John R. Petrie

Objective: Engaging in exercise presents unique challenges for those with type 2 diabetes (T2D) and diabetes‐related foot ulcer disease (DFUD). This brief report describes the development of practical considerations aiming to support exercise in people with T2D and DFUD. Research Design and Methods: An expert group of multidisciplinary healthcare professionals (HCPs), researchers and individuals with DFUD reviewed available evidence and developed practical considerations for the assessment, prescription and monitoring of exercise within an ongoing randomised controlled trial. Results: Key considerations include screening for contraindications, individualising exercise prescription, determining weight‐bearing status and initial supervision by HCPs. Self monitoring of exercise and appropriate foot protection advice and care are also encouraged. Conclusions: We have developed practical considerations to use when delivering an exercise intervention within a study aiming to improve cardiovascular health for people with T2D and DFUD. For this specific population, these recommendations include prescribing non‐weight bearing physical activity (such as arm ergometry or chair‐based upper limb exercises) for those with active foot ulcers, educating and encouraging footcare self‐management (including how to check feet and when to seek advice), monitoring glucose levels in participants at high risk of hypoglycaemia or hyperglycaemia and reducing the barriers to exercise. Pragmatic measures aimed at maintaining safety include determining the level of pre‐assessment and individualised monitoring based on clinical presentation and/or risk as well as equipment and staff resource. This approach may also be helpful when supporting exercise in a wider population.

From finger-stick blood glucose monitoring and mechanical insulin pens in the 1970s to modern automated insulin delivery systems, rapidly progressing advances in diabetes technology are transforming management options for people with diabetes, particularly those with type 1 diabetes but also, increasingly, people with type 2 diabetes. However, access to life-changing diabetes technologies is neither uniform nor universally covered, and there is no one-size-fits-all approach. In this position statement, we emphasize to health care professionals the importance of supporting individuals with diabetes to access and use the right diabetes technology according to personal needs, capabilities, and preferences. In doing so, we highlight the equal importance of avoiding disparities in the provision of diabetes technology by challenging preconceived barriers, which can be overcome with education and determination. We also make a series of suggestions for action to advance the more widespread adoption of diabetes technology while minimizing the “digital divide.”

From fingerstick blood glucose monitoring and mechanical insulin pens in the 1970s to modern automated insulin delivery systems, rapidly progressing advances in diabetes technology are transforming management options for people with diabetes, particularly those with type 1 diabetes but also, increasingly, people with type 2 diabetes. However, access to life-changing diabetes technologies is neither uniform nor universally covered, and there is no one size fits all approach. In this position statement, we emphasise to healthcare professionals the importance of supporting individuals with diabetes to access and use the right diabetes technology according to personal needs, capabilities and preferences. In doing so, we highlight the equal importance of avoiding disparities in the provision of diabetes technology by challenging preconceived barriers, which can be overcome with education and determination. We also make a series of suggestions for action to advance the more widespread adoption of diabetes technology while minimising the ‘digital divide’.

Aims/hypothesis Fasting hyperinsulinaemia is a key feature of obesity and is implicated in diabetes progression. However, the following aspects of insulin secretion remain unclear: (1) which index of obesity is most important; (2) what is the shape of the dose–response curve between obesity and insulin secretion; (3) what physiological mechanisms sustain insulin hypersecretion; (4) what are the underlying causes; and (5) whether sex-related differences exist. Methods We analysed data from 1250 healthy participants (547 men, 703 women) of the EGIR-RISC cohort followed up for 3.5 years, with age 30–60 years and BMI 18.5–40.0 kg/m². Assessments included body composition, insulin secretion, beta cell function modelling from an OGTT and clamp-derived insulin sensitivity. Endogenous glucose production (EGP) was measured in a subset of 368 participants. Multivariable regression models and stratifications for BMI, body fat per cent, WHR and fat mass were applied to evaluate the effect of obesity on insulin secretion and beta cell function. Results The impact of obesity on fasting insulin secretion (FIS) was continuous across the full spectrum of BMI and WHR values and was greater in men than women. Among adiposity indices, fat mass (standardised β coefficient [Stβ] 0.27, ppppp<0.002 for both) but not in weight gainers (−0.06 ± 1.1 U/h). Peripheral insulin resistance, plasma NEFA and leptin accounted for only part of obesity’s effect on insulin secretion. Subset analysis of fasting and clamp EGP data suggested a rightwards shift in the dose–response curve across fat mass quintiles, indicating progressive hepatic glucose overproduction despite a preserved hepatic insulin response. Conclusions/interpretation The effect of body mass on insulin secretion is continuous, more pronounced in men, driven by fat mass and waist, sustained by hyperglycaemia and by an upregulation of beta cell insulin secretion and is only partially explained by typical hormonal and metabolic consequences of obesity. We suggest that hepatic glucose overproduction contributes to the fasting hyperinsulinaemia observed in individuals with obesity. Graphical Abstract

Aims: Diabetic foot ulcer disease ( DFUD ) is common, life‐changing and associated with a lower 5‐Year survival rate than many cancers. However, the risk factors for DFUD have generally been identified in small, single‐centre, clinic‐based studies, many of which are cross‐sectional. This study aims to assess the incidence of DFUD and its related risk factors in two large, contemporary UK cohorts. Materials and Methods: We investigated common sociodemographic and clinical factors affecting the incidence rates of DFUD in two large representative independent cohorts of people with diabetes in England ( CPRD , n = 131 042) and Scotland (Scottish Diabetes Research Network‐National Diabetes Dataset [ SDRN ‐ NDS ] n = 260 748). The methods of case ascertainment differed between the two cohorts: in England, both primary and secondary care data were used, whereas in Scotland, secondary care and foot clinic data were used. Results and Conclusions: In the English cohort, 4.7% developed DFUD over a median of 4.3years (incidence rate 9.0[95%CI: 8.8–9.2] per 1000 person‐years) follow‐up; in the Scottish cohort, the equivalent figure was 2.9% over a median of 6.3 years (incidence rate 4.4 [95% CI: 4.3–4.5] per 1000 person‐years). Despite different methods of case ascertainment, multivariable analysis in both populations indicated that those who developed DFUD were more likely to be older, male, smokers, of White ethnicity, with higher systolic blood pressure and baseline HbA1c. These findings provide a robust evidence base for identifying people with diabetes at risk of DFUD for targeted efforts for prevention.

Aims: To generate expert consensus‐based clinical recommendations on the use of SGLT2 inhibitors in those with diabetes and diabetes‐related foot disease (DFD). Materials and Methods: This study employed a two‐round online Delphi technique. Participants were healthcare practitioners from a range of relevant clinical backgrounds, recruited using convenience sampling. The statements for consideration were iteratively developed by study team members with expertise in managing diabetes and prescribing SGLT2 inhibitors, supported by key professional organisations and people with lived experience of DFD. Statements were ranked using a 6‐point Likert Scale from Strongly Agree to Strongly Disagree. Consensus status for each statement was based on the Average Percent of Majority Opinions for each statement. Results: Twenty‐one participants completed round 1 of the survey, with 19 completing round 2. Participants represented a diverse range of healthcare professions, including Diabetologists, General Practitioners, Nurses and Pharmacists. Of the 25 total statements, 16 reached consensus (13 in round 1 and 3 in round 2), including: agreement on prescribing SGLT2 inhibitors to people with type 2 diabetes (regardless of ulceration status) with concurrent heart failure and/or chronic kidney disease; agreement that those with a previous healed ulcer or amputation should be prescribed SGLT2 inhibitors; disagreement that SGLT2 inhibitors per se increase amputation risk; agreement that canagliflozin should be avoided in this group. Conclusions: These findings evidence the relative confidence of experienced clinicians in prescribing SGLT2 inhibitors to those with DFD, provided that they do not have a current ulcer and that canagliflozin is not prescribed.

Background: In the United Kingdom, the prevalence of diabetes‐related foot ulcer disease (DFUD) is 6.3%, and cardiovascular disease (CVD) is the leading cause of mortality in people with DFUD. This study aims to evaluate the effectiveness of a multifactorial intervention to reduce CVD events and mortality in adults with type 2 diabetes (T2D) and DFUD. Methods: The MiFoot study is a multi‐centre, pragmatic randomised controlled trial to test intervention effectiveness and cost‐effectiveness compared to usual care that will include an internal feasibility study and a process evaluation. English‐speaking adults (≥18 years; n = 392) with T2D and current/previous (within 5 years) DFUD will be recruited from multiple sites across the United Kingdom and randomised 1:1 to intervention (MiFoot multifactorial intervention plus usual care) or control (usual care), with data collected at baseline, 12‐ and 24‐month follow‐up. The MiFoot intervention comprises an individualised assessment with a healthcare practitioner to optimise treatment and assess the suitability of physical activity participation; group‐based disease self management education and physical activity sessions; and a digital‐based programme, consisting of cohort‐relevant topics, physical activity guidance and peer support functionality. The primary outcome will be extended major adverse cardiovascular events (MACE, i.e. myocardial infarction, stroke, cardiovascular death, peripheral arterial bypass, coronary artery bypass, coronary angioplasty or peripheral artery angioplasty) at 24 months. DISCUSSION: This study will provide evidence on the feasibility and clinical effectiveness, and cost‐effectiveness of a multifactorial intervention to prevent or slow the progression of CVD‐related complications in the extremely high‐risk population with T2D and DFUD.

Aims: To undertake a Priority Setting Partnership (PSP), identifying the most important unanswered questions in type 1 diabetes in Ireland and the United Kingdom and to compare these to priorities identified in a 2011 PSP.Methods: A steering committee (including eight individuals with lived experience/charity representatives and six clinicians) designed a survey which asked stakeholders to list three questions about type 1 diabetes. This was disseminated through social media, direct email contact, and printed posters. Following analysis, a second survey asked participants to rank these priorities in order of importance. The top questions were then carried forward to an online, 2 days final workshop where the final top 10 were ranked.Results: There were 1050 responses (64% female, 78% adults living with type 1 diabetes, 9% healthcare professionals, 9% family members) to the first survey and 2937 individual questions were submitted. Sixty‐five summary questions were submitted into a second survey, completed by 497 individuals (76% adults living with type 1 diabetes, 9% healthcare professionals, and 11% family members). Nineteen questions from the interim survey progressed to a final workshop, which identified the top 10 priorities through group discussion. As in 2011, there was emphasis on psychological health, diabetes‐related complications, and hypoglycaemia. New themes prioritised included artificial intelligence and women's health.Conclusions: The research priorities, which have been identified using a robust and proven methodology, highlight the key concerns of those living with type 1 diabetes, their families and representatives, as well as clinicians in Ireland and the UK.

Metformin is best known as a foundational therapy for type 2 diabetes but is also used in other contexts in clinical medicine with a number of emerging and potential indications. Many of its beneficial effects may be mediated by modest effects on weight loss and insulin sensitivity, but it has multiple other known mechanisms of action. Current clinical uses beyond type 2 diabetes include: polycystic ovarian syndrome; diabetes in pregnancy/gestational diabetes; prevention of type 2 diabetes in prediabetes; and adjunct therapy in type 1 diabetes. As metformin has been in clinical use for almost 70 years, much of the underpinning evidence for its use in these conditions is, by definition, based on trials conducted before the advent of contemporary evidence‐based medicine. As a result, some of the above‐established uses are ‘off‐label’ in many regulatory territories and their use varies accordingly in different countries. Going forward, several current ‘repurposing’ investigational uses of metformin are also being investigated: prevention of cancer (including in Li Fraumeni syndrome), renal protection, Alzheimer's disease, metabolic dysfunction‐associated steatotic liver disease and promotion of healthy ageing. Despite the longevity of metformin and its important current roles beyond type 2 diabetes in clinical medicine, it has further potential and much research is ongoing.

Aim: To evaluate the effect of metformin on cancer incidence in subjects with overweight/obesity and/or prediabetes/diabetes. Materials and Methods: We searched MEDLINE, Embase and CENTRAL for randomized controlled trials (RCTs) in adults with overweight/obesity and/or prediabetes/diabetes that compared metformin to other interventions for ≥24 weeks. Independent reviewers selected and extracted data including population and intervention characteristics and new diagnoses of cancer. We used the RoB 2.0 risk‐of‐bias tool and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework to assess risk of bias and certainty of evidence. Results: From 14 895 records after removal of duplicates, 27 trials were included, providing a total of 10 717 subjects in the metformin group and 10 003 in the control group, with 170 and 208 new cases of cancer, respectively. Using a random‐effects model, the relative risk was 1.07 (95% confidence interval 0.87–1.31), with similar results in subgroup analyses by study duration or effect of control intervention on weight. Risk of bias in most studies was low, and no evidence of publication bias was found. Trial sequential analysis provided evidence that the cumulative sample size was large enough to exclude a significant effect of metformin on cancer incidence. Conclusions: Metformin did not reduce cancer incidence in RCTs involving subjects with overweight/obesity and/or prediabetes/diabetes.