Effectiveness and Tolerability of LABA/LAMA Fixed-Dose Combinations Aclidinium/Formoterol, Glycopyrronium/Indacaterol and Umeclidinium/Vilanterol in the Treatment of COPD in Daily Practice - Results of the Non-Interventional DETECT Study.

Background: LABA (long-acting ß2-agonists) and/or LAMA (long-acting muscarinic antagonists) represent the first treatment options for patients with symptomatic COPD. Although both display different mechanisms of activity, in combination they have a stronger broncho-dilating effect than monotherapy; hence, a combination of both LABA and LAMA is particularly recommended for patients whose symptoms cannot be sufficiently improved by a single active ingredient. To date, only few data have been collected regarding the therapeutic outcomes of approved LABA/LAMA fixed-dose combinations (FDCs) under everyday (real-life) conditions in non-clinical trial settings. Objective and Methods: The main objective of the DETECT study was to investigate the impact of aclidinium/formoterol (AB/FF, b.i.d.), glycopyrronium/indacaterol (GLY/IND, q.d.) and umeclidinium/vilanterol (UME/VL, q.d.) in patients with COPD in daily clinical practice. Therefore, a prospective, non-randomized, 12-month, observational study was implemented to assess the effectiveness of these treatments in patients who had been switched to FDC within the last 3 months or for whom such a changeover was intended. Changes in lung function were analyzed by the forced expiratory volume (FEV1) and forced vital capacity (FVC) measures. Quality of life and well-being were evaluated by the COPD Assessment Test (CAT™). Furthermore, a number of exacerbations and early morning COPD symptoms were documented. Results: In total, 3653 patients were enrolled. FEV1 and FVC values significantly improved during the study with AB/FF (increase by 0.09 ± 0.40 L and 0.10 ± 0.57 L, respectively; p<0.0001), GLY/IND (0.06±0.38/0.05±0.51 L; p<0.0001 and p=0.0025) and UME/VL (0.12±0.39/0.10±0.52 L; p<0.0001). CAT scores decreased indicating improved COPD (AB/FF, 4.17±8.30; GLY/IND, 3.66±7.88; UME/VL, 4.06±7.96; p<0.0001). Moreover, the number of exacerbations as well as early morning COPD symptoms similarly diminished in all treatment groups. A comparable proportion of patients with adverse drug reactions was recorded: AB/FF, 4.07% of patients; GLY/IND, 3.52%; UME/VL, 3.64%. Conclusion: In summary, AB/FF, GLY/IND and UME/VL provided clinical benefits in lung function, quality of life and early morning COPD symptoms in a broad cohort of COPD patients under routine medical practice conditions. All three treatments were well tolerated.

Hypoglycaemia is more frequent in type 2 diabetic patients with co-morbid vascular disease: an analysis of the DiaRegis registry.

BACKGROUND: Patients with type-2 diabetes are at risk for treatment- and disease-related complications. Little is known about the interrelation of hypoglycaemia and co-morbid vascular disease (VD), defined as coronary heart disease, stroke and peripheral arterial disease. HYPOTHESIS: Hypoglycaemia is associated with co-morbid VD in diabetic patients. METHODS: DiaRegis is a prospective registry that included patients with type-2 diabetes in 2009/2010. Metric variables are displayed as median and quartiles. For the comparison of patients with or without VD Odds Ratios (OR) were determined from univariate analyses and adjusted for differences in patient characteristics (multivariable analysis). RESULTS: Data on hypoglycaemia and VD within the last 12 months were available for 3741 patients (98.2%) with a median (IQR) age of 65.9 (57.6-72.9) years; 46.7% were female. VD patients (n = 909; 24.3%) were older (70.7 vs 63.9 years; p < 0.0001), less often female (33.6% vs 50.9%; p < 0.0001) and had had diabetes for a longer duration (6.4 vs 5.4 years; p < 0.0001). Mean cholesterol (total, HDL and LDL) was also slightly lower (p < 0.0001). Glycaemic control (HbA1c, fasting and postprandial glucose) was comparable. VD patients received less metformin (80.7 vs 85.2%; p < 0.01) and more sulfonylureas (31.8 vs 27.6%; p < 0.05). There was an increased incidence of symptomatic hypoglycaemia with or without requiring help and with a need for medical assistance. After adjusting a number of baseline variables the rates of symptomatic hypoglycaemias with help remained significantly increased (OR 3.73 (95% CI 1.31-10.65) in patients with VD. CONCLUSIONS: As hypothesized there is a strong association between the incidence of hypoglycaemia and vascular disease at comparable glycaemic control, which confirms prior randomized controlled trial data suggesting an interrelationship between hypoglycaemia and vascular disease.

Antidiabetic pharmacotherapy and anamnestic hypoglycemia in a large cohort of type 2 diabetic patients--an analysis of the DiaRegis registry.

BACKGROUND: We aimed to identify predictors of anamnestic hypoglycaemia in type-2 diabetic patients on oral mono- or dual oral combination antidiabetic pharmacotherapy. METHODS: DiaRegis is a prospective registry in type-2 diabetic patients in primary care. Odds ratios (OR) with 95% confidence intervals were determined from univariate logistic regression. Using multivariate logistic regression analysis with stepwise backward selection at an alpha of 0.05 independent predictors of hypoglycaemia were determined. RESULTS: 3,808 patients had data on hypoglycaemia available (median age 65.9 years, 46.6% female). 10.8% had at least one anamnestic hypoglycaemic episode within the previous 12 months. Patients with hypoglycaemia received more sulfonylureas (OR 2.16; 95%CI 1.75-2.67) and less metformin (OR 0.64; 95%CI 0.50-0.82). On top of metformin, patients with thiazolidine (OR 0.50; 95%CI 0.28-0.89) and DPP-4 inhibitor use (OR 0.34; 95%CI 0.16-0.70) had a decreased risk for hypoglycaemia while it was again increased with sulfonylureas (OR 2.08; 95%CI 1.44-2.99). Age < 65 years was an independent predictor of a reduced hypoglycaemia incidence (OR 0.76; 95%CI 0.59-0.96), low HbA1c (OR 1.68; 95%CI 1.31-2.14), stroke/TIA (OR 1.72; 95%CI 1.08-2.72), heart failure (OR 1.77; 95%CI 1.28-2.45), and the use of sulfonylureas (OR 2.58; 95%CI 2.03-3.29) were independent predictors of increased risk. CONCLUSIONS: The results indicate that the risk of hypoglycaemia might be substantially reduced by carefully selecting antidiabetic pharmacotherapy in patients with type-2 diabets in primary care.

Diabetes treatment patterns and goal achievement in primary diabetes care (DiaRegis) - study protocol and patient characteristics at baseline.

BACKGROUND: Patients with type 2 diabetes are at an increased risk for disease and treatment related complications after the initial approach of oral mono/dual antidiabetic therapy has failed. Data from clinical practice with respect to this patient group are however scarce. Therefore we set up a registry in primary care documenting the course and outcomes of this patient group. METHODS: Diabetes Treatment Patterns and Goal Achievement in Primary Diabetes Care (DiaRegis) is a prospective, observational, German, multicenter registry including patients with type-2 diabetes in which oral mono/dual antidiabetic therapy has failed. Data were recorded at baseline and will be prospectively documented during visits at 6 ± 1, 12 ± 2 and 24 ± 2 months. The primary objective is to estimate the proportion of patients with at least 1 episode of severe hypoglycemia within one year. RESULTS: 313 primary care offices included 4,048 patients between June 2009 and March 2010 of which 3,810 patients fulfilled the in- and exclusion criteria. 46.7% of patients were female; patients had a median diabetes duration of 5.5 years and most were obese with respect to BMI or waist circumference. HbA1c at baseline was 7.4%, fasting plasma glucose 142 mg/dl and postprandial glucose 185 mg/dl. Co-morbidity in this patient population was substantial with 17.9% having coronary artery disease, 14.4% peripheral neuropathy, 9.9% heart failure and 6.0% peripheral arterial disease. 68.6% of patients received oral monotherapy, 31.4% dual oral combination therapy. The most frequent antidiabetic agent used as monotherapy was metformin (79.0%) followed by sulfonylureas (14.8%). CONCLUSIONS: DiaRegis is a large, prospective registry in primary diabetes care to document the course and outcomes of patients with type-2 diabetes in which the initial approach of oral mono/dual antidiabetic therapy has failed. The two year follow-up will allow for a prospective evaluation of these patients during multiple adjustments of therapy.

CTLA-4-dependent mechanisms prevent T cell induced-liver pathology during the erythrocyte stage of Plasmodium berghei malaria.

During the course of malaria several organs develop pathology. Frequently also signs of hepatocyte damage are found. In the present work we studied the mechanisms leading to liver pathology during the erythrocyte stage of Plasmodium berghei malaria. During infection, mice developed an inflammation of the liver, associated with infiltration of T cells, although only little tissue damage could be observed. Histological analysis revealed the presence of CTL-associated antigen-4 (CTLA-4)-positive T cells in the liver parenchyma. To study the influence of CTLA-4 expression on liver inflammation, mice were treated with an antibody against CTLA-4. Treated mice suffered from a dramatically increased liver pathology. Using cytokine-deficient mice we found that pathology was dependent on the presence of IL-12 and IFN-gamma. To further study the mechanisms that lead to an enhanced pathology, we analyzed cytokine production from liver-derived T cells. In infected mice the frequency of IFN-gamma-producing cells in the liver was low. In contrast, in anti-CTLA-4-treated mice larger numbers of IFN-gamma-producing cells were detectable. Our results indicate that activated T cells during the erythrocyte stage of malaria can induce pathology due to secretion of pro-inflammatory cytokines. Moreover, these results provide evidence that CTLA-4 expression can restrict T cell function in inflamed organs and might therefore prevent pathology.