The effects of empagliflozin, dietary energy restriction, or both on appetite-regulatory gut peptides in individuals with type 2 diabetes and overweight or obesity: The SEESAW randomized, double-blind, placebo-controlled trial.

AIM: To assess the impact of the sodium-glucose co-transporter-2 (SGLT2) inhibitor empagliflozin (25 mg once-daily), dietary energy restriction, or both combined, on circulating appetite-regulatory peptides in people with type 2 diabetes (T2D) and overweight or obesity. MATERIALS AND METHODS: In a double-blind, placebo-controlled trial, 68 adults (aged 30-75 years) with T2D (drug naïve or on metformin monotherapy; HbA1c 6.0%-10.0% [42-86 mmol/mol]) and body mass index of 25 kg/m2 or higher were randomized to (a) placebo only, (b) placebo plus diet, (c) empagliflozin only or (d) empagliflozin plus diet for 24 weeks. Dietary energy restriction matched the estimated energy deficit elicited by SGLT2 inhibitor therapy through urinary glucose excretion (~360 kcal/day). The primary outcome was change in postprandial circulating total peptide-YY (PYY) during a 3-hour mixed-meal tolerance test from baseline to 24 weeks. Postprandial total glucagon-like peptide-1 (GLP-1), acylated ghrelin and subjective appetite perceptions formed secondary outcomes, along with other key components of energy balance. RESULTS: The mean weight loss in each group at 24 weeks was 0.44, 1.91, 2.22 and 5.74 kg, respectively. The change from baseline to 24 weeks in postprandial total PYY was similar between experimental groups and placebo only (mean difference [95% CI]: -8.6 [-28.6 to 11.4], 13.4 [-6.1 to 33.0] and 1.0 [-18.0 to 19.9] pg/ml in placebo-plus diet, empagliflozin-only and empagliflozin-plus-diet groups, respectively [all P ≥ .18]). Similarly, there was no consistent pattern of difference between groups for postprandial total GLP-1, acylated ghrelin and subjective appetite perceptions. CONCLUSIONS: In people with T2D and overweight or obesity, changes in postprandial appetite-regulatory gut peptides may not underpin the less than predicted weight loss observed with empagliflozin therapy. CLINICAL TRIALS REGISTRATION: NCT02798744, www. CLINICALTRIALS: gov; 2015-001594-40, www.EudraCT.ema.europa.eu; ISRCTN82062639, www.ISRCTN.org.

Self-Compassion, Metabolic Control and Health Status in Individuals with Type 2 Diabetes: A UK Observational Study.

AIMS: Self-compassion is a modifiable characteristic, linked with psychological well being and intrinsic motivation to engage in positive health behaviours. We aimed to explore levels of self-compassion in individuals with type 2 diabetes (T2DM) and their association with levels of depression, diabetes-related distress and glycaemic control. METHODS: A cross-sectional study in 176 patients with T2DM in Leicester, UK, using three self-report questionnaires: the Self Compassion Scale (SCS); Patient Health Questionnaire (PHQ-9), and Diabetes Distress Scale (DDS-17). Demographic data, medical history and blood samples were collected. RESULTS: Majority of participants were male (n=120, 68.2%), with median [IQR] age and HbA1c of 66 [60, 71] years and 7.3 [6.7, 8.0] %, respectively. Multivariable analysis adjusting for age, gender, ethnicity and diabetes duration revealed significant association of all three scores with HbA1c: per one standard deviation increase of each score, a -0.16% reduction in HbA1c for SCS (p=0.027), 0.21% increase for PHQ-9 (p=0.012) and 0.33% increase for DDS-17 (p<0.001). CONCLUSIONS: Higher levels of self-compassion and lower levels of depressive symptoms were associated with significantly better long-term diabetes control. These results reinforce the importance of emphasis on psychological parameters, including self-compassion, in the multi-disciplinary management of T2DM. We identify this as a potential area for intervention in UK practice.

Rationale and design of a cross-sectional study to investigate and describe the chronotype of patients with type 2 diabetes and the effect on glycaemic control: the CODEC study.

INTRODUCTION: A person's chronotype is their entrained preference for sleep time within the 24 hours clock. It is described by the well-known concept of the 'lark' (early riser) and 'owl' (late sleeper). Evidence suggests that the 'owl' is metabolically disadvantaged due to the standard organisation of our society which favours the 'lark' and places physiological stresses on this chronotype. The aim of this study is to explore cardiometabolic health between the lark and owl in a population with an established metabolic condition - type 2 diabetes. METHODS: This cross-sectional, multisite study aims to recruit 2247 participants from both secondary and primary care settings. The primary objective is to compare glycaemic control between late and early chronotypes. Secondary objectives include determining if late-chronotype is associated with poorer cardiometabolic health and other lifestyle factors, including well-being, compared with early-chronotype; describing the prevalence of the five different chronotypes in this cohort and examining the trends in glycaemic control, cardiometabolic health, well-being and lifestyle factors across chronotype. ANALYSIS: The primary outcome (glycated haemoglobin (HbA1c)), linear regression analysis will compare HbA1c between early and late chronotypes, with and without adjustment for confounding variables. Chronotype will be modelled as a categorical variable with all five levels (from extreme-morning to extreme-late type), and as a continuous variable to calculate p for trend across the five categories. A number of models will be created; unadjusted through to adjusted with age, sex, ethnicity, body mass index, duration of diabetes, family history of diabetes, current medication and dietary habits. All secondary outcomes will be analysed using the same method. ETHICS: Ethical approval from the West Midlands - Black Country Research Ethics Committee (16/WM/0457). DISSEMINATION: The results will be disseminated through publication in peer-reviewed medical journal, relevant medical/health conferences and a summary report sent to patients. TRIAL REGISTRATION NUMBER: NCT02973412 (Pre-Results).

Corrections to: Achieving Glycaemic Control with Concentrated Insulin in Patients with Type 2 Diabetes.

In several sections of this review article, insulin degludec U100 has been incorrectly referred to as a highly concentrated basal insulin. Although data for both the U100 and U200 formulations of insulin degludec are presented, only insulin degludec U200 and insulin glargine U300 should be referred to as highly concentrated basal insulins.

Correction to: Achieving Glycaemic Control with Concentrated Insulin in Patients with Type 2 Diabetes.

Page 7, Section 4.1, third paragraph, which previously read.

Achieving Glycaemic Control with Concentrated Insulin in Patients with Type 2 Diabetes.

The recent introduction of the second-generation long-acting analogue insulins degludec and insulin glargine U300 have increased the choice of basal insulin therapy for patients with type 2 diabetes. The pharmacokinetic and pharmacodynamic properties of these insulins result in a flatter profile that lasts over 24 h and provides an increased window of administration of 6 h once daily. Large-scale multicentre randomised clinical trial programmes (BEGIN for degludec U100 and U200 and EDITION for glargine U300) evaluating these insulin therapies against glargine U100 have demonstrated that they are either non-inferior or superior for glycaemic efficacy and safety, but less likely to result in severe or nocturnal hypoglycaemia than glargine U100. The disposable pen devices for these insulins have been designed with patient satisfaction and convenience in mind. No concerns have arisen with adverse events with insulin analogues or cardiovascular safety from the ORIGIN and DEVOTE trials. As they demonstrate equivalent glycaemic efficacy to other basal insulins, they should be considered more in selected patient groups including those with recurrent or increased risk of hypoglycaemia, especially severe or nocturnal episodes, in the elderly or those living alone, and in patients with multiple co-morbidities such as cardiovascular or renal disease.

Physical Activity after Cardiac EventS (PACES) - a group education programme with subsequent text-message support designed to increase physical activity in individuals with diagnosed coronary heart disease: study protocol for a randomised controlled trial.

BACKGROUND: Coronary heart disease (CHD) represents approximately 13% of deaths worldwide and is the leading cause of death in the UK with considerable associated health care costs. After a CHD event, timely cardiac rehabilitation optimises patient outcomes. However, a high percentage of these services do not meet necessary performance indicators such as course length and follow-up attendance. Uptake of such services is only 50% in UK patients and support provided 12 months after an event is often limited. To delay and prevent further CHD events leading to hospitalisation, supplementary self-management strategies such as group education, are necessary. METHODS: This is a single-centre, randomised controlled trial (RCT) recruiting participants (n = 290) aged ≥18 years who are 12 to 48 months post diagnosis of a CHD-related cardiac event (myocardial infarction, angina and any other acute coronary syndrome). The study aims to implement a structured education programme, with text-message support over 12 months, and identify whether delivery of the programme, to individuals who have a history of a cardiac event, would be an effective and cost-effective strategy for increasing walking. The primary outcome, objectively measured average daily physical activity, specifically step count through walking activity, is assessed using the wrist-worn GENEActiv accelerometer at baseline, 6 and 12 months. Secondary outcomes at 12 months include cardiovascular risk factors such as smoking status, blood pressure, lipid profile, glycated haemoglobin (HbA1c), obesity, self-efficacy, quality of life, physical activity and physical function. Participants are randomised to either the control group receiving standard care and a physical activity information leaflet, or the intervention group whose partcipants receive the leaflet and are invited to attend two group-based structured education sessions. These encourage participants to adopt and maintain healthy behaviours and self-manage their lifestyle. They are delivered approximately 2 weeks apart by trained facilitators and reinforced via subsequent text-message support. DISCUSSION: To our knowledge, this is the first trial designed to assess the effectiveness of a group education programme 12 to 48 months after a CHD event diagnosis. If successful, the PACES programme could be translated into effective post-operative cardiac care and complement the current post-operative services available. TRIAL REGISTRATION: ISRCTN, ID: ISRCTN91163727 . The trial was registered on 27 February 2017.

Association of hypoglycaemia and risk of cardiac arrhythmia in patients with diabetes mellitus: A systematic review and meta-analysis.

AIMS: Hypoglycaemia is associated with increased cardiovascular risk among individuals with diabetes mellitus. It has been hypothesized that hypoglycaemia may trigger autonomic changes leading to increased cardiac arrhythmia risk. We conducted a systematic review and meta-analysis to explore this association. MATERIALS AND METHODS: Ovid Medline, Embase, Scopus, Web of Science and Cochrane were searched from inception to October 10, 2017. We included studies of adults with diabetes (Type 1 or Type 2) that compared acute electrocardiogram (ECG) changes during episodes of hypoglycaemia and euglycaemia. RESULTS: Our search resulted in 4625 citations, among which 20 studies met the predefined inclusion criteria. Finally, 12 studies were included in the descriptive analysis and 15 in the meta-analysis. Overall hypoglycaemia was associated with a reduction in heart rate variability and an increase in arrhythmia occurrence. QTc interval length was more significantly prolonged during hypoglycaemia compared to euglycaemia (pooled mean difference [95% confidence intervals] [0.64 (0.27-1.01], P = ·001). Subgroup analysis based on diabetes type showed that QTc prolongation occurred in individuals with Type 1 and Type 2 diabetes; however, the change between euglycaemia reached statistical significance only among individuals with Type 1 diabetes. CONCLUSION: Our findings suggest that hypoglycaemia results in ECG alterations that are associated with increased risk of cardiac arrhythmia, which is associated with increased cardiovascular events and mortality. More clinical studies are needed to determine the cardiac risks of hypoglycaemia in individuals with diabetes, especially in Type 2 diabetes.

Do sulphonylureas still have a place in clinical practice?

Sulphonylureas have been commercially available since the 1950s, but their use continues to be associated with controversy. Although adverse cardiovascular outcomes in some observational studies have raised concerns about sulphonylureas, findings from relatively recent, robust, and high-quality systematic reviews have indicated no increased risk of all-cause mortality associated with sulphonylureas compared with other active treatments. Results from large, multicentre, randomised controlled trials such as the UK Prospective Diabetes Study and ADVANCE have confirmed the microvascular benefits of sulphonylureas, a reduction in the incidence or worsening of nephropathy and retinopathy, and no increase in all-cause mortality, although whether these benefits were due to sulphonylurea therapy and not an overall glucose-lowering effect could not be confirmed. A comparison of sulphonylureas and pioglitazone in the TOSCA.IT trial also confirmed the efficacy and cardiovascular safety of sulphonylureas. Investigators of randomised controlled trials have reported an increased risk of hypoglycaemia and weight gain with sulphonylureas, but data from observational studies suggest that the incidence of severe hypoglycaemia is lower in people taking sulphonylurea than in people taking insulin, and weight gain with sulphonylureas has been relatively modest in large cohort studies. 80% of people with diabetes live in low-to-middle income countries, so the effectiveness, affordability, and safety of sulphonylureas are particularly important considerations when prescribing glucose-lowering therapy. Results of ongoing head-to-head studies with new drugs, such as the comparison of glimepiride with linagliptin in the CAROLINA study and the comparison of various therapies (including sulphonylureas) for glycaemic control in the GRADE study, will determine the place of sulphonylureas in glucose-lowering therapy algorithms for patients with type 2 diabetes.

What have we learnt from "real world" data, observational studies and meta-analyses.

The incretin therapies glucagon-like peptide-1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase-IV (DPP-IV) inhibitors are now well-established as second and third-line therapies and in combination with insulin for the treatment of type 2 diabetes. Over the last decade, there is accumulating evidence of their efficacy and safety from both large multicentre randomized clinical trials (RCT) and observational studies. Cardiovascular outcome trials have confirmed that several of these agents are also non-inferior to placebo with the GLP-1 RA liraglutide and semaglutide recently found to be superior in terms of major adverse cardiovascular events. Observational studies and post-marketing surveillance provide real world evidence of safety and effectiveness of these agents and have provided reassurance that signals for pancreatitis and pancreatic cancer seen in clinical trials are not of major concern in large patient populations. Well-designed real world studies complement RCTs and systematic reviews but appropriate data and methodologies, which are constantly improving, are necessary to answer appropriate clinical questions relating to the use of incretin therapies.

Pharmaceutical Interventions for Diabetes Prevention in Patients at Risk.

With the rising incidence and prevalence rates of type 2 diabetes globally, it is imperative that diabetes prevention strategies are implemented to stem the flow of new cases. Successful interventions include both lifestyle modification and pharmaceutical agents, and large, multicentre, randomised, controlled studies in different populations have identified the benefits of both. However, translating positive trial outcomes to the real world is particularly challenging, as lifestyle interventions require regular reinforcement from healthcare professionals to be maintained. Pharmaceutical therapies may therefore play an adjunctive role in combination with lifestyle to prevent diabetes. Population-based strategies are also necessary to reduce sedentary behaviour and obesity. Well-established glucose-lowering therapies such as metformin, sulphonylureas, thiazolidinediones and insulin and newer agents such as incretin therapies and sodium glucose co-transporter 2 inhibitors have all been investigated in randomised controlled trials for diabetes prevention with varying success. Non-glucose-lowering therapies such as orlistat and renin angiotensin system blockers can prevent diabetes, whereas statins are associated with slightly increased risk. Diabetes prevention strategies should carefully consider the use of these agents according to individual patient circumstances and phenotypic profile.

Diabetes structured self-management education programmes: a narrative review and current innovations.

Both type 1 and type 2 diabetes are associated with long-term complications that can be prevented or delayed by intensive glycaemic management. People who are empowered and skilled to self-manage their diabetes have improved health outcomes. Over the past 20 years, diabetes self-management education programmes have been shown to be efficacious and cost-effective in promotion and facilitation of self-management, with improvements in patients' knowledge, skills, and motivation leading to improved biomedical, behavioural, and psychosocial outcomes. Diabetes self-management education programmes, developed robustly with an evidence-based structured curriculum, vary in their method of delivery, content, and use of technology, person-centred philosophy, and specific aims. They are delivered by trained educators, and monitored for quality by independent assessors and routine audit. Self-management education should be tailored to specific populations, taking into consideration the type of diabetes, and ethnic, social, cognitive, literacy, and cultural factors. Ways to improve access to and uptake of diabetes self-management programmes are needed globally.

Predicting hospital stay, mortality and readmission in people admitted for hypoglycaemia: prognostic models derivation and validation.

AIMS/HYPOTHESIS: Hospital admissions for hypoglycaemia represent a significant burden on individuals with diabetes and have a substantial economic impact on healthcare systems. To date, no prognostic models have been developed to predict outcomes following admission for hypoglycaemia. We aimed to develop and validate prediction models to estimate risk of inpatient death, 24 h discharge and one month readmission in people admitted to hospital for hypoglycaemia. METHODS: We used the Hospital Episode Statistics database, which includes data on all hospital admission to National Health Service hospital trusts in England, to extract admissions for hypoglycaemia between 2010 and 2014. We developed, internally and temporally validated, and compared two prognostic risk models for each outcome. The first model included age, sex, ethnicity, region, social deprivation and Charlson score ('base' model). In the second model, we added to the 'base' model the 20 most common medical conditions and applied a stepwise backward selection of variables ('disease' model). We used C-index and calibration plots to assess model performance and developed a calculator to estimate probabilities of outcomes according to individual characteristics. RESULTS: In derivation samples, 296 out of 11,136 admissions resulted in inpatient death, 1789/33,825 in one month readmission and 8396/33,803 in 24 h discharge. Corresponding values for validation samples were: 296/10,976, 1207/22,112 and 5363/22,107. The two models had similar discrimination. In derivation samples, C-indices for the base and disease models, respectively, were: 0.77 (95% CI 0.75, 0.80) and 0.78 (0.75, 0.80) for death, 0.57 (0.56, 0.59) and 0.57 (0.56, 0.58) for one month readmission, and 0.68 (0.67, 0.69) and 0.69 (0.68, 0.69) for 24 h discharge. Corresponding values in validation samples were: 0.74 (0.71, 0.76) and 0.74 (0.72, 0.77), 0.55 (0.54, 0.57) and 0.55 (0.53, 0.56), and 0.66 (0.65, 0.67) and 0.67 (0.66, 0.68). In both derivation and validation samples, calibration plots showed good agreement for the three outcomes. We developed a calculator of probabilities for inpatient death and 24 h discharge given the low performance of one month readmission models. CONCLUSIONS/INTERPRETATION: This simple and pragmatic tool to predict in-hospital death and 24 h discharge has the potential to reduce mortality and improve discharge in people admitted for hypoglycaemia.

Type 2 diabetes.

415 million people live with diabetes worldwide, and an estimated 193 million people have undiagnosed diabetes. Type 2 diabetes accounts for more than 90% of patients with diabetes and leads to microvascular and macrovascular complications that cause profound psychological and physical distress to both patients and carers and put a huge burden on health-care systems. Despite increasing knowledge regarding risk factors for type 2 diabetes and evidence for successful prevention programmes, the incidence and prevalence of the disease continues to rise globally. Early detection through screening programmes and the availability of safe and effective therapies reduces morbidity and mortality by preventing or delaying complications. Increased understanding of specific diabetes phenotypes and genotypes might result in more specific and tailored management of patients with type 2 diabetes, as has been shown in patients with maturity onset diabetes of the young. In this Seminar, we describe recent developments in the diagnosis and management of type 2 diabetes, existing controversies, and future directions of care.

Optimizing management of glycaemia.

The global epidemic of type 2 diabetes (T2DM) continues largely unabated due to an increasingly sedentary lifestyle and obesogenic environment. A cost-effective patient-centred approach, incorporating glucose-lowering therapy and modification of cardiovascular risk factors, could help prevent the inevitable development and progression of macrovascular and microvascular complications. Glycaemic optimization requires patient structured education, self-management and empowerment, and psychological support along with early and proactive use of glucose lowering therapies, which should be delivered in a system of care as shown by the Chronic Care Model. From diagnosis, intensive glycaemic control and individualised care is aimed at reducing complications. In older people, the goal is maintaining quality of life and minimizing morbidity, especially as overtreatment increases hypoglycaemia risk. Maintaining durable glycaemic control is challenging and complex to achieve without hypoglycaemia, weight gain and other significant adverse effects. Overcoming patient and physician barriers can help ensure adequate treatment initiation and intensification. Cardiovascular safety studies with newer glucose-lowering agents are now mandatory, with a sodium glucose co-transporter-2 inhibitor (empagliflozin), and two glucagon like peptide-1 receptor agonists (liraglutide and semaglutide) being the first to demonstrate superior CV outcomes compared with placebo.