Comparison of combined therapies in treatment of secondary failure to glyburide. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. Insulin versus a combination of insulin and sulfonylurea in the treatment of NIDDM patients with secondary oral failure. Efficacy of corticosteroids in the treatment of community-acquired pneumonia requiring hospitalization. Early asthma control and maintenance with eformoterol following reduction of inhaled corticosteroid dose. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. Ineffectiveness of cyclosporine as an adjuvant to corticosteroids in the treatment of pemphigus. Effect of rosiglitazone versus insulin on the pancreatic beta-cell function of subjects with type 2 diabetes. [Long-term effect of combination glibenclamide-insulin treatment in the secondary failure of sulfonylurea therapy--results of a one-year double blind study].
To compare the effectiveness of alternative combined treatments in patients with non-insulin-dependent diabetes mellitus (NIDDM) with secondary failure to sulfonylureas.
                A crossover study was carried out by randomly assigning 16 NIDDM patients to a combined treatment with the addition of either a single low-dose bedtime injection of 0.2 U/kg body wt NPH insulin or an oral three times a day administration of 1.5 g/day metformin to the previously ineffective glyburide treatment.
                Both combined therapies significantly (P less than 0.01) reduced fasting plasma glucose (FPG), postprandial plasma glucose (PPPG) and percentage of HbA1. The addition of metformin was more effective than the addition of insulin (P less than 0.01) in improving PPPG in the 8 patients with higher post-glucagon C-peptide levels. In contrast, the efficacy of neither combined therapy was related to patient age, age of diabetes onset, duration of the disease, percentage of ideal body weight, and FPG. The addition of insulin but not metformin caused a significant (P less than 0.01) increase of mean body weight. Neither combined treatment caused changes in serum cholesterol and triglyceride levels. No symptomatic hypoglycemic episode was reported in any of the 16 patients.
                The addition of bedtime NPH insulin or metformin was effective in improving the glycemic control in most NIDDM patients with secondary failure to glyburide. The combination of metformin and sulfonylurea was more effective in reducing PPPG and did not induce any increase of body weight. The efficacy of thiazolidinediones, as compared with other oral glucose-lowering medications, in maintaining long-term glycemic control in type 2 diabetes is not known.
                We evaluated rosiglitazone, metformin, and glyburide as initial treatment for recently diagnosed type 2 diabetes in a double-blind, randomized, controlled clinical trial involving 4360 patients. The patients were treated for a median of 4.0 years. The primary outcome was the time to monotherapy failure, which was defined as a confirmed level of fasting plasma glucose of more than 180 mg per deciliter (10.0 mmol per liter), for rosiglitazone, as compared with metformin or glyburide. Prespecified secondary outcomes were levels of fasting plasma glucose and glycated hemoglobin, insulin sensitivity, and beta-cell function.
                Kaplan-Meier analysis showed a cumulative incidence of monotherapy failure at 5 years of 15% with rosiglitazone, 21% with metformin, and 34% with glyburide. This represents a risk reduction of 32% for rosiglitazone, as compared with metformin, and 63%, as compared with glyburide (P<0.001 for both comparisons). The difference in the durability of the treatment effect was greater between rosiglitazone and glyburide than between rosiglitazone and metformin. Glyburide was associated with a lower risk of cardiovascular events (including congestive heart failure) than was rosiglitazone (P<0.05), and the risk associated with metformin was similar to that with rosiglitazone. Rosiglitazone was associated with more weight gain and edema than either metformin or glyburide but with fewer gastrointestinal events than metformin and with less hypoglycemia than glyburide (P<0.001 for all comparisons).
                The potential risks and benefits, the profile of adverse events, and the costs of these three drugs should all be considered to help inform the choice of pharmacotherapy for patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00279045 [ClinicalTrials.gov].).
                Copyright 2006 Massachusetts Medical Society. Comparison of the effectiveness of combined therapy vs. an insulin regimen in NIDDM patients with secondary failure of oral hypoglycemic agents. RESEARCH DESIGN, PATIENTS AND METHODS: 27 NIDDM patients were randomly allocated to Group A (n = 14, insulin) and Group B (n = 13, insulin and sulfonylurea) with crossover after 3 months. After the next 3 months a decision was made about the further treatment according to the metabolic control. The patients were then treated for another year with the more successful regimen. Metabolic control, residual beta-cell secretory capacity, degree of peripheral insulin resistance (clamp) and insulin dose were followed during the whole study.
                (median, interquartile range, in brackets; *, statistically significant difference at P < 0.05): the combined therapy was better than insulin alone in 2/3 of patients. Glycemic control was better (HbA1c at 3 months: Group A = 7.9(1.1)% vs. Group B = 7.0(0.5)%*; HbA1c at 6 months: Group A = 7.4(1.5)% vs. Group B = 8.1(1.5)%. Insulin dose was lower during the combined therapy in the first 3 months: Group A = 0.62(0.18) U/kg body weight vs. Group B = 0.39(0.16) U/kg body weight*. Combined treatment was associated with increased C-peptide excretion both fasting and postprandially. No significant differences in peripheral insulin resistance were noted between the two groups. The combined treatment remained successful even after one year. The two groups of patients with different effective treatment did not differ significantly in any of the observed parameters.
                the combined therapy was more effective than insulin alone. Its favourable effect persisted after treatment for a year. It seems better to start the treatment of the oral failure with combined therapy compared with insulin first and later followed by combined therapy. On the basis of the observed parameters it is impossible to determine in advance which kind of treatment is more suitable for the individual patient. Recent studies suggested that administration of corticosteroids may improve clinical outcomes in patients with severe pneumonia.
                The aim of this study was to assess the effectiveness of corticosteroids as an adjunctive therapy in community-acquired pneumonia (CAP) requiring hospitalization.
                An open label, prospective, randomized control study was conducted from September 2003 to February 2004 in a community general hospital in Japan.
                Thirty-one adult CAP patients who required hospitalization were enrolled.
                Fifteen patients received 40 mg of prednisolone intravenously for 3 days (steroid group). Sixteen patients did not receive prednisolone (control group). Both groups were also evaluated for their adrenal function. The primary endpoint was length of hospital stay. Secondary endpoints were duration of intravenous (IV) antibiotics and time required to stabilize vital signs. Both groups demonstrated similar baseline characteristics and length of hospital stay, and yet a shorter duration of IV antibiotics was observed in the steroid group (p < 0.05). In addition, vital signs were stabilized earlier in the steroid group (p < 0.05). These differences were more prominent in the moderate-severe subgroup but not as significant in the mild-moderate subgroup. The prevalence of relative adrenal insufficiency (RAI) in both groups was high (43%), yet there was no difference in baseline characteristics between patients, with or without RAI. In multiple regression models, RAI seemed to have no influence on clinical courses.
                In moderate-severe CAP, administration of corticosteroids promotes resolution of clinical symptoms and reduces the duration of intravenous antibiotic therapy. Previous studies have indicated the benefits of adding long acting beta(2) agonists to inhaled corticosteroids in the maintenance treatment of moderate to severe asthma. The effects of adding eformoterol to corticosteroids on asthma control and exacerbations in patients with mild to moderate asthma were studied.
                After a run in period of 7-14 days on existing medication, 663 symptomatic patients were randomised to receive budesonide Turbohaler 400 microg twice daily together with either eformoterol Turbohaler 9 micro g (delivered dose) or placebo twice daily. After 4 weeks patients whose asthma was well controlled (n=505) were re-randomised to receive budesonide 400 microg daily and either eformoterol 9 micro g or placebo twice daily for a further 6 months.
                Patients receiving eformoterol achieved asthma control 10 days sooner than those receiving budesonide alone, and improvements in lung function, symptoms, quality of life, and relief beta(2) agonist use were significantly greater with eformoterol. During the 6 month follow up the frequency of mild exacerbations was significantly lower in the eformoterol group than in those receiving budesonide alone (7.2 versus 10.5 per patient, 95% confidence interval for ratio 0.49 to 0.96, p=0.03). The time to first day of poorly controlled asthma was 97 days in the eformoterol group compared with 42 days in the placebo group (p=0.003).
                Adding eformoterol to a low or moderate dose of budesonide in mild asthma resulted in faster and more effective control than treatment with budesonide alone. Eformoterol allowed the corticosteroid dose to be reduced while also decreasing the rate of mild exacerbations compared with budesonide alone. These data suggest a therapeutic advantage of adding eformoterol to inhaled corticosteroids in patients with mild to moderate asthma. Although their clinical efficacy is unclear and they may cause serious adverse effects, systemic glucocorticoids are a standard treatment for patients hospitalized with exacerbations of chronic obstructive pulmonary disease (COPD). We conducted a double-blind, randomized trial of systemic glucocorticoids (given for two or eight weeks) or placebo in addition to other therapies, for exacerbations of COPD. Most other care was standardized over the six-month period of follow-up. The primary end point was treatment failure, defined as death from any cause or the need for intubation and mechanical ventilation, readmission to the hospital for COPD, or intensification of drug therapy.
                Of 1840 potential study participants at 25 Veterans Affairs medical centers, 271 were eligible for participation and were enrolled; 80 received an eight-week course of glucocorticoid therapy, 80 received a two-week course, and 111 received placebo. About half the potential participants were ineligible because they had received systemic glucocorticoids in the previous 30 days. Rates of treatment failure were significantly higher in the placebo group than in the two glucocorticoid groups combined at 30 days (33 percent vs. 23 percent, P=0.04) and at 90 days (48 percent vs. 37 percent, P=0.04). Systemic glucocorticoids (in both groups combined) were associated with a shorter initial hospital stay (8.5 days, vs. 9.7 days for placebo, P=0.03) and with a forced expiratory volume in one second that was about 0.10 liter higher than that in the placebo group by the first day after enrollment. Significant treatment benefits were no longer evident at six months. The eight-week regimen of therapy was not superior to the two-week regimen. The patients who received glucocorticoid therapy were more likely to have hyperglycemia requiring therapy than those who received placebo (15 percent vs. 4 percent, P=0.002).
                Treatment with systemic glucocorticoids results in moderate improvement in clinical outcomes among patients hospitalized for exacerbations of COPD. The maximal benefit is obtained during the first two weeks of therapy. Hyperglycemia of sufficient severity to warrant treatment is the most frequent complication. To compare the effectiveness and the adverse effects of 2 different regimens for the treatment of pemphigus: corticosteroids alone compared with a combination of corticosteroids and cyclosporine.
                Concurrently randomized trial.
                Tertiary care medical center.
                We studied 33 sequential hospitalized patients with newly diagnosed pemphigus vulgaris (n=29) or pemphigus foliaceous (n=4) based on clinical, histological, and immunofluorescence criteria who had not previously been treated with systemic corticosteroids or immununosuppressive drugs. Patients were randomly assigned to treatment with methylprednisolone or prednisolone plus cyclosporine.
                Both groups were treated with similar initial doses of prednisolone (prednisone equivalent, 1 mg/kg), which were increased 50% every 5 to 10 days based on persistence of disease activity. One group was treated in addition with cyclosporine (5 mg/kg).
                Patients were followed up closely for clinical outcome based on time required to control active manifestations of the disease, induction of partial and complete remissions, total amount of corticosteroids administered, frequency of relapses, and development of complications.
                The 2 groups were similar in terms of demographics and baseline disease severity. There was no difference between groups in any of the variables used to measure response to treatment or total amount of corticosteroids administered. Complications were more common in patients who received combination therapy.
                Combination treatment with corticosteroids and cyclosporine, 5 mg/kg, offers no advantage over treatment with corticosteroids alone in patients with pemphigus. In a previous study, we found observational evidence of improvement in beta-cell function when rosiglitazone was added to a failing oral antihyperglycemic regimen consisting of sulfonylureas and metformin. To confirm our previous observations, we designed and performed a prospective, randomized, and controlled study.
                A total of 17 subjects with type 2 diabetes, inadequately controlled on a maximized oral antihyperglycemic double regimen of glimepiride and metformin, were randomized to the addition of rosiglitazone or insulin to their treatment regimens for a period of 6 months. At baseline and at 6 months, the following were performed: measurement of fasting plasma glucose, fasting proinsulin, and insulin levels; frequently sampled intravenous glucose tolerance test; and glucagon stimulation test for C-peptide.
                Nine subjects were randomized to the addition of 8 mg rosiglitazone, and eight subjects were randomized to the addition of one injection of insulin (premixed 70/30) before their evening meal. The treatment groups were well matched for age, duration of diabetes, and BMI. Most important, the HbA(1c) was well matched between groups before treatment (8.7 +/- 0.3 and 9.0 +/- 0.3%; NS) and at the end of the 6 months (7.8 +/- 0.5 and 7.8 +/- 0.3%; NS). After 6 months, at the end of the study, there was a significant improvement in acute insulin response to glucose in the rosiglitazone group (+15.3 microIU x ml(-1) x 10 min(-1); P < 0.001) that led to an increase in the disposition index from 0.18 at baseline to 4.18 at 6 months (P = 0.02). Furthermore, at the end of the study, the proinsulin-to-insulin ratio had decreased in the rosiglitazone group by 36% (P = 0.03) but did not change significantly in the insulin treatment group.
                Rosiglitazone, but not insulin, induced a recovery of pancreatic beta-cell function, as evidenced by the restoration of the first-phase insulin response to glucose, improvement in the disposition index, and a decrease in the proinsulin-to-insulin ratio in subjects with type 2 diabetes in whom oral antihyperglycemic therapy failed. This improvement was independent of the correction of glucotoxicity. The long-term efficacy of combined insulin-glibenclamide treatment was investigated in 79 secondary drug failure patients by means of a double-blind, randomized placebo-controlled study. During a one-year follow-up period the patients on insulin plus glibenclamide required significantly lower exogenous insulin doses. Coincidentally, C-peptide concentrations were significantly raised in the verum versus the placebo group. Additionally, the administration of glibenclamide resulted in a decreased level of hyperglycaemia during the first six months of the observation period. Glibenclamide withdrawal after six and again after twelve months of the combined therapy provoked a deterioration of glycaemic control, as well as a lowering of the C-peptide concentrations. The findings demonstrate a prolonged beneficial effect of the combined treatment, in contrast to the solely short-term effects predicted by numerous studies. The metabolic improvement must be ascribed in part to the beta-cytotropic effect of glibenclamide. Extrapancreatic pathways via receptor/postreceptor mechanisms cannot be excluded.
According to moderate quality evidence, corticosteroids given alone do not significantly hasten recovery from GBS or affect the long-term outcome. According to low quality evidence oral corticosteroids delay recovery. Diabetes requiring insulin was significantly more common and hypertension less common with corticosteroids.