RESUMO
Sodium-glucose co-transporter-2 inhibitors (SGLT2i) have renal and cardiovascular benefits in addition to their glucose-lowering potential. Data on the efficacy and safety of SGLT2i in Australian Aboriginal and Torres-Strait Islanders are lacking. We conducted a single-centre retrospective study assessing the safety and effects on glycaemic control and albuminuria of SGLT2i in Aboriginal and Torres Strait Islander patients with type 2 diabetes mellitus.
Assuntos
Diabetes Mellitus Tipo 2 , Inibidores do Transportador 2 de Sódio-Glicose , Simportadores , Humanos , Austrália/epidemiologia , Povos Aborígenes Australianos e Ilhéus do Estreito de Torres , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose , Estudos Retrospectivos , Sódio , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêuticoRESUMO
OBJECTIVE: The objective of this study is to assess the relationship between hypothalamic-pituitary-adrenal (HPA) axis activity, vascular function and insulin sensitivity in healthy adults. DESIGN: Open observational study. PATIENTS: Thirty healthy adults were studied at the Endocrine Research Unit, Repatriation General Hospital, Adelaide, SA, Australia. MEASUREMENTS: HPA activity was assessed from the serum cortisol 30 min after 1 µg ACTH1-24 (Novartis Pharmaceuticals). Subjects with a cortisol below (n = 15) and above (n = 15) the median were categorized as low and high responders, respectively. Reactive hyperaemia index (RHI) was measured fasting to estimate endothelial function. Matsuda index was calculated from glucose and insulin concentrations collected fasting and 30 minutely for 2 h after a mixed meal (10 kcal/kg, 45% carbohydrate, 15% protein, 40% fat). The primary endpoint was the difference in RHI between low and high responders. RESULTS: There were no significant differences in age (61 ± 9 vs. 64 ± 7 years, p = .19), body mass index (BMI; 26 ± 3 vs. 24 ± 4 kg/m2 , p = .25) and sex (p = .71) between low and high responders. High responders had a lower RHI (2.1 ± 0.2 vs. 2.6 ± 0.2, p = .04) than low responders and there was a negative association between RHI and peak cortisol post ACTH1-24 (ß = -.56, p < .01). There were no significant differences in Matsuda index (15.0 ± 2.4 vs. 22.7 ± 5.2, p = .19) between high and low responders. CONCLUSION: In healthy adults, endothelial dysfunction is likely to contribute to the association between HPA hyperactivity and increased cardiovascular risk. As insulin sensitivity was not different in high and low responders, endothelial dysfunction is not primarily secondary to insulin resistance.
Assuntos
Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Hormônio Adrenocorticotrópico/metabolismo , Adulto , Humanos , Hidrocortisona , Sistema Hipotálamo-Hipofisário/metabolismo , Insulina , Sistema Hipófise-Suprarrenal/metabolismoRESUMO
AIM: Prednisolone causes hyperglycaemia predominantly between midday and midnight. Consequently, glargine-based basal-bolus insulin regimens may under treat daytime hyperglycaemia and cause nocturnal hypoglycaemia. We investigated whether an isophane-based insulin regimen is safer and more effective than a glargine-based regimen in hospitalized patients. MATERIALS AND METHODS: Fifty inpatients prescribed ≥20 mg/day prednisolone acutely with (1) finger prick blood glucose level (BGL) ≥15 mmol/L or (2) BGLs ≥10 mmol/L within the previous 24 hours were randomized to either insulin isophane or glargine before breakfast and insulin aspart before meals. The initial daily insulin dose was 0.5 U/kg bodyweight or 130% of the current daily insulin dose. Glycaemic control was assessed using a continuous glucose monitoring system. RESULTS: On Day 1, there were no significant differences in percentage of time outside a target glucose range of 4 to 10 mmol/L (41.3% ± 5.5% vs 50.0% ± 5.7%, P = .28), mean daily glucose (10.2 ± 0.7 vs 10.8 ± 0.8 mmol/L, P = .57) or glucose <4 mmol/L (2.2% ± 1.1% vs 2.0% ± 1.3%, P = .92) in patients randomized to isophane and glargine. In patients treated for 3 days, the prednisolone dose was reduced ( P = .02) and the insulin dose was increased over time ( P = .02), but the percentage of time outside the 4 to 10 mmol/L glucose range did not differ over time ( P = .45) or between groups ( P = .24). CONCLUSIONS: There were no differences in the efficacy or safety of the isophane and glargine-based insulin regimens. We recommend an initial daily insulin dose of 0.5 units/kg bodyweight if not on insulin, a greater than 30% increase in pre-prednisolone insulin dose and larger insulin dose adjustments in patients with prednisolone-induced hyperglycaemia.
Assuntos
Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Insulina Glargina/administração & dosagem , Insulina Isófana/administração & dosagem , Prednisolona/efeitos adversos , Idoso , Glicemia/efeitos dos fármacos , Esquema de Medicação , Feminino , Hospitalização , Humanos , Hiperglicemia/induzido quimicamente , Hipoglicemia/induzido quimicamente , Pacientes Internados , Insulina/administração & dosagem , Insulina Aspart/administração & dosagem , Masculino , Refeições , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
OBJECTIVE: Glucocorticoids can cause postprandial hyperglycaemia, but the effects on postprandial energy and fat metabolism are uncertain. We investigated the effects of acute and chronic low-dose prednisolone on fasting and postprandial energy expenditure and substrate metabolism. DESIGN: An open interventional and cross-sectional study was undertaken. PATIENTS AND MEASUREMENTS: Eighteen patients who had not taken oral glucocorticoids for ≥6 months were studied before and after 7 days prednisolone (6 mg/day) to assess the acute effects of prednisolone. Baseline data from patients, not on glucocorticoids, were compared with 18 patients on long-term prednisolone (6·5 ± 1·8 mg/day for >6 months) to assess the chronic effects. Energy expenditure and substrate oxidation were measured using indirect calorimetry before and after a mixed meal. Adipocyte insulin resistance index and insulin-mediated suppression of NEFA were calculated from fasting and postprandial insulin and NEFA concentrations. RESULTS: There were no significant differences in resting energy expenditure or diet-induced thermogenesis with prednisolone. Acute (-2·1 ± 6·2 vs -16·3 ± 4·8 mg/min, P = 0·01) and chronic (-1·4 ± 2·8 vs -16·3 ± 4·8 mg/min, P = 0·01) prednisolone attenuated postprandial suppression of fat oxidation. Chronic (31·6 ± 3·8 vs 17·0 ± 3·3, P = 0·007), but not acute, prednisolone increased adipocyte insulin resistance index. However, insulin-mediated suppression of NEFA was not significantly different after acute or chronic prednisolone. CONCLUSIONS: Prednisolone does not alter energy expenditure. However, even at low doses, prednisolone exerts adverse effects on fat metabolism, which could exacerbate insulin resistance and increase cardiovascular risk. Attenuated postprandial suppression of fat oxidation, but not lipolysis, suggests that prednisolone causes greater insulin resistance in skeletal muscle than in adipocytes.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Metabolismo Energético/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Prednisolona/farmacologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Idoso , Calorimetria Indireta , Ácidos Graxos não Esterificados/análise , Feminino , Humanos , Resistência à Insulina , Lipólise , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Oxirredução , Prednisolona/administração & dosagem , Termogênese/efeitos dos fármacosRESUMO
OBJECTIVE: Postprandial hyperglycaemia is associated with increased arterial stiffness and cardiovascular events. Low-dose prednisolone causes insulin resistance that typically manifests as postprandial hyperglycaemia. We investigated whether prednisolone causes postprandial vascular dysfunction in a cohort of patients with rheumatoid arthritis. DESIGN: An open interventional and cross-sectional study was undertaken. PATIENTS AND MEASUREMENTS: Eighteen subjects with rheumatoid arthritis who had not taken oral glucocorticoids for ≥6 months were studied before and after prednisolone 6 mg/day for 7 days to determine the acute effects of prednisolone. Pre-prednisolone data were compared to 18 subjects with rheumatoid arthritis taking long-term (>6 months) prednisolone (6·5 ± 1·8 mg/day) to assess the chronic effects of prednisolone. Augmentation index (by applanation tonometry) and reactive hyperaemia index (by peripheral artery tonometry) were measured before and after a mixed-meal (10 kcal/kg, 45% carbohydrate, 15% protein, 40% fat). Insulin sensitivity was estimated by the Matsuda index and sympathetic nervous system activity from urinary noradrenaline excretion. RESULTS: Matsuda index was lower after acute (2·0 ± 1·0 vs 3·6 ± 1·1, P = 0·01) and chronic (1·9 ± 1·0 vs 3·6 ± 1·1, P = 0·04) prednisolone. Postprandial augmentation index was lower after acute prednisolone (2551 ± 197 vs 2690 ± 272%*min, P ≤ 0·001), but not chronic prednisolone. There were no significant differences in reactive hyperaemia index with acute or chronic prednisolone. Noradrenaline excretion was lower after acute (54 ± 8 vs 93 ± 23 nmol/6 h, P = 0·02), but not chronic, prednisolone. CONCLUSIONS: Prednisolone-induced insulin resistance is not associated with postprandial vascular dysfunction in patients with rheumatoid arthritis. Reduced sympathetic activity may contribute to the reduction in postprandial arterial stiffness with acute prednisolone.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Glicemia/análise , Resistência à Insulina/fisiologia , Prednisolona/uso terapêutico , Idoso , Artrite Reumatoide/sangue , Artrite Reumatoide/fisiopatologia , Estudos Transversais , Esquema de Medicação , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Humanos , Hiperglicemia/sangue , Hiperglicemia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Prednisolona/administração & dosagem , Fatores de Tempo , Resultado do Tratamento , Rigidez Vascular/efeitos dos fármacosRESUMO
Few studies have evaluated the performance of flash glucose monitoring in hospitalized patients requiring intravenous insulin therapy. In this prospective study, an intravenous insulin infusion was adjusted hourly using flash glucose monitoring in hospitalized adults with prednisolone-associated hyperglycemia. The difference in paired point of care (POC) and flash glucose measurements and risk of severe hyper- or hypoglycemia (assessed by Clarke error grid analysis) were assessed. Glucose concentration measured by flash glucose monitoring was lower than POC glucose (mean difference 1.5 mmol/L [27 mg/dL], p < 0.001); however, mean POC glucose was within the target range (9.1 ± 4.1 mmol/L [164 ± 72 mg/dL]) and 97.8% of glucose measurements were within Zone A and B on error grid analysis. Flash glucose monitoring could be used in combination with POC glucose monitoring to minimize the frequency of finger prick blood glucose levels in hospitalized patients prescribed an intravenous insulin infusion.
Assuntos
Hiperglicemia , Insulina , Adulto , Humanos , Insulina/uso terapêutico , Glicemia/análise , Automonitorização da Glicemia , Monitoramento Contínuo da Glicose , Prednisolona/uso terapêutico , Estudos Prospectivos , Hiperglicemia/induzido quimicamente , Hiperglicemia/tratamento farmacológico , Hiperglicemia/prevenção & controle , Insulina Regular HumanaRESUMO
CONTEXT: Many adrenal adenomas exhibit mild autonomous cortisol secretion (MACS). Although MACS is associated with increased cardiovascular mortality, the underlying mechanisms are not fully defined. OBJECTIVE: To investigate mechanisms that may link MACS and cardiovascular mortality in adults with adrenal adenoma. DESIGN: Cross-sectional study. PATIENTS: Twenty adults with adrenal adenoma and MACS and 20 controls with nonfunctioning adrenal adenoma. METHODS: Reactive hyperemia index (RHI) was measured by peripheral artery tonometry and 24-hour ambulatory blood pressure monitoring (24h AMBP) was performed. Indices of insulin secretion and sensitivity were estimated by measuring glucose and insulin fasting and following a mixed meal. MAIN OUTCOME MEASURE: The primary outcome was the difference in RHI between participants with MACS vs nonfunctioning adrenal adenoma. RESULTS: The average cortisol after 1-mg dexamethasone and urinary free cortisol were higher in patients with MACS. There was no significant difference in fasting RHI (2.0 [interquartile range (IQR) 1.6-2.4] vs 2.0 [IQR 1.7-2.2, P = .72), but postprandial RHI was higher in patients with MACS (2.2 [1.8-2.7] vs 1.8 [1.5-2.2], P = .04). 24-hour ambulatory blood pressure monitoring and Matsuda index were not significantly different in the groups. Fasting glucose and glucose area under the curve after the mixed meal were higher and insulinogenic index was lower in participants with MACS. CONCLUSION: Adults with adrenal adenoma and MACS do not have fasting endothelial dysfunction and postprandial endothelial function may be better. These patients have fasting and postprandial hyperglycemia with lower insulin secretion, which may underlie the association between MACS and increased cardiovascular mortality.
Assuntos
Adenoma , Neoplasias das Glândulas Suprarrenais , Adenoma Adrenocortical , Doenças Cardiovasculares , Adulto , Humanos , Hidrocortisona , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Estudos Transversais , Monitorização Ambulatorial da Pressão Arterial , Fatores de Risco , Neoplasias das Glândulas Suprarrenais/complicações , Adenoma Adrenocortical/complicações , Adenoma/complicações , Glucose , Fatores de Risco de Doenças CardíacasRESUMO
AIMS: The optimal treatment of prednisolone-associated hyperglycaemia is unclear, but guidelines recommend using a body weight-based daily insulin dose. This study evaluated how clinical variables were associated with insulin requirements in hospitalised patients with prednisolone-associated hyperglycaemia. METHODS: In this prospective study, fifty adult inpatients who were taking prednisolone ≥20 mg/day and experienced hyperglycaemia were prescribed a 24-h intravenous insulin infusion. The daily insulin dose required to attain a mean glucose of 8 mmol/L was calculated. The associations between daily insulin dose and clinical variables were assessed. RESULTS: The participants age was 69 ± 10 years, daily prednisolone dose was 34 ± 10 mg, HbA1c was 7.7 ± 2.0 % (61 ± 10 mmol/mol), 77 % had known type 2 diabetes and 30 % were female. In univariate analysis, weight was associated with daily insulin dose (r2 = 0.11, p = 0.024). A multivariate model comprising sex, HbA1c, a prior diagnosis of diabetes, diabetes treatment and weight explained nearly-two thirds of the variability in daily insulin dose (r2 = 0.65, p < 0.001). CONCLUSIONS: In patients with prednisolone-associated hyperglycaemia, calculating insulin doses based on sex, HbA1c, diabetes status and regular diabetes treatment and weight may improve glycaemic control compared to weight-based dosing.
Assuntos
Diabetes Mellitus Tipo 2 , Hiperglicemia , Adulto , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Masculino , Insulina/efeitos adversos , Hiperglicemia/induzido quimicamente , Hiperglicemia/tratamento farmacológico , Prednisolona/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/efeitos adversos , Hemoglobinas Glicadas , Estudos Prospectivos , Insulina Regular Humana/uso terapêutico , GlicemiaRESUMO
Glucocorticoids are frequently prescribed to patients with a wide range of inflammatory and autoimmune diseases. The semi-synthetic glucocorticoid prednisolone is most commonly prescribed and in two main patterns. Prednisolone is prescribed short term at medium-high doses to treat an acute inflammatory illness or long term at lower doses to attenuate chronic inflammatory disease progression. In hospitalized patients with acute prednisolone-induced hyperglycaemia, there is a distinct circadian pattern of glucose elevation, which occurs predominantly in the afternoon and evening. As a morning dose of isophane insulin has a pharmacokinetic pattern that matches this pattern of glucose elevation, treatment comprising a basal dose of morning isophane insulin in combination with short-acting insulin boluses is generally recommended. However, evidence is lacking that isophane-based basal bolus insulin is more efficacious than other insulin regimens. In outpatients, low-dose prednisolone causes a small increase in post glucose-load glucose concentration but no change in overall glycaemic control as measured by glycosylated haemoglobin. If treatment is indicated, metformin has been shown to be effective and may attenuate other adverse effects of long-term prednisolone therapy. Further studies are necessary in order to identify factors underlying the variability in response to insulin therapy and clinical benefits of treatment in hospitalized patients with prednisolone-induced hyperglycaemia. In outpatients prescribed low-dose prednisolone, the cardiovascular risk associated with postprandial hyperglycaemia and efficacy of hypoglycaemic therapies should be evaluated in future randomized clinical trials.
Assuntos
Glucocorticoides/efeitos adversos , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina Isófana/uso terapêutico , Metformina/uso terapêutico , Prednisolona/efeitos adversos , Glicemia/metabolismo , Medicina Baseada em Evidências , Glucocorticoides/administração & dosagem , Hemoglobinas Glicadas/metabolismo , Humanos , Hiperglicemia/induzido quimicamente , Hiperglicemia/metabolismo , Prednisolona/administração & dosagemRESUMO
BACKGROUND AND AIMS: The effects of low dose prednisolone on circulating markers of endothelial function, the arginine metabolites asymmetric dimethyl arginine (ADMA), mono methyl arginine (MMA), and homoarginine, are uncertain. We assessed whether patients with rheumatoid arthritis have perturbations in arginine metabolite concentrations that are reversed by low dose prednisolone. METHODS: Eighteen rheumatoid arthritis patients who had not taken prednisolone for >6 months (non-glucocorticoid (GC) users), 18 rheumatoid arthritis patients taking continuous oral prednisolone (6.5 ± 1.8 mg/day) for >6 months (GC users) and 20 healthy controls were studied. Fasting plasma concentrations of ADMA, MMA, and homoarginine were measured by ultra-performance liquid-chromatography. Baseline data from non-GC users were compared with healthy controls to assess the effect of rheumatoid arthritis. The change in arginine metabolites in non-GC users after 7 days of prednisolone (6 mg/day) was used to assess the acute effects of prednisolone. Baseline data from non-GC users were compared with GC users to assess the chronic effects of prednisolone. RESULTS: Non-GC users had higher ADMA (0.59 ± 0.03 vs. 0.47 ± 0.01 µM, p = 0.004) and MMA concentrations (0.10 ± 0.01 vs. 0.05 ± 0.00 µM, p < 0.001) than controls. The only change with acute prednisolone was a reduction in homoarginine (1.23 ± 0.06 vs. 1.08 ± 0.06 µM, p = 0.04) versus baseline. GC users had lower concentrations of ADMA (0.51 ± 0.02 vs. 0.59 ± 0.03 µM, p = 0.03) than non-GC users. CONCLUSIONS: Rheumatoid arthritis patients have higher concentrations of ADMA and MMA, inhibitors of endothelial function. Chronic, but not acute, prednisolone therapy is associated with a lower ADMA concentration, suggesting a salutary effect of long-term glucocorticoid treatment on endothelial function.