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Introduction: Cholesteryl ester transfer protein (CETP) inhibitors, initially developed for treating hyperlipidemia, have shown promise in reducing the risk of new-onset diabetes during clinical trials. This positions CETP inhibitors as potential candidates for repurposing in metabolic disease treatment. Given their oral administration, they could complement existing oral medications like sodium-glucose cotransporter 2 (SGLT2) inhibitors, potentially delaying the need for injectable therapies such as insulin. Methods: We conducted a 2x2 factorial Mendelian Randomization analysis involving 233,765 participants from the UK Biobank. This study aimed to evaluate whether simultaneous genetic inhibition of CETP and SGLT2 enhances glycemic control compared to inhibiting each separately. Results: Our findings indicate that dual genetic inhibition of CETP and SGLT2 significantly reduces glycated hemoglobin levels compared to controls and single-agent inhibition. Additionally, the combined inhibition is linked to a lower incidence of diabetes compared to both the control group and SGLT2 inhibition alone. Discussion: These results suggest that combining CETP and SGLT2 inhibitor therapies may offer superior glycemic control over SGLT2 inhibitors alone. Future clinical trials should investigate the potential of repurposing CETP inhibitors for metabolic disease treatment, providing an oral therapeutic option that could benefit high-risk patients before they require injectable therapies like insulin or glucagon-like peptide-1 (GLP-1) receptor agonists. [ABSTRACT FROM AUTHOR]

Aim: To estimate risks of diabetic ketoacidosis (DKA), acute liver injury (ALI), acute kidney injury (AKI), chronic kidney disease (CKD), severe complications of urinary tract infection (UTI) and genital infection (GI) among patients with type 2 diabetes initiating empagliflozin versus those initiating a dipeptidyl peptidase‐4 (DPP‐4) inhibitor. Materials and Methods: In this large multinational, observational, new‐user cohort study in UK, Danish and US healthcare data sources, patients initiated empagliflozin or a DPP‐4 inhibitor between August 2014 and August 2019, were aged ≥18 years, and had ≥12 months' continuous health plan enrolment. Incidence rates by exposure and incidence rate ratios, adjusted for propensity‐score deciles, were calculated. Results: In total, 64 599 empagliflozin initiators and 203 315 DPP‐4 inhibitor initiators were included. There was an increased risk [pooled adjusted incidence rate ratios (95% confidence interval)] of DKA [2.19 (1.74‐2.76)] and decreased risks of ALI [0.77 (0.50‐1.19) in patients without predisposing conditions of liver disease; 0.70 (0.56‐0.88) in all patients] and AKI [0.54 (0.41‐0.73)]. In the UK data, there was an increased risk of GI [males: 4.04 (3.46‐4.71); females: 3.24 (2.81‐3.74)] and decreased risks of CKD [0.53 (0.43‐0.65)] and severe complications of UTI [0.51 (0.37‐0.72)]. The results were generally consistent in subgroup and sensitivity analyses. Conclusions: Compared with DDP‐4 inhibitor use, empagliflozin use was associated with increased risks of DKA and GI and decreased risks of ALI, AKI, CKD and severe complications of UTI. These associations are consistent with previous studies and known class effects of sodium‐glucose cotransporter 2 inhibitors, including renoprotective effects and beneficial effects on alanine aminotransferase levels. [ABSTRACT FROM AUTHOR]

There are now an estimated five million people living with diabetes in the UK, most have type 2 diabetes. The COVID-19 pandemic affected access to care, led to delays in diagnoses of diabetes and many people with diabetes experienced a deterioration in their diabetes control. This article provides guidance on how nurses can work with people at risk of diabetes to prevent diabetes, to induce remission and how to use medication to treat diabetes. [ABSTRACT FROM AUTHOR]

The article focuses on evaluating the safety and efficacy of SGLT-2 inhibitors (SGLT-2i) in kidney transplant recipients with pre-existing diabetes or post-transplant diabetes mellitus (PTDM). Topics include the benefits of SGLT-2i in preserving graft function, reducing glycemic burden, and potentially lowering cardiovascular risk in this patient group.

Objective Sodium-glucose cotransporter-2 inhibitors (SGLT2Is) reduce cardio-metabolic and renal outcomes in patients with type 2 diabetes (T2D) but their efficacy and safety in older or frail individuals remains unclear. Methods We searched PubMed, Scopus, Web of Science, Cochrane CENTRA and Google Scholar and selected randomised controlled trials and observational studies comparing SGLT2Is versus placebo/other glucose-lowering agent for people with frailty or older individuals (>65 years) with T2D and heart failure (HF). Extracted data on the change in HbA1c % and safety outcomes were pooled in a random-effects meta-analysis model. Results We included data from 20 studies (22 reports; N  = 77,083 patients). SGLT2Is did not significantly reduce HbA1c level (mean difference −0.13, 95%CI: −0.41 to 0.14). SGLT2Is were associated with a significant reduction in the risk of all-cause mortality (risk ratio (RR) 0.81, 95%CI: −0.69 to 0.95), cardiac death (RR 0.80, 95%CI: −0.94 to 0.69) and hospitalisation for heart failure (HHF) (RR 0.69, 95%CI: 0.59–0.81). However, SGLT2Is did not demonstrate significant effect in reducing in the risk of macrovascular events (acute coronary syndrome or cerebral vascular occlusion), renal progression/composite renal endpoint, acute kidney injury, worsening HF, atrial fibrillation or diabetic ketoacidosis. Conclusions In older or frail patients with T2D and HF, SGLT2Is are consistently linked with a decrease in total mortality and the overall burden of cardiovascular (CV) events, including HHF events and cardiac death, but not protective for macrovascular death or renal events. Adverse events were more difficult to quantify but the risk of diabetic ketoacidosis or acute kidney injury was not significantly increase. [ABSTRACT FROM AUTHOR]

Aims: To assess post‐initiation predictors of discontinuation of sodium‐glucose cotransporter‐2 (SGLT2) inhibitors compared to dipeptidyl‐peptidase‐4 (DPP‐4) inhibitors in the United Kingdom. Materials and Methods: We conducted a comparative population‐based retrospective cohort study using primary care data from the UK Clinical Practice Research Datalink (CPRD) with linked data to hospital and death records. We included new metformin users who initiated either SGLT2 inhibitors or DPP‐4 inhibitors between January 2013 and October 2019. The main outcome was treatment discontinuation, defined as the first 90‐day gap after the estimated treatment end date. We used a series of extended Cox models to assess which time‐dependent predictors were associated with treatment discontinuation. To test if the hazard ratio of discontinuation for each predictor was statistically different between SGLT2 and DPP‐4 inhibitors, an exposure‐predictor interaction term was added to each model. Results: There were 2550 new users of SGLT2 inhibitors and 8195 new users of DPP‐4 inhibitors. Approximately 69% of SGLT2 inhibitor and 74% of DPP‐4 inhibitor users had discontinued treatment by the end of follow‐up. Occurrence of fractures after treatment initiation was a significant predictor of discontinuation of SGLT2 inhibitors (hazard ratio [HR] 4.13, 95% confidence interval [CI] 2.12‐8.06) but not DPP‐4 inhibitors (HR 0.93, 95% CI 0.79‐1.11). The rate of treatment discontinuation was significantly higher for those with low estimated glomerular filtration rate and minimal contact with the healthcare system. Efficacy endpoints, such as heart failure and glycated haemoglobin level, were not associated with treatment discontinuation. Conclusions: Our findings reflect some discrepancy between the available evidence and prescribing behaviour for SGLT2 inhibitors. [ABSTRACT FROM AUTHOR]

The article focuses on the importance of early and accurate diagnosis and coding in managing Chronic Kidney Disease (CKD) to delay deterioration in kidney function and optimize cardiovascular risk reduction, aiming to review CKD pathophysiology, recognize diagnostic criteria, implement evidence-based recommendations, reflect on cardiovascular risk reduction, determine complications, support patient understanding, and consider timely referrals into secondary care.

The Diabetes UK Professional Conference, held this year in Liverpool, featured presentations on pharmacological treatment across the spectrum of diabetes care, promoting safe and effective use of medications to optimise outcomes. Dr Katherine Bishop reports on some key prescribing topics. [ABSTRACT FROM AUTHOR]

Aim: To conduct a pharmacoepidemiological study to explore the association between sodium‐glucose cotransporter‐2 (SGLT2) inhibitors and gout in patients with type 2 diabetes mellitus (T2DM). Materials and Methods: A retrospective open cohort study using the IQVIA Medical Research Data UK database was performed between November 1, 2012 and December 31, 2018, estimating the risk of gout in patients with T2DM who were new users of SGLT2 inhibitors, compared to propensity‐score‐matched new users of dipeptidyl peptidase‐4 (DPP‐4) inhibitors. Results: A total of 85 incident cases of gout were recorded over 30 389 person‐years of observation in 13 617 new users of SGLT2 inhibitors and 29 426 new users of DPP‐4 inhibitors. Crude incidence rates (IRs) per 1000 person‐years were 2.90 and 2.47 for new users of SGLT2 inhibitors and DPP‐4 inhibitors, respectively. The unadjusted hazard ratio (HR) was 1.18 (95% confidence interval [CI] 0.76‐1.83). The adjusted HR was 1.20 (95% CI 0.77‐1.86). In the at‐treatment analysis, crude IRs per 1000 person‐years were found to be 2.68 and 2.53 for SGLT2 inhibitor and DPP‐4 inhibitor users, respectively. In the adjusted model, the adjusted HR was 1.3 (95% CI 0.90‐2.29). Sensitivity analyses did not change the findings. Conclusions: In this nationwide study, no difference in the incidence of gout was documented in patients treated with SGLT2 inhibitors compared to DPP‐4 inhibitor users. This neutral finding remained consistent in sensitivity analyses. [ABSTRACT FROM AUTHOR]

Introduction: Research is ongoing to increase our understanding of how much a previous diagnosis of type 2 diabetes mellitus (T2DM) affects someone's risk of becoming seriously unwell following a COVID-19 infection. In this study we set out to determine the relative likelihood of death following COVID-19 infection in people with T2DM when compared to those without T2DM. This was conducted as an urban population study and based in the UK. Methods: Analysis of electronic health record data was performed relating to people living in the Greater Manchester conurbation (population 2.82 million) who had a recorded diagnosis of T2DM and subsequent COVID-19 confirmed infection. Each individual with T2DM (n = 13,807) was matched with three COVID-19-infected non-diabetes controls (n = 39,583). Data were extracted from the Greater Manchester Care Record (GMCR) database for the period 1 January 2020 to 30 June 2021. Social disadvantage was assessed through Townsend scores. Death rates were compared in people with T2DM to their respective non-diabetes controls; potential predictive factors influencing the relative likelihood of admission were ascertained using univariable and multivariable logistic regression. Results: For individuals with T2DM, their mortality rate after a COVID-19 positive test was 7.7% vs 6.0% in matched controls; the relative risk (RR) of death was 1.28. From univariate analysis performed within the group of individuals with T2DM, the likelihood of death following a COVID-19 recorded infection was lower in people taking metformin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i) or a glucagon-like peptide 1 (GLP-1) agonist. Estimated glomerular filtration rate (eGFR) and hypertension were associated with increased mortality and had odds ratios of 0.96 (95% confidence interval 0.96–0.97) and 1.92 (95% confidence interval 1.68–2.20), respectively. Likelihood of death following a COVID-19 infection was also higher in those people with a diagnosis of chronic obstructive pulmonary disease (COPD) or severe enduring mental illness but not with asthma, and in people taking aspirin/clopidogrel/insulin. Smoking in people with T2DM significantly increased mortality rate (odds ratio of 1.46; 95% confidence interval 1.29–1.65). In a combined analysis of patients with T2DM and controls, multiple regression modelling indicated that the factors independently relating to a higher likelihood of death (accounting for 26% of variance) were T2DM, age, male gender and social deprivation (higher Townsend score). Conclusion: Following confirmed infection with COVID-19 a number of factors are associated with mortality in individuals with T2DM. Prescription of metformin, SGLT2is or GLP-1 agonists and non-smoking status appeared to be associated with a reduced the risk of death for people with T2DM. Age, male sex and social disadvantage are associated with an increased risk of death. [ABSTRACT FROM AUTHOR]

Sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors are widely prescribed in people with type 2 diabetes. We aimed to investigate whether SGLT2 inhibitor prescription is associated with COVID‐19, when compared with an active comparator. We performed a propensity‐score‐matched cohort study with active comparators and a negative control outcome in a large UK‐based primary care dataset. Participants prescribed SGLT2 inhibitors (n = 9948) and a comparator group prescribed dipeptidyl peptidase‐4 (DPP‐4) inhibitors (n = 14 917) were followed up from January 30 to July 27, 2020. The primary outcome was confirmed or clinically suspected COVID‐19. The incidence rate of COVID‐19 was 19.7/1000 person‐years among users of SGLT2 inhibitors and 24.7/1000 person‐years among propensity‐score‐matched users of DPP‐4 inhibitors. The adjusted hazard ratio was 0.92 (95% confidence interval 0.66 to 1.29), and there was no evidence of residual confounding in the negative control analysis. We did not observe an increased risk of COVID‐19 in primary care amongst those prescribed SGLT2 inhibitors compared to DPP‐4 inhibitors, suggesting that clinicians may safely use these agents in the everyday care of people with type 2 diabetes during the COVID‐19 pandemic. [ABSTRACT FROM AUTHOR]

Sodium-glucose cotransporter 2 (SGLT2) inhibitor clinical studies in type 1 diabetes mellitus (T1DM) have demonstrated reduced HbA1c and lower glucose variability with increased time in optimal glucose range as well as additional benefits of reductions in weight and insulin dose without increasing the incidence of hypoglycaemia. However, the appropriate use of SGLT2 inhibitor therapies within clinical practise to treat people with T1DM remains unclear. In this article we have used consensus expert opinion alongside the available evidence, product indication and most recent clinical guidance to provide support for the diabetes healthcare community regarding the appropriate use of SGLT2 inhibitors, focussing on specific considerations for appropriate prescribing of dapagliflozin within the T1DM management pathway. Its purpose is to provide awareness of the issues surrounding treatment with dapagliflozin in T1DM as well as offer practical guidance that also includes a checklist tool for appropriate dapagliflozin prescribing. The checklist aims to support clinicians in identifying those people with T1DM most likely to benefit from dapagliflozin treatment as well as situations where caution may be required. Funding: AstraZeneca UK Ltd. [ABSTRACT FROM AUTHOR]

SGLT2 inhibitors (SGLT2i) block renal glucose reabsorption. Due to the unexpected beneficial observations in type 2 diabetic patients potentially related to increased natriuresis, SGLT2i are also studied for heart failure treatment. This study aimed to identify genetic variants mimicking SGLT2i to further our understanding of the potential underlying biological mechanisms. Using the UK Biobank resource, we identified 264 SNPs located in the SLC5A2 gene or within 25kb of the 5′ and 3′ flanking regions, of which 91 had minor allele frequencies >1%. Twenty-seven SNPs were associated with glycated hemoglobin (HbA1c) after Bonferroni correction in participants without diabetes, while none of the SNPs were associated with sodium excretion. We investigated whether these variants had a directionally consistent effect on sodium excretion, HbA1c levels, and SLC5A2 expression. None of the variants met these criteria. Likewise, we identified no common missense variants, and although four SNPs could be defined as 5′ or 3′ prime untranslated region variants of which rs45612043 was predicted to be deleterious, these SNPs were not annotated to SLC5A2. In conclusion, no genetic variant was found mimicking SGLT2i based on their location near SLC5A2 and their association with sodium excretion or HbA1c and SLC5A2 expression or function. [ABSTRACT FROM AUTHOR]