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BACKGROUND AND AIMS: Data describing the long-term efficacy, safety, and tolerability of inclisiran are limited. This was explored in ORION-8, an open-label extension study of preceding Phase 2 and Phase 3 placebo-controlled and open-label extension trials. METHODS: Adults with ASCVD, ASCVD risk equivalent, or HeFH received open-label inclisiran every 180 days (after completion of the parent trial) until Day 990, followed by an end-of-study (EOS) visit at Day 1080 or ≥90 days after last dose. Study endpoints included proportion of patients achieving pre-specified LDL-C goals (ASCVD: <1.8 mmol/L [<70 mg/dL]; ASCVD risk equivalent: <2.6 mmol/L [<100 mg/dL]), percentage and absolute changes in LDL-C at EOS, and safety of inclisiran. RESULTS: Of 3274 patients included in the analysis, 2446 (74.7%) were followed until EOS. Mean age was 64.9±9.9 years, 82.7% (n=2709) had ASCVD, and mean baseline LDL-C was 2.9±1.2 mmol/L. Mean cumulative exposure to inclisiran (including parent trials) was 3.7 years; maximum exposure was 6.8 years. With inclisiran, 78.4% (95% CI: 76.8, 80.0) of patients achieved pre-specified LDL-C goals and mean percentage LDL-C reduction was -49.4% (95% CI: -50.4, -48.3). No attenuation of LDL-C lowering over time was observed. Treatment-emergent adverse events at the injection site (all mild or moderate) occurred in 5.9% of inclisiran-treated patients. Inclisiran-associated anti-drug antibodies were infrequent (5.5%) and had no impact on the efficacy or safety of inclisiran. No new safety signals were identified. CONCLUSIONS: In the largest and longest follow-up to date, inclisiran demonstrated sustained and substantial LDL-C lowering with a favourable long-term safety and tolerability profile. ClinicalTrials.gov identifier: NCT03814187.
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Background: Management of low-density lipoprotein cholesterol (LDL-C) in Asia remains suboptimal, with â¼50% of patients who are treated with lipid-lowering therapies (LLTs) unable to achieve their guideline-recommended LDL-C goals. Asian-representative studies of the use of inclisiran are needed. Objectives: The authors sought to evaluate the efficacy and safety of inclisiran in Asian patients with atherosclerotic cardiovascular disease (ASCVD) or high risk of ASCVD, as an adjunct to diet and maximally tolerated statin dose, with or without additional LLTs. Methods: The ORION-18 was a phase 3 double-blind trial in which patients were randomized 1:1 to receive either 300 mg inclisiran sodium or matching placebo on days 1, 90, and 270. Percentage change in LDL-C from baseline to day 330 was the primary endpoint. Results: A total of 345 patients (mean age 59.5 years, mean baseline LDL-C 109 mg/dL, 74.7% male) were randomized to inclisiran or placebo. Baseline characteristics were similar in both groups. The percentage decrease in LDL-C from baseline to day 330 was 57.2% (P < 0.001); proprotein convertase subtilisin/kexin type 9 was reduced by 78.3% (P < 0.001). Time-adjusted percentage reduction in LDL-C from baseline after day 90 and up to day 360 was 56.3%. At day 330, 71.7% of participants with inclisiran achieved ≥50% reduction in LDL-C compared with 1.5% with placebo. Over the study period, total cholesterol, apolipoprotein B, and non-high-density lipoprotein cholesterol (HDL-C) levels were decreased significantly, and HDL-C levels increased. The incidence of adverse events with inclisiran was similar to that with placebo. Conclusions: In Asian patients with ASCVD or high risk of ASCVD, inclisiran was effective and safe. (Study of Efficacy and Safety of Inclisiran in Asian Participants With Atherosclerotic Cardiovascular Disease [ASCVD] or ASCVD High Risk and Elevated Low-Density Lipoprotein Cholesterol [LDL-C] [ORION-18]; NCT04765657).
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AIM: To evaluate the efficacy, safety, and pharmacokinetics (PK) of inclisiran in Japanese patients with high cardiovascular risk and elevated low-density lipoprotein cholesterol (LDL-C). METHODS: ORION-15 was a phase 2, double-blind, placebo-controlled randomized trial. Patients with hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH), were randomized to inclisiran sodium 100, 200, or 300 mg, or placebo and dosed subcutaneously on Days 1, 90, and 270. The primary endpoint was the percentage change from baseline to Day 180 to demonstrate the superiority of inclisiran vs. placebo. Patients who consented to the PK substudy had additional study procedures for blood collection and safety assessment. RESULTS: Overall, 312 patients (mean age, 63.6 years; male, 74.4%; baseline LDL-C, 114.0 mg/dL) were randomized. Baseline characteristics were well balanced among the groups. At Day 180, inclisiran at all doses demonstrated significant LDL-C and proprotein convertase subtilisin/kexin type 9 (PCSK9) reductions (pï¼0.0001 for both), which showed a dose-response relationship. The greatest reductions (LDL-C, 65.3%; PCSK9, 79.2%) were with inclisiran sodium 300 mg. At Day 180, ï¼86% of the patients receiving inclisiran achieved the Japan Atherosclerosis Society 2017 lipid management targets compared to 8.9% for placebo. The mean (SD) plasma half-life for inclisiran was 6.8 (2.0)-7.6 (0.8) h. The incidence of adverse events with inclisiran was similar to that with placebo. CONCLUSION: Inclisiran sodium 100, 200, and 300 mg demonstrated clinically meaningful and statistically significant LDL-C and PCSK9 reductions at Day 180, which were consistent over 12 months. Inclisiran was effective and well tolerated in Japanese patients with hypercholesterolemia, including HeFH.
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LDL-Colesterol , Hipercolesterolemia , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , LDL-Colesterol/sangre , Método Doble Ciego , Pueblos del Este de Asia , Hipercolesterolemia/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Japón/epidemiología , Proproteína Convertasa 9 , ARN Interferente Pequeño , Resultado del TratamientoRESUMEN
BACKGROUND: Homozygous familial hypercholesterolemia is a genetic disease characterized by extremely high levels of low-density lipoprotein cholesterol (LDL-C) and a high risk of premature cardiovascular events. The proof-of-concept study ORION-2 (A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia) showed that inclisiran, a small interfering RNA that prevents production of the hepatic PCSK9 protein (proprotein convertase subtilisin/kexin type 9), could lead to durable reductions in LDL-C levels when added to statins and ezetimibe in patients with homozygous familial hypercholesterolemia. METHODS: ORION-5 was a phase 3, 2-part, multicenter study in 56 patients with homozygous familial hypercholesterolemia and elevated LDL-C levels despite maximum tolerated doses of LDL-C-lowering therapies with or without lipoprotein apheresis. Patients eligible for part 1 (double-blind, 6 months) were randomized 2:1 to receive either 300 mg of inclisiran sodium (equivalent to 284 mg of inclisiran) or placebo. Placebo-treated patients from part 1 were transitioned to inclisiran in part 2 (open-label, 18 months). The primary end point was the percentage change in LDL-C levels from baseline to day 150. RESULTS: The mean age of the patients was 42.7 years, and 60.7% were women. The mean baseline LDL-C levels were 294.0 mg/dL and 356.7 mg/dL in the inclisiran and placebo groups, respectively. The placebo-corrected percentage change in LDL-C level from baseline to day 150 was -1.68% (95% CI, -29.19% to 25.83%; P=0.90), and the difference was not statistically significant between the inclisiran and placebo groups. The placebo-corrected percentage change in PCSK9 levels from baseline to day 150 was -60.6% with inclisiran treatment (P<0.0001); this was sustained throughout the study, confirming the effect of inclisiran on its biological target of PCSK9. No statistically significant differences between the inclisiran and placebo groups were observed in the levels of other lipids and lipoproteins (apolipoprotein B, total cholesterol, and non-high-density lipoprotein cholesterol). Adverse events and serious adverse events did not differ between the inclisiran and placebo groups throughout the study. CONCLUSIONS: Inclisiran treatment did not reduce LDL-C levels in patients with homozygous familial hypercholesterolemia despite substantial lowering of PCSK9 levels. Inclisiran was well-tolerated, and the safety findings were consistent with previously reported studies and the overall safety profile. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03851705.
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Anticolesterolemiantes , Hipercolesterolemia Familiar Homocigótica , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Humanos , Femenino , Adulto , Masculino , Proproteína Convertasa 9/metabolismo , LDL-Colesterol , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , ARN Interferente Pequeño/efectos adversos , Colesterol , Anticolesterolemiantes/efectos adversosRESUMEN
BACKGROUND: Inclisiran is a small interfering RNA agent to lower low-density lipoprotein cholesterol. OBJECTIVES: The purpose of this study was to provide reliable evidence to date on the long-term safety profile of inclisiran. METHODS: This post hoc analysis comprised patients treated with 300 mg inclisiran sodium or placebo in the completed (ORION-1, -3, -5, -9, -10, and -11) and ongoing (ORION-8) trials. Exposure-adjusted incidence rates and Kaplan-Meier estimates of cumulative incidence of reported treatment-emergent adverse events (TEAE), abnormal laboratory measurements, and incidence of antidrug antibodies were analyzed. RESULTS: This analysis included 3,576 patients treated with inclisiran for up to 6 years and 1,968 patients treated with placebo for up to 1.5 years, with 9,982.1 and 2,647.7 patient-years of exposure, respectively. Baseline characteristics were balanced between groups. Kaplan-Meier analyses showed that TEAEs that were serious or led to discontinuation; hepatic, muscle, and kidney events; incident diabetes; and elevations of creatine kinase or creatinine accrued at a comparable rate between groups for up to 1.5 years, with similar trends continuing for inclisiran beyond this period. Numerically fewer major cardiovascular events reported as TEAEs occurred with inclisiran during this period. Treatment-induced antidrug antibodies were uncommon with inclisiran (4.6%), with few of these persistent (1.4%) and not associated with greater incidence of TEAEs leading to study drug discontinuation or serious TEAEs. CONCLUSIONS: Long-term treatment with inclisiran was well tolerated in a diverse population, without new safety signals, supporting the safety of inclisiran in patients with dyslipidemia.
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Anticolesterolemiantes , Dislipidemias , Hipercolesterolemia , Humanos , Hipercolesterolemia/tratamiento farmacológico , LDL-Colesterol , ARN Interferente Pequeño , Dislipidemias/tratamiento farmacológico , Anticolesterolemiantes/uso terapéutico , Proproteína Convertasa 9RESUMEN
INTRODUCTION: Whether long-term treatment with the twice-yearly, siRNA therapeutic inclisiran, which reduces hepatic production of proprotein convertase subtilisin/kexin type 9 (PCSK9), results in sustained reductions in LDL cholesterol with an acceptable safety profile is not known. The aim of this study was to assess the effect of long-term dosing of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol. METHODS: ORION-3 was a 4-year open-label extension study of the placebo-controlled, phase 2 ORION-1 trial, conducted at 52 sites across five countries. Patients with prevalent atherosclerotic cardiovascular disease or high-risk primary prevention and elevated LDL cholesterol despite maximally tolerated statins or other LDL-lowering treatments, or with documented statin intolerance, who had completed the ORION-1 trial were eligible. Patients receiving inclisiran in ORION-1 received twice-yearly 300 mg subcutaneous inclisiran sodium throughout ORION-3 (inclisiran-only arm), whereas patients receiving placebo in ORION-1 first received subcutaneous evolocumab 140 mg every 2 weeks until day 360 thereafter transitioning to inclisiran twice-yearly for the remainder of ORION-3 study (switching arm). The primary efficacy endpoint was the percentage change in LDL cholesterol with inclisiran from the start of ORION-1 through to day 210 of the open label extension phase in the inclisiran-only arm (approximately 570 days of total inclisiran exposure in the modified intention-to-treat population). Secondary and exploratory endpoints included changes in LDL-C cholesterol and PCSK9 concentrations levels up to day 1440 (4 years) in each arm, and safety. ORION-3 is registered with ClinicalTrials.gov, NCT03060577. FINDINGS: Of the original ORION-1 cohort of 497 patients, 290 of 370 patients allocated to drug continued into the inclisiran-only arm and 92 of 127 patients allocated to placebo entered the switching-arm in the ORION-3 extension study conducted between March 24, 2017, and Dec 17, 2021. In the inclisiran-only arm, LDL cholesterol was reduced by 47·5% (95% CI 50·7-44·3) at day 210 and sustained over 1440 days. The 4-year averaged mean reduction of LDL-C cholesterol was 44·2% (95% CI: 47·1-41·4), with reductions in PCSK9 ranging from 62·2% to 77·8%. Adverse events at the injection site were reported in 39 (14%) of 284 patients in the inclisiran-only arm and 12 (14%) of 87 patients in the switching arm. The incidence of treatment-emergent serious adverse events possibly related to the study drug was 1% (three of 284) in the inclisiran-only arm and 1% (one of 87) in the switching arm. INTERPRETATION: Twice-yearly inclisiran provided sustained reductions in LDL cholesterol and PCSK9 concentrations and was well tolerated over 4 years in the extension study. This is the first prospective long-term study to assess repeat hepatic exposure to inclisiran. FUNDING: Novartis Pharma.
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Anticolesterolemiantes , Enfermedades Cardiovasculares , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Humanos , Anticolesterolemiantes/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/inducido químicamente , LDL-Colesterol , Factores de Riesgo de Enfermedad Cardiaca , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Proproteína Convertasa 9 , Estudios Prospectivos , Factores de Riesgo , ARN Interferente Pequeño/efectos adversosRESUMEN
OBJECTIVES: To determine the long-term effects of changing the amount or source of dietary carbohydrate on quality of life (QOL), symptoms and dietary satisfaction in people with type 2 diabetes. METHODS: Subjects with diabetes treated by diet alone (n=162) were randomly assigned to high-carbohydrate/high-glycemic-index (HGI) diets; high-carbohydrate/low-glycemic-index (LGI) diets; or lower-carbohydrate/high-monounsaturated-fat (LC) diets for 1 year. We measured QOL at baseline and at study's end, and we measured symptoms and dietary satisfaction quarterly. RESULTS: The HGI, LGI and LC diets contained, respectively, 47±1, 52±1 and 40±1% energy carbohydrate; 30±1, 27±1 and 40±1% fat with GI 64±0.4, 55±0.4 and 59±0.4. Significantly more participants reported increased flatulence on LGI than on LC and HGI diets at 3 months (41%, 19%, 14%; p<0.05), but not at 12 months (29%, 17%, 17%; ns). Abdominal distension was more severe (46% vs. 14%, 19%; p<0.05), and headache less severe (8% vs. 22%, 23%; p<0.05) on LGI than on both other diets. Increased appetite was more severe on LC (33%) than on HGI diets (14%, p<0.05). Joint/limb pains were less severe on LGI (16%) than HGI (28%) diets. LC elicited more severe gloomy thoughts (23%) than LGI (4%; p<0.05) but greater dietary-satisfaction (70%; p<0.05) than LGI (40%) and HGI (48%) diets. For all diets, glycated hemoglobin (A1C) levels increased less in those who gained less weight, had less increased appetite and were more satisfied with the enjoyment obtained from eating. CONCLUSIONS: Each diet elicited increased severity of 1 or more symptoms than the other diets. Although overall dietary satisfaction was greater on the 40% carbohydrate diet than on the 50% carbohydrate diet, the LGI diet was no less satisfying than the HGI diet. Changes in appetite and dietary satisfaction may influence body weight and glycemic control, or vice-versa.
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Diabetes Mellitus Tipo 2/dietoterapia , Carbohidratos de la Dieta/farmacología , Apetito , Peso Corporal , Dietoterapia/efectos adversos , Dietoterapia/métodos , Femenino , Flatulencia , Índice Glucémico , Hipo , Humanos , Masculino , Persona de Mediana Edad , Calidad de VidaRESUMEN
OBJECTIVE: To provide an update on glycaemic control in European patients with type 2 diabetes based on data from the nine-country, cross-sectional PANORAMA study (NCT00916513). DESIGN: Post-hoc analysis to report the number of patients achieving/not achieving glycaemic goal (HbA(1c) <7%). PATIENTS: Patients were randomly or consecutively selected from physician practices in nine countries. Eligible patients were aged ≥40 years, diagnosed with type 2 diabetes >1 year prior to study entry, and had an available medical record of >1 year. MEASUREMENTS: All data were collected at a single visit, including HbA1c measurement using a common device (A1CNow). Bivariate and multivariate analyses were used to investigate factors associated with not reaching glycaemic goal. RESULTS: Of 5817 patients enrolled (aged 65·9 ± 10·4 years, 53·7% male), 37·4% had an HbA(1c) ≥7%; (range 25·9% in The Netherlands to 52·0% in Turkey). In adjusted multivariate analyses, higher individual glycaemic target, younger age, poor physician-reported patient adherence to lifestyle/medication, longer diabetes duration, increasing treatment regimen complexity and physician-reported patient's unwillingness to intensify treatment were associated with not achieving goal. However, bivariate analyses also found gender, socioeconomic factors, body mass index, rate of complications and hypoglycaemia to be associated with not achieving goal. CONCLUSIONS: In PANORAMA, 37·4% of patients enrolled were not at glycaemic goal. Factors relating to patient characteristics, physician selection of individualized HbA1c target and diabetes itself (longer duration, more complex treatment) were strongly associated with not achieving goal. Further studies are warranted to explore these associations and evaluate strategies for improving glycaemic control.
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Diabetes Mellitus Tipo 2/sangre , Anciano , Glucemia/metabolismo , Europa (Continente) , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Análisis MultivarianteRESUMEN
OBJECTIVE: The PROMPT study compared efficacy and tolerability of two treatment intensification strategies: adding saxagliptin or uptitrating metformin monotherapy, in patients with type 2 diabetes (T2D) and inadequate glycaemic control on a sub-maximal metformin dose. RESEARCH DESIGN AND METHODS: In this double-blind, 24-week study, metformin-tolerant patients with T2D on metformin monotherapy were randomised to receive fixed-dose metformin 1500 mg/day, plus either add-on saxagliptin 5 mg/day (SAXA-MET) or a two-step metformin uptitration (MET-UP) to a maximum dose (2500 mg/day). CLINICAL TRIAL REGISTRATION: NCT01006590. MAIN OUTCOME MEASURES: Primary: absolute change from baseline in glycated haemoglobin A(1c) (HbA(1c)) (Week 24). Secondary: proportion of patients achieving a therapeutic glycaemic response (Week 24); change from baseline in fasting plasma glucose (Week 24); safety and tolerability. Exploratory analyses comprised three patient-related questionnaires, including the validated 5-dimension Digestive Health Status Index (DHSI). RESULTS: A total of 286 patients were randomised: (SAXA-MET: 147; MET-UP: 139). Baseline mean (SD) HbA(1c): 7.71 (0.85; SAXA-MET); 7.80 (0.82; MET-UP). Adjusted mean reductions from baseline in HbA(1c) (Week 24): -0.47% (SAXA-MET); -0.38% (MET-UP); mean (95% CI) difference in treatment effect, -0.10% (-0.26, 0.07); p = 0.260. The proportion of patients (95% CI) achieving a therapeutic glycaemic response (HbA(1c) < 7%): 43.8% (34.8, 49.6) (SAXA-MET) vs. 35.0% (29.0, 43.8) (MET-UP). Of the five DHSI domains, mean (95% CI) differences were observed for diarrhoea-predominant score (+0.8 [-2.5, 4.0] vs. +7.9 [4.6, 11.2]) and dysmotility score (-0.5 [-2.0, 1.0] vs. +1.9 [0.3, 3.4]), (SAXA-MET and MET-UP, respectively). The most common adverse event was diarrhoea: 6.1% (SAXA-MET) vs. 12.2% (MET-UP). CONCLUSIONS: In metformin-tolerant patients with T2D (inadequately controlled on sub-maximal metformin monotherapy), saxagliptin was well tolerated. Although HbA(1c) reduction was not significantly different between treatment groups, the lower occurrence of gastrointestinal symptoms in the SAXA-MET group suggests that saxagliptin add-on treatment may be a suitable alternative treatment strategy to metformin uptitration.
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Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipéptidos/administración & dosificación , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Tolerancia a Medicamentos , Hipoglucemiantes/administración & dosificación , Metformina/administración & dosificación , Adamantano/administración & dosificación , Adamantano/efectos adversos , Anciano , Diabetes Mellitus Tipo 2/fisiopatología , Dipéptidos/efectos adversos , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Método Doble Ciego , Femenino , Humanos , Hipoglucemiantes/efectos adversos , Masculino , Metformina/efectos adversos , Persona de Mediana EdadRESUMEN
OBJECTIVE: To assess the safety and efficacy of saxagliptin (5 mg once-daily) in older patients (≥65 years of age) with inadequately controlled type 2 diabetes. RESEARCH DESIGN AND METHODS: In this retrospective subgroup analysis, data from five randomized, double-blind, placebo-controlled, multicenter, 24-week, phase 3 trials were included. The primary studies evaluated saxagliptin 5 mg once-daily (monotherapy or add-on) in patients aged 18-77 years with HbA(1c) ≥7.0% (four studies) or ≥7.5% (add-on to glyburide study) versus placebo. MAIN OUTCOME MEASURES: The primary efficacy endpoint of each study included in this pooled analysis was HbA(1c) change from baseline to week 24. RESULTS: In the five-study pooled population, 279 (16.6%) patients were at least 65 years old; 142 received saxagliptin 5 mg once-daily and 137 received placebo. Treatment groups were well-balanced for baseline characteristics within each study. In older patients, the HbA(1c) adjusted mean change from a baseline of 8.1% was -0.73 ± 0.16% (mean ± SEM) with saxagliptin compared with -0.17 ± 0.14% for placebo from a baseline of 8.0%. Adverse event rates were similar with saxagliptin 5 mg once-daily compared with placebo in older patients. CONCLUSION: The pooled subgroup analysis of saxagliptin 5 mg once-daily monotherapy and add-on therapy trials demonstrated clinically relevant and significant efficacy for reducing HbA(1c) in older (≥65 years) patients. Saxagliptin was well-tolerated in older patients with a low incidence of hypoglycemia and no weight gain.
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Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipéptidos/efectos adversos , Dipéptidos/uso terapéutico , Adamantano/efectos adversos , Adamantano/uso terapéutico , Adolescente , Adulto , Factores de Edad , Anciano , Método Doble Ciego , Femenino , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéutico , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto/estadística & datos numéricos , Placebos , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The optimal source and amount of dietary carbohydrate for managing type 2 diabetes (T2DM) are unknown. OBJECTIVE: We aimed to compare the effects of altering the glycemic index or the amount of carbohydrate on glycated hemoglobin (HbA1c), plasma glucose, lipids, and C-reactive protein (CRP) in T2DM patients. DESIGN: Subjects with T2DM managed by diet alone (n=162) were randomly assigned to receive high-carbohydrate, high-glycemic-index (high-GI), high-carbohydrate, low-glycemic-index (low-GI), or low-carbohydrate, high-monounsaturated-fat (low-CHO) diets for 1 y. RESULTS: The high-GI, low-GI, and low-CHO diets contained, respectively, 47%, 52%, and 39% of energy as carbohydrate and 31%, 27%, and 40% of energy as fat; they had GIs of 63, 55, and 59, respectively. Body weight and HbA1c did not differ significantly between diets. Fasting glucose was higher (P=0.041), but 2-h postload glucose was lower (P=0.010) after 12 mo of the low-GI diet. With the low-GI diet, overall mean triacylglycerol was 12% higher and HDL cholesterol 4% lower than with the low-CHO diet (P<0.05), but the difference in the ratio of total to HDL cholesterol disappeared by 6 mo (time x diet interaction, P=0.044). Overall mean CRP with the low-GI diet, 1.95 mg/L, was 30% less than that with the high-GI diet, 2.75 mg/L (P=0.0078); the concentration with the low-CHO diet, 2.35 mg/L, was intermediate. CONCLUSIONS: In subjects with T2DM managed by diet alone with optimal glycemic control, long-term HbA1c was not affected by altering the GI or the amount of dietary carbohydrate. Differences in total:HDL cholesterol among diets had disappeared by 6 mo. However, because of sustained reductions in postprandial glucose and CRP, a low-GI diet may be preferred for the dietary management of T2DM.
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Proteína C-Reactiva/metabolismo , Diabetes Mellitus Tipo 2/dietoterapia , Carbohidratos de la Dieta/administración & dosificación , Grasas de la Dieta/administración & dosificación , Hemoglobina Glucada/análisis , Índice Glucémico , Adulto , Anciano , Área Bajo la Curva , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Colesterol/sangre , HDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/sangre , Carbohidratos de la Dieta/clasificación , Carbohidratos de la Dieta/metabolismo , Femenino , Humanos , Lípidos/sangre , Masculino , Persona de Mediana EdadRESUMEN
The aim of this review is to explore the dysregulation of adrenocortical secretions as a major contributor in the development of obesity and insulin resistance. Disturbance of adipose tissue physiology is one of the primary events in the development of pathologies associated with the metabolic syndrome, such as obesity and type 2 diabetes. Several studies indicate that alterations in metabolism of glucocorticoids (GC) and androgens, as well as aldosterone in excess, are involved in the emergence of metabolic syndrome. Cross talk among adipose tissue, the hypothalamo-pituitary complex, and adrenal gland activity plays a major role in the control of food intake, glucose metabolism, lipid storage, and energy balance. Perturbation of this cross talk induces alterations in the regulatory mechanisms of adrenocortical steroid synthesis, secretion, degradation, and/or recycling, at the level of the zonae glomerulosa (aldosterone), fasciculata (GC and GC metabolites), and reticularis (androgens and androgen precursors DHEA and DHEAS). As a whole, these adrenocortical perturbations contribute to the development of metabolic syndrome at both the paracrine and systemic level by favoring the physiological dysregulation of organs responsive to aldosterone, GC, and/or androgens, including adipose tissue.
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Corteza Suprarrenal/fisiopatología , Resistencia a la Insulina/fisiología , Obesidad/fisiopatología , Tejido Adiposo/metabolismo , Aldosterona/fisiología , Andrógenos/fisiología , Animales , Humanos , Modelos Biológicos , Obesidad/metabolismo , Sistema Renina-Angiotensina/fisiologíaRESUMEN
BACKGROUND: Heterogeneity in circulating lipid concentrations in response to dietary polyunsaturated fatty acids (PUFAs) may be due, in part, to genetic variations. Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that can induce hyperlipidemia and is known to be modulated by dietary PUFAs. OBJECTIVE: The objective was to determine whether TNF-alpha genotypes modify the association between dietary PUFA intake and serum lipid concentrations. DESIGN: The study involved 53 men and 56 women aged 42-75 y with type 2 diabetes. Dietary intakes were assessed with the use of a 3-d food record, and blood samples were collected to determine fasting serum lipids. DNA was isolated from blood for genotyping by polymerase chain reaction-restriction fragment length polymorphism for the TNF-alpha -238G-->A and -308G-->A polymorphisms. RESULTS: PUFA intake was positively associated with serum HDL cholesterol in carriers of the -238A allele (beta = 0.06 +/- 0.03 mmol/L per 1% of energy from PUFAs; P = 0.03), but negatively associated in those with the -238GG genotype (beta = -0.03 +/- 0.01, P = 0.03) (P = 0.004 for interaction). PUFA intake was inversely associated with HDL cholesterol in carriers of the -308A allele (beta = -0.07 +/- 0.02, P = 0.002), but not in those with the -308GG genotype (beta = 0.02 +/- 0.02, P = 0.13) (P = 0.001 for interaction). A stronger gene x diet interaction was observed when the polymorphisms at the 2 positions (-238/-308) were combined (P = 0.0003). Similar effects were observed for apolipoprotein A-I, but not with other dietary fatty acids and serum lipids. CONCLUSION: TNF-alpha genotypes modify the relation between dietary PUFA intake and HDL-cholesterol concentrations. These findings suggest that genetic variations affecting inflammation may explain some of the inconsistencies between previous studies relating PUFA intake and circulating HDL.
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Apolipoproteína A-I/sangre , HDL-Colesterol/sangre , Grasas Insaturadas en la Dieta/administración & dosificación , Polimorfismo de Longitud del Fragmento de Restricción , Factor de Necrosis Tumoral alfa/genética , Anciano , Diabetes Mellitus Tipo 2/sangre , Registros de Dieta , Ayuno/sangre , Femenino , Variación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Nutrigenómica , Reacción en Cadena de la PolimerasaRESUMEN
Inflammatory markers predict memory dysfunction in elderly patients, but their contribution to memory deficits in adults with Type 2 diabetes mellitus (T2DM) is less well understood. The present study determined whether specific single-nucleotide polymorphisms in the promoter region of tumor necrosis factor-alpha (TNF-alpha) predict verbal memory in older patients with T2DM. Immediate and delayed verbal memory were assessed using word list and paragraph recall tests in a cohort of subjects with T2DM during 2 sessions, separated by 48 weeks. The presence of the TNF-alpha-238A allele, which has been shown to decrease gene expression, consistently predicted better baseline performance and protected against memory decline over a period of 48 weeks. Therefore, inflammatory mediators may be important modulators of memory function in individuals with T2DM.
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Diabetes Mellitus Tipo 2/complicaciones , Trastornos de la Memoria/etiología , Trastornos de la Memoria/genética , Polimorfismo de Nucleótido Simple , Factor de Necrosis Tumoral alfa/genética , Adulto , Estudios de Cohortes , Femenino , Genotipo , Humanos , Masculino , Recuerdo Mental/fisiología , Persona de Mediana Edad , Pruebas Neuropsicológicas , Regiones Promotoras Genéticas/fisiología , Factores de Tiempo , Aprendizaje Verbal/fisiologíaRESUMEN
Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine that impairs insulin action and alters lipid metabolism. We investigated the effects of genetic polymorphisms of TNF-alpha on circulating biomarkers of insulin resistance and lipid metabolism during an 8-hour metabolic profile test and a 2-hour oral glucose tolerance test in subjects with type 2 diabetes mellitus. Subjects (N = 123) recruited were type 2 diabetic men (n = 56) and women (n = 67) aged 36 to 75 years with a body mass index of at least 25 kg/m(2). Blood samples were collected to determine postprandial changes in circulating lipid levels and biomarkers of insulin resistance. Subjects were genotyped by polymerase chain reaction-restriction fragment length polymorphism for the TNF-alpha -238G>A, -308G>A, and -863C>A polymorphisms. Compared with subjects who were homozygous for the -238G allele, carriers of the -238A allele had an altered ability to suppress postprandial free fatty acids as shown by an increased net incremental area under the curve (0.26 +/- 2.44 vs -1.33 +/- 2.71 mEq h(-1) L(-1), P = .002) during the 8-hour metabolic profile test. This effect was observed in obese (1.04 +/- 2.42 vs -1.68 +/- 2.70 mEq h(-1) L(-1), P = .0004) but not in non-obese (-0.63 +/- 2.20 vs -0.95 +/- 2.71 mEq h(-1) L(-1), P = .6) individuals. Among obese subjects, carriers of the -308A allele had greater insulin resistance as estimated by the homeostasis model assessment of insulin resistance index (4.36 +/- 2.83 vs 2.85 +/- 1.75, P = .01), but no differences were observed among non-obese subjects (2.19 +/- 1.24 vs 1.97 +/- 0.90, P = .6). Our findings suggest that the -238G>A and -308G>A polymorphisms of TNF-alpha alter circulating free fatty acids and insulin resistance in obese subjects with type 2 diabetes mellitus.
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Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/genética , Ácidos Grasos no Esterificados/sangre , Obesidad/sangre , Obesidad/genética , Factor de Necrosis Tumoral alfa/genética , Adulto , Anciano , Alelos , Colesterol/sangre , ADN/química , ADN/genética , Femenino , Genotipo , Prueba de Tolerancia a la Glucosa , Humanos , Resistencia a la Insulina , Metabolismo de los Lípidos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo de Nucleótido Simple , Periodo Posprandial , Triglicéridos/sangreRESUMEN
OBJECTIVES: Angiotensin-converting enzyme (ACE) inhibitors have been associated with an increased risk of acute pancreatitis. The pathogenesis of this condition remains unclear, but an activation of the kinin system and a resultant localized angioedema have been implicated in the initial step leading to acute pancreatic damage. The goal of the present study was to explore the impact of ACE inhibition on pancreatic microcirculation and capillary permeability in normal and insulin-resistant rats. METHODS: Chow- or fructose-fed Sprague-Dawley rats were treated with enalapril (dosage, 10 mg.kg.d) or vehicle for 4 weeks before measuring in vivo the extravasation of Evans blue (EB) dye in pancreas. Unanesthetized animals (n = 10-17 per group) were injected with EB 20 mg.kg in the caudal vein 10 minutes before killing, and EB dye was extracted from each pancreas by using formamide. RESULTS: Relative to controls, enalapril-treated animals showed a 5-fold increase in pancreatic extravasation of EB in the fructose-fed rat model (P < 0.001); smaller changes (2-fold) were observed in the chow-fed animals treated with enalapril (P < 0.001). The increase in pancreatic vasopermeability observed with enalapril in the fructose-fed animals was accompanied by a significant increase in total pancreatic nitric oxide synthase (NOS) activity compared to controls (Delta = +128%; P < 0.001). This increase in NOS activity seemed to be solely attributable to an upregulation of the endothelial NOS isoform because only the eNOS immunoreactive mass (as opposed to nNOS) seemed to be increased in the pancreas of these animals. Treatment with enalapril was not associated with any increase in serum amylase concentrations in either animal subgroup. CONCLUSIONS: Enalapril increases capillary permeability (extravasation of macromolecules) in the pancreas of the fructose-fed rat model. This suggests that ACE inhibition upregulates the eNOS isoform locally, increases vasopermeability of the pancreas, and can therefore result in local edema in the fructose-fed insulin-resistant rat model.
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Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Permeabilidad Capilar/efectos de los fármacos , Enalapril/farmacología , Resistencia a la Insulina , Óxido Nítrico Sintasa de Tipo III/biosíntesis , Páncreas/efectos de los fármacos , Animales , Western Blotting , Carbohidratos de la Dieta , Modelos Animales de Enfermedad , Azul de Evans , Fructosa , Indicadores y Reactivos , Masculino , Óxido Nítrico Sintasa de Tipo I/metabolismo , Páncreas/irrigación sanguínea , Páncreas/enzimología , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: Assess whether changes in permeability of the muscle regional microcirculation occur in the obese Zucker rat model. RESEARCH METHODS AND PROCEDURES: Capillary permeability to albumin was assessed in vivo in Zucker rats (n = 15) and lean controls (n = 15) by quantifying the extravasation of albumin-bound Evans Blue (EB) in different organs. Unanaesthetized animals were injected with EB 20 mg/kg in the caudal vein, and EB was extracted by formamide from selected organs collected after exsanguination. RESULTS: Relative to control animals, Zucker rats had higher body weight (Delta = +33%; p < 0.001), plasma triglycerides (Delta = +244%; p < 0.001), and insulin (Delta = +240%; p < 0.001) concentrations. Plasma glucose concentrations were not different between the two groups (p = not significant). Using the EB technique, we showed a 30% to 50% (p < 0.01) increase in the extravasation of EB in the obese rats, regardless of the skeletal muscle group studied. This increase in skeletal muscle vasopermeability was not paralleled by any increase in the expression of the muscle endothelium-nitric oxide (NO) system because the total NO synthase (NOS) activity in skeletal muscle of the obese Zucker rat was significantly lower (p < 0.001), as was the endothelial NOS immunoreactive mass (p < 0.001), compared with lean controls. DISCUSSION: In conclusion, there seems to be dissociation between capillary permeability and local regulation of microcirculation in skeletal muscles of the obese Zucker rat. It is suggested that the increase in skeletal muscle vasopermeability (extravasation of macromolecules) is a compensation for the loss of NO-dependent vasodilation and capillary recruitment noted in this model of obesity and insulin resistance.
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Albúminas/farmacocinética , Permeabilidad Capilar/fisiología , Músculo Esquelético/metabolismo , Obesidad/fisiopatología , Albúminas/química , Animales , Glucemia/metabolismo , Peso Corporal/fisiología , Modelos Animales de Enfermedad , Azul de Evans/química , Azul de Evans/farmacocinética , Extravasación de Materiales Terapéuticos y Diagnósticos/fisiopatología , Inmunohistoquímica , Insulina/sangre , Masculino , Músculo Esquelético/irrigación sanguínea , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/metabolismo , Nitritos/sangre , Obesidad/sangre , Ratas , Ratas Zucker , Triglicéridos/sangre , Factor A de Crecimiento Endotelial Vascular/sangre , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Lowering plasma lipid levels in patients in the months following hospital discharge for a myocardial infarction (MI) is clearly beneficial if recurrent cardiac events and mortality are to be prevented; traditionally, however, there has been a large gap between guidelines and levels achieved in routine practice. OBJECTIVES AND METHODS: A randomized, open-label clinical trial was conducted to assess the impact of nurse-centred surveillance and treatment in achieving nationally recognized lipid targets in post-MI patients. This program had the following features: systematic telephone follow-up of patients discharged from the University of Sherbrooke (Sherbrooke, Quebec) after an MI; systematic lipid testing three months after discharge; close liaison with, and guidance of, patients' primary care physicians to intervene on results of this test if targets were not obtained; and continued monitoring of patients until lipid profiles consistent with consensus targets were achieved. The impact of this approach was tested and compared with that of a control group that continued to be followed by a primary care physician for up to 18 months. RESULTS: A total of 127 patients were randomly assigned into an intervention group (n=64) or a control group (n=63). The intervention group was followed by telephone for an average (+/-SD) of 4.4+/-2.0 months post-MI. At this point, when intervention was optimized, the mean low-density lipoprotein cholesterol (LDL-C) level was 2.19+/-0.65 mmol/L in the intervention group, and 87.3% of patients had LDL-C levels of less than 2.5 mmol/L. Patients from both experimental groups returned at 12 months and 18 months post-MI for a new blood lipid assessment. In total, 12.5% of patients in each group were lost to follow-up. At 12 months and 18 months, the mean LDL-C level was not different between the two groups, nor was there a significant difference in the proportion of patients achieving LDL-C levels of less than 2.5 mmol/L (51.6% in the intervention group and 65% in the control group at 18 months; P>0.05). When the combined end point of an LDL-C level of less than 2.5 mmol/L, a triglyceride level of less than 2.0 mmol/L and a total cholesterol to high-density lipoprotein cholesterol ratio of less than 4.0 was considered, the proportion of patients achieving this composite at 18 months was low and not different between the two groups (23.4% in the intervention group and 38.3% in the control group; P>0.05). Over 95% of patients in both groups were on a lipid-lowering medication, and more than 90% had complied with their medication regimen at 18 months. CONCLUSIONS: This trial did not support the role of nurse-managers and a system of telephone-based contacts to ensure the continuity of care and aggressive intervention when considering cardiovascular risk factors in post-MI patients. This trial also re-emphasized the important remaining treatment gap in secondary prevention of coronary artery disease, particularly if composite lipid end points are to be targeted.
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Dislipidemias/enfermería , Hipolipemiantes/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Vigilancia de la Población , LDL-Colesterol/sangre , Dislipidemias/complicaciones , Dislipidemias/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Infarto del Miocardio/sangre , Infarto del Miocardio/complicaciones , Cooperación del Paciente , Pronóstico , Calidad de Vida , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: National guidelines for managing diabetes set standards for care. We sought to determine whether a 1-year intensive multitherapy program resulted in greater goal attainment than usual care among patients with poorly controlled type 2 diabetes mellitus. METHODS: We identified patients with poorly controlled type 2 diabetes receiving outpatient care in the community or at our hospital. Patients 30-70 years of age with a hemoglobin A1c concentration of 8% or greater were randomly assigned to receive intensive multitherapy (n = 36) or usual care (n = 36). RESULTS: The average hemoglobin A1c concentration at entry was 9.1% (standard deviation [SD] 1%) in the intensive therapy group and 9.3% (SD 1%) in the usual therapy group. By 12 months, a higher proportion of patients in the intensive therapy group than in the control group had achieved Canadian Diabetes Association (CDA) goals for hemoglobin A(1c) concentrations (goal < or = 7.0%: 35% v. 8%), diastolic blood pressure (goal < 80 mm Hg: 64% v. 37%), low-density lipoprotein cholesterol (LDL-C) levels (goal < 2.5 mmol/L: 53% v. 20%) and triglyceride levels (goal < 1.5 mmol/L: 44% v. 14%). There were no significant differences between the 2 groups in attaining the targets for fasting plasma glucose levels, systolic blood pressure or total cholesterol:high-density lipoprotein cholesterol ratio. None of the patients reached all CDA treatment goals. By 18 months, differences in goal attainment were no longer evident between the 2 groups, except for LDL-C levels. Quality of life, as measured by a specific questionnaire, increased in both groups, with a greater increase in the intensive therapy group (13% [SD 10%] v. 6% [SD 13%], p < 0.003). INTERPRETATION: Intensive multitherapy for patients with poorly controlled type 2 diabetes is successful in helping patients meet most of the goals set by a national diabetes association. However, 6 months after intensive therapy stopped and patients returned to usual care, the benefits had vanished.
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Diabetes Mellitus Tipo 2/terapia , Ejercicio Físico , Hipoglucemiantes/uso terapéutico , Adulto , Anciano , Glucemia , Presión Sanguínea , LDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/dietoterapia , Dislipidemias/complicaciones , Dislipidemias/tratamiento farmacológico , Ingestión de Energía , Femenino , Estudios de Seguimiento , Gliburida/uso terapéutico , Hemoglobina Glucada , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipertensión/complicaciones , Insulina/uso terapéutico , Masculino , Persona de Mediana Edad , Educación del Paciente como Asunto , Calidad de Vida , Triglicéridos/sangreRESUMEN
Reduced extravasation of macromolecules in skeletal muscle has recently been documented in the fructose-fed rat model, corroborating a hypothesis that a functional obliteration of muscle regional microcirculation might lead to hypertension and restrict access of nutrients and hormones to their target cells. The goal of this study was to assess the impact of a treatment with rosiglitazone on the reduced muscle vasopermeability observed previously in the fructose-fed rat model. Fructose-fed Sprague-Dawley rats were gavaged with rosiglitazone (10 micromol kg(-1) per day; n = 21) or the vehicle only (n = 19) for 3 consecutive weeks before assessing the extravasation of Evans Blue (EB) dye in vivo in distinct muscle groups. Relative to control group, rosiglitazone reduced mean arterial blood pressure (Delta = -16.7%, P < 0.001), plasma insulin (Delta= -39.1%, P < 0.05) and plasma triglyceride (Delta= -32.8 %, P < 0.01) concentrations in a significant manner. Plasma VEGF concentrations were significantly lower in the rosiglitazone-treated animals compared to the control animals (32.7 +/- 0.8 pg ml(-1) versus 46.1 +/- 1.2 pg ml(-1), P < 0.001). While no changes were observed in the lungs or the kidneys, fructose-fed rats treated with rosiglitazone had a 30-50% increase (P < 0.005) in the extravasation of EB regardless of the skeletal muscle group studied (rectus femoris, soleus, gastrocnemius lateralis, vastus lateralis and tibialis cranalis). In homogenates of skeletal muscles (vastus lateralis) of fructose-fed rats, rosiglitazone resulted in a significant increase in NO synthase (NOS) activity (Delta = +41.9 %, P < 0.003) as well as endothelial NOS immunoreactive mass (Delta = +37.8 %, P < 0.01) compared to the control animals. There was no change in the immunoreactive level of the nNOS isoform, the most abundant muscle isoform, or in the immunoreactive levels of VEGF. In conclusion, rosiglitazone appears to restore a vascular dysfunction previously documented in the skeletal muscle microcirculation, as evidenced by improved skeletal muscle vasopermeability and upregulation of the muscle endothelium-NO system in the fructose-fed rat model. These effects on muscle per se might also result in a partial improvement of the insulin resistance phenomenon by improving the distribution of nutrients and insulin to skeletal muscle. This effect appears to be independent of circulating levels of VEGF since changes in plasma concentrations of this permeability factor were lower in the rosiglitazone-treated group.