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.     

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     

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.     

Variants associated with type 2 diabetes identified by the transethnic meta-analysis study: assessment in American Indians and evidence for a new signal in LPP

Aim/hypothesis

A recent genome-wide trans-ancestry meta-analysis identified seven new loci associated with type 2 diabetes. We assessed the replication of the seven lead single nucleotide polymorphisms (SNPs) and evaluated these loci for additional signals in American Indians.

Methods

Seven SNPs were genotyped in 7,710 individuals from a longitudinally studied American Indian population, and associations with type 2 diabetes, BMI and related phenotypes were assessed. Previous genome-wide association study (GWAS) data from these individuals were used to screen for additional type 2 diabetes signals at these loci. A variant independent of the trans-ancestry meta-analysis was identified within LPP, and its replication was assessed in an additional 3,106 urban American Indians.

Results

SNP rs6813195 near to TMEM154 was nominally associated with type 2 diabetes (p?=?0.01, OR 1.12 [95% CI 1.03, 1.22]) and adiposity: the type 2 diabetes risk allele was associated with a lower percentage body fat (β?=??1.451%, p?=?4.8?×?10^?4). Another SNP, rs3130501 near to POU5F1–TCF19, was associated with BMI (β?=??0.012, p?=?0.004), type 2 diabetes adjusted for BMI (p?=?0.02, OR 1.11 [95% CI 1.02, 1.22]), 2 h glucose concentrations (β?=?0.080 mmol/l, p?=?0.02) and insulin resistance estimated by homeostatic model (β?=?0.039, p?=?0.009). The independent variant identified at the LPP locus in our American Indian GWAS for type 2 diabetes was replicated in the additional samples (all American Indian meta-analysis, p?=?8.9?×?10^?6, OR 1.29 [95% CI 1.15, 1.45]).

Conclusions/interpretation

For two of the seven newly identified variants, there was nominal evidence for association with type 2 diabetes and related traits in American Indians. Identification of an independent variant at the LPP locus suggests the existence of more than one type 2 diabetes signal at this locus.     

Lipopolysaccharide binding protein,obesity status and incidence of metabolic syndrome: a prospective study among middle-aged and older Chinese

Aims/hypothesis

Although microbiota-derived endotoxaemia has previously been shown to induce metabolic disorders, data from population-based longitudinal studies are scarce. This study therefore investigated the associations between lipopolysaccharide binding protein (LBP) levels and 6 year incident metabolic syndrome (MetS), as well as the potentially modifying effects of obesity status in middle-aged and older Chinese men and women.

Methods

A total of 2,529 men and women aged 50–70 years from Beijing and Shanghai, China, were followed for 6 years. Those free of MetS at baseline (1,312) were included in the analyses for the risk of developing MetS. Baseline plasma LBP was measured using an ELISA kit.

Results

During the 6 year follow-up, 449 (34.2%) participants developed MetS. Baseline LBP was significantly associated with BMI, waist circumference, blood lipid profile and C-reactive protein (CRP) both at baseline and during follow-up (all p?p _trend?=?0.002), but not in their overweight/obese counterparts (RR, comparing extreme tertiles, 0.99; 95% CI 0.80, 1.22; p _trend?=?0.880). A significant interaction was observed between LBP and obesity status (p _interaction?=?0.013).

Conclusions/interpretation

Our study suggested that elevated plasma LBP was associated with an increased risk of developing MetS among middle-aged and older Chinese, especially in normal-weight individuals.     

Nuts as a replacement for carbohydrates in the diabetic diet: a reanalysis of a randomised controlled trial

Aims/hypothesis

In line with current advice, we assessed the effect of replacing carbohydrate consumption with mixed nut consumption, as a source of unsaturated fat, on cardiovascular risk factors and HbA_1c in type 2 diabetes. The data presented here are from a paper that was retracted at the authors’ request ( https://doi.org/10.2337/dc16-rt02) owing to lack of adjustment for repeated measures in the same individual. Our aim, therefore, was to fix the error and add new complementary data of interest, including information on clotting factors and LDL particle size.

Methods

A total of 117 men and postmenopausal women with type 2 diabetes who were taking oral glucose-lowering agents and with HbA_1c between 47.5 and 63.9 mmol/mol (6.5–8.0%) were randomised after stratification by sex and baseline HbA_1c in a parallel design to one of three diets for 3 months: (1) ‘full-dose nut diet’ (n?=?40): a diet with 2.0 MJ (477 kcal) per 8.4 MJ (2000 kcal) energy provided as mixed nuts (75 g/day); (2) ‘full-dose muffin diet’ (n?=?39): a diet with 1.97 MJ (471 kcal) per 8.4 MJ (2000 kcal) energy provided as three whole-wheat muffins (188 g/day), with a similar protein content to the nuts, and the same carbohydrate-derived energy content as the monounsaturated fatty acid-derived energy content in the nuts; or (3) ‘half-dose nut diet’ (n?=?38): a diet with 1.98 MJ (474 kcal) per 8.4 MJ (2000 kcal) energy provided as half portions of both the nuts and muffins. The primary outcome was change in HbA_1c. The study was carried out in a hospital clinical research centre and concluded in 2008. Only the statistician, study physicians and analytical technicians could be blinded to the group assessment.

Results

A total of 108 participants had post-intervention data available for analysis (full-dose nut group, n?=?40; full-dose muffin group, n?=?35; half-dose nut group, n?=?33). Compared with the full-dose muffin diet, the full-dose nut diet provided 9.2% (95% CI 7.1, 11.3) greater total energy intake from monounsaturated fat. The full-dose nut diet (median intake, 75 g/day) also reduced HbA_1c compared with the full-dose muffin diet by ?2.0 mmol/mol (95% CI ?3.8, ?0.3 mmol/mol) (?0.19% [95% CI ?0.35%, ?0.02%]), (p?=?0.026). Estimated cholesterol levels in LDL particles with a diameter <255 ångström [LDL-c_<255Å]) and apolipoprotein B were also significantly decreased after the full-dose nut diet compared with the full-dose muffin diet. According to the dose response, the full-dose nut diet is predicted to reduce HbA_1c (?2.0 mmol/mol [?0.18%]; p?=?0.044), cholesterol (?0.25 mmol/l; p?=?0.022), LDL-cholesterol (?0.23 mmol/l; p?=?0.019), non-HDL-cholesterol (?0.26 mmol/l; p?=?0.020), apolipoprotein B (?0.06 g/l, p?=?0.013) and LDL-c<_255Å (?0.42 mmol/l; p?<?0.001). No serious study-related adverse events occurred, but one participant on the half-dose nut diet was hospitalised for atrial fibrillation after shovelling snow.

Conclusions/interpretation

Nut intake as a replacement for carbohydrate consumption improves glycaemic control and lipid risk factors in individuals with type 2 diabetes.

Trial registration

ClinicalTrials.gov NCT00410722

Funding

The study was funded by the International Tree Nut Council Nutrition Research and Education Foundation, the Peanut Institute, Loblaw Companies and the Canada Research Chairs Program of the Government of Canada

     

Efficacy and safety of enzyme replacement therapy with BMN 110 (elosulfase alfa) for Morquio A syndrome (mucopolysaccharidosis IVA): a phase 3 randomised placebo-controlled study

Objective

To assess the efficacy and safety of enzyme replacement therapy (ERT) with BMN 110 (elosulfase alfa) in patients with Morquio A syndrome (mucopolysaccharidosis IVA).

Methods

Patients with Morquio A aged ≥5 years (N?=?176) were randomised (1:1:1) to receive elosulfase alfa 2.0 mg/kg/every other week (qow), elosulfase alfa 2.0 mg/kg/week (weekly) or placebo for 24 weeks in this phase 3, double-blind, randomised study. The primary efficacy measure was 6-min walk test (6MWT) distance. Secondary efficacy measures were 3-min stair climb test (3MSCT) followed by change in urine keratan sulfate (KS). Various exploratory measures included respiratory function tests. Patient safety was also evaluated.

Results

At week 24, the estimated mean effect on the 6MWT versus placebo was 22.5 m (95 % CI 4.0, 40.9; P?=?0.017) for weekly and 0.5 m (95 % CI ?17.8, 18.9; P?=?0.954) for qow. The estimated mean effect on 3MSCT was 1.1 stairs/min (95 % CI ?2.1, 4.4; P?=?0.494) for weekly and ?0.5 stairs/min (95 % CI ?3.7, 2.8; P?=?0.778) for qow. Normalised urine KS was reduced at 24 weeks in both regimens. In the weekly dose group, 22.4 % of patients had adverse events leading to an infusion interruption/discontinuation requiring medical intervention (only 1.3 % of all infusions in this group) over 6 months. No adverse events led to permanent treatment discontinuation.

Conclusions

Elosulfase alfa improved endurance as measured by the 6MWT in the weekly but not qow dose group, did not improve endurance on the 3MSCT, reduced urine KS, and had an acceptable safety profile.     

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.     

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)

     

The impact of diet and lifestyle management strategies for obstructive sleep apnoea in adults: a systematic review and meta-analysis of randomised controlled trials

Purpose

To systematically evaluate the impact of diet, exercise and lifestyle modification programmes on indices of obesity, Obstructive Sleep Apnoea (OSA) parameters and quality of life (QoL) in adults with OSA.

Methods

Electronic databases were searched to identify randomised controlled trials published in English with an intervention based on dietary weight loss, exercise and/or lifestyle programme in adults with OSA. Meta-analyses were conducted using random-effects models.

Results

Twelve studies met the inclusion criteria with nine comparing similar interventions. Diet and diet plus continuous positive airway pressure (CPAP) therapy were compared in three studies (n?=?261), and intensive lifestyle programmes and routine care were compared in six studies (n?=?483). Diet with CPAP therapy reduced weight by ?2.64 kg (95 % Confidence Interval (CI) ?3.98, ?1.30, I ²?=?0 %) compared with diet alone. No differences were observed for QoL or Epworth Sleepiness Scale. A significant reduction in weight was seen in participants receiving an intensive lifestyle intervention of ?5.65 kg (95 % CI ?10.91, ?0.40, I ²?=?95.7 %) compared with controls. Reductions were also observed for waist circumference (?5.80 cm, 95 % CI ?8.64, ?2.96, I²?=?77.7 %), body mass index (BMI) (?2.33 kg/m², 95 % CI ?3.41, ?1.24, I²?=?78.8 %) and the Apnoea Hypopnoea Index (AHI) (?4.55 events/h, 95 % CI ?7.12, ?1.98, I ²?=?54.4 %) but with high levels of heterogeneity.

Conclusions

Intensive lifestyle management can significantly reduce obesity indices and improve AHI. Future research is required to investigate this effect due to a limited number of studies identified.     

Biodegradable Polymer Drug-Eluting Stents Versus Second-Generation Drug-Eluting Stents for Patients With Coronary Artery Disease: An Update Meta-Analysis

Objective

Permanent polymer drug-eluting stents (DES) are associated with a higher risk of late and very late stent thrombosis (ST); biodegradable polymer drug-eluting stents (BP-DES) were designed to reduce these risks. However, their benefits are not completely clear.

Method

We undertook a meta-analysis of randomized studies identified in systematic searches of MEDLINE, EMBASE, and the Cochrane Database. Eligible studies were those that compared BP-DES with second-generation permanent polymer DES in patients undergoing percutaneous coronary intervention.

Results

Five studies (8,740 patients) with a mean follow-up of 19.2 months were included. Overall, BP-DES were associated with a broadly equivalent risk of definite and probable ST (odds ratio [OR], 1.07; 95 % confidence interval [CI], 0.67 to 1.71; P?=?0.76; I ²?=?5.0 %), target vessel revascularization (OR, 1.04; 95 % CI, 0.87 to 1.24; P?=?0.68; I ²?=?38.0 %), all-cause mortality (OR, 1.10; 95 % CI, 0.87 to 1.41; P?=?0.42; I ²?=?0.0 %), and major adverse cardiac events (OR, 1.03; 95 % CI, 0.88 to 1.20; P?=?0.74; I ²?=?0.0 %) when compared with second-generation DES. However, BP-DES significantly decreased in-stent late luminal loss (standard mean difference [SMD], ?0.01; 95 % CI, ?0.12 to 0.11; P?=?0.93; I ²?=?0.0 %) and in-segment late luminal loss (SMD, ?0.06; 95 % CI, ?0.17 to 0.05; P?=?0.27; I ²?=?0.0 %) compared with second-generation DES.

Conclusions

Compared with second-generation permanent polymer DES, biodegradable stents appear to have equivalent short- to medium-term clinical benefits, and it remains unclear whether they reduce the incidence of very late ST.     

Effect of CPAP therapy on cardiovascular events and mortality in patients with obstructive sleep apnea: a meta-analysis

Purpose

Continuous positive airway pressure (CPAP) therapy may decrease the risk of mortality and cardiovascular events in patients with obstructive sleep apnea. However, these benefits are not completely clear.

Methods

We undertook a meta-analysis of randomized clinical trials identified in systematic searches of MEDLINE, EMBASE, and the Cochrane Database.

Results

Eighteen studies (4146 patients) were included. Overall, CPAP therapy did not significantly decrease the risk of cardiovascular events compared with the control group (odds ratio (OR), 0.84; 95 % confidence intervals (CI), 0.62–1.13; p = 0.25; I ² = 0 %). CPAP was associated with a nonsignificant trend of lower rate of death and stroke (for death: OR, 0.85; 95 % CI, 0.35–2.06; p = 0.72; I ² = 0.0 %; for stroke: OR, 0.56; 95 % CI, 0.18–1.73; p = 0.32; I ² = 12.0 %), a significantly lower Epworth sleepiness score (ESS) (mean difference (MD), ?1.78; 95 % CI, ?2.31 to ?1.24; p < 0.00001; I ² = 76 %), and a significantly lower 24 h systolic and diastolic blood pressure (BP) (for 24 h systolic BP: MD, ?2.03 mmHg; 95 % CI, ?3.64 to ?0.42; p = 0.01; I ² = 0 %; for diastolic BP: MD, ?1.79 mmHg; 95 % CI, ?2.89 to ?0.68; p = 0.001; I ² = 0 %). Daytime systolic BP and body mass index were comparable between the CPAP and control groups. Subgroup analysis did not show any significant difference between short- and mediate-to-long-term follow-up groups with regard to cardiovascular events, death, and stroke.

Conclusions

CPAP therapy was associated with a trend of decreased risk of cardiovascular events. Furthermore, ESS and BP were significantly lower in the CPAP group. Larger randomized studies are needed to confirm these findings.

     

Single-incision laparoscopic colectomy versus conventional multiport laparoscopic colectomy: a meta-analysis of comparative studies

Objective

This study aimed to compare single-incision laparoscopic colectomy (SILC) to conventional multiport laparoscopic colectomy (MLC).

Background

Single-incision laparoscopic surgery (SILS) is a minimally invasive technique being recently applied to colorectal surgery. A number of studies comparing SILC to conventional MLC have recently been published.

Methods

A literature search of PubMed and MEDLINE databases for studies comparing SILC to conventional MLC was conducted. The primary outcome measures for meta-analysis were postoperative complications, length of stay, and operative time. Secondary outcome measures were incision length, estimated blood loss, and number of lymph nodes harvested.

Results

Fifteen studies comparing 467 patients undergoing SILC to 539 patients undergoing conventional MLC were reviewed and the data pooled for analysis. Patients undergoing SILC had a shorter length of stay (pooled weighted mean difference (WMD)?=??0.68; 95 % CI?=??1.20 to ?0.16; p?=?0.0099), shorter incision length (pooled WMD?=??1.37; 95 % CI?=??2.74 to 0.000199; p?=?0.05), less estimated blood loss (pooled WMD?=??20.25; 95 % CI?=??39.25 to ?1.24; p?=?0.037), and more lymph nodes harvested (pooled WMD?=?1.75; 95 % CI?=?0.12 to 3.38; p?=?0.035), while there was no significant difference in the number of postoperative complications (pooled odds ratio?=?0.83; 95 % CI?=?0.57 to 1.20; p?=?0.33) or operative time (pooled WMD?=?5.06; 95 % CI?=??2.91 to 13.03; p?=?0.21).

Conclusion

SILC appears to have comparable results to conventional MLC in the hands of experienced surgeons. Prospective randomized trials are necessary to define the relative benefits of one procedure over the other.     

Pancreatic beta cell function following liraglutide-augmented weight loss in individuals with prediabetes: analysis of a randomised,placebo-controlled study

Aims/hypothesis

Liraglutide can modulate insulin secretion by directly stimulating beta cells or indirectly through weight loss and enhanced insulin sensitivity. Recently, we showed that liraglutide treatment in overweight individuals with prediabetes (impaired fasting glucose and/or impaired glucose tolerance) led to greater weight loss (?7.7% vs ?3.9%) and improvement in insulin resistance compared with placebo. The current study evaluates the effects on beta cell function of weight loss augmented by liraglutide compared with weight loss alone.

Methods

This was a parallel, randomised study conducted in a single academic centre. Both participants and study administrators were blinded to treatment assignment. Individuals who were 40–70 years old, overweight (BMI 27–40 kg/m²) and with prediabetes were randomised (via a computerised system) to receive liraglutide (n?=?35) or matching placebo (n?=?33), and 49 participants were analysed. All were instructed to follow an energy-restricted diet. Primary outcome was insulin secretory function, which was evaluated in response to graded infusions of glucose and day-long mixed meals.

Results

Liraglutide treatment (n?=?24) significantly (p?≤?0.03) increased the insulin secretion rate (% mean change [95% CI]; 21% [12, 31] vs ?4% [?11, 3]) and pancreatic beta cell sensitivity to intravenous glucose (229% [161, 276] vs ?0.5% (?15, 14]), and decreased insulin clearance rate (?3.5% [?11, 4] vs 8.2 [0.2, 16]) as compared with placebo (n?=?25). The liraglutide-treated group also had significantly (p?≤?0.03) lower day-long glucose (?8.2% [?11, ?6] vs ?0.1 [?3, 2]) and NEFA concentrations (?14 [?20, ?8] vs ?2.1 [?10, 6]) following mixed meals, whereas day-long insulin concentrations did not significantly differ as compared with placebo. In a multivariate regression analysis, weight loss was associated with a decrease in insulin secretion rate and day-long glucose and insulin concentrations in the placebo group (p?≤?0.05), but there was no association with weight loss in the liraglutide group. The most common side effect of liraglutide was nausea.

Conclusions/interpretation

A direct stimulatory effect on beta cell function was the predominant change in liraglutide-augmented weight loss. These changes appear to be independent of weight loss.

Trial registration

ClinicalTrials.gov NCT01784965

Funding

The study was funded by the ADA.     

Effects of hypoglycaemia on working memory and regional cerebral blood flow in type 1 diabetes: a randomised,crossover trial

Aims/hypothesis

The aim of this randomised, crossover trial was to compare cognitive functioning and associated brain activation patterns during hypoglycaemia (plasma glucose [PG] just below 3.1 mmol/l) and euglycaemia in individuals with type 1 diabetes mellitus.

Methods

In this patient-blinded, crossover study, 26 participants with type 1 diabetes mellitus attended two randomised experimental visits: one hypoglycaemic clamp (PG 2.8?±?0.2 mmol/l, approximate duration 55 min) and one euglycaemic clamp (PG 5.5 mmol/l?±?10%). PG levels were maintained by hyperinsulinaemic glucose clamping. Cognitive functioning was assessed during hypoglycaemia and euglycaemia conditions using a modified version of the digit symbol substitution test (mDSST) and control DSST (cDSST). Simultaneously, regional cerebral blood flow (rCBF) was measured in pre-specified brain regions by six H₂ ¹⁵O-positron emission tomographies (PET) per session.

Results

Working memory was impaired during hypoglycaemia as indicated by a statistically significantly lower mDSST score (estimated treatment difference [ETD] ?0.63 [95% CI ?1.13, ?0.14], p?=?0.014) and a statistically significantly longer response time (ETD 2.86 s [7%] [95% CI 0.67, 5.05], p?=?0.013) compared with euglycaemia. During hypoglycaemia, mDSST task performance was associated with increased activity in the frontal lobe regions, superior parietal lobe and thalamus, and decreased activity in the temporal lobe regions (p?<?0.05). Working memory activation (mDSST ? cDSST) statistically significantly increased blood flow in the striatum during hypoglycaemia (ETD 0.0374% [95% CI 0.0157, 0.0590], p?=?0.002).

Conclusions/interpretation

During hypoglycaemia (mean PG 2.9 mmol/l), working memory performance was impaired. Altered performance was associated with significantly increased blood flow in the striatum, a part of the basal ganglia implicated in regulating motor functions, memory, language and emotion.

Trial registration

NCT01789593, clinicaltrials.gov

Funding

This study was funded by Novo Nordisk.

     

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.     

Angiotensin-converting enzyme gene polymorphism in north Indian population with obstructive sleep apnea

Background

A deletion of 287-bp Alu repeat of angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene is associated with hypertension.

Purpose

The aim of this study is to determine the frequency of ACE (I/D) polymorphism in patients with obstructive sleep apnea (OSA).

Methods

Genotyping of ACE (I/D) gene polymorphism and estimation of serum angiotensin-converting enzyme (SACE) activity were done in 813 subjects who underwent polysomnography. Of these, 395 were apneics and 418 were non-apneics.

Results

The frequencies of II genotype (OR = 1.8, 95 % CI 1.26–2.60, p?=?0.001) and I allele (OR = 1.4, 95 % CI 1.13–1.69, p?=?0.001) of ACE gene were found to be significantly increased in patients with OSA as compared to patients without OSA. Frequency of II genotype was significantly decreased (OR = 0.46, 95 % CI 0.28–0.77, p?=?0.003) in OSA patients with hypertension. In contrast, the frequencies of ID (OR?=?1.80, 95 % CI 1.08–2.99, p?=?0.024) and DD genotypes (OR?=?2.15, 95 % CI 1.30–3.57, p?=?0.003) were significantly increased in this group. The activity of SACE was significantly decreased in the apneic group as compared to the non-apneic group (OR?=?0.99, 95 % CI 0.98–1.00, p?=?0.04).

Conclusions

The findings suggest that II genotype confers susceptibility towards development of OSA whereas DD genotype confers susceptibility towards hypertension irrespective of OSA.