Mobile health (m-health) smartphone interventions for adolescents and adults with overweight or obesity.

BACKGROUND: Obesity is considered to be a risk factor for various diseases, and its incidence has tripled worldwide since 1975. In addition to potentially being at risk for adverse health outcomes, people with overweight or obesity are often stigmatised. Behaviour change interventions are increasingly delivered as mobile health (m-health) interventions, using smartphone apps and wearables. They are believed to support healthy behaviours at the individual level in a low-threshold manner. OBJECTIVES: To assess the effects of integrated smartphone applications for adolescents and adults with overweight or obesity. SEARCH METHODS: We searched CENTRAL, MEDLINE, PsycINFO, CINAHL, and LILACS, as well as the trials registers ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform on 2 October 2023 (date of last search for all databases). We placed no restrictions on the language of publication. SELECTION CRITERIA: Participants were adolescents and adults with overweight or obesity. Eligible interventions were integrated smartphone apps using at least two behaviour change techniques. The intervention could target physical activity, cardiorespiratory fitness, weight loss, healthy diet, or self-efficacy. Comparators included no or minimal intervention (NMI), a different smartphone app, personal coaching, or usual care. Eligible studies were randomised controlled trials of any duration with a follow-up of at least three months. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology and the RoB 2 tool. Important outcomes were physical activity, body mass index (BMI) and weight, health-related quality of life, self-efficacy, well-being, change in dietary behaviour, and adverse events. We focused on presenting studies with medium- (6 to < 12 months) and long-term (≥ 12 months) outcomes in our summary of findings table, following recommendations in the core outcome set for behavioural weight management interventions. MAIN RESULTS: We included 18 studies with 2703 participants. Interventions lasted from 2 to 24 months. The mean BMI in adults ranged from 27 to 50, and the median BMI z-score in adolescents ranged from 2.2 to 2.5. Smartphone app versus no or minimal intervention Thirteen studies compared a smartphone app versus NMI in adults; no studies were available for adolescents. The comparator comprised minimal health advice, handouts, food diaries, smartphone apps unrelated to weight loss, and waiting list. Measures of physical activity: at 12 months' follow-up, a smartphone app compared to NMI probably reduces moderate to vigorous physical activity (MVPA) slightly (mean difference (MD) -28.9 min/week (95% confidence interval (CI) -85.9 to 28; 1 study, 650 participants; moderate-certainty evidence)). We are very uncertain about the results of estimated energy expenditure and cardiorespiratory fitness at eight months' follow-up. A smartphone app compared with NMI probably results in little to no difference in changes in total activity time at 12 months' follow-up and leisure time physical activity at 24 months' follow-up. Anthropometric measures: a smartphone app compared with NMI may reduce BMI (MD of BMI change -2.6 kg/m2, 95% CI -6 to 0.8; 2 studies, 146 participants; very low-certainty evidence) at six to eight months' follow-up, but the evidence is very uncertain. At 12 months' follow-up, a smartphone app probably resulted in little to no difference in BMI change (MD -0.1 kg/m2, 95% CI -0.4 to 0.3; 1 study; 650 participants; moderate-certainty evidence). A smartphone app compared with NMI may result in little to no difference in body weight change (MD -2.5 kg, 95% CI -6.8 to 1.7; 3 studies, 1044 participants; low-certainty evidence) at 12 months' follow-up. At 24 months' follow-up, a smartphone app probably resulted in little to no difference in body weight change (MD 0.7 kg, 95% CI -1.2 to 2.6; 1 study, 245 participants; moderate-certainty evidence). A smartphone app compared with NMI may result in little to no difference in self-efficacy for a physical activity score at eight months' follow-up, but the results are very uncertain. A smartphone app probably results in little to no difference in quality of life and well-being at 12 months (moderate-certainty evidence) and in little to no difference in various measures used to inform dietary behaviour at 12 and 24 months' follow-up. We are very uncertain about adverse events, which were only reported narratively in two studies (very low-certainty evidence). Smartphone app versus another smartphone app Two studies compared different versions of the same app in adults, showing no or minimal differences in outcomes. One study in adults compared two different apps (calorie counting versus ketogenic diet) and suggested a slight reduction in body weight at six months in favour of the ketogenic diet app. No studies were available for adolescents. Smartphone app versus personal coaching Only one study compared a smartphone app with personal coaching in adults, presenting data at three months. Two studies compared these interventions in adolescents. A smartphone app resulted in little to no difference in BMI z-score compared to personal coaching at six months' follow-up (MD 0, 95% CI -0.2 to 0.2; 1 study; 107 participants). Smartphone app versus usual care Only one study compared an app with usual care in adults but only reported data at three months on participant satisfaction. No studies were available for adolescents. We identified 34 ongoing studies. AUTHORS' CONCLUSIONS: The available evidence is limited and does not demonstrate a clear benefit of smartphone applications as interventions for adolescents or adults with overweight or obesity. While the number of studies is growing, the evidence remains incomplete due to the high variability of the apps' features, content and components, which complicates direct comparisons and assessment of their effectiveness. Comparisons with either no or minimal intervention or personal coaching show minor effects, which are mostly not clinically significant. Minimal data for adolescents also warrants further research. Evidence is also scarce for low- and middle-income countries as well as for people with different socio-economic and cultural backgrounds. The 34 ongoing studies suggest sustained interest in the topic, with new evidence expected to emerge within the next two years. In practice, clinicians and healthcare practitioners should carefully consider the potential benefits, limitations, and evolving research when recommending smartphone apps to adolescents and adults with overweight or obesity.

Thermal stability and storage of human insulin.

BACKGROUND: Health authorities stress the temperature sensitivity of human insulin, advising protection from heat and freezing, with manufacturers suggesting low-temperature storage for intact vials, and once opened, storage at room temperature for four to six weeks, though usage time and maximum temperature recommendations vary. For human insulin, the recommendations of current shelf life in use may range from 10 to 45 days, and the maximum temperature in use varies between 25 °C and 37 °C. Optimal cold-chain management of human insulin from manufacturing until the point of delivery to people with diabetes should always be maintained, and people with diabetes and access to reliable refrigeration should follow manufacturers' recommendations. However, a growing segment of the diabetes-affected global population resides in challenging environments, confronting prolonged exposure to extreme heat due to the climate crisis, all while grappling with limited access to refrigeration. OBJECTIVES: To analyse the effects of storing human insulin above or below the manufacturers' recommended insulin temperature storage range or advised usage time, or both, after dispensing human insulin to people with diabetes. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 12 July 2023. SELECTION CRITERIA: We included clinical and laboratory studies investigating the storage of human insulin above or below manufacturers' recommended temperature storage range, advised usage time, or both. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We used GRADE to assess the certainty of evidence for the clinical study. Most information emerged from in vitro studies, mainly from pharmaceutical companies. There is no validated risk of bias and certainty of evidence rating for in vitro studies. We thus presented a narrative summary of the results. MAIN RESULTS: We included 17 eligible studies (22 articles) and additional information from pharmaceutical companies. Pilot clinical study One pilot clinical study investigated temperature conditions for insulin stored for six weeks in an unglazed clay pot with temperatures ranging between 25 °C and 27 °C. The mean fall in plasma glucose in eight healthy volunteers after clay pot-stored insulin injection was comparable to refrigerator-stored insulin injection (very low-certainty evidence). In-vitro studies Nine, three and four laboratory studies investigated storage conditions for insulin vials, insulin cartridges/pens and prefilled plastic syringes, respectively. The included studies reported numerous methods, laboratory measurements and storage conditions. Three studies on prefilled syringes investigating insulin potency at 4 °C up to 23 °C for up to 28 days showed no clinically relevant loss of insulin activity. Nine studies examined unopened vials and cartridges. In studies with no clinically relevant loss of insulin activity for human short-acting insulin (SAI), intermediate-acting insulin (IAI) and mixed insulin (MI) temperatures ranged between 28.9 °C and 37 °C for up to four months. Two studies reported up to 18% loss of insulin activity after one week to 28 days at 37 °C. Four studies examined opened vials and cartridges at up to 37 °C for up to 12 weeks, indicating no clinically relevant reduction in insulin activity. Two studies analysed storage conditions for oscillating temperatures ranging between 25 °C and 37 °C for up to 12 weeks and observed no loss of insulin activity for SAI, IAI and MI. Four studies, two on vials (including one on opened vials), and two on prefilled syringes, investigated sterility and reported no microbial contamination. Data from pharmaceutical companies Four manufacturers (BIOTON, Eli Lilly and Company, Novo Nordisk and Sanofi) provided previously unreleased human insulin thermostability data mostly referring to unopened containers (vials, cartridges). We could not include the data from Sanofi because the company announced the permanent discontinuation of the production of human insulins Insuman Rapid, Basal and Comb 25. BIOTON provided data on SAI after one, three and six months at 25 °C: all investigated parameters were within reference values, and, compared to baseline, loss of insulin activity was 1.1%, 1.0% and 1.7%, respectively. Eli Lilly and Company provided summary data: at below 25 °C or 30 °C SAI/IAI/MI could be stored for up to 25 days or 12 days, respectively. Thereafter, patient in-use was possible for up to 28 days. Novo Nordisk provided extensive data: compared to baseline, after three and six months at 25 °C, loss of SAI activity was 1.8% and 3.2% to 3.5%, respectively. Loss of IAI activity was 1.2% to 1.9% after three months and 2.0% to 2.3% after six months. Compared to baseline, after one, two and three months at 37 °C, loss of SAI activity was 2.2% to 2.8%, 5.7% and 8.3% to 8.6%, respectively. Loss IAI activity was 1.4% to 1.8%, 3.0% to 3.8% and 4.7% to 5.3%, respectively. There was no relevant increase in insulin degradation products observed. Up to six months at 25 °C and up to two months at 37 °C high molecular weight proteins were within specifications. Appearance, visible particles or macroscopy, particulate matter, zinc, pH, metacresol and phenol complied with specifications. There were no data for cold environmental conditions and insulin pumps. AUTHORS' CONCLUSIONS: Under difficult living conditions, pharmaceutical companies' data indicate that it is possible to store unopened SAI and IAI vials and cartridges at up to 25 °C for a maximum of six months and at up to 37 °C for a maximum of two months without a clinically relevant loss of insulin potency. Also, oscillating temperatures between 25 °C and 37 °C for up to three months result in no loss of insulin activity for SAI, IAI and MI. In addition, ambient temperature can be lowered by use of simple cooling devices such as clay pots for insulin storage. Clinical studies on opened and unopened insulin containers should be performed to measure insulin potency and stability after varying storage conditions. Furthermore, more data are needed on MI, insulin pumps, sterility and cold climate conditions.

Incidence of Stroke in People With Diabetes Compared to Those Without Diabetes: A Systematic Review.

BACKGROUND: One of the goals of the St. Vincent Declaration was to reduce serious complications of diabetes, including strokes. However, it remains uncertain whether this goal has been achieved. STUDY AIM: To evaluate the incidence of stroke in the diabetic population and its differences regarding sex, ethnicity, age, and region, to compare the incidence rate in people with and without diabetes, and to investigate time trends. MATERIALS AND METHODS: A systematic review was conducted according to the guidelines for meta-analysis of observational studies in epidemiology (the MOOSE group) and the PRISMA group guidelines. RESULTS: Nineteen of the 6.470 studies retrieved were included in the analysis. The incidence of stroke in the population with diabetes ranged from 238 per 100,000 person-years in Germany in 2014 to 1191 during the 1990s in the United Kingdom. The relative risk comparing people with diabetes to those without diabetes varied between 1.0 and 2.84 for total stroke, 1.0 and 3.7 for ischemic stroke, and 0.68 and 1.6 for hemorrhagic stroke. Differences between fatal and non-fatal stroke were significant, depending on the time period and the population. We found decreasing time trends in people with diabetes and stable incidence rates of stroke over time in people without diabetes. CONCLUSION: The considerable differences between results can partly be explained by differences in study designs, statistical methods, definitions of stroke, and methods used to identify patients with diabetes. The lack of evidence arising from these differences ought to be rectified by new studies.

A systematic comparison of different composite measures (DAS 28, CDAI, SDAI, and Boolean approach) for determining treatment effects on low disease activity and remission in rheumatoid arthritis.

BACKGROUND: Some composite measures for determining the treatment effects of disease-modifying antirheumatic drugs on remission and low disease activity (LDA) in rheumatoid arthritis (RA) may produce misleading results if they include an acute phase reactant (APR). To inform the choice of appropriate measure, we performed a systematic comparison of treatment effects using different composite measures. METHODS: We used data generated for a systematic review of biologics in RA conducted by the Institute for Quality and Efficiency in Health Care and data from systematic reviews of newer biologics and Janus kinase (JAK) inhibitors provided by sponsors. The studies included had been conducted up to 2020 and investigated comparisons of biologics with placebo and head-to-head comparisons of biologics. Treatment effects on LDA and remission in studies investigating biologics or JAK inhibitors in RA were compared among 4 composite measures: the disease activity score 28 (DAS 28), the simplified disease activity index (SDAI), the Boolean approach (remission only), and the clinical disease activity index (CDAI)-only the latter does not include an APR. RESULTS: 49 placebo-controlled studies included 9 different biologics; 48 studies (16,233 patients) investigated LDA and 49 (16,338 patients) investigated remission. 11 active-controlled studies (5996 patients) investigated both LDA and remission and included 5 different head-to-head comparisons of biologics and 5 different comparisons (6 studies) of biologics with JAK inhibitors. Statistically significantly larger treatment effects were found for biologics or JAK inhibitors versus placebo or active control in 16% of pairwise comparisons of composite measures (27 of 168). Most of these larger effects were observed for composite measures with an APR, i.e. the DAS 28 (19 comparisons) followed by the SDAI (n = 7). Larger effects were most frequently detected in favour of interleukin (IL)-6 inhibitors and to a lesser extent for JAK inhibitors versus treatments with different modes of action. CONCLUSIONS: The use of the DAS 28 and SDAI in clinical studies may generate results favouring certain treatments based on their mode of action (e.g. IL-6 inhibitors versus other biologics). To enable unbiased comparative effectiveness research, a composite measure without an APR (i.e. the CDAI) should thus be the measure of choice.

Screw fixation in the treatment of displaced intra-articular calcaneus fractures: a systematic review protocol.

BACKGROUND: The Calcaneus is the largest bone of the foot and the most frequent tarsal bone to be fractured. Overall, it causes round about 10 cases per 100,000 residents per year mainly in men. Especially displaced intra-articular calcaneus fractures often have early and late complications and its associated disability. There are various strategies for the treatment of displaced intra-articular calcaneus fractures, but the gold standard is still subject of a long-standing controversy. Minimally invasive procedures became more common in an attempt to reduce the high rate of complications associated with open reduction and internal fixation. With the increase in minimally invasive techniques, screw fixation also gained in significance. The current literature does not sufficiently elucidate whether the screw fixation is superior to other treatment options especially in relation to adverse events, health-related quality of life and postoperative pain. This study aims to investigate benefits and harms of treating displaced intra-articular calcaneus fractures (types II, III and IV according to Sanders) with screw fixation in adults. METHODS: A systematic review will be conducted based on the principles described in the Cochrane Handbook. We will include adults with displaced intra-articular calcaneus fractures of Sanders type II, III and IV. The surgical method of screw fixation shall be compared to other surgical interventions to stabilise calcaneus fractures. Primary outcomes are serious adverse events, health-related quality of life and postoperative pain level. MEDLINE, CENTRAL, CINAHL, Web of Science and bibnet.org, ClinicalTrial.gov and the World Health Organization International Clinical Trials Registry Platform (ICTR) will be searched. Screening and data extraction will be performed by two authors independently. A third author will arbitrate disputes. Risk of Bias will be assessed with the Cochrane tool. Meta-analysis will be performed if participants, interventions, comparisons and outcomes are sufficiently similar to ensure a result that is clinically meaningful. DISCUSSION: Due to the increasing use of minimally invasive techniques and the increasing use of screw fixation instead of open reduction and plate fixation, it is important to analyse the benefits and harms of screw fixation for calcaneus fractures. Screw fixation could, in the future, help to operate in a less invasive and tissue preserving manner while still achieving an adequate functional result for the patient SYSTEMATIC REVIEW REGISTRATION: CRD42021244695.

Incidence of myocardial infarction in people with diabetes compared to those without diabetes: a systematic review protocol.

BACKGROUND: Diabetes mellitus is an established risk factor for acute myocardial infarction (AMI). Incidence of AMI in people with diabetes remains significantly higher than in those without diabetes. However, published data are conflicting, and previous reviews in this field have some limitations regarding the definitions of AMI and source population (general population or people with diabetes as a population at risk) and concerning the statistical presentation of results. AIMS: To analyse the incidence of AMI in people with diabetes compared to those without diabetes and to investigate time trends. METHODS: We will perform a systematic literature search in MEDLINE, Embase and LILACS designed by an experienced information scientist. Two review authors will independently screen the abstracts and full texts of all references on the basis of inclusion criteria regarding types of study, types of population and the main outcome. Data extraction and assessment of risk of bias will be undertaken by two review authors working independently. We will assess incidence rate or cumulative incidence and relative risk of AMI comparing populations with and without diabetes. DISCUSSION: This review will summarise the available data concerning the incidence of AMI in people with and without diabetes and will thus contribute to the assessment and interpretation of the wide variations of incidence, relative risks and time trends of AMI in these populations. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020145562.

(Ultra-)long-acting insulin analogues for people with type 1 diabetes mellitus.

BACKGROUND: People with type 1 diabetes mellitus (T1DM) need treatment with insulin for survival. Whether any particular type of (ultra-)long-acting insulin provides benefit especially regarding risk of diabetes complications and hypoglycaemia is unknown. OBJECTIVES: To compare the effects of long-term treatment with (ultra-)long-acting insulin analogues to NPH insulin (neutral protamine Hagedorn) or another (ultra-)long-acting insulin analogue in people with type 1 diabetes mellitus. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Scopus, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform and the reference lists of systematic reviews, articles and health technology assessment reports. We explored the US Food and Drug Administration (FDA) and European Medical Agency (EMA) web pages. We asked pharmaceutical companies, EMA and investigators for additional data and clinical study reports (CSRs). The date of the last search of all databases was 24 August 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with a duration of 24 weeks or more comparing one (ultra-)long-acting insulin to NPH insulin or another (ultra-)long-acting insulin in people with T1DM. DATA COLLECTION AND ANALYSIS: Two review authors assessed risk of bias using the new Cochrane 'Risk of bias' 2 (RoB 2) tool and extracted data. Our main outcomes were all-cause mortality, health-related quality of life (QoL), severe hypoglycaemia, non-fatal myocardial infarction/stroke (NFMI/NFS), severe nocturnal hypoglycaemia, serious adverse events (SAEs) and glycosylated haemoglobin A1c (HbA1c). We used a random-effects model to perform meta-analyses and calculated risk ratios (RRs) and odds ratios (ORs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) and 95% prediction intervals for effect estimates. We evaluated the certainty of the evidence applying the GRADE instrument. MAIN RESULTS: We included 26 RCTs. Two studies were unpublished. We obtained CSRs, clinical study synopses or both as well as medical reviews from regulatory agencies on 23 studies which contributed to better analysis of risk of bias and improved data extraction. A total of 8784 participants were randomised: 2428 participants were allocated to NPH insulin, 2889 participants to insulin detemir, 2095 participants to insulin glargine and 1372 participants to insulin degludec. Eight studies contributing 21% of all participants comprised children. The duration of the intervention varied from 24 weeks to 104 weeks. Insulin degludec versus NPH insulin: we identified no studies comparing insulin degludec with NPH insulin. Insulin detemir versus NPH insulin (9 RCTs): five deaths reported in two studies including adults occurred in the insulin detemir group (Peto OR 4.97, 95% CI 0.79 to 31.38; 9 studies, 3334 participants; moderate-certainty evidence). Three studies with 870 participants reported QoL showing no true beneficial or harmful effect for either intervention (low-certainty evidence). There was a reduction in severe hypoglycaemia in favour of insulin detemir: 171/2019 participants (8.5%) in the insulin detemir group compared with 138/1200 participants (11.5%) in the NPH insulin group experienced severe hypoglycaemia (RR 0.69, 95% CI 0.52 to 0.92; 8 studies, 3219 participants; moderate-certainty evidence). The 95% prediction interval ranged between 0.34 and 1.39. Only 1/331 participants in the insulin detemir group compared with 0/164 participants in the NPH insulin group experienced a NFMI (1 study, 495 participants; low-certainty evidence). No study reported NFS. A total of 165/2094 participants (7.9%) in the insulin detemir group compared with 102/1238 participants (8.2%) in the NPH insulin group experienced SAEs (RR 0.95, 95% CI 0.75 to 1.21; 9 studies, 3332 participants; moderate-certainty evidence). Severe nocturnal hypoglycaemia was observed in 70/1823 participants (3.8%) in the insulin detemir group compared with 60/1102 participants (5.4%) in the NPH insulin group (RR 0.67, 95% CI 0.39 to 1.17; 7 studies, 2925 participants; moderate-certainty evidence). The MD in HbA1c comparing insulin detemir with NPH insulin was 0.01%, 95% CI -0.1 to 0.1; 8 studies, 3122 participants; moderate-certainty evidence. Insulin glargine versus NPH insulin (9 RCTs): one adult died in the NPH insulin group (Peto OR 0.14, 95% CI 0.00 to 6.98; 8 studies, 2175 participants; moderate-certainty evidence). Four studies with 1013 participants reported QoL showing no true beneficial effect or harmful effect for either intervention (low-certainty evidence). Severe hypoglycaemia was observed in 122/1191 participants (10.2%) in the insulin glargine group compared with 145/1159 participants (12.5%) in the NPH insulin group (RR 0.84, 95% CI 0.67 to 1.04; 9 studies, 2350 participants; moderate-certainty evidence). No participant experienced a NFMI and one participant in the NPH insulin group experienced a NFS in the single study reporting this outcome (585 participants; low-certainty evidence). A total of 109/1131 participants (9.6%) in the insulin glargine group compared with 110/1098 participants (10.0%) in the NPH insulin group experienced SAEs (RR 1.08, 95% CI 0.63 to 1.84; 8 studies, 2229 participants; moderate-certainty evidence). Severe nocturnal hypoglycaemia was observed in 69/938 participants (7.4%) in the insulin glargine group compared with 83/955 participants (8.7%) in the NPH insulin group (RR 0.83, 95% CI 0.62 to 1.12; 6 studies, 1893 participants; moderate-certainty evidence). The MD in HbA1c comparing insulin glargine with NPH insulin was 0.02%, 95% CI -0.1 to 0.1; 9 studies, 2285 participants; moderate-certainty evidence. Insulin detemir versus insulin glargine (2 RCTs),insulin degludec versus insulin detemir (2 RCTs), insulin degludec versus insulin glargine (4 RCTs): there was no evidence of a clinically relevant difference for all main outcomes comparing (ultra-)long-acting insulin analogues with each other. For all outcomes none of the comparisons indicated differences in tests of interaction for children versus adults. AUTHORS' CONCLUSIONS: Comparing insulin detemir with NPH insulin for T1DM showed lower risk of severe hypoglycaemia in favour of insulin detemir (moderate-certainty evidence). However, the 95% prediction interval indicated inconsistency in this finding. Both insulin detemir and insulin glargine compared with NPH insulin did not show benefits or harms for severe nocturnal hypoglycaemia. For all other main outcomes with overall low risk of bias and comparing insulin analogues with each other, there was no true beneficial or harmful effect for any intervention. Data on patient-important outcomes such as QoL, macrovascular and microvascular diabetic complications were sparse or missing. No clinically relevant differences were found between children and adults.

Mapping the evidence regarding school-to-work/university transition and health inequalities among young adults: a scoping review protocol.

INTRODUCTION: School-to-work/university transition is a sensitive period that can have a substantial impact on health and health behaviour over the life course. There is some indication that health and health behaviour is socially patterned in the age span of individuals in this transition (16-24 years) and that there are differences by socioeconomic position (SEP). However, evidence regarding this phenomenon has not been systematically mapped. In addition, little is known about the role of institutional characteristics (eg, of universities, workplaces) in the development of health and possible inequalities in health during this transition. Hence, the first objective of this scoping review is to systematically map the existing evidence regarding health and health behaviours (and possible health inequalities, for example, differences by SEP) in the age group of 16-24 years and during school-to-work transition noted in Germany and abroad. The second objective is to summarise the evidence on the potential effects of contextual and compositional characteristics of specific institutions entered during this life stage on health and health behaviours. Third, indicators and measures of these characteristics will be summarised. METHODS AND ANALYSIS: We will systematically map the evidence on health inequalities during school-to-work-transitions among young adults (aged 16-24 years), following the methodological framework proposed by Arksey and O'Malley. The literature search is performed in Ovid MEDLINE, Web of Science, International Labour Organization and National Institute for Occupational Safety and Health, using a predetermined search strategy. Articles published between January 2000 and February 2020 in English or German are considered for the review. The selection process follows a two-step approach: (1) screening of titles and abstracts, and (2) screening of full texts, both steps by two independent reviewers. Any discrepancies in the selection process are resolved by a third researcher. Data extraction will be performed using a customised data extraction sheet. The results will be presented in tabular and narrative form. ETHICS AND DISSEMINATION: Ethical approval is not required for this scoping review. The results will be published in a peer-reviewed scientific journal and presented at international conferences and project workshops.

Pioglitazone for prevention or delay of type 2 diabetes mellitus and its associated complications in people at risk for the development of type 2 diabetes mellitus.

BACKGROUND: The term prediabetes is used to describe a population with an elevated risk of developing type 2 diabetes mellitus (T2DM). With projections of an increase in the incidence of T2DM, prevention or delay of the disease and its complications is paramount. It is currently unknown whether pioglitazone is beneficial in the treatment of people with increased risk of developing T2DM. OBJECTIVES: To assess the effects of pioglitazone for prevention or delay of T2DM and its associated complications in people at risk of developing T2DM. SEARCH METHODS: We searched CENTRAL, MEDLINE, Chinese databases, ICTRP Search Portal and ClinicalTrials.gov. We did not apply any language restrictions. Further, we investigated the reference lists of all included studies and reviews. We tried to contact all study authors. The date of the last search of databases was November 2019 (March 2020 for Chinese databases). SELECTION CRITERIA: We included randomised controlled trials (RCTs) with a minimum duration of 24 weeks, and participants diagnosed with intermediate hyperglycaemia with no concomitant diseases, comparing pioglitazone as monotherapy or part of dual therapy with other glucose-lowering drugs, behaviour-changing interventions, placebo or no intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently screened abstracts, read full-text articles and records, assessed risk of bias and extracted data. We performed meta-analyses with a random-effects model and calculated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, with 95% confidence intervals (CIs) for effect estimates. We evaluated the certainty of the evidence with the GRADE. MAIN RESULTS: We included 27 studies with a total of 4186 randomised participants. The size of individual studies ranged between 43 and 605 participants and the duration varied between 6 and 36 months. We judged none of the included studies as having low risk of bias across all 'Risk of bias' domains. Most studies identified people at increased risk of T2DM by impaired fasting glucose or impaired glucose tolerance (IGT), or both. Our main outcome measures were all-cause mortality, incidence of T2DM, serious adverse events (SAEs), cardiovascular mortality, nonfatal myocardial infarction or stroke (NMI/S), health-related quality of life (QoL) and socioeconomic effects. The following comparisons mostly reported only a fraction of our main outcome set. Three studies compared pioglitazone with metformin. They did not report all-cause and cardiovascular mortality, NMI/S, QoL or socioeconomic effects. Incidence of T2DM was 9/168 participants in the pioglitazone groups versus 9/163 participants in the metformin groups (RR 0.98, 95% CI 0.40 to 2.38; P = 0.96; 3 studies, 331 participants; low-certainty evidence). No SAEs were reported in two studies (201 participants; low-certainty evidence). One study compared pioglitazone with acarbose. Incidence of T2DM was 1/50 participants in the pioglitazone group versus 2/46 participants in the acarbose group (very low-certainty evidence). No participant experienced a SAE (very low-certainty evidence).One study compared pioglitazone with repaglinide. Incidence of T2DM was 2/48 participants in the pioglitazone group versus 1/48 participants in the repaglinide group (low-certainty evidence). No participant experienced a SAE (low-certainty evidence). One study compared pioglitazone with a personalised diet and exercise consultation. All-cause and cardiovascular mortality, NMI/S, QoL or socioeconomic effects were not reported. Incidence of T2DM was 2/48 participants in the pioglitazone group versus 5/48 participants in the diet and exercise consultation group (low-certainty evidence). No participant experienced a SAE (low-certainty evidence). Six studies compared pioglitazone with placebo. No study reported on QoL or socioeconomic effects. All-cause mortality was 5/577 participants the in the pioglitazone groups versus 2/579 participants in the placebo groups (Peto odds ratio 2.38, 95% CI 0.54 to 10.50; P = 0.25; 4 studies, 1156 participants; very low-certainty evidence). Incidence of T2DM was 80/700 participants in the pioglitazone groups versus 131/695 participants in the placebo groups (RR 0.40, 95% CI 0.17 to 0.95; P = 0.04; 6 studies, 1395 participants; low-certainty evidence). There were 3/93 participants with SAEs in the pioglitazone groups versus 1/94 participants in the placebo groups (RR 3.00, 95% CI 0.32 to 28.22; P = 0.34; 2 studies, 187 participants; very low-certainty evidence). However, the largest study for this comparison did not distinguish between serious and non-serious adverse events. This study reported that 121/303 (39.9%) participants in the pioglitazone group versus 151/299 (50.5%) participants in the placebo group experienced an adverse event (P = 0.03). One study observed cardiovascular mortality in 2/181 participants in the pioglitazone group versus 0/186 participants in the placebo group (RR 5.14, 95% CI 0.25 to 106.28; P = 0.29; very low-certainty evidence). One study observed NMI in 2/303 participants in the pioglitazone group versus 1/299 participants in the placebo group (RR 1.97: 95% CI 0.18 to 21.65; P = 0.58; very low-certainty evidence). Twenty-one studies compared pioglitazone with no intervention. No study reported on cardiovascular mortality, NMI/S, QoL or socioeconomic effects. All-cause mortality was 11/441 participants in the pioglitazone groups versus 12/425 participants in the no-intervention groups (RR 0.85, 95% CI 0.38 to 1.91; P = 0.70; 3 studies, 866 participants; very low-certainty evidence). Incidence of T2DM was 60/1034 participants in the pioglitazone groups versus 197/1019 participants in the no-intervention groups (RR 0.31, 95% CI 0.23 to 0.40; P < 0.001; 16 studies, 2053 participants; moderate-certainty evidence). Studies reported SAEs in 16/610 participants in the pioglitazone groups versus 21/601 participants in the no-intervention groups (RR 0.71, 95% CI 0.38 to 1.32; P = 0.28; 7 studies, 1211 participants; low-certainty evidence). We identified two ongoing studies, comparing pioglitazone with placebo and with other glucose-lowering drugs. These studies, with 2694 participants. may contribute evidence to future updates of this review. AUTHORS' CONCLUSIONS: Pioglitazone reduced or delayed the development of T2DM in people at increased risk of T2DM compared with placebo (low-certainty evidence) and compared with no intervention (moderate-certainty evidence). It is unclear whether the effect of pioglitazone is sustained once discontinued. Pioglitazone compared with metformin neither showed advantage nor disadvantage regarding the development of T2DM in people at increased risk (low-certainty evidence). The data and reporting of all-cause mortality, SAEs, micro- and macrovascular complications were generally sparse. None of the included studies reported on QoL or socioeconomic effects.

Comparative effectiveness of biological medicines in rheumatoid arthritis: systematic review and network meta-analysis including aggregate results from reanalysed individual patient data.

OBJECTIVE: To assess the comparative effectiveness of biological medicines in rheumatoid arthritis in sufficiently similar patient populations, based on the current definitions of key outcomes. DESIGN: Systematic review and network meta-analysis including aggregate results from reanalysed individual patient data. DATA SOURCES: Clinical study reports and aggregate results from reanalyses of individual patient data on key outcomes for rheumatoid arthritis provided by study sponsors for studies conducted up to 2017, and several databases and registries from inception up to February 2017. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials investigating patient relevant outcomes in adults with rheumatoid arthritis treated with biological medicines in combination with methotrexate after methotrexate failure for at least 24 weeks. RESULTS: 45 eligible trials were identified. Combining data from clinical study reports and aggregate results from reanalyses of individual patient data allowed extensive analyses yielding sufficiently similar populations and homogeneous study results for network meta-analyses, including up to 35 studies on eight biological medicines combined with methotrexate. These analyses showed few statistically significant differences between the combination treatments. For example, anakinra showed less benefit than almost all the other seven biological medicines regarding clinical remission or low disease activity (clinical disease activity index ≤2.8 or ≤10, respectively) and certolizumab pegol showed more harm than the other seven biological medicines regarding serious adverse events or infections. Some outcomes had very wide 95% confidence intervals, potentially implying unidentified differences between the eight biological medicines, but wide 95% confidence intervals were less prominent for low disease activity, serious adverse events, and infections. Owing to a lack of head-to-head trials, results were mainly based on indirect comparisons with a limited number of studies, and recently approved Janus kinase inhibitors could not be included. CONCLUSIONS: For patients with rheumatoid arthritis after methotrexate failure, only minor differences in benefits and harms were seen between biological medicines in combination with methotrexate. However, the analysis was hampered by a lack of long term direct comparisons. The substantial information gain achieved by the reanalysis of individual patient data calls for the routine availability of individual patient data.

The effect of exposure to long working hours on ischaemic heart disease: A systematic review and meta-analysis from the WHO/ILO Joint Estimates of the Work-related Burden of Disease and Injury.

BACKGROUND: The World Health Organization (WHO) and the International Labour Organization (ILO) are developing Joint Estimates of the work-related burden of disease and injury (WHO/ILO Joint Estimates), with contributions from a large network of experts. Evidence from mechanistic data suggests that exposure to long working hours may cause ischaemic heart disease (IHD). In this paper, we present a systematic review and meta-analysis of parameters for estimating the number of deaths and disability-adjusted life years from IHD that are attributable to exposure to long working hours, for the development of the WHO/ILO Joint Estimates. OBJECTIVES: We aimed to systematically review and meta-analyse estimates of the effect of exposure to long working hours (three categories: 41-48, 49-54 and ≥55 h/week), compared with exposure to standard working hours (35-40 h/week), on IHD (three outcomes: prevalence, incidence and mortality). DATA SOURCES: We developed and published a protocol, applying the Navigation Guide as an organizing systematic review framework where feasible. We searched electronic databases for potentially relevant records from published and unpublished studies, including MEDLINE, Scopus, Web of Science, CISDOC, PsycINFO, and WHO ICTRP. We also searched grey literature databases, Internet search engines and organizational websites; hand-searched reference lists of previous systematic reviews; and consulted additional experts. STUDY ELIGIBILITY AND CRITERIA: We included working-age (≥15 years) workers in the formal and informal economy in any WHO and/or ILO Member State but excluded children (aged < 15 years) and unpaid domestic workers. We included randomized controlled trials, cohort studies, case-control studies and other non-randomized intervention studies which contained an estimate of the effect of exposure to long working hours (41-48, 49-54 and ≥55 h/week), compared with exposure to standard working hours (35-40 h/week), on IHD (prevalence, incidence or mortality). STUDY APPRAISAL AND SYNTHESIS METHODS: At least two review authors independently screened titles and abstracts against the eligibility criteria at a first stage and full texts of potentially eligible records at a second stage, followed by extraction of data from qualifying studies. Missing data were requested from principal study authors. We combined relative risks using random-effect meta-analysis. Two or more review authors assessed the risk of bias, quality of evidence and strength of evidence, using Navigation Guide and GRADE tools and approaches adapted to this project. RESULTS: Thirty-seven studies (26 prospective cohort studies and 11 case-control studies) met the inclusion criteria, comprising a total of 768,751 participants (310,954 females) in 13 countries in three WHO regions (Americas, Europe and Western Pacific). The exposure was measured using self-reports in all studies, and the outcome was assessed with administrative health records (30 studies) or self-reported physician diagnosis (7 studies). The outcome was defined as incident non-fatal IHD event in 19 studies (8 cohort studies, 11 case-control studies), incident fatal IHD event in two studies (both cohort studies), and incident non-fatal or fatal ("mixed") event in 16 studies (all cohort studies). Because we judged cohort studies to have a relatively lower risk of bias, we prioritized evidence from these studies and treated evidence from case-control studies as supporting evidence. For the bodies of evidence for both outcomes with any eligible studies (i.e. IHD incidence and mortality), we did not have serious concerns for risk of bias (at least for the cohort studies). No eligible study was found on the effect of long working hours on IHD prevalence. Compared with working 35-40 h/week, we are uncertain about the effect on acquiring (or incidence of) IHD of working 41-48 h/week (relative risk (RR) 0.98, 95% confidence interval (CI) 0.91 to 1.07, 20 studies, 312,209 participants, I2 0%, low quality of evidence) and 49-54 h/week (RR 1.05, 95% CI 0.94 to 1.17, 18 studies, 308,405 participants, I2 0%, low quality of evidence). Compared with working 35-40 h/week, working ≥55 h/week may have led to a moderately, clinically meaningful increase in the risk of acquiring IHD, when followed up between one year and 20 years (RR 1.13, 95% CI 1.02 to 1.26, 22 studies, 339,680 participants, I2 5%, moderate quality of evidence). Compared with working 35-40 h/week, we are very uncertain about the effect on dying (mortality) from IHD of working 41-48 h/week (RR 0.99, 95% CI 0.88 to 1.12, 13 studies, 288,278 participants, I2 8%, low quality of evidence) and 49-54 h/week (RR 1.01, 95% CI 0.82 to 1.25, 11 studies, 284,474 participants, I2 13%, low quality of evidence). Compared with working 35-40 h/week, working ≥55 h/week may have led to a moderate, clinically meaningful increase in the risk of dying from IHD when followed up between eight and 30 years (RR 1.17, 95% CI 1.05 to 1.31, 16 studies, 726,803 participants, I2 0%, moderate quality of evidence). Subgroup analyses found no evidence for differences by WHO region and sex, but RRs were higher among persons with lower SES. Sensitivity analyses found no differences by outcome definition (exclusively non-fatal or fatal versus "mixed"), outcome measurement (health records versus self-reports) and risk of bias ("high"/"probably high" ratings in any domain versus "low"/"probably low" in all domains). CONCLUSIONS: We judged the existing bodies of evidence for human evidence as "inadequate evidence for harmfulness" for the exposure categories 41-48 and 49-54 h/week for IHD prevalence, incidence and mortality, and for the exposure category ≥55 h/week for IHD prevalence. Evidence on exposure to working ≥55 h/week was judged as "sufficient evidence of harmfulness" for IHD incidence and mortality. Producing estimates for the burden of IHD attributable to exposure to working ≥55 h/week appears evidence-based, and the pooled effect estimates presented in this systematic review could be used as input data for the WHO/ILO Joint Estimates.

Incidence of stroke in the diabetic compared with the non-diabetic population: A systematic review protocol.

People with diabetes have a largely increased risk of stroke compared with people without diabetes. Exact data on incidence of stroke in people with and without diabetes are important for improvements in preventive diabetes care, avoidance of fatal outcomes and as a solid basis for health policy and the economy. However, published data are conflicting, underlining the necessity for this systematic review of population-based studies on incidence, relative risks (RRs) and changes in stroke rates over time. The purpose of our review is to evaluate the incidence of stroke in the diabetic population and its differences with regard to sex, ethnicity, age and regions; to compare the incidence rate (IR) in the diabetic and non-diabetic populations and to investigate time trends. We will perform a systematic literature search in MEDLINE, Embase and LILACS designed by an experienced information scientist. Two review authors will independently screen the abstracts and full texts of all references on the basis of inclusion criteria regarding types of study, types of population and the main outcome. Data extraction and assessment of risk of bias will be undertaken by two review authors working independently. We will assess IR or cumulative incidence (CumI) and RR of stroke comparing the diabetic and non-diabetic populations. The attributable risk (AR = proportion of stroke among persons with diabetes that is attributable to diabetes) and the population attributable risk (PAR = proportion of stroke in the whole population that is attributable to diabetes) will be considered where available. In conclusion, this review will help to summarize the available evidence for incidence of stroke in the diabetic and nondiabetic population. The publication of this protocol will contribute to making the search strategy, methods, and assessment of reviews transparent and accessible for all involved professional groups.

Metformin for prevention or delay of type 2 diabetes mellitus and its associated complications in persons at increased risk for the development of type 2 diabetes mellitus.

BACKGROUND: The projected rise in the incidence of type 2 diabetes mellitus (T2DM) could develop into a substantial health problem worldwide. Whether metformin can prevent or delay T2DM and its complications in people with increased risk of developing T2DM is unknown. OBJECTIVES: To assess the effects of metformin for the prevention or delay of T2DM and its associated complications in persons at increased risk for the T2DM. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Scopus, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform and the reference lists of systematic reviews, articles and health technology assessment reports. We asked investigators of the included trials for information about additional trials. The date of the last search of all databases was March 2019. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with a duration of one year or more comparing metformin with any pharmacological glucose-lowering intervention, behaviour-changing intervention, placebo or standard care in people with impaired glucose tolerance, impaired fasting glucose, moderately elevated glycosylated haemoglobin A1c (HbA1c) or combinations of these. DATA COLLECTION AND ANALYSIS: Two review authors read all abstracts and full-text articles and records, assessed risk of bias and extracted outcome data independently. We used a random-effects model to perform meta-analysis and calculated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We included 20 RCTs randomising 6774 participants. One trial contributed 48% of all participants. The duration of intervention in the trials varied from one to five years. We judged none of the trials to be at low risk of bias in all 'Risk of bias' domains. Our main outcome measures were all-cause mortality, incidence of T2DM, serious adverse events (SAEs), cardiovascular mortality, non-fatal myocardial infarction or stroke, health-related quality of life and socioeconomic effects.The following comparisons mostly reported only a fraction of our main outcome set. Fifteen RCTs compared metformin with diet and exercise with or without placebo: all-cause mortality was 7/1353 versus 7/1480 (RR 1.11, 95% CI 0.41 to 3.01; P = 0.83; 2833 participants, 5 trials; very low-quality evidence); incidence of T2DM was 324/1751 versus 529/1881 participants (RR 0.50, 95% CI 0.38 to 0.65; P < 0.001; 3632 participants, 12 trials; moderate-quality evidence); the reporting of SAEs was insufficient and diverse and meta-analysis could not be performed (reported numbers were 4/118 versus 2/191; 309 participants; 4 trials; very low-quality evidence); cardiovascular mortality was 1/1073 versus 4/1082 (2416 participants; 2 trials; very low-quality evidence). One trial reported no clear difference in health-related quality of life after 3.2 years of follow-up (very low-quality evidence). Two trials estimated the direct medical costs (DMC) per participant for metformin varying from $220 to $1177 versus $61 to $184 in the comparator group (2416 participants; 2 trials; low-quality evidence). Eight RCTs compared metformin with intensive diet and exercise: all-cause mortality was 7/1278 versus 4/1272 (RR 1.61, 95% CI 0.50 to 5.23; P = 0.43; 2550 participants, 4 trials; very low-quality evidence); incidence of T2DM was 304/1455 versus 251/1505 (RR 0.80, 95% CI 0.47 to 1.37; P = 0.42; 2960 participants, 7 trials; moderate-quality evidence); the reporting of SAEs was sparse and meta-analysis could not be performed (one trial reported 1/44 in the metformin group versus 0/36 in the intensive exercise and diet group with SAEs). One trial reported that 1/1073 participants in the metformin group compared with 2/1079 participants in the comparator group died from cardiovascular causes. One trial reported that no participant died due to cardiovascular causes (very low-quality evidence). Two trials estimated the DMC per participant for metformin varying from $220 to $1177 versus $225 to $3628 in the comparator group (2400 participants; 2 trials; very low-quality evidence). Three RCTs compared metformin with acarbose: all-cause mortality was 1/44 versus 0/45 (89 participants; 1 trial; very low-quality evidence); incidence of T2DM was 12/147 versus 7/148 (RR 1.72, 95% CI 0.72 to 4.14; P = 0.22; 295 participants; 3 trials; low-quality evidence); SAEs were 1/51 versus 2/50 (101 participants; 1 trial; very low-quality evidence). Three RCTs compared metformin with thiazolidinediones: incidence of T2DM was 9/161 versus 9/159 (RR 0.99, 95% CI 0.41 to 2.40; P = 0.98; 320 participants; 3 trials; low-quality evidence). SAEs were 3/45 versus 0/41 (86 participants; 1 trial; very low-quality evidence). Three RCTs compared metformin plus intensive diet and exercise with identical intensive diet and exercise: all-cause mortality was 1/121 versus 1/120 participants (450 participants; 2 trials; very low-quality evidence); incidence of T2DM was 48/166 versus 53/166 (RR 0.55, 95% CI 0.10 to 2.92; P = 0.49; 332 participants; 2 trials; very low-quality evidence). One trial estimated the DMC of metformin plus intensive diet and exercise to be $270 per participant compared with $225 in the comparator group (94 participants; 1 trial; very-low quality evidence). One trial in 45 participants compared metformin with a sulphonylurea. The trial reported no patient-important outcomes. For all comparisons there were no data on non-fatal myocardial infarction, non-fatal stroke or microvascular complications. We identified 11 ongoing trials which potentially could provide data of interest for this review. These trials will add a total of 17,853 participants in future updates of this review. AUTHORS' CONCLUSIONS: Metformin compared with placebo or diet and exercise reduced or delayed the risk of T2DM in people at increased risk for the development of T2DM (moderate-quality evidence). However, metformin compared to intensive diet and exercise did not reduce or delay the risk of T2DM (moderate-quality evidence). Likewise, the combination of metformin and intensive diet and exercise compared to intensive diet and exercise only neither showed an advantage or disadvantage regarding the development of T2DM (very low-quality evidence). Data on patient-important outcomes such as mortality, macrovascular and microvascular diabetic complications and health-related quality of life were sparse or missing.

Metformin and second- or third-generation sulphonylurea combination therapy for adults with type 2 diabetes mellitus.

BACKGROUND: The number of people with type 2 diabetes mellitus (T2DM) is increasing worldwide. The combination of metformin and sulphonylurea (M+S) is a widely used treatment. Whether M+S shows better or worse effects in comparison with other antidiabetic medications for people with T2DM is still controversial. OBJECTIVES: To assess the effects of metformin and sulphonylurea (second- or third-generation) combination therapy for adults with type 2 diabetes mellitus. SEARCH METHODS: We updated the search of a recent systematic review from the Agency for Healthcare Research and Quality (AHRQ). The updated search included CENTRAL, MEDLINE, Embase, ClinicalTrials.gov and WHO ICTRP. The date of the last search was March 2018. We searched manufacturers' websites and reference lists of included trials, systematic reviews, meta-analyses and health technology assessment reports. We asked investigators of the included trials for information about additional trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) randomising participants 18 years old or more with T2DM to M+S compared with metformin plus another glucose-lowering intervention or metformin monotherapy with a treatment duration of 52 weeks or more. DATA COLLECTION AND ANALYSIS: Two review authors read all abstracts and full-text articles and records, assessed risk of bias and extracted outcome data independently. We used a random-effects model to perform meta-analysis, and calculated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the certainty of the evidence using the GRADE instrument. MAIN RESULTS: We included 32 RCTs randomising 28,746 people. Treatment duration ranged between one to four years. We judged none of these trials as low risk of bias for all 'Risk of bias' domains. Most important events per person were all-cause and cardiovascular mortality, serious adverse events (SAE), non-fatal stroke (NFS), non-fatal myocardial infarction (MI) and microvascular complications. Most important comparisons were as follows:Five trials compared M+S (N = 1194) with metformin plus a glucagon-like peptide 1 analogue (N = 1675): all-cause mortality was 11/1057 (1%) versus 11/1537 (0.7%), risk ratio (RR) 1.15 (95% confidence interval (CI) 0.49 to 2.67); 3 trials; 2594 participants; low-certainty evidence; cardiovascular mortality 1/307 (0.3%) versus 1/302 (0.3%), low-certainty evidence; serious adverse events (SAE) 128/1057 (12.1%) versus 194/1537 (12.6%), RR 0.90 (95% CI 0.73 to 1.11); 3 trials; 2594 participants; very low-certainty evidence; non-fatal myocardial infarction (MI) 2/549 (0.4%) versus 6/1026 (0.6%), RR 0.57 (95% CI 0.12 to 2.82); 2 trials; 1575 participants; very low-certainty evidence.Nine trials compared M+S (N = 5414) with metformin plus a dipeptidyl-peptidase 4 inhibitor (N = 6346): all-cause mortality was 33/5387 (0.6%) versus 26/6307 (0.4%), RR 1.32 (95% CI 0.76 to 2.28); 9 trials; 11,694 participants; low-certainty evidence; cardiovascular mortality 11/2989 (0.4%) versus 9/3885 (0.2%), RR 1.54 (95% CI 0.63 to 3.79); 6 trials; 6874 participants; low-certainty evidence; SAE 735/5387 (13.6%) versus 779/6307 (12.4%), RR 1.07 (95% CI 0.97 to 1.18); 9 trials; 11,694 participants; very low-certainty evidence; NFS 14/2098 (0.7%) versus 8/2995 (0.3%), RR 2.21 (95% CI 0.74 to 6.58); 4 trials; 5093 participants; very low-certainty evidence; non-fatal MI 15/2989 (0.5%) versus 13/3885 (0.3%), RR 1.45 (95% CI 0.69 to 3.07); 6 trials; 6874 participants; very low-certainty evidence; one trial in 64 participants reported no microvascular complications were observed (very low-certainty evidence).Eleven trials compared M+S (N = 3626) with metformin plus a thiazolidinedione (N = 3685): all-cause mortality was 123/3300 (3.7%) versus 114/3354 (3.4%), RR 1.09 (95% CI 0.85 to 1.40); 6 trials; 6654 participants; low-certainty evidence; cardiovascular mortality 37/2946 (1.3%) versus 41/2994 (1.4%), RR 0.78 (95% CI 0.36 to 1.67); 4 trials; 5940 participants; low-certainty evidence; SAE 666/3300 (20.2%) versus 671/3354 (20%), RR 1.01 (95% CI 0.93 to 1.11); 6 trials; 6654 participants; very low-certainty evidence; NFS 20/1540 (1.3%) versus 16/1583 (1%), RR 1.29 (95% CI 0.67 to 2.47); P = 0.45; 2 trials; 3123 participants; very low-certainty evidence; non-fatal MI 25/1841 (1.4%) versus 21/1877 (1.1%), RR 1.21 (95% CI 0.68 to 2.14); P = 0.51; 3 trials; 3718 participants; very low-certainty evidence; three trials (3123 participants) reported no microvascular complications (very low-certainty evidence).Three trials compared M+S (N = 462) with metformin plus a glinide (N = 476): one person died in each intervention group (3 trials; 874 participants; low-certainty evidence); no cardiovascular mortality (2 trials; 446 participants; low-certainty evidence); SAE 34/424 (8%) versus 27/450 (6%), RR 1.68 (95% CI 0.54 to 5.21); P = 0.37; 3 trials; 874 participants; low-certainty evidence; no NFS (1 trial; 233 participants; very low-certainty evidence); non-fatal MI 2/215 (0.9%) participants in the M+S group; 2 trials; 446 participants; low-certainty evidence; no microvascular complications (1 trial; 233 participants; low-certainty evidence).Four trials compared M+S (N = 2109) with metformin plus a sodium-glucose co-transporter 2 inhibitor (N = 3032): all-cause mortality was 13/2107 (0.6%) versus 19/3027 (0.6%), RR 0.96 (95% CI 0.44 to 2.09); 4 trials; 5134 participants; very low-certainty evidence; cardiovascular mortality 4/1327 (0.3%) versus 6/2262 (0.3%), RR 1.22 (95% CI 0.33 to 4.41); 3 trials; 3589 participants; very low-certainty evidence; SAE 315/2107 (15.5%) versus 375/3027 (12.4%), RR 1.02 (95% CI 0.76 to 1.37); 4 trials; 5134 participants; very low-certainty evidence; NFS 3/919 (0.3%) versus 7/1856 (0.4%), RR 0.87 (95% CI 0.22 to 3.34); 2 trials; 2775 participants; very low-certainty evidence; non-fatal MI 7/890 (0.8%) versus 8/1374 (0.6%), RR 1.43 (95% CI 0.49 to 4.18; 2 trials); 2264 participants; very low-certainty evidence; amputation of lower extremity 1/437 (0.2%) versus 1/888 (0.1%); very low-certainty evidence.Trials reported more hypoglycaemic episodes with M+S combination compared to all other metformin-antidiabetic agent combinations. Results for M+S versus metformin monotherapy were inconclusive. There were no RCTs comparing M+S with metformin plus insulin. We identified nine ongoing trials and two trials are awaiting assessment. Together these trials will include approximately 16,631 participants. AUTHORS' CONCLUSIONS: There is inconclusive evidence whether M+S combination therapy compared with metformin plus another glucose-lowering intervention results in benefit or harm for most patient-important outcomes (mortality, SAEs, macrovascular and microvascular complications) with the exception of hypoglycaemia (more harm for M+S combination). No RCT reported on health-related quality of life.

Study filters for non-randomized studies of interventions consistently lacked sensitivity upon external validation.

BACKGROUND: Little evidence is available on searches for non-randomized studies (NRS) in bibliographic databases within the framework of systematic reviews. For instance, it is currently unclear whether, when searching for NRS, effective restriction of the search strategy to certain study types is possible. The following challenges need to be considered: 1) For non-randomized controlled trials (NRCTs): whether they can be identified by established filters for randomized controlled trials (RCTs). 2) For other NRS types (such as cohort studies): whether study filters exist for each study type and, if so, which performance measures they have. The aims of the present analysis were to identify and validate existing NRS filters in MEDLINE as well as to evaluate established RCT filters using a set of MEDLINE citations. METHODS: Our analysis is a retrospective analysis of study filters based on MEDLINE citations of NRS from Cochrane reviews. In a first step we identified existing NRS filters. For the generation of the reference set, we screened Cochrane reviews evaluating NRS, which covered a broad range of study types. The citations of the studies included in the Cochrane reviews were identified via the reviews' bibliographies and the corresponding PubMed identification numbers (PMIDs) were extracted from PubMed. Random samples comprising up to 200 citations (i.e. 200 PMIDs) each were created for each study type to generate the test sets. RESULTS: A total of 271 Cochrane reviews from 41 different Cochrane groups were eligible for data extraction. We identified 14 NRS filters published since 2001. The study filters generated between 660,000 and 9.5 million hits in MEDLINE. Most filters covered several study types. The reference set included 2890 publications classified as NRS for the generation of the test sets. Twelve test sets were generated (one for each study type), of which 8 included 200 citations each. None of the study filters achieved sufficient sensitivity (≥ 92%) for all of the study types targeted. CONCLUSIONS: The performance of current NRS filters is insufficient for effective use in daily practice. It is therefore necessary to develop new strategies (e.g. new NRS filters in combination with other search techniques). The challenges related to NRS should be taken into account.

Development of type 2 diabetes mellitus in people with intermediate hyperglycaemia.

BACKGROUND: Intermediate hyperglycaemia (IH) is characterised by one or more measurements of elevated blood glucose concentrations, such as impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and elevated glycosylated haemoglobin A1c (HbA1c). These levels are higher than normal but below the diagnostic threshold for type 2 diabetes mellitus (T2DM). The reduced threshold of 5.6 mmol/L (100 mg/dL) fasting plasma glucose (FPG) for defining IFG, introduced by the American Diabetes Association (ADA) in 2003, substantially increased the prevalence of IFG. Likewise, the lowering of the HbA1c threshold from 6.0% to 5.7% by the ADA in 2010 could potentially have significant medical, public health and socioeconomic impacts. OBJECTIVES: To assess the overall prognosis of people with IH for developing T2DM, regression from IH to normoglycaemia and the difference in T2DM incidence in people with IH versus people with normoglycaemia. SEARCH METHODS: We searched MEDLINE, Embase, ClincialTrials.gov and the International Clinical Trials Registry Platform (ICTRP) Search Portal up to December 2016 and updated the MEDLINE search in February 2018. We used several complementary search methods in addition to a Boolean search based on analytical text mining. SELECTION CRITERIA: We included prospective cohort studies investigating the development of T2DM in people with IH. We used standard definitions of IH as described by the ADA or World Health Organization (WHO). We excluded intervention trials and studies on cohorts with additional comorbidities at baseline, studies with missing data on the transition from IH to T2DM, and studies where T2DM incidence was evaluated by documents or self-report only. DATA COLLECTION AND ANALYSIS: One review author extracted study characteristics, and a second author checked the extracted data. We used a tailored version of the Quality In Prognosis Studies (QUIPS) tool for assessing risk of bias. We pooled incidence and incidence rate ratios (IRR) using a random-effects model to account for between-study heterogeneity. To meta-analyse incidence data, we used a method for pooling proportions. For hazard ratios (HR) and odds ratios (OR) of IH versus normoglycaemia, reported with 95% confidence intervals (CI), we obtained standard errors from these CIs and performed random-effects meta-analyses using the generic inverse-variance method. We used multivariable HRs and the model with the greatest number of covariates. We evaluated the certainty of the evidence with an adapted version of the GRADE framework. MAIN RESULTS: We included 103 prospective cohort studies. The studies mainly defined IH by IFG5.6 (FPG mmol/L 5.6 to 6.9 mmol/L or 100 mg/dL to 125 mg/dL), IFG6.1 (FPG 6.1 mmol/L to 6.9 mmol/L or 110 mg/dL to 125 mg/dL), IGT (plasma glucose 7.8 mmol/L to 11.1 mmol/L or 140 mg/dL to 199 mg/dL two hours after a 75 g glucose load on the oral glucose tolerance test, combined IFG and IGT (IFG/IGT), and elevated HbA1c (HbA1c5.7: HbA1c 5.7% to 6.4% or 39 mmol/mol to 46 mmol/mol; HbA1c6.0: HbA1c 6.0% to 6.4% or 42 mmol/mol to 46 mmol/mol). The follow-up period ranged from 1 to 24 years. Ninety-three studies evaluated the overall prognosis of people with IH measured by cumulative T2DM incidence, and 52 studies evaluated glycaemic status as a prognostic factor for T2DM by comparing a cohort with IH to a cohort with normoglycaemia. Participants were of Australian, European or North American origin in 41 studies; Latin American in 7; Asian or Middle Eastern in 50; and Islanders or American Indians in 5. Six studies included children and/or adolescents.Cumulative incidence of T2DM associated with IFG5.6, IFG6.1, IGT and the combination of IFG/IGT increased with length of follow-up. Cumulative incidence was highest with IFG/IGT, followed by IGT, IFG6.1 and IFG5.6. Limited data showed a higher T2DM incidence associated with HbA1c6.0 compared to HbA1c5.7. We rated the evidence for overall prognosis as of moderate certainty because of imprecision (wide CIs in most studies). In the 47 studies reporting restitution of normoglycaemia, regression ranged from 33% to 59% within one to five years follow-up, and from 17% to 42% for 6 to 11 years of follow-up (moderate-certainty evidence).Studies evaluating the prognostic effect of IH versus normoglycaemia reported different effect measures (HRs, IRRs and ORs). Overall, the effect measures all indicated an elevated risk of T2DM at 1 to 24 years of follow-up. Taking into account the long-term follow-up of cohort studies, estimation of HRs for time-dependent events like T2DM incidence appeared most reliable. The pooled HR and the number of studies and participants for different IH definitions as compared to normoglycaemia were: IFG5.6: HR 4.32 (95% CI 2.61 to 7.12), 8 studies, 9017 participants; IFG6.1: HR 5.47 (95% CI 3.50 to 8.54), 9 studies, 2818 participants; IGT: HR 3.61 (95% CI 2.31 to 5.64), 5 studies, 4010 participants; IFG and IGT: HR 6.90 (95% CI 4.15 to 11.45), 5 studies, 1038 participants; HbA1c5.7: HR 5.55 (95% CI 2.77 to 11.12), 4 studies, 5223 participants; HbA1c6.0: HR 10.10 (95% CI 3.59 to 28.43), 6 studies, 4532 participants. In subgroup analyses, there was no clear pattern of differences between geographic regions. We downgraded the evidence for the prognostic effect of IH versus normoglycaemia to low-certainty evidence due to study limitations because many studies did not adequately adjust for confounders. Imprecision and inconsistency required further downgrading due to wide 95% CIs and wide 95% prediction intervals (sometimes ranging from negative to positive prognostic factor to outcome associations), respectively.This evidence is up to date as of 26 February 2018. AUTHORS' CONCLUSIONS: Overall prognosis of people with IH worsened over time. T2DM cumulative incidence generally increased over the course of follow-up but varied with IH definition. Regression from IH to normoglycaemia decreased over time but was observed even after 11 years of follow-up. The risk of developing T2DM when comparing IH with normoglycaemia at baseline varied by IH definition. Taking into consideration the uncertainty of the available evidence, as well as the fluctuating stages of normoglycaemia, IH and T2DM, which may transition from one stage to another in both directions even after years of follow-up, practitioners should be careful about the potential implications of any active intervention for people 'diagnosed' with IH.

Diet, physical activity or both for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk of developing type 2 diabetes mellitus.

BACKGROUND: The projected rise in the incidence of type 2 diabetes mellitus (T2DM) could develop into a substantial health problem worldwide. Whether diet, physical activity or both can prevent or delay T2DM and its associated complications in at-risk people is unknown. OBJECTIVES: To assess the effects of diet, physical activity or both on the prevention or delay of T2DM and its associated complications in people at increased risk of developing T2DM. SEARCH METHODS: This is an update of the Cochrane Review published in 2008. We searched the CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, ICTRP Search Portal and reference lists of systematic reviews, articles and health technology assessment reports. The date of the last search of all databases was January 2017. We continuously used a MEDLINE email alert service to identify newly published studies using the same search strategy as described for MEDLINE up to September 2017. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with a duration of two years or more. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology for data collection and analysis. We assessed the overall quality of the evidence using GRADE. MAIN RESULTS: We included 12 RCTs randomising 5238 people. One trial contributed 41% of all participants. The duration of the interventions varied from two to six years. We judged none of the included trials at low risk of bias for all 'Risk of bias' domains.Eleven trials compared diet plus physical activity with standard or no treatment. Nine RCTs included participants with impaired glucose tolerance (IGT), one RCT included participants with IGT, impaired fasting blood glucose (IFG) or both, and one RCT included people with fasting glucose levels between 5.3 to 6.9 mmol/L. A total of 12 deaths occurred in 2049 participants in the diet plus physical activity groups compared with 10 in 2050 participants in the comparator groups (RR 1.12, 95% CI 0.50 to 2.50; 95% prediction interval 0.44 to 2.88; 4099 participants, 10 trials; very low-quality evidence). The definition of T2DM incidence varied among the included trials. Altogether 315 of 2122 diet plus physical activity participants (14.8%) developed T2DM compared with 614 of 2389 comparator participants (25.7%) (RR 0.57, 95% CI 0.50 to 0.64; 95% prediction interval 0.50 to 0.65; 4511 participants, 11 trials; moderate-quality evidence). Two trials reported serious adverse events. In one trial no adverse events occurred. In the other trial one of 51 diet plus physical activity participants compared with none of 51 comparator participants experienced a serious adverse event (low-quality evidence). Cardiovascular mortality was rarely reported (four of 1626 diet plus physical activity participants and four of 1637 comparator participants (the RR ranged between 0.94 and 3.16; 3263 participants, 7 trials; very low-quality evidence). Only one trial reported that no non-fatal myocardial infarction or non-fatal stroke had occurred (low-quality evidence). Two trials reported that none of the participants had experienced hypoglycaemia. One trial investigated health-related quality of life in 2144 participants and noted that a minimal important difference between intervention groups was not reached (very low-quality evidence). Three trials evaluated costs of the interventions in 2755 participants. The largest trial of these reported an analysis of costs from the health system perspective and society perspective reflecting USD 31,500 and USD 51,600 per quality-adjusted life year (QALY) with diet plus physical activity, respectively (low-quality evidence). There were no data on blindness or end-stage renal disease.One trial compared a diet-only intervention with a physical-activity intervention or standard treatment. The participants had IGT. Three of 130 participants in the diet group compared with none of the 141 participants in the physical activity group died (very low-quality evidence). None of the participants died because of cardiovascular disease (very low-quality evidence). Altogether 57 of 130 diet participants (43.8%) compared with 58 of 141 physical activity participants (41.1%) group developed T2DM (very low-quality evidence). No adverse events were recorded (very low-quality evidence). There were no data on non-fatal myocardial infarction, non-fatal stroke, blindness, end-stage renal disease, health-related quality of life or socioeconomic effects.Two trials compared physical activity with standard treatment in 397 participants. One trial included participants with IGT, the other trial included participants with IGT, IFG or both. One trial reported that none of the 141 physical activity participants compared with three of 133 control participants died. The other trial reported that three of 84 physical activity participants and one of 39 control participants died (very low-quality evidence). In one trial T2DM developed in 58 of 141 physical activity participants (41.1%) compared with 90 of 133 control participants (67.7%). In the other trial 10 of 84 physical activity participants (11.9%) compared with seven of 39 control participants (18%) developed T2DM (very low-quality evidence). Serious adverse events were rarely reported (one trial noted no events, one trial described events in three of 66 physical activity participants compared with one of 39 control participants - very low-quality evidence). Only one trial reported on cardiovascular mortality (none of 274 participants died - very low-quality evidence). Non-fatal myocardial infarction or stroke were rarely observed in the one trial randomising 123 participants (very low-quality evidence). One trial reported that none of the participants in the trial experienced hypoglycaemia. One trial investigating health-related quality of life in 123 participants showed no substantial differences between intervention groups (very low-quality evidence). There were no data on blindness or socioeconomic effects. AUTHORS' CONCLUSIONS: There is no firm evidence that diet alone or physical activity alone compared to standard treatment influences the risk of T2DM and especially its associated complications in people at increased risk of developing T2DM. However, diet plus physical activity reduces or delays the incidence of T2DM in people with IGT. Data are lacking for the effect of diet plus physical activity for people with intermediate hyperglycaemia defined by other glycaemic variables. Most RCTs did not investigate patient-important outcomes.

Dipeptidyl-peptidase (DPP)-4 inhibitors and glucagon-like peptide (GLP)-1 analogues for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk for the development of type 2 diabetes mellitus.

BACKGROUND: The projected rise in the incidence of type 2 diabetes mellitus (T2DM) could develop into a substantial health problem worldwide. Whether dipeptidyl-peptidase (DPP)-4 inhibitors or glucagon-like peptide (GLP)-1 analogues are able to prevent or delay T2DM and its associated complications in people at risk for the development of T2DM is unknown. OBJECTIVES: To assess the effects of DPP-4 inhibitors and GLP-1 analogues on the prevention or delay of T2DM and its associated complications in people with impaired glucose tolerance, impaired fasting blood glucose, moderately elevated glycosylated haemoglobin A1c (HbA1c) or any combination of these. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials; MEDLINE; PubMed; Embase; ClinicalTrials.gov; the World Health Organization (WHO) International Clinical Trials Registry Platform; and the reference lists of systematic reviews, articles and health technology assessment reports. We asked investigators of the included trials for information about additional trials. The date of the last search of all databases was January 2017. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with a duration of 12 weeks or more comparing DPP-4 inhibitors and GLP-1 analogues with any pharmacological glucose-lowering intervention, behaviour-changing intervention, placebo or no intervention in people with impaired fasting glucose, impaired glucose tolerance, moderately elevated HbA1c or combinations of these. DATA COLLECTION AND ANALYSIS: Two review authors read all abstracts and full-text articles and records, assessed quality and extracted outcome data independently. One review author extracted data which were checked by a second review author. We resolved discrepancies by consensus or the involvement of a third review author. For meta-analyses, we planned to use a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the overall quality of the evidence using the GRADE instrument. MAIN RESULTS: We included seven completed RCTs; about 98 participants were randomised to a DPP-4 inhibitor as monotherapy and 1620 participants were randomised to a GLP-1 analogue as monotherapy. Two trials investigated a DPP-4 inhibitor and five trials investigated a GLP-1 analogue. A total of 924 participants with data on allocation to control groups were randomised to a comparator group; 889 participants were randomised to placebo and 33 participants to metformin monotherapy. One RCT of liraglutide contributed 85% of all participants. The duration of the intervention varied from 12 weeks to 160 weeks. We judged none of the included trials at low risk of bias for all 'Risk of bias' domains and did not perform meta-analyses because there were not enough trials.One trial comparing the DPP-4 inhibitor vildagliptin with placebo reported no deaths (very low-quality evidence). The incidence of T2DM by means of WHO diagnostic criteria in this trial was 3/90 participants randomised to vildagliptin versus 1/89 participants randomised to placebo (very low-quality evidence). Also, 1/90 participants on vildagliptin versus 2/89 participants on placebo experienced a serious adverse event (very low-quality evidence). One out of 90 participants experienced congestive heart failure in the vildagliptin group versus none in the placebo group (very low-quality evidence). There were no data on non-fatal myocardial infarction, stroke, health-related quality of life or socioeconomic effects reported.All-cause and cardiovascular mortality following treatment with GLP-1 analogues were rarely reported; one trial of exenatide reported that no participant died. Another trial of liraglutide 3.0 mg showed that 2/1501 in the liraglutide group versus 2/747 in the placebo group died after 160 weeks of treatment (very low-quality evidence).The incidence of T2DM following treatment with liraglutide 3.0 mg compared to placebo after 160 weeks was 26/1472 (1.8%) participants randomised to liraglutide versus 46/738 (6.2%) participants randomised to placebo (very low-quality evidence). The trial established the risk for (diagnosis of) T2DM as HbA1c 5.7% to 6.4% (6.5% or greater), fasting plasma glucose 5.6 mmol/L or greater to 6.9 mmol/L or less (7.0 mmol/L or greater) or two-hour post-load plasma glucose 7.8 mmol/L or greater to 11.0 mmol/L (11.1 mmol/L). Altogether, 70/1472 (66%) participants regressed from intermediate hyperglycaemia to normoglycaemia compared with 268/738 (36%) participants in the placebo group. The incidence of T2DM after the 12-week off-treatment extension period (i.e. after 172 weeks) showed that five additional participants were diagnosed T2DM in the liraglutide group, compared with one participant in the placebo group. After 12-week treatment cessation, 740/1472 (50%) participants in the liraglutide group compared with 263/738 (36%) participants in the placebo group had normoglycaemia.One trial used exenatide and 2/17 participants randomised to exenatide versus 1/16 participants randomised to placebo developed T2DM (very low-quality evidence). This trial did not provide a definition of T2DM. One trial reported serious adverse events in 230/1524 (15.1%) participants in the liraglutide 3.0 mg arm versus 96/755 (12.7%) participants in the placebo arm (very low quality evidence). There were no serious adverse events in the trial using exenatide. Non-fatal myocardial infarction was reported in 1/1524 participants in the liraglutide arm and in 0/55 participants in the placebo arm at 172 weeks (very low-quality evidence). One trial reported congestive heart failure in 1/1524 participants in the liraglutide arm and in 1/755 participants in the placebo arm (very low-quality evidence). Participants receiving liraglutide compared with placebo had a small mean improvement in the physical component of the 36-item Short Form scale showing a difference of 0.87 points (95% CI 0.17 to 1.58; P = 0.02; 1 trial; 1791 participants; very low-quality evidence). No trial evaluating GLP-1-analogues reported data on stroke, microvascular complications or socioeconomic effects. AUTHORS' CONCLUSIONS: There is no firm evidence that DPP-4 inhibitors or GLP-1 analogues compared mainly with placebo substantially influence the risk of T2DM and especially its associated complications in people at increased risk for the development of T2DM. Most trials did not investigate patient-important outcomes.

Insulin secretagogues for prevention or delay of type 2 diabetes mellitus and its associated complications in persons at increased risk for the development of type 2 diabetes mellitus.

BACKGROUND: The projected rise in the incidence of type 2 diabetes mellitus (T2DM) could develop into a substantial health problem worldwide. Whether insulin secretagogues (sulphonylureas and meglitinide analogues) are able to prevent or delay T2DM and its associated complications in people at risk for the development of T2DM is unknown. OBJECTIVES: To assess the effects of insulin secretagogues on the prevention or delay of T2DM and its associated complications in people with impaired glucose tolerance, impaired fasting blood glucose, moderately elevated glycosylated haemoglobin A1c (HbA1c) or any combination of these. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, and the reference lists of systematic reviews, articles and health technology assessment reports. We asked investigators of the included trials for information about additional trials. The date of the last search of all databases was April 2016. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with a duration of 12 weeks or more comparing insulin secretagogues with any pharmacological glucose-lowering intervention, behaviour-changing intervention, placebo or no intervention in people with impaired fasting glucose, impaired glucose tolerance, moderately elevated HbA1c or combinations of these. DATA COLLECTION AND ANALYSIS: Two review authors read all abstracts and full-text articles/records, assessed quality and extracted outcome data independently. One review author extracted data which were checked by a second review author. We resolved discrepancies by consensus or the involvement of a third review author. For meta-analyses we used a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We carried out trial sequential analyses (TSAs) for all outcomes that could be meta-analysed. We assessed the overall quality of the evidence by using the GRADE instrument. MAIN RESULTS: We included six RCTs with 10,018 participants; 4791 participants with data on allocation to intervention groups were randomised to a second- or third-generation sulphonylurea or a meglitinide analogue as monotherapy and 29 participants were randomised to a second-generation sulphonylurea plus metformin. Three trials investigated a second-generation sulphonylurea, two trials investigated a third-generation sulphonylurea and one trial a meglitinide analogue. A total of 4873 participants with data on allocation to control groups were randomised to a comparator group; 4820 participants were randomised to placebo, 23 to diet and exercise, and 30 participants to metformin monotherapy. One RCT of nateglinide contributed 95% of all participants. The duration of the intervention varied from six months to five years. We judged none of the included trials as at low risk of bias for all 'Risk of bias' domains.All-cause and cardiovascular mortality following sulphonylurea (glimepiride) treatment were rarely observed (very low-quality evidence). The RR for incidence of T2DM comparing glimepiride monotherapy with placebo was 0.75; 95% CI 0.54 to 1.04; P = 0.08; 2 trials; 307 participants; very low-quality evidence. One of the trials reporting on the incidence of T2DM did not define the diagnostic criteria used. The other trial diagnosed T2DM as two consecutive fasting blood glucose values ≥ 6.1 mmol/L. TSA showed that only 4.5% of the diversity-adjusted required information size was accrued so far. No trial reported data on serious adverse events, non-fatal myocardial infarction (MI), non-fatal stroke, congestive heart failure (HF), health-related quality of life or socioeconomic effects.One trial with a follow-up of five years compared a meglitinide analogue (nateglinide) with placebo. A total of 310/4645 (6.7%) participants allocated to nateglinide died compared with 312/4661 (6.7%) participants allocated to placebo (hazard ratio (HR) 1.00; 95% CI 0.85 to 1.17; P = 0.98; moderate-quality evidence). The two main criteria for diagnosing T2DM were a fasting plasma glucose level ≥ 7.0 mmol/L or a 2-hour post challenge glucose ≥ 11.1 mmol/L. T2DM developed in 1674/4645 (36.0%) participants in the nateglinide group and in 1580/4661 (33.9%) in the placebo group (HR 1.07; 95% CI 1.00 to 1.15; P = 0.05; moderate-quality evidence). One or more serious adverse event was reported in 2066/4602 (44.9%) participants allocated to nateglinide compared with 2089/4599 (45.6%) participants allocated to placebo. A total of 126/4645 (2.7%) participants allocated to nateglinide died because of cardiovascular disease compared with 118/4661 (2.5%) participants allocated to placebo (HR 1.07; 95% CI 0.83 to 1.38; P = 0.60; moderate-quality evidence). Comparing participants receiving nateglinide with those receiving placebo for the outcomes MI, non-fatal stroke and HF gave the following event rates: MI 116/4645 (2.5%) versus 122/4661 (2.6%), stroke 100/4645 (2.2%) versus 110/4661 (2.4%) and numbers hospitalised for HF 85/4645 (1.8%) versus 100/4661 (2.1%) - (HR 0.85; 95% CI 0.64 to 1.14; P = 0.27). The quality of the evidence was moderate for all these outcomes. Health-related quality of life or socioeconomic effects were not reported. AUTHORS' CONCLUSIONS: There is insufficient evidence to demonstrate whether insulin secretagogues compared mainly with placebo reduce the risk of developing T2DM and its associated complications in people at increased risk for the development of T2DM. Most trials did not investigate patient-important outcomes.

Drug interventions for the treatment of obesity in children and adolescents.

BACKGROUND: Child and adolescent obesity has increased globally, and can be associated with significant short- and long-term health consequences. OBJECTIVES: To assess the efficacy of drug interventions for the treatment of obesity in children and adolescents. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, PubMed (subsets not available on Ovid), LILACS as well as the trial registers ICTRP (WHO) and ClinicalTrials.gov. Searches were undertaken from inception to March 2016. We checked references and applied no language restrictions. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) of pharmacological interventions for treating obesity (licensed and unlicensed for this indication) in children and adolescents (mean age under 18 years) with or without support of family members, with a minimum of three months' pharmacological intervention and six months' follow-up from baseline. We excluded interventions that specifically dealt with the treatment of eating disorders or type 2 diabetes, or included participants with a secondary or syndromic cause of obesity. In addition, we excluded trials which included growth hormone therapies and pregnant participants. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data following standard Cochrane methodology. Where necessary we contacted authors for additional information. MAIN RESULTS: We included 21 trials and identified eight ongoing trials. The included trials evaluated metformin (11 trials), sibutramine (six trials), orlistat (four trials), and one trial arm investigated the combination of metformin and fluoxetine. The ongoing trials evaluated metformin (four trials), topiramate (two trials) and exenatide (two trials). A total of 2484 people participated in the included trials, 1478 participants were randomised to drug intervention and 904 to comparator groups (91 participants took part in two cross-over trials; 11 participants not specified). Eighteen trials used a placebo in the comparator group. Two trials had a cross-over design while the remaining 19 trials were parallel RCTs. The length of the intervention period ranged from 12 weeks to 48 weeks, and the length of follow-up from baseline ranged from six months to 100 weeks.Trials generally had a low risk of bias for random sequence generation, allocation concealment and blinding (participants, personnel and assessors) for subjective and objective outcomes. We judged approximately half of the trials as having a high risk of bias in one or more domain such as selective reporting.The primary outcomes of this review were change in body mass index (BMI), change in weight and adverse events. All 21 trials measured these outcomes. The secondary outcomes were health-related quality of life (only one trial reported results showing no marked differences; very low certainty evidence), body fat distribution (measured in 18 trials), behaviour change (measured in six trials), participants' views of the intervention (not reported), morbidity associated with the intervention (measured in one orlistat trial only reporting more new gallstones following the intervention; very low certainty evidence), all-cause mortality (one suicide in the orlistat intervention group; low certainty evidence) and socioeconomic effects (not reported).Intervention versus comparator for mean difference (MD) in BMI change was -1.3 kg/m2 (95% confidence interval (CI) -1.9 to -0.8; P < 0.00001; 16 trials; 1884 participants; low certainty evidence). When split by drug type, sibutramine, metformin and orlistat all showed reductions in BMI in favour of the intervention.Intervention versus comparator for change in weight showed a MD of -3.9 kg (95% CI -5.9 to -1.9; P < 0.00001; 11 trials; 1180 participants; low certainty evidence). As with BMI, when the trials were split by drug type, sibutramine, metformin and orlistat all showed reductions in weight in favour of the intervention.Five trials reported serious adverse events: 24/878 (2.7%) participants in the intervention groups versus 8/469 (1.7%) participants in the comparator groups (risk ratio (RR) 1.43, 95% CI 0.63 to 3.25; 1347 participants; low certainty evidence). A total 52/1043 (5.0%) participants in the intervention groups versus 17/621 (2.7%) in the comparator groups discontinued the trial because of adverse events (RR 1.45, 95% CI 0.83 to 2.52; 10 trials; 1664 participants; low certainty evidence). The most common adverse events in orlistat and metformin trials were gastrointestinal (such as diarrhoea, mild abdominal pain or discomfort, fatty stools). The most frequent adverse events in sibutramine trials included tachycardia, constipation and hypertension. The single fluoxetine trial reported dry mouth and loose stools. No trial investigated drug treatment for overweight children. AUTHORS' CONCLUSIONS: This systematic review is part of a series of associated Cochrane reviews on interventions for obese children and adolescents and has shown that pharmacological interventions (metformin, sibutramine, orlistat and fluoxetine) may have small effects in reduction in BMI and bodyweight in obese children and adolescents. However, many of these drugs are not licensed for the treatment of obesity in children and adolescents, or have been withdrawn. Trials were generally of low quality with many having a short or no post-intervention follow-up period and high dropout rates (overall dropout of 25%). Future research should focus on conducting trials with sufficient power and long-term follow-up, to ensure the long-term effects of any pharmacological intervention are comprehensively assessed. Adverse events should be reported in a more standardised manner specifying amongst other things the number of participants experiencing at least one adverse event. The requirement of regulatory authorities (US Food and Drug Administration and European Medicines Agency) for trials of all new medications to be used in children and adolescents should drive an increase in the number of high quality trials.