Efficacy and safety of adding liraglutide to existing insulin regimens in Japanese patients with type 2 diabetes mellitus: A post‐hoc analysis of a phase 3 randomized clinical trial

Aims/Introduction

To determine the efficacy and safety of adding liraglutide to three different insulin regimens in Japanese patients with type 2 diabetes mellitus.

Materials and Methods

In this post‐hoc analysis, results from a 36‐week, randomized, double‐blind, placebo‐controlled, parallel‐group trial are reported. Individuals with type 2 diabetes mellitus were stratified according to their pre‐trial insulin regimen (basal, basal–bolus and premix). The primary objective was to determine whether adding liraglutide (0.9 mg/day) to fixed‐dose insulin therapy was superior vs fixed‐dose insulin monotherapy, assessed by the effect on glycemic control after 16 weeks of treatment.

Results

The treatment effect on glycated hemoglobin reduction was independent of the pre‐trial insulin regimen. Comparing liraglutide with a placebo, liraglutide was associated with glycated hemoglobin reduction in all insulin regimens, with placebo‐corrected reductions at 16 weeks ranging from ?1.45 to ?1.17%, and maintained at 36 weeks. Liraglutide resulted in a greater reduction in mean plasma glucose obtained from seven‐point self‐monitoring, and greater proportions of patients achieved target glycated hemoglobin. With liraglutide, slightly higher proportions of patients receiving basal and basal–bolus insulin reported confirmed hypoglycemia from 0 to 16 weeks.

Conclusions

The efficacy and safety of adding liraglutide to insulin therapy was confirmed, regardless of pre‐trial insulin regimen.

     

Comparison between sodium–glucose cotransporter 2 inhibitors and pioglitazone as additions to insulin therapy in type 2 diabetes patients: A systematic review with an indirect comparison meta‐analysis

Aims/Introduction

We aimed to evaluate the efficacy and safety of pioglitazone (PIO) and sodium–glucose cotransporter 2 inhibitors (SGLT2i) as additions to insulin therapy for the management of type 2 diabetes mellitus.

Materials and Methods

We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov through December 2016. Randomized controlled trials published in English that compared SGLT2i plus insulin (SGLT2i/INS) or PIO plus insulin (PIO/INS) with placebo plus insulin (PCB/INS) in type 2 diabetes mellitus patients were included. We compared the efficacy and safety between SGLT2i/INS and PIO/INS indirectly.

Results

A total of 14 randomized controlled trials comparing 7,226 participants were included (8 SGLT2i and 6 PIO studies). SGLT2i/INS achieved similar reductions in hemoglobin A1c (weighted mean difference [WMD] ?0.01% [?0.1 mmol/mol], 95% confidence interval [CI] ?0.25 to 0.22% [?2.7 to ?2.4 mmol/mol]; P = 0.896) and fasting plasma glucose (WMD ?0.90 mg/dL, 95% CI: ?15.50 to 13.71 mg/dL; P = 0.904), and a similar proportion of participants achieved hemoglobin A1c <7.0% (<53.0 mmol/mol; relative risk 0.98, 95% CI: 0.73 to 1.33; P = 0.917) as compared with the PIO/INS group, with greater weight reduction (WMD ?4.54 kg, 95% CI: ?5.67 to ?3.41 kg; P < 0.001). PIO/INS showed non‐significant trends toward a higher risk of hypoglycemia (relative risk 1.15, 95% CI: 0.97 to 1.35; P = 0.102) and higher reduction of total daily insulin doses (WMD ?2.45 IU/day, 95% CI: ?7.30 to 2.40 IU/day; P = 0.438).

Conclusions

Both PIO and SGLT2i are feasible adjunctive oral agents to pre‐existing insulin therapy in individuals with inadequately controlled type 2 diabetes mellitus.

     

Weekly glucagon‐like peptide‐1 receptor agonist albiglutide as monotherapy improves glycemic parameters in Japanese patients with type 2 diabetes mellitus: A randomized,double‐blind,placebo‐controlled study

Aims/Introduction

The present phase 3, randomized, double‐blind 24‐week study with extension to 1 year assessed the efficacy and safety of albiglutide compared with placebo in Japanese patients with type 2 diabetes mellitus inadequately controlled by diet and exercise with or without a single oral antidiabetic drug.

Materials and Methods

Patients received weekly albiglutide 30 mg (n = 160), albiglutide 50 mg (n = 150) or a placebo switched to albiglutide 30 mg after 24 weeks (n = 77). Open‐label daily liraglutide 0.9 mg (n = 103) was included as a reference. Oral antidiabetic drug use was discontinued before baseline. The primary end‐point was 24‐week change from baseline in glycated hemoglobin (HbA1c). Secondary end‐points included fasting plasma glucose, bodyweight and adverse events.

Results

At 24 weeks, mean HbA1c changes from baseline were ?1.10, ?1.30, and 0.25% for albiglutide 30, 50 mg and placebo, respectively (P vs placebo <0.0001 for both albiglutide doses), ?1.19% for liraglutide. Decreases in HbA1c with albiglutide were sustained through the study. Mean fasting plasma glucose decreased by ≥20 mg/dL, and the mean change in bodyweight was ≤0.5 kg through 1 year across groups. Most commonly reported adverse events were nasopharyngitis, constipation and nausea. The incidence of adverse events was higher in active treatment groups than in the placebo group. Few hypoglycemia events were reported; no patient withdrew as a result of hypoglycemia. No new safety signals were detected.

Conclusions

Albiglutide monotherapy achieved clinically significant decreases in HbA1c and fasting plasma glucose with good tolerability in Japanese patients with type 2 diabetes mellitus inadequately controlled by diet and exercise with or without a single oral antidiabetic drug.

     

Lower mean blood glucose during short‐term intensive insulin therapy is associated with long‐term glycemic remission in patients with newly diagnosed type 2 diabetes: Evidence‐based recommendations for standardization

Aims/Introduction

Optimal glycemic targets during short‐term intensive insulin therapy in patients with newly diagnosed type 2 diabetes are not standardized. The present study was carried out to determine the optimal glycemic targets during therapy by analyzing the impacts of glucose levels on therapeutic outcomes.

Materials and Methods

A total of 95 individuals with newly diagnosed type 2 diabetes were enrolled. Short‐term intensive insulin therapy was carried out using an insulin pump to achieve and maintain glycemic targets (fasting blood glucose ≤6.0 mmol/L, 2‐h postprandial blood glucose ≤7.8 mmol/L) for 14 days, with daily eight‐point capillary blood glucose profiles recorded. Patients were followed up for 1 year after discharge.

Results

In most participants, the mean blood glucose and glycemic excursion parameters during the therapy were controlled within the normal range. Mean blood glucose was independently associated with amelioration of acute insulin response (r = ?0.25, P = 0.015) and 1‐year remission (odds ratio 0.12, 95% confidence interval 0.034–0.426), but negatively associated with more level 1 hypoglycemia (r = ?0.34, P = 0.001), although major hypoglycemia was rare. Among mean blood glucose tertiles, patients in the middle (68.7%) and lower (75.0%) tertiles had a higher 1‐year remission rate compared with the upper tertile (32.3%, both P < 0.001), whereas only the middle tertile did not have increased hypoglycemia compared with the upper tertile (8.1 ± 5.4 vs 7.2 ± 3.9 events/person, P = 0.48).

Conclusions

Stricter glycemic control during short‐term intensive insulin therapy produced more remission despite self‐manageable hypoglycemia. Based on glycemic parameters in the middle mean tertile, we propose new glycemic targets that are approximately 0.4 mmol/L lower than current the targets, as long‐term benefit outweighs short‐term risks.

     

Effects of pioglitazone treatment on blood leptin levels in patients with type 2 diabetes

Aims/Introduction

The aim of the present study was to carry out a meta‐analysis of randomized controlled trials (RCTs) that investigated the effects of pioglitazone on blood leptin levels in patients with type 2 diabetes.

Materials and Methods

Literature searches were carried out using Medline, the Cochrane Controlled Trials Registry and ClinicalTrials.gov, and RCTs that investigated the effects of pioglitazone on blood leptin levels in patients with type 2 diabetes were selected. Standardized mean differences and 95% confidence intervals were calculated.

Results

A total of 10 RCTs met the eligibility criteria and were included in the meta‐analysis. Significantly lower blood leptin levels were observed in the pioglitazone group (standardized mean difference ?0.58, 95% confidence interval ?1.12 to ?0.05%, P = 0.03) than in the placebo group. There was no significant difference in blood leptin levels observed between the pioglitazone and oral antidiabetic drug groups (standardized mean difference ?0.01, 95% confidence interval ?0.20 to 0.19%, P = 0.93).

Conclusions

There was a significant difference in blood leptin levels between the pioglitazone and placebo groups. However, relatively few RCTs were included in the study, and there was a high level of statistical heterogeneity; we believe that this could have affected the results.

     

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

Aims

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

Methods

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

Results

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

Conclusions

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

     

Efficacy and safety of combination therapy with an α‐glucosidase inhibitor and a dipeptidyl peptidase‐4 inhibitor in patients with type 2 diabetes mellitus: A systematic review with meta‐analysis

Aims/Introduction

The combination of dipeptidyl peptidase‐4 (DPP4) inhibitors and α‐glucosidase inhibitors (AGIs) might provide an additive or synergistic glucose‐lowering effect, as they have a complementary mode of action. In the present study, we examined the efficacy and safety of the addition of a DPP4 inhibitor to patients with type 2 diabetes inadequately controlled with an AGI.

Materials and Methods

We carried out an electronic search of MEDLINE, EMBASE, the Cochrane Library and Clinicaltrials.gov through October 2016. Randomized controlled trials written in English that compared DPP4 inhibitors plus AGI (DPP4i/AGI) and placebo plus AGI (PCB/AGI) in patients with type 2 diabetes were selected. Data on the study characteristics, efficacy and safety outcomes were extracted, and the risk of potential biases was assessed. The efficacy and safety of DPP4i/AGI and PCB/AGI were compared.

Results

Of 756 potentially relevant published articles and 40 registered trials, five studies including 845 patients randomized to DPP4i/AGI and 832 patients randomized to PCB/AGI were included for meta‐analysis. Compared with PCB/AGI, DPP4i/AGI showed a greater reduction in glycated hemoglobin (weighted mean difference ?1.2%, 95% confidence interval ?1.6 to ?0.8), fasting plasma glucose and 2‐h postprandial plasma glucose levels, with no increase in bodyweight. The risks of hypoglycemia and gastrointestinal adverse events were similar between DPP4i/AGI and PCB/AGI.

Conclusions

The addition of a DPP4 inhibitor to patients with type 2 diabetes inadequately controlled with an AGI achieved better glycemic control without further increasing the risk of weight gain and hypoglycemia.

     

Safety and efficacy of the combination of the glucagon‐like peptide‐1 receptor agonist liraglutide with an oral antidiabetic drug in Japanese patients with type 2 diabetes: Post‐hoc analysis of a randomized, 52‐week,open‐label,parallel‐group trial

Aims/Introduction

The aim of the present post‐hoc analysis was to investigate the safety and efficacy of liraglutide in combination with one oral antidiabetic drug (OAD) across different OAD classes.

Materials and Methods

This was a post‐hoc analysis using data from a 52‐week, open‐label, parallel‐group trial, in which patients with type 2 diabetes inadequately controlled with a single OAD (α‐glucosidase inhibitor, glinide, metformin or thiazolidinedione) were randomized to either pretrial OAD in combination with liraglutide 0.9 mg/day (liraglutide group) or pretrial OAD in combination with an additional OAD (additional OAD group). The primary outcome investigated in this post‐hoc analysis was the incidence of adverse events.

Results

The proportions of patients experiencing adverse events across the different groups of pretrial OADs were comparable between liraglutide and additional OAD (α‐glucosidase inhibitor 74.6 vs 70.0%; glinide 93.1 vs 87.1%; metformin 91.8 vs 87.1%; thiazolidinedione 86.2 vs 96.4%, respectively). Minor hypoglycemia was infrequent (seven episodes in two patients randomized to liraglutide, and two episodes in two patients randomized to additional OAD). The mean reduction in glycated hemoglobin appeared greater with liraglutide therapy, with the estimated mean treatment difference (95% confidence interval [CI]) for liraglutide vs additional OAD ranging from ?0.14%, 95% CI: ?0.48 to 0.21 (?1.5 mmol/mol, 95 CI: ?5.2 to 2.3) to ?0.44%, 95% CI:?0.79 to ?0.09 (?4.8 mmol/mol, 95% CI: ?8.6 to ?1.0).

Conclusions

The present analysis suggests that Japanese patients on OAD monotherapy might benefit from a greater improvement in glycemic control, without impacting tolerability, by combining their OAD with liraglutide rather than another OAD, regardless of which OAD monotherapy they are receiving.

     

Effects of circulating member B of the family with sequence similarity 3 on the risk of developing metabolic syndrome and its components: A 5‐year prospective study

Aims/Introduction

Member B of the family with sequence similarity 3 (FAM3B), also known as pancreatic‐derived factor, is mainly synthesized and secreted by islet β‐cells, and plays a role in abnormal metabolism of glucose and lipids. However, the prospective association of FAM3B with metabolic disorders remains unclear. The present study aimed to reveal the predictive relationship between pancreas‐specific cytokine and metabolic syndrome (MetS).

Materials and Methods

A total of 210 adults (88 men and 122 women) without MetS, aged between 40 and 65 years, were recruited and received a comprehensive health examination. Baseline serum FAM3B levels were determined by sandwich enzyme‐linked immunosorbent assay. Subsequently, all participants underwent a follow‐up examination after 5 years. MetS was identified in accordance with the International Diabetes Federation criteria.

Results

During follow up, 35.7% participants developed MetS. In comparison with the non‐MetS group, participants with MetS had an increased serum FAM3B at baseline (21.85 ng/mL [19.38, 24.17 ng/mL] vs 28.56 ng/mL [25.32, 38.10 ng/mL], P < 0.001). Moreover, serum FAM3B was significantly associated with variations in fasting plasma insulin (r = ?0.306, P < 0.001), homeostasis model assessment of β‐cell function (r = ?0.328, P < 0.001) and homeostasis model assessment of insulin resistance (r = ?0.191, P = 0.006). Furthermore, a positive correlation between baseline FAM3B and the incidence of MetS was observed, even after multivariable adjustment (relative risk 1.23 [1.15, 1.31], P < 0.001). Furthermore, the optimal cut‐off values of FAM3B was 23.98 ng/mL for predicting MetS based on the Youden Index.

Conclusions

Elevated circulating FAM3B might be considered as a predictor of newly‐onset MetS and its progression.

     

Insulin degludec improves health‐related quality of life (SF‐36®) compared with insulin glargine in people with Type 2 diabetes starting on basal insulin: a meta‐analysis of phase 3a trials

Aim

To compare the effect of insulin degludec and insulin glargine on health‐related quality of life in patients with Type 2 diabetes starting on insulin therapy.

Methods

Patient‐level data from three open‐label, randomized, treat‐to‐target trials of 26 or 52 weeks' duration were pooled using a weighted analysis in conjunction with a fixed‐effects model. Insulin‐naive patients received either insulin degludec (n = 1290) or insulin glargine (n = 632) once daily, in combination with oral anti‐diabetic drugs. Glycaemic control was assessed via HbA_1c and fasting plasma glucose concentrations. Rates of hypoglycaemia, defined as plasma glucose < 3.1 mmol/l (< 56 mg/dl), were recorded. Health‐related quality of life was evaluated using the 36‐item Short Form (SF‐36^®) version 2 questionnaire. Statistical analysis was performed using a generalized linear model with treatment, trial, anti‐diabetic therapy at baseline, gender, region and age as explanatory variables.

Results

Insulin degludec was confirmed as non‐inferior to insulin glargine based on HbA_1c concentrations. In each trial comprising the meta‐analysis, fasting plasma glucose and confirmed overall and nocturnal (00.01–05.59 h) hypoglycaemia were all numerically or significantly lower with insulin degludec vs. insulin glargine. At endpoint, the overall physical health component score was significantly higher (better) with insulin degludec vs. insulin glargine [+0.66 (95% CI 0.04–1.28)], largely attributable to a difference [+1.10 (95% CI 0.22–1.98)] in the bodily pain domain score. In the mental domains, vitality was significantly higher with insulin degludec vs. insulin glargine [+0.81 (95% CI 0.01–1.59)].

Conclusions

Compared with insulin glargine, insulin degludec leads to improvements in both mental and physical health status for patients with Type 2 diabetes initiating insulin therapy.

     

Efficacy of a web‐based intervention with and without guidance for employees with risky drinking: results of a three‐arm randomized controlled trial

Aims

To test the efficacy of a web‐based alcohol intervention with and without guidance.

Design

Three parallel groups with primary end‐point after 6 weeks.

Setting

Open recruitment in the German working population.

Participants

Adults (178 males/256 females, mean age 47 years) consuming at least 21/14 weekly standard units of alcohol (SUA) and scoring ≥ 8/6 on the Alcohol Use Disorders Identification Test.

Intervention

Five web‐based modules including personalized normative feedback, motivational interviewing, goal setting, problem‐solving and emotion regulation during 5 weeks. One intervention group received an unguided self‐help version (n=146) and the second received additional adherence‐focused guidance by eCoaches (n=144). Controls were on a waiting list with full access to usual care (n=144).

Measurements

Primary outcome was weekly consumed SUA after 6 weeks. SUA after 6 months was examined as secondary outcome, next to numbers of participants drinking within the low‐risk range, and general and work‐specific mental health measures.

Findings

All groups showed reductions of mean weekly SUA after 6 weeks (unguided: ?8.0; guided: ?8.5; control: ?3.2). There was no significant difference between the unguided and guided intervention (P=0.324). Participants in the combined intervention group reported significantly fewer SUA than controls [B=?4.85, 95% confidence interval (CI)=?7.02 to ?2.68, P < 0.001]. The intervention groups also showed significant reductions in SUA consumption after 6 months (B=?5.72, 95% CI=?7.71 to ?3.73, P < 0.001) and improvements regarding general and work‐related mental health outcomes after 6 weeks and 6 months.

Conclusions

A web‐based alcohol intervention, administered with or without personal guidance, significantly reduced mean weekly alcohol consumption and improved mental health and work‐related outcomes in the German working population.

     

Effects of home‐based exercise and branched‐chain amino acid supplementation on aerobic capacity and glycemic control in patients with cirrhosis

Aim

The aim of the current study is to examine whether home‐based step exercise at anaerobic threshold (AT) and branched‐chain amino acid (BCAA) supplementation improve aerobic capacity, ectopic fat in liver and muscle, and glycemic control in patients with liver cirrhosis.

Methods

Six female patients with compensated liver cirrhosis received oral BCAA and were instructed to undertake bench step exercises at an intensity that corresponded to AT, with a goal of performing 140 min of exercise per week at home for 12 months. Fat deposition in liver (liver to spleen ratio) and intramuscular adipose tissue content were assessed at baseline and after 6 and 12 months by computed tomography. Glycemic control indices (homeostasis model assessment of insulin resistance, hemoglobin A_1c [HbA_1c], glycated albumin [GA] and chronic liver disease [CLD]‐HbA_1c [average of HbA_1c and GA/3]) were also measured.

Results

Twelve months of moderate training significantly increased AT, which is an index of aerobic capacity, but no changes were observed in body weight, liver to spleen ratio, or intramuscular adipose tissue content. Glycated albumin significantly decreased (P < 0.05) and there tended to be a similar decrease in CLD‐HbA_1c (P < 0.1) after the exercise. The baseline serum triglyceride level correlated with changes in GA (P < 0.01) and CLD‐HbA_1c (P < 0.1).

Conclusion

The current results suggest that the combination of home‐based step exercise at AT and BCAA supplementation enhances aerobic capacity and potentially improves glycemic control in patients with cirrhosis without changes in body weight. The baseline serum serum triglyceride may partially explain the degree of improvement in glycemic control with exercise and BCAA intervention.

     

Community Program Improves Quality of Life and Self‐Management in Older Adults with Diabetes Mellitus and Comorbidity

Objectives

To compare the effect of a 6‐month community‐based intervention with that of usual care on quality of life, depressive symptoms, anxiety, self‐efficacy, self‐management, and healthcare costs in older adults with type 2 diabetes mellitus (T2DM ) and 2 or more comorbidities.

Design

Multisite, single‐blind, parallel, pragmatic, randomized controlled trial.

Setting

Four communities in Ontario, Canada.

Participants

Community‐dwelling older adults (≥65) with T2DM and 2 or more comorbidities randomized into intervention (n = 80) and control (n = 79) groups (N = 159).

Intervention

Client‐driven, customized self‐management program with up to 3 in‐home visits from a registered nurse or registered dietitian, a monthly group wellness program, monthly provider team case conferences, and care coordination and system navigation.

Measurements

Quality‐of‐life measures included the Physical Component Summary (PCS , primary outcome) and Mental Component Summary (MCS , secondary outcome) scores of the Medical Outcomes Study 12‐item Short‐Form Health Survey (SF ‐12). Other secondary outcome measures were the Generalized Anxiety Disorder Scale, Center for Epidemiologic Studies Depression Scale (CES ‐D‐10), Summary of Diabetes Self‐Care Activities (SDSCA ), Self‐Efficacy for Managing Chronic Disease, and healthcare costs.

Results

Morbidity burden was high (average of eight comorbidities). Intention‐to‐treat analyses using analysis of covariance showed a group difference favoring the intervention for the MCS (mean difference = 2.68, 95% confidence interval (CI ) = 0.28–5.09, P  = .03), SDSCA (mean difference = 3.79, 95% CI  = 1.02–6.56, P  = .01), and CES ‐D‐10 (mean difference = ?1.45, 95% CI  = ?0.13 to ?2.76, P  = .03). No group differences were seen in PCS score, anxiety, self‐efficacy, or total healthcare costs.

Conclusion

Participation in a 6‐month community‐based intervention improved quality of life and self‐management and reduced depressive symptoms in older adults with T2DM and comorbidity without increasing total healthcare costs.

     

‘Real‐world’ compensatory behaviour with low nicotine concentration e‐liquid: subjective effects and nicotine,acrolein and formaldehyde exposure

Aims

To compare the effects of (i) high versus low nicotine concentration e‐liquid, (ii) fixed versus adjustable power and (iii) the interaction between the two on: (a) vaping behaviour, (b) subjective effects, (c) nicotine intake and (d) exposure to acrolein and formaldehyde in e‐cigarette users vaping in their everyday setting.

Design

Counterbalanced, repeated measures with four conditions: (i) low nicotine (6 mg/ml)/fixed power; (ii) low nicotine/adjustable power; (iii) high nicotine (18 mg/ml)/fixed power; and (iv) high nicotine/adjustable power.

Setting

London and the South East, England.

Participants

Twenty experienced e‐cigarette users (recruited between September 2016 and February 2017) vaped ad libitum using an eVic Supreme? with a ‘Nautilus Aspire’ tank over 4 weeks (1 week per condition).

Measurements

Puffing patterns [daily puff number (PN), puff duration (PD), interpuff interval (IPI)], ml of e‐liquid consumed, changes to power (where permitted) and subjective effects (urge to vape, nicotine withdrawal symptoms) were measured in each condition. Nicotine intake was measured via salivary cotinine. 3‐Hydroxypropylmercapturic acid (3‐HPMA), a metabolite of the toxicant acrolein, and formate, a metabolite of the carcinogen formaldehyde, were measured in urine.

Findings

There was a significant nicotine concentration × power interaction for PD (P < 0.01). PD was longer with low nicotine/fixed power compared with (i) high nicotine/fixed power (P < 0.001) and (ii) low nicotine/adjustable power (P < 0.01). PN and liquid consumed were higher in the low versus high nicotine condition (main effect of nicotine, P < 0.05). Urge to vape and withdrawal symptoms were lower, and nicotine intake was higher, in the high nicotine condition (main effects of nicotine: P < 0.01). While acrolein levels did not differ, there was a significant nicotine × power interaction for formaldehyde (P < 0.05).

Conclusions

Use of a lower nicotine concentration e‐liquid may be associated with compensatory behaviour (e.g. higher number and duration of puffs) and increases in negative affect, urge to vape and formaldehyde exposure.

     

The effect of basal–bolus therapy varies with baseline 1,5‐anhydroglucitol level in people with Type 2 diabetes: a post hoc analysis

Aims

To investigate the impact of baseline 1,5‐anhydroglucitol on the treatment effect of basal–bolus therapy in people with Type 2 diabetes.

Methods

Post hoc analysis of onset 3, an 18‐week, randomized, phase 3 trial evaluating the efficacy and safety of fast‐acting insulin aspart in basal–bolus therapy (n = 116) vs. basal insulin‐only therapy (n = 120) in people with Type 2 diabetes. The estimated treatment difference in change from baseline in HbA_1c was investigated for different cut‐off values of baseline 1,5‐anhydroglucitol (2, 3, 4, 5 and 6 μg/ml).

Results

The estimated treatment difference in change from baseline in HbA_1c between basal–bolus therapy and basal insulin‐only therapy was statistically significantly greater in participants with baseline 1,5‐anhydroglucitol ≤3 μg/ml (n = 34) vs. >3 μg/ml (n = 198) [estimated treatment difference (95% CI): ?1.53% (?2.12; ?0.94) vs. ?0.82% (?1.07; ?0.57); P‐value for interaction = 0.03]. The estimated treatment difference became more pronounced when comparing participants with 1,5‐anhydroglucitol ≤2 μg/ml (n = 15) vs. >2 μg/ml (n = 217) [estimated treatment difference (95% CI): ?2.26% (?3.15; ?1.36) vs. ?0.85% (?1.08; ?0.62); P‐value for interaction = 0.003]. For cut‐off values ≥4 μg/ml, estimated treatment differences were numerically greater below the cut‐off compared with above, although the interaction terms were not statistically significant.

Conclusion

This analysis indicates that people with Type 2 diabetes with low 1,5‐anhydroglucitol have an added treatment benefit with basal–bolus therapy compared with people with higher 1,5‐anhydroglucitol. Further research is needed to clarify any clinical utility of these findings. Clinical Trials Registry No: NCT01850615

     

Men Lacking a Caregiver Have Greater Risk of Long‐Term Nursing Home Placement After Stroke

Background/Objectives

Social support can prevent or delay long‐term nursing home placement (NHP ). The purpose of our study was to understand how the availability of a caregiver can affect NHP after ischemic stroke and how this affects different subgroups differently.

Design

Nested cohort study.

Setting

Nationally based RE asons for Geographic and Racial Differences in Stroke (REGARDS ) study.

Participants

Stroke survivors aged 65 to 100 (256 men, 304 women).

Measurements

Data were from Medicare claims from January 2003 to December 2013 and REGARDS baseline interviews conducted from January 2003 to October 2007. Caregiver support was measured by asking, “If you had a serious illness or became disabled, do you have someone who would be able to provide care for you on an on‐going basis?” Diagnosis of ischemic stroke was derived from inpatient claims. NHP was determined using a validated claims algorithm for stays of 100 days and longer. Risk was estimated using Cox regression.

Results

Within 5 years of stroke, 119 (21.3%) participants had been placed in a nursing home. Risk of NHP was greater in those lacking available caregivers (log‐rank P  = .006). After adjustment for covariates, lacking an available caregiver increased the risk of NHP after stroke within 1 year by 70% (hazard ratio (HR ) = 1.70, 95% confidence interval (CI ) = 0.97–2.99) and within 5 years by 68% (HR  = 1.68, 95% CI  = 1.10–2.58). The effect of caregiver availability on NHP within 5 years was limited to men (HR  = 3.15, 95% CI  = 1.49–6.67).

Conclusion

In men aged 65 and older who have survived an ischemic stroke, the lack of an available caregiver is associated with triple the risk of NHP within 5 years.

     

Comparison of insulin detemir and insulin glargine using a basal‐bolus regimen in a randomized,controlled clinical study in patients with type 2 diabetes

Background

This treat‐to‐target study compared the efficacy and safety of insulin detemir (IDet) and insulin glargine (IGla) in a basal‐bolus (insulin aspart) regimen in type 2 diabetes.

Methods

385 patients were randomized 2 : 1 (IDet : IGla). Non‐inferiority of IDet to IGla was determined by HbA_1c 95% CI upper limit <0.4.

Results

IDet and IGla showed similar efficacy in HbA_1c reduction at 26 weeks, as the non‐inferiority criterion was met at 26 weeks (LS mean [Det–Gla]: 0.207; 95% CI: 0.0149,0.3995). It appeared that IGla in some cases did better than IDet in terms of HbA_1c, but the difference (0.207%) was not clinically meaningful. Based on the CONSORT guideline, non‐inferiority analysis using the LOCF approach was inconclusive regarding possible inferiority of delta 0.4 (LS mean of [Det–Gla]: 0.307; 95% CI: 0.1023, 0.5109). HbA_1c decreased significantly from baseline in IDet (?1.1% [26 weeks], ?0.9% [LOCF], p < 0.001) and in IGla (?1.3% [26 weeks, LOCF], p < 0.001). Final HbA_1c were 7.1% (26 weeks) and 7.3% (LOCF) in IDet, and 6.9% (26 weeks) and 7.0% (LOCF) in IGla. Final FPG were 130 mg/dL (26 weeks) and 135 mg/dL (LOCF) in IDet, and 134 mg/dL (26 weeks) and 137 mg/dL (LOCF) in IGla. There was significantly less weight gain in IDet‐treated patients (1.2 ± 3.96 kg versus 2.7 ± 3.94 kg, p = 0.001). Hypoglycemia risk was comparable between groups. The majority of IDet‐treated patients (87.4%) remained on a once‐daily basal insulin regimen throughout the study.

Conclusions

IDet and IGla were both effective and safe treatments for glycemic control in a basal‐bolus regimen for type 2 diabetes. Clinically significant reductions in HbA_1c were achieved in both groups, but with significantly less weight gain in the IDet group at comparable basal insulin dosage. Copyright © 2009 John Wiley & Sons, Ltd.

     

Systematic review and meta‐analysis to determine the impact of iron depletion in dysmetabolic iron overload syndrome and non‐alcoholic fatty liver disease

Aims

Iron reduction has been proposed as treatment for dysmetabolic iron overload syndrome (DIOS) and non‐alcoholic fatty liver disease (NAFLD), but results of published trials are conflicting. We undertook a systematic review and meta‐analysis to determine the impact of phlebotomy in DIOS and NAFLD.

Methods

We searched multiple databases systematically for studies evaluating the impact of phlebotomy in DIOS and NAFLD. We calculated weighted summary estimates using the inverse variance method. Study quality was assessed using the Cochrane collaboration tool.

Results

We identified nine studies with 820 patients (427 had phlebotomy, 393 lifestyle changes alone). Iron depletion did not improve the Homeostasis Model Assessment (HOMA) index (mean difference [MD] ?0.6; confidence interval (CI), ?1.7, 0.5; P = 0.3), insulin level (MD ?0.8 mU/L; CI, ?5.3, 3.7; P = 0.73), or aspartate aminotransferase (AST) (MD ?0.7 IU/L; CI, ?3.2, 1.8; P = 0.6) in DIOS and/or NAFLD patients as compared to lifestyle changes alone (five studies, 626 patients). There was mild improvement in alanine aminotransferase (ALT) (MD ?6.6 IU/L; CI, ?11, ?2.1); P < 0.01), but the effect size was very small (Cohen's d, 0.15; r statistic, 0.07). Even in the subgroup of patients with NAFLD and hyperferritinemia, phlebotomy did not improve the HOMA index, insulin level, ALT, or AST. Additionally, no study showed significant improvement in liver inflammation or fibrosis with iron reduction.

Conclusions

Phlebotomy does not bring about significant improvement in indices of insulin resistance, liver enzymes, or liver histology in patients with DIOS and/or NAFLD compared to lifestyle changes alone. Current evidence does not support the use of phlebotomy in patients with DIOS or NAFLD.

     

Adherence to Mediterranean Diet Reduces Incident Frailty Risk: Systematic Review and Meta‐Analysis

Objectives

To conduct a systematic review of the literature on prospective cohort studies examining associations between adherence to a Mediterranean diet and incident frailty and to perform a meta‐analysis to synthesize the pooled risk estimates.

Design

Systematic review and meta‐analysis.

Setting

Embase, MEDLINE , CINAHL , PsycINFO , and Cochrane Library were systematically searched on September 14, 2017. We reviewed references of included studies and relevant review papers and performed forward citation tracking for additional studies. Corresponding authors were contacted for additional data necessary for a meta‐analysis.

Participants

Community‐dwelling older adults (mean age ≥60).

Measurements

Incident frailty risk according to adherence to a Mediterranean diet.

Results

Two reviewers independently screened the title, abstract, and full text to ascertain the eligibility of 125 studies that the systematic search of the literature identified, and four studies were included (5,789 older people with mean follow‐up of 3.9 years). Two reviewers extracted data from the studies independently. All four studies provided adjusted odds ratios (OR s) of incident frailty risk according to three Mediterranean diet score (MDS ) groups (0–3, 4–5, and 6–9). Greater adherence to a Mediterranean diet was associated with significantly lower incident frailty risk (pooled OR = 0.62, 95% CI = 0.47–0.82, P  = .001 for MDS 4–5; pooled OR  = 0.44, 95% CI  = 0.31–0.64, P  < .001 for MDS 6–9) than poorer adherence (MDS 0–3). Neither significant heterogeneity (I ² = 0–16%, P  = .30) nor evidence of publication bias was observed.

Conclusion

Greater adherence to a Mediterranean diet is associated with significantly lower risk of incident frailty in community‐dwelling older people. Future studies should confirm these findings and evaluate whether adherence to a Mediterranean diet can reduce the risk of frailty, including in non‐Mediterranean populations.