Dual targeting of the androgen receptor and PI3K/AKT/mTOR pathways in prostate cancer models improves antitumor efficacy and promotes cell apoptosis.

Prostate cancer is a frequent malignancy in older men and has a very high 5-year survival rate if diagnosed early. The prognosis is much less promising if the tumor has already spread outside the prostate gland. Targeted treatments mainly aim at blocking androgen receptor (AR) signaling and initially show good efficacy. However, tumor progression due to AR-dependent and AR-independent mechanisms is often observed after some time, and novel treatment strategies are urgently needed. Dysregulation of the PI3K/AKT/mTOR pathway in advanced prostate cancer and its implication in treatment resistance has been reported. We compared the impact of PI3K/AKT/mTOR pathway inhibitors with different selectivity profiles on in vitro cell proliferation and on caspase 3/7 activation as a marker for apoptosis induction, and observed the strongest effects in the androgen-sensitive prostate cancer cell lines VCaP and LNCaP. Combination treatment with the AR inhibitor darolutamide led to enhanced apoptosis in these cell lines, the effects being most pronounced upon cotreatment with the pan-PI3K inhibitor copanlisib. A subsequent transcriptomic analysis performed in VCaP cells revealed that combining darolutamide with copanlisib impacted gene expression much more than individual treatment. A comprehensive reversal of the androgen response and the mTORC1 transcriptional programs as well as a marked induction of DNA damage was observed. Next, an in vivo efficacy study was performed using the androgen-sensitive patient-derived prostate cancer (PDX) model LuCaP 35 and a superior efficacy was observed after the combined treatment with copanlisib and darolutamide. Importantly, immunohistochemistry analysis of these treated tumors showed increased apoptosis, as revealed by elevated levels of cleaved caspase 3 and Bcl-2-binding component 3 (BBC3). In conclusion, these data demonstrate that concurrent blockade of the PI3K/AKT/mTOR and AR pathways has superior antitumor efficacy and induces apoptosis in androgen-sensitive prostate cancer cell lines and PDX models.

Pan-PI3K inhibition with copanlisib overcomes Treg- and M2-TAM-mediated immune suppression and promotes anti-tumor immune responses.

The PI3K pathway is one of the most frequently altered signaling pathways in human cancer. In addition to its function in cancer cells, PI3K plays a complex role in modulating anti-tumor immune responses upon immune checkpoint inhibition (ICI). Here, we evaluated the effects of the pan-Class I PI3K inhibitor copanlisib on different immune cell types in vitro and on tumor growth and immune cell infiltration in syngeneic murine cancer models. Intermittent treatment with copanlisib resulted in a strong in vivo anti-tumor efficacy, increased tumor infiltration of activated T cells and macrophages, and increased CD8+ T cell/regulatory T cell and M1/M2 macrophage ratios. The strong in vivo efficacy was at least partially due to immunomodulatory activity of copanlisib, as in vitro these murine cancer cells were resistant to PI3K inhibition. Furthermore, the combination of copanlisib with the ICI antibody anti-PD-1 demonstrated enhanced anti-tumor efficacy in both ICI-sensitive and insensitive syngeneic mouse tumor models. Importantly, in an ICI-sensitive model, combination therapy resulted in complete remission and prevention of tumor recurrence. Thus, the combination of ICIs with PI3K inhibition by intermittently dosed copanlisib represents a promising new strategy to increase sensitivity to ICI therapies and to treat human solid cancers.

Referral to the NHS Diabetes Prevention Programme and conversion from nondiabetic hyperglycaemia to type 2 diabetes mellitus in England: A matched cohort analysis.

BACKGROUND: The NHS Diabetes Prevention Programme (NDPP) is a behaviour change programme for adults who are at risk of developing type 2 diabetes mellitus (T2DM): people with raised blood glucose levels, but not in the diabetic range, diagnosed with nondiabetic hyperglycaemia (NDH). We examined the association between referral to the programme and reducing conversion of NDH to T2DM. METHODS AND FINDINGS: Cohort study of patients attending primary care in England using clinical Practice Research Datalink data from 1 April 2016 (NDPP introduction) to 31 March 2020 was used. To minimise confounding, we matched patients referred to the programme in referring practices to patients in nonreferring practices. Patients were matched based on age (≥3 years), sex, and ≥365 days of NDH diagnosis. Random-effects parametric survival models evaluated the intervention, controlling for numerous covariates. Our primary analysis was selected a priori: complete case analysis, 1-to-1 practice matching, up to 5 controls sampled with replacement. Various sensitivity analyses were conducted, including multiple imputation approaches. Analysis was adjusted for age (at index date), sex, time from NDH diagnosis to index date, BMI, HbA1c, total serum cholesterol, systolic blood pressure, diastolic blood pressure, prescription of metformin, smoking status, socioeconomic status, a diagnosis of depression, and comorbidities. A total of 18,470 patients referred to NDPP were matched to 51,331 patients not referred to NDPP in the main analysis. Mean follow-up from referral was 482.0 (SD = 317.3) and 472.4 (SD = 309.1) days, for referred to NDPP and not referred to NDPP, respectively. Baseline characteristics in the 2 groups were similar, except referred to NDPP were more likely to have higher BMI and be ever-smokers. The adjusted HR for referred to NDPP, compared to not referred to NDPP, was 0.80 (95% CI: 0.73 to 0.87) (p < 0.001). The probability of not converting to T2DM at 36 months since referral was 87.3% (95% CI: 86.5% to 88.2%) for referred to NDPP and 84.6% (95% CI: 83.9% to 85.4%) for not referred to NDPP. Associations were broadly consistent in the sensitivity analyses, but often smaller in magnitude. As this is an observational study, we cannot conclusively address causality. Other limitations include the inclusion of controls from the other 3 UK countries, data not allowing the evaluation of the association between attendance (rather than referral) and conversion. CONCLUSIONS: The NDPP was associated with reduced conversion rates from NDH to T2DM. Although we observed smaller associations with risk reduction, compared to what has been observed in RCTs, this is unsurprising since we examined the impact of referral, rather than attendance or completion of the intervention.

Epidemiology and determinants of non-diabetic hyperglycaemia and its conversion to type 2 diabetes mellitus, 2000-2015: cohort population study using UK electronic health records.

OBJECTIVES: To study the characteristics of UK individuals identified with non-diabetic hyperglycaemia (NDH) and their conversion rates to type 2 diabetes mellitus (T2DM) from 2000 to 2015, using the Clinical Practice Research Datalink. DESIGN: Cohort study. SETTINGS: UK primary Care Practices. PARTICIPANTS: Electronic health records identified 14 272 participants with NDH, from 2000 to 2015. PRIMARY AND SECONDARY OUTCOME MEASURES: Baseline characteristics and conversion trends from NDH to T2DM were explored. Cox proportional hazards models evaluated predictors of conversion. RESULTS: Crude conversion was 4% within 6 months of NDH diagnosis, 7% annually, 13% within 2 years, 17% within 3 years and 23% within 5 years. However, 1-year conversion fell from 8% in 2000 to 4% in 2014. Individuals aged 45-54 were at the highest risk of developing T2DM (HR 1.20, 95% CI 1.15 to 1.25- compared with those aged 18-44), and the risk reduced with older age. A body mass index (BMI) above 30 kg/m2 was strongly associated with conversion (HR 2.02, 95% CI 1.92 to 2.13-compared with those with a normal BMI). Depression (HR 1.10, 95% CI 1.07 to 1.13), smoking (HR 1.07, 95% CI 1.03 to 1.11-compared with non-smokers) or residing in the most deprived areas (HR 1.17, 95% CI 1.11 to 1.24-compared with residents of the most affluent areas) was modestly associated with conversion. CONCLUSION: Although the rate of conversion from NDH to T2DM fell between 2010 and 2015, this is likely due to changes over time in the cut-off points for defining NDH, and more people of lower diabetes risk being diagnosed with NDH over time. People aged 45-54, smokers, depressed, with high BMI and more deprived are at increased risk of conversion to T2DM.

Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial.

BACKGROUND: Oral semaglutide is the first oral glucagon-like peptide-1 (GLP-1) receptor agonist for glycaemic control in patients with type 2 diabetes. Type 2 diabetes is commonly associated with renal impairment, restricting treatment options. We aimed to investigate the efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment. METHODS: This randomised, double-blind, phase 3a trial was undertaken at 88 sites in eight countries. Patients aged 18 years and older, with type 2 diabetes, an estimated glomerular filtration rate of 30-59 mL/min per 1·73 m2, and who had been receiving a stable dose of metformin or sulfonylurea, or both, or basal insulin with or without metformin for the past 90 days were eligible. Participants were randomly assigned (1:1) by use of an interactive web-response system, with stratification by glucose-lowering medication and renal function, to receive oral semaglutide (dose escalated to 14 mg once daily) or matching placebo for 26 weeks, in addition to background medication. Participants and site staff were masked to assignment. Two efficacy-related estimands were defined: treatment policy (regardless of treatment discontinuation or rescue medication) and trial product (on treatment without rescue medication) in all participants randomly assigned. Endpoints were change from baseline to week 26 in HbA1c (primary endpoint) and bodyweight (confirmatory secondary endpoint), assessed in all participants with sufficient data. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered on ClinicalTrials.gov, number NCT02827708, and the European Clinical Trials Registry, number EudraCT 2015-005326-19, and is now complete. FINDINGS: Between Sept 20, 2016, and Sept 29, 2017, of 721 patients screened, 324 were eligible and randomly assigned to oral semaglutide (n=163) or placebo (n=161). Mean age at baseline was 70 years (SD 8), and 168 (52%) of participants were female. 133 (82%) participants in the oral semaglutide group and 141 (88%) in the placebo group completed 26 weeks on treatment. At 26 weeks, oral semaglutide was superior to placebo in decreasing HbA1c (estimated mean change of -1·0 percentage point (SE 0·1; -11 mmol/mol [SE 0·8]) vs -0·2 percentage points (SE 0·1; -2 mmol/mol [SE 0·8]); estimated treatment difference [ETD]: -0·8 percentage points, 95% CI -1·0 to -0·6; p<0·0001) and bodyweight (estimated mean change of -3·4 kg [SE 0·3] vs -0·9 kg [SE 0·3]; ETD, -2·5, 95% CI -3·2 to -1·8; p<0·0001) by the treatment policy estimand. Significant differences were seen for the trial product estimand: mean change in HbA1c -1·1 percentage points (SE 0·1; -12 mmol/mol [SE 0·8] versus -0·1 percentage points (SE 0·1; -1 mmol/mol [SE 0·8]; ETD -1·0 percentage points, 95% CI -1·2 to -0·8; p<0·0001); mean change in bodyweight -3·7 kg (SE 0·3) versus -1·1 kg (SE 0·3; ETD -2·7 kg, 95% CI -3·5 to -1·9; p<0·0001). More patients taking oral semaglutide than placebo had adverse events (120 [74%] of 163 vs 105 [65%] of 161), and discontinued treatment as a result (24 [15%] vs eight [5%]). Gastrointestinal events, mainly mild-to-moderate nausea, were more common with oral semaglutide than with placebo. Three deaths occurred during the treatment period that were not condsidered to be treatment related, one in the semaglutide group and two in the placebo group. INTERPRETATION: Oral semaglutide was effective in patients with type 2 diabetes and moderate renal impairment, potentially providing a new treatment option for this population. Safety, including renal safety, was consistent with the GLP-1 receptor agonist class. FUNDING: Novo Nordisk A/S.

Effect of once-weekly semaglutide on the counterregulatory response to hypoglycaemia in people with type 2 diabetes: A randomized, placebo-controlled, double-blind, crossover trial.

AIMS: To investigate the effects of semaglutide vs placebo on glucagon and other counterregulatory hormones during hypoglycaemia in type 2 diabetes (T2D). METHODS: In this double-blind, placebo-controlled, single-centre trial, we randomized 38 men and women (treated only with metformin) 1:1 to 2 12-week crossover periods of once-weekly subcutaneous semaglutide or placebo, each followed by a hypoglycaemic clamp procedure. The primary endpoint was change in glucagon concentration from target plasma glucose (PG) level 5.5 mmol/L to nadir (target 2.5 mmol/L). RESULTS: The mean (range) participant age was 54.2 (41-64) years, body mass index 29.4 (23.3-36.1) kg/m2 , glycated haemoglobin 60.8 (44.3-83.6) mmol/mol (7.7 [6.2-9.8]%), and diabetes duration 4.5 (0.3-13.2) years. A total of 35 participants completed the trial and were included in the analyses. During the hypoglycaemic clamp from 5.5 mmol/L PG to nadir, the absolute change in mean glucagon concentration was similar for semaglutide vs placebo: 88.3 vs 83.1 pg/mL (estimated difference 5.2 pg/mL [95% confidence interval -7.7 to 18.1]). Concentrations of other counterregulatory hormones increased with both treatments, with a statistically significantly lower increase for noradrenaline and cortisol with semaglutide vs placebo. The glucose infusion rate to maintain constant clamp levels was similar for each treatment group, suggesting an overall similar counterregulatory response. The mean hypoglycaemic symptom score and proportion of participants recognizing hypoglycaemia during the study were lower for semaglutide vs placebo treatment at nadir, but cognitive function test results were similar. No new safety issues were observed for semaglutide. CONCLUSIONS: Semaglutide treatment did not compromise the counterregulatory glucagon response during experimental hypoglycaemia in people with T2D.

Cost-effectiveness of insulin pumps compared with multiple daily injections both provided with structured education for adults with type 1 diabetes: a health economic analysis of the Relative Effectiveness of Pumps over Structured Education (REPOSE) randomised controlled trial.

OBJECTIVES: To assess the long-term cost-effectiveness of insulin pumps and Dose Adjustment for Normal Eating (pumps+DAFNE) compared with multiple daily insulin injections and DAFNE (MDI+DAFNE) for adults with type 1 diabetes mellitus (T1DM) in the UK. METHODS: We undertook a cost-utility analysis using the Sheffield Type 1 Diabetes Policy Model and data from the Relative Effectiveness of Pumps over Structured Education (REPOSE) trial to estimate the lifetime incidence of diabetic complications, intervention-based resource use and associated effects on costs and quality-adjusted life years (QALYs). All economic analyses took a National Health Service and personal social services perspective and discounted costs and QALYs at 3.5% per annum. A probabilistic sensitivity analysis was performed on the base case. Further uncertainties in the cost of pumps and the evidence used to inform the model were explored using scenario analyses. SETTING: Eight diabetes centres in England and Scotland. PARTICIPANTS: Adults with T1DM who were eligible to receive a structured education course and did not have a strong clinical indication or a preference for a pump. INTERVENTION: Pumps+DAFNE. COMPARATOR: MDI+DAFNE. MAIN OUTCOME MEASURES: Incremental costs, incremental QALYs gained and incremental cost-effectiveness ratios (ICERs). RESULTS: Compared with MDI+DAFNE, pumps+DAFNE was associated with an incremental discounted lifetime cost of +£18 853 (95% CI £6175 to £31 645) and a gain in discounted lifetime QALYs of +0.13 (95% CI -0.70 to +0.96). The base case mean ICER was £142 195 per QALY gained. The probability of pump+DAFNE being cost-effective using a cost-effectiveness threshold of £20 000 per QALY gained was 14.0%. All scenario and subgroup analyses examined indicated that the ICER was unlikely to fall below £30 000 per QALY gained. CONCLUSIONS: Our analysis of the REPOSE data suggests that routine use of pumps in adults without an immediate clinical need for a pump, as identified by National Institute for Health and Care Excellence, would not be cost-effective. TRIAL REGISTRATION NUMBER: ISRCTN61215213.

The role of structured education in the management of hypoglycaemia.

The role of intensive glycaemic control in preventing microvascular disease in diabetes is well established. Iatrogenic hypoglycaemia is, however, a major barrier to effective treatment. Hypoglycaemia is associated with a significant level of morbidity and, despite pharmacological and technological therapeutic advances, reported rates of severe hypoglycaemia in clinical practice have not fallen over the last 20 years. This suggests that human factors are of major relevance and that ensuring the effective self-management of diabetes is an important strategy for the reduction of hypoglycaemic risk. Most of the evidence for the impact of this strategy on hypoglycaemia risk is confined to adults with type 1 diabetes although, in this review, we also cite studies that have specifically addressed this in type 2 diabetes. There are relatively few adequately powered RCTs that have rigorously evaluated the effectiveness of structured education and training programmes on hypoglycaemia; however, the available data suggest a subsequent reduction in severe hypoglycaemia rates of around 50%, a rate reduction that is comparable with that observed following technological interventions. Furthermore, longitudinal observational cohorts support these data, showing similar reductions in rates of hypoglycaemia following structured education. Those who continue to experience recurrent hypoglycaemia and impaired awareness of hypoglycaemia despite education and training in diabetes self-management may benefit from technological interventions and/or interventions that specifically address psychological factors that contribute to hypoglycaemia risk; however, there is urgent need for further research in this area. In the meantime, structured education for effective self-management of diabetes should be part of routine therapy for all those with type 1 diabetes.

Prandial Options to Advance Basal Insulin Glargine Therapy: Testing Lixisenatide Plus Basal Insulin Versus Insulin Glulisine Either as Basal-Plus or Basal-Bolus in Type 2 Diabetes: The GetGoal Duo-2 Trial.

OBJECTIVE: To provide evidence-based options on how to intensify basal insulin, we explored head-to-head prandial interventions in overweight patients with type 2 diabetes inadequately controlled on basal insulin glargine with or without 1-3 oral antidiabetic agents (OADs). RESEARCH DESIGN AND METHODS: Patients were randomized to lixisenatide once daily or insulin glulisine given once or thrice daily, added to glargine, with or without metformin, if HbA1c remained ≥7 to ≤9% (≥53 to ≤75 mmol/mol) after 12 weeks of glargine optimization with OADs other than metformin stopped at the start of optimization. Coprimary end points at 26 weeks were 1) noninferiority (95% CI upper bound <0.4% [<4.4 mmol/mol]) in HbA1c reduction with lixisenatide versus glulisine once daily, and either 2a) noninferiority in HbA1c reduction for lixisenatide versus glulisine thrice daily or 2b) superiority in body weight change for lixisenatide versus glulisine thrice daily. Fasting and postprandial plasma glucose, composite efficacy/safety end points, and adverse events were also assessed. RESULTS: Baseline characteristics were similar between arms (n = 298, diabetes and basal insulin duration of 12.2 and 3.2 years, respectively; BMI 32.2 kg/m(2)). HbA1c improved from 8.5% to 7.9% (69 to 63 mmol/mol) with glargine optimization and further to 7.2%, 7.2%, and 7.0% (55, 55, and 53 mmol/mol) with lixisenatide and glulisine once daily and thrice daily, respectively; all coprimary end points were met. Symptomatic hypoglycemia and body weight were lower in lixisenatide versus glulisine patients. More gastrointestinal events occurred with lixisenatide. CONCLUSIONS: Short-acting glucagon-like peptide-1 receptor agonists as add-on to basal insulin may become a preferred treatment intensification option, attaining meaningful glycemic targets with fewer hypoglycemic events without weight gain versus basal-plus or basal-bolus in uncontrolled basal insulin-treated type 2 diabetes.

The Relative Effectiveness of Pumps Over MDI and Structured Education (REPOSE): study protocol for a cluster randomised controlled trial.

INTRODUCTION: People with type 1 diabetes (T1DM) require insulin therapy to sustain life, and need optimal glycaemic control to prevent diabetic ketoacidosis and serious long-term complications. Insulin is generally administered using multiple daily injections but can also be delivered using an infusion pump (continuous subcutaneous insulin infusion), a more costly option with benefits for some patients. The UK National Institute for Health and Care Excellence (NICE) recommend the use of pumps for patients with the greatest need, citing insufficient evidence to approve extension to a wider population. Far fewer UK adults use pumps than in comparable countries. Previous trials of pump therapy have been small and of short duration and failed to control for training in insulin adjustment. This paper describes the protocol for a large randomised controlled trial comparing pump therapy with multiple daily injections, where both groups are provided with high-quality structured education. METHODS AND ANALYSIS: A multicentre, parallel group, cluster randomised controlled trial among 280 adults with T1DM. All participants attended the week-long dose adjustment for normal eating (DAFNE) structured education course, and receive either multiple daily injections or pump therapy for 2 years. The trial incorporates a detailed mixed-methods psychosocial evaluation and cost-effectiveness analysis. The primary outcome will be the change in glycosylated haemoglobin (HbA1c) at 24 months in those participants whose baseline HbA1c is at or above 7.5% (58 mmol/mol). The key secondary outcome will be the proportion of participants reaching the NICE target of an HbA1c of 7.5% (58 mmol/mol) or less at 24 months. ETHICS AND DISSEMINATION: The protocol was approved by the Research Ethics Committee North West, Liverpool East and received Medicines and Healthcare products Regulatory Agency (MHRA) clinical trials authorisation. Each participating centre gave National Health Service R&D approval. We shall disseminate study findings to study participants and through peer reviewed publications and conference presentations, including lay user groups. TRIAL REGISTRATION NUMBER: ISRCTN 61215213.

Type 1 diabetes patients' experiences of, and need for, social support after attending a structured education programme: a qualitative longitudinal investigation.

AIMS AND OBJECTIVES: To explore patients' experiences of, views about and need for, social support after attending a structured education programme for type 1 diabetes. BACKGROUND: Patients who attend structured education programmes attain short-term improvements in biomedical and quality-of-life measures but require support to sustain self-management principles over the longer term. Social support can influence patients' self-management practices; however, little is known about how programme graduates use other people's help. DESIGN: This study was informed by the principles of grounded theory and involved concurrent data collection and analysis. Data were analysed using an inductive, thematic approach. METHODS: In-depth interviews were undertaken postcourse, six and 12 months later, with 30 adult patients with type 1 diabetes recruited from Dose Adjustment for Normal Eating courses in the United Kingdom. RESULTS: Patients' preferences for social support from other people ranged from wanting minimal involvement, to benefiting from auxiliary forms of assistance, to regular monitoring and policing. New self-management skills learnt on their courses prompted and facilitated patients to seek and obtain more social support. Support received/expected from parents varied according to when patients were diagnosed, but parents' use of outdated knowledge could act as a barrier to effective support. Support sought from others, including friends/colleagues, was informed by patients' domestic/employment circumstances. CONCLUSION: This study responds to calls for deeper understanding of the social context in which chronic illness self-management occurs. It highlights how patients can solicit and receive more social support from family members and friends after implementing self-care practices taught on education programmes. RELEVANCE TO CLINICAL PRACTICE: Health professionals including diabetes specialist nurses and dietitians should explore: patients' access to and preferences for social support; how patients might be encouraged to capitalise on social support postcourse; and new ways to inform/educate people within patients' social networks.

Alogliptin after acute coronary syndrome in patients with type 2 diabetes.

BACKGROUND: To assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes, regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new antidiabetic therapies. We assessed cardiovascular outcomes with alogliptin, a new inhibitor of dipeptidyl peptidase 4 (DPP-4), as compared with placebo in patients with type 2 diabetes who had had a recent acute coronary syndrome. METHODS: We randomly assigned patients with type 2 diabetes and either an acute myocardial infarction or unstable angina requiring hospitalization within the previous 15 to 90 days to receive alogliptin or placebo in addition to existing antihyperglycemic and cardiovascular drug therapy. The study design was a double-blind, noninferiority trial with a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. RESULTS: A total of 5380 patients underwent randomization and were followed for up to 40 months (median, 18 months). A primary end-point event occurred in 305 patients assigned to alogliptin (11.3%) and in 316 patients assigned to placebo (11.8%) (hazard ratio, 0.96; upper boundary of the one-sided repeated confidence interval, 1.16; P<0.001 for noninferiority). Glycated hemoglobin levels were significantly lower with alogliptin than with placebo (mean difference, -0.36 percentage points; P<0.001). Incidences of hypoglycemia, cancer, pancreatitis, and initiation of dialysis were similar with alogliptin and placebo. CONCLUSIONS: Among patients with type 2 diabetes who had had a recent acute coronary syndrome, the rates of major adverse cardiovascular events were not increased with the DPP-4 inhibitor alogliptin as compared with placebo. (Funded by Takeda Development Center Americas; EXAMINE ClinicalTrials.gov number, NCT00968708.).

Group follow-up compared to individual clinic visits after structured education for type 1 diabetes: a cluster randomised controlled trial.

AIM: To compare the effectiveness of group follow-up with individual follow-up after participation in the Dose Adjustment for Normal Eating (DAFNE) structured education programme. METHODS: Cluster randomised controlled trial involving 437 adults with type 1 diabetes attending hospital diabetes clinics in Ireland. All participants received DAFNE at baseline. Intervention arm participants received 2 group education sessions post-DAFNE and did not attend clinics. Control arm participants received 2 one-to-one clinic visits post-DAFNE. RESULTS: We observed no significant difference in the primary outcome (change in HbA1c) at 18 months follow-up (mean difference 0.14%; 95% CI -0.33 to 0.61; p=0.47). Secondary outcomes, including rates of severe hypoglycaemia, anxiety, depression, the burden of living with diabetes and quality of life did not differ between groups. Mean level of HbA1c for the entire sample (regardless of treatment arm) did not change between baseline and 18 month follow-up (p=0.09), but rates of severe hypoglycaemia, diabetes related hospital attendance, levels of anxiety, depression, the burden of living with diabetes, quality of life and treatment satisfaction all significantly improved. CONCLUSIONS: Our data suggest that group follow-up as the sole means of follow-up after structured education for individuals with type 1 diabetes is as effective as a return to one-to-one clinic visits.

Once-weekly exenatide versus once- or twice-daily insulin detemir: randomized, open-label, clinical trial of efficacy and safety in patients with type 2 diabetes treated with metformin alone or in combination with sulfonylureas.

OBJECTIVE: This multicenter, open-label, parallel-arm study compared the efficacy and safety of exenatide once weekly (EQW) with titrated insulin detemir in patients with type 2 diabetes inadequately controlled with metformin (with or without sulfonylureas). RESEARCH DESIGN AND METHODS: Patients were randomized to EQW (2 mg) or detemir (once or twice daily, titrated to achieve fasting plasma glucose ≤5.5 mmol/L) for 26 weeks. The primary outcome was proportion of patients achieving A1C ≤7.0% and weight loss ≥1.0 kg at end point, analyzed by means of logistic regression. Secondary outcomes included measures of glycemic control, cardiovascular risk factors, and safety and tolerability. RESULTS: Of 216 patients (intent-to-treat population), 111 received EQW and 105 received detemir. Overall, 44.1% (95% CI, 34.7-53.9) of EQW-treated patients compared with 11.4% (6.0-19.1) of detemir-treated patients achieved the primary outcome (P < 0.0001). Treatment with EQW resulted in significantly greater reductions than detemir in A1C (least-square mean ± SE, -1.30 ± 0.08% vs. -0.88 ± 0.08%; P < 0.0001) and weight (-2.7 ± 0.3 kg vs. +0.8 ± 0.4 kg; P < 0.0001). Gastrointestinal-related and injection site-related adverse events occurred more frequently with EQW than with detemir. There was no major hypoglycemia in either group. Five (6%) patients in the EQW group and six (7%) patients in the detemir group experienced minor hypoglycemia; only one event occurred without concomitant sulfonylureas (detemir group). CONCLUSIONS: Treatment with EQW resulted in a significantly greater proportion of patients achieving target A1C and weight loss than treatment with detemir, with a low risk of hypoglycemia. These results suggest that EQW is a viable alternative to insulin detemir treatment in patients with type 2 diabetes with inadequate glycemic control using oral antidiabetes drugs.

Does an intensive self-management structured education course improve outcomes for children and young people with type 1 diabetes? The Kids In Control OF Food (KICk-OFF) cluster-randomised controlled trial protocol.

INTRODUCTION: The Kids In Control OF Food (KICk-OFF) is a cluster-randomised controlled trial, which aims to determine the efficacy of a 5 day structured education course for 11-year-olds to 16-year-olds with type 1 diabetes (T1DM) when compared with standard care, and its cost effectiveness. Less than 15% of children and young people with T1DM in the UK meet the recommended glycaemic target. Self-management education programmes for adults with T1DM improve clinical and psychological outcomes, but none have been evaluated in the paediatric population. KICk-OFF is a 5-day structured education course for 11-year-olds to 16- year-olds with T1DM. It was developed with input from young people, parents, teachers and educationalists. METHODS AND ANALYSIS: 36 paediatric diabetes centres across the UK randomised into intervention and control arms. Up to 560 participants were recruited prior to centre randomisation. KICk-OFF courses are delivered in the intervention centres, with standard care continued in the control arm. Primary outcomes are change in glycaemic control (HbA1c) and quality of life between baseline and 6 months postintervention, and the incidence of severe hypoglycaemia. Sustained change in self-management behaviour is assessed by follow-up at 12 and 24 months. Health economic analysis will be undertaken. Data will be reported according to the CONSORT statement for cluster-randomised clinical trials. All analyses will be by intention-to-treat with a two-sided p value of <0.05 being regarded as statistically significant. The study commenced in 2008. Data collection from participants is ongoing and the study will be completed in 2013. ETHICS: The study has been approved by the Sheffield Research Ethics Committee. DISSEMINATION: Results will be reported in peer reviewed journals and conferences. TRIAL REGISTRATION: Current Controlled Trials ISRCTN37042683.

Structured type 1 diabetes education delivered within routine care: impact on glycemic control and diabetes-specific quality of life.

OBJECTIVE: To determine whether improvements in glycemic control and diabetes-specific quality of life (QoL) scores reported in research studies for the type 1 diabetes structured education program Dose Adjustment For Normal Eating (DAFNE) are also found when the intervention is delivered within routine U.K. health care. RESEARCH DESIGN AND METHODS: Before and after evaluation of DAFNE to assess impact on glycemic control and QoL among 262 adults with type 1 diabetes. RESULTS: There were significant improvements in HbA(1c) from baseline to 6 and 12 months (from 9.1 to 8.6 and 8.8%, respectively) in a subgroup with suboptimal control. QoL was significantly improved by 3 months and maintained at both follow-up points. CONCLUSIONS: Longer-term improved glycemic control and QoL is achievable among adults with type 1 diabetes through delivery of structured education in routine care, albeit with smaller effect sizes than reported in trials.

Supporting self-management after attending a structured education programme: a qualitative longitudinal investigation of type 1 diabetes patients' experiences and views.

BACKGROUND: Structured education programmes for patients with diabetes and other chronic conditions are being widely adopted. However, follow-up studies suggest that course graduates may struggle to sustain the self-care practices taught on their courses over time. This study explored the support needs of patients with type 1 diabetes after attending a structured education programme promoting an empowerment approach and training in use of flexible intensive insulin therapy, a regimen now widely advocated and used to manage this condition. The objective was to inform future support offered to course graduates. METHODS: Repeat, in-depth interviews with 30 type 1 diabetes patients after attending Dose Adjustment for Normal Eating (DAFNE) courses in the UK, and six and 12 months later. Data were analysed using an inductive, thematic approach. RESULTS: While the flexible intensive insulin treatment approach taught on DAFNE courses was seen as a logical and effective way of managing one's diabetes, it was also considered more technically complex than other insulin regimens. To sustain effective disease self-management using flexible intensive insulin treatment over time, patients often expected, and needed, on-going input and support from health care professionals trained in the approach. This included: help determining insulin dose adjustments; reassurance; and, opportunities to trouble-shoot issues of concern. While some benefits were identified to receiving follow-up support in a group setting, most patients stated a preference or need for tailored and individualised support from appropriately-trained clinicians, accessible on an 'as and when needed' basis. CONCLUSIONS: Our findings highlight potential limitations to group-based forms of follow-up support for sustaining diabetes self-management. To maintain the clinical benefits of structured education for patients with type 1 diabetes over time, course graduates may benefit from and prefer ongoing, one-to-one support from health care professionals trained in the programme's practices and principles. This support should be tailored and personalised to reflect patients' specific and unique experiences of applying their education and training in the context of their everyday lives, and could be the subject of future research.

Improved biomedical and psychological outcomes 1 year after structured education in flexible insulin therapy for people with type 1 diabetes: the U.K. DAFNE experience.

OBJECTIVE: DAFNE (Dose Adjustment For Normal Eating), a structured education program in flexible insulin therapy, has been widely adopted in the U.K. after validation in a randomized trial. To determine benefits in routine practice, we collected biomedical and psychological data from all participants attending during a 12-month period. RESEARCH DESIGN AND METHODS: HbA(1c), weight, self-reported hypoglycemia awareness, severe hypoglycemia frequency, PAID (Problem Areas In Diabetes), HADS (Hospital Anxiety and Depression Scale), and EuroQol Group 5-Dimension Self-Report Questionnaire scores were recorded prior to DAFNE and after 1 year. RESULTS: Complete baseline and follow-up HbA(1c) data were available for 639 (54.9%) of 1,163 attendees. HbA(1c) fell from 8.51 ± 1.41 (mean ± SD) to 8.24 ± 1.29% (difference 0.27 [95% CI 0.16-0.38]; P < 0.001), with a greater mean fall of 0.44% from baseline HbA(1c) >8.5%. Severe hypoglycemia rate fell from 1.7 ± 8.5 to 0.6 ± 3.7 episodes per person per year (1.1 [0.7-1.4]) and hypoglycemia recognition improved in 43% of those reporting unawareness. Baseline psychological distress was evident, with a PAID score of 25.2 and HADS scores of 5.3 (anxiety) and 4.8 (depression), falling to 16.7 (8.5 [6.6-10.4]), 4.6 (0.7 [0.4-1.0]), and 4.2 (0.6 [0.3-0.8]), respectively (all P < 0.001 at 1 year). Clinically relevant anxiety and depression (HADS ≥ 8) fell from 24.4 to 18.0% and 20.9 to 15.5%, respectively. CONCLUSIONS: A structured education program delivered in routine clinical practice not only improves HbA(1c) while reducing severe hypoglycemia rate and restoring hypoglycemia awareness but also reduces psychological distress and improves perceived well-being.

Effectiveness of a diabetes education and self management programme (DESMOND) for people with newly diagnosed type 2 diabetes mellitus: three year follow-up of a cluster randomised controlled trial in primary care.

OBJECTIVE: To measure whether the benefits of a single education and self management structured programme for people with newly diagnosed type 2 diabetes mellitus are sustained at three years. DESIGN: Three year follow-up of a multicentre cluster randomised controlled trial in primary care, with randomisation at practice level. SETTING: 207 general practices in 13 primary care sites in the United Kingdom. PARTICIPANTS: 731 of the 824 participants included in the original trial were eligible for follow-up. Biomedical data were collected on 604 (82.6%) and questionnaire data on 513 (70.1%) participants. INTERVENTION: A structured group education programme for six hours delivered in the community by two trained healthcare professional educators compared with usual care. MAIN OUTCOME MEASURES: The primary outcome was glycated haemoglobin (HbA(1c)) levels. The secondary outcomes were blood pressure, weight, blood lipid levels, smoking status, physical activity, quality of life, beliefs about illness, depression, emotional impact of diabetes, and drug use at three years. RESULTS: HbA(1c) levels at three years had decreased in both groups. After adjusting for baseline and cluster the difference was not significant (difference -0.02, 95% confidence interval -0.22 to 0.17). The groups did not differ for the other biomedical and lifestyle outcomes and drug use. The significant benefits in the intervention group across four out of five health beliefs seen at 12 months were sustained at three years (P<0.01). Depression scores and quality of life did not differ at three years. CONCLUSION: A single programme for people with newly diagnosed type 2 diabetes mellitus showed no difference in biomedical or lifestyle outcomes at three years although there were sustained improvements in some illness beliefs. TRIAL REGISTRATION: Current Controlled Trials ISRCTN17844016.