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ItemThe 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(WILEY, 2022-08)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.
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ItemEffects of liraglutide versus sitagliptin on circulating cardiovascular biomarkers, including circulating progenitor cells, in individuals with type 2 diabetes and obesity: Analyses from the LYDIA trial(WILEY, 2021-06)The mechanisms behind the beneficial cardiovascular effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) compared with dipeptidyl peptidase-4 inhibitors (DPP4is) remain largely unknown, despite both targeting the incretin pathway to improve glycaemic control. In these prespecified secondary analyses of the LYDIA trial, we examined the impact of the GLP-1RA liraglutide (1.8 mg once-daily) and the DPP4i sitagliptin (100 mg once-daily) on circulating cardiovascular biomarkers associated with atherosclerotic risk, including circulating progenitor cells (CPCs). LYDIA was a 26-week, randomized, active-comparator trial in 61 adults with type 2 diabetes and obesity (mean ± SD: age 43.8 ± 6.5 years, body mass index 35.3 ± 6.4 kg/m2 , HbA1c 7.5% ± 0.83% [58.5 ± 9.1 mmol/mol]). Vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1-alpha (SDF-1ɑ), both of which are implicated in endothelial function, were higher at 26 weeks with liraglutide therapy compared with sitagliptin (mean between-group difference [95% CI]: 77.03 [18.29, 135.77] pg/mL, p = .010; and 996.25 [818.85, 1173.64] pg/mL, p < .001, respectively). There were no between-group differences in CPCs, nitric oxide, C-reactive protein, interleukin-6, tumour necrosis factor alpha and advanced glycation end-products. These analyses suggest a favourable impact of liraglutide on VEGF and SDF-1ɑ levels compared with sitagliptin. These factors may therefore be implicated in the differential cardiovascular effects observed between these agents in large cardiovascular outcome trials. However, these are secondary analyses from a previous trial and thus hypothesis-generating. Purposive trials are required to examine these findings further.
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ItemNo Preview AvailableIn-shoe pressure thresholds for people with diabetes and neuropathy at risk of ulceration: A systematic review(ELSEVIER SCIENCE INC, 2021-03)INTRODUCTION: In-shoe pressure thresholds play an increasingly important role in the prevention of diabetes-related foot ulceration (DFU). The evidence of their effectiveness, methodological consistency and scope for refinement are the subject of this review. METHODS: 1107 records were identified (after duplicate removal) based on a search of five databases for studies which applied a specific in-shoe pressure threshold to reduce the risk of ulceration. 37 full text studies were assessed for eligibility of which 21 were included. RESULTS: Five in-shoe pressure thresholds were identified, which are employed to reduce the risk of diabetes-related foot ulceration: a mean peak pressure threshold of 200 kPa used in conjunction with a 25% baseline reduction target; a sustained pressure threshold of 35 mm Hg, a threshold matrix based on risk, shoe size and foot region, and a 40-80% baseline pressure reduction target. The effectiveness of the latter two thresholds have not been assessed yet and the evidence for the effectiveness of the other in-shoe pressure thresholds is limited, based only on two RCTs and two cohort studies. CONCLUSIONS: The heterogeneity of current measures precludes meta-analysis and further research and methodological standardisation is required to facilitate ready comparison and the further development of these pressure thresholds.
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ItemAge at diagnosis of type 2 diabetes and cardiovascular risk factor profile: A pooled analysis(BAISHIDENG PUBLISHING GROUP INC, 2022-03-15)BACKGROUND: The diagnosis of type 2 diabetes (T2D) in younger adults, an increasingly common public health issue, is associated with a higher risk of cardiovascular complications and mortality, which may be due to a more adverse cardiovascular risk profile in individuals diagnosed at a younger age. AIM: To investigate the association between age at diagnosis and the cardiovascular risk profile in adults with T2D. METHODS: A pooled dataset was used, comprised of data from five previous studies of adults with T2D, including 1409 participants of whom 196 were diagnosed with T2D under the age of 40 years. Anthropometric and blood biomarker measurements included body weight, body mass index (BMI), waist circumference, body fat percentage, glycaemic control (HbA1c), lipid profile and blood pressure. Univariable and multivariable linear regression models, adjusted for diabetes duration, sex, ethnicity and smoking status, were used to investigate the association between age at diagnosis and each cardiovascular risk factor. RESULTS: A higher proportion of participants diagnosed with T2D under the age of 40 were female, current smokers and treated with glucose-lowering medications, compared to participants diagnosed later in life. Participants diagnosed with T2D under the age of 40 also had higher body weight, BMI, waist circumference and body fat percentage, in addition to a more adverse lipid profile, compared to participants diagnosed at an older age. Modelling results showed that each one year reduction in age at diagnosis was significantly associated with 0.67 kg higher body weight [95% confidence interval (CI): 0.52-0.82 kg], 0.18 kg/m2 higher BMI (95%CI: 0.10-0.25) and 0.32 cm higher waist circumference (95%CI: 0.14-0.49), after adjustment for duration of diabetes and other confounders. Younger age at diagnosis was also significantly associated with higher HbA1c, total cholesterol, low-density lipoprotein cholesterol and triglycerides. CONCLUSION: The diagnosis of T2D earlier in life is associated with a worse cardiovascular risk factor profile, compared to those diagnosed later in life.
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ItemClinical associations with stage B heart failure in adults with type 2 diabetes(SAGE PUBLICATIONS LTD, 2021-06)BACKGROUND: There is a high prevalence of asymptomatic (American Heart Association Stage B) heart failure (SBHF) in people with type 2 diabetes (T2D). We aimed to identify associations between clinical characteristics and markers of SBHF in adults with T2D, which may allow therapeutic interventions prior to symptom onset. METHODS: Adults with T2D from a multi-ethnic population with no prevalent cardiovascular disease [n = 247, age 52 ± 12 years, glycated haemoglobin A1c (HbA1c) 7.4 ± 1.1% (57 ± 12 mmol/mol), duration of diabetes 61 (32, 120) months] underwent echocardiography and adenosine stress perfusion cardiovascular magnetic resonance imaging. Multivariable linear regression analyses were performed to identify independent associations between clinical characteristics and markers of SBHF. RESULTS: In a series of multivariable linear regression models containing age, sex, ethnicity, smoking history, number of glucose-lowering agents, systolic blood pressure (BP) duration of diabetes, body mass index (BMI), HbA1c, serum creatinine, and low-density lipoprotein (LDL)-cholesterol, independent associations with: left ventricular mass:volume were age (β = 0.024), number of glucose-lowering agents (β = 0.022) and systolic BP (β = 0.027); global longitudinal strain were never smoking (β = -1.196), systolic BP (β = 0.328), and BMI (β = -0.348); myocardial perfusion reserve were age (β = -0.364) and male sex (β = 0.458); and aortic distensibility were age (β = -0.629) and systolic BP (β = -0.348). HbA1c was not independently associated with any marker of SBHF. CONCLUSIONS: In asymptomatic adults with T2D, age, systolic BP, BMI, and smoking history, but not glycaemic control, are the major determinants of SBHF. Given BP and BMI are modifiable, these may be important targets to reduce the development of symptomatic heart failure.
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ItemWhere Does Metformin Stand in Modern Day Management of Type 2 Diabetes?(MDPI, 2020-12)Metformin is the most commonly used glucose-lowering therapy (GLT) worldwide and remains the first-line therapy for newly diagnosed individuals with type 2 diabetes (T2D) in management algorithms and guidelines after the UK Prospective Diabetes Study (UKPDS) showed cardiovascular mortality benefits in the overweight population using metformin. However, the improved Major Adverse Cardiovascular Events (MACE) realised in some of the recent large cardiovascular outcomes trials (CVOTs) using sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have challenged metformin's position as a first-line agent in the management of T2D. Many experts now advocate revising the existing treatment algorithms to target atherosclerotic cardiovascular disease (ASCVD) and improving glycaemic control as a secondary aim. In this review article, we will revisit the major cardiovascular outcome data for metformin and include a critique of the UKPDS data. We then review additional factors that might be pertinent to metformin's status as a first-line agent and finally answer key questions when considering metformin's role in the modern-day management of T2D.
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ItemToe gaps and their assessment in footwear for people with diabetes: a narrative review(BMC, 2020-12-04)BACKGROUND: Adequate footwear fit is critical in preventing diabetes-related foot ulcers. One important element is the toe gap, the difference between foot length and internal footwear length available to the foot. We summarised the literature on toe gaps in studies assessing footwear worn by people with diabetes, the methods used to measure both foot length and internal footwear length and identify ambiguities which may impact on toe gap assessment in clinical practice, and suggest pragmatic solutions. METHODS: The Google Scholar database was searched to April 2020 for peer-reviewed studies using keywords related to incorrectly fitting or ill-fitting and diabetes, foot and ulcer which returned 979 results. Included studies within this narrative review encompassed toe gap measurement to assess footwear worn by people with diabetes. RESULTS: A total of eight studies were included after full paper review. Toe gap ranges as used in assessments of footwear worn by people with diabetes vary, with a minimum of 1.0-1.6 cm and a maximum of 1.5-2.0 cm, as do methods of measuring internal footwear length. Only three published studies suggested possible measuring devices. CONCLUSIONS: Toe gap ranged as used when assessing footwear fit in people with diabetes vary and a gold standard device for internal footwear length measurement has yet to emerge. International guidelines provide welcome standardisation, but further research is needed to evaluate both the effect of toe gap ranges upon pressure, plantar stress response and ulceration and available measuring devices to facilitate development of toe gap measurement protocols that may further enhance consistency in practical assessments.
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ItemAdults with early-onset type 2 diabetes (aged 18-39 years) are severely underrepresented in diabetes clinical research trials(SPRINGER, 2020-08)AIMS/HYPOTHESIS: Early-onset adult type 2 diabetes (diagnosed between ages 18 and 39 years) is increasingly prevalent and associated with poor long-term outcomes. We hypothesised that individuals with early-onset adult type 2 diabetes were underrepresented in the prominent research trials that underpin type 2 diabetes management guidelines. METHODS: We reviewed the mean age of the study populations recruited to 90 prominent trials in type 2 diabetes, including 37 cardio-renal outcomes trials across a range of pharmacological, non-pharmacological and multifactorial interventions, 28 trials from the phase III programmes of three representative glucose-lowering therapies used routinely in clinical practice (empagliflozin, liraglutide and sitagliptin) and 25 prominent trials of diabetes self-management education and support or intensive lifestyle interventions (diet or supervised exercise training). We then estimated the number of individuals within these trials who were aged between 18 and 39 years. RESULTS: Across all 90 trials, the mean age of 268,978 participants was 63 years (range 51-69 years in individual trials). In 73 trials (81%), <5% of participants were estimated to be aged 18-39 years, despite this age group representing ~15-20% of the adult type 2 diabetes population. Twenty-nine of these trials (32%; total 164,953 participants) excluded individuals below 40 years of age altogether. CONCLUSIONS/INTERPRETATION: Guidelines for early-onset adult type 2 diabetes are extrapolated predominantly from evidence in older individuals. Strategies to support the participation of individuals with early-onset adult type 2 diabetes in future research are imperative to ensure guidelines for these high-risk individuals are evidence-based.
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ItemConsultation rates in people with type 2 diabetes with and without vascular complications: a retrospective analysis of 141,328 adults in England(BMC, 2022-01-10)OBJECTIVE: To assess trends in primary and specialist care consultation rates and average length of consultation by cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), or cardiometabolic multimorbidity exposure status. METHODS: Observational, retrospective cohort study used linked Clinical Practice Research Datalink primary care data from 01/01/2000 to 31/12/2018 to assess consultation rates in 141,328 adults with newly diagnosed T2DM, with or without CVD. Patients who entered the study with either a diagnosis of T2DM or CVD and later developed the second condition during the study are classified as the cardiometabolic multimorbidity group. Face to face primary and specialist care consultations, with either a nurse or general practitioner, were assessed over time in subjects with T2DM, CVD, or cardiometabolic multimorbidity. Changes in the average length of consultation in each group were investigated. RESULTS: 696,255 (mean 4.9 years [95% CI, 2.02-7.66]) person years of follow up time, there were 10,221,798 primary and specialist care consultations. The crude rate of primary and specialist care consultations in patients with cardiometabolic multimorbidity (N = 11,881) was 18.5 (95% CI, 18.47-18.55) per person years, 13.5 (13.50, 13.52) in patients with T2DM only (N = 83,094) and 13.2 (13.18, 13.21) in those with CVD (N = 57,974). Patients with cardiometabolic multimorbidity had 28% (IRR 1.28; 95% CI: 1.27, 1.31) more consultations than those with only T2DM. Patients with cardiometabolic multimorbidity had primary care consultation rates decrease by 50.1% compared to a 45.0% decrease in consultations for those with T2DM from 2000 to 2018. Specialist care consultation rates in both groups increased from 2003 to 2018 by 33.3% and 54.4% in patients with cardiometabolic multimorbidity and T2DM, respectively. For patients with T2DM the average consultation duration increased by 36.0%, in patients with CVD it increased by 74.3%, and in those with cardiometabolic multimorbidity it increased by 37.3%. CONCLUSIONS: Annual primary care consultation rates for individuals with T2DM, CVD, or cardiometabolic multimorbidity have fallen since 2000, while specialist care consultations and average consultation length have both increased. Individuals with cardiometabolic multimorbidity have significantly more consultations than individuals with T2DM or CVD alone. Service redesign of health care delivery needs to be considered for people with cardiometabolic multimorbidity to reduce the burden and health care costs.
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ItemA UK nationwide study of people with type 1 diabetes admitted to hospital with COVID-19 infection(SPRINGER, 2021-08)AIMS/HYPOTHESIS: The aim of this work was to describe the clinical characteristics of adults with type 1 diabetes admitted to hospital and the risk factors associated with severe coronavirus disease-2019 (COVID-19) in the UK. METHODS: A retrospective cohort study was performed using data collected through a nationwide audit of people admitted to hospital with diabetes and COVID-19, conducted by the Association of British Clinical Diabetologists from March to October 2020. Prespecified demographic, clinical, medication and laboratory data were collected from the electronic and paper medical record systems of the participating hospitals by local clinicians. The primary outcome of the study, severe COVID-19, was defined as death in hospital and/or admission to the adult intensive care unit (AICU). Logistic regression models were used to generate age-adjusted ORs. RESULTS: Forty UK centres submitted data. The final dataset included 196 adults who were admitted to hospital and had both type 1 diabetes and COVID-19 on admission (male sex 55%, white 70%, with mean [SD] age 62 [19] years, BMI 28.3 [7.3] kg/m2 and last recorded HbA1c 76 [31] mmol/mol [9.1 (5.0)%]). The prevalence of pre-existing microvascular disease and macrovascular disease was 56% and 39%, respectively. The prevalence of diabetic ketoacidosis on admission was 29%. A total of 68 patients (35%) died or were admitted to AICU. The proportions of people that died were 7%, 38% and 38% of those aged <55, 55-74 and ≥75 years, respectively. BMI, serum creatinine levels and having one or more microvascular complications were positively associated with the primary outcome after adjusting for age. CONCLUSIONS/INTERPRETATION: In people with type 1 diabetes and COVID-19 who were admitted to hospital in the UK, higher BMI, poorer renal function and presence of microvascular complications were associated with greater risk of death and/or admission to AICU. Risk of severe COVID-19 is reassuringly very low in people with type 1 diabetes who are under 55 years of age without microvascular or macrovascular disease. IN PEOPLE WITH TYPE 1 DIABETES AND COVID-19 ADMITTED TO HOSPITAL IN THE UK, BMI AND ONE OR MORE MICROVASCULAR COMPLICATIONS HAD A POSITIVE ASSOCIATION AND LOW SERUM CREATINE LEVELS HAD A NEGATIVE ASSOCIATION WITH DEATH/ADMISSION TO INTENSIVE CARE UNIT AFTER ADJUSTING FOR AGE.