To determine the respective associations of premorbid glucagon-like peptide-1 receptor agonist (GLP1-RA) and sodium-glucose cotransporter 2 inhibitor (SGLT2i) use, compared with premorbid dipeptidyl ...peptidase 4 inhibitor (DPP4i) use, with severity of outcomes in the setting of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
We analyzed observational data from SARS-CoV-2-positive adults in the National COVID Cohort Collaborative (N3C), a multicenter, longitudinal U.S. cohort (January 2018-February 2021), with a prescription for GLP1-RA, SGLT2i, or DPP4i within 24 months of positive SARS-CoV-2 PCR test. The primary outcome was 60-day mortality, measured from positive SARS-CoV-2 test date. Secondary outcomes were total mortality during the observation period and emergency room visits, hospitalization, and mechanical ventilation within 14 days. Associations were quantified with odds ratios (ORs) estimated with targeted maximum likelihood estimation using a super learner approach, accounting for baseline characteristics.
The study included 12,446 individuals (53.4% female, 62.5% White, mean ± SD age 58.6 ± 13.1 years). The 60-day mortality was 3.11% (387 of 12,446), with 2.06% (138 of 6,692) for GLP1-RA use, 2.32% (85 of 3,665) for SGLT2i use, and 5.67% (199 of 3,511) for DPP4i use. Both GLP1-RA and SGLT2i use were associated with lower 60-day mortality compared with DPP4i use (OR 0.54 95% CI 0.37-0.80 and 0.66 0.50-0.86, respectively). Use of both medications was also associated with decreased total mortality, emergency room visits, and hospitalizations.
Among SARS-CoV-2-positive adults, premorbid GLP1-RA and SGLT2i use, compared with DPP4i use, was associated with lower odds of mortality and other adverse outcomes, although DPP4i users were older and generally sicker.
Despite three decades of increasing prevalence of type 2 diabetes (T2D) in adolescents (1), the diabetes community continues to grapple with the pathophysiology of youth-onset T2D. Accumulating ...evidence indicates that when compared with T2D in adults, T2D in youth follows a more aggressive course (2–4). Adolescents are therefore entering adulthood with an advanced and perhaps misunderstood disease that puts them at risk for morbidity from micro- and macrovascular complications. Moreover, as the susceptibility of individuals with diabetes to poor outcomes during the coronavirus pandemic became increasingly apparent (5), the urgency to address the health crisis of T2D in youth has been amplified.The Restoring Insulin Secretion (RISE) study, designed in 2014, tested interventions in both adolescents and adults to determine whether β-cell decline could be halted in people with prediabetes or early T2D (6). The primary analyses were overall disheartening regarding slowing the progression of T2D in youth (7–12). However, the RISE study provides the most direct opportunity yet to examine differences between T2D in youth and adults. In this issue of Diabetes Care, the RISE Consortium delivers three articles that offer mechanistic insights into the pathogenesis of T2D and potentially a path forward for the treatment of T2D in youth (13–15). A summary of these articles is presented in Table 1 and discussed in subsequent paragraphs.
To assess the impact of concomitant metformin use on gastrointestinal adverse events during the initiation and titration of a glucagon-like peptide 1 receptor agonist (GLP-1RA).
Using data from four ...clinical trials of liraglutide and semaglutide (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results LEADER, Semaglutide Treatment Effect in People with Obesity STEP 2, Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes SUSTAIN-6, and Peptide Innovation for Early Diabetes Treatment PIONEER 6), we compared the incidence of gastrointestinal adverse events during GLP-1RA initiation and titration in participants with and without concomitant metformin use.
Of 16,996 participants, 12,928 (76%) were treated with metformin. Concomitant metformin use did not increase the percentage of participants who developed gastrointestinal adverse events or their severity during the observation window. Among participants experiencing gastrointestinal adverse events, metformin use did not increase study product discontinuation. Within treatment arms (GLP-1RA and placebo), a numerically higher percentage of metformin nonusers experienced gastrointestinal adverse events and discontinued the study product compared with metformin users.
Concomitant metformin use does not increase occurrence of gastrointestinal symptoms during GLP-1RA initiation or impact GLP-1RA discontinuation.
Signal transducer and activator of transcription 3 (STAT3) is a member of the Janus kinase (JAK)-STAT pathway, which is one of the key pathways contributing to cancer. STAT3 regulates transcription ...downstream of many cytokines including interleukin (IL)-6 and IL-10. In cancer, STAT3 is mainly described as a tumor promoter driving tumor cell proliferation, resistance to apoptosis, angiogenesis and metastasis and aberrant activation of STAT3 is associated with poor prognosis. STAT3 is also an important driver of immune evasion. Among many other immunosuppressive mechanisms, STAT3 aids tumor cells to escape natural killer (NK) cell-mediated immune surveillance. NK cells are innate lymphocytes, which can directly kill malignant cells but also regulate adaptive immune responses and contribute to the composition of the tumor microenvironment. The inborn ability to lyse transformed cells renders NK cells an attractive tool for cancer immunotherapy. Here, we provide an overview of the role of STAT3 in the dynamic interplay between NK cells and tumor cells. On the one hand, we summarize the current knowledge on how tumor cell-intrinsic STAT3 drives the evasion from NK cells. On the other hand, we describe the multiple functions of STAT3 in regulating NK-cell cytotoxicity, cytokine production and their anti-tumor responses
in vivo
. In light of the ongoing research on STAT3 inhibitors, we also discuss how targeting STAT3 would affect the two arms of STAT3-dependent regulation of NK cell-mediated anti-tumor immunity. Understanding the complexity of this interplay in the tumor microenvironment is crucial for future implementation of NK cell-based immunotherapies.
A new synthesis of di- and trisubstituted pyrroles was achieved by treating in situ generated vinylogous diazoesters and readily available nitriles with a catalytic amount of silver(I) antimony ...hexafluoride at room temperature. This method showcased the potential of utilizing silver(I) carbenoids in preparing heterocyclic compounds.
GI symptoms are common side effects reported with both GLP-1RA and metformin use, yet these agents are often prescribed in combination. GLP-1RA are initiated at low dose and escalated to minimize the ...occurrence of GI side effects. Still, most treatment related GI adverse events occur during the dose titration period. We evaluated whether concomitant metformin use increases the rate of GI adverse events during the GLP-1RA titration period.
Using data from 4 clinical trials, LEADER (1.8 mg liraglutide), STEP-2 (1/2.4 mg semaglutide), SUSTAIN-6 (0.5/1 mg semaglutide), and PIONEER-6 (14 mg oral semaglutide), we compared the incidence of GI adverse events during the titration period defined as the expected time to steady state of the respective drug (3 weeks-5 months, see table) in participants with and without concomitant metformin use.
Of the 16,996 participants in these trials, 12,928 (76%) were treated with metformin. The percent of participants who developed new or serious GI adverse events during the titration period was similar across those with or without concomitant metformin use in each group (GLP-1RA or placebo) in all trials (Table). The occurrence of individual GI event (nausea, vomiting, diarrhea, and constipation) was also similar (data not shown).
In summary, concomitant metformin use does not increase the occurrence of GI symptoms during early GLP-1RA treatment.
Disclosure
K.R.Klein: None. K.K.B.Clemmensen: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. E.Fong: Employee; Novo Nordisk A/S. S.Olsen: None. T.J.Abrahamsen: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S, Genmab A/S. I.Lingvay: Advisory Panel; Novo Nordisk A/S, Lilly Diabetes, Boehringer-Ingelheim, Sanofi, Consultant; Carmot Therapeutics, Inc., Merck Sharp & Dohme Corp., Janssen Scientific Affairs, LLC, Pfizer Inc., Intercept, Intarcia, Valeritas, TargetRWE, Shionogi, Zealand Pharma, Structure, Bayer, Research Support; Novo Nordisk A/S, Boehringer-Ingelheim.
Atypical 7-transmembrane receptors, often called decoy receptors, act promiscuously as molecular sinks to regulate ligand bioavailability and consequently temper the signaling of canonical G ...protein-coupled receptor (GPCR) pathways. Loss of mammalian CXCR7, the most recently described decoy receptor, results in postnatal lethality due to aberrant cardiac development and myocyte hyperplasia. Here, we provide the molecular underpinning for this proliferative phenotype by demonstrating that the dosage and signaling of adrenomedullin (Adm, gene; AM, protein)—a mitogenic peptide hormone required for normal cardiovascular development—is tightly controlled by CXCR7. To this end, Cxcr7−/− mice exhibit gain-of-function cardiac and lymphatic vascular phenotypes that can be reversed upon genetic depletion of adrenomedullin ligand. In addition to identifying a biological ligand accountable for the phenotypes of Cxcr7−/− mice, these results reveal a previously underappreciated role for decoy receptors as molecular rheostats in controlling the timing and extent of GPCR-mediated cardiac and vascular development.
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•Adrenomedullin (AM) is a biological ligand for CXCR7•CXCR7 scavenges AM peptide and dampens AM-mediated pERK in vitro and in vivo•Dynamic expression of CXCR7 is required for proper lymphangiogenesis•Genetic reduction of AM reverses lymphatic and cardiac hyperplasia of Cxcr7−/− mice
Atypical 7-transmembrane receptors, often called decoy receptors, act as molecular sinks to regulate ligand bioavailability and temper the signaling of canonical GPCR pathways. Here, Klein et al. identify a peptide hormone adrenomedullin as a biological ligand for one such decoy receptor, CXCR7, and discover a role for CXCR7 during lymphangiogenesis.
Aims
To validate the clusters of Swedish individuals with recent‐onset diabetes at differential risk of complications, which were identified in a previous study, in three global populations with ...long‐standing type 2 diabetes (T2D) who were at high cardiovascular risk, and to test for differences in the risk of major diabetes complications and survival endpoints.
Materials and methods
We assigned participants from recent global outcomes trials (DEVOTE n = 7637, LEADER n = 9340 and SUSTAIN‐6 n = 3297) to the previously defined clusters according to age at diabetes diagnosis, baseline glycated haemoglobin (HbA1c) and body mass index (BMI). Outcomes were assessed using Kaplan–Meier analysis and log‐rank tests.
Results
The T2D clusters were consistently replicated across the three trial cohorts. The risk of major adverse cardiovascular events and cardiovascular death differed significantly, in all trials, across clusters over a median follow‐up duration of 2.0, 3.8 and 2.1 years, respectively, and was highest for the cluster of participants with high HbA1c and low BMI (P < 0.05 in DEVOTE and LEADER). In LEADER and SUSTAIN‐6, the risk of nephropathy differed across clusters (P < 0.0001 and P = 0.003, respectively). The risk of severe hypoglycaemia differed in DEVOTE (P = 0.006).
Conclusions
Previously identified clusters can be replicated in three geographically diverse cohorts of long‐standing T2D and are associated with cluster‐specific risk profiles for additional clinical and survival outcomes, providing further validation of the clustering methodology. The external validity and stability of clusters across cohorts provides a premise for future work to optimize the clustering approach to yield T2D subgroups with maximum predictive validity who may benefit from subtype‐specific treatment paradigms.
Over the past decade, we have begun to appreciate that the lymphatic vascular system does more than simply return plasma back into the circulatory system and, in fact, contributes to a wide variety ...of normal and disease states. For this reason, much research has been devoted to understanding how lymphatic vessels form and function, with a particular interest in which molecules contribute to lymphatic vessel growth and maintenance. In the following review, we focus on a potent lymphangiogenic factor, adrenomedullin, and its known roles in lymphangiogenesis, lymphatic function, and human lymphatic disease. As one of the first, pharmacologically tractable G protein-coupled receptor pathways characterized in lymphatic endothelial cells, the continued study of adrenomedullin effects on the lymphatic system may open new avenues for the modulation of lymphatic growth and function in a variety of lymphatic-related diseases that currently have few treatments.
Receptor activity modifying proteins (RAMPs) associate with G-protein-coupled receptors (GPCRs) at the plasma membrane and together bind a variety of peptide ligands, serving as a communication ...interface between the extracellular and intracellular environments. The collection of RAMP-interacting GPCRs continues to expand and now consists of GPCRs from families A, B and C, suggesting that RAMP activity is extremely prevalent. RAMP association with GPCRs can regulate GPCR function by altering ligand binding, receptor trafficking and desensitization, and downstream signaling pathways. Here, we elaborate on these RAMP-dependent mechanisms of GPCR regulation, which provide opportunities for pharmacological intervention.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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