106677

Funding

This study was supported by Janssen Research & Development, LLC.     

In patients with type 1 diabetes simultaneous pancreas and kidney transplantation preserves long-term kidney graft ultrastructure and function better than transplantation of kidney alone

Aims/hypothesis

In patients with type 1 diabetes and end-stage renal disease (ESRD) we aimed to determine whether long-term normoglycaemia, as achieved by successful simultaneous pancreas and kidney (SPK) transplantation, would preserve kidney graft structure and function better than live donor kidney (LDK) transplantation alone.

Methods

Estimated GFR (eGFR) was calculated in SPK (n?=?25) and LDK (n?=?17) recipients in a stable phase 3 months after transplantation and annually during follow-up. Kidney graft biopsies were obtained at follow-up for measurement of glomerular volume (light microscopy), glomerular basement membrane (GBM) and podocyte foot process widths and mesangial volume fraction (electron microscopy).

Results

SPK and LDK recipients were similar in age and diabetes duration at engraftment. Donor age was higher in the LDK group. Median follow-up time was 10.1 years. Mean HbA_1c levels during follow-up were 5.5?±?0.4% (37?±?5 mmol/mol) and 8.3?±?1.5% (68?±?16 mmol/mol) in the SPK and LDK group, respectively (p?p?=?0.008) and increased mesangial volume fraction (median 0.23 [range 0.13–0.59] vs 0.16 [0.10–0.41]; p?=?0.007) at follow-up. Absolute eGFR change from baseline was ?11?±?21 and ?23?±?15 ml min^?1 1.73 m^?2 (p?=?0.060), whereas eGFR slope was ?1.1 (95% CI ?1.7, ?0.5) and ?2.6 (95% CI ?3.1, ?2.1)?ml min^?1 1.73 m^?2 per year in the SPK and LDK group, respectively (p?=?0.001).

Conclusions/interpretation

In patients with type 1 diabetes and long-term normoglycaemia after successful SPK transplantation, kidney graft ultrastructure and function were better preserved compared with LDK transplantation alone.     

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.     

Fibre supplementation for the prevention of type 2 diabetes and improvement of glucose metabolism: the randomised controlled Optimal Fibre Trial (OptiFiT)

Aims/hypothesis

Insoluble cereal fibres have been shown in large prospective cohort studies to be highly effective in preventing type 2 diabetes, but there is a lack of interventional data. Our 2 year randomised double-blind prospective intervention study compared the effect of an insoluble oat fibre extract with that of placebo on glucose metabolism and incidence of diabetes.

Methods

A total of 180 participants with impaired glucose tolerance underwent a modified version of the 1 year lifestyle training programme PREvention of DIAbetes Self-management (PREDIAS) and were randomised to receive a fibre supplement (n?=?89; 7.5 g of insoluble fibre per serving) or placebo (n?=?91; 0.8 g of insoluble fibre per serving) twice daily for 2 years. Eligible participants were men and women, were at least 18 years old and did not report corticosteroid or other intensive anti-inflammatory treatment, fibre intolerance or any of the following disorders: overt diabetes, chronic or malignant disease, or severe cardiopulmonary, endocrine, psychiatric, gastrointestinal, autoimmune or eating disorder. Participants were recruited at two clinical wards in Berlin and Nuthetal. The allocation was blinded to participants and study caregivers (physicians, dietitians, study nurses). Randomisation was conducted by non-clinical staff, providing neutrally numbered supplement tins. Both supplements were similar in their visual, olfactory and gustatory appearance. Intention-to-treat analysis was applied to all individuals.

Results

After 1 year, 2 h OGTT levels decreased significantly in both groups but without a significant difference between the groups (fibre ?0.78?±?1.88 mmol/l [p?≤ 0.001] vs placebo ?0.46?±?1.80 mmol/l [p?=?0.020]; total difference 0.32?±?0.29 mmol/l; not significant). The 2 year incidence of diabetes was 9/89 (fibre group) compared with 16/91 (placebo group; difference not significant). As secondary outcomes, the change in HbA_1c level was significantly different between the two groups (?0.2?±?4.6 mmol/mol [?0.0?±?0.0%; not significant] vs +1.2?±?5.2 mmol/mol [+0.1?±?0.0%; not significant]; total difference 1.4?±?0.7 mmol/mol [0.1?+?0.0%]); p?=?0.018); insulin sensitivity and hepatic insulin clearance increased in both groups. After 2 years, improved insulin sensitivity was still present in both groups, although the effect size had diminished. Separate analysis of the sexes revealed a significantly greater reduction in 2 h glucose levels for women in the fibre group (?0.88?±?1.59 mmol/l [p?≤ 0.001] vs ?0.22?±?1.52 mmol/l [p?=?0.311]; total difference 0.67?±?0.31 mmol/l; p?=?0.015). Levels of fasting glucose, adipokines and inflammatory markers remained unchanged in the two groups. Significantly increased fibre intake was restricted to the fibre group, despite dietary counselling for both groups. No severe side effects occurred.

Conclusions/interpretation

We cannot currently provide strong evidence for a beneficial effect of insoluble cereal fibre on glycaemic metabolism, although further studies may support minor effects of fibre supplementation in reducing glucose levels, insulin resistance and the incidence of type 2 diabetes.Trial registration: clinicaltrials.gov NCT01681173Funding: German Diabetes Foundation (grant no. 232/11/08)

     

Impact of different training modalities on glycaemic control and blood lipids in patients with type 2 diabetes: a systematic review and network meta-analysis

Aims/hypothesis

This study aimed to systematically review randomised controlled trials comparing the effects of aerobic exercise training (AET), resistance training (RT) and combined training (CT) on glycaemic control and blood lipids in patients with type 2 diabetes mellitus.

Methods

Searches were performed in MEDLINE, EMBASE and the Cochrane Library. Inclusion criteria were: type 2 diabetes mellitus, adult, supervised training and a minimum intervention period of 8 weeks. Pooled effects were calculated by fixed/random effect pairwise and Bayesian fixed/random effects network meta-analyses.

Results

A total of 14 trials enrolling 915 participants were included. AET was more effective than RT in improving HbA_1c levels (mean difference [MD] ?0.20% [?2.2 mmol/mol]; 95% CI ?0.32, ?0.08; p?=?0.0007, 10 trials/515 participants) and fasting glucose (MD ?0.9 mmol/l; 95% CI ?1.71, ?0.09; p?=?0.03, 8 trials/245 participants). Compared with AET, CT resulted in a significantly more pronounced reduction in HbA_1c (MD ?0.17% [?1.87 mmol/mol]; 95% CI ?0.31, ?0.03; p?=?0.02, 9 trials/493 participants). Compared with RT, the MD of the change in HbA_1c (MD ?0.62%, [?6.82 mmol/mol]; 95% CI ?0.95, ?0.30; p?=?0.0002, 5 trials/362 participants], fasting glucose (MD ?1.99 mmol/l; 95% CI ?3.07, ?0.90; p?=?0.0003, 3 trials/99 participants) and triacylglycerols (MD ?0.28 mmol/l; 95% CI ?0.46, ?0.10; p?=?0.003, 4 trials/213 participants) were all in favour of CT. The exclusion of trials with a high risk of bias yielded only non-significant results.

Conclusions/interpretation

The present data suggest that CT might be the most efficacious exercise modality to improve glycaemic control and blood lipids. Interpretation with respect to clinical relevance is limited by the low quality of the studies included and the limited information on the clinically important outcomes or adverse effects of exercise.     

Contrasting the clinical care and outcomes of 2,622 children with type 1 diabetes less than 6 years of age in the United States T1D Exchange and German/Austrian DPV registries

Aims/hypothesis

The study aimed to compare participant characteristics, treatment modalities and clinical outcomes in registry participants less than 6 years old.

Methods

Participant characteristics, treatment modalities and clinical outcomes (HbA_1c, severe hypoglycaemia [SH] and diabetic ketoacidosis [DKA]) as well as frequencies of attaining HbA_1c goals in line with the International Society for Pediatric and Adolescent Diabetes (<7.5% [<58 mmol/mol]) and ADA (<8.5% [<69 mmol/mol]) were compared.

Results

Insulin pump use was more frequent (74% vs 50%, p?<?0.001) and HbA_1c levels lower in the Prospective Diabetes Follow-up Registry (DPV) than in the T1D Exchange (T1DX) (mean 7.4% vs 8.2%, p?<?0.001). A lower HbA_1c level was seen in the DPV compared with the T1DX for both pump users (p?<?0.001) and injection users (p?<?0.001). More children from DPV were meeting the recommended HbA_1c goals, compared with children from T1DX (HbA_1c <7.5%: 56% vs 22%, p?<?0.001; HbA_1c <8.5%: 90% vs 66%, p?<?0.001). The adjusted odds of having an HbA_1c level <7.5% or <8.5% were 4.2 (p?<?0.001) and 3.6 (p?<?0.001) higher for the DPV than the T1DX, respectively. The frequency of SH did not differ between registries or by HbA_1c, whereas the frequency of DKA was higher for the T1DX and greater in those with higher HbA_1c levels.

Conclusions/interpretation

DPV data indicate that an HbA_1c of <7.5% can frequently be achieved in children with type 1 diabetes who are under 6 years old. An improved metabolic control of type 1 diabetes in young patients appears to decrease the risk of DKA without increasing SH. The greater frequency of suboptimal control in young patients in the T1DX compared with the DPV is not fully explained by a less frequent use of insulin pumps and may relate to the higher HbA_1c targets that are recommended for this age group in the USA.