Efficacy and safety of lobeglitazone versus sitagliptin as an add-on to metformin in patients with type 2 diabetes with two or more components of metabolic syndrome over 24 weeks

We aimed to evaluate the efficacy and safety profile of lobeglitazone compared with sitagliptin as an add-on to metformin in patients with type 2 diabetes as well as other components of metabolic syndrome. Patients inadequately controlled by metformin were randomly assigned to lobeglitazone (0.5 mg, n = 121) or sitagliptin (100 mg, n = 126) for 24 weeks. The mean changes in HbA1c of the lobeglitazone and sitagliptin groups were −0.79% and −0.86%, respectively; the between-group difference was 0.08% (95% confidence interval, −0.14% to 0.30%), showing non-inferiority. The proportion of patients having two or more factors of other metabolic syndrome components decreased to a greater extent in the lobeglitazone group than in the sitagliptin group (−11.9% vs. −4.8%; P < .0174). Favourable changes in the lipid metabolism were also observed with lobeglitazone, which had a similar safety profile to sitagliptin. Lobeglitazone was comparable with sitagliptin as an add-on to metformin in terms of efficacy and safety.     

The effect of high-protein,low-carbohydrate diets in the treatment of type 2 diabetes: a 12 month randomised controlled trial

Aims/hypothesis  

Short-term dietary studies suggest that high-protein diets can enhance weight loss and improve glycaemic control in people with type 2 diabetes. However, the long-term effects of such diets are unknown. The aim of this study was to determine whether high-protein diets are superior to high-carbohydrate diets for improving glycaemic control in individuals with type 2 diabetes.     

Long-term treatment with metformin in type 2 diabetes and methylmalonic acid: Post hoc analysis of a randomized controlled 4.3 year trial

Aims

Metformin treatment is associated with a decrease of serum vitamin B12, but whether this reflects tissue B12 deficiency is controversial. We studied the effects of metformin on serum levels of methylmalonic acid (MMA), a biomarker for tissue B12 deficiency, and on onset or progression of neuropathy.

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     

The Diabetes Excess Weight Loss (DEWL) Trial: a randomised controlled trial of high-protein versus high-carbohydrate diets over 2 years in type 2 diabetes

Aims/hypothesis  

To compare the effectiveness of low-fat high-protein and low-fat high-carbohydrate dietary advice on weight loss, using group-based interventions, among overweight people with type 2 diabetes.     

The effects of 2 weeks of interval vs continuous walking training on glycaemic control and whole-body oxidative stress in individuals with type 2 diabetes: a controlled,randomised, crossover trial

Aims/hypothesis

The aim of this study was to evaluate the effects of oxygen consumption-matched short-term interval walking training (IWT) vs continuous walking training (CWT) on glycaemic control, including glycaemic variability, in individuals with type 2 diabetes. We also assessed whether any training-induced improvements in glycaemic control were associated with systemic oxidative stress levels.

Methods

Participants (n?=?14) with type 2 diabetes completed a crossover trial using three interventions (control intervention [CON], CWT and IWT), each lasting 2 weeks. These were performed in a randomised order (computerised generated randomisation) and separated by washout periods of 4 or 8 weeks after CON or training interventions, respectively. Training included ten supervised treadmill sessions, lasting 60 min/session, and was performed at the research facility. CWT was performed at moderate walking speed (75.6%?±?2.5% of walking peak oxygen consumption [\( \overset{.}{V}{\mathrm{O}}_{2\mathrm{peak}} \)]), while IWT was performed as alternating 3 min repetitions at slow (58.9%?±?2.0% \( \overset{.}{V}{\mathrm{O}}_{2\mathrm{peak}} \)) and fast (90.0%?±?3.6% \( \overset{.}{V}{\mathrm{O}}_{2\mathrm{peak}} \)) walking speed. Before and after each intervention, the following was assessed: 24 h continuous glucose monitoring (CGM) and urinary free 8-iso prostaglandin F_2α (8-iso PGF_2α; a marker for oxidative stress), physical fitness and body composition. Neither participants nor assessors were blinded to the interventions.

Results

No intervention-induced changes were seen in physical fitness or body composition. Compared with baseline, IWT reduced mean glucose levels non-significantly (?0.7?±?0.3 mmol/l, p?=?0.08) and significantly reduced maximum glucose levels (?1.8?±?0.5 mmol/l, p?=?0.04) and mean amplitude of glycaemic excursions (MAGE; ?1.7?±?0.4 mmol/l, p?=?0.02), whereas no significant within-group changes were seen with CON or CWT. Although 8-iso PGF_2α was associated with minimum glucose levels at baseline, no change in 8-iso PGF_2α was seen with any intervention, nor were there any associations between changes in 8-iso PGF_2α and changes in glycaemic control (p?>?0.05 for all). No adverse effects were observed with any of the interventions.

Conclusions/interpretation

Short-term IWT, but not CWT, improves CGM-derived measures of glycaemic control independent of changes in physical fitness and body composition in individuals with type 2 diabetes. Systemic oxidative stress levels are unaffected by short-term walking and changes in oxidative stress levels are not associated with changes in glycaemic control.

Trial registration

ClinicalTrials.gov NCT02320526

Funding

The Centre for Physical Activity Research (CFAS) is supported by a grant from TrygFonden. During the study period, the Centre of Inflammation and Metabolism (CIM) was supported by a grant from the Danish National Research Foundation (DNRF55). The study was further supported by grants from Diabetesforeningen, Augustinusfonden and Krista og Viggo Petersens Fond. CIM/CFAS is a member of the Danish Center for Strategic Research in Type 2 Diabetes (DD2; the Danish Council for Strategic Research, grant no. 09-067009 and 09-075724). MR-L was supported by a post-doctoral grant from the Danish Diabetes Academy supported by the Novo Nordisk Foundation.

     

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 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.     

A randomized, parallel group, double-blind, multicentre study comparing the efficacy and safety of Avandamet (rosiglitazone/metformin) and metformin on long-term glycaemic control and bone mineral density after 80 weeks of treatment in drug-naïve type 2 diabetes mellitus patients

Aim: The purpose of this study was to evaluate if superior glycaemic control could be achieved with Avandamet® (rosiglitazone/metformin/AVM) compared with metformin (MET) monotherapy, and if glycaemic effects attained with AVM are durable over 18 months of treatment. Bone mineral density (BMD) and bone biomarkers were evaluated in a subgroup of patients. Methods: This was a phase IV, randomized, double‐blind, multi‐centre study in 688, drug naÏve, male and female patients who had an established clinical diagnosis of type 2 diabetes mellitus (T2DM). Patients were randomized in a 1 : 1 ratio either to AVM or MET. Results: As initial therapy in patients with T2DM, AVM was superior to MET in achieving statistically significant reductions in glycated haemoglobin (HbA1c) (p < 0.0001) and fasting plasma glucose (FPG) (p < 0.001), with more patients reaching recommended HbA1c and FPG targets for intensive glycaemic control. The glycaemic effects attained with AVM compared to MET monotherapy were durable over 18 months of treatment. In the bone substudy, AVM was associated with a significantly lower BMD in comparison with MET at week 80 in the lumbar spine and total hip (p < 0.0012 and p = 0.0005, respectively). Between‐treatment differences were not statistically significant for distal one‐third of radius BMD, femoral neck BMD or total BMD. Conclusion: Superior glycaemic control was achieved with AVM compared with MET monotherapy. The superior glycaemic effects were shown to be durable over 18 months of treatment. AVM was associated with a significantly reduced BMD in comparison with MET at week 80 in the lumbar spine and total hip.