Real-World Clinical Effectiveness of Glucagon-Like Peptide-1 Receptor Agonist on Mild-to-Moderate Diabetic Kidney Disease in Patients with Type 2 Diabetes: A Retrospective, Single-Arm Clinical Trial.

Background: Cardiovascular outcome trials indicate renal benefits of glucagon-like peptide-1 receptor agonists (GLP-1RAs); however, real-world efficacy and safety studies in Diabetic kidney disease (DKD) are scarce. Methods: This retrospective, single-arm real-world trial involved adults with DKD treated with GLP-1RA for at least 6 months. The primary endpoint was hemoglobin A1c (HbA1c) levels after 6 months. Results: This study included a total of 364 patients with DKD, 153 (42.0%) of whom were female. The median disease duration was 8.0 years, and the mean values of age, HbA1c level, body mass index, and the urinary albumin-to-creatinine ratio (UACR) were 52.1 years, 8.6%, 27.8 kg/m2, and 88.0 mg/g, respectively. Additionally, 73.6% and 26.4% of patients had mild and moderate DKD, respectively. Following 6 months of GLP-1RA treatment, the mean HbA1c level and UACR declined by 1.77% and 40.3%, respectively (both p < 0.001). Compared to their baseline values, patients exhibited significant improvements in 24-h urinary protein, estimated glomerular filtration rate (eGFR), fasting blood glucose, body weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol (all p < 0.001). Patients with a disease duration of <10 years had more pronounced changes in the HbA1c level, UACR, and eGFR (all p < 0.001) than those with a disease duration of ≥10 years. Changes in SBP and DBP were more pronounced in patients also taking angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEis/ARBs) than in those not taking ACEis/ARBs, whereas the changes in UACR and eGFR did not significantly differ. Conclusion: Six-month GLP-1RA treatment improves glucose, blood pressure, lipids, and body weight in patients with mild-to-moderate DKD while slowing down kidney disease progression. It independently reduces proteinuria beyond ACEi/ARB impact, with early use yielding faster outcomes, supporting evidence-based practice.

Efficacy and Safety of Escalating the Dose of Oral Semaglutide from 7 to 14 mg: A Single-Center, Retrospective Observational Study.

INTRODUCTION: The efficacy and safety of oral semaglutide, the first glucagon-like peptide 1 receptor agonist available in tablet form for the treatment of type 2 diabetes, were established in the phase 3a PIONEER program. However, evidence regarding the titration of oral semaglutide in real-world clinical settings remains insufficient. This study aimed to elucidate the therapeutic advantages of escalating the dose of oral semaglutide from 7 to 14 mg through clinical data analysis. METHODS: This retrospective observational study was conducted at a single center in Japan, focusing on adults with type 2 diabetes who were initiated on 14 mg oral semaglutide. The primary endpoint was the alteration in HbA1c levels 24 weeks after the initial prescription of 14 mg oral semaglutide. Secondary endpoints included changes in metabolic parameters and the incidence of adverse events. RESULTS: Data from 66 patients who met the inclusion criteria were analyzed. The mean change in HbA1c levels from baseline to 24 weeks following dose escalation was - 0.5 ± 0.8% [from 7.4 ± 1.0% at baseline to 7.0 ± 0.9% at 24 weeks (p < 0.01)]. Moreover, a significant reduction in body weight of - 2.0 ± 4.4 kg was observed at 24 weeks [from 90.0 ± 20.5 kg at baseline to 88.2 ± 21.4 kg at 24 weeks (p < 0.01)], with 41% of patients achieving at least a 3% reduction compared to baseline. Gastrointestinal disorders emerged as the most prevalent adverse event (10.6%), particularly nausea (7.6%), although predominantly of mild or moderate severity, with no instances of serious adverse events necessitating drug discontinuation. CONCLUSION: Escalating the dose of oral semaglutide to 14 mg could be an effective approach for enhancing glycemic control and managing body weight in individuals with type 2 diabetes.

Semaglutide as a promising treatment for hypothalamic obesity: a six-month case series on four females with craniopharyngioma.

PURPOSE: Patients with hypothalamic pathology often develop hypothalamic obesity, causing severe metabolic alterations resulting in increased morbidity and mortality. Treatments for hypothalamic obesity have not proven very effective, although the glucagon-like peptide-1 receptor agonist semaglutide has been shown to have positive effects. We examined semaglutide's effect on weight loss in a sample of patients with hypothalamic obesity. METHODS: Four female patients with hypothalamic obesity resulting from treatment of craniopharyngiomas were treated with semaglutide for six months. Whole Body Dual-energy x-ray absorptiometry scans were performed, and blood samples drawn at baseline and after six months. Semaglutide dosages were increased monthly along with tracking of body weight and eating behavior (Three Factor Eating Questionnaire, TFEQ-R18). RESULTS: BMI was reduced in all cases, with an average of 7.9 BMI (range: 6.7 to 10.1) corresponding to a weight loss of 17.0% (range: 11.3-22.4%) or 20.2 kg (range 16.2 kg to 23.4 kg). We found a comparable reduction in total fat mass (17.2%, p = 0.006) and lean mass (16.0%, p = 0.05), whereas bone mass was unchanged (2.6%, p = 0.12). All cases reported an increase in energy levels, improved mobility and physical activity. Unfavorable eating behaviors were reduced after 1 month of treatment (emotional eating - 41 points, p = 0.02, uncontrolled eating - 23 points, p = 0.11). HbA1c and total cholesterol were significantly reduced (p = 0.014 for both). CONCLUSION: Semaglutide is a promising and safe treatment option for HO, that improves eating behavior, reduces weight, and improves metabolic markers.

Association of glucagon-like peptide-1 receptor agonists with suicidal ideation and self-injury in individuals with diabetes and obesity: a propensity-weighted, population-based cohort study.

AIMS/HYPOTHESIS: Regulators worldwide are reviewing safety data on glucagon-like peptide-1 receptor agonists (GLP-1RA), following reports by the Icelandic Medicines Agency in July 2023 of suicidal ideation and self-injury (SIS) in individuals taking liraglutide and semaglutide. We aimed to assess the risk of SIS in new users of GLP-1RA when compared with sodium-glucose cotransporter 2 inhibitors (SGLT-2i) users, prescribed to treat type 2 diabetes in individuals with obesity. METHODS: This is a cohort study combining several population-wide databases and covering a Spanish population of five million inhabitants, including all adults with obesity who initiated treatment with either GLP-1RA or SGLT-2i for type 2 diabetes from 2015 to 2021. To estimate the comparative effect of GLP-1RA on the risk of SIS, we employed a new user, active comparator design and we carried out multivariable Cox regression modelling with inverse probability of treatment weighting (IPTW) based on propensity scores. We performed several stratified and sensitivity analyses. RESULTS: We included 3040 patients initiating treatment with GLP-1RA and 11,627 with SGLT-2i. When compared with patients treated with SGLT-2i, those in the GLP-1RA group were younger (55 vs 60 years old, p<0.001), had more anxiety (49.4% vs 41.5%, p<0.001), sleep disorders (43.2% vs 34.1%, p<0.001) and depression (24.4% vs 19.0%, p<0.001), and were more obese (35.1% of individuals with BMI ≥40 vs 15.1%, p<0.001). After propensity score weighting, standardised mean differences between groups were <0.1 for all covariates, showing adequate balance between groups at baseline after adjustment. In the main per-protocol analyses we found no evidence that GLP-1RA increased the incidence of SIS (HR 1.04; 95% CI 0.35, 3.14). Intention-to-treat analyses resulted in an HR of 1.36 (95% CI 0.51, 3.61). In analyses excluding individuals with no BMI information and using imputation for BMI missing values, respective HRs were 0.89 (95% CI 0.26, 3.14) and 1.29 (95% CI 0.42, 3.92). Stratified analyses showed no differences between subgroups. CONCLUSIONS/INTERPRETATION: Our findings do not support an increased risk of SIS when taking GLP-1RA in individuals with type 2 diabetes and obesity; however, the rarity of SIS events and the wide uncertainty of effect size (although null, effect may be compatible with a risk as high as threefold) calls for a cautious interpretation of our results. Further studies, including final evaluations from regulatory bodies, are called for to discard a causal link between GLP-1RA and suicidality.

Efficacy and safety of visepegenatide, a long-acting weekly GLP-1 receptor agonist as monotherapy in type 2 diabetes mellitus: a randomised, double-blind, parallel, placebo-controlled phase 3 trial.

Background: Type 2 diabetes (T2DM) remains a challenge to treat despite the expansion of various therapeutic classes. Visepegenatide (PB-119) is a once a week, subcutaneous, glucagon-like peptide-1 receptor agonist (GLP-1 RA) injection without the requirement of dose titration that has shown glycaemic control and safety profile in two phase 2 studies conducted in China and the United States, respectively. The aim of this study was to evaluate the efficacy and safety of visepegenatide as a monotherapy in treatment-naïve patients with T2DM. Methods: This was a multicentre, double-blind, parallel, placebo-controlled, phase 3 trial conducted in 30 centres in China. Adult participants (aged 18-75 years) with T2DM, glycated haemoglobin (HbA1c) of 7.5%-11.0% [58.47-96.73 mmol/mol], body mass index (BMI) of 18-40 kg/m2, and who had been treated with diet and exercise alone for at least 8 weeks before the screening visit were eligible for enrolment. After a 4-week placebo injection run-in period, participants with HbA1c of 7.0%-10.5% [53.0-91.3 mmol/mol] and fasting plasma glucose (FPG) < 15 mmol/L were randomised in a ratio of 1:1 to receive visepegenatide (150 µg) or placebo subcutaneous injections once a week for 24 weeks. The treatment was extended to another 28 weeks during which all participants received visepegenatide. The primary outcome was a change in HbA1c from baseline to week 24. This study was registered with ClinicalTrials.gov, as NCT04504370. Findings: Between November 2, 2020, and November 2, 2022, we randomly assigned 273 adult participants to the visepegenatide (n = 137) and placebo (n = 136) groups. In total, 257 (94.12%) participants, 131 (95.6%) on visepegenatide, and 126 (92.6%) on placebo, completed the double-blinded treatment period. At baseline, the mean (SD) HbA1c was 8.47% (0.81) [69.07 [8.81] mmol/mol], which rapidly decreased to 7.63% (0.80) [59.94 [8.70] mmol/mol] with visepegenatide by week 4 of treatment, and the change from baseline was significantly greater than that in the placebo group (-0.82% [-0.90 to -0.74]; [-8.99 [-9.89 to -8.10] mmol/mol] vs -0.30% [-0.41 to -0.19]; [-3.30 [-4.50 to -2.09] mmol/mol]). At week 24, when evaluating the effects of treatment with treatment policy estimand, the least square mean (LSM change in HbA1c from baseline was -1.36 (95% confidence interval [CI] -1.52 to -1.20) [-14.84 [-16.60 to -13.08] mmol/mol] in the visepegenatide group vs -0.63 (-0.79 to -0.46) [-6.84 [-8.61 to -5.07] mmol/mol] in the placebo group. The reduction in HbA1c was significantly greater with visepegenatide than placebo (LSM difference -0.73, 95% CI -0.96 to -0.50; p < 0.001). When evaluating the treatment estimand with hypothetic policy, the LSM change in HbA1c from baseline in the visepegenatide group (-1.37 [-1.53 to -1.20]) [-14.95 [-16.76 to -13.14] mmol/mol] was significantly greater than the placebo group (-0.63 [-0.81 to -0.45]) [6.90 (-8.89 to -4.90) mmol/mol]. The LSM difference was (-0.74, 95% CI -0.98 to -0.49; [-8.00 [-10.50 to -5.50] mmol/mol]; p < 0.001]. A significantly greater proportion of the visepegenatide group achieved a target HbA1c level of <7% (<53 mmol/mol) than the placebo (50.4% vs 14.2%; p < 0.05) and stringent HbA1c level of ≤6.5% (≤48 mmol/mol) (26.7% vs 7.9%), respectively. There was also a significantly greater improvement in FPG, 2-h postprandial glucose, homeostasis model assessment (HOMA) of beta cell function, post-prandial insulin, fasting, and post-prandial C-peptide level (p < 0.05) with visepegenatide treatment. The number (3 [2.2%]) of participants who received rescue therapy in the visepegenatide group was remarkably lower compared with those (17 [12.5%]) in the placebo group (p < 0.05). During the extended treatment period, visepegenatide consistently maintained the efficacy till week 52 confirmed by all the above endpoints. The reduction in HbA1c at week 52 was -1.39% (-1.58 to -1.19) [-15.14 [-17.28 to -13.01] mmol/mol], which was even greater than that at week 24. There was also a significant improvement in HOMA-insulin resistance (p = 0.004) at week 52 compared with the baseline value. For the placebo→visepegenatide group, which received visepegenatide in the extended treatment period, a notable decrease in HbA1c at week 52 compared to baseline was observed. The change from baseline in HbA1c was -1.49% (-1.68 to -1.30) [-16.27 [-18.37 to -14.16] mmol/mol]. The outcome was in the same direction as the visepegenatide group from the double-blind treatment period. Comprehensive benefits of visepegenatide including weight loss, improvement in lipid profile, and reduction in blood pressure have been demonstrated in this study. Visepegenatide reduced the body weight in a BMI-dependent manner that was prominent in BMI ˃32 kg/m2 with a mean (SD) reduction of -4.77 (13.94) kg at week 52 (p < 0.05). Incidences of gastrointestinal adverse events were less common than other weekly GLP-1 RA in the market, and most of the adverse events were mild and moderate in nature, occurring in the first weeks of the treatment, and were transient. No serious hypoglycaemia or grade 2 hypoglycaemia (blood glucose: ≤3 mmol/L) was reported during the study. Interpretation: As a monotherapy, visepegenatide provided rapid without the risk of hypoglycaemia, significant, and sustainable glycaemic control by improving islet ß-cell function and insulin resistance. Treatment with visepegenatide induced early treatment response in reducing HbA1c and maintaining glycaemic control for 52 weeks. Meanwhile, visepegenatide provided a comprehensive benefit in body weight loss, lipids, and blood pressure reduction. Visepegenatide had a better safety profile than other weekly GLP-1 RA in participants with T2DM even without the requirement of dose titration. Visepegenatide would provide an optimal treatment approach with its high benefit and low-risk balance. Funding: PegBio Co., Ltd.

Glucagon-like peptide-1 receptor agonist and new-onset diabetes in overweight/obese individuals with prediabetes: A systematic review and meta-analysis of randomized trials.

BACKGROUND: Glucagon-like peptide-1 receptor agonist (GLP-1RA) is incretin-based therapy that possessed significant glucose lowering and weight loss properties. The present study aims to analyze the efficacy of GLP-1RA in the management of overweight/obese individuals with prediabetes. METHODS: A thorough search was carried out on the Cochrane Library, ClinicalTrials.gov, Scopus, and Medline databases until April 3rd, 2024, using a mix of pertinent keywords. This review incorporates randomized clinical trials (RCTs) concerning the efficacy of GLP-1RA for prediabetes. The primary outcome was regression to normoglycemia and/or progression to type 2 diabetes (T2D). We used random-effect models to examine the odds ratio (OR) and mean difference (MD). RESULTS: A total of eight RCTs were incorporated. The results of our meta-analysis indicated that GLP-1RA therapy was associated with higher odds of regression to normoglycemia (OR 4.80; 95%CI: 3.40-6.77, p < 0.00001, I2 = 67 %) and lower risk of progression into T2D (OR 0.27; 95%CI: 0.18-0.42, p < 0.00001, I2 = 0 %) in overweight/obese individuals with prediabetes. Administration of GLP-1RA was also associated with higher reduction in HbA1c (MD -0.28 %; p < 0.00001), fasting glucose (MD -0.45 mmol/L; p < 0.00001), and BMI (MD -1.71 kg/m2; p < 0.00001) in comparison to placebo. However, the administration of GLP-1RA was associated with higher incidence of total adverse events (TAEs), treatment discontinuation due to AEs, hypoglycemia, and gastrointestinal AEs. CONCLUSIONS: This study indicates that while GLP-1RA is a potent therapeutic agent for prediabetes, its adverse effects are concerning, thereby precluding its recommendation as a prediabetes therapy.

No Differences in Kidney Function Decline Between People With Type 2 Diabetes Starting a Sodium-Glucose Cotransporter 2 Inhibitor or a Glucagon-like Peptide-1 Receptor Agonist: A Real-world Retrospective Comparative Observational Study.

PURPOSE: Diabetic nephropathy represents the leading cause of end-stage kidney disease in developed countries. Cardiovascular outcome trials have found that in participants who received a glucagon-like peptide-1 receptor agonist (GLP1RA) and a sodium-glucose cotransporter 2 inhibitor (SGLT2i), the risk of incidence and progression of diabetic nephropathy in type 2 diabetes mellitus was reduced. The aim of this study was to compare the decline in estimated glomerular filtration rate (eGFR) among people taking a GLP1RA with that among people taking an SGLT2i in a real-world setting. METHODS: Data for 478 patients with type 2 diabetes mellitus who initiated therapy with a GLP1RA (n = 254) or an SGLT2i (n = 224) between January 1, 2018 and December 31, 2021 were extracted. The primary outcome was any reduction ≥30% in eGFR after the start of therapy. Weight loss and drug discontinuation were also assessed. FINDINGS: Over a median follow-up of 24 months, an eGFR reduction ≥30% occurred in 34 of 254 patients (13.4%) starting a GLP1RA and in 26 of 223 patients (11.6%) starting an SGLT2i (hazard ratio = 0.89; 95% CI, 0.54-1.49; P = 0.67). Median eGFR change over the whole follow-up was similar between groups (SGLT2i: median, -2 mL/min/1.73 m2; 25th, 75th percentile, -13, 8 mL/min/1.73 m2; GLP1RA: median, 0 mL/min/1.73 m2; 25th, 75th percentile, -10, 7 mL/min/1.73 m2; P = 0.54). No worsening of kidney function was observed, even when considering the ratio eGFR mean. The value of eGFR at baseline indicated a statistically significant indirect correlation with the observed absolute value of eGFR change over the follow-up (ρ = -0.36; P < 0.001). The difference in eGFR changes over time observed by eGFR categories was statistically significant (P = 0.0001) in both treatment groups. No significant differences in weight loss and drug discontinuations were observed between groups. IMPLICATIONS: Although acting on different molecular mechanisms, both GLP1RA and SGLT2i might have similar effects on eGFR decline in diabetes, as suggested by the results of the present study conducted in a real-world setting. (Clin Ther. 2024;46:XXX-XXX) © 2024 Elsevier HS Journals, Inc.

Ecological momentary assessment and cue-elicited drug craving as primary endpoints: study protocol for a randomized, double-blind, placebo-controlled clinical trial testing the efficacy of a GLP-1 receptor agonist in opioid use disorder.

BACKGROUND: Despite continuing advancements in treatments for opioid use disorder (OUD), continued high rates of relapse indicate the need for more effective approaches, including novel pharmacological interventions. Glucagon-like peptide 1 receptor agonists (GLP-1RA) provide a promising avenue as a non-opioid medication for the treatment of OUD. Whereas GLP-1RAs have shown promise as a treatment for alcohol and nicotine use disorders, to date, no controlled clinical trials have been conducted to determine if a GLP-1RA can reduce craving in individuals with OUD. The purpose of the current protocol was to evaluate the potential for a GLP-1RA, liraglutide, to safely and effectively reduce craving in an OUD population in residential treatment. METHOD: This preliminary study was a randomized, double-blinded, placebo-controlled clinical trial designed to test the safety and efficacy of the GLP-1RA, liraglutide, in 40 participants in residential treatment for OUD. Along with taking a range of safety measures, efficacy for cue-induced craving was evaluated prior to (Day 1) and following (Day 19) treatment using a Visual Analogue Scale (VAS) in response to a cue reactivity task during functional near-infrared spectroscopy (fNIRS) and for craving. Efficacy of treatment for ambient craving was assessed using Ecological Momentary Assessment (EMA) prior to (Study Day 1), across (Study Days 2-19), and following (Study Days 20-21) residential treatment. DISCUSSION: This manuscript describes a protocol to collect clinical data on the safety and efficacy of a GLP-1RA, liraglutide, during residential treatment of persons with OUD, laying the groundwork for further evaluation in a larger, outpatient OUD population. Improved understanding of innovative, non-opioid based treatments for OUD will have the potential to inform community-based interventions and health policy, assist physicians and health care professionals in the treatment of persons with OUD, and to support individuals with OUD in their effort to live a healthy life. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04199728. Registered 16 December 2019, https://clinicaltrials.gov/study/NCT04199728?term=NCT04199728 . PROTOCOL VERSION: 10 May 2023.

The first report of leukocytoclastic vasculitis induced by once-weekly subcutaneous semaglutide.

INTRODUCTION: Leukocytoclastic vasculitis (LCV) is a small vessel vasculitis involving arterioles, capillaries and postcapillary venules. LCV is generally confined to the skin, with extracutaneous manifestations occurring less frequently. LCV has multiple potential etiologies. Indeed, histological LCV can be found in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, immune complex vasculitis, vasculitis associated with systemic diseases (i.e. sarcoidosis, Sjögren's syndrome, rheumatoid arthritis, and systemic lupus erythematosus), or in vasculitis associated with cancer, infections, sepsis and use of certain medications. LCV can also be idiopathic in up to 50% of cases. CASE REPORT: Semaglutide is a glucagon-like peptide 1 (GLP-1) receptor agonist used for management of type 2 diabetes mellitus (T2DM), obesity and overweight associated with one or more weight-related comorbidities. A case of drug-induced LCV has already been described with the use of once-daily oral semaglutide. Herein, we describe the first case of skin-limited LCV induced by once-weekly subcutaneous semaglutide in a 73-year-old man with T2DM, who experienced the complete resolution of the skin lesions shortly after the discontinuation of semaglutide therapy. CONCLUSION: Future prospective studies, adverse event reporting and post-marketing surveillance will certainly contribute to establishing if LCV represents a less rare than expected side effect of both oral and subcutaneous semaglutide formulations.

Sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide 1 receptor agonists and cancer mortality. A real-world registry.

INTRODUCTION AND OBJECTIVES: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1ra) reduce cardiovascular events through different mechanisms, but their association with cancer remains unclear. The aim of this study was to compare the effect of combined treatment (SGLT2i and GLP1ra) and monotherapy (SGLT2i or GLP1ra) on hospitalization and/or death from cancer in a general population and a subgroup of patients with cardiovascular disease (CVD). METHODS: We conducted a nonconcurrent observational prospective study of patients prescribed SGLT2i, GLP1ra, or both. Multinomial propensity scores were performed in the entire population and in a subgroup of patients with CVD. A multivariate Cox regression analysis was used to determine the hazard ratio (HR) for age, sex, risk factors, and treatment for each outcome. RESULTS: We included 14 709 patients (11366 with SGLT2i, 1016 with GLP1ra, and 2327 with both treatments) from treatment initiation. Diabetes was present in 97% of the patients. The subgroup with CVD included 4957 (33.7%) patients. After a median of 33 months of follow-up, the risk of adverse cancer events was similar between patients with and without CVD (3.4% or 3.7%, respectively). The main risk factors for cancer mortality were male sex and age. Combined treatment and its duration reduced the risk of cancer mortality compared with monotherapy with SGLT2i or GLP1ra in the overall population (HR, 0.2216; 95%CI, 0.1106-0.4659; P < .001; and HR, 0.1928; 95%CI, 0.071-0.5219; P = .001, respectively) and in the subgroup of patients with CVD (HR, 0.2879; 95%CI, 0.0878-0.994; P < .049; and HR, 0.1329; 95%CI, 0.024-0.6768; P = .014, respectively). CONCLUSIONS: Initiation of combined therapy (SGLT2i and GLP1ra) vs monotherapy with SGLT2i or GLP1ra was associated with a lower risk of cancer mortality, mostly in diabetic patients with or without CVD. Although clinical trials are needed, these results might be explained by the complementary mechanisms of these drugs, including their antiproliferative, anti-inflammatory, and metabolic effects. Future clinical trials and mechanistic studies will clarify the possible role of these drugs in carcinogenesis.

SGLT2 Inhibitors, but Not GLP-1 Receptor Agonists, Reduce Incidence of Gout in People Living With Type 2 Diabetes Across the Therapeutic Spectrum.

PURPOSE: This study aimed to evaluate the relative association between sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1Ra) with the incidence of gout in patients with type 2 diabetes (T2D) using real-world data. METHODS: We conducted a cohort study using data from TriNetX (an international federated database). We included patients commenced on metformin or insulin, either alone or with an SGLT2i or GLP-1Ra, at least 2 years prior to date of analysis. We propensity score matched (PSM) (1:1) for 26 relevant characteristics. Time to event analysis was performed to assess the incidence of gout, all-cause mortality (positive control), and herpes zoster infection (negative control) at 5 years following drug initiation. FINDINGS: Prior to PSM, the cohort numbers were as follows: metformin control, 1,111,449; SGLT2i with metformin, 101,706; GLP-1Ra with metformin, 110,180, insulin control, 1,398,066; SGLT2i with insulin, 68,697; and GLP-1Ra with insulin, 99,693. SGLT2i with metformin demonstrated a statistically significant decreased incidence of gout at 5 years compared to the metformin control cohort (HR 0.75 [95% CI 0.69-0.82], P < 0.0001). Similarly, SGLT2i with insulin demonstrated a statistically significant decreased incidence of gout at 5 years compared to the insulin control cohort (HR 0.83 [95% CI 0.74-0.92], P < 0.0001). Conversely, no significant disparity in gout incidence was observed between the use of GLP-1Ra and matched controls. Subgroup analysis showed an associated reduced incidence of gout with SGLT2i use compared to GLP-1Ra, in groups using metformin (HR 0.77 [95% CI 0.70-0.86], P < 0.0001) or insulin (HR 0.82 [95% CI 0.73-0.91)], P < 0.0001). IMPLICATIONS: In this large-scale real-world study, SGLT2i use was associated with a lower incidence of gout in patients with T2D compared to both insulin and metformin controls. These findings suggest the potential of SGLT2i as a promising therapeutic option for treating gout in this population.

Sex, racial, ethnic, and geographical disparities in major adverse cardiovascular outcome of glucagon-like peptide-1 receptor agonists among patients with and without diabetes mellitus: A meta-analysis of placebo-controlled randomized controlled trials.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been pivotal in the management of type 2 diabetes mellitus (T2DM) and in the reduction of major adverse cardiovascular events (MACE). Notably, large cardiovascular outcomes trials (CVOTs) demonstrate significant disparities in inclusion, based on sex, race, ethnicity, and geographical regions. OBJECTIVES: We examined the impact of GLP-1RA on MACE in patients with or without T2DM, based on sex, race, ethnicity, and geography. METHODS: A literature search for placebo controlled RCTs on GLP-1RA treatment was conducted. Thorough data extraction and quality assessment were carried out, focusing on key outcome, and ensuring a robust statistical analysis using a random effects model to calculate log odds ratio with 95% confidence intervals (CIs). RESULTS: A total of 8 CVOTs comprising 71,616 patients were included. Compared with placebo, GLP-1RAs significantly reduced MACE in both sexes (females: logOR -0.19, (95% CI, -0.28 to -0.10), p < 0.01] versus males: logOR -0.17, 95% CI, -0.23 to -0.10), p < 0.01], (p interaction NS)], and among Asians (logOR -34 (95% CI, -0.53 to -0.15, p < 0.01), and Whites (logOR -17 (95% CI, -0.25 to -0.09, p < 0.01), with no difference in MACE among Blacks and Hispanics. Odds of MACE were also reduced in Asia (logOR -31 (95% CI, -0.50 to -0.11, p < 0.01), and Europe (logOR -27 (95% CI, -0.40 to -0.13, p < 0.01), but there was no statistical difference in MACE in North America and Latin America. CONCLUSION: Significant reductions in MACE with GLP-1RA treatment were demonstrated between both sexes and across certain ethnicities and certain geographical regions.

FDG-PET/CT-based respiration-gated lung segmentation and quantification of lung inflammation in COPD patients.

OBJECTIVE AND RESULTS DESCRIPTION: The study objective was to investigate the potential of quantitative measures of pulmonary inflammation by [18 F]Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) as a surrogate marker of inflammation in COPD. Patients treated with anti-inflammatory Liraglutide were compared to placebo and correlated with inflammatory markers. 27 COPD-patients (14 receiving Liraglutide treatment and 13 receiving placebo) underwent 4D-respiratory-gated FDG-PET/CT before and after treatment. Two raters independently segmented the lungs from CT images and measured activity in whole lung, mean standard uptake values (SUVmean) corrected for lean-body-mass in the phase-matched PET images of the whole segmented lung volume, and total lesion glycolysis (TLG; SUVmean multiplied by volume). Inter-rater reliability was analyzed with Bland-Altman analysis and correlation plots. We found no differences in metabolic activity in the lungs between the two groups as a surrogate of pulmonary inflammation, and no changes in inflammation markers. The purpose of the research and brief summary of main findings. The degree of and changes in pulmonary inflammation in chronic obstructive pulmonary disease (COPD) may be difficult to ascertain. Measuring metabolic activity as a surrogate marker of inflammation by FDG-PET/CT may be useful, but data on its use in COPD including reproducibility is still limited, especially with respiration-gated technique, which should improve quantification in the lungs. We assessed several quantitative measures of metabolic activity and correlated them with inflammation markers, and we assessed reproducibility of the methods. We found no differences in metabolic activity between the two groups (before and after 40 weeks treatment with Liraglutide vs. placebo). Bland-Altman analysis showed good agreement between the two raters. TRIAL REGISTRATION: The study was conducted between February 2018 and March 2020 at the Department of Pulmonary Diseases at Hospital South West Jutland and Lillebaelt Hospital, Denmark, and registered from March 2018 at clinicaltrials.gov with trial registration number NCT03466021.

GLP-1 receptor agonists for weight reduction in people living with obesity but without diabetes: a living benefit-harm modelling study.

Background: The benefit of Glucagon-like Peptide-1 (GLP-1) receptor agonists (RAs) in weight reduction against potential harms remains unclear. This study aimed at evaluating the benefit-harm balance of initiating GLP-1 RAs versus placebo for weight loss in people living with overweight and obesity but without diabetes. Methods: We performed benefit-harm balance modelling, which will be updated as new evidence emerges. We searched for randomised controlled trials (RCTs) in PubMed, controlled trials registry, drug approval and regulatory documents, and outcome preference weights as of April 10, 2024. We synthesize data using pairwise meta-analysis to estimate the effect of GLP-1 RAs to inform the benefit-harm balance modelling. We predicted the absolute effects of the positive and negative outcomes over 1 and 2 years of treatment using exponential models. We applied preference weights to the outcomes, ranging from 0 for least concerning to 1.0 for most concerning. We then calculated whether the benefit of achieving 5% and 10% weight loss outweighed the harms on a common scale. The analyses accounted for the statistical uncertainties of treatment effects, preference weights, and outcome risks. Findings: We included 8 RCTs involving 8847 participants. The pooled average age was 46.7 years, with the majority being women (74%) and people living with obesity (96%). Of 1000 persons treated with GLP-1 RAs for 2 years, 375 (95% confidence interval 352 to 399) achieved a 10% weight loss, and 318 (296 to 339) achieved a 5% weight loss compared to those treated with placebo. Several harm outcomes were more frequent in the GLP-1 RA group, including 41 abdominal pain events per 1000 persons over 2 years (19 to 69), cholelithiasis (8, 1 to 21), constipation (118, 78 to 164), diarrhoea (100, 42 to 173), alopecia (57, 10 to 176), hypoglycaemia (17, 1 to 68), injection site reactions (4, -3 to 19), and vomiting (110, 80 to 145) among others. Achieving a 10% weight loss with GLP-1 RA therapy outweighed the cumulative harms, with a net benefit probability of 0.97 at year 1 and 0.91 at year 2. The absolute net benefit was equivalent to 104 (100 to 112) per 1000 persons achieving a 10% weight loss over 2 years without experiencing any worrisome harm. A 5% weight loss did not show a net benefit, with probabilities of 0.13 and 0.01 at year 1 and year 2, respectively. However, these benefits were sensitive to preference weights, suggesting that even a 5% weight loss could be net beneficial for individuals with less concern about harm outcomes. The net benefit for a 10% weight loss was highest for semaglutide, followed by liraglutide and tirzepatide, with 2-year probabilities of 0.96, 0.72, and 0.60, respectively. Interpretation: The benefit of GLP-1 RAs exceeded the harms for weight loss in the first 2 years of treatment, yet the net benefit was dependent on individual' treatment goals (10% or 5% weight loss) and willingness to accept harms in pursuit of weight loss. This implies that treatment decisions have to be personalized to individuals to optimize benefits and reduce harms and overuse of treatments. Due to varying evidence, especially regarding harm outcomes across studies, it is necessary to continuously update and monitor the benefit-harm balance of GLP-1 RAs. Funding: SNSF and LOOP Zurich.

Patient Adherence to a Real-World Digital, Asynchronous Weight Loss Program in Australia That Combines Behavioural and GLP-1 RA Therapy: A Mixed Methods Study.

Increasingly large numbers of people are using digital weight loss services (DWLSs) to treat being overweight and obesity. Although it is widely agreed that digital modalities improve access to care in general, obesity stakeholders remain concerned that many DWLSs are not comprehensive or sustainable enough to deliver meaningful health outcomes. This study adopted a mixed methods approach to assess why and after how long patients tend to discontinue Australia's largest DWLS, a program that combines behavioural and pharmacological therapy under the guidance of a multidisciplinary care team. We found that in a cohort of patients who commenced the Eucalyptus DWLS between January and June 2022 (n = 5604), the mean program adherence was 171.2 (±158.2) days. Inadequate supplying of a patient's desired glucose-like peptide-1 receptor agonist medication was the most common reason for discontinuation (43.7%), followed by program cost (26.2%), result dissatisfaction (9.9%), and service dissatisfaction (7.2%). Statistical tests revealed that ethnicity and age both had a significant effect on patient adherence. These findings suggest that DWLSs have the potential to improve access to comprehensive, continuous obesity care, but care models need to improve upon the one observed in the Eucalyptus Australia DWLS to mitigate common real-world program attrition factors.

Real-world HbA1c changes and prescription characteristics among type 2 diabetes mellitus patients initiating treatment with once weekly semaglutide for diabetes.

Purpose: The purpose of this study was to evaluate patient, prescriber, and dose characteristics and evaluate changes in glycated hemoglobin (HbA1c) for patients prescribed once weekly semaglutide for diabetes (OW sema T2D). Methods: This study was a retrospective claims-based study using the Optum Research Database. The sample included adult patients who had at least one claim for OW sema T2D between Jan 1, 2018, and Dec 31, 2019, were continuously enrolled in the health plan and had a diagnosis of type 2 diabetes (T2DM) during the pre-index or post-index periods. Demographic and clinical characteristics of patients using OW sema T2D were collected, as were the dose and prescriber specialty and the change between pre-index and post-index HbA1c measures was calculated. Results were stratified by the latest pre-index HbA1c measurement (HbA1c greater than or equal to 9.0%, uncontrolled vs. HbA1c less than 9%, controlled). Statistical comparisons between HbA1c groups were conducted. Results: Most patients, 76.3%, were prescribed a 0.25/0.50 mg dose of OW sema T2D. Patients had an overall decrease in HbA1c of 0.8% and patients with uncontrolled diabetes had a greater reduction in mean HbA1c compared to those with controlled diabetes (-2.1% vs. -0.3%, p < 0.001). Most patients had their index dose of OW sema T2D prescribed by endocrinologists (27.6%) primary care providers (24.6%) and internal medicine providers (21.6%). Conclusions: OW sema T2D is an effective real-world T2DM treatment. Future research should further investigate real-world use patterns of this medication.

Effects of newer anti-hyperglycemic agents on cardiovascular outcomes in older adults: Systematic review and meta-analysis.

AIM: To demonstrate cardiovascular safety of dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and sodium/glucose cotransporter 2 inhibitors (SGLT-2i) across age-groups. METHODS: PubMed, Embase and Cochrane were searched for cardiovascular outcome trials (CVOTs) testing newer agents until August 31, 2022 (PROSPERO ID CRD42021260167). Studies with ≥1000 T2D participants enrolled for ≥12 months were included. Random effect models were used to report relative-risk (RR) for three-point major adverse cardiovascular events (3P-MACE) and its components by age subgroups (65 years; 75 years). RESULTS: For SGLT-2is, five CVOTs (46,969 patients, 45-50 % ≥65 years) were included. SGLT-2is reduced risk of MACE (RR; 0.91 [CI, 0.85-0.98]); cardiovascular death (CV-death) (RR; 0.84 [CI, 0.73-0.96]); and all-cause mortality (ACM) (RR; 0.86 [CI, 0.79-0.93]) with no difference in subgroups <65 or ≥65 years. For GLP-1RAs, nine CVOTs (n = 64,236, 34-75 % ≥65 years) were included. GLP-1RAs reduced risk of MACE (RR; 0.89 [CI, 0.83-0.95]), stroke (RR; 0.86 [CI, 0.76-0.97]) and ACM (RR; 0.90 [CI, 0.83-0.97]) with no significant difference in subgroups <65 or ≥65 years. Additionally, GLP-1RAs reduced risk of MACE (10 %), ACM (12 %) and CV-death (12 %) with no significant difference in subgroups <75 or ≥75 years. Four CVOTs (n = 33,063; 35-58 % ≥65 years) with DPP-4is were included. There were no significant differences in risk for CV outcomes with DPP-4is compared to placebo in any of the age subgroups. CONCLUSION: The overall cardiovascular safety profile of newer anti-hyperglycemic agents is consistent in older and younger individuals.

Comparation of fixed-ratio (IDegLira and iGlarLixi) versus free combination of basal insulin and glucagon-like peptide-1 receptor agonist for uncontrolled type 2 diabetes: A systematic review and network meta-analysis.

OBJECTIVE: This study aimed to evaluate the safety and efficacy of the fixed-ratio combination (FRC) and free combination of basal insulin and glucagon-like peptide-1 receptor agonist (GLP-1RA) in patients with type 2 diabetes mellitus (T2DM). METHODS: PubMed, Web of Science, Embase, The Cochrane Library, and four Chinese databases were searched for relevant studies from inception to April 13, 2023. Phase III clinical trials involving FRC or free combination in patients with uncontrolled T2DM were included. A network meta-analysis (NMA) was used to evaluate the effects of FRC and free combination. The Cochrane Collaboration's tool was used to evaluate the risk-of-bias. The primary outcomes were changes in hemoglobin A1c (HbA1c), body weight, and incident hypoglycemia. Secondary outcomes included changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP). This study was registered with PROSPERO (CRD42023409585). RESULTS: Forty-two trials with 23,619 patients were included in the NMA, and treatments were categorized as FRC, free combination and NOINSGLP (neither FRC nor free combination). The forest plots revealed comparable HbA1c control (mean difference (MD) = 0.07%, 95% confidence interval (CI): -0.17 to -0.30) between free combination and FRC. However, there were significant differences in the body weight (MD = -2.06 kg; 95% CI: -3.34 to -0.77), SBP (MD = -1.22 mmHg; 95% CI: -2.41 to -0.04), and DBP (MD = -1.09 mmHg; 95% CI: -1.94 to -0.24) between the two groups. CONCLUSIONS: In patients with uncontrolled T2DM, the safety and efficacy of FRC and free combination therapy were comparable. The use of FRC is justifiable in patients requiring free combination.