Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.

BACKGROUND: Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A1c (HbA1c) concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control. METHODS: This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA1c 7·2% [IQR 6·6-8·1], 4589 [46·3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). During a median follow-up of 5·4 years (IQR 5·1-5·9), the primary composite outcome occurred in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in 663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio [HR] 0·88, 95% CI 0·79-0·99; p=0·026). All-cause mortality did not differ between groups (536 [10·8%] in the dulaglutide group vs 592 [12·0%] in the placebo group; HR 0·90, 95% CI 0·80-1·01; p=0·067). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p<0·0001). INTERPRETATION: Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors. FUNDING: Eli Lilly and Company.

Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial.

BACKGROUND: Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease. METHODS: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m2 (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1-5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77-0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68-0·87; p<0·0001), with HRs of 0·89 (0·78-1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39-1·44; p=0·39) for chronic renal replacement therapy. INTERPRETATION: Long-term use of dulaglutide was associated with reduced composite renal outcomes in people with type 2 diabetes. FUNDING: Eli Lilly and Company.

Design and baseline characteristics of participants in the Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial on the cardiovascular effects of dulaglutide.

The aim was to determine the effects of dulaglutide, a synthetic once-weekly, injectable human glucagon-like peptide 1 analogue that lowers blood glucose, body weight, appetite and blood pressure, on cardiovascular outcomes. People with type 2 diabetes, aged ≥50 years, with glycated haemoglobin (HbA1c) ≤9.5%, and either a previous cardiovascular event, evidence of cardiovascular disease or ≥2 cardiovascular risk factors were randomly allocated to a weekly subcutaneous injection of either dulaglutide (1.5 mg) or placebo and followed within the ongoing Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial every 3 to 6 months. The primary cardiovascular outcome is the first occurrence of the composite of cardiovascular death or non-fatal myocardial infarction or non-fatal stroke. Secondary outcomes include each component of the primary composite cardiovascular outcome, a composite clinical microvascular outcome comprising retinal or renal disease, hospitalization for unstable angina, heart failure requiring hospitalization or an urgent heart failure visit, and all-cause mortality. Follow-up will continue until the accrual of 1200 confirmed primary outcomes. Recruitment of 9901 participants (mean age 66 years, 46% women) occurred in 370 sites located in 24 countries over a period of 2 years. The mean duration of diabetes was 10 years, mean baseline HbA1c was 7.3%, and 31% had prior cardiovascular disease. The REWIND trial's international scope, high proportion of women, high proportion of people without prior cardiovascular disease and inclusion of participants whose mean baseline HbA1c was 7.3% suggests that its cardiovascular and safety findings will be directly relevant to the typical middle-aged patient seen in general practice throughout the world.

Effect of smoking status on the efficacy of the SMART regimen in high risk asthma.

BACKGROUND AND OBJECTIVE: The optimal management of people with asthma with a significant smoking history is uncertain. The aim of this study was to determine whether the efficacy/safety profile of single combination inhaled corticosteroid (ICS)/long acting beta-agonist (LABA) inhaler maintenance and reliever therapy is influenced by smoking status. METHODS: We undertook secondary analyses from an open-label 24-week randomized study of 303 high risk adult asthma patients randomized to budesonide/formoterol 200/6-µg-metred dose inhaler for maintenance (two actuations twice daily) and either budesonide/formoterol 200/6-µg-metred dose inhaler one actuation ('single ICS/LABA maintenance and reliever therapy (SMART)' regimen) or salbutamol 100 µg 1-2 actuations for symptom relief ('Standard' regimen). Smoking status was classified in to three groups, as 'current', 'ex' or 'never', and a smoking/treatment interaction term tested for each outcome variable. The primary outcome variable was number of participants with at least one severe exacerbation. RESULTS: There were 59 current, 97 ex and 147 never smokers included in the analyses. The smoking status/treatment interaction term was not statistically significant for any of the outcome measures. With adjustment for smoking status, the number of participants with severe exacerbations was lower with the SMART regimen (OR 0.45, 95% CI: 0.26-0.77, P = 0.004; P value for interaction between smoking status and treatment 0.29). CONCLUSION: We conclude that the favourable safety/efficacy profile of the SMART regimen applies to patients with high risk asthma, irrespective of smoking status.

Cohort study of a simple 'Step-Up' regimen with the Asthma Control Test.

This prospective cohort study investigates whether simple guideline-based asthma management using a 'Step-Up' regimen with the Asthma Control Test score improves asthma control in patients with inadequately controlled asthma in primary care. Seventy out of ninety-three (75%) participants achieved a score of > 19 (good control), and the mean increase in Asthma Control Test score was 6.0 (95% confidence interval: 5.3-6.8), P < 0.001. The improvement was independent of baseline inhaled corticosteroid use.

The etiology of notalgia paresthetica: a descriptive study of 117 patients.

BACKGROUND: Notalgia paresthetica (NP) is a neuropathic itching condition unilaterally localized in the midscapular area. It is a common but an underdiagnosed disease, and only a few studies investigating NP etiology with a limited number of patients have been reported in the literature. OBJECTIVE: We aimed to evaluate the demographic, clinical, histopathological, neurological, and radiological findings of NP patients and investigate correlations between them and symptoms of NP to elucidate the etiology of NP. METHODS: One hundred and seventeen consecutive patients diagnosed with NP were included and assessed in a multidisciplinary and prospective manner. We recorded demographic and clinical data and obtained a skin biopsy from the pruritic or hyperpigmented region. Pruritus severity was assessed by visual analogue scale (VAS). All patients were evaluated neurologically with magnetic resonance imaging. RESULTS: The mean age of the patients was 47.08 ± 12.28 years. The disease was more common in females (87.2%). Statistical analysis revealed that VAS scores were independent of the age, gender, and skin type of the patient. We found no significant difference in VAS scores between NP patients with or without comorbidities. Vertebral pathologies detected by MRI and amyloid deposition revealed in histopathology were not among the main factors affecting VAS scores. STUDY LIMITATION: Since consecutive patients enrolled into the study, we could not include equal number of male and female patients. CONCLUSION: We found no correlation between symptom severity and findings from neurological and histopathological evaluations. Further microneurological studies should be carried out to elucidate the etiology of NP.

Treatment of Notalgia Paresthetica with Bee Venom and Capsaicin: A Pilot Study with 20 Patients.

Notalgia paresthetica (NP) is a common clinical disorder characterized by hyperpigmentation, pruritus, paresthesia, and/or pain, located on the back. There is no effective treatment for patients with NP. We investigated the efficacy of a product containing bee venom (0.04%) and capsaicin (0.025%) for treating NP. Twenty patients (10 men and 10 women) with NP were included in this open-label pilot study. A biopsy was performed for each patient to exclude other dermatologic diseases. The patients were asked to apply the product to the pruritic areas once daily for 2 weeks. No other product was used during the study. The Visual Analogue Scale (VAS) score was used to evaluate the efficacy of the product. VAS scores before and after treatment were statistically different ( p = 0.005). The pretreatment median of VAS score was 8 (7-10) (8.20 ± 1.03), while the median after treatment was 3 (1-7) (3.40 ± 1.71). The product containing bee venom and capsaicin is effective in treating NP. A double-blind and placebo-controlled study has been planned and initiated with a greater sample size.

Efficacy and safety of maintenance and reliever combination budesonide-formoterol inhaler in patients with asthma at risk of severe exacerbations: a randomised controlled trial.

BACKGROUND: The Single combination budesonide-formoterol inhaler Maintenance And Reliever Therapy (SMART) regimen reduces severe asthma exacerbations in patients, but whether the high doses of corticosteroid and ß agonist increase the risk of adverse effects with both short-term and cumulative exposure is not certain. Our aim was to investigate whether the SMART regimen would reduce the risk of overuse of ß agonist, reduce the likelihood of patients to seek medical review when such episodes occurred, and if any reduction in severe asthma exacerbations would be at the cost of a higher burden of systemic corticosteroid. METHODS: In this 24-week trial undertaken at four primary health-care practices and one hospital in New Zealand, patients (aged 16-65 years) with a recent asthma exacerbation were randomly assigned in a 1:1 ratio to the SMART or standard fixed-dose regimen. Treatment in the SMART group consisted of two actuations of budesonide-formoterol (200 µg and 6 µg, respectively, per actuation) twice daily, delivered through a combination metered dose inhaler (MDI), with one extra actuation as needed for relief of symptoms; treatment in the standard group consisted of two actuations of budesonide-formoterol (200 µg and 6 µg, respectively, per actuation) twice daily through a combination MDI with one to two actuations of salbutamol (100 µg per actuation) by MDI as needed for relief of symptoms. MDIs were monitored electronically to measure actual use of medication. The allocation sequence for randomisation was computer generated, with a block size of eight per site. Participants, investigators, and the statistician were not masked to group assignment. The primary outcome was the proportion of participants with at least one high-use episode of ß agonist (more than eight actuations per day of budesonide-formoterol in addition to the four maintenance doses in the SMART group or more than 16 actuations per day of salbutamol in the standard group). Analysis was by intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12610000515099. FINDINGS: 303 patients were randomly assigned to the SMART (n=151) or standard group (n=152). No significant difference was noted between the SMART and standard groups in the proportion of participants with at least one high-use episode of ß agonist (84 [56%] vs 68 [45%], respectively, relative risk 1·24 [95% CI 0·99-1·56]; p=0·058). There were fewer days of high use in the SMART group (mean 5·1 days [SD 14·3] vs 8·9 days [20·9], relative rate 0·58 [0·39-0·88]; p=0·01). Of the patients who had at least one high-use episode, those in the SMART group had fewer days of high use without medical review (8·5 days [17·8] vs 18·3 days [24·8], 0·49 [0·31-0·75]; p=0·001). The SMART regimen resulted in higher inhaled corticosteroid exposure (943·5 µg budesonide per day [1502·5] vs 684·3 µg budesonide per day [390·5], respectively; ratio of means 1·22 [1·06-1·41]; p=0·006), but reduced oral corticosteroid exposure (77·5 mg prednisone [240·5] vs 126·6 mg prednisone [382·1], respectively; p=0·011), with no significant difference in composite systemic corticosteroid exposure (793·7 mg prednisone equivalent per year [893·1] vs 772·1 mg prednisone equivalent per year [1062·7], respectively; 1·03 [0·86-1·22]; p=0·76). Participants in the SMART group had fewer severe asthma exacerbations (35 [weighted mean rate per year 0·53] vs 66 [0·97]; relative rate 0·54 [0·36-0·82]; p=0·004). INTERPRETATION: The SMART regimen has a favourable risk-to-benefit profile and can be recommended for use in adults at risk of severe asthma exacerbations. FUNDING: Health Research Council of New Zealand.

Using the asthma control test to improve asthma outcomes.

There is a major gap between what can be achieved with modern asthma management and what is currently being achieved. One of the main reasons for this is a lack of recognition of asthma control and the requirement for more effective treatment-it is only through identifying those patients with uncontrolled asthma that appropriate treatment will be prescribed. In part, the difficulty in the assessment of control relates to the lack of a clear therapeutic target in asthma. This contrasts with other chronic diseases such as hypertension or diabetes where treatment is prescribed in order to achieve a definite therapeutic target. One approach to this difficulty is to develop a simple test which is a screening tool to identify patients with poorly controlled asthma. The Asthma Control Test (ACT) has been developed and validated for this purpose. It involves patients completing a simple written questionnaire of 5 questions, from which a score (out of 25) is obtained. It has been shown that the ACT is a simple, quick and accurate tool for assessing asthma control and it has been shown to be responsive to changes in asthma control over time. It can easily be incorporated into the routine assessment of patients with asthma and enable busy healthcare professionals to more easily identify patients whose asthma control can be improved, enabling changes to their management to be made and thereby improve outcomes.

High blood pressure advice given by natural health food stores.

AIM: Complimentary and alternative medicines are widely used but are not registered medicines. The aim of the study was to compare advice given by health food stores and pharmacists for hypertension. METHODS: Twenty-six health food stores and 26 pharmacies were visited by an individual for advise on a hypothetical problem of hypertension. RESULTS: Staff in 25 out of 26 health food stores did not refer the researcher to a medical practitioner; instead they recommended and sold a wide variety of compounds of unproven efficacy. CONCLUSIONS: We recommend the implementation of a formal training programme for health food stores staff and that complimentary and alternative medicines-use in New Zealand is regulated.

Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial

Background Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease. Methods REWIND was a multicenter, randomized, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952. Findings Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m² (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1­5·9) comprising 51 820 person years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77­0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68­0·87; p<0·0001), with HRs of 0·89 (0·78­1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39­1·44; p=0·39) for chronic renal replacement therapy. (AU)

An audiovisual reminder function improves adherence with inhaled corticosteroid therapy in asthma.

BACKGROUND: Adherence to medication regimens is poor in the management of chronic diseases, including asthma. OBJECTIVE: To determine whether an audiovisual reminder device improves adherence with inhaled corticosteroid (ICS) therapy in adult asthma. METHODS: A randomized open-label parallel group study of 110 adult or adolescent subjects with asthma was undertaken. Subjects were randomized to receive 24 weeks of fluticasone propionate 250 microg, 1 actuation twice daily via a metered dose inhaler (MDI) with or without an audiovisual reminder function (AVRF). All MDIs had electronic covert adherence monitors. The primary outcome variable was adherence, defined as the proportion of medication taken as prescribed over the final 12 weeks of the study. Adherence was also assessed as the proportion of subjects who took >50%, >80%, or >90% of prescribed medication. RESULTS: The proportion of medication taken in the last 12 weeks was greater in the AVRF group (93%) compared with the control group (74%), with a difference of 18% (95% confidence interval [CI] 10-26%; P < .0001). The proportion of subjects taking >50%, >80%, or >90% of their medication was greater in the AVRF group, with a ratio of proportions adherent of 1.33 (95% CI, 1.10-1.61; P = .003), 2.27 (95% CI, 1.56-3.3; P < .0001), and 3.25 (95% CI, 1.74-6.1%; P < .0001), respectively. CONCLUSION: An audiovisual reminder function can significantly improve adherence with ICS therapy in adult asthma. CLINICAL IMPLICATIONS: An audiovisual reminder function has potential to improve adherence with medication regimens across a wide spectrum of diseases, in both research and clinical practice.