RESUMEN
Aim: The purpose of this work was to determine the feasibility of supporting a clinical microdose study for PF-06882961 (danuglipron), an oral small molecule agonist of the GLP-1 receptor, by LC-MS/MS. Methodology: Statistical instrument parameter optimization using response surface methodology was employed to develop a LC-MS/MS method for the analyte, PF-06882961. Results: An LC-MS/MS method was developed and validated to support a proof of concept microdose pharmacokinetics preclinical study in monkeys, administered PF-06882961 (0.005 mg total, average dose = 0.0007 mg/kg) via intravenous bolus injection. Conclusion: The present study demonstrated the feasibility of analyzing human microdose plasma samples for PF-06882961 by LC-MS/MS, instead of accelerator mass spectrometry, thereby reducing cost and eliminating synthesis and exposure to 14C labeled material.
[Box: see text].
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Receptor del Péptido 1 Similar al Glucagón , Espectrometría de Masas en Tándem , Espectrometría de Masas en Tándem/métodos , Humanos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Cromatografía Liquida/métodos , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Cromatografía Líquida con Espectrometría de MasasRESUMEN
OBJECTIVE: To explore trends in prognosis and use of glucose-lowering drugs (GLD) in patients with diabetes and coronary artery disease (CAD). RESEARCH DESIGN AND METHODS: All patients with diabetes and CAD undergoing a coronary angiography between 2010 and 2021 according to the Swedish Angiography and Angioplasty Registry were included. Information on GLD (dispended 6 months before or after coronary angiography) was collected from the Swedish Prescribed Drug Registry. Data on major cardiovascular events (MACE; mortality, myocardial infarction, stroke, heart failure) through December 2021 were obtained from national registries. Cox proportional survival analysis was used to assess outcomes where cardioprotective GLD (any of Sodium Glucose Lowering Transport 2 receptor inhibitors [SGLT2i] and Glucagon Like Peptide Receptor Agonists [GLP-1 RA]) served as a reference. RESULTS: Among all patients (n = 38,671), 31% had stable CAD, and 69% suffered an acute myocardial infarction. Mean age was 69 years, 67% were male, and 81% were on GLD. The use of cardioprotective GLD increased rapidly in recent years (2016-2021; 7-47%) and was more common in younger patients (66 vs. 68 years) and men (72.9% vs. 67.1%) than other GLD. Furthermore, compared with other GLD, the use of cardioprotective GLD was more common in patients with a less frequent history of heart failure (5.0% vs. 6.8%), myocardial infarction (7.7% vs. 10.5%) and chronic kidney disease (3.7% vs. 5.2%). The adjusted hazard ratio (HR) (95% CI) for MACE was greater in patients on other GLD than in those on cardioprotective GLD (1.10; 1.03-1.17, p = 0.004). Trend analyses for the years 2010-2019 revealed improved one-year MACE in patients with diabetes and CAD (year 2019 vs. 2010; 0.90; 0.81-1.00, p = 0.045), while 1-year mortality was unchanged. CONCLUSIONS: The prescription pattern of diabetes medication is changing quickly in patients with diabetes and CAD; however, there are worrying signals of inefficient use prioritizing cardioprotective GLD to younger and healthier individuals at lower cardiovascular risk. Despite this, there are improving trends in 1-year morbidity.
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Enfermedad de la Arteria Coronaria , Receptor del Péptido 1 Similar al Glucagón , Sistema de Registros , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Masculino , Femenino , Anciano , Suecia/epidemiología , Enfermedad de la Arteria Coronaria/mortalidad , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Persona de Mediana Edad , Factores de Tiempo , Receptor del Péptido 1 Similar al Glucagón/agonistas , Medición de Riesgo , Resultado del Tratamiento , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Factores de Riesgo , Incretinas/uso terapéutico , Incretinas/efectos adversos , Pautas de la Práctica en Medicina/tendencias , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/mortalidad , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiología , Angiografía Coronaria/tendencias , Anciano de 80 o más Años , Glucemia/metabolismo , Glucemia/efectos de los fármacosRESUMEN
Previously, no randomized controlled trials investigated the renoprotective effects of glucagon-like peptide-1 receptor agonists (GLP-1RA) as the primary endpoint in patients with diabetes and chronic kidney disease. In the FLOW trial, Perkovic et al. showed that once-weekly semaglutide reduced kidney failure, kidney-related death, and cardiovascular death by 24% as compared with placebo in patients with type 2 diabetes at high risk of renal progression.1.
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Diabetes Mellitus Tipo 2 , Receptor del Péptido 1 Similar al Glucagón , Péptidos Similares al Glucagón , Insuficiencia Renal Crónica , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Insuficiencia Renal Crónica/tratamiento farmacológico , Péptidos Similares al Glucagón/uso terapéutico , Péptidos Similares al Glucagón/farmacología , Péptidos Similares al Glucagón/administración & dosificación , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Nefropatías Diabéticas/tratamiento farmacológicoAsunto(s)
Péptido 1 Similar al Glucagón , Receptor del Péptido 1 Similar al Glucagón , Obesidad , Humanos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Péptido 1 Similar al Glucagón/agonistas , Obesidad/tratamiento farmacológico , Polipéptido Inhibidor Gástrico/uso terapéutico , Receptores de la Hormona Gastrointestinal/agonistas , Fármacos Antiobesidad/efectos adversos , Fármacos Antiobesidad/uso terapéutico , Fármacos Antiobesidad/administración & dosificación , Pérdida de Peso/efectos de los fármacos , Animales , Agonistas Receptor de Péptidos Similares al GlucagónAsunto(s)
Diabetes Mellitus Tipo 2 , Polipéptido Inhibidor Gástrico , Péptido 1 Similar al Glucagón , Receptor del Péptido 1 Similar al Glucagón , Hipoglucemiantes , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Péptido 1 Similar al Glucagón/agonistas , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacología , Polipéptido Inhibidor Gástrico/uso terapéutico , Receptores de la Hormona Gastrointestinal/agonistas , Animales , Agonistas Receptor de Péptidos Similares al GlucagónRESUMEN
We recently reported that a novel chimeric peptide (GEP44) targeting both the glucagon-like peptide-1 receptor (GLP-1R) and neuropeptide Y1- and Y2 receptor (Y1R and Y2R) reduced energy intake and body weight (BW) in diet-induced obese (DIO) rats. We hypothesized that GEP44 reduces energy intake and BW primarily through a GLP-1R dependent mechanism. To test this hypothesis, GLP-1R+/+ mice and GLP-1R null (GLP-1R-/-) mice were fed a high fat diet for 4 months to elicit diet-induced obesity prior to undergoing a sequential 3-day vehicle period, 3-day drug treatment (5, 10, 20 or 50 nmol/kg; GEP44 vs the selective GLP-1R agonist, exendin-4) and a 3-day washout. Energy intake, BW, core temperature and activity were measured daily. GEP44 (10, 20 and 50 nmol/kg) reduced BW after 3-day treatment in DIO male GLP-1R+/+ mice by -1.5 ± 0.6, -1.3 ± 0.4 and -1.9 ± 0.4 grams, respectively (P<0.05), with similar effects being observed in female GLP-1R+/+ mice. These effects were absent in male and female DIO GLP-1R-/- mice suggesting that GLP-1R signaling contributes to GEP44-elicited reduction of BW. Further, GEP44 decreased energy intake in both male and female DIO GLP-1R+/+ mice, but GEP44 appeared to produce more consistent effects across multiple doses in males. In GLP-1R-/- mice, the effects of GEP44 on energy intake were only observed in males and not females, suggesting that GEP44 may reduce energy intake, in part, through a GLP-1R independent mechanism in males. In addition, GEP44 reduced core temperature and activity in both male and female GLP-1R+/+ mice suggesting that it may also reduce energy expenditure. Lastly, we show that GEP44 reduced fasting blood glucose in DIO male and female mice through GLP-1R. Together, these findings support the hypothesis that the chimeric peptide, GEP44, reduces energy intake, BW, core temperature, and glucose levels in male and female DIO mice primarily through a GLP-1R dependent mechanism.
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Peso Corporal , Dieta Alta en Grasa , Ingestión de Energía , Receptor del Péptido 1 Similar al Glucagón , Ratones Obesos , Obesidad , Animales , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Femenino , Masculino , Ratones , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Dieta Alta en Grasa/efectos adversos , Ingestión de Energía/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Ratones Noqueados , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Emerging data suggest that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve kidney outcomes for people with type 2 diabetes (T2D). Direct comparisons of the kidney and cardiovascular effectiveness of GLP-1 RA with sodium-glucose cotransporter 2 inhibitors (SGLT2i), a first-line therapy for this population, are needed. OBJECTIVES: The authors compared kidney and cardiovascular outcomes for new users of SGLT2i and GLP-1 RAs with T2D. METHODS: Using propensity score overlap weighting, we analyzed electronic health record data from 20 U.S. health systems contributing to PCORnet between 2015 and 2020. The primary kidney outcome was a composite of sustained 40% estimated glomerular filtration rate (eGFR) decline, incident end-stage kidney disease, or all-cause mortality over 2 years or until censoring. In addition, we examined cardiovascular and safety outcomes. RESULTS: The weighted study cohort included 35,004 SGLT2i and 47,268 GLP-1 RA initiators. Over a median of 1.2 years, the primary outcome did not differ between treatments (HR: 0.91; 95% CI: 0.81-1.02), although SGLT2i were associated with a lower risk of 40% eGFR decline (HR: 0.77; 95% CI: 0.65-0.91). Risks of mortality (HR: 1.08; 95% CI: 0.92-1.27), a composite of stroke, myocardial infarction, or death (HR: 1.03; 95% CI: 0.93-1.14), and heart failure hospitalization (HR: 0.95; 95% CI: 0.80-1.13) did not differ. Genital mycotic infections were more common for SGLT2i initiators, but other safety outcomes did not differ. The results were similar regardless of chronic kidney disease status. CONCLUSIONS: SGLT2i and GLP-1 RAs led to similar kidney and cardiovascular outcomes in people with T2D, though SGLT2i initiation was associated with a lower risk of 40% eGFR decline. (Evaluating Comparative Effectiveness of Empagliflozin in Type 2 Diabetes Population With and Without Chronic Kidney Disease; NCT05465317).
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Diabetes Mellitus Tipo 2 , Tasa de Filtración Glomerular , Receptor del Péptido 1 Similar al Glucagón , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Masculino , Femenino , Receptor del Péptido 1 Similar al Glucagón/agonistas , Persona de Mediana Edad , Anciano , Tasa de Filtración Glomerular/efectos de los fármacos , Enfermedades Cardiovasculares , Hipoglucemiantes/uso terapéutico , Fallo Renal Crónico , Agonistas Receptor de Péptidos Similares al GlucagónAsunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Receptor del Péptido 1 Similar al Glucagón , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Enfermedades Cardiovasculares/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Agonistas Receptor de Péptidos Similares al GlucagónRESUMEN
The landscape of diabetes management has changed, such that the goal of pharmacotherapy extends beyond glucose-lowering to prioritize risk reduction of cardiovascular disease and diabetic kidney disease. Two newer classes of medications, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2-Is), have become first line therapies for many patients with type 2 diabetes to reduce cardiovascular and renal complications of type 2 diabetes. This review article will describe the mechanism of action, evidence for cardiovascular and kidney outcomes, contraindications, adverse effects, and risk mitigation strategies for the GLP-1 RA and SGLT2-I drug classes. In addition, we will provide a practical approach for primary care clinicians to prescribe, adjust, and combine these medication classes, while considering patient preference, tolerability, comorbidities, cost, and availability.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Receptor del Péptido 1 Similar al Glucagón , Hipoglucemiantes , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/etiología , Receptor del Péptido 1 Similar al Glucagón/agonistas , Nefropatías Diabéticas/prevención & control , Nefropatías Diabéticas/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Glucemia/efectos de los fármacosRESUMEN
New anti-diabetic medications, including glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter 2 (SGLT2) inhibitors are recommended in guidelines to reduce cardio-renal events in type 2 diabetes mellitus (T2DM), independent of glucose control. Yet they might be underused in real world. This study aims to address the knowledge gap, prescription patterns and barriers faced by Chinese doctors. Cardio-Metabolic Survey was a cross-sectional study conducted among doctors managing diabetic patients in clinical practice, via a designated online questionnaire from May 1st, to Dec. 31th, 2022. A total of 358 doctors from 57 hospitals across Beijing participated in this survey, 34.9% from tertiary hospitals. Only 30-40% doctors demonstrated somewhat understanding of the mechanism and clinical applications of GLP-1RA or SGLT2 inhibitors. There is no difference in understanding of these two medications overall (p = 0.336). However, doctors in tertiary hospitals have a higher understanding of GLP-1RA and SGLT2 inhibitors compared to those in non-tertiary hospitals (p = 0.049, and 0.008, respectively). 40.2% doctors have never prescribed GLP-1RA, and 36.6% for SGLT2 inhibitors. The frequency of prescribing SGLT2 inhibitors was significantly higher than prescribing GLP-1RA (p = 0.005). The main barriers on prescription include high cost, poor adherence, side effects concern, and insufficient knowledge about these medications. Chinese doctors currently have limited understanding and low prescription frequency for GLP-1RA and SGLT2 inhibitors. Multifaceted approaches are needed to improve doctors' knowledge and strengthen their ability to manage T2DM effectively.
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Diabetes Mellitus Tipo 2 , Receptor del Péptido 1 Similar al Glucagón , Pautas de la Práctica en Medicina , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Pautas de la Práctica en Medicina/estadística & datos numéricos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Estudios Transversales , China , Masculino , Encuestas y Cuestionarios , Hipoglucemiantes/uso terapéutico , Femenino , Médicos , Conocimientos, Actitudes y Práctica en Salud , Adulto , Persona de Mediana Edad , Agonistas Receptor de Péptidos Similares al Glucagón , Pueblos del Este de AsiaRESUMEN
Obesity is a chronic disease caused primarily by the imbalance between the amount of calories supplied to the body and energy expenditure. Not only does it deteriorate the quality of life, but most importantly it increases the risk of cardiovascular diseases and the development of type 2 diabetes mellitus, leading to reduced life expectancy. In this review, we would like to present the molecular pathomechanisms underlying obesity, which constitute the target points for the action of anti-obesity medications. These include the central nervous system, brain-gut-microbiome axis, gastrointestinal motility, and energy expenditure. A significant part of this article is dedicated to incretin-based drugs such as GLP-1 receptor agonists (e.g., liraglutide and semaglutide), as well as the brand new dual GLP-1 and GIP receptor agonist tirzepatide, all of which have become "block-buster" drugs due to their effectiveness in reducing body weight and beneficial effects on the patient's metabolic profile. Finally, this review article highlights newly designed molecules with the potential for future obesity management that are the subject of ongoing clinical trials.
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Fármacos Antiobesidad , Obesidad , Humanos , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Fármacos Antiobesidad/uso terapéutico , Fármacos Antiobesidad/farmacología , Animales , Metabolismo Energético/efectos de los fármacos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Microbioma Gastrointestinal/efectos de los fármacosRESUMEN
The newfound knowledge in type 2 diabetes (T2D) during the past decade for the sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) is wealthy in favorable results for key patient-important outcomes including morbidity, mortality and health-related quality of life (HRQoL). The SGLT-2i and GLP-1RA offer cardiovascular and renal protection beyond their glucose lowering effect, reduce body weight and hypoglycemia and improve diabetes-related distress, physical function and HRQoL. Along with the fixed-ratio combinations of basal insulin/GLP-1RA, they make feasible a regimen simplification and de-escalation from high dose and multiple injections of insulin reducing treatment burden. Besides cardiorenal risk reduction, the SGLT-2i and GLP-1RA reduce the incidence of depression, cognitive decline, respiratory disease, gout, arrhythmias and other co-occurring conditions of T2D, namely multimorbidity, which frequently complicates T2D and adversely affects HRQoL. The alleviation of multimorbidity by the pleiotropic effects of the SGLT-2i and GLP-1RA, could improve patients' HRQoL. The use of the SGLT-2i and GLP-1RA should be increased within a shared decision-making in which they are reframed as cardiorenal risk-reducing medications with the potential to lower blood glucose. By improving outcomes that patients may highly perceive and value, the SGLT-2i and GLP-1RA may facilitate the contemporary person-centered management of T2D.
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Glucemia , Diabetes Mellitus Tipo 2 , Receptor del Péptido 1 Similar al Glucagón , Hipoglucemiantes , Calidad de Vida , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/sangre , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Resultado del Tratamiento , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/efectos adversos , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Factores de Riesgo , Control Glucémico/efectos adversos , Incretinas/uso terapéutico , Incretinas/efectos adversos , Biomarcadores/sangre , Medición de Resultados Informados por el Paciente , Medición de Riesgo , Estado de Salud , Agonistas Receptor de Péptidos Similares al GlucagónRESUMEN
Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and holds significant pharmacological potential. Nevertheless, the regulation of energy homeostasis by centrally-produced GLP-1 remains partially understood. Preproglucagon cells, known to release GLP-1, are found in the olfactory bulb (OB). We show that activating GLP-1 receptors (GLP-1R) in the OB stimulates insulin secretion in response to oral glucose in lean and diet-induced obese male mice. This is associated with reduced noradrenaline content in the pancreas and blocked by an α2-adrenergic receptor agonist, implicating functional involvement of the sympathetic nervous system (SNS). Inhibiting GABAA receptors in the paraventricular nucleus of the hypothalamus (PVN), the control centre of the SNS, abolishes the enhancing effect on insulin secretion induced by OB GLP-1R. Therefore, OB GLP-1-dependent regulation of insulin secretion relies on a relay within the PVN. This study provides evidence that OB GLP-1 signalling engages a top-down neural mechanism to control insulin secretion via the SNS.
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Péptido 1 Similar al Glucagón , Receptor del Péptido 1 Similar al Glucagón , Secreción de Insulina , Ratones Endogámicos C57BL , Bulbo Olfatorio , Núcleo Hipotalámico Paraventricular , Animales , Péptido 1 Similar al Glucagón/metabolismo , Masculino , Bulbo Olfatorio/metabolismo , Bulbo Olfatorio/efectos de los fármacos , Secreción de Insulina/efectos de los fármacos , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Ratones , Núcleo Hipotalámico Paraventricular/metabolismo , Insulina/metabolismo , Obesidad/metabolismo , Sistema Nervioso Simpático/metabolismo , Neuronas/metabolismo , Transducción de Señal , Norepinefrina/metabolismo , Glucosa/metabolismoRESUMEN
Importance: Despite its demonstrated benefits in improving cardiovascular risk profiles, the association of tirzepatide with mortality and cardiovascular and kidney outcomes compared with glucagon-like peptide 1 receptor agonists (GLP-1 RAs) remains unknown. Objective: To investigate the association of tirzepatide with mortality and adverse cardiovascular and kidney outcomes compared with GLP-1 RAs in patients with type 2 diabetes. Design, Setting, and Participants: This retrospective cohort study used US Collaborative Network of TriNetX data collected on individuals with type 2 diabetes aged 18 years or older initiating tirzepatide or GLP-1 RA between June 1, 2022, and June 30, 2023; without stage 5 chronic kidney disease or kidney failure at baseline; and without myocardial infarction or ischemic or hemorrhagic stroke within 60 days of drug initiation. Exposures: Treatment with tirzepatide compared with GLP-1 RA. Main Outcomes and Measures: The primary outcome was all-cause mortality, and secondary outcomes included major adverse cardiovascular events (MACEs), the composite of MACEs and all-cause mortality, kidney events, acute kidney injury, and major adverse kidney events. All outcomes were analyzed using Cox proportional hazards regression models. Results: There were 14â¯834 patients treated with tirzepatide (mean [SD] age, 55.4 [11.8] years; 8444 [56.9%] female) and 125â¯474 treated with GLP-1 RA (mean [SD] age, 58.1 [13.3] years; 67â¯474 [53.8%] female). After a median (IQR) follow-up of 10.5 (5.2-15.7) months, 95 patients (0.6%) in the tirzepatide group and 166 (1.1%) in the GLP-1 RA group died. Tirzepatide treatment was associated with lower hazards of all-cause mortality (adjusted hazard ratio [AHR], 0.58; 95% CI, 0.45-0.75), MACEs (AHR, 0.80; 95% CI, 0.71-0.91), the composite of MACEs and all-cause mortality (AHR, 0.76; 95% CI, 0.68-0.84), kidney events (AHR, 0.52; 95% CI, 0.37-0.73), acute kidney injury (AHR, 0.78; 95% CI, 0.70-0.88), and major adverse kidney events (AHR, 0.54; 95% CI, 0.44-0.67). Treatment with tirzepatide was associated with greater decreases in glycated hemoglobin (treatment difference, -0.34 percentage points; 95% CI, -0.44 to -0.24 percentage points) and body weight (treatment difference, -2.9 kg, 95% CI, -4.8 to -1.1 kg) compared with GLP-1 RA. An interaction test for subgroup analysis revealed consistent results stratified by estimated glomerular filtration rate, glycated hemoglobin level, body mass index, comedications, and comorbidities. Conclusions and Relevance: In this study, treatment with tirzepatide was associated with lower hazards of all-cause mortality, adverse cardiovascular events, acute kidney injury, and adverse kidney events compared with GLP-1 RA in patients with type 2 diabetes. These findings support the integration of tirzepatide into therapeutic strategies for this population.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Receptor del Péptido 1 Similar al Glucagón , Hipoglucemiantes , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/mortalidad , Diabetes Mellitus Tipo 2/complicaciones , Masculino , Femenino , Persona de Mediana Edad , Receptor del Péptido 1 Similar al Glucagón/agonistas , Estudios Retrospectivos , Anciano , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/epidemiología , Hipoglucemiantes/uso terapéutico , Resultado del Tratamiento , Agonistas Receptor de Péptidos Similares al Glucagón , Receptor del Péptido 2 Similar al Glucagón , Polipéptido Inhibidor GástricoAsunto(s)
Receptor del Péptido 1 Similar al Glucagón , Obesidad , Humanos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Obesidad/tratamiento farmacológico , Grupo de Atención al Paciente/organización & administración , Manejo de la Obesidad/métodos , Fármacos Antiobesidad/uso terapéutico , Fármacos Antiobesidad/farmacología , Agonistas Receptor de Péptidos Similares al GlucagónRESUMEN
BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are effective in diabetes and obesity, reducing hyperglycemia by increasing insulin release and delaying gastric emptying. However, they can cause gastroparesis, raising concerns about aspiration during procedures. Recent guidelines advise discontinuing GLP-1 RA before surgery to reduce the risk of pulmonary aspiration. AIM: To evaluate the effect of GLP-1 RAs on gastric residual contents during endoscopic procedures. METHODS: A retrospective chart review at BronxCare Health System, New York, from January 2019 to October 2023, assessed gastric residue and aspiration in GLP-1 RA patients undergoing endoscopic procedures. Two groups were compared based on dietary status before the procedure. Data included demographics, symptoms of gastroparesis, opiate use, hemoglobin A1c, GLP-1 agonist indication, endoscopic details, and aspiration occurrence. IBM SPSS was used for analysis, calculating means, standard deviations, and applying Pearson's chi-square and t-tests for associations, with P < 0.05 as being significant. RESULTS: During the study, 306 patients were included, with 41.2% on a clear liquid/low residue diet and 58.8% on a regular diet before endoscopy. Most patients (63.1%) were male, with a mean age of 60 ± 12 years. The majority (85.6%) were on GLP-1 RAs for diabetes, and 10.1% reported digestive symptoms before endoscopy. Among those on a clear liquid diet, 1.5% had residual food at endoscopy compared to 10% on a regular diet, which was statistically significant (P = 0.03). Out of 31 patients with digestive symptoms, 13% had residual food, all from the regular diet group (P = 0.130). No complications were reported during or after the procedures. CONCLUSION: The study reflects a significant rise in GLP-1 RA use for diabetes and obesity. A 24-hour liquid diet seems safe for endoscopic procedures without aspiration. Patients with upper gastrointestinal symptoms might have a higher residual food risk, though not statistically significant. Further research is needed to assess risks based on diabetes duration, gastroparesis, and GLP-1 RA dosing, aiming to minimize interruptions in therapy during procedures.
Asunto(s)
Gastroparesia , Receptor del Péptido 1 Similar al Glucagón , Humanos , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Receptor del Péptido 1 Similar al Glucagón/agonistas , Anciano , Gastroparesia/prevención & control , Gastroparesia/etiología , Gastroparesia/epidemiología , Gastroparesia/tratamiento farmacológico , Vaciamiento Gástrico/efectos de los fármacos , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/administración & dosificación , Endoscopía Gastrointestinal/métodos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Adulto , Agonistas Receptor de Péptidos Similares al GlucagónRESUMEN
To investigate the safety and efficacy of long-acting glucagon like peptide-1 receptor agonists in overweight or obese patients with type 2 diabetes. Overweight or obese patients with type 2 diabetes from July 2021 to June 2022 were randomly divided into control group (metformin) and experimental group (metformin + dulaglitide or semaglutide). Repeated measures analysis of variance was used to compare Hemoglobin A1c, fasting plasma glucose and body mass index (BMI) of patients before treatment, 6 months and 12 months after treatment. The adverse reactions of patients before treatment and 12 months after treatment were analyzed. The time effect of Hemoglobin A1c, fasting plasma glucose and BMI in the control group (nâ =â 35) and the experimental group (nâ =â 32) were statistically significant (Pâ <â .001), and the intergroup effect of BMI was statistically significant (Pâ <â .05). The interaction effect of BMI was statistically significant (Pâ <â .001). The BMI level of the experimental group was lower than that of the control group at 6 and 12 months after treatment (Pâ <â .001). There was no significant difference in the incidence of adverse reactions between the 2 groups (Pâ >â .05). Long-acting glucagon like peptide-1 receptor agonists, such as dulaglitide and semaglutide, not only reduce glycosylated hemoglobin levels, but also significantly improve BMI in overweight or obese patients with type 2 diabetes.
Asunto(s)
Glucemia , Índice de Masa Corporal , Diabetes Mellitus Tipo 2 , Receptor del Péptido 1 Similar al Glucagón , Péptidos Similares al Glucagón , Hemoglobina Glucada , Hipoglucemiantes , Metformina , Obesidad , Sobrepeso , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Masculino , Persona de Mediana Edad , Femenino , Receptor del Péptido 1 Similar al Glucagón/agonistas , Hipoglucemiantes/uso terapéutico , Péptidos Similares al Glucagón/uso terapéutico , Péptidos Similares al Glucagón/administración & dosificación , Péptidos Similares al Glucagón/análogos & derivados , Hemoglobina Glucada/efectos de los fármacos , Hemoglobina Glucada/análisis , Obesidad/tratamiento farmacológico , Obesidad/complicaciones , Metformina/uso terapéutico , Sobrepeso/tratamiento farmacológico , Sobrepeso/complicaciones , Glucemia/efectos de los fármacos , Glucemia/análisis , Anciano , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Fragmentos Fc de Inmunoglobulinas/efectos adversos , Análisis de Varianza , Adulto , Quimioterapia Combinada , Agonistas Receptor de Péptidos Similares al Glucagón , Proteínas Recombinantes de FusiónRESUMEN
OBJECTIVE: To assess the risk of all-cause mortality and major adverse cardiovascular events (MACE) in patients with immune-mediated inflammatory diseases (IMIDs) and type 2 diabetes newly initiating glucagon-like peptide-1 receptor agonists (GLP-1-RAs) versus dipeptidyl peptidase-4 inhibitors (DPP-4is). METHODS: We performed a population-based cohort study using administrative health data from British Columbia. Patients with an IMID (i.e., rheumatoid arthritis, psoriatic disease, ankylosing spondylitis, inflammatory bowel disease, or a systemic autoimmune rheumatic disease) and type 2 diabetes who newly initiated a GLP-1-RA or DPP-4i between January 1, 2010, and December 31, 2021 were identified using ICD-9/10 codes. The primary outcome was all-cause mortality. Secondary outcomes included MACE and its components (i.e., cardiovascular death, myocardial infarction, and ischemic stroke). Cox proportional hazard regressions were used with propensity score overlap weighting. The analysis was repeated in age- and sex-matched adults without IMIDs. RESULTS: We identified 10,855 adults with IMIDs and type 2 diabetes who newly initiated a GLP-1-RA or DPP-4i. All-cause mortality rate was lower among initiators of GLP-1-RAs compared to initiators of DPP-4is, with a weighted hazard ratio (HR) of 0.48 (95% confidence interval [CI], 0.31-0.75) and rate difference (RD) of -9.4 (95% CI, -16.0 to -2.7) per 1000 person-years. Rate of MACE was also lower with GLP-1-RA exposure (HR 0.66 [0.50-0.88], RD -10.5 [-20.4 to -0.8]). Effect sizes were similar in adults without IMIDs. CONCLUSION: In patients with IMIDs and type 2 diabetes, GLP-1-RA exposure is associated with a lower risk of all-cause mortality and MACE compared to a cardioneutral active comparator.