Comment on "Exploratory real-world experience with glucagon-like peptide 1 receptor agonists vs. metformin in youth with new-onset type 2 diabetes: a single-center retrospective study".

ObjectivesIn youth with type 2 diabetes (YT2D), glucagon-like peptide 1 receptor agonists (GLP1) are recommended as adjuncts to metformin (Met) when glycemic targets are not achieved. Early GLP1 use may improve weight and glycemic control, but its efficacy as monotherapy in treatment-naïve YT2D remains unstudied. This exploratory study compares GLP1 and Met monotherapy for glycemic and weight outcomes in newly diagnosed YT2D.MethodsThis retrospective study analyzed patients<21 diagnosed with T2D between January 2022 and March 2024 at a single center. Data were collected for up to 1 year following diagnosis for patients prescribed GLP1 or Met alone. Records were excluded if additional diabetes medication or bariatric surgery was introduced. A mixed effects linear regression model adjusted for baseline BMI, HbA1c, age, and gender.ResultsThe cohort included 12 GLP1 and 113 Met patients. About 83 % GLP1 patients were female (vs. Met 51 %). All were publicly insured. Median age at diagnosis was 14.8 years. Baseline and final HbA1c were similar: GLP1 (52–36 mmol/mol) and Met (52–44 mmol/mol), with 83 % GLP1 and 67 % Met patients achieving HbA1c≤48 mmol/mol (6.5 %) (p=0.253). Baseline BMI was higher in GLP1 (46.37 vs. Met 35.06 kg/m2). Percentage BMI reduction favored GLP1 (−5.10 %) over Met (−0.59 %). Regression analysis showed GLP1 was associated with greater monthly percentage BMI reduction (β= −1.08 %, p=0.001) but not with HbA1c change (β= −1.1, p=0.308).ConclusionsGLP1 led to greater BMI reduction with comparable glycemic control relative to Met in newly diagnosed YT2D.

ObjectivePresent clinicians with an updated overview of empagliflozin for the treatment of type 2 diabetes mellitus (T2DM), with focus on its use in combination regimens. MethodsUsing the Medline database, keyword searches were undertaken to identify literature reporting the use of empagliflozin treatment in clinical trials with a minimum duration of 12 weeks relating to patients with T2DM.

Background: Glucagon-like peptide-1 (GLP-1) receptor agonists are known to have a protective effect on the risk of developing atrial fibrillation (AF). However, it is unknown if this benefit is primarily due to the weight loss driven by these medications, as weight loss has been shown to reduce the risk of AF. Prior large-scale studies have not examined the confounding effect of weight loss. Therefore, in this study we investigated relationship between weight loss and time-to-diagnosis of AF in a cohort of patients on a GLP-1. As prior studies focused mostly on semaglutide, we also examined how different GLP-1s affect AF risk. Research Hypothesis: Patients with a larger degree of weight loss while on a GLP-1 will have longer diagnosis-free survival of atrial fibrillation. Methods: In this single-center retrospective study, we evaluated 13,034 patients at the University of Virginia without a prior diagnosis of AF who were started on a GLP-1 between 2020–2024. A 1:1 matched control group was created using propensity score matching based on covariates known to effect the risk of AF. The time-to-diagnosis of AF was collected based on manual review of electrocardiograms and other cardiac rhythm assessment modalities, and the amount of weight loss was recorded. Hazard ratios (HRs) for AF incidence were calculated, with stratification based on both weight loss amount and specific GLP-1 selection. Results: GLP-1 use was associated with a lower risk of atrial fibrillation vs controls (HR 0.74, 95% CI 0.63–0.86, p &lt; 0.001). Stratification by weight loss revealed that patients with robust (&gt;10%) loss experienced the greatest reduction in AF risk (HR 0.40, 95% CI 0.24–0.66, p &lt; 0.001). Those with mild (0–10%) weight loss also had a reduced risk (HR 0.77, 95% CI 0.62–0.95, p = 0.017). Surprisingly, those who gained weight while on a GLP-1 still saw benefit (HR 0.70, 95% CI 0.53–0.92, p = 0.012). By agent, semaglutide had the most significant reduction in AF incidence (HR 0.66, 95% CI 0.52–0.82, p &lt; 0.001), while liraglutide, dulaglutide, and tirzepatide showed non-significant trends toward risk reduction. Conclusion: GLP-1 therapy is associated with reduced atrial fibrillation risk regardless of weight change, although patients with robust weight loss saw the greatest benefit. Compared to other GLP-1s, semaglutide had the most protective effect on atrial fibrillation risk.

Diabetes mellitus, defined as a fasting plasma glucose of ≥126 mg/dL or a glycosylated hemoglobin A1c level (HbA1c) of ≥6.5%, afflicts ≈12.9% of adults in the United States and nearly 285 million adults worldwide.1,2 Diabetes mellitus is a major risk factor for the development of cardiovascular disease, independently conferring a 2-fold excess risk of coronary heart disease and stroke.3 Macrovascular events in diabetes mellitus remain the leading cause of mortality, and the burden of cardiovascular disease attributable to diabetes mellitus has increased over the past decade.4 An increase in the prevalence of obesity has contributed to the rise in diabetes mellitus. Additionally, obesity independently increases the risk of cardiovascular disease in patients with diabetes mellitus.5 Although strict glycemic control unequivocally reduces the microvascular complications of diabetes mellitus, the macrovascular benefits of intensive therapy have been difficult to establish, with conflicting results from large clinical trials.6–9 Multifactorial strategies are recommended to reduce cardiovascular risk in diabetes mellitus through enhanced glycemic control, blood pressure reduction, lipid management, weight loss, and physical activity.10 Unfortunately, despite aggressive interventions for hyperglycemia, <50% of patients achieve standard HbA1c targets with conventional therapy.11 Polypharmacy is required to achieve glycemic control in the majority of patients within 3 years of diagnosis.12 Although combinations of drug classes can synergistically target multiple pathophysiological defects, novel therapies are required to manage diabetes mellitus and mitigate cardiovascular risks. Dipeptidyl-peptidase IV (DPP-IV) inhibitor and glucagon-like peptide-1 (GLP-1) receptor agonist incretin therapies were developed to complement conventional treatment options for diabetes mellitus. Despite promising initial reports of cardioprotective effects, DPP-IV inhibitors have failed to demonstrate improved cardiovascular outcomes in large clinical trials.13–15 Randomized studies to evaluate cardiovascular outcomes associated with GLP-1 receptor agonists are currently underway. This review presents …

ObjectiveTo examine longitudinal changes in the initial prescribing of glucagon‐like peptide 1 (GLP‐1) receptor agonists for women of reproductive age in Australia; to determine whether contraception recommendations are being followed; and to estimate the frequency of pregnancy among women using GLP‐1 receptor agonists.Study designRetrospective open cohort study; analysis of MedicineInsight general practice data.Setting, participantsWomen aged 18–49 years who visited participating general practices three or more times during the study period (1 January 2011 – 31 July 2022).Main outcome measuresAge‐standardised incidence of initial GLP‐1 receptor agonist prescribing, by year and type 2 diabetes status; proportion of women using highly effective contraception at the time of GLP‐1 receptor agonist initiation (contraception overlap); age‐standardised incidence of pregnancy within six months of the first prescribing of GLP‐1 receptor agonists.ResultsOf 1 635 684 women aged 18–49 years, 18 010 (1.1%) were first prescribed GLP‐1 receptor agonists during 2011–2022, of whom 3739 (20.8%) had type 2 diabetes. The age‐standardised incidence of GLP‐1 receptor agonist prescribing for women with type 2 diabetes increased from 13.0 per 1000 women in 2011 to 88.5 per 1000 women in 2022; for women without type 2 diabetes, it increased from 0 to 14.9 per 1000 women. Of the 6293 women first prescribed GLP‐1 receptor agonists during 2022, 6954 (90.5%) did not have type 2 diabetes. Contraception overlap with first prescribing of GLP‐1 receptor agonists was determined for 3825 women (21.2%). Pregnancies within six months of GLP‐1 receptor agonist prescribing were documented for 232 of 10 781 women for whom at least six months of follow‐up data were available.ConclusionsThe prescribing of GLP‐1 receptor agonists for women of reproductive age is increasing in Australia, and most prescriptions are for women not diagnosed with type 2 diabetes. Fewer than one in four women are using contraception at the time of treatment initiation, and a considerable number are pregnant within six months of the initial prescribing of GLP‐1 receptor agonists. Further evidence and guidelines are needed to support the safe and effective use of GLP‐1 receptor agonists by women of reproductive age.

Preoperative considerations of new long-acting glucagon-like peptide-1 receptor agonists in diabetes mellitus

An Albumin-Exendin-4 Conjugate Engages Central and Peripheral Circuits Regulating Murine Energy and Glucose Homeostasis

Introduction: Sacituzumab govitecan (SG) is FDA-approved for the treatment of both metastatic triple negative breast cancer (mTNBC) and hormone receptor positive (HR+)/HER2- metastatic breast cancer (MBC). In phase III clinical trials, SG caused grade 3 neutropenia in ∼50% of patients. However, the real-world incidence of SG-induced neutropenia and the practice patterns regarding the use of adjuvant growth factor use are not well characterized. Methods: In this single retrospective cohort study, we identified patients with HR+/HER2- or TNBC MBC who received SG between 2020-2024 per standard of care. We used manual review of electronic health records to identify key clinical characteristics, treatment history, safety parameters, and documented use of growth factor support via granulocyte colony stimulating factor (GCSF, either filgrastim or pegfilgrastim) while on treatment with SG. Results: We identified 74 patients with MBC who were treated with SG, including 45 patients with mTNBC (60.8%), 27 patients with HR+/HER2- MBC (36.5%), and 2 patients with heterogenous expression who were categorized as HR+/HER2+ MBC (2.7%). Median age was 56.5 years (range 28.4 - 81.1 years). Patients with mTNBC received a median of 2 prior lines of chemotherapy (range 0-5) and patients with HR+/HER2- disease received a median of 8 lines of prior therapy including 4 prior lines of chemotherapy (range 2-14 total lines, 0-8 lines of chemotherapy). Median time on SG was 4.4 months (range 0.26-39.8 months) for patients with mTNBC and 1.9 months (range 0.26-15.6 months) for patients with HR+/HER2- MBC. Most patients experienced any grade neutropenia while on SG (n=60, 81.1%), including most patients with mTNBC (n=37, 82.2%) and HR+/HER2- MBC (n=21, 77.8%). Grade 3 neutropenia was common during SG (n=39, 52.7%), with similar rates among patients with mTNBC (n=25, 55.6%) and HR+/HER2- MBC (n=12, 44.4%). Rates of neutropenic fever were low: in total 5/74 (6.8%), of whom 4/45 (8.9%) were mTNBC. A total of 8/74 (10.8%) patients were hospitalized for SG-related neutropenia with median length of stay 3.5 (range 1-10) days. Dose delays for any reason occurred in patients with mTNBC (n=18, 40.0%) and HR+/HER2- MBC (n=8, 29.6%), about half of which were due to neutropenia (for mTNBC n=7, 15.6%, HR+/HER2- MBC n=4, 14.8%). Dose reductions for any reason were also common among patients with mTNBC (n=21, 46.7%) and HR+/HER2- MBC (n=18, 66.7%), including some due to neutropenia (for mTNBC n=7, 15.6%, for HR+/HER2- n=4, 14.8%). Most patients discontinued SG due to disease progression for both mTNBC (n=43, 95.6%) and HR+/HER2- MBC (n=24, 88.9%). Two patients with HR+/HER2- MBC (7.4%) discontinued therapy due to toxicity. The remaining patients are still on therapy or discontinued for unrelated reasons. Most patients received GCSF during treatment with SG (n=64, 86.5%), most of whom received filgrastim (n=62, 83.8%) and a minority of whom received peg-filgrastim (n=7, 9.5%). In total 34/74 (45.9%) patients received primary GCSF prophylaxis and 24/74 (32.4%) patients received secondary GCSF prophylaxis. Rates of primary and secondary prophylaxis varied by subtype for mTNBC and HR+/HER2- respectively (primary: 37.8% and 55.6%; secondary: 40.0% and 22.2% respectively). Conclusion: In this single center retrospective study, &amp;gt;80% patients with mTNBC and HR+/HER2- MBC on SG experienced any grade neutropenia. Similar to published trials, nearly half of patients in both subgroups experienced grade 3 neutropenia but rates of hospitalizations and neutropenic fever were &amp;lt;10% in this heavily pre-treated, real-world cohort. Rates of SG dose reduction occurred in ∼50% of patients, but rates of discontinuation due to toxicity were low. GCSF prophylaxis, either primary or secondary, was used in ∼80% of patients. Additional studies are needed to clarify which patients may be at highest risk for SG-induced neutropenia and the optimal growth factor regimens to improve outcomes. Citation Format: Samantha Fisch, Joshua Chin, Laura Quintal, Melanie Majure, Michelle Melisko, Jo Chien, Hope S. Rugo, Laura A. Huppert. Single-center retrospective cohort study evaluating neutropenia and growth factor use with sacituzumab govitecan in patients with HR+/HER2- and triple negative metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-12-25.

Objective Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has been shown to improve hepatic inflammation and steatosis in patients with type 2 diabetes. However, whether its effects on Fibrosis-4 (FIB-4), a surrogate marker of liver fibrosis, differ between patients naїve to GLP-1 receptor agonists (GLP-1RAs) and those who have switched from a GLP-1RA remains unclear. Methods In this single-center retrospective study, 65 Japanese patients with type 2 diabetes received tirzepatide for ≥6 months (GLP-1RA-naïve: n=15; GLP-1RA-treated: n=50). The primary outcome was change in the FIB-4. The secondary endpoints included changes in glycated hemoglobin (HbA1c), body weight, urinary protein, and estimated glomerular filtration rate (eGFR). Multivariable analyses were performed to identify the predictors of FIB-4 improvement. Results FIB-4 significantly decreased in the GLP-1RA-naïve group (from 1.55±1.01 to 1.25±0.74, Δ-0.26±0.32, p<0.01) but not in the GLP-1RA-treated group (Δ-0.02±0.23), with a significant between-group difference (p<0.05). HbA1c decreased in both groups, with a greater reduction in GLP-1RA-naïve patients (Δ-2.0±1.3% vs. -1.0±1.3%, p<0.01). Body weight decreased significantly in both groups (-3.5±5.5 kg vs. -2.2±3.5 kg), with no between-group difference. A multivariable analysis identified age, baseline FIB-4, and GLP-1RA-naïve status as independent predictors of FIB-4 reduction. Conclusion Tirzepatide significantly reduced FIB-4, particularly in patients who were GLP-1RA-naïve, and produced substantial reductions in HbA1c and body weight. As an exploratory and hypothesis-generating analysis, these findings suggest that initiating tirzepatide in GLP-1RA-naïve patients may be associated with favorable changes in fibrosis-related risk markers in patients with type 2 diabetes at a high risk of liver fibrosis.

Response to comment on "Exploratory real-world experience with GLP-1 receptor agonists vs. metformin in youth with new-onset type 2 diabetes: a single-center retrospective study".

ObjectivesVasopressors are not recommended by current trauma guidelines, but recent reports indicate that they are commonly used. We aimed to describe the early hemodynamic management of trauma patients outside densely populated urban centers.MethodsWe conducted a single-center retrospective cohort study in a Canadian regional trauma center. All adult patients treated for traumatic injury in 2013 who died within 24 hours of admission or were transferred to the intensive care unit were included. A systolic blood pressure <90 mmHg, a mean arterial pressure <60 mmHg, the use of vasopressors or ≥2 L of intravenous fluids defined hemodynamic instability. Main outcome measures were use of intravenous fluids and vasopressors prior to surgical or endovascular management.ResultsOf 111 eligible patients, 63 met our criteria for hemodynamic instability. Of these, 60 (95%) had sustained blunt injury and 22 (35%) had concomitant severe traumatic brain injury. The subgroup of patients referred from a primary or secondary hospital (20 of 63, 32%) had significantly longer transport times (243 vs. 61 min, p<0.01). Vasopressors, used in 26 patients (41%), were independently associated with severe traumatic brain injury (odds ratio 10.2, 95% CI 2.7–38.5).ConclusionsIn this cohort, most trauma patients had suffered multiple blunt injuries. Patients were likely to receive vasopressors during the early phase of trauma care, particularly if they exhibited signs of neurologic injury. While these results may be context-specific, determining the risk-benefit trade-offs of fluid resuscitation, vasopressors and permissive hypotension in specific patients subgroups constitutes a priority for trauma research going forwards.

New Glucose-Lowering Agents for Diabetic Kidney Disease.

Weight gain and associated metabolic complications are increasingly prevalent among people with human immunodeficiency virus (PWH). Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are incretin-based therapies for diabetes and weight management that have been shown to result in substantial weight loss; however, studies of their effects in PWH are limited. A retrospective single-center cohort study was conducted among PWH who were taking GLP-1RAs at the University of California, San Diego Owen Clinic between 1 February 2021 and 1 February 2023. Baseline clinical data were collected and changes in weight, body mass index (BMI), and hemoglobin A1C (A1C) before starting GLP-1RAs compared to the most recent clinic visit were calculated (with a minimum of 3 months follow-up time required). Logistic regression was performed to identify variables associated with >5% of total body weight loss. A total of 225 patients received on average 13 months of GLP-1RA therapy, with 85 (37.8%) achieving the maximum GLP-1RA dose. GLP-1RA therapy resulted, on average, in a weight loss of 5.4 kg, decrease in BMI by 1.8 kg/m2, and decrease in A1C by 0.6%. In the multivariable analysis, higher baseline BMI (odds ratio [OR], 1.10 [95% confidence interval {CI}, 1.03-1.16]), treatment duration of GLP-1RA therapy >6 months (OR, 3.12 [95% CI, 1.49-6.49]), and use of tirzepatide (OR, 5.46 [95% CI, 1.44-20.76]) were significantly more likely to be associated with >5% weight loss. Use of GLP-1RAs led to declines in weight, BMI, and A1C among PWH and offers an additional strategy to address weight gain and diabetes.

BackgroundThe initial diagnosis of ductal carcinoma in situ (DCIS) can be upstaged to invasive cancer after definitive surgery. This study aimed to identify risk factors for DCIS upstaging using routine breast ultrasonography and mammography (MG) and to propose a prediction model.MethodsIn this single-center retrospective study, patients initially diagnosed with DCIS (January 2016–December 2017) were enrolled (final sample size = 272 lesions). Diagnostic modalities included ultrasound-guided core needle biopsy (US-CNB), MG-guided vacuum-assisted breast biopsy, and wire-localized surgical biopsy. Breast ultrasonography was routinely performed for all patients. US-CNB was prioritized for lesions visible on ultrasound. Lesions initially diagnosed as DCIS on biopsy with a final diagnosis of invasive cancer at definitive surgery were defined as “upstaged.”ResultsThe postoperative upstaging rates were 70.5%, 9.7%, and 4.8% in the US-CNB, MG-guided vacuum-assisted breast biopsy, and wire-localized surgical biopsy groups, respectively. US-CNB, ultrasonographic lesion size, and high-grade DCIS were independent predictive factors for postoperative upstaging, which were used to construct a logistic regression model. Receiver operating characteristic analysis showed good internal validation (area under the curve = 0.88).ConclusionsSupplemental screening breast ultrasonography possibly contributes to lesion stratification. The low upstaging rate for ultrasound-invisible DCIS diagnosed by MG-guided procedures suggests that it is unnecessary to perform sentinel lymph node biopsy for lesions invisible on ultrasound. Case-by-case evaluation of DCIS detected by US-CNB can help surgeons determine if repeating biopsy with vacuum-assisted breast biopsy is necessary or if sentinel lymph node biopsy should accompany breast-preserving surgery.Trial registrationThis single-center retrospective cohort study was conducted with the approval of the institutional review board of our hospital (approval number 201610005RIND). As this was a retrospective review of clinical data, it was not registered prospectively.

Prepectoral implant-based breast reconstruction with TiLOOP® Bra Pocket – a single-centre retrospective study