The Role of Obesity as a Cardiac Disease Risk Factor in Patients with Type 2 Diabetes.

PURPOSE OF REVIEW: Cardiovascular disease (CVD) is the leading cause of death globally and is closely associated with obesity and type 2 diabetes mellitus (T2DM). This review examines the interplay between obesity, T2DM, and CVD, highlighting the increasing prevalence and economic burden of these conditions. RECENT FINDINGS: Pharmacologic therapies, particularly glucagon-like peptide-1 receptor agonists, show promise in substantial weight loss and subsequent reduction of adverse cardiovascular events in obese individuals with and without diabetes. Obesity significantly contributes to the development of insulin resistance and T2DM, further escalating CVD risk. The common co-occurrence of these three conditions may involve several other pathophysiological mechanisms, such as chronic inflammation, increased visceral adiposity, and endothelial dysfunction. Until recently, lifestyle modifications and bariatric surgery had been the primary methods for weight loss and mitigating obesity-associated cardiovascular risk. Newer pharmacological options have led to a paradigm shift in our approach to obesity management as they provide substantial benefits in weight loss, glycemic control, and cardiovascular risk reduction.

Frequently asked questions to the 2023 obesity medicine association position statement on compounded peptides: A call for action.

Background: In 2023, the Obesity Medicine Association (OMA) published "Compounded peptides: An Obesity Medicine Association Position Statement." Since this publication, the use of compounded peptides for the treatment of obesity has continued to evolve, leading to additional confusion and questions from obesity medicine clinicians and their patients. Methods: This frequently asked questions (FAQ) document and "Call for Action" commentary is based upon the existing evidence and practical clinical experiences of the authors. Results: This FAQ is intended to provide insights beyond the original 2023 OMA Position Statement regarding the use of "compounded peptides" for treating obesity. Three obstacles impair patient access to highly effective peptide anti-obesity medications: insufficient production especially during times of high demand, high costs, and lack of clarity surrounding the role of compounded peptides. Solutions to enhance patient access to these medications lie within the existing legal and regulatory framework and Food and Drug Administration policies. Implementing these solutions necessitates dispelling misinformation and providing clear guidance on the appropriate prescribing and administration of compounded peptides, particularly during times of acknowledged shortage. Conclusion: Among stakeholders with aligned priorities, challenges can often be overcome by collaboration and communication. Towards the goal of providing patient-centered care, the OMA calls on applicable stakeholders (e.g., pharmaceutical companies, compounding pharmacy organizations, health insurance companies, and the Food and Drug Administration) to work collaboratively to achieve a consensus that improves patient access to safe anti-obesity medications. The purpose of this "Call to Action" is to ask stakeholders to provide clinicians and their patients clarity regarding the role of compounded peptide anti-obesity medications during times of FDA-acknowledged shortages. Finally, this FAQ review provides clinicians with a simple and practical checklist respective to the potential use of compounded peptides.

Association between glucagon-like peptide-1 receptor agonists and risk of suicidality: A comprehensive analysis of the global pharmacovigilance database.

AIM: To evaluate the potential association between suicidality and glucagon-like peptide-1 receptor agonists (GLP-1RAs), as well as other medications used for obesity and diabetes, using comprehensive global data. MATERIALS AND METHODS: This study utilized the World Health Organization's pharmacovigilance database, encompassing adverse drug reaction reports from 1967 to 2023, from 170 countries (total reports, N = 131 255 418). We present the reported odds ratios (RORs) with 95% confidence intervals (CIs) and information component (IC) with IC025 regarding the association between GLP-1RA use and suicidality. RESULTS: Although reports of GLP-1RA-associated suicidality increased gradually from 2005 to 2023 (n = 332), no evidence of an association was observed (ROR 0.15 [95% CI 0.13 to 0.16]; IC -2.77 [IC025 -2.95]). The lack of evidence of an association persisted regardless of whether GLP-1RAs were used for diabetes treatment (ROR 0.13 [95% CI 0.11 to 0.14]; IC -2.95 [IC025 -3.14]) or obesity treatment (ROR 0.44 [95% CI 0.34 to 0.58]; IC -1.16 [IC025 -1.62]). However, an association was found between suicidality and other diabetes medications excluding GLP-1RAs (ROR 1.13 [95% CI 1.10 to 1.15]; IC 0.17 [IC025 0.13]). Similarly, the potential association with suicidality was observed in medications used to treat obesity excluding GLP-1RAs (ROR 1.08 [95% CI 1.01 to 1.14]; IC 0.10 [IC025 0.01]). CONCLUSIONS: The suspected association between GLP-1RA use and suicidality, as raised by the European Medicines Agency, was not found in our global analysis. This indicates that the sporadic reports of GLP-1RA-associated suicidality are likely influenced by factors such as comorbidities present in the GLP-1RA user population.

Real-world safety profile of once-weekly semaglutide in people with type 2 diabetes: Analysis of pooled data from the SemaglUtide Real-world Evidence (SURE) programme.

AIM: To investigate, through post hoc analysis of nine studies from the SemaglUtide Real-world Evidence (SURE) programme, the safety of once-weekly (OW) semaglutide in adults with type 2 diabetes (T2D) and in subpopulations in routine clinical practice, complementing findings from the phase 3 randomized clinical trial (RCT) SUSTAIN programme. METHODS: The SURE studies had a duration of ~30 weeks and included adults with diagnosed T2D treated with OW semaglutide. Safety information, including hypoglycaemic events, were collected and analysed for the total study population and for patient subgroups based on baseline patient characteristics, baseline co-medication and prescriber specialty. RESULTS: Of the total 3505 patients, 24.3% reported adverse events (AEs), with most patients reporting non-serious (22.3%) and mild (17.1%) AEs. AEs mainly belonged to the gastrointestinal disorders system organ class (16.3% of patients). In total, 5.1% of patients reported AEs that led to treatment discontinuation, 0.5% reported serious adverse drug reactions and 0.2% had an AE with a fatal outcome, reported as unrelated to treatment. Overall, 1.1% and 0.1% of patients reported level 2 and 3 hypoglycaemic events, respectively. A higher rate of level 2 hypoglycaemia was observed in patients with baseline microvascular complications treated with insulin versus those on insulin without these complications. CONCLUSIONS: Safety data reported in the real-world SURE studies were generally consistent with observations in phase 3 OW semaglutide RCTs. No new safety concerns were identified, highlighting that OW semaglutide is well tolerated by adults with T2D and in subpopulations in routine clinical practice.

Efficacy and safety of switching from a dipeptidyl peptidase-4 inhibitor to oral semaglutide in Japanese patients with type 2 diabetes mellitus.

Background: Dipeptidyl peptidase-4 inhibitors (DPP-4is) are the most widely used oral hypoglycemic drugs in Japan. However, once-daily oral semaglutide has been reported to reduce glycated hemoglobin (HbA1c) and body weight (BW) without causing significant hypoglycemia. Here, we aimed to evaluate the efficacy and safety of switching from a DPP-4i to oral semaglutide in Japanese patients with type 2 diabetes (T2D). Methods: We performed a single-center retrospective study of the changes in HbA1c and BW in 68 patients with T2D who were switched from a DPP-4i and took oral semaglutide for ≥ 6 months, without changes in any other oral hypoglycemic agent. Results: Mean HbA1c decreased from 7.8 to 7.0% (p < 0.001) and BW decreased from 74.2 to 71.2 kg (p < 0.001) over 6 months. The decrease in HbA1c was more pronounced in participants with high baseline HbA1c (r = - 0.542, p < 0.001). There was also a trend (r = 0.236, p = 0.052) toward a decrease in BW in individuals with shorter disease duration. There were reductions in either HbA1c or BW in 65 participants (95.6%). In addition, the larger the decrease in HbA1c was, the greater was the decrease in BW (r = 0.480, p < 0.001). Eighteen participants (20.1%) discontinued the drug within 6 months, of whom 10 (11.6% of the total) did so because of suspected adverse effects and the discontinuation rate was the highest in older, non-obese patients. Conclusions: Switching from a DPP-4i to oral semaglutide may be useful for Japanese patients with T2D who have inadequate glycemic or BW control. However, its utility may be limited by gastrointestinal adverse effects in certain patients.

The effect of dulaglutide on glycated hemoglobin is associated with PNPLA3 Ι148Μ gene polymorphism in patients with type 2 diabetes mellitus.

PURPOSE: The evaluation of the effect of dulaglutide on glycated hemoglobin (HbA1c) and non-invasive indices of hepatic steatosis among different genotypes of the PNPLA3 I148M (rs738409) and CETP Taq1B (rs708272) polymorphisms in patients with type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). METHODS: Relevant data from patients with inadequately controlled T2DM, also displaying NAFLD, administered 1.5 mg dulaglutide weekly for 6 months were retrospectively retrieved. The non-invasive indices, fatty liver index (FLI) and hepatic steatosis index (HSI), were calculated. Genotyping for rs738409 and rs708272 were performed with polymerase chain reaction. RESULTS: Data from 80 patients (39 females), aged 64.4 ± 9.5 years and displaying a baseline BMI of 34.5 ± 5.8 kg/m2, were retrieved at baseline and after 6 months (endpoint) of dulaglutide treatment. Glycated hemoglobin (HbA1c; -0.72 ± 1.10%; p < 0.001), FLI (-5.8 ± 9.8; p < 0.001) and HSI (-1.18 ± 3.51; p = 0.004) significantly decreased after treatment. Lipid profile and liver function tests also improved after treatment. Overall, homozygotes for the reference rs738409 allele (CC) displayed a 2.4-fold decrease (p = 0.002) and heterozygotes (CG) an 1.6-fold decrease (p = 0.013) compared to GG homozygotes after treatment, but the effect was largely limited to female patients. No similar effect was observed in FLI, HSI and other relevant parameters. No association was observed between rs708272 and any of the parameters studied. CONCLUSIONS: rs738409, but not rs708272, was associated with the effect of dulaglutide on HbA1c, but not on presumed hepatic steatosis or other relevant parameters. Sex-specific effects were also noticed.

Unravelling the ties that bind: The intersection of obesity, osteoarthritis, and inflammatory pathways with emphasis on glucagon-like peptide-1 agonists.

This narrative review article explores the complex interplay between obesity, osteoarthritis, and their associated inflammatory cascades, offering a deeper understanding of the underlying of mechanisms of inflammation and potential therapeutic interventions targeting both diseases. Through examination of the shared inflammatory pathway of obesity and osteoarthritis, our objective is to directly elucidate the relationship between these two conditions, highlighting the promising role of glucagon-like peptide-1 agonists in modulating inflammation and its therapeutic implications for patients with obesity and osteoarthritis.

Effects of semaglutide on gut microbiota, cognitive function and inflammation in obese mice.

Objective: This study aims to investigate the effects of semaglutide on gut microbiota, cognitive function, and inflammation in obese mice. Method: Twenty-four C57BL/6J male mice were randomly assigned to three groups: a normal-chow diet group (NCD, n = 8), high-fat diet group (HFD, n = 8), and HFD+semaglutide group (Sema, n = 8). The mice were fed a HFD to establish an animal model of obesity and then administered with semaglutide or saline for 12 weeks. Cognitive function was assessed using the Morris water maze test. Serum pro-inflammatory cytokines were measured. 16S rRNA gene sequencing technology was used to explore gut microbiota characteristics in obese mice. Result: Obese mice showed significant cognitive impairment and inflammation. Semaglutide improved cognitive function and attenuated inflammation induced by a HFD diet. The abundance of gut microbiota was significantly changed in the HFD group, including decreased Akkermansia, Muribaculaceae, Coriobacteriaceae_UCG_002, Clostridia_UCG_014 and increased Romboutsia, Dubosiella, Enterorhabdus. Whereas semaglutide could dramatically reverse the relative abundance of these gut microbiota. Correlation analysis suggested that cognitive function was positively correlated with Muribaculaceae and Clostridia_UCG_014, and negatively associated with Romboutsia and Dubosiella. Romboutsia was positively correlated with TNFα, IL-6 and IL-1ß. While Clostridia_UCG_014 was negatively related to TNFα, IL-6 and IL-1ß. Conclusions: For the first time semaglutide displayed different regulatory effects on HFD-induced gut microbiota dysbiosis. Semaglutide could regulate the structure and composition of gut microbiota associated with cognitive function and inflammation. Thus, affecting gut microbiota might be a potential mechanism of semaglutide in attenuating cognitive function and inflammation.

Comparisons of the risks of new-onset prostate cancer in type 2 diabetes mellitus between SGLT2I and DPP4I users: a population-based cohort study.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2I) have been suggested to reduce new-onset cancer amongst type-2 diabetes mellitus (T2DM) patients. This study aims to compare the risks of prostate cancer between SGLT2I and dipeptidyl peptidase-4 inhibitors (DPP4I) amongst T2DM patients. DESIGN, SETTING AND PARTICIPANTS: This was a retrospective population-based cohort study of prospectively recorded data on male patients with T2DM who were prescribed either SGLT2I or DPP4I between 1st January 2015 and 31st December 2020 from Hong Kong. METHODS: The primary outcome was new-onset prostate cancer. The secondary outcomes included cancer-related mortality and all-cause mortality. Propensity score matching (1:1 ratio) using the nearest neighbor search was performed and multivariable Cox regression was applied. A three-arm analysis including the glucagon-like peptide-1 receptor agonist (GLP1a) cohort was conducted. RESULTS: This study included 42129 male T2DM patients (median age: 61.0 years old [SD: 12.2]; SGLT2I: n = 17,120; DPP4I: n = 25,009). In the propensity score matched cohort, the number of prostate cancers was significantly lower in SGLT2I users (n = 60) than in DPP4I (n = 102). Over a follow-up duration of 5.61 years, SGLT2I was associated with lower prostate cancer risks (HR: 0.45; 95% CI: 0.30-0.70) than DPP4I after adjustments. The subgroup analyses showed that the interactions between SGLT2I and age, hypertension, heart failure, and GLP-1a were not statistically significant. The result remained consistent in the sensitivity analysis. CONCLUSION: The study demonstrated SGLT2I was associated with lower risks of new-onset prostate cancer after propensity score matching and adjustments compared to DPP4I amongst T2DM patients.

Use of continuous glucose monitoring when initiating glucagon-like peptide-1 receptor agonist therapy in insulin-treated diabetes.

Glucagon-like peptide-1 receptor agonist (GLP-1RA) medications have been shown to be effective in achieving optimal glucose control and reducing all-cause death, cardiovascular death, nonfatal myocardial infarction, hospitalization for heart failure, and end-stage kidney disease in individuals with type 1 (T1D) and type 2 diabetes (T2D). However, use of these medications has been associated with increased hypoglycaemia risk in patients treated with concomitant antihyperglycaemic medications. The risk is particularly high in patients with T1D due to their loss of glucagon counter-regulatory response. This article reviews the effect of GLP-1RA formulations on the development of hypoglycaemia in individuals with T1D and T2D treated with insulin therapy, discusses the benefits of continuous glucose monitoring with GLP-1RA treatment, and presents strategies for safely initiating GLP-1RA therapy in these individuals.

Cardiovascular Protective Properties of GLP-1 Receptor Agonists: More than Just Diabetic and Weight Loss Drugs.

Owing to their potent glucose-lowering efficacy and substantial weight loss effects, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are now considered part of the frontline therapeutic options to treat both type 2 diabetes mellitus and nondiabetic overweight/obesity. Stemming from successful demonstration of their cardiometabolic modulation and reduction of major adverse cardiovascular events in clinical outcome trials, GLP-1 RAs have since been validated as agents with compelling cardiovascular protective properties. Studies spanning from the bench to preclinical and large-scale randomised controlled trials have consistently corroborated the cardiovascular benefits of this pharmacological class. Most notably, there is converging evidence that they exert favourable effects on atherosclerotic ischaemic endpoints, with preclinical data indicating that they may do so by directly modifying the burden and composition of atherosclerotic plaques. This narrative review examines the underlying pharmacology and clinical evidence behind the cardiovascular benefits of GLP-1 RAs, with particular focus on atherosclerotic cardiovascular disease. It also delves into the mechanisms that underpin their putative plaque-modifying actions, addresses existing knowledge gaps and therapeutic challenges and looks to future developments in the field, including the use of combination incretin agents for diabetes and weight loss management.

Kidney and cardiovascular-protective benefits of combination drug therapies in chronic kidney disease associated with type 2 diabetes.

Given the substantial burden of chronic kidney disease associated with type 2 diabetes, an aggressive approach to treatment is required. Despite the benefits of guideline-directed therapy, there remains a high residual risk of continuing progression of chronic kidney disease and of cardiovascular events. Historically, a linear approach to pharmacologic management of chronic kidney disease has been used, in which drugs are added, then adjusted, optimized, or stopped in a stepwise manner based on their efficacy, toxicity, effects on a patient's quality of life, and cost. However, there are disadvantages to this approach, which may result in missing a window of opportunity to slow chronic kidney disease progression. Instead, a pillar approach has been proposed to enable earlier treatment that simultaneously targets multiple pathways involved in disease progression. Combination therapy in patients with chronic kidney disease associated with type 2 diabetes is being investigated in several clinical trials. In this article, we discuss current treatment options for patients with chronic kidney disease associated with type 2 diabetes and provide a rationale for tailored combinations of therapies with complementary mechanisms of action to optimize therapy using a pillar-based treatment strategy. [This article includes a plain language summary as an additional file].

Real-World Evaluation of Once-Weekly Subcutaneous Semaglutide in Patients with Type 2 Diabetes Mellitus in Spain (SEMA-RW Study).

Although, in randomized clinical trials, once-weekly subcutaneous semaglutide (OW s.c.) has demonstrated superior efficacy in comparison with placebo and active controls in terms of glycemic control and body weight reduction in patients with type 2 diabetes mellitus (T2DM), these results need to be confirmed in a real-world (RW) setting. An RW ambispective study (6 months retrospective and 6 months prospective) was conducted in 10 tertiary hospitals in Spain. We evaluated changes in HbA1c and body weight in patients with T2DM treated with semaglutide OW s.c. Additionally, we analyzed different subgroups of patients treated with semaglutide OW s.c. as an add-on to glucose-lowering therapy. A total of 752 patients with a mean age of 60.2 years, a mean HbA1c level of 8.5%, a mean body weight of 101.6 kg, and a mean T2DM duration of 10 years were included. At 12 months, compared with baseline, there was a mean difference of -2.1% in HbA1c levels (p < 0.001) and a mean difference of 9.2 kg in body weight (p < 0.001). Moreover, there were statistically significant differences (p < 0.001) between baseline and month 12 in both HbA1c and body weight in the four subgroups receiving semaglutide OW s.c. as an add-on to glucose-lowering therapy. Semaglutide OW s.c. was well tolerated, with gastrointestinal disorders being the most commonly reported side effects. In this RW study, 12 months of treatment with semaglutide OW s.c. in patients with T2DM was associated with significant and clinically relevant improvements in glycemic control and weight loss, regardless of the glucose-lowering therapy received, and the overall safety profile was positive.

Embracing an era of targeted combination therapy for heart failure with preserved ejection fraction.

The concept of quadruple therapy as a "one-size-fit-all" approach is effective among all eligible patients with heart failure with reduced ejection fraction, with consistent and significant clinical benefits including reduced mortality across various subgroups. However, with exception of sodium-glucose cotransporter 2 inhibitors, the consistency of benefit with therapies does not extend to patients with heart failure with preserved ejection fraction. The clinical benefits of other promising medical therapies, such as angiotensin receptor-neprilysin inhibitors, mineralocorticoid receptor antagonists, and glucagon-like peptide-1 receptor agonists, have been demonstrated only in certain phenotypes of the highly heterogenous heart failure with preserved ejection fraction population. This variability can confuse frontline practicing cardiologists, potentially leading to the under-implementation of these medications. Therefore, we propose a simple approach: "targeted" combination therapy. This strategy aims to optimize evidence-based medications in heart failure with preserved ejection fraction by tailoring treatments to specific subgroups within the heart failure with preserved ejection fraction population where significant benefits are most evident.

Glucagon-Like Peptide-1 Receptor Agonists and Risk of Parkinson's Disease in Patients with Type 2 Diabetes: A Population-Based Cohort Study.

BACKGROUND: Previous studies have suggested that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may have a disease-modifying effect in the development of Parkinson's disease (PD), but population studies yielded inconsistent results. OBJECTIVE: The aim was to compare the risk of PD associated with GLP-1RAs compared to dipeptidyl peptidase 4 inhibitors (DPP4i) among older adults with type 2 diabetes (T2D). METHODS: Using U.S. Medicare administrative data from 2016 to 2020, we conducted a population-based cohort study comparing the new use of GLP-1RA with the new use of DPP4i among adults aged ≥66 years with T2D. The primary endpoint was a new diagnosis of PD. A stabilized inverse probability of treatment weighting (sIPTW)-adjusted Cox proportional hazards regression model was employed to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for PD between GLP-1RA and DPP4i users. RESULTS: This study included 89,074 Medicare beneficiaries who initiated either GLP-1RA (n = 30,091) or DPP4i (n = 58,983). The crude incidence rate of PD was lower among GLP-1RA users than DPP4i users (2.85 vs. 3.92 patients per 1000 person-years). An sIPTW-adjusted Cox model showed that GLP-1RA users were associated with a 23% lower risk of PD than DPP4i users (HR, 0.77; 95% CI, 0.63-0.95). Our findings were largely consistent across different subgroup analyses such as sex, race, and molecular structure of GLP-1RA. CONCLUSION: Among Medicare beneficiaries with T2D, the new use of GLP-1RAs was significantly associated with a decreased risk of PD compared to the new use of DPP4i. © 2024 International Parkinson and Movement Disorder Society.

Multiple sclerosis patients taking glucagon-like peptide-1 receptor (GLP-1) agonists: a single-institution retrospective cohort study of tolerability and weight loss.

Obesity is a risk factor for developing and worsening multiple sclerosis (MS) and is often comorbid with MS, exacerbating disability. We retrospectively studied MS patients starting glucagon-like peptide-1 (GLP-1) agonists at the [redacted for review] U.S.A. (January 2005-June 2024). Patients (n = 49) were mostly female (73%), average age 54 years old, with relapsing disease (78%) and an average starting body mass index (BMI) of 39.7 kg/m2 (range 25.9, 58.9 kg/m2; n = 43 clinically obese or BMI > 30 kg/m2) and weight of 110.6 kg (245.6 lbs.; range 68-155.8 kg, 150-343.4 lbs.). The most commonly taken disease modifying therapy (DMT) was ocrelizumab (39%) while 24% of patients were not taking any DMT. The most common comorbidities were hypertension (59%), hyperlipidemia (55%), and diabetes mellitus (41%). Patients took GLP-1 agonists for an average of 24.2 months (median 21.4; range 3.2, 88.5 months). Patients lost on average 0.47 kg/month (1.03 lbs./month; range of total weight change: 27.7 kg (61.1 lbs.) lost, 7.7 kg (17.0 lbs.) gained). Among overweight and obese patients with MS, those with a higher starting BMI tended to lose more weight. 29% experienced side effects of the GLP-1 drugs with 3 discontinuations due to tolerability. Four patients accrued new demyelinating lesions on MRI (one on no DMT, two started on a high-efficacy DMT for the first time in the past 6 months, and one on a high-efficacy DMT) and one patient experienced a new MS attack (treated with interferon beta-1a). Our early experience suggests GLP-1 agonists are safe in MS patients, who have a similar tolerability to the general population on this medication class and measurable and sustained but somewhat less than anticipated weight loss.

Effects of semaglutide, empagliflozin and their combination on renal diffusion-weighted MRI and total kidney volume in patients with type 2 diabetes: a post hoc analysis from a 32 week randomised trial.

AIMS/HYPOTHESIS: The apparent diffusion coefficient (ADC) derived from diffusion-weighted MRI (DWI-MRI) has been proposed as a measure of changes in kidney microstructure, including kidney fibrosis. In advanced kidney disease, the kidneys often become atrophic; however, in the initial phase of type 2 diabetes, there is an increase in renal size. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors both provide protection against progression of kidney disease in diabetes. However, the mechanisms are incompletely understood. To explore this, we examined the effects of semaglutide, empagliflozin and their combination on renal ADC and total kidney volume (TKV). METHODS: This was a substudy of a randomised clinical trial on the effects of semaglutide and empagliflozin alone or in combination. Eighty patients with type 2 diabetes and high risk of CVD were randomised into four groups (n=20 in each) receiving either tablet placebo, empagliflozin, a combination of semaglutide and tablet placebo (herein referred to as the 'semaglutide' group), or the combination of semaglutide and empagliflozin (referred to as the 'combination-therapy' group). The semaglutide and the combination-therapy group had semaglutide treatment for 16 weeks and then had either tablet placebo or empagliflozin added to the treatment, respectively, for a further 16 weeks; the placebo and empagliflozin groups were treated with the respective monotherapy for 32 weeks. We analysed the effects of treatment on changes in ADC (cortical, medullary and the cortico-medullary difference [ΔADC; medullary ADC subtracted from cortical ADC]), as well as TKV measured by MRI. RESULTS: Both semaglutide and empagliflozin decreased cortical ADC significantly compared with placebo (semaglutide: -0.20×10-3 mm2/s [95% CI -0.30, -0.10], p<0.001; empagliflozin: -0.15×10-3 mm2/s [95% CI -0.26, -0.04], p=0.01). No significant change was observed in the combination-therapy group (-0.05×10-3 mm2/s [95%CI -0.15, 0.05]; p=0.29 vs placebo). The changes in cortical ADC were not associated with changes in GFR, albuminuria, TKV or markers of inflammation. Further, there were no changes in medullary ADC in any of the groups compared with placebo. Only treatment with semaglutide changed ΔADC significantly from placebo, showing a decrease of -0.13×10-3 mm2/s (95% CI -0.22, -0.04; p=0.01). Compared with placebo, TKV decreased by -3% (95% CI -5%, -0.3%; p=0.04), -3% (95% CI -5%, -0.4%; p=0.02) and -5% (95% CI -8%, -2%; p<0.001) in the semaglutide, empagliflozin and combination-therapy group, respectively. The changes in TKV were associated with changes in GFR, albuminuria and HbA1c. CONCLUSIONS/INTERPRETATION: In a population with type 2 diabetes and high risk of CVD, semaglutide and empagliflozin significantly reduced cortical ADC compared with placebo, indicating microstructural changes in the kidneys. These changes were not associated with changes in GFR, albuminuria or inflammation. Further, we found a decrease in TKV in all active treatment groups, which was possibly mediated by a reduction in hyperfiltration. Our findings suggest that DWI-MRI may serve as a promising tool for investigating the underlying mechanisms of medical interventions in individuals with type 2 diabetes but may reflect effects not related to fibrosis. TRIAL REGISTRATION: European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) 2019-000781-38.

The Use of Semaglutide in Patients With Renal Failure-A Retrospective Cohort Study.

OBJECTIVE: Semaglutide, a glucagon-like peptide-1 receptor agonist is approved for weight loss and diabetes treatment, but limited literature exists regarding semaglutide use in patients with advanced chronic kidney disease (CKD). Therefore, this project assessed the safety and efficacy of semaglutide among patients with estimated glomerular filtration rate (eGFR) 15-29 mL/min/1.73 m2 (CKD stage 4), eGFR<15 mL/min/1.73 m2 (CKD stage 5) or on dialysis. METHODS: This is a retrospective electronic medical record based analysis of consecutive patients with advanced CKD (defined as CKD 4 or greater) who were started on semaglutide (injectable or oral). Data was collected between January 2018 and January 2023. Investigators verified CKD diagnosis and manually extracted data. Data were analyzed using Fisher's exact test, paired t test, linear mixed effects models and Wilcoxon signed rank test. RESULTS: Seventy-six patients with CKD 4 or greater who initiated semaglutide were included. Most patients had a history of type 2 diabetes mellitus (96.0%), and most were males (53.9%). The mean age was 66.8 y (SD 11.5) with the mean body mass index was 36.2 (SD 7.5). The initial doses were 3 mg orally and 0.25 mg by injection. Maximum prescribed dose was 1 mg (injectable) in 28 (45.2%) patients and 14 mg (orally) in 2 (14.2%) patients. Patients received semaglutide for a median duration of 17.4 (IQR 0.43, 48.8) months. Forty-eight (63.1%) patients reported no adverse effects associated with the therapy. Mean weight decreased from 106.2 (SD 24.2) to 101.3 (SD 27.3) kg (P < .001). Eight patients (16%) with type 2 diabetes mellitus T2DM discontinued insulin after starting semaglutide. Mean hemoglobin A1c (HbA1c) decreased from 8.0% (SD 1.7) to 7.1% (SD 1.3) (P < .001). Adverse effects were the primary reason for semaglutide discontinuation (37.0%), with nausea, vomiting, and abdominal pain being the most common complaints. CONCLUSIONS: Based on this retrospective study semaglutide appears to be tolerated by most individuals with CKD 4 or greater despite associated gastrointestinal side effects similar to those observed in patients with better kidney function and leads to an improvement of glycemic control and insulin discontinuation in patients with T2DM. Modest weight loss (approximately 4.6% of the total body weight) was observed on the prescribed doses. Larger prospective randomized studies are needed to comprehensively assess the risks and benefits of semaglutide in patients with CKD 4 or greater and obesity.

Economic evaluation of weight loss and transplantation strategies for kidney transplant candidates with obesity.

Novel antiobesity medications, particularly glucagon-like peptide-1 receptor agonists (GLP-1RAs), have expanded weight loss (WL) options for kidney transplantation (KT) candidates with obesity beyond lifestyle modifications and bariatric surgery. However, varying effectiveness, risk profiles, and costs make strategy choices challenging. To aid decision-making, we used a Markov model to examine the cost-effectiveness of different WL strategies over a 10-year horizon. A target WL of 15% of total body weight was used for the base case scenario, and we compared these strategies to a "liberal" KT strategy of transplanting candidates with obesity. Outcomes included costs (2023 US dollars), quality-adjusted life years, and incremental cost-effectiveness ratios. In analysis, a liberal KT strategy was favored over lifestyle modifications and GLP-1RAs. Among WL strategies, bariatric surgery was the most effective and cost the least, whereas lifestyle modification had the highest cumulative costs and was the least effective. Compared to liberal KT, bariatric surgery costs $45 859 per quality-adjusted life year gained. GLP-1RAs were favored over bariatric surgery only when drug costs were below $5000 per year (base cost $12 077). In conclusion, for KT candidates with obesity, a liberal KT strategy and bariatric surgery are preferred over lifestyle modifications alone and GLP-1RAs based on outcomes and cost-effectiveness.