RESUMEN
By applying morphological and molecular data on two genera of the nudibranch molluscs it is shown that the tension between taxonomic practice and evolutionary processes persists. A review of the related genera Catriona and Tenellia is used to demonstrate that the fine-scale taxonomic differentiation is an important tool in the integration of morphological and molecular data. This is highlighted by the hidden species problem and provides strong argument that the genus must be kept as a maximally narrowly-defined entity. Otherwise, we are forced to compare a highly disparate species under the putatively lumped name "Tenellia". We demonstrate this in the present study by applying a suite of delimitation methods and describing a new species of Tenellia from the Baltic Sea. The new species possesses fine-scale morphological distinguishing features, which were not investigated before. The true, narrowly defined genus Tenellia represents a peculiar taxon with a clearly expressed paedomorphic characters and predominantly brackish-water habitats. The phylogenetically related genus Catriona, of which three new species are described here, clearly demonstrates different features. A lumping decision to call many morphologically and evolutionary different taxa as "Tenellia" will downgrade the taxonomic and phylogenetic resolution of the entire family Trinchesiidae to just a single genus. The dissolution of the dilemma of "lumpers & splitters", which still significantly affects taxonomy, will further help to make systematics a true evolutionary discipline.
RESUMEN
Using the nudibranch genus Amphorina as a model, ongoing speciation is demonstrated, as well as how periodic-like patterns in colouration can be included in an integrated method of fine-scale species delimitation. By combining several methods, including BPP analysis and the study of molecular, morphological, and ecological data from a large number of specimens within a broad geographic range from northern Europe to the Mediterranean, five species are recognised within the genus Amphorina, reviewed here for the first time. Two new species from the southwestern coast of Sweden are described, A. viriola sp. nov. and A. andra sp. nov. Evidence is provided of a recent speciation process between the two closely related, yet separate, species which inhabit the same geographic localities but demonstrate strict water depth differentiation, with one species inhabiting the shallow brackish top layer above the halocline and the other species inhabiting the underlying saltier water. The results presented here are of relevance for currently debated issues such as conservation in relation to speciation, fine species delimitation, and integration of molecular, morphological and ecological information in biodiversity studies. The periodic approach to biological taxonomy has considerable practical potential for various organismal groups.
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Paedomorphosis is an important evolutionary force. It has previously been suggested that a soft-substrate sediment-dwelling (infaunal) environment facilitates paedomorphic evolution in marine invertebrates. However, until recently this proposal was never rigorously tested with robust phylogeny and broad taxon selection. Here, for the first time, we present a molecular phylogeny for a majority of the 21 families of one of the largest nudibranch subgroups (Aeolidacea) and show that the externally highly simplified vermiform nudibranch family, Pseudovermidae, with clearly defined paedomorphic traits and inhabiting a soft-substrata environment, is a sister group to the complex nudibranch family, Cumanotidae. We also report the rediscovery of one of the most enigmatic nudibranchs-Xenocratena suecica-on the Swedish and Norwegian coasts 70 years after it was first found. Xenocratena was described from the same location and environment in the Swedish Gullmar fjord as one of the most enigmatic vermiform organisms, Xenoturbella bocki, which represents either an original simple bilaterian body plan or secondary simplification of a more complex organisation. Our results show that Xenocratena suecica reveals an onset of parallel paedomorphic evolution so we have proposed the new family, Xenocratenidae fam. n., to accommodate the molecular and morphological disparities we discovered. The paedomorphic origin of another aeolidacean family, Embletoniidae, is also demonstrated for the first time. Thus, by presenting three independent lineages from non-closely related aeolidacean families, Xenocratenidae fam. n., Cumanotidae and Embletoniidae, we confirm with phylogenetic data that a soft-substrata burrowing-related environment strongly favours paedomorphic evolution. We suggest criteria to distinguish ancestral and derived characters in the context of modifications of ontogenetic cycles. Applying an evolutionary model of the soft substrate-driven multiple paedomorphic origin of several families of nudibranch molluscs we propose that it is plausible to extend this model to other marine invertebrates and suggest that the ancestral organisation of the enigmatic metazoan, Xenoturbella, might correspond to the larval part of a complex ancestral bilaterian ontogenetic cycle with sedentary/semi-sedentary adult stages and planula-like larval stages.
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Evolución Biológica , Gastrópodos/clasificación , Gastrópodos/genética , Larva , Filogenia , Animales , Regiones Árticas , Teorema de Bayes , ADN Ribosómico/genética , Gastrópodos/anatomía & histología , Cadenas de Markov , Océanos y Mares , Reacción en Cadena de la PolimerasaRESUMEN
'Cryptic' species are an emerging biological problem that is broadly discussed in the present study. Recently, a cryptic species definition was suggested for those species which manifest low morphological, but considerable genetic, disparity. As a case study we present unique material from a charismatic group of nudibranch molluscs of the genus Trinchesia from European waters to reveal three new species and demonstrate that they show a dual nature: on one hand, they can be considered a 'cryptic' species complex due to their overall similarity, but on the other hand, stable morphological differences as well as molecular differences are demonstrated for every species in that complex. Thus, this species complex can equally be named 'cryptic', 'pseudocryptic' or 'non-cryptic'. We also present evidence for an extremely rapid speciation rate in this species complex and link the species problem with epigenetics. Available metazoan-wide data, which are broadly discussed in the present study, show the unsuitability of a 'cryptic' species concept because the degree of crypticity represents a continuum when a finer multilevel morphological and molecular scale is applied to uncover more narrowly defined species making the 'cryptic' addition to 'species' redundant. Morphological and molecular methods should be applied in concordance to form a fine-scale multilevel taxonomic framework, and not necessarily implying only an a posteriori transformation of exclusively molecular-based 'cryptic' species into morphologically-defined 'pseudocryptic' ones. Implications of the present study have importance for many fields, including conservation biology and fine-scale biodiversity assessments.
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Biodiversidad , Gastrópodos/clasificación , Gastrópodos/genética , Especiación Genética , Animales , Gastrópodos/anatomía & histología , Gastrópodos/ultraestructura , Variación Genética , Filogenia , Especificidad de la EspecieRESUMEN
OBJECTIVE: In observational cohorts, adiponectin is inversely associated and free fatty acids (FFAs) are directly associated with incident coronary heart disease (CHD). Adiponectin tends to be reduced and FFAs elevated in type 2 diabetes. We investigated relationships of adiponectin and FFA and major adverse cardiovascular events (MACEs) and death in patients with acute coronary syndrome (ACS) and type 2 diabetes using data from the AleCardio (Effect of Aleglitazar on Cardiovascular Outcomes After Acute Coronary Syndrome in Patients With Type 2 Diabetes Mellitus) trial, which compared the PPAR-α/γ agonist aleglitazar with placebo. RESEARCH DESIGN AND METHODS: Using Cox regression adjusted for demographic, laboratory, and treatment variables, we determined associations of baseline adiponectin and FFAs, or the change in adiponectin and FFAs from baseline, with MACEs (cardiovascular death, myocardial infarction, or stroke) and death. RESULTS: A twofold higher baseline adiponectin (n = 6,998) was directly associated with risk of MACEs (hazard ratio [HR] 1.17 [95% CI 1.08-1.27]) and death (HR 1.53 [95% CI 1.35-1.73]). A doubling of adiponectin from baseline to month 3 (n = 6,325) was also associated with risk of death (HR 1.20 [95% CI 1.03-1.41]). Baseline FFAs (n = 7,038), but not change in FFAs from baseline (n = 6,365), were directly associated with greater risk of MACEs and death. There were no interactions with study treatment. CONCLUSIONS: In contrast to prior observational data for incident CHD, adiponectin is prospectively associated with MACEs and death in patients with type 2 diabetes and ACS, and an increase in adiponectin from baseline is directly related to death. These findings raise the possibility that adiponectin has different effects in patients with type 2 diabetes and ACS than in populations without prevalent cardiovascular disease. Consistent with prior data, FFAs are directly associated with adverse outcomes.
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Síndrome Coronario Agudo/tratamiento farmacológico , Adiponectina/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Angiopatías Diabéticas/tratamiento farmacológico , Ácidos Grasos no Esterificados/sangre , Oxazoles/uso terapéutico , Tiofenos/uso terapéutico , Síndrome Coronario Agudo/complicaciones , Síndrome Coronario Agudo/epidemiología , Anciano , Enfermedad Coronaria/complicaciones , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Angiopatías Diabéticas/sangre , Angiopatías Diabéticas/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/complicaciones , Infarto del Miocardio/epidemiología , Estudios Retrospectivos , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/epidemiología , Resultado del TratamientoRESUMEN
Objective: Insulin resistance has been linked to development and progression of atherosclerosis and is present in most patients with type 2 diabetes. Whether the degree of insulin resistance predicts adverse outcomes in patients with type 2 diabetes and acute coronary syndrome (ACS) is uncertain. Design: The Effect of Aleglitazar on Cardiovascular Outcomes after Acute Coronary Syndrome in Patients with Type 2 Diabetes Mellitus trial compared the peroxisome proliferator-activated receptor-α/γ agonist aleglitazar with placebo in patients with type 2 diabetes and recent ACS. In participants not treated with insulin, we determined whether baseline homeostasis model assessment of insulin resistance (HOMA-IR; n = 4303) or the change in HOMA-IR on assigned study treatment (n = 3568) was related to the risk of death or major adverse cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in unadjusted and adjusted models. Because an inverse association of HOMA-IR with N-terminal pro-B-type natriuretic peptide (NT-proBNP) has been described, we specifically examined effects of adjustment for the latter. Results: In unadjusted analysis, twofold higher baseline HOMA-IR was associated with lower risk of death [hazard ratio (HR): 0.79, 95% CI: 0.68 to 0.91, P = 0.002]. Adjustment for 24 standard demographic and clinical variables had minimal effect on this association. However, after further adjustment for NT-proBNP, the association of HOMA-IR with death was no longer present (adjusted HR: 0.99, 95% CI: 0.83 to 1.19, P = 0.94). Baseline HOMA-IR was not associated with major adverse cardiovascular events, nor was the change in HOMA-IR on study treatment associated with death or major adverse cardiovascular events. Conclusions: After accounting for levels of NT-proBNP, insulin resistance assessed by HOMA-IR is not related to the risk of death or major adverse cardiovascular events in patients with type 2 diabetes and ACS.
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Síndrome Coronario Agudo/mortalidad , Diabetes Mellitus Tipo 2/mortalidad , Resistencia a la Insulina , Medición de Riesgo/métodos , Síndrome Coronario Agudo/etiología , Síndrome Coronario Agudo/fisiopatología , Anciano , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Homeostasis , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico/sangre , Oxazoles/uso terapéutico , Fragmentos de Péptidos/sangre , Modelos de Riesgos Proporcionales , Factores de Riesgo , Análisis de Supervivencia , Tiofenos/uso terapéuticoRESUMEN
A unique example of brackish water fjord-related diversification of a new nudibranch genus and species Bohuslania matsmichaeli gen. n., sp. n. is presented. There are only few previously known brackish-water opisthobranchs and B. matsmichaeli gen. n., sp. n. is the first ever described brackish-water nudibranch with such an extremely limited known geographical range and apparently strict adherence to salinity levels lower than 20 per mille. Up to date the new taxon has been found only in a very restricted area in the Idefjord, bordering Sweden and Norway, but not in any other apparently suitable localities along the Swedish and Norwegian coasts. We also show in this study for the first time the molecular phylogenetic sister relationship between the newly discovered genus Bohuslania and the genus Cuthona. This supports the validity of the family Cuthonidae, which was re-established recently. Furthermore, it contributes to the understanding of the evolutionary patterns and classification of the whole group Nudibranchia. Molecular and morphological data indicate that brackish water speciation was triggered by paedomorphic evolution among aeolidacean nudibranchs at least two times independently. Thus, the present discovery of this new nudibranch genus contributes to several biological fields, including integration of molecular and morphological data as well as phylogenetic and biogeographical patterns.
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Evolución Biológica , Gastrópodos/anatomía & histología , Gastrópodos/clasificación , Gastrópodos/fisiología , Filogenia , Salinidad , Animales , Noruega , Filogeografía , SueciaRESUMEN
AIM: To define the predictors of long-term mortality in patients with type 2 diabetes mellitus and recent acute coronary syndrome. METHODS AND RESULTS: A total of 7226 patients from a randomized trial, testing the effect on cardiovascular outcomes of the dual peroxisome proliferator-activated receptor agonist aleglitazar in patients with type 2 diabetes mellitus and recent acute coronary syndrome (AleCardio trial), were analysed. Median follow-up was 2 years. The independent mortality predictors were defined using Cox regression analysis. The predictive information provided by each variable was calculated as percent of total chi-square of the model. All-cause mortality was 4.0%, with cardiovascular death contributing for 73% of mortality. The mortality prediction model included N-terminal proB-type natriuretic peptide (adjusted hazard ratio = 1.68; 95% confidence interval = 1.51-1.88; 27% of prediction), lack of coronary revascularization (hazard ratio = 2.28; 95% confidence interval = 1.77-2.93; 18% of prediction), age (hazard ratio = 1.04; 95% confidence interval = 1.02-1.05; 15% of prediction), heart rate (hazard ratio = 1.02; 95% confidence interval = 1.01-1.03; 10% of prediction), glycated haemoglobin (hazard ratio = 1.11; 95% confidence interval = 1.03-1.19; 8% of prediction), haemoglobin (hazard ratio = 1.01; 95% confidence interval = 1.00-1.02; 8% of prediction), prior coronary artery bypass (hazard ratio = 1.61; 95% confidence interval = 1.11-2.32; 7% of prediction) and prior myocardial infarction (hazard ratio = 1.40; 95% confidence interval = 1.05-1.87; 6% of prediction). CONCLUSION: In patients with type 2 diabetes mellitus and recent acute coronary syndrome, mortality prediction is largely dominated by markers of cardiac, rather than metabolic, dysfunction.
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Síndrome Coronario Agudo/mortalidad , Diabetes Mellitus Tipo 2/mortalidad , Síndrome Coronario Agudo/sangre , Síndrome Coronario Agudo/diagnóstico , Síndrome Coronario Agudo/terapia , Anciano , Biomarcadores/sangre , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Distribución de Chi-Cuadrado , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Método Doble Ciego , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemiantes/uso terapéutico , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Revascularización Miocárdica , Péptido Natriurético Encefálico/sangre , Oxazoles/uso terapéutico , Fragmentos de Péptidos/sangre , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Medición de Riesgo , Factores de Riesgo , Tiofenos/uso terapéutico , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVE: Adiponectin and leptin are associated with insulin resistance and cardiovascular disease. Information on the prognostic value after an acute myocardial infarction is still conflicting. METHODS: Patients (n = 180) without known diabetes and with admission glucose of <11 mmol/L admitted for an acute myocardial infarction in 1998-2000 were followed for mortality and cardiovascular events (first of cardiovascular mortality/acute myocardial infarction/stroke/heart failure) until the end of 2011 (median: 11.6 years). Plasma adiponectin and leptin were related to outcome in Cox proportional-hazard regression analyses. RESULTS: Median age was 64 years and 69% were male. Total mortality was 34% (n = 61) and 44% (n = 80) experienced a cardiovascular event. Adiponectin at discharge predicted cardiovascular events (hazard ratio; 95% confidence interval; 1.45; 1.02-2.07, p = 0.038), total mortality (2.53; 1.64-3.91, p < 0.001) and cancer mortality (3.64; 1.51-8.74, p = 0.004). After adjustment for age, sex, body mass index, previous myocardial infarction and heart failure, adiponectin predicted total mortality (1.79; 1.07-3.00, p = 0.027) but not cardiovascular events. High levels of leptin were associated with cardiovascular events during the first 7 years, after which the association was attenuated. Leptin did not predict total mortality. CONCLUSION: In patients with acute myocardial infarction but without previously known diabetes, high levels of adiponectin at discharge predicted total mortality. The present results support the hypothesis that high rather than low levels of adiponectin predict mortality after acute myocardial infarction.
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Adiponectina/sangre , Glucemia/metabolismo , Intolerancia a la Glucosa/sangre , Leptina/sangre , Infarto del Miocardio/sangre , Anciano , Biomarcadores/sangre , Causas de Muerte , Distribución de Chi-Cuadrado , Femenino , Intolerancia a la Glucosa/diagnóstico , Intolerancia a la Glucosa/mortalidad , Humanos , Resistencia a la Insulina , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/mortalidad , Oportunidad Relativa , Alta del Paciente , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Factores de Riesgo , Suecia , Factores de TiempoRESUMEN
BACKGROUND: Insulin-resistant states, including type 2 diabetes (T2D) and prediabetes, are associated with elevated cardiovascular (CV) risk. Aleglitazar is a dual peroxisome proliferator-activated receptor α/γ agonist with favorable insulin-sensitizing and glucose-lowering actions, favorable effects on blood lipids, and an acceptable safety profile in short-time studies. Therefore, it was hypothesized that aleglitazar would reduce CV morbidity and mortality in patients with T2D mellitus and prediabetes (defined as glycosylated hemoglobin ≥5.7% to <6.5%) with previous CV complications. STUDY DESIGN: ALEPREVENT was a phase III, multicenter, randomized, double-blind, trial comparing aleglitazar 150 µg or placebo daily in patients with T2D or prediabetes with established, stable CV disease. The intended sample size was 19,000 with a primary efficacy measure of major adverse CV events. However, the trial was halted prematurely after 1,999 patients had been randomized because of futility and an unfavorable benefit risk ratio in another CV outcomes trial evaluating aleglitazar. RESULTS: At study termination after 58 ± 38 days of treatment, data had been collected from 1,996 patients (1,581 with T2D and 415 with pre-T2D). Despite the brief duration of treatment, aleglitazar induced favorable changes in glycosylated hemoglobin and blood lipids, similar for participants with T2D or prediabetes. However, compared with placebo, aleglitazar increased the incidence of hypoglycemia (86 vs 166; P < .0001), and muscular events (3 vs12; P = .012). CONCLUSIONS: Even within a short duration of exposure, aleglitazar was associated with excess adverse events, corroborating the findings of a larger and longer trial in T2D. Coupled with the previous failure of several other peroxisome proliferator-activated receptor α/γ activators, this class now holds little promise for CV therapeutics.
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Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Terminación Anticipada de los Ensayos Clínicos , Hipoglucemiantes/uso terapéutico , Oxazoles/uso terapéutico , Estado Prediabético/tratamiento farmacológico , Tiofenos/uso terapéutico , Anciano , Enfermedades Cardiovasculares/complicaciones , Trastornos Cerebrovasculares/complicaciones , Enfermedad Coronaria/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Método Doble Ciego , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemia/inducido químicamente , Masculino , Persona de Mediana Edad , Mialgia/inducido químicamente , Infarto del Miocardio/complicaciones , Infarto del Miocardio/prevención & control , Miositis/inducido químicamente , PPAR alfa/agonistas , PPAR gamma/agonistas , Enfermedad Arterial Periférica/complicaciones , Estado Prediabético/complicaciones , Estado Prediabético/metabolismo , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/prevención & control , Resultado del TratamientoRESUMEN
OBJECTIVE: To investigate long-term prognostic importance of newly discovered glucose disturbances in patients with acute myocardial infarction (AMI). METHODS: During 1998-2001, consecutive patients with AMI (n = 167) and healthy controls (n = 184) with no previously known diabetes were investigated with an oral glucose tolerance test (OGTT). Patients and controls were separately followed up for cardiovascular events (first of cardiovascular mortality/AMI/stroke/heart failure) during a decade. RESULTS: In all, 68% of the patients and 35% of the controls had newly detected abnormal glucose tolerance (AGT). Cardiovascular event (n = 72, p = 0.0019) and cardiovascular mortality (n = 31, p = 0.031) were more frequent in patients with newly detected AGT. Regarding patients, a Cox proportional-hazard regression analysis identified AGT (hazard ratio (HR): 2.30; 95% confidence interval (CI): 1.24-4.25; p = 0.008) and previous AMI (HR: 2.39; CI: 1.31-4.35; p = 0.004) as prognostically important. CONCLUSION: An OGTT at discharge after AMI disclosed a high proportion of patients with previously unknown AGT which had a significant and independent association with long-term prognosis.
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Enfermedades Cardiovasculares/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Cardiomiopatías Diabéticas/diagnóstico , Intolerancia a la Glucosa/diagnóstico , Infarto del Miocardio/complicaciones , Anciano , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/mortalidad , Estudios de Cohortes , Diabetes Mellitus Tipo 2/complicaciones , Cardiomiopatías Diabéticas/sangre , Cardiomiopatías Diabéticas/epidemiología , Cardiomiopatías Diabéticas/mortalidad , Femenino , Estudios de Seguimiento , Intolerancia a la Glucosa/complicaciones , Prueba de Tolerancia a la Glucosa , Humanos , Masculino , Persona de Mediana Edad , Mortalidad , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/epidemiología , Infarto del Miocardio/mortalidad , Alta del Paciente , Prevalencia , Pronóstico , Estudios Prospectivos , Recurrencia , Factores de Riesgo , Análisis de Supervivencia , Suecia/epidemiologíaRESUMEN
BACKGROUND: Type 2 diabetes is a major risk factor for chronic kidney disease, which substantially increases the risk of cardiovascular disease mortality. This Phase IIb safety study (AleNephro) in patients with stage 3 chronic kidney disease and type 2 diabetes, evaluated the renal effects of aleglitazar, a balanced peroxisome proliferator-activated receptor-α/γ agonist. METHODS: Patients were randomized to 52 weeks' double-blind treatment with aleglitazar 150 µg/day (n=150) or pioglitazone 45 mg/day (n=152), followed by an 8-week off-treatment period. The primary endpoint was non-inferiority for the difference between aleglitazar and pioglitazone in percentage change in estimated glomerular filtration rate from baseline to end of follow-up. Secondary endpoints included change from baseline in estimated glomerular filtration rate and lipid profiles at end of treatment. RESULTS: Mean estimated glomerular filtration rate change from baseline to end of follow-up was -2.7% (95% confidence interval: -7.7, 2.4) with aleglitazar versus -3.4% (95% confidence interval: -8.5, 1.7) with pioglitazone, establishing non-inferiority (0.77%; 95% confidence interval: -4.5, 6.0). Aleglitazar was associated with a 15% decrease in estimated glomerular filtration rate versus 5.4% with pioglitazone at end of treatment, which plateaued to 8 weeks and was not progressive. Superior improvements in high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides, with similar effects on glycosylated hemoglobin were observed with aleglitazar versus pioglitazone. No major safety concerns were identified. CONCLUSIONS: The primary endpoint in AleNephro was met, indicating that in stage 3 chronic kidney disease patients with type 2 diabetes, the decrease in estimated glomerular filtration rate after 52 weeks' treatment with aleglitazar followed by 8 weeks off-treatment was reversible and comparable (non-inferior) to pioglitazone. TRIAL REGISTRATION: NCT01043029 January 5, 2010.
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Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Hipolipemiantes/uso terapéutico , Riñón/efectos de los fármacos , Oxazoles/uso terapéutico , PPAR alfa/agonistas , PPAR gamma/agonistas , Insuficiencia Renal Crónica/tratamiento farmacológico , Tiofenos/uso terapéutico , Anciano , Diabetes Mellitus Tipo 2/sangre , Nefropatías Diabéticas/fisiopatología , Método Doble Ciego , Dislipidemias/sangre , Dislipidemias/complicaciones , Dislipidemias/tratamiento farmacológico , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/farmacología , Hipolipemiantes/farmacología , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Oxazoles/farmacología , Pioglitazona , Insuficiencia Renal Crónica/fisiopatología , Equivalencia Terapéutica , Tiazolidinedionas/farmacología , Tiazolidinedionas/uso terapéutico , Tiofenos/farmacologíaRESUMEN
BACKGROUND: The benefits of intensified glycaemic control after acute myocardial infarction are uncertain. We report the 20 year follow-up results of the first Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI 1) trial. METHODS: DIGAMI 1 was a prospective, randomised, open-label trial with blinded endpoint evaluation (PROBE) done at coronary care units in 19 Swedish hospitals between Jan 1, 1990 and Dec 31, 1993. Patients with and without previously diagnosed diabetes and with blood glucose concentrations of more than 11 mmol/L who had had a suspected acute myocardial infarction in the previous 24 h were randomly assigned (1:1), with sealed envelopes, to intensified insulin-based glycaemic control for at least 3 months, or to a control group prescribed conventional glucose-lowering treatment. Masking was not considered feasible or safe on the basis of insulin use. The primary endpoint was mortality, in both the original study and the present follow-up analysis. Analysis was by intention to treat. FINDINGS: 620 patients were randomised to intensified insulin-based glycaemic control (n=306) or the control group (n=314). During a mean follow-up period of 7·3 years (SD 6·6; range 0·0-21·8) years, 271 patients (89%) died in the intensified glycaemic control group and 285 (91%) patients died in the standard glycaemic control group. Median survival time was 7·0 years (IQR 1·8-12·4) in patients in the intensified glycaemic control group and 4·7 (1·0-11·4) in those in the standard group (hazard ratio 0·83, 95% CI 0·70-0·98; p=0·027). The effect of intensified glycaemic control was apparent during 8 years after randomisation, increasing survival by 2·3 years. INTERPRETATION: Intensified insulin-based glycaemic control after acute myocardial infarction in patients with diabetes and hyperglycaemia at admission had a long-lasting effect on longevity. Although the effect of glucose lowering might be less apparent with presently available, more effective lipid-lowering and blood-pressure-lowering drugs, improved glycaemic control might still be important for longevity after acute myocardial infarction. FUNDING: Swedish Heart-Lung Foundation, Kronoberg County Council.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Angiopatías Diabéticas/terapia , Cardiomiopatías Diabéticas/terapia , Hiperglucemia/prevención & control , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Infarto del Miocardio/complicaciones , Anciano , Glucemia/análisis , Estudios de Cohortes , Unidades de Cuidados Coronarios , Diabetes Mellitus Tipo 2/complicaciones , Angiopatías Diabéticas/epidemiología , Angiopatías Diabéticas/mortalidad , Cardiomiopatías Diabéticas/epidemiología , Cardiomiopatías Diabéticas/mortalidad , Monitoreo de Drogas , Femenino , Estudios de Seguimiento , Glucosa/administración & dosificación , Glucosa/uso terapéutico , Humanos , Hipoglucemiantes/administración & dosificación , Infusiones Intravenosas , Inyecciones Subcutáneas , Insulina/administración & dosificación , Análisis de Intención de Tratar , Masculino , Persona de Mediana Edad , Infarto del Miocardio/epidemiología , Infarto del Miocardio/mortalidad , Infarto del Miocardio/terapia , Riesgo , Análisis de Supervivencia , Suecia/epidemiologíaRESUMEN
IMPORTANCE: No therapy directed against diabetes has been shown to unequivocally reduce the excess risk of cardiovascular complications. Aleglitazar is a dual agonist of peroxisome proliferator-activated receptors with insulin-sensitizing and glucose-lowering actions and favorable effects on lipid profiles. OBJECTIVE: To determine whether the addition of aleglitazar to standard medical therapy reduces cardiovascular morbidity and mortality among patients with type 2 diabetes mellitus and a recent acute coronary syndrome (ACS). DESIGN, SETTING, AND PARTICIPANTS: AleCardio was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial conducted in 720 hospitals in 26 countries throughout North America, Latin America, Europe, and Asia-Pacific regions. The enrollment of 7226 patients hospitalized for ACS (myocardial infarction or unstable angina) with type 2 diabetes occurred between February 2010 and May 2012; treatment was planned to continue until patients were followed-up for at least 2.5 years and 950 primary end point events were positively adjudicated. INTERVENTIONS: Randomized in a 1:1 ratio to receive aleglitazar 150 µg or placebo daily. MAIN OUTCOMES AND MEASURES: The primary efficacy end point was time to cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Principal safety end points were hospitalization due to heart failure and changes in renal function. RESULTS: The trial was terminated on July 2, 2013, after a median follow-up of 104 weeks, upon recommendation of the data and safety monitoring board due to futility for efficacy at an unplanned interim analysis and increased rates of safety end points. A total of 3.1% of patients were lost to follow-up and 3.2% of patients withdrew consent. The primary end point occurred in 344 patients (9.5%) in the aleglitazar group and 360 patients (10.0%) in the placebo group (hazard ratio, 0.96 [95% CI, 0.83-1.11]; P = .57). Rates of serious adverse events, including heart failure (3.4% for aleglitazar vs 2.8% for placebo, P = .14), gastrointestinal hemorrhages (2.4% for aleglitazar vs 1.7% for placebo, P = .03), and renal dysfunction (7.4% for aleglitazar vs 2.7% for placebo, P < .001) were increased. CONCLUSIONS AND RELEVANCE: Among patients with type 2 diabetes and recent ACS, use of aleglitazar did not reduce the risk of cardiovascular outcomes. These findings do not support the use of aleglitazar in this setting with a goal of reducing cardiovascular risk. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01042769.
Asunto(s)
Síndrome Coronario Agudo/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Oxazoles/uso terapéutico , Tiofenos/uso terapéutico , Anciano , Método Doble Ciego , Femenino , Humanos , Hipoglucemiantes/efectos adversos , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Infarto del Miocardio , Receptores Activados del Proliferador del Peroxisoma/agonistas , Riesgo , Accidente Cerebrovascular , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) regulate transcription of genes involved in glucose uptake, lipid metabolism, and inflammation. Aleglitazar is a potent dual PPAR agonist with insulin-sensitizing and glucose-lowering actions and favorable effects on lipid profiles and biomarkers of cardiovascular risk. The AleCardio trial examines whether the addition of aleglitazar to standard medical therapy reduces the risk of cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus and recent acute coronary syndrome. STUDY DESIGN: AleCardio is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. A total of 7,228 patients were randomized to aleglitazar 150 µg or placebo daily in addition to standard medical therapy. The primary efficacy end point is time to the first event of cardiovascular death, myocardial infarction, or stroke. Principal safety end points are hospitalization due to heart failure and changes in renal function. Treatment will continue until 7,000 patients are followed up for at least 2.5 years and 950 primary end point events are adjudicated. CONCLUSIONS: AleCardio will establish whether the PPAR-α/γ agonist aleglitazar improves cardiovascular outcomes in patients with diabetes and high-risk coronary disease.
Asunto(s)
Síndrome Coronario Agudo/complicaciones , Síndrome Coronario Agudo/mortalidad , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Oxazoles/uso terapéutico , Receptores Activados del Proliferador del Peroxisoma/agonistas , Tiofenos/uso terapéutico , Diabetes Mellitus Tipo 2/complicaciones , Método Doble Ciego , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Morbilidad , Infarto del Miocardio/mortalidad , Infarto del Miocardio/prevención & control , Factores de Riesgo , Accidente Cerebrovascular/mortalidad , Accidente Cerebrovascular/prevención & control , Resultado del TratamientoRESUMEN
AIMS: Hyperglycaemia during hospitalization for acute myocardial infarction (AMI) is a risk predictor, but attempts to improve the prognosis by insulin-based glucose control have not been consistently successful. Increased glycaemic variability, a potential effect of insulin treatment, has been linked to a worse prognosis in critically ill patients. The present aim was to study the possibility of such a relation in patients with type 2 diabetes (T2DM) and AMI. METHOD AND RESULTS: We studied 578 T2DM patients who had glucose levels measured hourly while receiving an insulin-glucose infusion during the first 48 h of hospitalization for AMI. Three measures of glycaemic variability: root mean square error (RMSE), range, and slope were studied in relation to a composite endpoint of mortality, stroke, and reinfarction and to mortality. In unadjusted analyses, the mean level of glycaemic variability did not differ between patients who died during 12 months of follow-up compared with those who survived. In a Cox regression model adjusting for age and previous congestive heart failure, there was no increased risk for the composite endpoint associated with increased glycaemic variability; RMSE: hazard ratio (HR) 1.09 [95% confidence interval (CI) 0.93-1.27; P = 0.28], range: HR 1.01 (95% CI: 0.98-1.05; P = 0.47), and slope: HR 1.01 (95% CI: 0.99-1.04; P = 0.40). There was furthermore no increased risk in mortality; RMSE HR 1.14 (95% CI: 0.93-1.38; P = 0.21), range HR 1.03 (95% CI: 0.98-1.08; P = 0.28), and slope HR 1.01 (95% CI: 0.98-1.04; P = 0.55). CONCLUSION: The 1-year risk for death, reinfarction, or stroke did not relate to glycaemic variability in T2DM patients with AMI treated with insulin infusion.
Asunto(s)
Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Cardiomiopatías Diabéticas/sangre , Infarto del Miocardio/sangre , Anciano , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Cardiomiopatías Diabéticas/tratamiento farmacológico , Femenino , Glucosa/administración & dosificación , Hospitalización , Humanos , Hiperglucemia/sangre , Hiperglucemia/prevención & control , Hipoglucemiantes/administración & dosificación , Infusiones Intravenosas , Insulina/administración & dosificación , Masculino , Infarto del Miocardio/tratamiento farmacológico , Pronóstico , Estudios Prospectivos , Recurrencia , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/mortalidadRESUMEN
AIMS: Patients with type 2 diabetes (T2DM) have a high restenosis rate after percutaneous coronary intervention (PCI). This study investigated whether markers of inflammation and the adipo-insular axis associated with T2DM and poor metabolic control were able to predict restenosis after PCI in T2DM patients. METHODS AND RESULTS: The predictive value of traditional and non-traditional risk markers, including IL-1ß, IL-6, TNF-α, hsCRP, interferon gamma, leptin, IGF-I, insulin, proinsulin and NT-proBNP, was investigated in 82 patients with T2DM. A re-angiography 6 months after the index percutaneous coronary intervention (PCI) revealed that 43% of the patients had a restenosis. In a multiple regression analysis, the only independent predictors of restenosis were fasting glucose before the PCI and previous myocardial infarction (odds ratio [OR] 1.44, 95% confidence interval [CI] 1.07-1.92; p = 0.015 and OR 8.00, 95% CI 2.49-25.67; p ≤ 0.001, respectively). None of the other markers remained as significant predictors. CONCLUSION: Fasting glucose prior to the PCI was an independent predictor of restenosis in patients with T2DM while analyses of a variety of markers related to inflammation and the adipo-insular axis did not add any further information.
Asunto(s)
Angioplastia Coronaria con Balón/efectos adversos , Reestenosis Coronaria/etiología , Estenosis Coronaria/terapia , Diabetes Mellitus Tipo 2/complicaciones , Anciano , Biomarcadores/sangre , Glucemia/metabolismo , Angiografía Coronaria , Reestenosis Coronaria/sangre , Reestenosis Coronaria/diagnóstico por imagen , Reestenosis Coronaria/inmunología , Estenosis Coronaria/sangre , Estenosis Coronaria/complicaciones , Estenosis Coronaria/inmunología , Citocinas/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/inmunología , Femenino , Humanos , Hipoglucemiantes/uso terapéutico , Mediadores de Inflamación/sangre , Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/análisis , Leptina/sangre , Modelos Logísticos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/etiología , Péptido Natriurético Encefálico/sangre , Oportunidad Relativa , Fragmentos de Péptidos/sangre , Proinsulina/sangre , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Suecia , Factores de Tiempo , Resultado del TratamientoRESUMEN
Worldwide prevalence of diabetes mellitus in the adult population is increasing and when explicitly searched within specific groups of patients, as those presenting cardiovascular disease (CVD), dysglycaemia is detected in about three-quarters of the patients. Dysglycaemia alone is a major risk factor for microvascular and macrovascular complications that impair quality of life and diminish survival. The coexistence of CVD and dysglycaemia in the same individual increases its cardiovascular risk considerably. Since a significant proportion of dysglycaemic individuals develop vascular damage and the disturbed glucose metabolism remains undetected until the first cardiovascular event, there is imperative need for improved strategies for glucometabolic health assessment and management in patients with CVD. The present review has the aim to discuss the importance of glycaemic control for future cardiovascular events starting from the in-hospital setting and continuing to long-term management based on available literature and recently updated international guidelines.
Asunto(s)
Glucemia/metabolismo , Enfermedades Cardiovasculares/prevención & control , Complicaciones de la Diabetes/prevención & control , Diabetes Mellitus/tratamiento farmacológico , Adulto , Diabetes Mellitus Tipo 2/complicaciones , Prueba de Tolerancia a la Glucosa , Hospitalización , Humanos , Pacientes Ambulatorios , Estado Prediabético/diagnósticoRESUMEN
BACKGROUND: Previously unknown glucose perturbations are common in patients with myocardial infarction (MI). We evaluated the accuracy of an early oral glucose tolerance test OGTT in relation to the extent of the MI. MATERIAL AND METHODS: An OGTT was performed in 134 patients with MI without known diabetes (DM) after 4-5 days (predischarge) and 3 months. The MI was classified as transmural (TMI; n=70) or subendocardial (SEMI; n=102). RESULTS: Predischarge TMI-patients had normal GT, impaired GT or DM in 31%, 33% and 36%. These proportions were 35%, 39% and 26% after 3 months. The corresponding proportions in SEMI-patients were 35%, 35% and 30% and 35%, 40% and 25%. At admission and the first 2 days fasting glucose was higher in TMI than SEMI-patients. CONCLUSION: The outcome of an early OGTT is valid but the test should not be performed earlier than 4-5 days after the event especially in patients with extensive infarctions.
Asunto(s)
Glucemia/metabolismo , Diabetes Mellitus/sangre , Diabetes Mellitus/diagnóstico , Infarto del Miocardio/sangre , Infarto del Miocardio/diagnóstico , Anciano , Diagnóstico Precoz , Femenino , Prueba de Tolerancia a la Glucosa/métodos , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
AIMS: Myocardial diastolic dysfunction (MDD) and impaired coronary flow reserve (CFR) are early signs of myocardial involvement in patients with diabetes. The important question of whether this may be reversed by glucose normalization has not been tested in a controlled clinical trial. We hypothesized that strict glycaemic control, particularly if insulin based, will improve MDD and CFR. METHODS AND RESULTS: Thirty-nine type 2 diabetes patients (mean age 61.0 +/- 7 years) with signs of diastolic dysfunction were randomly assigned to strict metabolic control by insulin (I-group; n = 21) or oral glucose lowering agents (O-group; n = 18). MDD and CFR were studied with Doppler-echocardiography including Tissue Doppler Imaging and myocardial contrast enhanced echocardiography. Fasting glucose (I-group = -2.2 +/- 2.1; O-group -1.5 +/- 0.8 mmol/L) and HbA(1c) were normalized (-0.6 +/- 0.4 and -0.7 +/- 0.4%, respectively) in both groups, but this did not significantly improve MDD in either of the groups (P = 0.65). There was no difference in CFR before and after improved glycaemic control. CONCLUSION: The hypothesis that strict glycaemic control would reverse early signs of MDD and improve CFR in patients with type 2 diabetes could not be confirmed, despite achieved normalization. Whether it is possible to influence a more pronounced diastolic dysfunction, particularly in less well-controlled diabetic patients, remains to be established.