RESUMEN
AIMS: Large outcome trials have demonstrated cardiovascular benefits of selected glucagon-like peptide-1 (GLP-1) receptor agonists. We examined coronary disease outcomes in the Harmony Outcomes trial of the GLP-1 receptor agonist albiglutide. METHODS AND RESULTS: Harmony Outcomes was an event-driven, multicenter, double-blind, and placebo-controlled trial involving 9463 patients >40 years of age with type-2 diabetes and established atherosclerotic cardiovascular disease. It tested the effects of albiglutide on the occurrence of a composite primary endpoint, consisting of cardiovascular death, myocardial infarction (MI), or stroke. Within this post-hoc analysis, the effects of albiglutide on MI subtypes and other ischaemic endpoints were analysed.During the median-follow up of 1.6 years, a total of 421 patients (4.5%) experienced at least one MI, with 72 patients having more than one event. Treatment with albiglutide reduced both first events [hazard ratio (HR) 0.75 (0.62-0.91)] and overall events [HR 0.75 (0.61-0.91)] as well as first type 1 [HR 0.73 (0.57-0.92)] and type 2 myocardial infarctions [HR 0.65 (0.46-0.92)]. The effect of albiglutide treatment was consistent for ST-segment elevation [HR 0.69 (0.38-1.26)] and non-ST elevation (HR 0.86 (0.66-1.2) MI. CONCLUSION: Treatment with the GLP-1 receptor agonist albiglutide resulted in a 25% relative risk reduction in MI that was consistent for type of infarction and presence or absence of ST elevation. Our findings add novel information about the effects of GLP-1 receptor agonists on ischaemic events in patients with type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2 , Péptido 1 Similar al Glucagón , Receptor del Péptido 1 Similar al Glucagón , Hipoglucemiantes , Infarto del Miocardio , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/mortalidad , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/complicaciones , Masculino , Femenino , Método Doble Ciego , Persona de Mediana Edad , Resultado del Tratamiento , Anciano , Infarto del Miocardio/mortalidad , Infarto del Miocardio/tratamiento farmacológico , Péptido 1 Similar al Glucagón/análogos & derivados , Péptido 1 Similar al Glucagón/uso terapéutico , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/efectos adversos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Factores de Tiempo , Incretinas/uso terapéutico , Incretinas/efectos adversos , Medición de Riesgo , Isquemia Miocárdica/mortalidad , Isquemia Miocárdica/tratamiento farmacológico , Isquemia Miocárdica/diagnóstico , Factores de RiesgoRESUMEN
AIM: Glucagon-like peptide-1 receptor agonists (GLP1-RA) improve cardiovascular outcomes in patients with type 2 diabetes (T2D). However, some studies suggest that their effects in patients with heart failure (HF) may be attenuated. We aimed to explore the effects of the GLP1-RA albiglutide on HF outcomes in patients with and without HF history enrolled in the Harmony Outcomes trial. METHODS AND RESULTS: Harmony Outcomes enrolled patients with T2D and cardiovascular disease randomized to either albiglutide or placebo over a median follow-up of 1.6 years. A total of 9462 patients were included, of whom 1922 (20%) had HF history. Patients with HF had more cardiovascular comorbidities, poorer renal function, and had a three to four-fold higher risk of HF events compared to patients without HF. Compared to placebo, the effect of albiglutide on the composite of cardiovascular death or HF hospitalization was more pronounced among patients without HF (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.56-0.95) than in patients with HF (HR 1.06, 95% CI 0.79-1.43) (interaction p = 0.062). A similar pattern was observed for HF hospitalizations (interaction p = 0.025). The effect of albiglutide on cardiovascular death, sudden death or 'pump failure' death, and all-cause mortality was also attenuated among patients with HF history, but without significant interaction (p > 0.1). The benefit of albiglutide to reduce atherosclerotic events was consistent regardless of HF history. CONCLUSIONS: In patients with T2D and cardiovascular disease, albiglutide appeared to have no effect in reducing HF-related events among patients with HF history. These findings, placed in the context of other trials, suggest that GLP1-RA may not improve HF outcomes in patients with HF.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Insuficiencia Cardíaca , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/efectos adversos , Enfermedades Cardiovasculares/tratamiento farmacológico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/complicacionesRESUMEN
BACKGROUND AND AIM: The importance of glucagon-like peptide-1 (GLP-1) agonists is increasing because of its blood sugar controlling and weight loss properties. The data regarding safety of GLP-1 agonists are limited. This study aims to review case reports and case series on adverse drug reactions (ADRs) of GLP-1 agonist. METHODOLOGY: A comprehensive search was performed in PubMed/Medline, Scopus and Embase to identify literatures. Bibliographic search and open search in Google, Google Scholar, SpringerLink and ResearchGate was performed to identify additional studies. Case reports and case series published the ADRs by the use of GLP-1 agonists in type 2 diabetes patients were included in the study. Reviews, experimental studies, observational studies, grey literature and non English studies were excluded. RESULTS: The study identified 120 cases of GLP-1 agonists associated ADRs (liraglutide - 46, exenatide - 46, dulaglutide - 20, semaglutide - 4, albiglutide - 2, lixisenatide - 2). The major ADRs reported was gastrointestinal disorders (n = 40) followed by renal (n = 23), dermatologic (n = 14), hepatic (n = 10), immunologic (n = 13), endocrine/metabolic (n = 7), hematologic (n = 3), angioedema (n = 3), neurologic (n = 2), cardiovascular (n = 2) and 1 from each of psychiatric, reproductive, generalized edema problems. CONCLUSION: Gastrointestinal problems, particularly pancreatitis was the more frequently reported adverse drug reaction associated with GLP-1 agonist. The most adverse drug reactions were observed with liraglutide and exenatide.
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Diabetes Mellitus Tipo 2 , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Péptido 1 Similar al Glucagón/efectos adversos , Receptor del Péptido 1 Similar al Glucagón , Humanos , Hipoglucemiantes/efectos adversos , LiraglutidaRESUMEN
BACKGROUND: A meta-analysis is presented of cardiovascular outcome trials (CVOTs) comparing glucagon-like peptide-1 receptor agonists (GLP-1RA) versus placebo on cardiorenal outcomes in patients with type 2 diabetes mellitus (T2DM). METHODS: We did an electronic search up to June 30, 2021, for eligible trials. We did a meta-analysis of available trial data using a random-effects model to calculate overall hazard ratios (HRs) and 95% CI (confidence intervals). We included data from 8 CVOTs and 60,080 patients (72.4% with established cardiovascular disease). RESULTS: GLP-1RA reduced major cardiovascular events (MACE) by 14% (HR = 0.86, 95% CI 0.79-0.94, P = 0.006) with a non-significant heterogeneity between subgroups of patients with and without cardiovascular disease (P = 0.127). GLP-1RA also reduced the risk of cardiovascular death by 13% (P = 0.016), nonfatal stroke by 16% (P = 0.007), hospitalization for heart failure by 10% (P = 0.023), all-cause mortality by 12% (P = 0.012), and the broad composite kidney outcome by 17% (P = 0.012), which was driven by a reduction in macroalbuminuria only (HR = 0.74, 0.67-0.82, P < 0.001). CONCLUSIONS: GLP-1RA have moderate benefits on MACE, and also reduce hospitalization for heart failure and all-cause mortality; they also have robust benefits on reducing the incidence of macroalbuminuria.
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Síndrome Cardiorrenal/prevención & control , Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Hipoglucemiantes/uso terapéutico , Incretinas/uso terapéutico , Enfermedades Renales/prevención & control , Anciano , Síndrome Cardiorrenal/diagnóstico , Síndrome Cardiorrenal/mortalidad , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/mortalidad , Causas de Muerte , Ensayos Clínicos como Asunto , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/mortalidad , Femenino , Hospitalización , Humanos , Hipoglucemiantes/efectos adversos , Incidencia , Incretinas/efectos adversos , Enfermedades Renales/diagnóstico , Enfermedades Renales/mortalidad , Masculino , Persona de Mediana Edad , Medición de Riesgo , Factores de Riesgo , Resultado del TratamientoRESUMEN
The processing of proglucagon in intestinal L cells results in the formation of glucagon, GLP-1, and GLP-2. The GLP-1 molecule becomes active through the effect of proconvertase 1, and it is inactivated by dipeptidyl peptidase IV (DPP-IV), so that the half-life of endogenous GLP-1 is 2-3 min. GLP-1 stimulates insulin secretion from ß cells in the islets of Langerhans. Human studies show that infusion of GLP-1 results in slowing of gastric emptying and increased fasting and postprandial gastric volumes. Retardation of gastric emptying reduces postprandial glycemia. Exendin-4 is a peptide agonist of the GLP-1 receptor that promotes insulin secretion. Chemical modifications of exendin-4 and GLP-1 molecules have been accomplished to prolong the half-life of GLP-1 agonists or analogs. This chapter reviews the effects of GLP-1-related drugs used in treatment of diabetes or obesity on gastric motor functions, chiefly gastric emptying. The literature shows that diverse methods have been used to measure effects of the GLP-1-related drugs on gastric emptying, with most studies using the acetaminophen absorption test which essentially measures gastric emptying of liquids during the first hour and capacity to absorb the drug over 4-6 h, expressed as AUC. The most valid measurements by scintigraphy (solids or liquids) and acetaminophen absorption at 30 or 60 min show that GLP-1-related drugs used in diabetes or obesity retard gastric emptying, and this is associated with reduced glycemia and variable effects on food intake and appetite. GLP-1 agonists and analogs are integral to the management of patients with type 2 diabetes mellitus and obesity. The effects on gastric emptying are reduced with long-acting preparations or long-term use of short-acting preparations as a result of tachyphylaxis. The dual agonists targeting GLP-1 and another receptor (GIP) do not retard gastric emptying, based on reports to date. In summary, GLP-1 agonists and analogs are integral to the management of patients with type 2 diabetes mellitus and obesity, and their effects are mediated, at least in part, by retardation of gastric emptying.
Asunto(s)
Diabetes Mellitus Tipo 2 , Vaciamiento Gástrico , Péptido 1 Similar al Glucagón , Obesidad , Glucemia , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptido 1 Similar al Glucagón/agonistas , Péptido 1 Similar al Glucagón/análogos & derivados , Receptor del Péptido 1 Similar al Glucagón , Humanos , Hipoglucemiantes , Obesidad/tratamiento farmacológicoRESUMEN
BACKGROUND: GLP-1 receptor agonists (GLP-1 RAs) with exenatide b.i.d. first approved to treat type 2 diabetes in 2005 have been further developed to yield effective compounds/preparations that have overcome the original problem of rapid elimination (short half-life), initially necessitating short intervals between injections (twice daily for exenatide b.i.d.). SCOPE OF REVIEW: To summarize current knowledge about GLP-1 receptor agonist. MAJOR CONCLUSIONS: At present, GLP-1 RAs are injected twice daily (exenatide b.i.d.), once daily (lixisenatide and liraglutide), or once weekly (exenatide once weekly, dulaglutide, albiglutide, and semaglutide). A daily oral preparation of semaglutide, which has demonstrated clinical effectiveness close to the once-weekly subcutaneous preparation, was recently approved. All GLP-1 RAs share common mechanisms of action: augmentation of hyperglycemia-induced insulin secretion, suppression of glucagon secretion at hyper- or euglycemia, deceleration of gastric emptying preventing large post-meal glycemic increments, and a reduction in calorie intake and body weight. Short-acting agents (exenatide b.i.d., lixisenatide) have reduced effectiveness on overnight and fasting plasma glucose, but maintain their effect on gastric emptying during long-term treatment. Long-acting GLP-1 RAs (liraglutide, once-weekly exenatide, dulaglutide, albiglutide, and semaglutide) have more profound effects on overnight and fasting plasma glucose and HbA1c, both on a background of oral glucose-lowering agents and in combination with basal insulin. Effects on gastric emptying decrease over time (tachyphylaxis). Given a similar, if not superior, effectiveness for HbA1c reduction with additional weight reduction and no intrinsic risk of hypoglycemic episodes, GLP-1RAs are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment. However, GLP-1 RAs can be combined with (basal) insulin in either free- or fixed-dose preparations. More recently developed agents, in particular semaglutide, are characterized by greater efficacy with respect to lowering plasma glucose as well as body weight. Since 2016, several cardiovascular (CV) outcome studies have shown that GLP-1 RAs can effectively prevent CV events such as acute myocardial infarction or stroke and associated mortality. Therefore, guidelines particularly recommend treatment with GLP-1 RAs in patients with pre-existing atherosclerotic vascular disease (for example, previous CV events). The evidence of similar effects in lower-risk subjects is not quite as strong. Since sodium/glucose cotransporter-2 (SGLT-2) inhibitor treatment reduces CV events as well (with the effect mainly driven by a reduction in heart failure complications), the individual risk of ischemic or heart failure complications should guide the choice of treatment. GLP-1 RAs may also help prevent renal complications of type 2 diabetes. Other active research areas in the field of GLP-1 RAs are the definition of subgroups within the type 2 diabetes population who particularly benefit from treatment with GLP-1 RAs. These include pharmacogenomic approaches and the characterization of non-responders. Novel indications for GLP-1 RAs outside type 2 diabetes, such as type 1 diabetes, neurodegenerative diseases, and psoriasis, are being explored. Thus, within 15 years of their initial introduction, GLP-1 RAs have become a well-established class of glucose-lowering agents that has the potential for further development and growing impact for treating type 2 diabetes and potentially other diseases.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Animales , Glucemia , Peso Corporal , Sistema Cardiovascular/efectos de los fármacos , Exenatida/farmacología , Péptido 1 Similar al Glucagón/análogos & derivados , Péptidos Similares al Glucagón/análogos & derivados , Péptidos Similares al Glucagón/farmacología , Humanos , Hipoglucemia , Fragmentos Fc de Inmunoglobulinas , Insulina/farmacología , Liraglutida/farmacología , Enfermedades Neurodegenerativas , Péptidos/farmacología , Psoriasis , Proteínas Recombinantes de FusiónRESUMEN
CONTEXT: GLP-1 receptor agonists are an established therapy in patients with type 2 diabetes; however, their role in type 1 diabetes remains to be determined. OBJECTIVE: Determine efficacy and safety of once-weekly albiglutide 30 mg (up-titration to 50 mg at week 6) versus placebo together with insulin in patients with new-onset type 1 diabetes and residual insulin production. DESIGN: 52-week, randomized, phase 2 study (NCT02284009). METHODS: A prespecified Bayesian approach, incorporating placebo data from a prior study, allowed for 3:1 (albiglutide:placebo) randomization. The primary endpoint was 52-week change from baseline in mixed meal tolerance test (MMTT) stimulated 2-h plasma C-peptide area under the curve (AUC). Secondary endpoints included metabolic measures and pharmacokinetics of albiglutide. RESULTS: 12/17 (70.6%, placebo) and 40/50 (80.0%, albiglutide) patients completed the study. Within our study, mean (standard deviation) change from baseline to week 52 in MMTT-stimulated 2-h plasma C-peptide AUC was -0.16 nmol/L (0.366) with placebo and -0.13 nmol/L (0.244) with albiglutide. For the primary Bayesian analysis (including prior study data) the posterior treatment difference (95% credible interval) was estimated at 0.12 nmol/L (0-0.24); the probability of a difference ≥0.2 nmol/L between treatments was low (0.097). A transient significant difference in maximum C-peptide was seen at week 28. Otherwise, no significant secondary endpoint differences were noted. On-therapy adverse events were reported in 82.0% (albiglutide) and 76.5% (placebo) of patients. CONCLUSION: In newly diagnosed patients with type 1 diabetes, albiglutide 30 to 50 mg weekly for 1 year had no appreciable effect on preserving residual ß-cell function versus placebo.
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Biomarcadores/análisis , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Péptido 1 Similar al Glucagón/análogos & derivados , Incretinas/uso terapéutico , Adolescente , Adulto , Glucemia/análisis , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patología , Femenino , Estudios de Seguimiento , Péptido 1 Similar al Glucagón/uso terapéutico , Humanos , Masculino , Pronóstico , Adulto JovenRESUMEN
A meta-analysis of cardiovascular outcome trials (CVOTs) comparing glucagon-like peptide-1 receptor agonists (GLP-1RAs) and placebo concerning cardiorenal outcomes in patients with type 2 diabetes (T2D) is presented. An electronic search without language restrictions up to June 15, 2019 was conducted to determine eligible trials. A meta-analysis of available trial data was undertaken, using a random-effects model to calculate overall hazard ratios (HRs) and 95% confidence intervals (CIs). Data from seven CVOTs, comprising 56 004 patients (68.9% with established cardiovascular disease) were included. GLP-1RA reduced major cardiovascular events (MACE) by 13% (HR, 0.87; 95% CI, 0.80-0.96; P = 0.011) with a non-significant heterogeneity between subgroups of patients with and without cardiovascular disease (CVD) (P = 0.220). GLP-1RA also reduced the risk of cardiovascular death by 12%, of non-fatal stroke by 16%, of hospitalization for heart failure by 9%, of all-cause mortality by 11%, and the broad composite kidney outcome by 17%; the latter appeared to be driven only by a reduction in macroalbuminuria (HR, 0.76 [0.68-0.86]; P = 0.003). GLP-1RAs have moderate benefits concerning MACE, and also reduce hospitalization for heart failure and all-cause mortality; they also robustly reduce the incidence of macroalbuminuria, without affecting the progression of diabetic renal disease.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Cardiomiopatías Diabéticas/prevención & control , Nefropatías Diabéticas/prevención & control , Receptor del Péptido 1 Similar al Glucagón/agonistas , Hipoglucemiantes/uso terapéutico , Humanos , Resultado del TratamientoRESUMEN
Diabetic kidney disease (DKD) still remains a progressive condition that is associated with higher risk of end-stage kidney disease and significant cardiovascular morbidity and mortality. Twelve cardiovascular outcome trials in type 2 diabetes (T2D) have been published to date. Most trials with dipeptidyl-peptidase inhibitors (SAVOR-TIMI 53 with saxagliptin, EXAMINE with alogliptin, TECOS with sitagliptin, and CARMELINA with linagliptin) and with glucagon-like peptide-1 receptor agonists (GLP-1RAs) (ELIXA with lixisenatide, LEADER with liraglutide, SUSTAIN-6 with semaglutide, EXCSEL with exenatide once-weekly, and HARMONY with albiglutide) pointed towards reduced albuminuria, which is a surrogate endpoint possibly heralding renal function preservation. The three trials with sodium-glucose co-transporter-2 inhibitors (SGLT-2is) (empagliflozin, canagliflozin and dapagliflozin) also showed a salutary effect on long-term estimated glomerular filtration rate, suggesting that SGLT-2is are more effective at mitigating loss of kidney function than incretin-based therapies; moreover, SGLT-2is also have the advantage of plausible haemodynamic mechanisms for improved renal outcomes. Despite some residual limitations linked to differences in study populations and patient characteristics, the cardiorenal protective actions of SGLT-2is, and to a lesser extent some GLP-1RAs, make them favourable medications for patients with T2D at increased cardiorenal risk. There is room for optimism that their use may change the paradigm of the ineluctable progression of DKD.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Angiopatías Diabéticas/prevención & control , Nefropatías Diabéticas/prevención & control , Hipoglucemiantes/uso terapéutico , Ensayos Clínicos como Asunto , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Angiopatías Diabéticas/etiología , Nefropatías Diabéticas/etiología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Tasa de Filtración Glomerular/efectos de los fármacos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Humanos , Incretinas/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Resultado del TratamientoRESUMEN
AIMS: Compare the efficacy and safety of albiglutide from a ready-to-use, single-dose, auto-injector system with the lyophilized product in patients with type 2 diabetes mellitus (T2DM). METHODS: In this phase 3 study, 308 patients between 18 and 80â¯years with T2DM and experiencing inadequate glycemic control on their current regimen of diet/exercise alone or in combination with metformin were randomized 1:1 to weekly injections for 26â¯weeks with an active albiglutide auto-injector and placebo lyophilized dual-chamber cartridge (DCC) pen injector (nâ¯=â¯154) or active albiglutide lyophilized DCC pen injector and placebo liquid auto-injector (nâ¯=â¯154). Participants received liquid or lyophilized albiglutide 30â¯mg for 4â¯weeks, and then 50â¯mg for the remaining 22â¯weeks. Change in HbA1c and fasting plasma glucose (FPG), pharmacokinetics, and safety were assessed. RESULTS: In the albiglutide liquid and lyophilized drug product groups, 55.6% (85/153) and 45.5% of patients (70/154) had a baseline HbA1câ¯≥â¯8.0%, respectively. The model-adjusted least squares (LS) mean change in HbA1c from baseline at week 26 was -1.1% (95% CI: -1.3, -1.0) and -1.2% (95% CI: -1.3, -1.0; noninferiority Pâ¯=â¯0.0002) in the albiglutide liquid and lyophilized product groups, respectively. Similarly, the model-adjusted LS mean change in FPG from baseline at week 26 in the albiglutide liquid and lyophilized product groups was -2.2 (95% CI: -2.6, -1.8) mmol/L and -1.9 (95% CI: -2.3, -1.5) mmol/L, respectively. No new safety concerns were identified. CONCLUSION: Change from baseline in HbA1c for albiglutide liquid was noninferior to lyophilized drug product in patients with T2DM.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptido 1 Similar al Glucagón/análogos & derivados , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Composición de Medicamentos , Femenino , Liofilización , Péptido 1 Similar al Glucagón/administración & dosificación , Péptido 1 Similar al Glucagón/efectos adversos , Hemoglobina Glucada/análisis , Hemoglobina Glucada/efectos de los fármacos , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Masculino , Metformina/administración & dosificación , Metformina/efectos adversos , Persona de Mediana Edad , Soluciones , Resultado del Tratamiento , Adulto JovenRESUMEN
An excess risk of heart failure (HF) persists in patients with type 2 diabetes (T2D) despite optimal control of an array of conventional risk factors, including hyperglycaemia. Twelve cardiovascular outcome trials (CVOTs) have been published to date, although none, with the exception of the DECLARE trial with dapagliflozin, has included HF as a primary endpoint. The four trials with dipeptidyl-peptidase inhibitors (DPP-4i) (SAVOR-TIMI 53 with saxagliptin, EXAMINE with alogliptin, TECOS with sitagliptin and CARMELINA with linagliptin) failed to show any significant effect on HF risk in patients with T2D, with the notable exception of saxagliptin which was associated with a 27% increased risk. Five completed CVOTs with the GLP-1 RAs lixisenatide (ELIXA), liraglutide (LEADER), semaglutide (SUSTAIN-6), exenatide once weekly (EXSCEL) and albiglutide (HARMONY) also failed to reveal any significant effect on HF risk. The three trials with sodium glucose co-transporter-2 inhibitors (SGLT-2i) (EMPA-REG OUTCOME with empagliflozin, CANVAS with canagliflozin and DECLARE with dapagliflozin) all revealed a robust and significant reduction in the hazard ratios of hospitalization for HF, from 27% to 35%, which remained consistent, significant and of similar magnitude regardless of the presence of a history of HF or established atherosclerotic cardiovascular disease. There is no association between reductions in HF risk and haemoglobin A1c (A1C) levels, while there is a significant association between reductions in HR for MACE and A1C levels (Spearman's correlation, r = 0.695; P = 0.013). All of the 12 CVOTs completed to date have provided reassurance of the overall cardiovascular safety of the newer anti-hyperglycaemic drugs. At present, the robust, consistent and reproducible reduction of approximately 30% in the risk of HF with SGLT-2i may be considered a class effect. The beneficial effect on MACE outcome observed with the use of some GLP-1RAs and SGLT-2i must be interpreted within the frame of the single trial.
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Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/terapia , Angiopatías Diabéticas/epidemiología , Insuficiencia Cardíaca/etiología , Ensayos Clínicos como Asunto/estadística & datos numéricos , Diabetes Mellitus Tipo 2/epidemiología , Angiopatías Diabéticas/etiología , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/prevención & control , Humanos , Factores de Riesgo , Resultado del TratamientoRESUMEN
Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are an important class of drugs with a well-established efficacy and safety profile in patients with type 2 diabetes mellitus. Agents in this class are derived from either exendin-4 (a compound present in Gila monster venom) or modifications of human GLP-1 active fragment. Differences among these drugs in duration of action (ie, short-acting vs long-acting), effects on glycaemic control and weight loss, immunogenicity, tolerability profiles, and administration routes offer physicians several options when selecting the most appropriate agent for individual patients. Patient preference is also an important consideration. The aim of this review is to discuss the differences between and similarities of GLP-1 RAs currently approved for clinical use, focusing particularly on the properties characterising the single short-acting and long-acting GLP-1 RAs rather than on their individual efficacy and safety profiles. The primary pharmacodynamic difference between short-acting (ie, exenatide twice daily and lixisenatide) and long-acting (ie, albiglutide, dulaglutide, exenatide once weekly, liraglutide, and semaglutide) GLP-1 RAs is that short-acting agents primarily delay gastric emptying (lowering postprandial glucose) and long-acting agents affect both fasting glucose (via enhanced glucose-dependent insulin secretion and reduced glucagon secretion in the fasting state) and postprandial glucose (via enhanced postprandial insulin secretion and inhibition of glucagon secretion). Other advantages of long-acting GLP-1 RAs include smaller fluctuations in plasma drug concentrations, improved gastrointestinal tolerability profiles, and simpler, more convenient administration schedules (once daily for liraglutide and once weekly for albiglutide, dulaglutide, the long-acting exenatide formulation, and semaglutide), which might improve treatment adherence and persistence.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Hipoglucemiantes/uso terapéutico , Exenatida/uso terapéutico , Péptido 1 Similar al Glucagón/análogos & derivados , Péptido 1 Similar al Glucagón/uso terapéutico , Péptidos Similares al Glucagón/análogos & derivados , Péptidos Similares al Glucagón/uso terapéutico , Humanos , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Resultado del TratamientoRESUMEN
Abextide, synthesized by conjugating an albumin-binding moiety-truncated Evans blue-to glucagon-like peptide 1 receptor (GLP-1R) agonist exendin-4, shows extended drug release and enhanced hypoglycemic effect in diabetic mice. The aim of this study is to evaluate the pharmacodynamics of Abextide in nonhuman primates. Two batches of elderly cynomolgus monkeys with naturally occurring diabetes are used for this study. During the whole experiment period, no abnormalities such as swelling at the injection site, lethargy, or hypoglycemia are observed in all animals. The monkeys in the Abextide group lose appetite after drug administration and then recover over time. In the single dose treatment, at day 1 and day 3 after treatment, decreased plasma glucose level is observed in the Abextide-treated group but not in placebo or Albiglutide-treated group. For monkeys that receive two doses of drug, the blood glucose level in all subjects in Abextide group decreases rapidly upon drug administration and return to a plateau by day 3. A similar pattern of response is seen after the second dose administration. The delayed drug release and hypoglycemic effect of Abextide make it potentially useful as an antidiabetic drug for weekly subcutaneous administration.
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Exenatida/análogos & derivados , Exenatida/farmacología , Hipoglucemiantes/farmacología , Naftalenosulfonatos/farmacología , Péptidos/farmacología , Animales , Peso Corporal/efectos de los fármacos , Colesterol/sangre , Relación Dosis-Respuesta a Droga , Conducta Alimentaria/efectos de los fármacos , Péptido 1 Similar al Glucagón/análogos & derivados , Péptido 1 Similar al Glucagón/farmacología , Insulina/sangre , Lípidos/sangre , Lipoproteínas HDL/sangre , Macaca fascicularis , Triglicéridos/sangreRESUMEN
Albiglutide, developed for treatment of type 2 diabetes mellitus, is provided in a dual-chamber cartridge (DCC) single-dose pen-injector containing lyophilized drug that must be reconstituted with diluent prior to use. A liquid formulation of albiglutide has been developed that does not require mixing. In this 2-period, randomized, crossover, double-blind, phase I study (NCT02660736) in 59 healthy volunteers, pharmacokinetic parameters were determined and the bioequivalence of the 2 formulations was assessed. Participants received injections from each type of pen-injector, one containing albiglutide 50 mg and one containing placebo, followed by an 8-week washout period between regimens: albiglutide 50-mg liquid formulation from an auto-injector and lyophilized placebo from a DCC pen-injector (Regimen A), or placebo liquid from an auto-injector and lyophilized albiglutide 50 mg from a DCC pen-injector (Regimen B). Geometric mean total exposures (area under the drug concentration-time curve [AUC](0-t) [1345.4 vs 1426.9 (µg · h/mL)], AUC(0-∞) [1376.2 vs 1454.6 (µg · h/mL)], and maximum concentration of drug in blood plasma [4968.5 vs 5314.7 ng/mL]) were comparable between Regimens A and B. Ratios of geometric least square means (90% confidence interval) were 95.3% (89.49-101.52) for AUC(0-∞) , 95.1% (89.12-101.49) for AUC(0-t) , and 93.2% (86.76-100.17) for maximum concentration of drug in blood plasma, falling within the 90% confidence interval of 0.80 to 1.25 for bioequivalence. No new safety concerns were observed.
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Péptido 1 Similar al Glucagón/análogos & derivados , Hipoglucemiantes/sangre , Adolescente , Adulto , Anciano , Anticuerpos Neutralizantes/sangre , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Método Doble Ciego , Sistemas de Liberación de Medicamentos/instrumentación , Sistemas de Liberación de Medicamentos/métodos , Femenino , Péptido 1 Similar al Glucagón/administración & dosificación , Péptido 1 Similar al Glucagón/efectos adversos , Péptido 1 Similar al Glucagón/sangre , Semivida , Voluntarios Sanos , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Inmunoglobulina E/sangre , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
PURPOSE OF REVIEW: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have positive effects on weight loss, blood pressure, hyperlipidemia, and glycemic control. They exhibit a broad range of effects on the cardiovascular system that are independent of changes in blood glucose. Cardiovascular outcome trials have demonstrated safety of GLP-1 RAs but results for cardiovascular efficacy were varied. The aim of the present review is the assessment of the effects of GLP-1 RAs on cardiovascular risk factors, and major cardiovascular events. RECENT FINDINGS: Use of GLP-1 RAs was associated with relative risk reduction in cardiovascular mortality and all-cause mortality with no significant differences for the incidence of severe hypoglycemia, pancreatitis, pancreatic cancer, or medullary thyroid cancer when compared to placebo. Although there are differences between individual medications with respect to their effects on cardiovascular events, GLP-1 RAs offer a favorable risk-benefit profile. The present review confirms the cardiovascular safety and efficacy vs placebo of GLP-1 RAs in patients with type 2 diabetes at moderate-to-high atherosclerotic cardiovascular risk without significant side effects. Although professional guidelines recommend metformin as the sole first-line agent, GLP-1 RAs can be used as first-line therapy in individuals with type 2 diabetes who either are intolerant to metformin or have high cardiovascular risk factors.
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Sistema Cardiovascular/patología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Biomarcadores/metabolismo , Presión Sanguínea , Diabetes Mellitus Tipo 2/fisiopatología , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Humanos , Factores de RiesgoRESUMEN
Albiglutide is a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist administered by weekly injection. Albiglutide-treated patients experience incidences of adverse effects, including cardiovascular, renal, and gastrointestinal symptoms and injection-site reactions. We report the first case of generalized edema induced by albiglutide. We present a 35-year-old female with type-2 diabetes. She developed generalized edema after the start of albiglutide. Her physical examination and all the laboratory tests, including thyroid function tests, albumin level test, and renal function test were unremarkable, and did not explain her generalized edema. Later on, her albiglutide was discontinued, which lead to the resolution of her edema. We conclude that her generalized edema could be due to a possible side effect of albiglutide.
RESUMEN
OBJECTIVE: to evaluate the efficacy and safety of albiglutide compared with placebo and active comparators from an integrated trial subpopulation of Latino/Hispanic patients whose type 2 diabetes mellitus (T2DM) was inadequately controlled on their current regimen of diet and exercise, with or without oral antidiabetic drugs (OADs) and/or insulin. METHODS: Latino/Hispanic patient subpopulations (N = 1204) across 7 phase III albiglutide studies (N = 4400) were evaluated post-hoc for efficacy and safety. Comparators were placebo, sulfonylureas, insulin, thiazolidinediones, and dipeptidyl peptidase-4 inhibitors. Glycatedhemoglobin (HbA1c) change from baseline to the time of the primary endpoint assessment (from 26 to 104 weeks) was evaluated in patients on diet and exercise and/or OADs, with or without insulin. Patients were allowed to continue in the study if hyperglycemic rescue was required, according to a prespecified algorithm and at the discretion of the investigator. RESULTS: At baseline in the Latino/Hispanic subpopulation, the mean HbA1c was 8.3%, mean age was 53 years, mean body mass index was 32 kg/m2, and mean duration of T2DM was 8.0 years. The primary endpoint of mean HbA1c difference (albiglutide - placebo) was -0.94% for the Latino/Hispanic subpopulation and -0.86% (p < 0.001) for the overall phase III population. Changes in fasting plasma glucose mirrored those of HbA1c. Weight loss with albiglutide was numerically greater than with OADs and insulin in both populations, but it was smaller than with liraglutide. Within the Latino/Hispanic subpopulation, more injection-site reactions were reported with albiglutide vs all comparators, while gastrointestinal and hypoglycemic adverse events were comparable between the two groups, and the latter was uncommon when used without insulin and/or a sulfonylurea. CONCLUSIONS: In the Latino/Hispanic population, albiglutide resulted in effective lowering of glucose and modest weight loss, and it was generally well tolerated.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptido 1 Similar al Glucagón/análogos & derivados , Hispánicos o Latinos , Hipoglucemiantes/uso terapéutico , Adulto , Anciano , Glucemia , Índice de Masa Corporal , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Método Doble Ciego , Quimioterapia Combinada , Femenino , Péptido 1 Similar al Glucagón/administración & dosificación , Péptido 1 Similar al Glucagón/efectos adversos , Péptido 1 Similar al Glucagón/uso terapéutico , Hemoglobina Glucada , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Insulina/uso terapéutico , Masculino , Persona de Mediana Edad , Compuestos de Sulfonilurea/uso terapéutico , Tiazolidinedionas/uso terapéutico , Pérdida de PesoRESUMEN
BACKGROUND: It is estimated that 29.1 million people or 9.3% of the US population have diabetes, which contributes to considerable medical and financial burden. Type 2 diabetes mellitus is characterized by insulin resistance and insulin secretion impairment leading to hyperglycemia. The presence of insulin resistance is strongly correlated with obesity. OBJECTIVE: This article reviews the available glucagon-like peptide-1 (GLP-1) receptor agonists and their role in the management of patients with diabetes, to help guide the selection of the most suitable agent for the individualized treatment of patients with type 2 diabetes. DISCUSSION: This article reviews the evidence from phase 3 clinical trials for each of the 5 GLP-1 receptor agonists by comparing them against one another and with other existing therapies, including metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sulfonylureas. Incretin-based therapies have emerged as attractive agents for the treatment of type 2 diabetes. They target the GLP-1 hormone, which is partly responsible for insulin release and for attenuating hyperglycemia during meals (ie, the incretin effect). The 2 classes of incretin-based therapy currently available are GLP-1 receptor agonists and DPP-4 inhibitors, which prevent the breakdown of GLP-1. Both classes are attractive options, given their glucose-lowering effects without the adverse effects of hypoglycemia and weight gain. The different mechanisms of action of these therapies result in generally greater efficacy with GLP-1 receptor agonists, albeit at the expense of slightly increased gastrointestinal symptoms. These agents exert their effects by improving glucose-dependent insulin release, suppressing glucagon release, suppressing hepatic glucose output, and decreasing the rate of gastric emptying, thereby reducing appetite. Currently, 5 GLP-1 receptor agonists are available, including exenatide, liraglutide, albiglutide, dulaglutide, and lixisenatide; semaglutide may soon become available as the newest agent. With the exception of the investigational oral semaglutide, which has shown promising results, the other 5 agents are administered as subcutaneous injections, at different dosing intervals. CONCLUSION: Currently, 5 GLP-1 receptor agonists are available for use in the United States. Although they are all in the same drug class, some significant differences exist among the various GLP-1 receptor agonists. The choice of a specific GLP-1 receptor agonist will depend on the patient preferences, potential adverse effects, and cost.