RESUMEN
Rationale: Current therapies for obstructive sleep apnea (OSA) are limited by insufficient efficacy, compliance, or tolerability. An effective pharmacological treatment for OSA is warranted. Carbonic anhydrase inhibition has been shown to ameliorate OSA. Objectives: To explore safety and tolerability of the carbonic anhydrase inhibitor sulthiame (STM) in OSA. Methods: A 4-week double-blind, randomized, placebo-controlled dose-guiding trial was conducted in patients with moderate and/or severe OSA not tolerating positive airway pressure treatment. Measurements and Main Results: Intermittent paresthesia was reported by 79%, 67%, and 18% of patients receiving 400 mg STM (n = 34), 200 mg STM (n = 12), and placebo (n = 22), respectively. Dyspnea was reported after 400 mg STM (18%). Six patients in the higher dose group withdrew because of adverse events. There were no serious adverse events. STM reduced the apnea-hypopnea index from 55.2 to 33.0 events/h (-41.0%) in the 400-mg group and from 61.1 to 40.6 events/h (-32.1%) after 200 mg (P < 0.001 for both). Corresponding placebo values were 53.9 and 50.9 events/h (-5.4%). The apnea-hypopnea index reduction threshold of ⩾50% was reached in 40% of patients after 400 mg, 25% after 200 mg, and 5% after placebo. Mean overnight oxygen saturation improved by 1.1% after 400 and 200 mg (P < 0.001 and P = 0.034, respectively). Patient-related outcomes were unchanged. Conclusions: STM showed a satisfactory safety profile in moderate and/or severe OSA. STM reduced OSA, on average, by more than 20 events/h, one of the strongest reductions reported in a drug trial in OSA. Larger scale clinical studies of STM in OSA are justified. Clinical trial registered with www.clinicaltrialsregister.eu (2017-004767-13).
Asunto(s)
Síndromes de la Apnea del Sueño , Apnea Obstructiva del Sueño , Tiazinas , Presión de las Vías Aéreas Positiva Contínua , Método Doble Ciego , Humanos , Síndromes de la Apnea del Sueño/tratamiento farmacológico , Apnea Obstructiva del Sueño/terapia , Tiazinas/uso terapéuticoRESUMEN
Whole blood carbonic anhydrase activity (CAa) is increased in patients with obstructive sleep apnea (OSA). Our study investigated the influence of positive airway pressure (PAP) or CA inhibitor acetazolamide (ACT) therapy on CAa, OSA and blood pressure. Thirty-three OSA patients (21 hypertensive, body mass index (BMI) 37 ± 7 kg/m2 and apnea-hypopnea index (AHI) of 47 ± 31 events/hr) were followed-up after PAP treatment (compliance, 4.7 ± 1.5 hr/day; duration, median 6 [IQR 6,6] months) (Cohort A). A second OSA Cohort (B) contained nine hypertensive patients (BMI, 29 ± 4 kg/m2 ; AHI, 39 ± 20 events/hr) with 2-week treatment of ACT, PAP or ACT + PAP in an open crossover study. CAa was assessed at baseline and at the end of each treatment period. In Cohort A, baseline CAa was higher in hypertensive, compared with normotensive, patients (1,033 ± 204 versus 861 ± 201 units, p = .028). PAP treatment reduced systolic/diastolic blood pressure but not CAa (-9 ± 11/-5 ± 7 mmHg and -20 ± 289 units, p < .001, <.001 and .70). In Cohort B, blood pressure was reduced in both ACT-treated groups (-10 ± 10/-5 ± 7 mmHg, p = .043 and .019; and -5 ± 5/-13 ± 13 mmHg, p < .001 and .009). AHI was reduced in both groups: ACT only, -17 ± 9 events/hr p = .001; and ACT + PAP, -39 ± 19 events/hr, p < .001. PAP did not change CAa (p = .98) but activity tended to decrease after ACT with or without PAP (p = .081 and .056). CAa is elevated in hypertensive OSA patients. Long-term PAP reduced blood pressure without affecting CAa. ACT reduced blood pressure and CAa. Increased CAa may constitute a physiological characteristic in OSA, contributing to comorbid hypertension.
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Anhidrasas Carbónicas/efectos adversos , Presión de las Vías Aéreas Positiva Contínua/métodos , Hipertensión/etiología , Polisomnografía/métodos , Apnea Obstructiva del Sueño/fisiopatología , Anhidrasas Carbónicas/sangre , Estudios de Cohortes , Estudios Cruzados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Apnea Obstructiva del Sueño/patología , Apnea Obstructiva del Sueño/terapiaRESUMEN
STUDY QUESTION: Does an intensive weight reduction programme prior to IVF increase live birth rates for infertile obese women? SUMMARY ANSWER: An intensive weight reduction programme resulted in a large weight loss but did not substantially affect live birth rates in obese women scheduled for IVF. WHAT IS ALREADY KNOWN: Among obese women, fertility and obstetric outcomes are influenced negatively with increased risk of miscarriage and a higher risk of maternal and neonatal complications. A recent large randomized controlled trial found no effect of lifestyle intervention on live birth in infertile obese women. STUDY DESIGN, SIZE, DURATION: A prospective, multicentre, randomized controlled trial was performed between 2010 and 2016 in the Nordic countries. In total, 962 women were assessed for eligibility and 317 women were randomized. Computerized randomization with concealed allocation was performed in the proportions 1:1 to one of two groups: weight reduction intervention followed by IVF-treatment or IVF-treatment only. One cycle per patient was included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Nine infertility clinics in Sweden, Denmark and Iceland participated. Women under 38 years of age planning IVF, and having a BMI ≥30 and <35 kg/m2 were randomized to two groups: an intervention group (160 patients) with weight reduction before IVF, starting with 12 weeks of a low calorie liquid formula diet (LCD) of 880 kcal/day and thereafter weight stabilization for 2-5 weeks, or a control group (157 patients) with IVF only. MAIN RESULTS AND ROLE OF CHANCE: In the full analysis set (FAS), the live birth rate was 29.6% (45/152) in the weight reduction and IVF group and 27.5% (42/153) in the IVF only group. The difference was not statistically significant (difference 2.2%, 95% CI: 12.9 to -8.6, P = 0.77). The mean weight change was -9.44 (6.57) kg in the weight reduction and IVF group as compared to +1.19 (1.95) kg in the IVF only group, being highly significant (P < 0.0001). Significantly more live births were achieved through spontaneous pregnancies in the weight reduction and IVF group, 10.5% (16) as compared to the IVF only group 2.6% (4) (P = 0.009). Miscarriage rates and gonadotropin dose used for IVF stimulation did not differ between groups. Two subgroup analyses were performed. The first compared women with PCOS in the two randomized groups, and the second compared women in the weight reduction group reaching BMI ≤ 25 kg/m2 or reaching a weight loss of at least five BMI units to the IVF only group. No statistical differences in live birth rates between the groups in either subgroup analysis were found. LIMITATIONS, REASON FOR CAUTION: The study was not powered to detect a small increase in live births due to weight reduction and was not blinded for the patients or physician. Further, the intervention group had a longer time to achieve a spontaneous pregnancy, but were therefore slightly older than the control group at IVF. The study only included women with a BMI lower than 35 kg/m2. WIDER IMPLICATIONS OF THE FINDINGS: The study suggests that weight loss for obese women (BMI: 30-34.9 kg/m2) may not rectify the outcome in IVF cycles, although a significant higher number of spontaneous conceptions occurred in the weight loss group. Also, the study suggests that intensive weight reduction with LCD treatment does not negatively affects the results. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by Sahlgrenska University Hospital (ALFGBG-70 940), Merck AB, Solna, Sweden (an affiliate of Merck KGaA, Darmstadt, Germany), Impolin AB, Hjalmar Svensson Foundation and Jane and Dan Olsson Foundation. Dr Thurin-Kjellberg reports grants from Merck, non-financial support from Impolin AB, during the conduct of the study, and personal fees from Merck outside the submitted work. Dr Friberg reports personal fees from Ferring, Merck, MSD, Finox and personal fees from Studentlitteratur, outside the submitted work. Dr Englund reports personal fees from Ferring, and non-financial support from Merck, outside the submitted work. Dr Bergh reports and has been reimbursed for: writing a newsletter twice a year (Ferring), lectures (Ferring, MSD, Merck), and Nordic working group meetings (Finox). Dr Karlström reports lectures (Ferring, Finox, Merck, MSD) and Nordic working group meetings (Ferring). Ms Kluge, Dr Einarsson, Dr Pinborg, Dr Klajnbard, Dr Stenlöf, Dr Larsson, Dr Loft and Dr Wistrand have nothing to disclose. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number, NCT01566929. TRIAL REGISTRATION DATE: 23-03-2012. DATE OF FIRST PATIENT'S ENROLMENT: 05-10-2010.
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Infertilidad Femenina/terapia , Obesidad/terapia , Adulto , Tasa de Natalidad , Femenino , Fertilización In Vitro , Humanos , Infertilidad Femenina/complicaciones , Nacimiento Vivo , Obesidad/complicaciones , Inducción de la Ovulación/métodos , Embarazo , Resultado del Embarazo , Estudios Prospectivos , Resultado del Tratamiento , Pérdida de PesoRESUMEN
PURPOSE: The aim of this study was to investigate whether the dependency of midlife stroke survivors had any long-term impact on their spouses' QALY-weights. METHOD: Data on stroke survivors, controls, and spouses were collected from the 7-year follow-up of the Sahlgrenska Academy Study on Ischemic Stroke. Health-related quality of life was assessed by the SF-36, and the preference-based health state values were assessed with the SF-6D. Spouses of dependent and independent stroke survivors were categorized according to their scores on the modified Rankin Scale. An ordinary least squares regression analysis was used to evaluate whether the dependency of the stroke survivors had any impact on the spouses' QALY-weights. RESULT: Cohabitant dyads of 247 stroke survivors aged <70 at stroke onset and 245 dyads of controls were included in the study. Spouses of dependent stroke survivors (n = 50) reported a significant lower mean QALY-weight of 0.69 in comparison to spouses of independent stroke survivors (n = 197) and spouses of controls, (n = 245) who both reported a mean QALY-weight of 0.77. The results from the regression analysis showed that higher age of the spouse and dependency of the stroke survivor had a negative association with the spouses' QALY-weights. CONCLUSION: The QALY-weights for spouses of dependent midlife stroke survivors were significantly reduced compared to spouses of independent midlife stroke survivors. This indicates that the inclusion of spouses' QALYs in evaluations of early treatment and rehabilitation efforts to reduce stroke patients' dependency would capture more of the total effect in dyads of stroke survivors.
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Años de Vida Ajustados por Calidad de Vida , Esposos/psicología , Accidente Cerebrovascular/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Accidente Cerebrovascular/mortalidad , SobrevivientesRESUMEN
AIMS/HYPOTHESIS: Canagliflozin, a sodium glucose co-transporter 2 inhibitor, reduces HbA1c, body weight and systolic BP (SBP) in patients with type 2 diabetes. As weight loss is known to reduce both HbA1c and SBP, these analyses were performed to evaluate the contribution of weight loss resulting from treatment with canagliflozin to HbA1c and SBP reductions in patients with type 2 diabetes. METHODS: Pooled data from four placebo-controlled Phase 3 studies (N = 2,250) in patients with type 2 diabetes were used in the analyses. In each study, patients were treated with placebo, canagliflozin 100 mg or canagliflozin 300 mg, once daily for 26 weeks. Changes from baseline in body weight, HbA1c and SBP were measured at week 26, and the contribution of weight loss to the lowering of HbA1c and SBP was obtained using ANCOVA. RESULTS: Canagliflozin 100 and 300 mg reduced mean body weight, HbA1c and SBP compared with placebo (p < 0.001 for each), and more patients had body-weight reductions >0%, ≥5% and ≥10% with canagliflozin treatment than with placebo. Weight-loss-independent and weight-loss-associated mechanisms contributed to HbA1c and SBP lowering with canagliflozin: ~85% of HbA1c lowering and ~60% of SBP lowering was independent of weight loss. CONCLUSIONS/INTERPRETATION: In patients with type 2 diabetes, canagliflozin provided clinically meaningful body-weight reductions, and the weight loss contributed to reductions in HbA1c and SBP.
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Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Canagliflozina/administración & dosificación , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hemoglobina Glucada/metabolismo , Adulto , Anciano , Canagliflozina/uso terapéutico , Diabetes Mellitus Tipo 2/complicaciones , Esquema de Medicación , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/uso terapéutico , Masculino , Persona de Mediana Edad , Sístole/efectos de los fármacos , Pérdida de PesoRESUMEN
Carbonic anhydrase inhibition reduces apnoeic events in sleep disordered breathing. Zonisamide inhibits carbonic anhydrase, and induces weight loss in obese patients. This study explored the relative influence of these two properties, which may both alleviate obstructive sleep apnoea (OSA). Continuous positive airway pressure (CPAP) was used as a standard care comparator. 47 patients with moderate-to-severe OSA and a body mass index of 27-35 kg·m(-2) were randomised to receive either zonisamide, placebo or CPAP for 4 weeks. The open extension phase (20 weeks) compared CPAP and zonisamide. Polysomnography, biochemistry and symptoms were evaluated. At 4 weeks, zonisamide reduced apnoea/hypopnoea index (AHI) by a mean±sd 33±39% and oxygen desaturation index by 28±31% (p=0.02 and 0.014, respectively; placebo adjusted). The mean compliance adjusted reduction of AHI after zonisamide and CPAP was 13 and 61%, respectively, (p=0.001) at 24 weeks. Body weight was marginally changed at 4 weeks, but reduced after zonisamide and increased after CPAP at 24 weeks (-2.7±3.0 kg versus 2.3±2.0 kg, p<0.001). Zonisamide decreased bicarbonate at 4 and 24 weeks. Side-effects were more common after zonisamide. Zonisamide reduced OSA independent of body weight potentially by mechanisms related to carbonic anhydrase inhibition. The effect was less pronounced than that obtained by CPAP.
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Inhibidores de Anhidrasa Carbónica/uso terapéutico , Isoxazoles/uso terapéutico , Apnea Obstructiva del Sueño/tratamiento farmacológico , Anciano , Antropometría , Índice de Masa Corporal , Peso Corporal , Anhidrasas Carbónicas/metabolismo , Presión de las Vías Aéreas Positiva Contínua , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cooperación del Paciente , Placebos , Polisomnografía , Sueño , Pérdida de Peso , ZonisamidaRESUMEN
BACKGROUND: The carbonic anhydrase inhibitor sulthiame reduces OSA severity, increases overnight oxygenation, and improves sleep quality. Insights into how sulthiame modulates OSA pathophysiologic features (endotypic traits) adds to our understanding of the breathing disorder itself, as well as the effects of carbonic anhydrases in respiratory regulation. RESEARCH QUESTION: How does sulthiame treatment modify endotypic traits in OSA? STUDY DESIGN AND METHODS: Per-protocol tertiary analysis of a randomized controlled trial with the inclusion criteria as follow: BMI, ≥ 20 to ≤ 35 kg/m2; age, 18-75 years; apnea-hypopnea index (AHI) ≥ 15 events/h; Epworth sleepiness scale score, ≥ 6; as well as nonacceptance or nontolerance of positive airway pressure treatment. Patients were randomized to receive placebo (n = 22), sulthiame 200 mg (n = 12), or sulthiame 400 mg (n = 24) during 4 weeks of treatment. Polysomnography was applied twice at baseline and follow-up. Endotypic traits were determined from polysomnography tracings (PUPBeta). Sulthiame plasma concentration was analyzed. Differences from baseline to follow-up (Δs) were analyzed with the analysis of covariance or Kruskal-Wallis H test and Pearson (r) or Spearman correlations (rs). RESULTS: Sulthiame (200-mg and 400-mg groups) consistently reduced loop gain (response to a 1-cycle/min disturbance, LG1; mean, -0.16 [95% CI, -0.18 to -0.13]; P < .05) in addition to increased ventilation at lowest decile of ventilatory drive (Vmin; median, +12 [95% CI, 4-20]; P < .05) and median ventilation at eupneic ventilatory drive (Vpassive; median, +4 [95% CI, 0-5]; P < .05). ΔLG1 correlated with ΔAHI percentage (200 mg: r = 0.65; P < .05). Vmin and Vpassive correlated with ΔAHI (all sulthiame: rs = -0.59 and rs = -0.65; P < .05 for all). The reduction of LG1 was seen already in the lower sulthiame concentration range, whereas changes in Vmin peaked in the higher range. INTERPRETATION: The effect of sulthiame in OSA may be explained by a reduction of ventilatory instability (LG1) as well as upper airway collapsibility (Vmin and Vpassive). TRIAL REGISTRY: European Union Drug Regulating Authorities Clinical Trials Database; No.: EudraCT 2017-004767-13; URL: https://www.clinicaltrialsregister.eu.
Asunto(s)
Bencenosulfonamidas , Apnea Obstructiva del Sueño , Tiazinas , Humanos , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/uso terapéutico , Apnea Obstructiva del Sueño/terapia , Tiazinas/farmacología , Tiazinas/uso terapéutico , Polisomnografía , Presión de las Vías Aéreas Positiva Contínua/métodosRESUMEN
OBJECTIVE: New drug treatments are under development in obstructive sleep apnea (OSA). The placebo effect is well recognized in various conditions, but its relevance in OSA is debated. In the current study we determined the influence of a placebo effect in studies of drug therapy in OSA. METHODS: A systematic review and meta-analysis (PROSPERO CRD42021229410) with searches in MEDLINE, Scopus, Web of Science and Cochrane CENTRAL from inception to 2021-01-19. Inclusion criteria were (i) RCTs of adults with OSA, (ii) drug intervention with placebo baseline and follow-up sleep study (iii) outcomes: apnea hypopnea index (AHI), mean oxygen saturation (mSaO2), oxygen desaturation index (ODI) and/or Epworth Sleepiness Scale (ESS). Risk-of-bias was assessed with Cochrane RoB 2. RESULTS: 7436 articles were identified and 29 studies included (n = 413). Studies were generally small (median n = 14), with 78% men, baseline AHI range 9-74 events/h and treatment duration range 1-120 days. Meta-analyses were conducted for main outcomes. Mean change of the primary outcome, AHI, was -0.84 (95% CI -2.98 to 1.30); mSaO2 and ODI estimations were also non-significant. ESS showed a trend towards a reduction of -1 unit. Subgroup analysis did not show significant differences. Risk-of-bias assessment indicated mostly low risk but studies were small with wide confidence intervals. CONCLUSIONS: In this meta-analysis we did not identify systematic placebo effects on the AHI, ODI or mSaO2 while ESS score showed a trend for a small reduction. These results have an impact on the design and interpretation of drug trials in OSA.
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Apnea Obstructiva del Sueño , Humanos , Oxígeno/metabolismo , Efecto Placebo , Apnea Obstructiva del Sueño/tratamiento farmacológico , Apnea Obstructiva del Sueño/metabolismo , Apnea Obstructiva del Sueño/fisiopatología , SomnolenciaRESUMEN
BACKGROUND: Obesity is associated with increased mortality. Weight loss improves cardiovascular risk factors, but no prospective interventional studies have reported whether weight loss decreases overall mortality. In fact, many observational studies suggest that weight reduction is associated with increased mortality. METHODS: The prospective, controlled Swedish Obese Subjects study involved 4047 obese subjects. Of these subjects, 2010 underwent bariatric surgery (surgery group) and 2037 received conventional treatment (matched control group). We report on overall mortality during an average of 10.9 years of follow-up. At the time of the analysis (November 1, 2005), vital status was known for all but three subjects (follow-up rate, 99.9%). RESULTS: The average weight change in control subjects was less than +/-2% during the period of up to 15 years during which weights were recorded. Maximum weight losses in the surgical subgroups were observed after 1 to 2 years: gastric bypass, 32%; vertical-banded gastroplasty, 25%; and banding, 20%. After 10 years, the weight losses from baseline were stabilized at 25%, 16%, and 14%, respectively. There were 129 deaths in the control group and 101 deaths in the surgery group. The unadjusted overall hazard ratio was 0.76 in the surgery group (P=0.04), as compared with the control group, and the hazard ratio adjusted for sex, age, and risk factors was 0.71 (P=0.01). The most common causes of death were myocardial infarction (control group, 25 subjects; surgery group, 13 subjects) and cancer (control group, 47; surgery group, 29). CONCLUSIONS: Bariatric surgery for severe obesity is associated with long-term weight loss and decreased overall mortality.
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Cirugía Bariátrica , Enfermedades Cardiovasculares/mortalidad , Obesidad/mortalidad , Obesidad/cirugía , Pérdida de Peso , Índice de Masa Corporal , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Factores de Riesgo , Suecia/epidemiologíaRESUMEN
BACKGROUND: Obesity is a risk factor for cancer. Intentional weight loss in the obese might protect against malignancy, but evidence is limited. To our knowledge, the Swedish Obese Subjects (SOS) study is the first intervention trial in the obese population to provide prospective, controlled cancer-incidence data. METHODS: The SOS study started in 1987 and involved 2010 obese patients (body-mass index [BMI] >or=34 kg/m(2) in men, and >or=38 kg/m(2) in women) who underwent bariatric surgery and 2037 contemporaneously matched obese controls, who received conventional treatment. While the main endpoint of SOS was overall mortality, the main outcome of this exploratory report was cancer incidence until Dec 31, 2005. Cancer follow-up rate was 99.9% and the median follow-up time was 10.9 years (range 0-18.1 years). FINDINGS: Bariatric surgery resulted in a sustained mean weight reduction of 19.9 kg (SD 15.6 kg) over 10 years, whereas the mean weight change in controls was a gain of 1.3 kg (SD 13.7 kg). The number of first-time cancers after inclusion was lower in the surgery group (n=117) than in the control group (n=169; HR 0.67, 95% CI 0.53-0.85, p=0.0009). The sex-treatment interaction p value was 0.054. In women, the number of first-time cancers after inclusion was lower in the surgery group (n=79) than in the control group (n=130; HR 0.58, 0.44-0.77; p=0.0001), whereas there was no effect of surgery in men (38 in the surgery group vs 39 in the control group; HR 0.97, 0.62-1.52; p=0.90). Similar results were obtained after exclusion of all cancer cases during the first 3 years of the intervention. INTERPRETATION: Bariatric surgery was associated with reduced cancer incidence in obese women but not in obese men. FUNDING: Swedish Research Council, Swedish Foundation for Strategic Research, Swedish Federal Government under the LUA/ALF agreement, Hoffmann La Roche, Cederoths, AstraZeneca, Sanofi-Aventis, Ethicon Endosurgery.
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Cirugía Bariátrica , Neoplasias/epidemiología , Neoplasias/prevención & control , Obesidad/cirugía , Pérdida de Peso , Adulto , Estudios de Casos y Controles , Ingestión de Energía , Femenino , Humanos , Masculino , Análisis por Apareamiento , Persona de Mediana Edad , Análisis Multivariante , Neoplasias/mortalidad , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Distribución por Sexo , Suecia/epidemiologíaRESUMEN
OBJECTIVE: The greater weight loss achieved following Biliopancreatic Diversion with Duodenal Switch (BPDS) versus Roux-en-Y Gastric Bypass (RYGB) has been attributed to the malabsorptive effects of BPDS. Increased weight loss after BPDS could also be underpinned by larger increases in energy expenditure. Hypothetically, the more radical reconfiguration of the small intestine in BPDS could result in an accentuated increase in meal associated thermogenesis (MAT). DESIGN: Female subjects (baseline mean age 40 years, mean BMI-55kg/m2) were assessed four years after randomization to BPDS (n = 6) or RYGB (n = 6). Energy expenditure (EE) and respiratory quotient (RQ) were measured by indirect calorimetry over 24 hours. A detailed protocol allowed for discrimination of basal metabolic rate (BMR), fasting EE and MAT as components of total energy expenditure (TEE) normalised for total and lean tissue by dual-energy x-ray absorptiometry. RESULTS: Median weight loss at follow-up was 1.5-fold higher following BPDS relative to RYGB, resulting in respective median BMIs of 29.5 kg/m2 (21.7 to 36.7) after BPDS and 37.8 kg/m2 (34.1 to 45.7) after RYGB (p = 0.015). The BPDS group had a lower fat:lean ratio compared to the RYGB group (p = 0.009). Overall 24-hour TEE adjusted for total tissue was higher in the BPDS group, as were BMR, fasting EE and MAT (all p<0.05). Differences between RYGB and BPDS in BMR and TEE were nullified when normalised for lean mass. Postprandial RQ increased significantly but to a similar extent in both groups. CONCLUSION: Enhanced and prolonged MAT and lower fat:lean mass ratios after BPDS may explain relative increases in total energy expenditure as compared to RYGB.
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Desviación Biliopancreática/métodos , Metabolismo Energético , Derivación Gástrica/métodos , Obesidad Mórbida/terapia , Adulto , Metabolismo Basal , Calorimetría Indirecta , Femenino , Humanos , Obesidad Mórbida/metabolismoRESUMEN
STUDY OBJECTIVES: To evaluate the effect of bariatric surgery on sleep apnea symptoms and obesity-associated morbidity in patients with severe obesity. DESIGN: Prospective study. SETTING: University hospitals and community centers in Sweden. INTERVENTION: We investigated the influence of weight loss surgery (n=1729) on sleep apnea symptoms and obesity-related morbidity using a conservatively treated group (n=1748) as a control. MEASUREMENTS AND RESULTS: Baseline BMI in surgical group (42.2+/-4.4 kg/m(2)) and control group (40.1+/-4.6 kg/m(2)) changed -9.7+/-5 kg/m(2) and 0+/-3 kg/m(2), respectively, at 2-year follow-up. In the surgery group, there was a marked improvement in all obstructive sleep apnea (OSA) symptoms compared with the control group (P <0.001). Persistence of snoring (21.6 vs 65.5%, adjusted OR 0.14, 95% CI 0.10-0.19) and apnea (27.9 vs 71.3%, adjusted OR 0.16, 95% I 0.10-0.23) were much less in the surgery group compared with controls. Compared with subjects with no observed apnea at follow-up (n=2453), subjects who continued to have or developed observed apnea (n=404) had a higher incidence of diabetes (adjusted OR 2.03, 95% CI 1.19-3.47) and hypertriglyceridemia (adjusted OR 1.86, 95% CI 1.07-3.25) but not hypertension (adjusted OR 1.09, 95% CI 0.65-1.83) or hypercholesterolemia (adjusted OR 0.91, 95% CI 0.53-1.58). CONCLUSION: Bariatric surgery results in a marked improvement in sleep apnea symptoms at 2 years. Despite adjustment for weight change and baseline central obesity, subjects reporting loss of OSA symptoms had a lower 2-year incidence of diabetes and hypertriglyceridemia. Improvement in OSA in patients losing weight may provide health benefits in addition to weight loss alone.
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Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiología , Obesidad/epidemiología , Apnea Obstructiva del Sueño/epidemiología , Pérdida de Peso , Adulto , Femenino , Humanos , Hipercolesterolemia/epidemiología , Hipertensión/epidemiología , Hipertrigliceridemia/epidemiología , Incidencia , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Factores de TiempoAsunto(s)
Cirugía Bariátrica , Obesidad Mórbida/cirugía , Adulto , Cirugía Bariátrica/economía , Cirugía Bariátrica/métodos , Cirugía Bariátrica/estadística & datos numéricos , Índice de Masa Corporal , Niño , Continuidad de la Atención al Paciente , Humanos , Obesidad Mórbida/prevención & control , Evaluación de Resultado en la Atención de Salud , Seguridad del Paciente , Evaluación de Programas y Proyectos de Salud , Programas Médicos Regionales , Asignación de Recursos , Suecia , Listas de EsperaRESUMEN
OBJECTIVES: Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, has been associated with weight loss in a broad range of patients with type 2 diabetes mellitus (T2DM). This analysis further evaluated changes in body weight and composition with canagliflozin in two 104-week, Phase 3 studies. METHODS: In Study 1, patients aged 18-80 years (N = 1,450) received canagliflozin 100 or 300 mg or glimepiride as add-on to metformin for a 52-week core treatment period, followed by a 52-week extension period. In Study 2, patients aged 55-80 years (N = 714) received canagliflozin 100 or 300 mg or placebo added to stable background antihyperglycemic agents for a 26-week core treatment period, followed by a 78-week extension period. Percent change from baseline in body weight; proportion of patients with any weight loss, ≥5% weight loss, and ≥10% weight loss; change in body mass index (BMI) and waist circumference; change in body weight across weight-loss quartiles; and changes in body composition were evaluated in both studies. RESULTS: Canagliflozin 100 and 300 mg provided sustained weight loss versus either glimepiride or placebo over 104 weeks. More patients experienced any weight loss and ≥5% weight loss with canagliflozin versus comparator. Across the 3 highest weight-loss quartiles, canagliflozin provided greater weight loss versus glimepiride or placebo. BMI and waist circumference reductions were observed with canagliflozin 100 and 300 mg versus either glimepiride or placebo over 104 weeks; more patients had BMI or waist circumference reductions with canagliflozin versus comparator. Body composition analysis indicated that the majority of weight loss was due to loss of fat mass. Canagliflozin was generally well tolerated, with increased incidence of adverse events related to the SGLT2 inhibition mechanism. CONCLUSIONS: Canagliflozin 100 and 300 mg provided sustained reductions in body weight, BMI, and waist circumference in a greater proportion of patients with T2DM versus glimepiride or placebo over 104 weeks. TRIAL REGISTRATION: ClinicalTrials.gov NCT00968812, NCT01106651.
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Adiposidad/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Canagliflozina/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacología , Pérdida de Peso , Anciano , Composición Corporal/efectos de los fármacos , Índice de Masa Corporal , Canagliflozina/uso terapéutico , Ensayos Clínicos Fase III como Asunto , Femenino , Humanos , Hipoglucemiantes/uso terapéutico , Masculino , Metformina/farmacología , Metformina/uso terapéutico , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Compuestos de Sulfonilurea/farmacología , Compuestos de Sulfonilurea/uso terapéutico , Factores de Tiempo , Circunferencia de la Cintura/efectos de los fármacosRESUMEN
OBJECTIVE: The mechanisms determining long-term weight maintenance after Roux-en-Y gastric bypass (RYGB) remain unclear. Cross sectional studies have suggested that enhanced energy expenditure (EE) may play a significant role and the aim of this study was to reveal the impact of RYGB on each major component constituting total EE. DESIGN: Six obese female subjects, without other co-morbidities, were assessed before and at 10 days, 3 and 20 months after RYGB. Indirect calorimetry in a metabolic chamber was used to assess 24 h EE at each study visit. Other measurements included body composition by DEXA, gut hormone profiles and physical activity (PA) using high sensitivity accelerometers. RESULTS: Median Body Mass Index decreased from 41.1 (range 39.1-44.8) at baseline to 28 kg/m2 (range 22.3-30.3) after 20 months (p<0.05). Lean tissue decreased from 55.9 (range 47.5-59.3) to 49.5 (range 41.1-54.9) kg and adipose tissue from 61 (range 56-64.6) to 27 (range 12-34.3) kg (both p<0.05). PA over 24 h did not change after surgery whereas 24 h EE and basal metabolic rate (BMR) decreased. EE after a standard meal increased after surgery when adjusted for total tissue (p<0.05). After an initial drop, RQ (respiratory quotient) had increased at 20 months, both as measured during 24 h and after food intake (p<0.05). CONCLUSION: RYGB surgery up-regulates RQ and EE after food intake resulting in an increased contribution to total EE over 24 h when corrected for total tissue.
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Anastomosis en-Y de Roux/efectos adversos , Ingestión de Alimentos , Metabolismo Energético , Obesidad/cirugía , Respiración , Composición Corporal , Femenino , HumanosRESUMEN
Recently, we demonstrated that intracerebroventricular injection of IL-6 increases energy expenditure and decreases body fat in rodents. Therefore, IL-6 may play a role in appetite and body weight control in the central nervous system. In the present study we evaluated cerebrospinal fluid (CSF) and serum IL-6 levels in humans in relation to body fat content and to CSF and serum levels of leptin. Thirty-two healthy overweight/obese male subjects with a body mass index range of 29.3-36.0 kg/m(2) were studied. Total and sc body fat were measured by dual energy x-ray absorptiometry and computed tomography, respectively. CSF IL-6 levels were in some individuals higher than serum IL-6 levels and correlated negatively with total body weight, sc and total body fat. In contrast, CSF leptin levels were 30-60 times lower than serum leptin levels and correlated positively with serum leptin, body weight, sc and total body fat. Furthermore, there was a negative correlation between CSF IL-6 and leptin. In conclusion, CSF IL-6 differs in many ways from CSF leptin. CSF IL-6 may be locally produced rather than serum derived, and body fat-regulating regions in the central nervous system may be exposed to insufficient IL-6 levels in more severe obesity.
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Tejido Adiposo/anatomía & histología , Composición Corporal/fisiología , Sistema Nervioso Central/metabolismo , Interleucina-6/líquido cefalorraquídeo , Obesidad/líquido cefalorraquídeo , Absorciometría de Fotón , Adulto , Peso Corporal/fisiología , Ensayo de Inmunoadsorción Enzimática , Humanos , Leptina/sangre , Leptina/líquido cefalorraquídeo , Masculino , Persona de Mediana Edad , Obesidad/patología , Albúmina Sérica/metabolismoRESUMEN
OBJECTIVE: Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed for treatment of type 2 diabetes mellitus (T2DM). The long-term efficacy and safety of canagliflozin monotherapy were evaluated over 52 weeks in patients with T2DM inadequately controlled with diet and exercise. RESEARCH DESIGN AND METHODS: This randomized, double-blind, Phase 3 study included a placebo-controlled, 26-week core period (canagliflozin 100 or 300 mg vs placebo) and an active-controlled, 26-week extension (blinded switch of placebo-treated patients to sitagliptin 100 mg [placebo/sitagliptin]). CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01081834. MAIN OUTCOME MEASURES: Efficacy endpoints assessed at 52 weeks included changes in hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), and systolic blood pressure (BP); and percentage changes in body weight and fasting plasma lipids. Adverse events (AEs) were recorded throughout the study. Efficacy data are reported for canagliflozin 100 and 300 mg (placebo/sitagliptin group was used to maintain the double-blind and to serve as a control group for safety purposes; not as an efficacy comparator); safety data are reported for canagliflozin 100 and 300 mg and placebo/sitagliptin. RESULTS: Efficacy analyses included 451 patients who were randomized and dosed, entered the extension, and did not receive rescue therapy during the core period. Safety analyses included 584 patients who were randomized and dosed. At Week 52, canagliflozin 100 and 300 mg provided dose-related decreases from baseline in HbA1c of -0.81% and -1.11%. Canagliflozin 100 and 300 mg decreased FPG (-1.5 and -2.2 mmol/L [-27.4 and -39.1 mg/dL]), body weight (-3.3% and -4.4%), and systolic BP (-1.4 and -3.9 mmHg); decreased triglycerides and increased HDL-C and LDL-C were also seen. Over 52 weeks, overall AE rates were 67.2%, 66.0%, and 64.1% with canagliflozin 100 and 300 mg and placebo/sitagliptin; rates of serious AEs and AE-related discontinuations were low across groups. Compared with placebo/sitagliptin, canagliflozin was associated with higher rates of genital mycotic infections and AEs related to osmotic diuresis; these led to few discontinuations. Rates of volume depletion AEs and documented hypoglycemia were low across groups. CONCLUSIONS: Canagliflozin monotherapy provided sustained improvement in glycemic control and body weight reduction, and was generally well tolerated in patients with T2DM over 52 weeks.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucósidos/uso terapéutico , Hipoglucemiantes/uso terapéutico , Pirazinas/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Tiofenos/uso terapéutico , Triazoles/uso terapéutico , Glucemia , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Canagliflozina , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Dieta , Método Doble Ciego , Ejercicio Físico , Femenino , Glucósidos/efectos adversos , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemia/inducido químicamente , Hipoglucemiantes/efectos adversos , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , Pirazinas/efectos adversos , Fosfato de Sitagliptina , Tiofenos/efectos adversos , Resultado del Tratamiento , Triazoles/efectos adversos , Triglicéridos/sangre , Pérdida de Peso/efectos de los fármacosRESUMEN
INTRODUCTION: Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed for the treatment of patients with type 2 diabetes mellitus (T2DM). Our randomized, double-blind, placebo-controlled, phase 3 study (www.clinicaltrials.gov: NCT01106651) evaluated the efficacy and safety of canagliflozin therapy in older subjects (aged 55-80 years) with T2DM inadequately controlled on their current regimen of blood glucose-lowering agents (any approved oral or injectable treatment). METHODS: Subjects (N = 716) aged 55 to 80 years (mean, 63.6 years) with glycated hemoglobin (HbA1c) levels ≥ 7.0% to ≤ 10.0% were randomized. Seven hundred fourteen received canagliflozin 100 mg or 300 mg or placebo (1:1:1) daily. The prespecified primary endpoint was change from baseline in HbA1c level at week 26. Prespecified secondary endpoints included proportion of subjects achieving HbA1c levels < 7.0%, change from baseline in fasting plasma glucose (FPG) level and systolic blood pressure (BP), and percent change from baseline in body weight, triglyceride levels, and high-density lipoprotein cholesterol (HDL-C) level. Adverse events (AEs) were reported throughout the study. RESULTS: At week 26, treatment with canagliflozin 100 mg and 300 mg significantly reduced HbA1c levels compared with placebo (-0.60%, -0.73%, -0.03%, respectively; P < 0.001); more subjects achieved HbA1c levels < 7.0% with both canagliflozin doses compared with placebo (P < 0.001). Both canagliflozin doses significantly reduced body weight, FPG level, and systolic BP, and increased HDL-C level compared with placebo (P < 0.001); low-density lipoprotein cholesterol level was increased with both canagliflozin doses compared with placebo. The overall AE incidence was slightly higher with canagliflozin 300 mg than with canagliflozin 100 mg or placebo (78.0%, 72.2%, 73.4%, respectively). Serious AE and AE-related discontinuation rates were low across groups. Both canagliflozin doses were associated with higher rates than placebo of genital mycotic infections, urinary tract infections, and osmotic diuresis-related AEs (ie, pollakiuria, polyuria). Documented hypoglycemia rates were modestly higher with both canagliflozin doses compared with placebo. CONCLUSION: Canagliflozin improved glycemic control, reduced body weight and systolic BP, and was generally well tolerated in older subjects with T2DM who were on background therapy with a variety of blood glucose-lowering agents.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucósidos/uso terapéutico , Hipoglucemiantes/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Tiofenos/uso terapéutico , Factores de Edad , Anciano , Anciano de 80 o más Años , Canagliflozina , Método Doble Ciego , Femenino , Glucósidos/efectos adversos , Glucósidos/farmacología , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Seguridad , Tiofenos/efectos adversos , Tiofenos/farmacologíaRESUMEN
BACKGROUND AND AIMS: Gastric bypass results in greater weight loss than Vertical banded gastroplasty (VBG), but the underlying mechanisms remain unclear. In addition to effects on energy intake the two bariatric techniques may differentially influence energy expenditure (EE). Gastric bypass in rats increases postprandial EE enough to result in elevated EE over 24 hours. This study aimed to investigate alterations in postprandial EE after gastric bypass and VBG in humans. METHODS: Fourteen women from a randomized clinical trial between gastric bypass (n = 7) and VBG (n = 7) were included. Nine years postoperatively and at weight stability patients were assessed for body composition and calorie intake. EE was measured using indirect calorimetry in a respiratory chamber over 24 hours and focused on the periods surrounding meals and sleep. Blood samples were analysed for postprandial gut hormone responses. RESULTS: Groups did not differ regarding body composition or food intake either preoperatively or at study visit. Gastric bypass patients had higher EE postprandially (p = 0.018) and over 24 hours (p = 0.048) compared to VBG patients. Postprandial peptide YY (PYY) and glucagon like peptide 1 (GLP-1) levels were higher after gastric bypass (both p<0.001). CONCLUSIONS: Gastric bypass patients have greater meal induced EE and total 24 hours EE compared to VBG patients when assessed 9 years postoperatively. Postprandial satiety gut hormone responses were exaggerated after gastric bypass compared to VBG. Long-term weight loss maintenance may require significant changes in several physiological mechanisms which will be important to understand if non-surgical approaches are to mimic the effects of bariatric surgery.