Showing papers in "Diabetes Therapy in 2022"

Reductions in HbA1c with Flash Glucose Monitoring Are Sustained for up to 24 Months: A Meta-Analysis of 75 Real-World Observational Studies

Abstract: Real-world evidence (RWE) confirms that reductions in HbA1c for children and adults with type 1 diabetes (T1DM) and adults with type 2 diabetes (T2DM) are associated with use of the FreeStyle Libre system. This current meta-analysis aims to investigate whether HbA1c benefits are sustained over 24 months and to identify patterns of change in HbA1c for users of the FreeStyle Libre system for people living with T1DM or T2DM. A bibliographic search up to December 2020 identified 75 studies reporting data on change in lab HbA1c in 30,478 participants with type 1 (n = 28,063; 62 trials) or type 2 diabetes (n = 2415; 13 trials) using the FreeStyle Libre system, including observations on children, adolescents and adults. Meta-analysis was performed using a random effects model. Reductions in HbA1c at 3–4 months were similar for adults with T1DM (− 0.53%, 95% CI − 0.69 to − 0.38) or with T2DM (− 0.45%, 95% CI − 0.57 to − 0.33), continuing through 4.5–7.5 months in T1DM (− 0.42%, 95% CI − 0.58 to − 0.27) and in T2DM (− 0.59%, 95% CI − 0.80 to − 0.39). Meta-regression analysis shows that higher starting HbA1c is correlated with greater reductions in HbA1c in T1DM and in T2DM. These patterns of change in HbA1c were sustained for 24 months in T1DM and for at least 12 months in T2DM. Meta-analysis of RWE confirms that using the FreeStyle Libre system is associated with significant reductions in HbA1c for adults with T1DM or with T2DM. Reductions are greater for people with higher baseline HbA1c and are sustained for 24 and 12 months in T1DM and TD2M respectively.

Emerging Horizons in Heart Failure with Preserved Ejection Fraction: The Role of SGLT2 Inhibitors

Abstract: Heart failure with preserved ejection fraction (HFpEF) is a condition with increasing disease burden. Prevalence of HFpEF is increasing, reflecting an increasingly elderly and comorbid population, as well as reinforcing the need for more treatments for this disease. The pathophysiology of HFpEF is complex. Some inflammatory processes seen in HFpEF are shared with diabetes mellitus (DM) and there is an association seen between the two conditions. It is therefore no wonder that treatments for diabetes may have some effect on heart failure outcomes. Current treatment strategies in HFpEF are limited, with treatments focusing on symptom control rather than morbidity or mortality benefit. However, there are now promising results from the EMPEROR-Preserved study that show significantly reduced cardiovascular death or hospitalisation for heart failure (HHF) in patients taking empagliflozin, compared to those taking placebo. These results indicate a promising future for sodium-glucose co-transporter 2 (SGLT2) inhibitors in HFpEF. The ongoing DELIVER trial (investigating the use of dapagliflozin in HFpEF) is awaited but could provide further evidence of support for SGLT2 inhibitors in HFpEF. With hospital admissions for HFpEF increasing in the UK, the economic impact of treatments that reduce HHF is vast. The European Society of Cardiology (ESC) recently added SGLT2 inhibitors to their guidelines for treatment of heart failure with reduced ejection fraction (HFrEF) following DAPA-HF and EMPEROR-Reduced trials and we suggest that similar changes be made to guidelines to support the use of SGLT2 inhibitors in the management of HFpEF in upcoming months.

Liraglutide Improved Cardiometabolic Parameters More in Obese than in Non-obese Patients with Type 2 Diabetes: A Real-World 18-Month Prospective Study

Abstract: The glucagon-like peptide-1 agonist (GLP1-RA) liraglutide is currently approved for the treatment of both obesity and type 2 diabetes (T2DM). We investigated whether the effect of this agent on cardiometabolic parameters in subjects with T2DM varied in relation to the concomitant presence of obesity.One hundred thirty-five subjects (78 men and 57 women; age: 62 ± 10 years) naïve to incretin-based therapies were treated with low-dose liraglutide (1.2 mg/day) as an add-on to metformin for 18 months. Patients were divided into two subgroups based on their body-mass index (BMI): (a) obese (BMI ≥ 30) and (b) non-obese (BMI < 30). Clinical and laboratory analyses were assessed at baseline and every 6 months.During follow-up, significant improvements were seen in both groups in fasting glycemia, glycated hemoglobin, waist circumference, and carotid intima-media thickness (cIMT), while body weight, BMI, total cholesterol, and low-density lipoprotein cholesterol decreased significantly in obese subjects only. Correlation analysis revealed that changes in subclinical atherosclerosis (assessed by cIMT) were associated with changes in triglycerides (r = 0.488, p < 0.0001) in the obese group only.Liraglutide had beneficial actions on glycemic parameters and cardiometabolic risk factors in both non-obese and obese patients with T2DM, with a greater efficacy in the latter. These findings reinforce the benefits of liraglutide for the cardiometabolic outcomes of obese patients with T2DM in the real-world setting. This has critical importance during the current pandemic, since patients with diabetes and obesity are exposed globally to the most severe forms of COVID-19, related complications, and death.ClinicalTrials.gov identifier, NCT01715428.

The Risk Factors Potentially Influencing Hospital Admission in People with Diabetes, Following SARS-CoV-2 Infection: A Population-Level Analysis

Abstract: Since early 2020 the whole world has been challenged by the SARS-CoV-2 virus and the associated global pandemic (Covid-19). People with diabetes are particularly at high risk of becoming seriously unwell after contracting this virus.This population-based study included people living in the Greater Manchester conurbation who had a recorded diagnosis of type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) and subsequent Covid-19 infection. Each individual with T1DM (n = 862) or T2DM (n = 13,225) was matched with three Covid-19-infected non-diabetes controls.For individuals with T1DM, hospital admission rate in the first 28 days after a positive Covid-19 test was 10% vs 4.7% in age/gender-matched controls [relative risk (RR) 2.1]. For individuals with T2DM, hospital admission rate after a positive Covid-19 test was 16.3% vs 11.6% in age/gender-matched controls (RR 1.4). The average Townsend score was higher in T2DM (1.8) vs matched controls (0.4), with a higher proportion of people with T2DM observed in the top two quintiles of greatest disadvantage (p < 0.001). For Covid-19-infected individuals with T1DM, factors influencing admission likelihood included age, body mass index (BMI), hypertension, HbA1c, low HDL-cholesterol, lower estimated glomerular filtration rate (eGFR), chronic obstructive pulmonary disease (COPD) and being of African/mixed ethnicity. In Covid-19-infected individuals with T2DM, factors related to a higher admission rate included age, Townsend index, comorbidity with COPD/asthma and severe mental illness (SMI), lower eGFR. Metformin prescription lowered the likelihood. For multivariate analysis in combined individuals with T2DM/controls, factors relating to higher likelihood of admission were having T2DM/age/male gender/diagnosed COPD/diagnosed hypertension/social deprivation (higher Townsend index) and non-white ethnicity (all groups).In a UK population we have confirmed a significantly higher likelihood of admission in people with diabetes following Covid-19 infection. A number of factors mediate that increased likelihood of hospital admission. For T2DM, the majority of factors related to increased admission rate are common to the general population but more prevalent in T2DM. There was a protective effect of metformin in people with T2DM.

The Dual Pandemics of COVID-19 and Obesity: Bidirectional Impact

Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the COVID-19 pandemic, has been shown to disrupt many organ systems in the human body. Though several medical disorders have been affected by this infection, a few illnesses in addition may also play a role in determining the outcome of COVID-19. Obesity is one such disease which is not only affected by the occurrence of COVID-19 but can also result in a worse clinical outcome of COVID-19 infection. This manuscript summarizes the most recent evidence supporting the bidirectional impact of COVID-19 and obesity. It highlights how the presence of obesity can be detrimental to the outcome of COVID-19 in a given patient because of the mechanical limitations in lung compliance and also by the activation of several thrombo-inflammatory pathways. The sociodemographic changes brought about by the pandemic in turn have facilitated the already increasing prevalence of obesity. This manuscript highlights the importance of recognizing these pathways which may further help in policy changes that facilitate appropriate measures to prevent the further worsening of these two pandemics.

Mortality in People with Type 2 Diabetes Following SARS-CoV-2 Infection: A Population Level Analysis of Potential Risk Factors

Abstract: 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.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.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).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.

Effectiveness in Real World of Once Weekly Semaglutide in People with Type 2 Diabetes: Glucagon-Like Peptide Receptor Agonist Naïve or Switchers from Other Glucagon-Like Peptide Receptor Agonists: Results from a Retrospective Observational Study in Umbria

Abstract: To complement results of the SUSTAIN program, this study assessed effectiveness and safety of once weekly subcutaneous semaglutide in people with type 2 diabetes (T2D) managed under routine care.This was a multicenter, observational, retrospective study including all patients treated with semaglutide. Changes in clinical outcomes from baseline to 6 and 12 months were assessed in patients who were glucagon-like peptide receptor agonist (GLP-1RA) naïve or switching from another GLP-1RA. Discontinuation rate was assessed.Overall, 216 patients (mean age 64 years, 65.7% men) were evaluated: 135 (61.5%) naïve and 81 (38.5%) switchers from another GLP-1RA. In the naïve cohort, after 6 months from semaglutide initiation, levels of HbA1c significantly decreased by - 1.31% (p < 0.0001). All obesity indices improved, with mean reductions in body weight of - 3.92 kg, in BMI of - 1.43 kg/m2, and in waist circumference of - 5.03 cm. In the switcher cohort, statistically significant improvements in HbA1c (- 0.78%), body weight (- 2.64 kg), and waist circumference (- 3.03 cm) were obtained after 6 months. Reductions were sustained after 12 months in both cohorts (mean semaglutide dose: 0.86 mg in naïve and 0.96 mg in switcher cohort). Blood pressure and lipid profile mean levels decreased after 12 months from semaglutide initiation in both cohorts. No severe hypoglycemia occurred; 6.5% of patients discontinued semaglutide (2.8% due to gastrointestinal side effects).Effectiveness and tolerability of semaglutide have been confirmed in the real world irrespective of diabetes duration and severity. As expected, more marked reductions in HbA1c and obesity indices were obtained in naïve patients, but it is noteworthy that relevant improvements were also obtained in patients already treated with GLP-1RAs.

Association of British Clinical Diabetologists, Diabetes Technology Network UK and Association of Children’s Diabetes Clinicians Survey of UK Healthcare Professional Attitudes Towards Open-Source Automated Insulin Delivery Systems

Abstract: Automated insulin delivery (AID) systems can enable improved glycaemic outcomes with reduced mental burden. Open-source AID (OS-AID) systems overcome some of the developmental and access barriers enabling a wider use of these systems. Limited data are available on healthcare professional (HCP) opinions and current practice regarding these systems. The aim of this survey was to gain insight into HCP perceptions and practices around OS-AID.This survey was developed collaboratively with OS-AID users and distributed to adult and children's teams, using an online survey tool. Results were received between February and April 2019. Responses were assessed using simple descriptive statistics with analyses stratified by respondent characteristics.317 responses were obtained from a range of HCPs in both adult and paediatric services. Key results include: HCP perception of OS-AID as "risky in the wrong hands" (43%); 91% felt uncomfortable initiating discussions around OS-AID because of lack of regulation (67%) and/or their own lack of knowledge (63%). Half of HCPs (47%) reported that they would choose OS-AID if they themselves had type 1 diabetes.HCPs are generally supportive of OS-AID users but many feel uncomfortable with the technicalities of the systems given the lack of approval. Knowledge around the use of these systems was limited. Re-assessment of HCP perceptions should be performed in the future given the evolving landscape of diabetes technology, recent consensus statements and emerging ethical and legal perspectives.Open-source automated insulin delivery systems are an increasingly encountered diabetes technology. These involve a small glucose sensor and an insulin delivery device called an insulin pump. These two devices interact to allow adjustment of insulin delivery to maintain glucose levels in a desirable range. The computer codes which drive these systems are developed by people with diabetes or their families rather than by device companies; as such, they have not been through formal approval processes and therefore there is limited formal evidence concerning whether they are safe or beneficial to use. Users report high satisfaction with these devices and improvements in their diabetes management. This survey was performed to assess the opinions of UK healthcare professionals and their usual practice. Key results include: UK healthcare professionals would not routinely recommend the use of these devices and there was concern about the medicolegal implications of use. However, UK healthcare professionals were generally supportive of those who chose to use the devices. Interestingly, almost half of the healthcare professionals would use the systems if they had diabetes.

Expert Panel Guidance and Narrative Review of Treatment Simplification of Complex Insulin Regimens to Improve Outcomes in Type 2 Diabetes

Abstract: Given the progressive nature of type 2 diabetes (T2D), most individuals with the disease will ultimately undergo treatment intensification. This usually involves the stepwise addition of a new glucose-lowering agent or switching to a more complex insulin regimen. However, complex treatment regimens can result in an increased risk of hypoglycaemia and high treatment burden, which may impact negatively on both therapeutic adherence and overall quality of life. Individuals with good glycaemic control may also be overtreated with unnecessarily complex regimens. Treatment simplification aims to reduce individual treatment burden, without compromising therapeutic effectiveness or safety. Despite data showing that simplifying therapy can achieve good glycaemic control without negatively impacting on treatment efficacy or safety, it is not always implemented in clinical practice. Current clinical guidelines focus on treatment intensification, rather than simplification. Where simplification is recommended, clear guidance is lacking and mostly focused on treatment of the elderly. An expert, multidisciplinary panel evaluated the current treatment landscape with respect to guidance, published evidence, recommendations and approaches regarding simplification of complex insulin regimens. This article outlines the benefits of treatment simplification and provides practical recommendations on simplifying complex insulin treatment strategies in people with T2D using illustrative cases.

Real-World Effectiveness and Safety of Insulin Glargine 300 U/mL in Insulin-Naïve People with Type 2 Diabetes: the ATOS Study

Abstract: The clinical benefits of insulin glargine 300 U/mL (Gla-300) have been confirmed in randomised clinical trials (EDITION programme and BRIGHT) and real-world studies in the USA and Western Europe. ATOS evaluated the real-world effectiveness and safety of Gla-300 in wider geographic regions (Asia, the Middle East, North Africa, Latin America and Eastern Europe).This prospective observational, international study enrolled adults (≥ 18 years) with type 2 diabetes mellitus (T2DM) uncontrolled [haemoglobin A1c (HbA1c) > 7% to ≤ 11%] on one or more oral anti-hyperglycaemic drugs (OADs) who had been advised by their treating physician to add Gla-300 to their existing treatment. The primary endpoint was achievement of a pre-defined individualised HbA1c target at month 6.Of the 4550 participants included, 4422 (51.8% female) were eligible for assessment. The mean ± standard deviation (SD) age was 57.2 ± 10.8 years, duration of diabetes was 10.2 ± 6.2 years and baseline HbA1c was 9.28 ± 1.0%. The proportion of participants reaching their individualised glycaemic target was 25.2% [95% confidence interval (CI) 23.8-26.6%] at month 6 and 44.5% (95% CI 42.9-46.1%) at month 12. At months 6 and 12, reductions were observed in HbA1c (-1.50% and -1.87%) and fasting plasma glucose (-3.42 and -3.94 mmol/L). Hypoglycaemia incidence was low, and body weight change was minimal. Adverse events were reported in 283 (6.4%) participants, with 57 (1.3%) experiencing serious adverse events.In a real-world setting, initiation of Gla-300 in people with T2DM uncontrolled on OADs resulted in improved glycaemic control and low rates of hypoglycaemia with minimal weight change.Clinicaltrials.gov number NCT03703869.

Overt Diabetes in Pregnancy

Abstract: Overt diabetes in pregnancy is defined as hyperglycemia first recognized during pregnancy which meets the diagnostic threshold of diabetes in non-pregnant adults. This case-based narrative review aims to describe this unique condition and discuss the potential implications for its accurate diagnosis and management.We conducted a literature search in PubMed for relevant articles published in English language up to January 2022. Women with overt diabetes have a higher risk for adverse pregnancy outcomes and postpartum diabetes, compared to their counterparts with gestational diabetes mellitus (GDM). Such women often need aggressive management, including early and prompt initiation of insulin therapy, and a close follow-up during pregnancy and in the postpartum period. Not all pregnant women with overt diabetes have persistent diabetes in the postpartum period. Early diagnosis, especially during the first trimester, and fasting plasma glucose elevation (≥ 126 mg/dl or 7 mmol/L) at the time of initial diagnosis are predictors of postpartum diabetes.Both GDM and overt diabetes in pregnancy are hyperglycemic conditions first recognized during pregnancy, but the two conditions differ in severity; the latter is a more severe form of hyperglycemia associated with worse maternal and fetal outcomes, and a higher risk of postpartum diabetes.

Manifestation of Heart Failure and Chronic Kidney Disease are Associated with Increased Mortality Risk in Early Stages of Type 2 Diabetes Mellitus: Analysis of a Japanese Real-World Hospital Claims Database

Abstract: To assess the initial manifestation of comorbidities and their impact on mortality risk in patients with type 2 diabetes mellitus (T2DM) without a history of cardiovascular or renal complications (i.e., in the early stages of T2DM) compared with patients without T2DM.We performed a retrospective cohort study using a Japanese hospital claims database. The incidence rates of comorbidities (chronic kidney disease [CKD], heart failure [HF], myocardial infarction [MI], peripheral arterial disease [PAD], and stroke) and mortality risk were compared between patients with T2DM and age-/sex-matched patients without T2DM (matched 1:2).Among the comorbidities assessed in this study, CKD and/or HF was the most frequent initial manifestation in the patients with T2DM (n = 426,186) with an incidence rate 2.02 times greater than that in matched patients without T2DM (n = 1,018,609). The mortality risk was also greater in patients with T2DM than in patients without T2DM with a hazard ratio of 1.73. In both patients with and without T2DM, the presence of CKD or HF was associated with greater mortality risks compared with the presence of MI, PAD, or stroke.The high incidence of CKD or HF manifestation can contribute to the augmented mortality risk in patients in the early stages of T2DM compared with patients without T2DM. These findings highlight the importance of early interventions for preventing/treating CKD and HF to improve the prognosis of patients with T2DM.

Expert Opinion: Optimum Clinical Approach to Combination-Use of SGLT2i + DPP4i in the Indian Diabetes Setting

Abstract: The Asian-Indian phenotype of type 2 diabetes mellitus is uniquely characterized for cardio-metabolic risk. In the context of implementing patient-centric holistic cardio-metabolic risk management as a priority, the choice of various combinations of antidiabetic agents should be individualized. Combined therapy with two classes of antidiabetic agents, namely, dipeptidyl peptidase 4 inhibitors and sodium-glucose co-transporter-2 inhibitors, target several pathophysiological pathways. The wide-ranging clinical outcomes associated with this combination, including improvement of glycemia and adiposity, reduction of metabolic and vascular risk, safety, and simplicity for sustainable compliance, are extremely relevant to the Asian Indian patient population living with T2DM. In this review we describe the available evidence in detail and present a rational practical guidance for the optimum clinical use of this combination in this patient population.

Cost-Effectiveness Analysis of Initiating Type 2 Diabetes Therapy with a Sodium–Glucose Cotransporter 2 Inhibitor Versus Conventional Therapy in Japan

Abstract: Many patients with type 2 diabetes mellitus (T2DM) suffer from complications that impose substantial burdens on prognosis and medical costs. Accumulating evidence has demonstrated the clinical benefit of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on cardiovascular and renal complications. However, the health economic impact of SGLT2i remains unclear. The aim of this study was to evaluate the cost-effectiveness of initiating antidiabetic therapy with an SGLT2i using Japanese real-world data.We constructed a natural history model incorporating heart failure (HF), myocardial infarction, stroke, chronic kidney disease, and end-stage renal disease (ESRD) as complications. The target population comprised patients with T2DM who newly initiated their first oral glucose-lowering drugs. By using a population-based microsimulation, we estimated the 10-year medical costs in Japanese yen (JPY) and outcomes (hospitalization for/development of complications and quality-adjusted life years [QALY]) for patients who initiated antidiabetic therapy with an SGLT2i or conventional therapy. Sensitivity analyses included a probabilistic sensitivity analysis (PSA) with 1,000,000 iterations.In the base-case analysis, the total medical cost per person was JPY 1,638,806 versus JPY 1,825,033 and the QALYs were 8.732 versus 8.513 for the SGLT2i strategy versus the conventional strategy, respectively. Thus, initiating treatment with an SGLT2i was dominant, more effective (QALY gain), and lower cost. When treating 10,000 patients, the SGLT2i strategy would reduce all-cause deaths by 410 (552 vs 962), HF events by 201 (897 vs 1098), and ESRD events by 16 (16 vs 32) versus the conventional strategy. The PSA revealed that the probability of dominance for initiating SGLT2i therapy was 90.5%, demonstrating the robustness of the results.Our results suggest that initiating T2DM treatment with SGLT2i, aimed at managing cardiovascular and renal complications from the early stages of diabetes, can improve the clinical outcome and reduce cost burden of T2DM.

Practical Guidance on Open Source and Commercial Automated Insulin Delivery Systems: A Guide for Healthcare Professionals Supporting People with Insulin-Requiring Diabetes

Abstract: As increasing numbers of people with insulin-managed diabetes use automated insulin delivery (AID) systems or seek such technologies, healthcare providers are faced with a steep learning curve. Healthcare providers need to understand how to support these technologies to help inform shared decision making, discussing available options, implementing them in the clinical setting, and guiding users in special situations. At the same time, there is a growing diversity of commercial and open source automated insulin delivery systems that are evolving at a rapid pace. This practical guide seeks to provide a conversational framework for healthcare providers to first understand and then jointly assess AID system options with users and caregivers. Using this framework will help HCPs in learning how to evaluate potential new commercial or open source AID systems, while also providing a guide for conversations to help HCPs to assess the readiness and understanding of users for AID systems. The choice of an AID system is not as simple as whether the system is open source or commercially developed, and indeed there are multiple criteria to assess when choosing an AID system. Most importantly, the choices and preferences of the person living with diabetes should be at the center of any decision around the ideal automated insulin delivery system or any other diabetes technology. This framework highlights issues with AID use that may lead to burnout or perceived failures or may otherwise cause users to abandon the use of AID. It discusses the troubleshooting of basic AID system operation and discusses more advanced topics regarding how to maximize the time spent on AID systems, including how to optimize settings and behaviors for the best possible outcomes with AID technology for people with insulin-requiring diabetes. This practical approach article demonstrates how healthcare providers will benefit from assessing and better understanding all available AID system options to enable them to best support each individual.Automated insulin delivery (AID) systems are a useful tool for people with insulin-requiring diabetes. AID systems include an insulin pump, continuous glucose monitor (CGM), and an algorithm embedded within the pump or a separate mobile device that can determine and automatically adjust insulin delivery in response to glucose levels. There are now a number of AID systems available, some which are made and distributed by commercial manufacturers and some that are available open source. Both open source and commercially developed automated insulin delivery systems have been proven to be safe and effective. Open source and commercially developed automated insulin delivery systems have also been proven to improve the quality of life of people with insulin-requiring diabetes. The choice of an AID system is not merely whether the system is open source or commercially developed. There are multiple criteria to assess when choosing an AID system: pump, CGM, smartphone connectivity and algorithm capabilities, flexibility of the system overall, and interoperability with connected platforms for real-time data access. Most importantly, the choices and preferences of the person living with diabetes should be at the center of any decision around the ideal automated insulin delivery system or any other diabetes technology. Healthcare providers will benefit from assessing and better understanding all available AID system options to enable them to best support each individual. This practical guide seeks to provide a conversational framework for healthcare providers to first understand and then jointly assess AID system options with users and caregivers.

Real-World Treatment Patterns of Glucose-Lowering Agents Among Patients with Type 2 Diabetes Mellitus and Cardiovascular Disease or At Risk for Cardiovascular Disease: An Observational, Cross-Sectional, Retrospective Study

Abstract: There is limited published literature on longitudinal utilization of glucose-lowering agents (GLAs) among patients with type 2 diabetes (T2D) and cardiovascular disease (CVD or risk of CVD). This retrospective, observational study aimed to provide updated evidence on patient characteristics and utilization of GLAs among patients with T2D and CVD or risk of CVD in the United States.This was a cross-sectional evaluation of patients with T2D aged 50-89 years with annual continuous enrolment in a Medicare Advantage and Prescription Drug plan, identified from administrative claims data (Humana Research Database). Patients with T2D and atherosclerotic cardiovascular disease (ASCVD) or heart failure (HF) (CVD cohort), or T2D and an additional CVD risk factor without pre-existing CVD (CVD risk cohort) were identified from 2015 to 2019. Patients were followed from their first observed ASCVD/HF diagnosis or CVD risk factor for each year they were continuously enrolled or until occurrence of a CVD diagnosis (CVD risk cohort only). Use of GLA classes were reported by year, cohort, and age groups (50-64 years and ≥ 65 years).The percentage of patients on sodium-glucose co-transporter-2 inhibitors (SGLT-2is), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and GLP-1 RAs with proven cardiovascular benefit, respectively, increased from 2015 to 2019 among ≥ 65 years (CVD cohort: 1.1-3.4%, 1.6-4.0%, and 1.2-3.8%; CVD risk cohort: 1.4-3.7%, 2.0-4.3%, and 1.5-4.1%); and among 50-64 years (CVD cohort: 2.6-7.3%, 4.3-10.1%, and 3.4-9.4%; CVD risk cohort: 3.3-6.8%, 4.6-9.6%, and 3.5-8.9%).Although use of SGLT-2is and GLP-1 RAs increased over time, overall utilization of these agents in patients with T2D and ASCVD/HF or at risk for ASCVD/HF remained low, especially for those aged ≥ 65 years.Sodium-glucose co-transporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are types of glucose-lowering medications for patients with type 2 diabetes (T2D). The American Diabetes Association, the American Association of Clinical Endocrinologists, and American College of Endocrinology have recommended these medications for patients who have been diagnosed with T2D and atherosclerotic cardiovascular disease or heart failure (ASCVD/HF). The purpose of this study was to find out how many patients in a US-based health insurance population with T2D and ASCVD/HF were treated with SGLT-2is, GLP-1 RAs, and other glucose-lowering medications from 2015 to 2019. Using insurance claims data, we identified 50- to 89-year-old patients with T2D and either ASCVD/HF or at least one risk factor for ASCVD/HF. We tracked the number of patients with T2D and either ASCVD/HF or ASCVD/HF risk factors who were using different glucose-lowering medications. Glucose-lowering medications were used in most patients (60–78%), but fewer than 11% of patients aged 50–64 years, and fewer than 5% of patients over 65 years of age were prescribed SGLT-2i and GLP-1 RA medications, despite clinical guidelines recommending their use for the above-mentioned indications. Increasing awareness among healthcare providers may be required to ensure patients with T2D and ASCVD/HF or ASCVD/HF risk factors are prescribed the guideline-recommended cardioprotective glucose-lowering agents.

A Podcast Discussing Aldosterone and Mineralocorticoid Receptor Antagonists in 2021: A Paradigm Shift

Abstract: The classic focus on the mechanisms of action of aldosterone was directed primarily on its role in modulating renal excretory function and maintaining volume homeostasis. In contrast, many recent studies have demonstrated a much wider and expanded role for aldosterone and for the mineralocorticoid receptor (MR). Activation of the MR promotes inflammation, collagen formation, fibrosis, and necrosis with consequent renal injury. Increasing evidence has accrued that implicates the pathophysiological overactivation of the MR as a major determinant of progression of both diabetic and nondiabetic chronic kidney disease (CKD). By promoting cascades of injury encompassing inflammation and fibrosis, MR overactivation constitutes a pivotal determinant of CKD progression and consequently its associated morbidity and mortality. Based on this mechanism of action, blockade of the MR with the nonsteroidal MR antagonist finerenone is currently being investigated as a novel treatment regimen to slow the progression of CKD. The recently reported FIDELIO-DKD (FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease) study demonstrated that patients with CKD and type 2 diabetes (T2D) who were treated with finerenone manifested a lower risk of a composite primary outcome event compared with patients in the placebo arm (defined as kidney failure or a sustained decrease of ≥ 40% in the estimated glomerular filtration rate from baseline, or death from renal causes). In addition, patients in the finerenone group also manifested a lower risk of a key secondary outcome event (defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure). Based on the success of these major clinical trials, finerenone was approved by the FDA on 9 July 2021 as a novel treatment for retarding CKD progression in patients with T2D ( https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-reduce-risk-serious-kidney-and-heart-complications-adults-chronic-kidney-disease ). Podcast Video (MP4 258973 KB).

The Prevalence of Cardiovascular Disease in Adults with Type 2 Diabetes in China: Results from the Cross-Sectional CAPTURE Study

Abstract: Cardiovascular disease (CVD) is the leading cause of death in Chinese adults with type 2 diabetes (T2D), and treatment guidelines have increasingly focused on the comprehensive management of T2D and CVD. Here, we report data from the Chinese population within the CAPTURE study, including CVD prevalence in patients with T2D and insights into their management.CAPTURE (a multinational, non-interventional, cross-sectional study in adults with T2D) included data from eight centers in China from July to September 2019. Overall CVD prevalence estimates were calculated, and descriptive data regarding CVD subtypes and treatment were collected and reported here.Of 805 adults with T2D enrolled in China (61.9% male, median age 59 years), 273 had established CVD, with an estimated prevalence (95% CI) of 33.9% (30.6%, 37.3%). Most CVD cases were atherosclerotic (94.9%). Coronary heart disease had the highest estimated prevalence (16.0%), followed by carotid artery disease (9.6%) and cerebrovascular disease (7.7%). Use of glucose-lowering agents (GLAs) with proven cardiovascular benefits (glucagon-like peptide-1 receptor agonists and/or sodium-glucose cotransporter-2 inhibitors) was low in the China sample (7.7%). Approximately half of the CVD subgroup in the China sample was receiving cardiovascular medication, but use of guideline-directed agents was low (e.g., statins: 35.9%; angiotensin II receptor blockers: 15%; angiotensin-converting enzyme inhibitors: 2.6%).In the Chinese CAPTURE population, one-third of patients had established CVD, with atherosclerotic CVD largely accounting for the CVD burden; use of GLAs with proven cardiovascular benefits and cardiovascular medications was low, suggesting an unmet need for optimal management in this group.

The Effects of Imeglimin on the Daily Glycemic Profile Evaluated by Intermittently Scanned Continuous Glucose Monitoring: Retrospective, Single-Center, Observational Study

Abstract: Imeglimin is a novel antidiabetic drug that amplifies glucose-stimulated insulin secretion (GSIS) and improves insulin sensitivity. Several randomized clinical studies have shown the efficacy of imeglimin for glycemic control in patients with type 2 diabetes (T2D). We aimed to evaluate the short-term effects and safety of imeglimin in terms of glycemic control, as assessed by intermittently scanned continuous glucose monitoring (isCGM).This retrospective and observational study of 32 patients who were administered imeglimin in addition to existing treatment regimens was designed to evaluate glycemic profiles. The patients were monitored for more than 4 weeks, including the day of starting imeglimin. The changes in glycemic indices, including mean glucose level, coefficient of variation (CV), time in range (TIR) and time above range (TAR), before and after imeglimin administration were analyzed, and data on adverse effects were collected by interview.Imeglimin administration significantly improved the mean values of glucose (from 159.0 ± 27.5 mg/dL to 141.7 ± 22.1 mg/dL; p < 0.001), TIR (from 67.9 ± 17.0% to 79.5 ± 13.3%; p < 0.001) and TAR (from 29.4 ± 17.5% to 17.9 ± 13.7%; p < 0.001) and tended to improve CV (from 29.0 ± 6.1 to 27.4 ± 5.58; p = 0.058). The curves of 24-h mean glucose level for all 32 subjects were shifted downward from the baseline after imeglimin administration. The high mean glucose level, high TAR, low TIR, low body mass index and low C-peptide were related to the efficacy of imeglimin for glycemic control. The main adverse effects were gastrointestinal disorders, and the incidence of hypoglycemia was increased in cases receiving a combination of imeglimin plus insulin or a glinide agent.Imeglimin clearly shifted the daily glucose profile into an appropriate range in Japanese T2D patients, indicating improvement of short-term glycemic control. Imeglimin is thought to be a promising therapeutic agent for T2D patients, especially those with a low insulin secretory capacity, which is a common phenotype in East-Asian subjects with glucose intolerance.

Effect of Oral Semaglutide on Cardiovascular Parameters and Their Mechanisms in Patients with Type 2 Diabetes: Rationale and Design of the Semaglutide Anti-Atherosclerotic Mechanisms of Action Study (SAMAS)

Abstract: Type 2 diabetes (T2D) management has reached a point where not only optimal glycaemic control is necessary, but also additional interventions with proven cardiovascular risk reduction benefit. Subcutaneous semaglutide has been shown to provide cardiovascular protection, but its use may be limited by its injection formulation. To overcome this limitation, an oral semaglutide tablet has been developed, which could potentially be of the same value as its injection counterpart, but in a much wider group of patients with T2D, thereby allowing for broader cardiovascular risk reduction in this vulnerable patient population.A total of 100 consecutive patients with T2D and a disease duration of up to 10 years, without manifest cardiovascular disease, who are treated with metformin (± sulphonylurea) and optimal cardioprotective therapy, will be recruited in a single-blinded, randomized trial named "Semaglutide Anti-atherosclerotic Mechanisms of Action Study (SAMAS)." After 1:1 randomization, patients will receive either oral semaglutide 14 mg daily or placebo for 1 year. The primary outcome comprises changes in atherosclerosis-related structural and functional characteristics of the arterial wall, namely: reduction of the carotid intima-media thickness, improvement of endothelial function and decrease in arterial stiffness. Secondary outcomes are changes in atherogenic small dense low-density lipoproteins, glucose control (HbA1c) and inflammatory markers (hsCRP). Possible correlations between primary endpoints and changes in lipids, HbA1c and high-sensitivity C-reactive protein will be sought.This is the first study to investigate the direct and indirect anti-atherosclerotic mechanisms of oral semaglutide. The results are expected to confirm the position of oral semaglutide in the multifactorial management of T2D with an emphasis on cardiovascular disease prevention.ClinicalTrials.gov Identifier: NCT05147896.

The Emerging Role of Continuous Glucose Monitoring in the Management of Diabetic Peripheral Neuropathy: A Narrative Review

Abstract: The aim of this narrative review is to present data on the role of continuous glucose monitoring (CGM) in the management of peripheral diabetic neuropathy (DPN) among individuals with type 1 and type 2 diabetes mellitus. Adequate glycaemic control is crucial to prevent the development or progression of DPN. CGM systems are valuable tools for improving glycaemic control and reducing glycaemic variability (GV). Chronic hyperglycaemia is known to be a risk factor for the development of diabetic microvascular complications, including DPN. In addition, there is now evidence that GV, evaluated by mean amplitude of glycaemic excursions, may be a novel factor in the pathogenesis of diabetic complications. Increased GV appears to be an independent risk factor for DPN and correlates with painful neuropathy. Similarly, time-in-range correlates positively with peripheral nerve function and negatively with sudomotor dysfunction. However, relevant studies are rather limited in scope, and the vast majority are cross-sectional and use different methodologies for the assessment of DPN. Therefore, the causal relationship between CGM-derived data and the development of DPN cannot be firmly established at the present time. It also remains to be elucidated whether CGM measures can be considered the new therapeutic targets for DPN management.

Review of SGLT2i for the Treatment of Renal Complications: Experience in Patients with and Without T2D

Abstract: The management of type 2 diabetes (T2D) involves decreasing plasma glucose levels and reducing cardiovascular and microvascular complications. Diabetic kidney disease (DKD), defined as presence of albuminuria, impaired glomerular filtration, or both, is an insidious microvascular complication of diabetes that generates a substantial personal and clinical burden. The progressive reduction in renal function and increased albuminuria results in an increase of cardiovascular events. Thus, patients with DKD require exhaustive control of the associated cardiovascular risk factors. People with diabetes and renal impairment have fewer options of antidiabetic drugs because of contraindications, adverse effects, or altered pharmacokinetics. Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) reduce blood glucose concentrations by blocking the uptake of sodium and glucose in the proximal tubule and promoting glycosuria, and these agents now have an important role in the management of T2D. The results of several cardiovascular outcomes trials suggested that SGLT2i are associated with improvements in renal endpoints in addition to their reduction in cardiovascular events and mortality, which represents a major advance in the care of this population. The dedicated kidney outcomes trials have confirmed the renoprotective action of SGLT2i across different glomerular filtration and albuminuria values, even in patients with non-diabetic chronic kidney disease. Notably, this improvement in kidney function may indirectly benefit cardiac function through multifaceted interorgan cross talk, which can break the cardiorenal vicious circle linked to T2D. In this article, we briefly review the different mechanisms of action that may explain the renal beneficial effects of SGLT2i and disclose the results of the key renal outcome trials and the subsequent update of related clinical guidelines.

Self-Monitoring of Blood Glucose as an Integral Part in the Management of People with Type 2 Diabetes Mellitus

Abstract: For decades, self-monitoring of blood glucose (SMBG) has been considered a cornerstone of adequate diabetes management. Structured SMBG can follow different monitoring patterns, and it results in improved glycemic control, reduced hypoglycemia, and a better quality of life of people with diabetes. The technology, usability, and accuracy of SMBG systems have advanced markedly since their introduction a few decades ago. Current SMBG systems are small and easy to use, require small (capillary) blood sample volumes, and provide measurement results within seconds. In addition, devices are increasingly equipped with features such as connectivity to other devices and/or digital diaries and diabetes management tools. Although measurement quality can come close to or equal that of the glucose monitoring systems used by healthcare professionals, several available SMBG systems still do not meet internationally accepted accuracy standards, such as the International Organization for Standardization 15197 standard. Reports from China, India, and Brazil based on local experience suggest that in addition of the accuracy issues of SMBG systems, other obstacles also need to be overcome to optimize SMBG usage. Nonetheless, adequate usage of SMBG data is of high relevance for the management of people with type 2 diabetes mellitus.

Exploring a Suitable Marker of Glycemic Response to Dulaglutide in Patients with Type 2 Diabetes: A Retrospective Study

Abstract: Previous studies suggested that β-cell function markers such as fasting and postprandial serum C-peptide and C-peptide increment (FCPR, PCPR, and ΔCPR, respectively) may be useful in estimating glycemic response to glucagon-like peptide-1 receptor agonists. However, it remains elusive whether baseline glycemic control confounds these markers. Here we aimed to identify the least confounded β-cell function markers and investigate whether these markers could predict glycemic response to dulaglutide.We evaluated FCPR, PCPR, and ΔCPR levels in patients with type 2 diabetes who initiated dulaglutide treatment after a standardized meal tolerance test (MTT). We first investigated the confounding effects of baseline HbA1c on β-cell function markers using Pearson's correlation test. Then, we evaluated the association between each β-cell function marker and glycemic response (HbA1c change 0-6 months) to dulaglutide using generalized linear model and logistic regression analysis with adjustment for baseline HbA1c.In 141 patients, baseline HbA1c was significantly inversely correlated with PCPR and ΔCPR (P < 0.01 for both) but not with FCPR (r = 0.02; P = 0.853), suggesting that FCPR was the marker least confounded by baseline glycemic control. Of all patients, 59 continued dulaglutide for at least 6 months without initiating any additional glucose-lowering medications. Mean ± SE HbA1c change 0-6 months was - 1.16 ± 0.17% (P < 0.001 vs. baseline). The β-cell function markers were significantly associated with HbA1c change 0-6 months in the generalized linear model. FCPR was also a significant predictor for achieving a reduction in HbA1c of at least 1% (P = 0.044) with an area under the receiver operating characteristic curve of 0.83 (sensitivity = 0.81 and specificity = 0.79).Fasting and meal-induced C-peptide levels are associated with glycemic response to dulaglutide, among which FCPR is least confounded by baseline glycemic control, suggesting its utility as a marker for glycemic response to dulaglutide.

Cost-Effectiveness Evaluation of a Remote Monitoring Programme Including Lifestyle Education Software in Type 2 Diabetes: Results of the Educ@dom Study

Abstract: Telemedicine programs using health technological innovation to remotely monitor the lifestyles of patients with type 2 diabetes (T2D) can improve glycaemic control and thus reduce the incidence of complications as well as management costs. In this context, an assessment was made of the 1-year and 2-year cost-effectiveness of the EDUC@DOM telemonitoring and tele-education program.The EDUC@DOM study was a multicentre randomized controlled trial conducted between 2013 and 2017 that compared a telemonitoring group (TMG) to a control group (CG) merged with health insurance databases to extract economic data on resource consumption. Economic analysis was performed from the payer perspective, and direct costs and indirect costs were considered. The clinical outcome used was the intergroup change in glycated haemoglobin (HbA1c) levels from baseline. Missing economic data were imputed using multiple imputation, and fitted values from a generalized linear mixed model were used to calculate the incremental cost-effectiveness ratio (ICER). Bootstrapped 95% confidence ellipses were drawn in the cost-effectiveness plan.The main analysis included data from 256 patients: 126 in the TMG and 130 in the CG. Incremental costs over 1 and 2 years were equal to €2129 and €5101, respectively, in favour of the TMG. Once imputed and adjusted for confounding factors, the TMG trends to a 21% cost decrease over 1 and 2 years of follow-up (0.79 [0.58; 1.08], p = 0.1452 and 0.79 [0.61; 1.03], p = 0.0879, respectively). The EDUC@DOM program led to a €1334 cost saving and a 0.17 decrease in HbA1c over 1 year and a €3144 cost saving and a 0.14 decrease in HbA1c over 2 years. According to the confidence ellipse, EDUC@DOM was a cost-effective strategy.This study provides additional economic information on telemonitoring and tele-education programs to enhance their acceptance and promote their use. In the light of this work, the EDUC@DOM program is a cost-saving strategy in T2D management.This trial was registered in the Clinical Trials Database on 27 September 2013 under no. NCT01955031 and bears ID-RCB no. 2013-A00391-44.

The Cost-Effectiveness of Subcutaneous Semaglutide Versus Empagliflozin in Type 2 Diabetes Uncontrolled on Metformin Alone in Denmark

Abstract: International and Danish guidelines recommend the use of glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter 2 (SGLT-2) inhibitors already in second line in the management of type 2 diabetes (T2D). The objective of this study was to evaluate the long-term cost-effectiveness (CE) of subcutaneous (SC) semaglutide (GLP-1 RA) versus empagliflozin (SGLT-2 inhibitor) in individuals with T2D uncontrolled on metformin alone from a Danish payer's perspective.Cost-effectiveness analyses (CEA) were conducted from a Danish payer's perspective, using the IQVIA Core Diabetes model (CDM 9.5), with a time horizon of 50 years and an annual discount of 4% on costs and effects. Patients received either SC semaglutide or empagliflozin, in addition to metformin, until HbA1c threshold of 7.5% (58 mmol/mol) was reached, following which treatment intensification with insulin glargine in addition to empagliflozin or SC semaglutide plus metformin was considered. Baseline cohort characteristics and treatment effects were sourced from a published CEA. Utilities and cost of diabetes-related complications were also obtained from published sources. Treatment costs were derived from Danish official sources. Scenario analyses were also performed to test the accuracy of the base case results.Individuals with T2D on SC semaglutide plus metformin gained 0.065 life-years (LYs) and 0.130 quality-adjusted LYs (QALYs), respectively, at an incremental cost of DKK 96,923 (€ 13,031) compared to empagliflozin plus metformin, resulting in an incremental cost-effectiveness ratio (ICER) of DKK 745,561(€ 100,239) per QALY gained. The probabilistic sensitivity analysis (PSA) results showed that the SC semaglutide plus metformin was cost-effective in 19% of simulations assuming a willingness-to-pay (WTP) threshold of DKK 357,100 (€ 48,011)/QALY gained. Duration of therapy with SC semaglutide seems the key driver of results.The current analyses suggest that SC semaglutide plus metformin is not cost-effective compared to empagliflozin plus metformin from a Danish payer's perspective.

The Association Between HbA1c and 1-Year Diabetes-Related Medical Costs: A Retrospective Claims Database Analysis

Abstract: The American Diabetes Association (ADA) has identified a target hemoglobin A1c (HbA1c) < 7% as appropriate for most adults with type 2 diabetes (T2D). This research examines US diabetes-related healthcare costs for adults with T2D for individuals with glycemic control (HbA1c < 7%) compared to poor glycemic control (HbA1c ≥ 7%).The Optum Clinformatics® Data Mart database from 2016 to 2020 was used to identify a cohort of adults with T2D who had a recorded HbA1c test (with first such date identified as the index date) and continuous insurance from 1 year prior through 1 year post index date. Patients with glycemic control were propensity matched to patients with poor glycemic control. Generalized linear models and two-part models examined diabetes-related outpatient, drug, acute care, and total costs over the 1-year post-period.There were 34,538 propensity matched individuals included in the study. Results indicate that glycemic control (HbA1c < 7%), compared to poor glycemic control (HbA1c ≥ 7%) ,was associated with statistically significantly lower annual diabetes-related acute ($5671 ± $4216 vs $6138 ± $4211), outpatient ($6051 ± $4216 vs $7259 ± $7771), drug ($3739 ± $4581 vs $4288 ± $4788), and total costs care ($13,704 ± $10,635 vs $16,460 ± $10,885) (all P < 0.0001). Sensitivity analyses also examined results based upon alternative HbA1c thresholds which were chosen on the basis of expert guidelines and prior clinical trial thresholds (< 6%, ≤ 6.5%, < 8%, and ≤ 9%). In all cases, being below threshold was associated with statistically significantly lower diabetes-related total costs and component costs. Results also illustrate that, in general, higher HbA1c thresholds are associated with higher diabetes-related costs.Glycemic control was found to be associated with significantly lower annual diabetes-related component and total costs. Results suggest economic benefits associated with having HbA1c at or below target.

Additional Effect of Luseogliflozin on Semaglutide in Nonalcoholic Steatohepatitis Complicated by Type 2 Diabetes Mellitus: An Open-Label, Randomized, Parallel-Group Study

Abstract: Untreated nonalcoholic fatty liver may progress to nonalcoholic steatohepatitis (NASH) and cirrhosis and induce hepatocellular carcinoma and liver failure. Type 2 diabetes mellitus (T2DM), often complicated with nonalcoholic fatty liver disease (NAFLD), is a driver of NAFLD progression. Thus, efficacious treatment strategies for patients with coexisting NAFLD and T2DM are important for preventing NAFLD progression. Although previous studies have demonstrated that either sodium-glucose transporter 2 inhibitors (SGLT2is) or glucagon-like peptide 1 receptor agonists (GLP-1 RAs) benefit NASH patients with T2DM, the rate of NASH resolution has not sufficiently improved. Therefore, we developed a protocol for a randomized controlled trial to examine whether the addition of an SGLT2i to the treatment regimen of patients receving a GLP-1 RA (combination therapy), within the therapeutic dose range for T2DM, increases the rate of NASH resolution in patients with coexisting NASH and T2DM.This open-label, randomized, parallel-group study commenced in June 2021, will conclude recruitment in May 2023, and will end by March 2025. Sixty patients with NASH complicated by T2DM are enrolled at the Ehime University Hospital in Toon, Japan. Participants will be randomized into: (1) an intervention group receiving combination therapy with the SGLT2i luseogliflozin 2.5 mg, once daily (Taisho Pharmaceutical, Tokyo, Japan) and the GLP-1 RA semaglutide 0.5 mg, once per week (Novonordisk, Copenhagen, Denmark); and (2) a control group receiving monotherapy with the GLP-1 analog semaglutide. The primary endpoints, which will be ascertained by liver biopsy, are: (1) NASH resolution rate from baseline without worsening of liver fibrosis after 52 weeks of intervention; (2) rate of improvement from baseline of at least 1 point in the NAFLD activity score without worsening of liver fibrosis after 52 weeks of intervention; and (3) rate of improvement from baseline of at least one fibrosis stage without worsening of NASH after 52 weeks of intervention.University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR) number: UMIN000045003. Japan Registry of Clinical Trials registration number: jRCTs061210009.

The Place and Value of Sodium-Glucose Cotransporter 2 Inhibitors in the Evolving Treatment Paradigm for Type 2 Diabetes Mellitus: A Narrative Review

Abstract: Over recent years, the expanding evidence base for sodium-glucose cotransporter-2 inhibitor (SGLT2i) therapies has revealed benefits beyond their glucose-lowering efficacy in the treatment of Type 2 diabetes mellitus (T2DM), resulting in their recognition as cardiorenal medicines. While SGLT2is continue to be recommended among the second-line therapies for the treatment of hyperglycaemia, their true value now extends to the prevention of debilitating and costly cardiovascular and renal events for high-risk individuals, with particular benefit shown in reducing major adverse cardiac events and heart failure (HF) and slowing the progression of chronic kidney disease. However, SGLT2i usage is still suboptimal among groups considered to be at greatest risk of cardiorenal complications. The ongoing coronavirus disease 2019 (COVID-19) pandemic has intensified financial pressures on healthcare systems, which may hamper further investment in newer effective medicines. Emerging evidence indicates that glycaemic control should be prioritised for people with T2DM in the era of COVID-19 and practical advice on the use of T2DM medications during periods of acute illness remains important, particularly for healthcare professionals working in primary care who face multiple competing priorities. This article provides the latest update from the Improving Diabetes Steering Committee, including perspectives on the value of SGLT2is as cost-effective therapies within the T2DM treatment paradigm, with particular focus on the latest published evidence relating to the prevention or slowing of cardiorenal complications. The implications for ongoing and future approaches to diabetes care are considered in the light of the continuing coronavirus pandemic, and relevant aspects of international treatment guidelines are highlighted with practical advice on the appropriate use of SGLT2is in commonly occurring T2DM clinical scenarios. The 'SGLT2i Prescribing Tool for T2DM Management', previously published by the Steering Committee, has been updated to reflect the latest evidence and is provided in the Supplementary Materials to help support clinicians delivering T2DM care.