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Aachen, Germany

Bramlage P.,Institute For Pharmakologie Und Praventive Medizin | Schmieder R.E.,Friedrich - Alexander - University, Erlangen - Nuremberg | Gitt A.K.,Institute fur Herzinfarktforschung GmbH | Baumgart P.,Clemens Hospital Munster | And 6 more authors.
Trials | Year: 2015

Background: Patient characteristics and blood pressure-related outcomes in randomized clinical trials (RCTs) differ from clinical practice because of stringent selection criteria. The present study aimed to explore the relationship between clinical trials and clinical practice. We analyzed data from patients enrolled in the "Treatment with Azilsartan Compared to ACE-Inhibitors in Anti-Hypertensive Therapy" (EARLY) registry comparing blood pressure (BP) effects of the angiotensin receptor blocker (ARB) azilsartan medoxomil (AZL-M) with the angiotensin-converting enzyme (ACE) inhibitor ramipril between patients who met the eligibility criteria of a previous RCT and those who did not. Methods: Patients with primary arterial hypertension were consecutively enrolled from primary care offices in Germany into the EARLY registry in a 7:3 ratio for treatment with AZL-M or an ACE inhibitor, provided that they met the following criteria at baseline: 1) no antihypertensive treatment prior to inclusion or a non-renin-angiotensin system (RAS) based monotherapy; 2) initiation of treatment with either AZL-M or an ACE inhibitor alone. Analyses were performed to evaluate BP effects for patients in the EARLY registry who met the selection criteria of a prior RCT (RCT+) versus those who did not (RCT-). Results: Out of 3,698 patients considered, 1,644 complied with the RCT criteria (RCT+) while 2,054 did not (RCT-). RCT- patients (55.5 %) displayed a higher risk profile in terms of age and comorbidities, and a wider spectrum of BP values at baseline, as highlighted by the grades of hypertension and mean BP values. The proportion of patients who achieved target blood pressure control in the RCT+ group was significantly higher for AZL-M versus ramipril (64.1 versus 56.1 %; P <0.01), in accordance with the result of the clinical trial. In the RCT- AZL-M group, the proportion of patients who met BP targets was lower (58.1 %) than in the RCT+ AZL-M group (64.1 %), whereas the proportion of patients with target BP values in the RCT- ramipril and the RCT+ ramipril groups was similar (57.7 versus 56.1 %). Thus, in contrast to results for the RCT+ group, in the RCT- group, the target BP attainment rate for AZL-M was not significantly superior to that for ramipril. However, the tolerability profile of AZL-M and ramipril was comparable in both populations. At the 12-month follow-up, death and stroke rates were low (≤0.5 %) and adverse events did not differ between the AZL-M and ramipril groups, irrespective of RCT eligibility. Conclusions: These data confirm that the EARLY population comprised a broader spectrum of hypertensive patients than RCTs, and the differences in patient characteristics were accompanied by disparate rates of blood pressure goal attainment. Overall, the validity of the RCT was demonstrated and confirmed in clinical practice with a broader range of patients with various comorbidities. © 2015 Bramlage et al.

Pfutzner A.,Institute for Clinical Research and Development | Pfutzner A.,Bingen University of Applied Sciences | Schondorf T.,Institute for Clinical Research and Development | Schondorf T.,Nurnberg University of Applied Sciences | And 7 more authors.
Diabetes Technology and Therapeutics | Year: 2011

Objective: Dyslipidemia in patients with type 2 diabetes is characterized by elevated triglyceride levels, decreased high-density lipoprotein (HDL) cholesterol, and a predominance of small dense low-density lipoprotein (LDL) particles. Also, patients suffer from β-cell dysfunction, chronic systemic inflammation, increased hormonal visceral adipose tissue activity, and an increased risk of cardiovascular events. The aim of our study was to investigate the effect of a fixed pioglitazone + metformin (PM) combination (vs. glimepiride + metformin [GM]) on diabetic dyslipidemia. Research Design and Methods: A total of 288 type 2 diabetes patients completed this double-blind parallel study (187 men, 101 women; age [mean ± SD], 59 ± 10 years; body mass index, 32.6 ± 5.1 kg/m 2; hemoglobin A1c [HbA1c], 7.3 ± 0.8%). They were randomized to PM or GM for 6 months. Observation parameters at baseline and end point included HDL, LDL, triglycerides, fasting insulin, fasting glucose, total adiponectin, intact proinsulin, and high-sensitivity C-reactive peptide (hsCRP). Results: HDL increased in the PM group by 0.08 ± 0.25 mmol/L (GM, -0.01 ± 0.2.8 mmol/L; P < 0.001 vs. PM), whereas LDL increased in both groups (GM, 0.25 ± 0.90 mmol/L; PM, 0.29 ± 0.66 mmol/L; difference not significant between groups). Improvements were seen for triglycerides (PM, -0.47 ± 1.30; GM, -0.19 ± 1.39 mmol/L), HbA1c (PM, -0.8 ± 0.9%; GM, -1.0 ± 0.9%), and glucose (PM, -1.2 ± 2.1; GM, -1.2 ± 2.2 mmol/L). Decreases in fasting insulin (PM, -5.2 ± 11.9; GM, -0.1 ± 9.8 μU/mL; P < 0.001 between groups), hsCRP (PM, -0.9 ± 1.9; GM, 0.0 ± 1.8 mg/L; P < 0.001), and fasting intact proinsulin (PM, -5.5 ± 11.1; GM, -0.1 ± 10.0 pmol/L; P < 0.001) and an increase in adiponectin (PM, +6.8 ± 6.4 mg/L; GM, +0.7 ± 2.7 mg/L; P < 0.001) were seen in the PM arm, only. Conclusions: With comparable glycemic control, the fixed PM combination was more efficacious on HDL cholesterol improvement than the GM combination. Additional positive effects were observed for biomarkers of lipid metabolism, β-cell function, activity of the visceral adipose tissue, and chronic systemic inflammation. © 2011 Mary Ann Liebert, Inc.

Schondorf T.,Institute for Clinical Research and Development | Schondorf T.,University of Cologne | Schondorf T.,Nurnberg University of Applied Sciences | Musholt P.B.,Institute for Clinical Research and Development | And 8 more authors.
Journal of Diabetes Science and Technology | Year: 2011

Background: Type 2 diabetes mellitus (T2DM) is characterized by a proinflammatory and procoagulant condition. This study investigates the impact of a pioglitazone plus metformin therapy on biomarkers of inflammation and platelet activation in comparison to a treatment with glimepiride plus metformin. Methods: The study was designed as a multicenter, randomized, double-blinded two-arm trial. Patients with T2DM and dyslipidemia under metformin monotherapy with hemoglobin A1c value between 6.5% and 9.0% were eligible for trial participation. Blood was drawn at baseline and after 24 weeks of treatment from patients of five centers. Markers of inflammation and thrombocyte function (soluble CD40 ligand, thromboxane, vWillebrand factor, adhesion molecules, clotting reaction) were evaluated subsequently in a central laboratory. Results: A total of 46 patients were included in the final analyses. Mean (± standard deviation) age was 58.5 ± 9.0 years (13 women, 33 men; disease duration 6.3 ± 5.0 years; body mass index 32.0 ± 4.8 kg/m2). A total of 25 patients were treated with pioglitazone plus metformin, and 21 patients were in the glimepiride arm. There was a significant decline of E-selectin (-3.7 ± 4.8 ng/ml, p < .001 versus baseline), vWillebrand factor (-19.5 ± 32.0%, p < .05), and high-sensitivity C-reactive protein concentrations (-1.08 ± 0.91 mg/liter, p < .05) in the metformin + pioglitazone arm only (metformin + glimepiride, -0.5 ± 3.4 ng/ml, +1.4 ± 33.2%, + 0.08 ± 0.72 mg/liter, respectively, all not significant). Also, all other surrogate markers for platelet function and inflammation showed slight improvements in the metformin + pioglitazone arm but not in the metformin + glimepiride arm. Conclusions: The fixed metformin + pioglitazone combination treatment showed an overall improvement of laboratory surrogate markers, indicating improvement of platelet function and of chronic systemic inflammation, which was not seen with metformin + glimepiride. © Diabetes Technology Society.

Pfutzner A.,IKFE Institute for Clinical Research and Development | Pfutzner A.,Nurnberg University of Applied Sciences | Weise A.,IKFE Institute for Clinical Research and Development | Pfutzner-Riehn E.,University Hospital of Mainz | And 6 more authors.
PPAR Research | Year: 2011

Background. This study was performed to investigate the influence of a short-term treatment with pioglitazone versus placebo on inflammatory activation of mononuclear cells (mRNA expression/protein secretion of inflammatory markers). Methods and Results. Sixty-three patients with well-controlled type 2 diabetes (52 males, 11 females, age (Mean±SD): 66 ± 7 yrs, disease duration: 6.6 ± 9.6 yrs, HbA1c: 6.7 ± 0.6 ) were randomized to additional 45mg of pioglitazone or placebo to their existing metformin and sulfonylurea therpay for four weeks in a double-blind study design. Protein risk marker levels (hsCRP, MMP-9, MCP-1, etc.) and the expression of NFB subunits and NFB-modulated cytokines from isolated peripheral monocyte/macrophages were determined at baseline and endpoint. There were no changes in HbA1c, but significant biomarker improvements were seen with pioglitazone only. The mRNA marker expression was downregulated by pioglitazone and further up-regulated with placebo (e.g., P105 pioglitazone: -19/placebo: +6, RelA: -20/+2, MMP-9: -36/+9, TNF: -10/+14, P < 0.05 between groups in all cases). Conclusions. Pioglitazone very rapidly down-regulated the activated state of peripheral monocytes/macrophages as assessed by mRNA expression of NFB and NFB-modulated cytokines and decreased plasma levels of cardiovascular risk marker proteins independent of glycemic control. © 2011 Andreas Pftzner et al.

Schondorf T.,Institute For Klinische Forschung Und Entwicklung | Schondorf T.,Bonn-Rhein-Sieg University of Applied Sciences | Schondorf T.,Universitatsklinikum Cologne | Pfutzner A.,Institute For Klinische Forschung Und Entwicklung | And 4 more authors.
Diabetes, Stoffwechsel und Herz | Year: 2010

Type 2 diabetes therapy requires regular revision and tailoring when indicated. A fixed combination of 850 mg metformin + 15 mg pioglitazone (Competact®) is a treatment option for patients with insufficient metabolic control with metformin alone. This non-interventional study examined safety and efficacy of a therapy with the fixed combination under routine conditions. The study was conducted in 1 480 centres throughout Germany. Clinical data, as well as metabolic markers (e.g., blood pressure, HbA1c, fasting glucose, lipid profile), were collected at baseline and after 16 weeks of the therapy. The treatment was carried out according to the manufacturer's recommendations. In total, 4 866 patients were enrolled (45 % women, 55 % men, mean (± SD) age 60.8 ± 9.6 years, mean disease duration 6.7 ± 4.7 years). All investigated parameters improved significantly (all, p < 0.001) after four months on the fixed combination, except BMI which remained constant. The safety profile resembled that of each drug if taken individually. This non-interventional study revealed the benefits a pioglitazone/metformin combination therapy has on the metabolic markers of diabetes patients under daily routine conditions.

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