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Glucagon-like peptide-1 receptor (GLP-1R) agonists have garnered significant attention for their therapeutic potential in addressing the interconnected health challenges of diabetes, obesity, and cancer. The role of GLP-1R in type 2 diabetes mellitus (T2DM) is highlighted, emphasizing its pivotal contribution to glucose homeostasis, promoting β-cell proliferation, and facilitating insulin release. GLP-1R agonists have effectively managed obesity by reducing hunger, moderating food intake, and regulating body weight. Beyond diabetes and obesity, GLP-1R agonists exhibit a multifaceted impact on cancer progression across various malignancies. The mechanisms underlying these effects involve the modulation of signaling pathways associated with cell growth, survival, and metabolism. However, the current literature reveals a lack of in vivo studies on specific GLP-1R agonists such as semaglutide, necessitating further research to elucidate its precise mechanisms and effects, particularly in cancer. While other GLP-1R agonists have shown promising outcomes in mitigating cancer progression, the association between some GLP-1R agonists and an increased risk of cancer remains a topic requiring more profound investigation. This calls for more extensive research to unravel the intricate relationships between the GLP-1R agonist and different cancers, providing valuable insights for clinicians and researchers alike.

Despite the significant impact of statin therapy, patients continue to face substantial residual cardiovascular risk. These risks are particularly prominent in patients with both type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD). We examine the effectiveness of a cardiometabolic clinic, embedded within a suburban cardiology private practice, in identifying and managing several of these multifaceted risks. We collated interventions for the first 100 patients with T2D and ASCVD who attended a minimum of two appointments at the clinic. Following an average of 2.4 clinic visits, 44 of 100 patients had undergone intensification of lipid-lowering therapy, with 16 initiated on PCSK9-directed therapies. This resulted in 85 of 100 patients achieving LDL-C levels below the 2022 ACC Expert Consensus Decision Pathway recommendations for intensification. Lipoprotein(a) was measured in 80 patients, revealing elevated levels in 22. At baseline, 18 and 32 patients were on glucagon-like peptide-1 receptor agonists (GLP1RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i), respectively. This increased to 80 and 66 patients on GLP1RA and SGLT2i, respectively, with 94 patients on either class and 52 patients on both. Figure 1 presents baseline and follow-up use of cardiometabolic therapies. The cardiometabolic clinic effectively identified and intensified management of several residual cardiovascular risks in patients with T2D and ASCVD. Extensive use of combination lipid-lowering therapies substantially addressed cholesterol-related risk, and initial experiences support the feasibility of high-volume implementation of GLP1RA and SGLT2i therapies in this population.

To determine national prevalence of sodium-glucose contransporter-2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP1RA) use among adults with type 2 diabetes mellitus (T2DM). We studied adults with T2DM and eGFR ≥ 30 mL/min/1.73 m2 who participated in the cross-sectional National Health and Nutrition Examination Survey (NHANES), focusing on the 2017–2020 examination cycle, a key time period prior to widespread dissemination of pivotal trial results and corresponding clinical practice guidelines. We tested prevalence of SGLT2i and GLP1RA use among subgroups based on demographic variables and relevant comorbidities, including chronic kidney disease (CKD), congestive heart failure (CHF), and atherosclerotic cardiovascular disease (ASCVD). We compared use of SGLT2i and GLP1RA to other glucose-lowering medications and assessed trends from prior NHANES cycles. Among 1375 participants studied in 2017–2020, mean age was 60 years, 46% were women, 13% self-identified as non-Hispanic Black, 10% self-identified as Mexican American, 37% had CKD, 8.5% had CHF, and 23% had ASCVD. The prevalence of SGLT2i and GLP1RA use was 5.8% and 4.4%, respectively. Among adults with CKD, CHF, or ASCVD, SGLT2i were used by 7.7% and GLP1RA were used by 3.5%. Differences in SGLT2i or GLP1RA use were observed by age, race, ethnicity, health insurance status, body mass index, and by whether a single healthcare provider was identified as responsible for diabetes management. Biguanides, sulfonylureas, DPP-4 inhibitors, and insulin were used more frequently than SGLT2i or GLP1RA. Prevalence of SGLT2i but not GLP1RA use increased significantly from 2013–2014 to 2017–2020. SGLT2i and GLP1RA use is low among adults with T2DM, including among those with strong indications. Enhanced implementation of these agents is crucial to improving kidney and cardiovascular outcomes and mitigating health disparities in T2DM. •SGLT2i and GLP1RA use is low in adults with T2DM.•Prevalence of SGLT2i but not GLP1RA use increased from 2013–2014 to 2017–2020.•SGLT2i or GLP1RA use differed by age, race, ethnicity, and health insurance status.

IntroductionOver half of Americans and up to 78% of US Veteran population meet criteria for obesity. Perioperatively placed intragastric balloon (IGB) can accelerate weight loss goals for safe surgical candidacy, however weight regain is common after removal. Glucagon-like peptide-1-receptor agonists (GLP1RA) may provide a more sustainable weight loss solution after surgery. We hypothesize that weight regain will be less at 1 year after initiation of GLP1RA than IGB placement in Veterans.MethodsRetrospective review of prospective databases of perioperatively placed intragastric balloon cohort from 1/2019–1/2023 compared to patients who received initiatory GLP1RA from 6/2021–8/2022 at a VA Medical Center(VAMC). All patients were enrolled in the VAMC MOVE! multidisciplinary weight management program for a minimum of 12 weeks. Outcomes measured were patients’ weights at 0, 3, 6, and 12 months and weight change for these intervals. Exclusion criteria included history of bariatric surgery and incomplete weight loss data.ResultsTwo-hundred-twenty-three patients met inclusion criteria; 110 (49%) patients excluded. Mean age was 54 ± 11 years, the majority (78, 69%) were male, and the mean initial BMI was 37 ± 5.9 kg/m2. Seventeen (15%) patients underwent IGB placement and 96 (85%) patients received semaglutide. Weight (kg) change was measured at intervals: 0–3 months:− 11.8(− 17,− 9.5) IGB vs. − 5.1(− 7.4,− 2.3) semaglutide, p < 0.0001; 0–6 months:− 12.7(− 18.4,− 9.9) vs. − 9.4(− 12.6,− 6.1), p = 0.03; 3–6 months:− 0.5(− 2.3,2.3) vs. − 4.3(− 6.8,− 1.6), p < 0.0001; 6–12 months:3(0,7.3) vs. − 1.9(− 4.7,1), p = 0.0006.ConclusionWeight loss occurs more rapidly in the first 6 months after intragastric balloon placement compared to semaglutide (− 12.7 vs. − 9.4 kg, p = 0.03). Despite ongoing attendance in a comprehensive weight loss program, weight regain is common after IGB removal by an average of 3 kg (23.6%) at 1 year. In contrast, patients on GLP1RA (semaglutide) continue to lose weight during this period. Further studies are needed to determine if optimal long-term outcomes may result from combination therapy with intragastric balloon and semaglutide.

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.

•No head-to-head RCT has been conducted comparing GLP1RA and SGLT2i renal benefits.•This is a real-world study comparing eGFR decline in people on GLP1RA or SGLT2i.•A similar eGFR decline was observed between study groups over 36 months.•GLP1RA and SGLT2i lead to equal weight loss, with very similar changes in BMI.•Different side effects leading to equal rates of drug discontinuation were reported. 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. 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. 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. 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.

This communication provides a contemporary classification of glucagon-like peptide 1 receptor agonists (GLP1RAs) based on indication, route, and frequency of administration, which could support a person-centric approach to treatment choice. It includes all recently developed GLP1RAs as well as those in advanced stages of clinical study. Keeping pace with current trends in pharmacology and metabolic medicine, it attempts to bring clarity and simplicity to a complex spread of information.

Background Type 2 diabetes (T2D) is sub-optimally managed for many in Aotearoa New Zealand, and disproportionately affects Māori and Pacific peoples. In February 2021, SGLT2i/GLP1RA agents were funded for use for the first time with prioritisation for Māori, Pacific and those with cardiovascular and/or renal disease or risk (CVRD). This study evaluates the impact of health system factors on initiation of SGLT2i/GLP1RA therapy. Methods Primary care data was collected for patients with T2D aged 18–75 years from four primary care organisations (302 general practices) in the Auckland / Waikato region of New Zealand (Feb 2021 – July 2022). Initiation of SGLT2i/GLP1RA therapy was reviewed by patient (age, gender, ethnicity, CVRD status) and health system variables (funding, provider type, staffing, patient numbers, rurality, after-hours access). Logistic regression was used to estimate the odds ratio of a patient being dispensed SGLT2i/GLP1RA. Results Of 57,743 patients with T2D, 22,331 were eligible for funded SGLT2i/GLP1RA access and 10,272 of those (46.0%) were prescribed. Initiation of therapy was highest in Māori (50.8%) and Pacific (48.8%) patients (vs. 36·2–40·7% of other ethnic groups; P  < 0.001), but was comparable in those with and without CVRD (47·1% vs. 48·9%; P  = 0.2). Prescribing was highest in practices with higher doctor/patient numbers, low-cost fees, Māori health providers and clinics without after-hours access. Conclusion Prioritised access for SGLT2i/GLP1RA appears to be associated with a reduced health equity gap for Māori and Pacific patients with T2D in NZ, but work is required to improve prescribing for patients with CVRD.

Background Orforglipron is a novel once‐daily oral non‐peptide glucagon‐like peptide‐1 receptor agonist with several recently published randomized controlled trials (RCTs) evaluating its role in diabetes and obesity. No meta‐analysis has analyzed the efficacy and safety of orforglipron; this meta‐analysis aimed to address this knowledge gap. Methods A systematic search was conducted in electronic databases to identify RCTs that included individuals with obesity who were administered orforglipron and compared to either a placebo or an active comparator. The primary outcome of interest was the percent change in body weight. Results From 12 initially screened articles, data from three RCTs involving 774 people were analyzed with a follow‐up duration of up to 36 weeks. Compared to placebo, patients receiving orforglipron 12 mg/day (mean difference (MD), MD −5.48%, 95% CI [−7.64, −3.33], p < 0.01), 24 mg/day (MD −8.51%, 95% confidence interval (CI) [−9.88, −7.14], p < 0.01), 36 mg/day (MD −8.84%, 95% CI [−11.68, −6.00], p < 0.01) and 45 mg/day (MD −8.24%, 95% CI [−12.84, −3.63], p < 0.01) had a significantly greater percent reduction in body weight. The percentage of patients being able to achieve >15% weight loss from baseline was significantly higher with orforglipron 24 mg/day [Odds ratio (OR) 21.90 (95% CI [4.06, 118.15], p = 0.0003), 36 mg/day (OR 17.43, 95% CI [3.18, 95.66], p = 0.001) and 45 mg/day (OR 23.17, 95% CI [4.37, 123.03], p = 0.0002). Total but not severe adverse events were significantly higher with all the doses of orforglipron compared to placebo, with the hazard ratios being higher with higher doses. Gastrointestinal side‐effects were predominant side effects, being dose‐dependent, with nausea, vomiting, constipation, and gastroesophageal reflux being the predominant ones. Conclusion Orforglipron at 24–45 mg/day doses is an effective weight loss medication. The efficacy versus side effect profile suggests that 24–36 mg/day is the most optimal dose for orforglipron as an anti‐obesity medicine. Orforglipron at doses of 24–45 mg/day is an effective weight loss medication. The efficacy versus side effect profile suggests that 24–36 mg/day is the most optimal dose for orforglipron as an anti‐obesity medicine.