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CONTEXT: Glycemic variability and hypoglycemia during diabetes treatment may impact therapeutic effectiveness and safety, even when glycated hemoglobin (HbA1c) reduction is comparable between therapies. OBJECTIVE: We employed masked continuous glucose monitoring (CGM) during a randomized trial of dapagliflozin plus saxagliptin (DAPA+SAXA) vs insulin glargine (INS) to compare glucose variability and patient-reported outcomes (PROs). DESIGN: 24-week sub-study of a randomized, open-label, two-arm, parallel-group, phase 3b study. SETTING: Multicenter study (112 centers in 11 countries). PATIENTS: 283 adults with type 2 diabetes (T2D) inadequately controlled with metformin ± sulfonylurea. INTERVENTIONS: DAPA+SAXA vs INS. MAIN OUTCOME MEASURES: Changes in CGM profiles, HbA1c, and PROs. RESULTS: Changes from baseline in HbA1c with DAPA+SAXA were similar to those observed with INS, with mean difference [95% CI] between decreases of -0.12% [-0.37 to 0.12%], P = .33. CGM analytics were more favorable for DAPA+SAXA, including greater percent time in range (> 3.9 and ≤ 10 mmol/L; 34.3 ± 1.9 vs 28.5 ± 1.9%, P = .033), lower percent time with nocturnal hypoglycemia (area under the curve ≤ 3.9 mmol/L; 0.6 ± 0.5 vs 2.7 ± 0.5%, P = .007), and smaller mean amplitude of glycemic excursions (-0.7 ± 0.1 vs -0.3 ± 0.1 mmol/L, P = .017). Improvements in CGM were associated with greater satisfaction, better body weight image, less weight interference, and improved mental and emotional well-being. CONCLUSIONS: DAPA+SAXA and INS were equally effective in reducing HbA1c at 24 weeks, but people with T2D treated with DAPA+SAXA achieved greater time in range, greater reductions in glycemic excursions and variability, less time with hypoglycemia, and improved patient-reported health outcomes.
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Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin), although initially developed as glucose-lowering drugs, provide significant beneficial effects on cardiorenal outcomes, including heart failure, regardless of type 2 diabetes status. Integration of SGLT-2is into clinical practice requires practical guidance for physicians about their use. To overcome physicians' clinical inertia for SGLT-2i use, including addressing safety, potentially a barrier to their use, a roundtable discussion with physicians from three specialties (cardiology, endocrinology, and nephrology) was conducted. This review summarizes the physicians' clinical experience and recommendations about SGLT-2i use across different patient populations, taking into consideration the beneficial effects of SGLT-2is and their safety. The key aspects discussed regarding SGLT-2i safety include acute effects on kidney function (estimated glomerular filtration rate acute dip upon SGLT-2i initiation and acute kidney injury), volume depletion, diabetic ketoacidosis, genitourinary infections, hyperkalemia, and hypoglycemia. To mitigate any potential risks related to SGLT-2i safety, physicians can make minor adjustments to an individual patient's treatment plan, while retaining the SGLT-2i cardiorenal benefits for effective disease management. Recognition by physicians that the benefits of SGLT-2i use on clinical outcomes outweigh the risks will result in the integration of SGLT-2is into clinical practice and lead to improved patient care and outcomes.
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OBJECTIVE: Data on the real-world burden of herpes zoster (HZ) in adults with type 2 diabetes (T2D) in the U.S. are limited. We assessed HZ in patients with and without T2D and measured the impact of HZ on health care resource use (HCRU) and costs. RESEARCH DESIGN AND METHODS: This retrospective cohort analysis used U.S. commercial claims data (sourced from claims incurred between 1 January 2012 and 31 July 2018). HZ incidence rates/1,000 person-years (PYs) were calculated in patients with and without T2D. HZ risk was evaluated using Poisson regression to generate adjusted incidence rate ratios (aIRRs). Patients with T2D with HZ were propensity score matched to patients with T2D only and to patients with HZ without T2D. HCRU and costs were compared across cohorts during a 1-year follow-up period. Cox proportional hazards analyses evaluated factors associated with HZ-related complications. RESULTS: Crude HZ incidence rates in patients with and without T2D were 9.8/1,000 PY and 2.6/1,000 PY, respectively. T2D patients were almost twice as likely to be diagnosed with HZ (aIRR 1.84; 95% CI 1.82-1.85). HZ was associated with increased HCRU and health care costs. At 12 months, unadjusted incremental all-cause health care costs for patients with T2D with HZ versus patients with T2D without HZ were $5,216. The unadjusted incremental HZ-related health care costs for patients with T2D with HZ versus patients with HZ without T2D were $2,726. Age was the most important predictor for HZ-related complications. CONCLUSIONS: Given the increased risk of HZ and HCRU and cost burden in patients with T2D, HZ prevention in patients with T2D may be beneficial.
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Diabetes Mellitus Tipo 2 , Herpes Zoster , Adulto , Humanos , Incidência , Estudos Retrospectivos , Bases de Dados FactuaisRESUMO
In the original article, the Table 1 has published with error.
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OBJECTIVE: In patients with type 2 diabetes uncontrolled with metformin, exenatide once weekly (QW) plus dapagliflozin produced greater reductions in glycemic parameters (glycated hemoglobin [HbA1c], fasting plasma glucose [FPG], and 2-h postprandial glucose [2-h PPG]), weight, and systolic blood pressure (SBP) than exenatide QW or dapagliflozin alone after 28 weeks of treatment in DURATION-8. Following a 24-week extension period, improvements were sustained at 52 weeks. In this study, we investigated efficacy and safety at 104 weeks after randomization. RESEARCH DESIGN AND METHODS: DURATION-8 was a 104-week, multicenter, double-blind, randomized, active-controlled, phase 3 trial. In total, 695 adults (aged ≥18 years) with type 2 diabetes and inadequate glycemic control (HbA1c 8.0-12.0% [64-108 mmol/mol]) despite stable metformin monotherapy (≥1,500 mg/day) were randomly assigned (1:1:1) to receive exenatide 2 mg QW plus once-daily dapagliflozin 10 mg, exenatide QW plus placebo, or dapagliflozin plus placebo. All 104-week evaluations were exploratory. RESULTS: At week 104, 431 (62.0%) patients completed treatment. The adjusted least squares mean change (SE) from baseline to week 104 in HbA1c was greater with exenatide QW plus dapagliflozin (-1.70% [0.11]) versus exenatide QW plus placebo (-1.29% [0.12]; P = 0.007) and dapagliflozin plus placebo (-1.06% [0.12]; P < 0.001). Clinically relevant changes in FPG, 2-h PPG, weight, and SBP were also observed with exenatide QW plus dapagliflozin. There were no unexpected safety findings, and exenatide QW plus dapagliflozin was well tolerated, with no episodes of major hypoglycemia. CONCLUSIONS: In this exploratory analysis, among those individuals who completed the trial without rescue therapy, there was clinically relevant efficacy over 2 years with exenatide QW plus dapagliflozin, with no unexpected safety findings.
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Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Exenatida/administração & dosagem , Exenatida/efeitos adversos , Glucosídeos/administração & dosagem , Glucosídeos/efeitos adversos , Adolescente , Adulto , Idoso , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Hemoglobinas Glicadas/efeitos dos fármacos , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Masculino , Metformina/administração & dosagem , Metformina/efeitos adversos , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: The safety and efficacy of exenatide once weekly (EQW) is overall well established. EQW is primarily renally eliminated. In this study, the efficacy and renal and gastrointestinal tolerability of EQW were summarised in participants with type 2 diabetes and chronic kidney disease stage 3 (CKD3; moderate renal impairment; estimated glomerular filtration rate [eGFR] ≥ 30 to < 60 mL/min/1.73 m2) or CKD stage 2 (CKD2; mild renal impairment; eGFR ≥ 60 to < 90 mL/min/1.73 m2). METHODS: Data on participants with type 2 diabetes and baseline CKD3 or CKD2 from eight phase 3, double-blind or open-label studies with 26- or 28-week controlled treatment periods were pooled. Participants received EQW or a placebo/non-glucagon-like peptide-1 receptor agonist comparator (sitagliptin, metformin, pioglitazone, dapagliflozin and insulin). RESULTS: Participants with baseline CKD3 (N = 182) or CKD2 (N = 772) receiving EQW differed in a number of baseline characteristics, such as age < 65 years, race, mean body mass index and mean type 2 diabetes duration, whereas mean blood pressure and glycated haemoglobin (HbA1c) were similar. Mean reductions in HbA1c, body weight and systolic blood pressure from baseline to week 26/28 in participants receiving EQW were similar between the CKD subgroups. The proportions of participants (CKD3 and CKD2) with any adverse event (AE) were 81% and 72%, respectively, for EQW and 74% and 68%, respectively, for all comparators; those for serious AEs were 2.7% and 3.4%, respectively, for EQW and 6% and 5%, respectively, for all comparators. Gastrointestinal AE rates were higher in the EQW CKD3 subgroup (42.2% of participants) than in the CKD2 (32.8%) subgroup, although rates for nausea and vomiting were similar. There were no dehydration events; one participant in each treatment group had a serious AE of acute kidney injury (EQW with CKD3, n = 1; pioglitazone with CKD2, n = 1). CONCLUSION: Exenatide once weekly was well tolerated and demonstrated similar efficacy in participants with type 2 diabetes with mild and moderate renal impairment. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00637273, NCT00676338, NCT02229383, NCT02229396, NCT00641056, NCT01652729, NCT00935532, NCT01003184.
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Lichen myxedematosus (LM), commonly referred to as papular mucinosis, is a rare papular eruption defined by mucin deposition in the dermis. Scleromyxedema (SM) is a generalized papular and sclerodermoid form of LM. It is a progressive disease of unknown etiology with systemic manifestations that cause serious morbidity and mortality. Current criteria list thyroid dysfunction as an exclusion for the diagnosis of SM. Cases of LM associated with thyroid dysfunction have been defined as atypical. We describe a patient with uncontrolled hypothyroidism due to Hashimoto thyroiditis who subsequently developed a diffuse papular eruption with systemic signs and symptoms attributable to SM. Diagnostic workup, including laboratory studies and histologic specimens from the skin and muscle, were consistent with SM. Furthermore, our patient responded clinically to intravenous immunoglobulin (IVIg) and lenalidomide. We discuss the diagnostic criteria, differential diagnoses, and diagnostic challenges associated with LM in association with thyroid dysfunction. We propose that the presence of thyroid disease should not preclude the diagnosis of SM. Finally, we add to the case reports and series of successful treatments of SM with IVIg and lenalidomide.
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Doença de Hashimoto/complicações , Hipotireoidismo/complicações , Escleromixedema/diagnóstico , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Lenalidomida/administração & dosagem , Escleromixedema/tratamento farmacológicoRESUMO
AIM: Efficacy and safety of dapagliflozin plus saxagliptin (DAPA + SAXA) were compared with insulin glargine (INS) in patients with type 2 diabetes (T2D) in a 52-week extension study. MATERIALS AND METHODS: This international Phase 3 study randomized adults with T2D on metformin with/without sulphonylurea. They received DAPA + SAXA or INS for 24 weeks (short-term) with a 28-week (long-term) extension. Week 52 exploratory endpoints included adjusted mean change from baseline in glycated haemoglobin A1c (HbA1c) and body weight, and a proportion of patients achieving optimal glycaemic response without hypoglycaemia and without requiring rescue medication. RESULTS: Of the 1163 patients enrolled, 643 received treatment; 600 (DAPA + SAXA, 306; INS, 294) entered the long-term phase. At 52 weeks, HbA1c [adjusted least squares (LS) mean; 95% confidence interval (CI)] decreased more with DAPA + SAXA (-1.5% [-1.6%, -1.4%]) than with INS (-1.3% [-1.4%, -1.1%]); the LS mean difference (95% CI) was -0.25% (-0.4%, -0.1%; P = 0.009). Total body weight reduced with DAPA + SAXA [LS mean (95% CI): -1.8 kg (-2.4, -1.3)] and increased with INS [LS mean (95% CI): +2.8 kg (2.2, 3.3)]. More patients on DAPA + SAXA (17.6%) achieved HbA1c <7.0% without hypoglycaemia versus those on INS (9.1%). Rescue medication was required by 77 patients (23.8%) and 97 patients (30.4%) in the DAPA + SAXA and INS groups, respectively. CONCLUSION: DAPA + SAXA treatment was non-inferior to INS in reducing HbA1c and body weight, and in achieving optimal glycaemic control without hypoglycaemia in patients with T2D 52 weeks after initiation.
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Compostos Benzidrílicos , Diabetes Mellitus Tipo 2 , Glucosídeos , Insulina Glargina , Metformina , Adamantano/análogos & derivados , Adamantano/uso terapêutico , Adulto , Compostos Benzidrílicos/uso terapêutico , Glicemia , Peso Corporal , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptídeos/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Glucosídeos/uso terapêutico , Hemoglobinas Glicadas , Humanos , Hipoglicemiantes/efeitos adversos , Insulina Glargina/uso terapêutico , Masculino , Metformina/efeitos adversos , Metformina/uso terapêutico , Resultado do TratamentoRESUMO
AIM: To determine the effects of individual and combined therapies on plasma insulin, glucagon, ß-hydroxybutyrate (ß-OH) and associated metabolites. MATERIALS AND METHODS: In DURATION-8, the combination of once-weekly exenatide (EQW) + 10 mg dapagliflozin (Dapa) in patients with type 2 diabetes poorly controlled with metformin-reduced HbA1c levels and body weight (at weeks 28 and 52) was compared with EQW + placebo (Plb) or Dapa + Plb. The study included 678 patients randomized 1:1:1 to EQW + Dapa, EQW + Plb, or Dapa + Plb. Plasma insulin and glucagon were measured at fasting and 2 hours after a mixed meal. Fasting plasma free fatty acids (FFA) and ß-OH concentrations were measured. RESULTS: The fasting insulin-to-glucagon molar ratio (I/Glg) increased with EQW + Plb only; postprandial I/Glg increased in all groups but significantly more with EQW + Plb. ß-OH, FFA, and glycerol concentrations showed a parallel response: larger increments with Dapa + Plb, larger decrements with EQW + Plb, and intermediate changes with EQW + Dapa. ß-OH levels and I/Glg were inversely related to one another. Patients in the top quartile of ß-OH changes from baseline [median (interquartile range): +207 (305) vs. -65 (-154) µmol/L; P < .0001] were more frequently treated with Dapa + Plb, had higher urine glucose-to-creatinine ratios, and lower fasting insulin [52 (51) vs. 68 (53) pmol/L; P = .0013) and I/Glg [1.76 (1.49) vs. 2.23 (1.70) mol/mol; P = .0020]. Haematocrit increased only in the Dapa group. CONCLUSIONS: The EQW + Dapa combination abolished the Dapa-induced rise in ß-OH, reduced the EQW-induced increase in I/Glg, maintained glycosuria, and increased haematocrit in patients with poorly controlled type 2 diabetes. The drug combination may preserve any putative benefits while mitigating the risk of ketoacidosis.
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Compostos Benzidrílicos/administração & dosagem , Diabetes Mellitus Tipo 2 , Exenatida/administração & dosagem , Glucosídeos/administração & dosagem , Compostos Benzidrílicos/uso terapêutico , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Quimioterapia Combinada , Exenatida/uso terapêutico , Glucosídeos/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêuticoRESUMO
AIM: To assess the efficacy of exenatide (EXE) once weekly + dapagliflozin once daily (DAPA) versus each drug alone in reducing biomarkers of fatty liver/steatosis and fibrosis in a post hoc analysis of DURATION-8, a 104-week study in 695 patients with type 2 diabetes uncontrolled by metformin monotherapy. MATERIALS AND METHODS: We evaluated the impact of the study treatments on non-invasive markers of hepatic steatosis (fatty liver index [FLI] and non-alcoholic fatty liver disease [NAFLD] liver fat score), fibrosis (fibrosis-4 index [FIB-4]) and severe fibrosis (NAFLD fibrosis score), along with liver enzymes and insulin resistance, at weeks 28 and 52. All outcomes in this analysis were exploratory, with nominal P values reported. RESULTS: At week 28, biomarkers of fatty liver/steatosis and fibrosis were reduced from baseline in all treatment groups. At week 28, EXE once weekly + DAPA effects for decrease in FLI were stronger than those of EXE once weekly + placebo (PLB; -2.92, 95% confidence interval [CI] -5.11, -0.73; P = 0.0092) or DAPA+PLB (-2.77 [95% CI -4.93, -0.62]; P = 0.0119), and stronger than those of EXE once weekly + PLB at week 52 (-3.23 [95% CI -5.79, -0.68]; P = 0.0134). FIB-4 showed reduction versus baseline only in the EXE once weekly + DAPA group at both week 28 (-0.06 [95% CI -0.11, -0.01]; P = 0.0135) and week 52 (-0.05 [95% CI -0.09, -0.004]; P = 0.0308). CONCLUSIONS: The EXE once weekly + DAPA combination showed stronger effects than EXE once weekly + PLB or DAPA + PLB in ameliorating markers of hepatic steatosis and fibrosis in patients with type 2 diabetes. Prospective trials are needed to validate these findings.
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Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Compostos Benzidrílicos , Biomarcadores , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Exenatida/uso terapêutico , Fibrose , Glucosídeos , Humanos , Hipoglicemiantes/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Estudos ProspectivosRESUMO
OBJECTIVE: Among patients with type 2 diabetes uncontrolled with metformin, exenatide once weekly (QW) plus dapagliflozin combination produced greater reductions in glycemia, weight, and systolic blood pressure (SBP) at 28 weeks than exenatide QW or dapagliflozin alone (DURATION-8). Here, we investigated the safety and maintenance of efficacy at 52 weeks, after a 24-week extension. RESEARCH DESIGN AND METHODS: This phase 3, multicenter, double-blind study randomized adults with type 2 diabetes (with glycated hemoglobin [HbA1c] 8.0-12.0% [64-108 mmol/mol] and on metformin ≥1,500 mg/day) to exenatide QW (2-mg subcutaneous injection) plus once-daily dapagliflozin (10-mg oral tablet), exenatide QW plus oral placebo, or dapagliflozin plus injected placebo. Extension-period P values were nominal. RESULTS: Of 1,375 patients screened, 695 were randomized (mean baseline HbA1c 9.3% [78 mmol/mol]); 81.2% completed the study, and 75.3% completed treatment. At 52 weeks, HbA1c reductions were greater with exenatide QW plus dapagliflozin (least squares mean change -1.75% [-19.1 mmol/mol]) versus exenatide QW (-1.38% [-15.1 mmol/mol]; P = 0.006) or dapagliflozin (-1.23% [-13.4 mmol/mol]; P < 0.001); mean HbA1c values were 6.9% (52 mmol/mol), 7.2% (55 mmol/mol), and 7.4% (57 mmol/mol), respectively. Weight and SBP reductions were greater with exenatide QW plus dapagliflozin (-3.31 kg and -4.5 mmHg) versus exenatide QW (-1.51 kg and -0.7 mmHg; both P < 0.001) but similar to those with dapagliflozin (-2.28 kg and -2.7 mmHg; P = 0.057 and P = 0.100, respectively). The exenatide QW plus dapagliflozin regimen was well tolerated with no unexpected safety findings; more patients treated with exenatide QW experienced gastrointestinal and injection site-related adverse events. No major hypoglycemia occurred. CONCLUSIONS: Among patients with type 2 diabetes uncontrolled with metformin, exenatide QW plus dapagliflozin provided sustained improvements in glycemia, weight, and SBP over 52 weeks, with no unexpected safety findings.
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Compostos Benzidrílicos/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Exenatida/administração & dosagem , Glucosídeos/administração & dosagem , Hipoglicemiantes/administração & dosagem , Metformina/uso terapêutico , Administração Oral , Adulto , Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemia/induzido quimicamente , Injeções Subcutâneas , Masculino , Pessoa de Meia-IdadeRESUMO
This post hoc analysis assessed the effects on cardiovascular risk factors of body weight, systolic blood pressure (SBP) and triglycerides after 28 weeks' treatment with exenatide once weekly plus dapagliflozin, as compared with exenatide once weekly or dapagliflozin, in patient subpopulations from the DURATION-8 trial of patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin alone. Subgroups of patients were stratified according to their baseline body weight, SBP and triglyceride levels. Body weight, SBP and triglyceride levels were reduced across most respective subgroups, with no significant subgroup-by-treatment interactions. For each treatment, weight loss was numerically greater as baseline body mass index increased. SBP reductions were greater among patients with SBP ≥140 vs <140 mm Hg for exenatide once weekly plus dapagliflozin and exenatide once weekly. Reductions in triglyceride levels were greater among patients with baseline triglycerides <1.69 vs ≥1.69 mmol/L for each treatment. The combination of exenatide once weekly plus dapagliflozin reduced cardiovascular risk factors across baseline subgroups for each variable to a greater extent than did either individual drug; the greatest effects were observed in the high baseline subgroups for body weight and SBP.
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Compostos Benzidrílicos/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Exenatida/administração & dosagem , Glucosídeos/administração & dosagem , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Fármacos Antiobesidade/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Índice de Massa Corporal , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Hemoglobinas Glicadas/metabolismo , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Triglicerídeos/metabolismoRESUMO
Primary hyperparathyroidism (PHPT) can be associated with a variety of musculoskeletal complaints, which occasionally can be the leading or presenting manifestation. In this paper, we describe the musculoskeletal manifestations observed in patients with primary hyperparathyroidism. Medical record reviews of a select population of 74 patients with primary hyperparathyroidism are seen in a rheumatology practice. Bone manifestations included back pain in 11 patients (15.2 %), generalized bone pain in 7 patients (9.7 %), rib cage/chest pain in 6 (8.3 %), pseudoclubbing in 3, and a giant cell tumor of the mandible in 2 (2.3 %) patients. Articular manifestations such as chondrocalcinosis with or without apatite deposition disease were seen in 13 (17.7 %), arthralgias in 11 (15.2 %), and non-specific synovitis in 7 (9.7 %). Muscle weakness was observed in six patients (8.3 %) and myalgias in three (4.6 %). Less common manifestations such as Achilles tendon rupture, Jaccoud-like arthropathy, sacral insufficiency fracture, arthritis associated with fever of unknown origin (FUO), meningitis, cervical cord compression, and persistent headache were observed in single patients. Musculoskeletal findings are still a frequent and important presentation in patients with primary hyperparathyroidism seen in rheumatology practice. Some of these manifestations can be quite unusual and may represent diagnostic dilemmas to the practicing rheumatologist and/or endocrinologist.
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Hiperparatireoidismo Primário/complicações , Doenças Musculoesqueléticas/complicações , Condrocalcinose/sangue , Condrocalcinose/complicações , Condrocalcinose/diagnóstico , Feminino , Humanos , Hiperparatireoidismo Primário/diagnóstico , Masculino , Pessoa de Meia-Idade , Doenças Musculoesqueléticas/sangue , Doenças Musculoesqueléticas/diagnóstico , Osteíte Fibrosa Cística/sangue , Osteíte Fibrosa Cística/complicações , Osteíte Fibrosa Cística/diagnóstico , Hormônio Paratireóideo/sangue , ReumatologiaRESUMO
BACKGROUND: Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce glycaemia and weight, and improve cardiovascular risk factors via different mechanisms. We aimed to compare the efficacy and safety of co-initiation of the GLP-1 receptor agonist exenatide and the SGLT2 inhibitor dapagliflozin with exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled by metformin. METHODS: DURATION-8 was a 28 week, multicentre, double-blind, randomised, active-controlled phase 3 trial done at 109 sites in six countries. Adults (aged ≥18 years) with type 2 diabetes and inadequate glycaemic control (HbA1c 8-12% [64-108 mmol/mol]) despite stable metformin monotherapy (≥1500 mg/day) were randomly assigned (1:1:1), via an interactive voice and web-response system, to receive once-weekly exenatide 2 mg by subcutaneous injection plus once-daily dapagliflozin 10 mg oral tablets, exenatide with dapagliflozin-matched oral placebo, or dapagliflozin with exenatide-matched placebo injections. Randomisation was stratified by baseline HbA1c (<9·0% vs ≥9·0% [<75 mmol/mol vs ≥75 mmol/mol]). The primary endpoint was change in HbA1c from baseline to week 28. Secondary endpoints were the change from baseline in fasting plasma glucose at week 2 and week 28, and 2 h postprandial glucose at week 28; the proportion of patients with an HbA1c less than 7·0% (<53 mmol/mol) at week 28; change in weight at week 28; the proportion of patients with weight loss of 5% or more at week 28; and change in systolic blood pressure at week 28. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02229396. FINDINGS: Between Sept 4, 2014, and Oct 15, 2015, we randomly assigned 695 patients to receive exenatide plus dapagliflozin (n=231), exenatide alone (n=231; n=1 untreated), or dapagliflozin alone (n=233). The intention-to-treat population comprised 685 participants (mean HbA1c 9·3% [SD 1·1]; 78 mmol/mol [12]), of whom 611 (88%) completed the study. After 28 weeks, the change in baseline HbA1c was -2·0% (95% CI -2·1 to -1·8) in the exenatide plus dapagliflozin group, -1·6% (-1·8 to -1·4) in the exenatide group, and -1·4% (-1·6 to -1·2) in the dapagliflozin group. Exenatide plus dapagliflozin significantly reduced HbA1c from baseline to week 28 compared with exenatide alone (-0·4% [95% CI -0·6 to -0·1]; p=0·004) or dapagliflozin alone (-0·6% [-0·8 to -0·3]; p<0·001). Exenatide plus dapagliflozin was significantly superior to either drug alone for all secondary efficacy endpoints, with greater reductions in fasting plasma and postprandial glucose, more patients with an HbA1c less than 7·0% (<53 mmol/mol), greater weight loss, a greater proportion of patients with weight loss of 5% or more, and greater reductions in systolic blood pressure (all p≤0·025). Adverse events were recorded in 131 (57%) of 231 patients in the exenatide plus dapagliflozin group, 124 (54%) of 230 patients in the exenatide group, and 121 (52%) of 233 patients in the dapagliflozin group. The most common adverse events (≥5% of patients in any group) were diarrhoea, injection-site nodules, nausea, and urinary tract infections. No episodes of major hypoglycaemia or minor hypoglycaemia were reported. INTERPRETATION: Co-initiation of exenatide and dapagliflozin improved various glycaemic measures and cardiovascular risk factors in patients with type 2 diabetes inadequately controlled by metformin monotherapy. The dual treatment regimen was well tolerated, with the expected safety profile for this combination. Additional data from an ongoing study (eg, AWARD-10; NCT02597049) will further inform the use of these drug classes in combination. FUNDING: AstraZeneca.
Assuntos
Compostos Benzidrílicos/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/administração & dosagem , Hipoglicemiantes/administração & dosagem , Peptídeos/administração & dosagem , Peçonhas/administração & dosagem , Adulto , Idoso , Compostos Benzidrílicos/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Exenatida , Feminino , Glucosídeos/efeitos adversos , Humanos , Hipoglicemiantes/efeitos adversos , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Peptídeos/efeitos adversos , Falha de Tratamento , Peçonhas/efeitos adversosRESUMO
BACKGROUND: While many patients experience prolonged survival after pancreatic resection for benign or malignant disease, the long-term risk of pancreatogenic diabetes mellitus (DM) remains poorly characterized. METHODS: One thousand one hundred seven patients underwent pancreatectomy at Thomas Jefferson University between 2006 and 2013. Attempts were made to contact all living patients by telephone and a DM-focused questionnaire was administered. RESULTS: Two hundred fifty-nine of 691 (37 %) surviving patients completed the survey, including 179 pancreaticoduodenectomies (PD), 78 distal pancreatectomies (DP), and 2 total pancreatectomies. In the PD group, 44 (25 %) patients reported having DM prior to resection. Of these, 5 (12 %) had improved glucose control after resection and 21 (48 %) reported escalated DM medication requirements post-resection. Of 135 PD patients without preoperative DM, 24 (18 %) had new-onset DM postoperatively. In the DP group, 23 patients (29 %) had DM preoperatively. None had improved glucose control after resection, while six (26 %) had worse control after resection. Seventeen of 55 DP patients (31 %) without preoperative DM developed new-onset DM postoperatively (p = 0.04 vs. PD). Preoperative HgbA1C >6.0 %, glucose >124 mg/dL, and insulin use >2 units per day were associated with an increased risk of new-onset postoperative DM. CONCLUSIONS: The development or worsening of DM after pancreatic resection is extremely common, with different types of resections conveying different risks for disease progression. DP places patients at a greater risk for the development of new-onset postoperative diabetes when compared to PD. In contrast, patients with preoperative diabetes are more likely to experience worsening of their disease after PD as compared to DP. Patients should be screened prospectively, particularly those at highest risk, and informed of and educated about the potential for post-resection DM.
Assuntos
Diabetes Mellitus/etiologia , Pancreatectomia/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Glicemia/metabolismo , Diabetes Mellitus/sangue , Diabetes Mellitus/tratamento farmacológico , Progressão da Doença , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pancreatectomia/métodos , Pancreatopatias/cirurgia , Pancreaticoduodenectomia/efeitos adversos , Período Pós-Operatório , Índice de Gravidade de Doença , Fatores de TempoRESUMO
Objective. To report an unusual case of ovarian Leydig cell hyperplasia resulting in virilization in a postmenopausal woman. Methods. Patient's medical history and pertinent literature were reviewed. Results. A 64-year-old woman presented with virilization with worsening hirsutism, deepening of her voice, male musculature, and male pattern alopecia. Her pertinent past medical history included type 1 diabetes, hyperlipidemia, and hypertension. Her pertinent past surgical history included hysterectomy due to fibroids. On further work-up, her serum total testosterone was 506 ng/dL (nl range: 2-45) and free testosterone was 40 pg/mL (nl range: 0.1-6.4). After ruling out adrenal causes, the patient underwent an empiric bilateral oophorectomy that showed Leydig cell hyperplasia on pathology. Six weeks postoperatively, serum testosterone was undetectable with significant clinical improvement. Conclusion. Postmenopausal hyperandrogenism can be the result of numerous etiologies ranging from normal physiologic changes to ovarian or rarely adrenal tumors. Our patient was found to have Leydig cell hyperplasia of her ovaries, a rarely reported cause of virilization.
RESUMO
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents with a novel insulin-independent mechanism of action. The SGLT2 is a transporter found in the proximal tubule of the kidney and is responsible for approximately 90% of renal glucose reabsorption. The SGLT2 inhibitors reduce reabsorption of glucose in the kidney, resulting in glucose excretion in the urine (50-90 g of ~180 g filtered by the kidneys daily), which in turn lowers plasma glucose levels in people with diabetes. The insulin-independent mechanism of action of SGLT2 inhibitors dictates that they are associated with a very low risk of hypoglycemia and can be used in patients with any degree of ß-cell function or insulin sensitivity. Clinical trials have shown that SGLT2 inhibitors are effective at reducing blood glucose levels, body weight, and blood pressure when used as monotherapy or in combination with other antidiabetic agents in patients with type 2 diabetes mellitus. Treatment with SGLT2 inhibitors is generally well tolerated, although these agents have been associated with an increased incidence of genital infections. The SGLT2 inhibitors have become a valuable addition to the armory of drugs used to treat patients with type 2 diabetes mellitus, and several agents within the class are currently under investigation in phase III clinical trials.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Glucose/metabolismo , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose , Glicemia/metabolismo , Pressão Sanguínea , Peso Corporal , Ensaios Clínicos como Assunto , Quimioterapia Combinada , Glicosúria/metabolismo , Humanos , Hipoglicemia/epidemiologia , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Rim/metabolismoRESUMO
OBJECTIVE: To assess the efficacy and safety of dapagliflozin as add-on therapy in patients with type 2 diabetes who were inadequately controlled with a dipeptidyl peptidase-4 inhibitor with or without metformin. RESEARCH DESIGN AND METHODS: In this 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 study with a 24-week blinded extension period, 432 patients were randomized to receive dapagliflozin 10 mg/day or placebo added to sitagliptin (100 mg/day) ± metformin (≥1,500 mg/day). RESULTS: Baseline HbA1c and FPG levels were 7.9% (63.0 mmol/mol) and 162.2 mg/dL (9.0 mmol/L) for the dapagliflozin group and 8.0% (64.0 mmol/mol) and 163 mg/dL (9.0 mmol/L) for placebo. At week 24, dapagliflozin significantly reduced mean HbA1c levels (-0.5% [-4.9 mmol/mol]) versus placebo (0.0% [+0.4 mmol/mol]). Dapagliflozin reduced body weight versus placebo (-2.1 and -0.3 kg) and reduced HbA1c levels in patients with baseline values ≥8.0% (-0.8% [8.7 mmol/mol] and 0.0% [0.3 mmol/mol]) and fasting plasma glucose levels (-24.1 mg/dL [-1.3 mmol/L] and 3.8 mg/dL [0.2 mmol/L]). Similar results were observed when data were stratified by background therapy. Glycemic and weight benefits observed at week 24 were maintained through week 48. Changes from baseline in systolic blood pressure at week 8 were not significantly different between treatment groups. Over 48 weeks, fewer patients receiving dapagliflozin were discontinued or rescued for failing to achieve glycemic targets compared with placebo. Adverse events were balanced between groups, and discontinuation rates were low. At week 48, signs and symptoms suggestive of genital infection were more frequent with dapagliflozin (9.8%) than with placebo (0.4%). Signs and symptoms suggestive of urinary tract infection were balanced between dapagliflozin (6.7%) and placebo (6.2%). CONCLUSIONS: These results suggest that in patients with type 2 diabetes, inadequately controlled on sitagliptin with or without metformin, add-on treatment with dapagliflozin provides additional clinical benefit and is well tolerated.
Assuntos
Compostos Benzidrílicos/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/administração & dosagem , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Pirazinas/administração & dosagem , Triazóis/administração & dosagem , Compostos Benzidrílicos/efeitos adversos , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Glucosídeos/efeitos adversos , Hemoglobinas Glicadas/efeitos dos fármacos , Humanos , Hipoglicemiantes/efeitos adversos , Masculino , Metformina/efeitos adversos , Pessoa de Meia-Idade , Pirazinas/efeitos adversos , Fosfato de Sitagliptina , Resultado do Tratamento , Triazóis/efeitos adversos , Infecções Urinárias/induzido quimicamente , Redução de Peso/efeitos dos fármacosRESUMO
Sodium-glucose co-transporter 2 (SGLT2) plays a key role in glucose homeostasis as the key transporter responsible for most renal glucose reabsorption in the proximal tubules of the kidney. Dapagliflozin is a potent, selective, and reversible inhibitor of SGLT2 that lowers blood glucose levels in an insulin-independent fashion. This novel agent has been studied extensively in patients with type 2 diabetes mellitus (T2DM). In these clinical trials, dapagliflozin significantly decreased glycated hemoglobin and fasting plasma glucose levels when administered alone or as add-on treatment in patients who were already receiving metformin, a sulfonylurea (glimepiride), pioglitazone, or insulin. Moreover, dapagliflozin decreased body weight when taken as monotherapy or in combination with metformin, a sulfonylurea, or insulin, and mitigated weight gain in patients receiving pioglitazone. Consistent with preclinical toxicology studies, dapagliflozin has a manageable adverse event profile that is largely predictable from its mechanism of action. While there are no clinically significant negative effects on renal function or electrolytes, dapagliflozin treatment is associated with increased frequencies of urinary tract infections and vulvovaginitis/balanitis. With a mechanism of action that is distinct from and complementary to that of existing antihyperglycemic therapies, dapagliflozin is an effective antihyperglycemic agent that is well tolerated and may enhance weight loss. As such, dapagliflozin promises to become an important adjunctive therapy for comprehensive treatment of T2DM.