Use of Dental Practices for the Identification of Adults With Undiagnosed Type 2 Diabetes Mellitus or Nondiabetic Hyperglycemia: Protocol for a Systematic Review.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a growing global health burden and is expected to affect more than 590 million people by the year 2035. Evidence exists to demonstrate that dental settings have been used for risk assessment and identification of individuals who may be at high risk for T2DM or who may already unknowingly have the condition. OBJECTIVE: This protocol aims to outline the methodology that will be undertaken to synthesize the literature relating to the use of primary care (nonhospital-based) dental services for the identification of undiagnosed T2DM or prediabetes-often termed nondiabetic hyperglycemia-in adult patients. METHODS: This paper outlines the protocol that will be followed to conduct a systematic review and meta-analysis of the available literature. The protocol outlines the aims, objectives, search strategy, data extraction and data management methods, as well as the statistical analysis plan. The Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines were followed in developing the protocol as were elements of the Cochrane handbook. RESULTS: We expect the systematic review to be completed within 18 months of publication of this protocol and expect to see a high degree of heterogeneity in the existing literature. CONCLUSIONS: This review is of importance as it will synthesize the existing evidence base and inform future studies in the field. Following the publication of the protocol, the review will be registered on Prospective Register of Systematic Reviews. Following the completion of the review, results will be published in a suitable peer-reviewed journal. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/11843

Sample size calculations for stepped-wedge cluster randomised trials with unequal cluster sizes

Background The current methodology for sample size calculation for steppedwedge cluster randomised trials (SW-CRTs) is based on the assumption of the clusters being of equal size. However, as is often the case in CRTs, the clusters in SW-CRTs are likely to vary in size which in CRTs of other designs leads to a reduction in power. The effect of an imbalance in cluster sizes on SW-CRTs was not known, nor what an appropriate adjustment to the sample size should be. Trials 2016, Volume 17 Suppl 1 Page 4 of 6 Methods We proposed three adjusted design effects (DEs) for use in the calculation of the sample size for SW-CRTs with varying degrees of imbalance in cluster size, based on those suggested for use in CRTs with unequal cluster sizes. A simulation study was conducted which investigated the effect of unequal cluster sizes on the power of SW-CRTs, when the sample size was calculated using both the standard method and the three proposed adjusted DEs. Results An imbalance in cluster size was not found to significantly affect the power of a SW-CRT, and the proposed adjusted DEs generally resulted in trials that were severely over-powered. Conclusions We recommend that the standard method of sample size calculation for SW-CRTs be used when any imbalance in cluster size is expected to be small. When there is likely to be a large imbalance in cluster size it is recommended that simulations be used to determine if additional clusters are needed

The use of feasibility studies for stepped-wedge cluster randomised trials: a review of impact and scope

Background The stepped-wedge cluster randomised trial (SW-CRT) is a complex design for which many decisions must be made during the design stage, such as the required number and length of steps. Feasibility studies might help to inform these decisions and increase the likelihood of the main trial’s success. However, there is currently no guidance on how feasibility studies for SW-CRTs should be conducted. This review, the first in a series of related projects, aims to establish how often feasibility studies are being conducted for SW- CRTs and determine which feasibility issues are currently being investigated. Ultimately this work will lead to guidance on how feasibility studies in SW- CRTs should be conducted. Methods and analysis Searches for feasibility studies for SW- CRTs were conducted in Ovid MEDLINE, Scopus, and psycinfo. Relevant studies were identified via titles, abstracts and full-text retrievals according to pre-defined study inclusion criteria. Data were abstracted on the aims of these studies and how these studies were able to inform the main trial. In order to also identify unpublished feasibility studies for SW- CRTs, fully published SW- CRTs were identified from the most recent systematic reviews. The authors of these studies were contacted with the aim of determining whether any unpublished feasibility work was conducted prior to the main trial. In addition, the lead statisticians for registered UK clinical trials units were contacted to acquire information on feasibility work that is being undertaken by these units to inform SW- CRTs. Conclusion This review, which is pending final results, will determine how often feasibility studies are being used to inform SW- CRTs and identify which feasibility issues are being investigated. Any information that is gained on how these feasibility studies have informed the main trials, will allow us to gain an insight into how feasibility studies can benefit SW- CRTs. Future qualitative work will determine which aspects of feasibility studies are considered most useful and what barriers are commonly encountered when conducting a SW-CRT

Identification of participants for a questionnaire and interview study investigating the feasibility issues encountered during stepped-wedge cluster randomised trials

Background The stepped-wedge cluster randomised trial (SW-CRT) is a complex design for which many decisions must be made during the design stage, such as the required number and length of steps. Feasibility studies might help to inform these decisions and increase the likelihood of the main trial’s success. However, there is currently no guidance on how feasibility studies for SW-CRTs should be conducted. This review, the first in a series of related projects, aims to establish how often feasibility studies are being conducted for SW- CRTs and determine which feasibility issues are currently being investigated. Ultimately this work will lead to guidance on how feasibility studies in SW- CRTs should be conducted. Methods and analysis Searches for feasibility studies for SW- CRTs were conducted in Ovid MEDLINE, Scopus, and psycinfo. Relevant studies were identified via titles, abstracts and full-text retrievals according to pre-defined study inclusion criteria. Data were abstracted on the aims of these studies and how these studies were able to inform the main trial. In order to also identify unpublished feasibility studies for SW- CRTs, fully published SW- CRTs were identified from the most recent systematic reviews. The authors of these studies were contacted with the aim of determining whether any unpublished feasibility work was conducted prior to the main trial. In addition, the lead statisticians for registered UK clinical trials units were contacted to acquire information on feasibility work that is being undertaken by these units to inform SW- CRTs. Conclusion This review, which is pending final results, will determine how often feasibility studies are being used to inform SW- CRTs and identify which feasibility issues are being investigated. Any information that is gained on how these feasibility studies have informed the main trials, will allow us to gain an insight into how feasibility studies can benefit SW- CRTs. Future qualitative work will determine which aspects of feasibility studies are considered most useful and what barriers are commonly encountered when conducting a SW-CRT

Changing cluster composition in cluster randomised controlled trials: design and analysis considerations

BACKGROUND: There are many methodological challenges in the conduct and analysis of cluster randomised controlled trials, but one that has received little attention is that of post-randomisation changes to cluster composition. To illustrate this, we focus on the issue of cluster merging, considering the impact on the design, analysis and interpretation of trial outcomes. METHODS: We explored the effects of merging clusters on study power using standard methods of power calculation. We assessed the potential impacts on study findings of both homogeneous cluster merges (involving clusters randomised to the same arm of a trial) and heterogeneous merges (involving clusters randomised to different arms of a trial) by simulation. To determine the impact on bias and precision of treatment effect estimates, we applied standard methods of analysis to different populations under analysis. RESULTS: Cluster merging produced a systematic reduction in study power. This effect depended on the number of merges and was most pronounced when variability in cluster size was at its greatest. Simulations demonstrate that the impact on analysis was minimal when cluster merges were homogeneous, with impact on study power being balanced by a change in observed intracluster correlation coefficient (ICC). We found a decrease in study power when cluster merges were heterogeneous, and the estimate of treatment effect was attenuated. CONCLUSIONS: Examples of cluster merges found in previously published reports of cluster randomised trials were typically homogeneous rather than heterogeneous. Simulations demonstrated that trial findings in such cases would be unbiased. However, simulations also showed that any heterogeneous cluster merges would introduce bias that would be hard to quantify, as well as having negative impacts on the precision of estimates obtained. Further methodological development is warranted to better determine how to analyse such trials appropriately. Interim recommendations include avoidance of cluster merges where possible, discontinuation of clusters following heterogeneous merges, allowance for potential loss of clusters and additional variability in cluster size in the original sample size calculation, and use of appropriate ICC estimates that reflect cluster size

South Asian individuals at high risk of type 2 diabetes have lower plasma vitamin C levels than white Europeans.

Individuals of South Asian origin are at high risk of developing type 2 diabetes; the relationship between this risk and diet remains to be investigated fully. Furthermore, fruit and vegetable intake remains low throughout the world and previous data suggest that intake is associated with risk of diabetes. The aim of this research study was to compare plasma vitamin C concentrations, measured as a biomarker for fruit and vegetable intake, in South Asian and white European individuals. Participants recruited as part of the Let's Prevent Diabetes Study provided samples for the quantification of plasma vitamin C. We compared vitamin C levels by ethnicity using multiple regression, both unadjusted and adjusted for confounders, including glycaemic status. Mean plasma vitamin C was significantly lower in the South Asian participants compared with white European participants (34.5 (sd 19·8) v. 39·9 (sd 22·1) µmol/l, respectively; P ≤ 0·0001). Significantly fewer South Asian individuals consumed five portions of fruit and vegetables per d, as determined by a plasma vitamin C concentration of ≥ 50 µmol/l (23·2 % (n 58) v. 31·4 % (n 558); P = 0·01). Vitamin C reflects habitual fruit and vegetable consumption; thus results suggest that South Asians have lower fruit and vegetable intake. However, it cannot be excluded that vitamin C is utilised differently. Dietary advice specifically targeting the South Asian population should be developed

Safety and effectiveness of non-insulin glucose-lowering agents in the treatment of people with type 2 diabetes who observe Ramadan: a systematic review and meta-analysis

Aim: To determine which non-insulin glucose-lowering treatment regimens are most appropriate in people with type 2 diabetes who choose to fast during Ramadan. Methods: Electronic databases were searched for randomized controlled trials (RCTs) and observational studies that compared non-insulin glucose-lowering agents in people with type 2 diabetes fasting during Ramadan. Those studies which reported hypoglycaemia, weight and glycated haemoglobin (HbA1c) change were included. Data were pooled using random effects models. Results: A total of 16 studies were included: 9 RCTs and 7 observational studies. There was evidence that dipeptidyl peptidase-4 (DPP-4) inhibitors led to fewer hypoglycaemic events compared with sulphonylureas. Sitagliptin significantly reduced the number of patients with ≥1 hypoglycaemic episodes during Ramadan [risk ratio (RR) 0.48, 95% confidence interval (CI) 0.36, 0.64; p > 0.0001]. This was not replicated in the RCTs of vildagliptin, but a significant reduction was found in the observational studies (RR 0.28, 95% CI 0.10, 0.75; p = 0.01) with high heterogeneity (I[superscript: 2] = 86.7%). Significant reductions in HbA1c and weight were seen in the observational studies of vildagliptin versus sulphonylureas. The use of liraglutide led to significant weight loss (−1.81 kg, 95% CI −2.91, −0.71; p = 0.001) compared with sulphonylureas. Pioglitazone significantly increased weight compared with placebo (3.48 kg, 95% CI 2.82, 4.14; p < 0.0001). Conclusions: The analysis supports the use of DPP-4 inhibitors during Ramadan rather than sulphonylureas for reduction in hypoglycaemia without a cost to diabetes control and weight. The glucagon-like peptide (GLP)-1 agonist liraglutide provides clinical benefits, but more studies are required. RCTs of DPP-4 inhibitors compared with GLP-1 agonists and novel therapies including the sodium-glucose co-transporter 2 and α-glucosidase inhibitors are needed to inform evidence-based guidelines

Impact of depression and anxiety on change to physical activity following a pragmatic diabetes prevention programme within primary care: pooled analysis from two randomized controlled trials

OBJECTIVE The impact of major affective disorders on the effectiveness of diabetes prevention programs at promoting health behaviors has not been established. We investigated whether depression modifies the effectiveness of two pragmatic diabetes prevention programs at promoting increased physical activity.RESEARCH DESIGN AND METHODS This study pooled data from two cluster randomized controlled trials (Walking Away from Type 2 Diabetes and Let’s Prevent Type 2 Diabetes) that included individuals at high risk of type 2 diabetes who were recruited from primary care. The trials used very similar intervention methods to promote physical activity and had annual follow-up over a 36-month period. Depressive symptoms were measured by the Hospital Anxiety and Depression Scale, and physical activity was measured by a piezoelectric pedometer (Let’s Prevent Type 2 Diabetes) or an accelerometer (Walking Away from Type 2 Diabetes) and expressed as steps per day.RESULTS This analysis included 1,163 individuals (571 control, 592 intervention) who had concurrent baseline and follow-up data for ambulatory activity, depression, and anxiety. The median depression score was 3 at baseline; 11% of individuals were classified as having mild to severe depression. Those with no depressive symptoms at baseline or during follow-up increased their ambulatory activity by 592 steps per day (P CONCLUSIONS Both depressive symptom burden at baseline and change in this burden are associated with a graded reduction in the effectiveness of diabetes prevention programs at increasing physical activity in primary care.</div

The safety and effectiveness of non-insulin glucose lowering agents in the treatment of people with Type 2 Diabetes who observe Ramadan: A systematic review and meta-analysis

Aims: To determine which non-insulin glucose lowering treatment regimens are most appropriate in people with type 2 diabetes who choose to fast during Ramadan. Materials and methods: Electronic databases were searched for randomised controlled trials (RCT) and observational studies comparing non-insulin glucose lowering agents in people with type 2 diabetes fasting during Ramadan reporting hypoglycaemia, weight and HbA1c change were included. Data were pooled using random effects models. Results: Sixteen studies included; nine RCTs and seven observational studies. There was evidence that DPP-4 inhibitors led to less hypoglycaemic events compared to sulphonylureas. Sitagliptin significantly reduced the number of patients ≥1 hypoglycaemic episodes during Ramadan (RR 0.48, 95%CI 0.36, 0.64, p>0.0001), this was not replicated in the RCTs of vildagliptin but a significant reduction was found in the observational studies (RR 0.28, 95%CI 0.10, 0.75, p=0.01) with high heterogeneity (I2=86.7%). Significant reductions in HbA1c and weight were seen in the observational studies of vildagliptin vs. sulfonylureas. The use of liraglutide led to significant weight loss (-1.81kg, 95%CI -2.91, -0.71, p=0.001) compared to sulfonylureas. Pioglitazone significantly increased weight compared to placebo (3.48kg, 95%CI 2.82, 4.14, p<0.0001). Conclusions: The analysis supports the use of DPP-4 inhibitors during Ramadan over sulfonylureas for reduction in hypoglycaemic episodes without a cost to diabetes control and weight. The GLP-1 agonist liraglutide provides clinical benefits, but more studies are required. RCTs of DPP-4 inhibitors against GLP-1 agonists and novel therapies including the SGLT-2 and alpha-glucosidase inhibitors are needed to inform evidence based guidelines

Engagement, Retention, and Progression to Type 2 Diabetes: A Retrospective Analysis of the Cluster-Randomised "Let's Prevent Diabetes" Trial

Background: Prevention of type 2 diabetes mellitus (T2DM) is a global priority. Let’s Prevent Diabetes is a group-based diabetes prevention programme; it was evaluated in a cluster-randomised trial, in which the primary analysis showed a reduction in T2DM (hazard ratio [HR] 0.74, 95% CI 0.48–1.14, p = 0.18). We examined the association of engagement and retention with the Let’s Prevent Diabetes prevention programme and T2DM incidence. Methods and Findings: We used data from a completed cluster-randomised controlled trial including 43 general practices randomised to receive either standard care or a 6-h group structured education programme with an annual refresher course for 2 y. The primary outcome was progression to T2DM at 3 y. The characteristics of those who attended the initial education session (engagers) versus nonengagers and those who attended all sessions (retainers) versus nonretainers were compared. Risk reduction of progression to T2DM by level of attendance was compared to standard care. Eight hundred and eighty participants were recruited, with 447 to the intervention arm, of which 346 (77.4%) were engagers and 130 (29.1%) were retainers. Retainers and engagers were more likely to be older, leaner, and nonsmokers than nonretainers/nonengagers. Engagers were also more likely to be male and be from less socioeconomically deprived areas than nonengagers. Participants who attended the initial session and at least one refresher session were less likely to develop T2DM compared to those in the control arm (30 people of 248 versus 67 people of 433, HR 0.38 [95% CI 0.24–0.62]). Participants who were retained in the programme were also less likely to develop T2DM compared to those in the control arm (7 people of 130 versus 67 people of 433, HR 0.12 [95% CI 0.05–0.28]). Being retained in the programme was also associated with improvements in glucose, glycated haemoglobin (HbA1c), weight, waist circumference, anxiety, quality of life, and daily step count. Given that the data used are from a clinical trial, those taking part might reflect a more motivated sample than the population, which should be taken into account when interpreting the results. Conclusions: This study suggests that being retained/engaged in a relatively low-resource, pragmatic diabetes prevention programme for those at high risk is associated with reductions in the progression to T2DM in comparison to those who receive standard care. Nonengagers and nonretainers share similar high-risk traits. Service providers of programmes should focus on reaching these hard-to-reach groups