Personalized medicine for allergy treatment: Allergen immunotherapy still a unique and unmatched model.

The introduction of personalized medicine (PM) has been a milestone in the history of medical therapy, because it has revolutionized the previous approach of treating the disease with that of treating the patient. It is known today that diseases can occur in different genetic variants, making specific treatments of proven efficacy necessary for a given endotype. Allergic diseases are particularly suitable for PM, because they meet the therapeutic success requirements, including a known molecular mechanism of the disease, a diagnostic tool for such disease, and a treatment blocking the mechanism. The stakes of PM in allergic patients are molecular diagnostics, to detect specific IgE to single-allergen molecules and to distinguish the causative molecules from those merely cross-reactive, pursuit of patient's treatable traits addressing genetic, phenotypic, and psychosocial features, and omics, such as proteomics, epi-genomics, metabolomics, and breathomics, to forecast patient's responsiveness to therapies, to detect biomarker and mediators, and to verify the disease control. This new approach has already improved the precision of allergy diagnosis and is likely to significantly increase, through the higher performance achieved with the personalized treatment, the effectiveness of allergen immunotherapy by enhancing its already known and unique characteristics of treatment that acts on the causes.

An observational, real-life safety study of a 5-grass pollen sublingual tablet in children and adolescents.

BACKGROUND: The safety and efficacy of pre- and coseasonal sublingual allergen immunotherapy (SLIT) with a 5-grass pollen sublingual tablet have been demonstrated in a randomized clinical trial (RCT) in children and adolescents. Observational, 'real-life' studies can usefully complement the results of RCTs. METHODS: A prospective, open-label, observational, multicentre post-marketing study of children and adolescents (aged 5-17, with grass pollen-induced allergic rhinitis) treated with the 5-grass pollen sublingual tablet was performed between June 2009 and January 2011 in Germany. Adverse events (AEs) were recorded during consultations with the investigating physicians; AEs judged to have at least a possible causal link to the tablet were classified as adverse drug reactions (ADRs). RESULTS: Eight hundred and forty-nine patients were enrolled (by 207 investigating physicians), 829 (mean ± s.d. age: 10.9 ± 3.3 yr) completed the study without major protocol deviations, and 796 were fully documented with respect to AEs. Ninety-four of the 796 patients (11.8%) experienced at least one ADR on the first day of SLIT and 218 (27.4%) experienced at least one ADR during the study. Four hundred and sixty-six of the 596 ADRs (78.2%) were mild or moderate. The most common ADRs were throat irritation (19.1% of the reactions), oral paresthesia (8.2%), oral pruritus (6.5%) and oedema mouth (6.2%). Serious ADRs occurred in five patients. No epinephrine use was reported. Seventy-six of the 829 patients (9.2%) discontinued SLIT due to AEs. Tolerability was judged to be good or very good by patients (84.7%), parents (87.0%) and investigators (89.7%). CONCLUSIONS: In clinical practice, pre- and coseasonal treatment with a 5-grass pollen sublingual tablet is safe and well tolerated in children and adolescents.

Relevant Patient Benefit of Sublingual Immunotherapy with Birch Pollen Allergen Extract in Allergic Rhinitis: An Open, Prospective, Non-Interventional Study.

INTRODUCTION: Sublingual immunotherapy (SLIT) with birch pollen extract has been shown to be an efficacious treatment of allergic rhinitis (AR). An as-yet unanswered question is whether and how clinical benefit translates into patient benefit, i.e. what benefit patients derive from this treatment. METHODS: This 1-year, open, prospective, multicenter, non-interventional study conducted in 75 German centers measured patient-relevant benefit of birch pollen SLIT (Staloral® Birch) using the questionnaire "Patient Benefit Index for Allergic Rhinitis (PBI-AR)". At treatment onset, patients rated the importance of 25 treatment needs; after the first birch pollen season on treatment, goal achievement was evaluated. A preference-weighted benefit index was calculated and its association with gender, asthma, allergy status, and severity of AR symptoms was determined. RESULTS: Mean age of the 291 adult patients was 38.8 years; 58.4% were female. The most important treatment goals were to "be able to stay outdoors without symptoms" (87.3% quite or very important), "no longer have a runny or stuffed-up nose" (86.9%), and "be able to breathe through your nose more freely" (86.9%). The treatment goals with the highest benefit ratings (referring to those patients to whom the respective goal applied) were to "have confidence in the therapy" (60.5% has helped "quite" or "very much"), "have an easily applicable treatment" (55.6%), and "be able to breathe through my nose more freely" (51.7%). The average PBI-AR global score was 2.19 (SD 1.04) (0-4; with 4 indicating maximum benefit). No significant differences in PBI-AR global score or subscales were found between men and women, poly- and monoallergic patients, or patients with severe versus mild rhinoconjunctivitis. Patients with asthma reported relevant but lower benefit than patients without asthma. CONCLUSION: After 1 year of birch pollen SLIT treatment, patients reported considerable benefit, mainly due to a reduction of physical symptoms and treatment burden.

Competact, a fixed combination of pioglitazone and metformin, improves metabolic markers in type 2 diabetes patients with insufficient glycemic control by metformin alone--results from a post-marketing surveillance trial under daily routine conditions.

BACKGROUND: In patients with type 2 diabetes, glycemic control to target goals can only be achieved for a while by single-drug treatment. Antidiabetes therapy has to be adapted according to the individual course of the disease. This trial investigates the impact of Competact (Takeda Pharma, Aachen, Germany) (marketed as ActoplusMet in the United States)-a fixed combination of 850 mg of metformin with 15 mg of pioglitazone-for diabetes treatment in patients with insufficient glycemic control by metformin alone. STUDY DESIGN: This observational drug monitoring trial was performed at 1,480 study sites in Germany, and 4,866 complete patient data sets were included into the final analyses. Mean +/- SD age was 60.8 +/- 9.6 years (2,171 women, 2,691 men; disease duration, 6.7 +/- 4.7 years; body mass index [BMI], 31.0 +/- 5.2 kg/m(2)). In total, 43.8% of the patients received lipid-lowering drugs (antihypertensive medication, 74.3%). Main inclusion criteria were type 2 diabetes, metformin monotherapy, and an initial hemoglobin A1c (HbA1c) value between 6.6% and 9.9%. Parameters of glycemic control (HbA1c, fasting blood glucose [FBG]), blood pressure (BP), inflammation (high-sensitivity C-reactive protein [hsCRP]), and lipid metabolism (total cholesterol, high-density lipoprotein [HDL]-cholesterol, non-HDL-cholesterol, and triglycerides) were collected at baseline and after 4 months. RESULTS: All investigated parameters improved significantly (all P < 0.001) after 4 months of therapy with Competact (baseline vs. end point: systolic BP, 139.7 +/- 15.1 vs. 134.4 +/- 12.0 mm Hg; diastolic BP, 83.1 +/- 8.9 vs. 80.5 +/- 7.5 mm Hg; HbA1c, 7.8 +/- 1.0% vs. 7.0 +/- 0.8%; FBG, 9.0 +/- 2.6 vs. 7.0 +/- 1.7 mM; cholesterol, 5.7 +/- 1.1 mM vs. 5.3 +/- 0.9 mM; HDL-cholesterol, 1.2 +/- 0.4 mM vs. 1.3 +/- 0.4 mM; non-HDL-cholesterol, 4.5 +/- 1.2 mM vs. 4.0 +/- 0.9 mM; triglycerides, 2.5 +/- 1.0 mM vs. 2.1 +/- 0.8 mM; hsCRP, 3.2 +/- 2.6 mg/L vs. 2.7 +/- 2.3 mg/L). It is noteworthy that the BMI was not affected by Competact (31.0 +/- 5.2 kg/m(2) vs. 31.1 +/- 6.1 kg/m(2), P = 0.221). CONCLUSIONS: These observational results, obtained from a non-selected patient population under daily routine conditions, show the beneficial effects of a pioglitazone/metformin combination for diabetes patients with insufficient glycemic control under daily routine conditions.

Clinical efficacy of sublingual immunotherapy tablets for allergic rhinitis is unlikely to be derived from in vitro allergen-release data.

Introduction: Allergen bioavailability underpins the efficacy and safety of SLIT tablets. Three product-related factors are likely to influence this: tablet potency, formulation and sublingual holding time. Areas covered: Tablet formulation determines the rate and extent of solubilized allergen release. Using validated in vitro dissolution assays, the two licensed grass pollen SLIT tablets are shown to release ≥85% of their total allergenic activity within several minutes. Sublingual holding time affects the contact duration between solubilized allergens and sublingual tissue. Maximal uptake of allergens by sublingual tissue requires ~5 minutes, with little uptake occurring within the first minute. A higher potency tablet with longer sublingual holding time would provide higher bioavailability, while faster rates of allergen release in vitro are unlikely to translate to a greater increase in bioavailability. Differences in dissolution times cannot serve as a surrogate of in vivo bioavailability, and are not related to differences in efficacy at the marketed tablet dosages. Rapid in vitro dissolution is likely not a key requirement for inducing a potent immune response. Expert opinion: In vitro dissolution cannot predict the clinical efficacy of SLIT tablets but could be important in immune tolerance and safety. In addition, a discontinuous administration regimen may have benefits for adherence and cost without compromising efficacy.

The IRIS V study: pioglitazone improves systemic chronic inflammation in patients with type 2 diabetes under daily routine conditions.

BACKGROUND: The peroxisome proliferator-activated receptor-gamma agonist pioglitazone is established as a drug to treat patients with type 2 diabetes mellitus. In addition to lowering blood glucose levels, one of the favorable effects of pioglitazone is improvement of systemic chronic inflammation particularly affecting vessel walls. The effect can be monitored by the measurement of the biomarker C-reactive protein in the range of 0-10 mg/L (high-sensitivity C-reactive protein [hsCRP]). This observational trial was performed to evaluate the effects of pioglitazone on hsCRP values in a large population under daily life conditions. METHODS: A total of 1,170 subjects could be included into the final analysis (633 men, 537 women; age [mean +/- SD], 63.5 +/- 10.4 years, body mass index, 31.0 +/- 5.5 kg/m2; duration of diabetes, 6.9 +/- 8.1 years; glycosylated hemoglobin [HbA1c], 7.5 +/- 1.1%). All patients were glitazone-naive prior to study entry. The patients received pioglitazone alone or in combination with their previous treatment (acarbose, sulfonylurea drugs, and/or metformin). Patients were evaluated at baseline and after 10 +/- 2 weeks and 20 +/- 2 weeks of treatment. Observation parameters were fasting blood glucose, lipids, and blood pressure. The level of hsCRP was determined in a central laboratory at baseline and at end point. RESULTS: All markers showed a significant improvement at trial end point. A decrease of hsCRP (baseline 3.3 +/- 1.0 mg/L vs. end point 2.8 +/- 2.3 mg/L, P < 0.01), HbA1c (7.5 +/- 1.1% vs. 6.8 +/- 0.9%, P < 0.001), fasting blood glucose (8.7 +/- 2.6 mM vs. 7.2 +/- 2.1 mM, P < 0.001), low-density lipoproteins (3.3 +/- 1.0 mM vs. 3.2 +/- 0.9 mM, P < 0.001), and triglycerides (2.4 +/- 2.0 mM vs. 2.2 +/- 2.5 mM, P < 0.001) and an increase in high-density lipoproteins (1.3 +/- 0.4 mM vs. 1.4 +/- 0.4 mM, P < 0.001) was observed. Parallel to the metabolic improvement, both systolic and diastolic blood pressure values were reduced (141 +/- 17 mm Hg vs. 137 +/- 15 mm Hg and 83 +/- 9 mm Hg vs. 80 +/- 9 mm Hg, respectively; P < 0.001 in both cases). CONCLUSIONS: These observational results, obtained from a nonselected patient population under daily routine conditions, confirm the benefits of pioglitazone treatment on blood glucose, lipid metabolism, and blood pressure. The results show that pioglitazone treatment improves chronic vascular inflammation, which may be associated with reduced cardiovascular risk.

Effect of simvastatin and/or pioglitazone on insulin resistance, insulin secretion, adiponectin, and proinsulin levels in nondiabetic patients at cardiovascular risk--the PIOSTAT Study.

We investigated the effect of pioglitazone in comparison with and in combination with simvastatin on insulin resistance, plasma adiponectin, postprandial plasma glucose, insulin, and intact proinsulin levels in a nondiabetic population at cardiovascular risk. One hundred twenty-five nondiabetic patients at cardiovascular risk were randomized to pioglitazone (PIO), pioglitazone and simvastatin (PIO/SIM), or simvastatin (SIM) treatments. Blood samples were taken for the measurement of adiponectin and lipid levels. In addition, an oral glucose load with the measurements of glucose, insulin, and intact proinsulin levels was performed. Adiponectin levels increased from 14.0+/-8.2 to 27.6+/-14.5 microg/mL (P<.0001) during PIO treatment and from 11.7+/-10.0 to 26.7+/-15.7 microg/mL (P<.0001) during PIO/SIM treatment. A decrease in adiponectin levels from 15.5+/-12.7 to 11.6+/-7.0 microg/mL (P<.05) was observed during SIM treatment. Although fasting intact proinsulin levels remained unchanged, the increase in postprandial intact proinsulin levels could be reduced from 29.5+/-21.4 to 22.1+/-17.5 pmol/L (P<.01) during PIO treatment and from 24.3+/-27.4 to 21.1+/-16.5 mmol/L (P<.05) during PIO/SIM treatment. Lipid parameters improved during SIM treatment but not during PIO treatment. Combined treatment with PIO/SIM was superior in improving overall cardiovascular risk profile than every single drug.

Management of Grass Pollen Allergy with 5-Grass Pollen Tablet: Results of a 2-Year Real-Life Study.

INTRODUCTION: Allergen immunotherapy is the only treatment option for allergic rhinitis with disease-altering potential. It was the objective of this study to assess the effectiveness and tolerability of a 5-grass pollen tablet in a large population of non-selected grass pollen allergic patients, i.e. patients with different clinical profiles in daily clinical practice. METHODS: In a 2-year, prospective, open-label, multicenter, non-controlled, observational study patients were included from 327 centers across Germany. Rhinoconjunctivitis symptoms, symptomatic medication intake and adverse events were recorded. RESULTS: A total of 1482 patients aged 4-75 years were included. During the 2-year period of 5-grass pollen tablet therapy, mean rhinoconjunctivitis score decreased significantly in the overall study population by 65.5% (P < 0.001). The percentage of patients taking symptomatic medication decreased from 83.8% to 42.7%. Mean 2-year improvements in rhinoconjunctivitis scores and decreases in the percentage of patients taking symptomatic medication were broadly similar in adults, adolescents and children, in patients with polyallergy versus monoallergy, and in patients with/without asthma. Among polyallergic patients, concomitant application of another specific immunotherapy did not impair treatment outcomes. Adverse drug reactions, predominantly affecting the local application area, occurred in 15.4% of the overall patient population (n = 229). No cases of anaphylaxis or epinephrine use were documented. CONCLUSION: This study indicates that sublingual immunotherapy with the 5-grass pollen tablet is well tolerated and provides sustained effectiveness over 2 years in patients with different clinical profiles, producing a significant decrease in allergic symptoms and a reduction in the use of symptomatic medication. FUNDING: Stallergenes GmbH.

Treatment Satisfaction During Sublingual Immunotherapy with a Five-Grass Pollen Tablet for Allergic Rhinoconjunctivitis: A Prospective, Non-Interventional Study.

BACKGROUND: Sublingual immunotherapy (SLIT) is a safe/well-tolerated alternative to allergen injection immunotherapy for allergic rhinoconjunctivitis (ARC). Patient adherence is essential and patient-related outcome measures including treatment satisfaction are informative/indicative of adherence. OBJECTIVE: The aim was to assess treatment satisfaction with five-grass pollen tablet SLIT under real-life conditions. METHODS: Treatment satisfaction among adults taking SLIT with a five-grass pollen tablet for grass pollen-related ARC was assessed with QUARTIS, a self-report questionnaire dedicated to the management of patients treated with SLIT for ARC. This 1-year prospective, non-interventional, post-authorization study was conducted in Germany between 2008 and 2010. RESULTS: Of the 327 patients treated with the five-grass pollen tablet, 253 completed the QUARTIS questionnaire before and during (at least one item) treatment and were included in this analysis. Between the baseline and the treatment season, significant improvements were documented in nasal and ocular symptoms, and in the impact of allergy on everyday life. At the end of the first treatment period, patients had an improved opinion of the ease of SLIT intake and a significantly improved perception of SLIT. Compliance, overall satisfaction and motivation to continue SLIT the following year were good. Physicians' assessments showed reduced symptoms and a reduced need for symptomatic medication throughout the study. SLIT was also well tolerated. CONCLUSION: Under real-life conditions, five-grass pollen tablet treatment was associated with a good level of treatment satisfaction, good symptom control, a reduced need for symptomatic medication, and favourable tolerability. These facets impacted favourably on patient functioning, disposition towards this medication, and adherence.

Optimum treatment strategies for polyallergic patients - analysis of a large observational trial.

OBJECTIVES: To document the effectiveness and safety of sublingual allergen immunotherapy (SLIT) with a five-grass pollen tablet (Oralair ) and compare different treatment options in a broad, non-selected population of patients in a real-world clinical setting. RESEARCH DESIGN AND METHODS: This was a 2 year, open, prospective, multicenter, single-arm, non-interventional study. Patients with a history of clinically relevant allergic symptoms caused by grass pollen, confirmed by skin prick testing, received treatment with the five-grass pollen tablet. Concomitant treatment with symptomatic medication and/or additional SLIT or subcutaneous immunotherapy (SCIT) was permitted. Twelve-month data are presented here. Effectiveness was assessed comparing a combined rhinoconjunctivitis (RC) score derived from the severity of rhinitis and conjunctivitis symptoms under treatment with retrospective data of the previous year. RESULTS: A total of 1408 patients participated in the study, of whom 434 were children/adolescents and 962 polyallergic. Compared with the grass pollen season preceding five-grass pollen tablet treatment, a statistically significant reduction of 49.9% was achieved in RC score for the total population (p < 0.001), and an improvement in overall health was perceived by 90.9% of patients. The overall population of polyallergic patients derived similar benefits from treatment with the five-grass pollen tablet as monoallergic patients. The percentage reduction in RC score was larger in polyallergic patients taking no additional therapy (60.2%) than in those taking concomitant symptomatic medication (38.1%) or allergen immunotherapy (AIT) (50.8%). Within the last of these groups, RC score improved by 47.6% among patients receiving additional SCIT, versus 54.8% with additional SLIT. Adverse drug reactions, reported in 15.3% of study participants, were mostly local in nature and mild or moderate in intensity. CONCLUSIONS: After 1 year of treatment, polyallergic patients responded similarly to the five-grass pollen tablet as monoallergic patients. For polyallergic patients in whom additional treatment was needed, a second SLIT may be more beneficial than a SCIT or symptomatic co-medication.

Sublingual Immunotherapy with a Five-Grass Pollen Tablet in Adult Patients with Allergic Rhinitis: An Open, Prospective, Noninterventional, Multicenter Study.

BACKGROUND: Although the safety and efficacy of sublingual immunotherapy (SLIT) with a five-grass pollen tablet have been demonstrated in randomized clinical trials (RCTs), these outcomes must always be evaluated in real-life medical practice. METHODS: In a prospective, open-label, noninterventional, "real-life" study in Germany, we evaluated the safety, tolerability, and effectiveness of SLIT with a five-grass pollen tablet in adults with grass-pollen-induced allergic rhinoconjunctivitis. RESULTS: 808 adults were enrolled between September 2008 and December 2009. 35.3% of the participants experienced at least one adverse drug reaction (ADR), the most common of which were mild-to-moderate gastrointestinal and respiratory disorders. Serious ADRs considered causally related to SLIT treatment occurred in four patients. Overall, the five-grass pollen tablet was considered to have good or very good tolerability by most investigators and patients. Treatment was associated with the relief of nasal, ocular, and bronchial symptoms and decreased symptomatic medication use. However, interpretation of clinical improvements was limited by lower atmospheric grass pollen levels during the study season (relative to the preceding season). CONCLUSIONS: In a large population of patients treated in real-life medical practice, SLIT with a five-grass pollen tablet was safe and well tolerated. The patient-reported symptom relief suggests that SLIT was associated with clinical benefits.

Downregulation of the proinflammatory state of circulating mononuclear cells by short-term treatment with pioglitazone in patients with type 2 diabetes mellitus and coronary artery disease.

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 45 mg 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 NFκB subunits and NFκB-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%, TNFα: -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 NFκB and NFκB-modulated cytokines and decreased plasma levels of cardiovascular risk marker proteins independent of glycemic control.

Increased prevalence of cardiovascular disease and risk biomarkers in patients with unknown type 2 diabetes visiting cardiology specialists: results from the DIASPORA study.

BACKGROUND: Patients with diabetes mellitus and IGT have a high risk for cardiovascular events. It is tempting to speculate that these patients are often first seen by cardiologists. DESIGN: This cross-sectional study investigates the diabetes prevalence in cardiology care units and the correlated metabolic conditions as assessed by several circulating biomarkers. METHODS: Patients aged 55 or older with suspected or overt coronary heart disease were eligible for trial participation. Fasting blood samples were drawn from patients to determine HOMA score, glycaemic and lipid profile, and several risk biomarkers. An OGTT was performed in patients without known diabetes. RESULTS: We enrolled 530 patients (181 male, 349 female, mean age, 68+/-7 years) in this study from 22 German cardiology centres; 156 patients (29.4%) had known diabetes and OGTT revealed that 184 patients (34.7%) had no diabetes, 106 patients (20.0%) had IGT or IFG and 84 patients (15.9%) were newly diagnosed with diabetes. Increased cardiovascular risk as reflected by increased hsCRP, ICAM and MMP-9 values was observed in diabetes patients. A higher cardiovascular biomarkers risk profile was seen in the IGT/IFG cohort. CONCLUSIONS: This study confirms the observation that one third of patients of a cardiologic care unit suffer from impaired glucose regulation. Furthermore, the cardiology patients with previously unknown glucose homeostasis abnormalities had a higher prevalence of macrovacular disease and an impaired biomarker risk profile. This study underlines the importance of joint treatment efforts by cardiologists in concert with diabetologists for treatment of this patient group at high risk for cardiovascular events.

Pioglitazone improves metabolic markers in patients with type 2 diabetes independently from physical activities: results from the IRIS III study.

AIM: Pioglitazone is an established peroxisome proliferator-activated receptor gamma agonist for the treatment of insulin resistance in patients with type 2 diabetes mellitus. This analysis of the observational IRIS III study was performed to evaluate the effects of pioglitazone treatment in relation to the degree of physical exercise activities in a large patient population under daily life conditions. METHODS: A total of 1298 patients out of 2092 enrolled into the IRIS III study who had provided information about their exercise level could be included in the final analysis (622 female, 676 male; age: 63.1 +/- 10.4 years, diabetes duration: 6.6 +/- 5.0 years, mean +/- SD). All patients were glitazone naïve prior to study entry. They received pioglitazone in addition to their previous oral antidiabetic treatment. The patients were stratified according to their physical activity level (never, sometimes, and regularly). Data were evaluated at baseline and after 20 +/- 2 weeks of treatment. Observation parameters were fasting blood glucose, lipids, and blood pressure. Hemoglobin A1c (HbA1c) was determined in a central laboratory, and insulin sensitivity was assessed by the IRIS II score. RESULTS: Glycemic control, blood pressure, and the lipid profile improved independently from the degree of physical activity (e.g., no exercise vs frequent exercise: DeltaHbA1c: -0.89 +/- 1.2% vs -0.72 +/- 1.1%, not significant). A positive impact of exercise on insulin resistance could be observed at baseline, which, however, was further decreased by pioglitazone treatment [IRIS II score (baseline/end point): no exercise vs frequent exercise: 74.0 +/- 15.9/62.5 +/- 20.2 vs 66.7 +/- 19.0/58.0 +/- 21.8, p < 0.001/not significant]. CONCLUSIONS: These observational results, obtained from a nonselected patient population under daily routine conditions, confirm that the benefits of pioglitazone treatment on glycemic control, lipid metabolism, and blood pressure are independent from physical activity. Exercise has a positive influence on insulin sensitivity, but pioglitazone shows additional favorable effects and is, therefore, recommended for use independently from the activity level of the patients.

Effects of pioglitazone and/or simvastatin on low density lipoprotein subfractions in non-diabetic patients with high cardiovascular risk: A sub-analysis from the PIOSTAT study.

BACKGROUND: We analyzed the efficacy and possible synergistic actions of pioglitazone and simvastatin monotherapy versus their combination on LDL subfractions from a subpopulation from the PIOSTAT three-arm randomized controlled trial. PPARgamma agonists, such as pioglitazone, improve insulin sensitivity and glycemic control and appear to lower the concentration of atherogenic small dense LDL particles. Insulin resistance frequently occurs in non-diabetic patients with cardiovascular disease. Statins, such as simvastatin, reduce cardiovascular events by lowering LDL-C. So far, only scarce information exists for comparative efficacy and possible synergistic effects of combination therapy on LDL subfractions, cholesterol particle load, and particle number of atherogenic small dense LDL. METHODS: 125 non-diabetic patients with high cardiovascular risk were randomized to therapy with pioglitazone 45 mg/day, simvastatin 40 mg/day, or the combination of both, for 12 weeks. In the present sub-study, LDL subfractions from 88 patients were separated by very-fast ultracentrifugation. RESULTS: Simvastatin monotherapy significantly reduced cholesterol and triglyceride concentrations in IDL, LDL1, and LDL2. The lipid concentrations and lipid loads in LDL3 remained unchanged. By contrast, treatment with pioglitazone reduced the cholesterol concentration in LDL3 (density 1.040-1.066 kg/l) from 0.38 to 0.31 mmol/l (p=0.0004) and of the cholesterol load per particle from 1058 to 934 mol/mol (p=0.0149). Even greater reductions of cholesterol in LDL3 were observed with the combination of pioglitazone and simvastatin: from 0.38 to 0.29 mmol/l (p=0.0006) and from 1021 to 903 mol/mol (p=0.0011), respectively. In addition, combination therapy reduced the particle number of LDL3 from 356 to 316 nmol/l (p=0.0074). CONCLUSIONS: Simvastatin preferentially lowered LDL1 and LDL2 subfractions, whereas pioglitazone reduced LDL3 cholesterol and cholesterol load. In addition, the combination reduced the LDL3 particle number. Thus, our data suggest a synergistic action of pioglitazone and simvastatin on atherogenicity of small dense LDL particles.

Anti-inflammatory effects of pioglitazone and/or simvastatin in high cardiovascular risk patients with elevated high sensitivity C-reactive protein: the PIOSTAT Study.

OBJECTIVES: The purpose of this study was to test the safety and efficacy of pioglitazone and simvastatin in combination versus each drug individually in non-diabetic subjects with cardiovascular disease (CVD) and elevated high-sensitivity C-reactive protein (hs-CRP) levels. BACKGROUND: Low-grade inflammation is a pathogenic factor for atherosclerosis. High-sensitivity CRP, matrix metalloproteinase (MMP)-9, and plasminogen activator inhibitor (PAI)-1 are markers of inflammation. Statins and peroxisome proliferator-activated receptor (PPAR)-gamma agonists lower inflammatory markers and reduce CVD in type 2 diabetes. METHODS: In a 12-week, prospective, double-blind trial, 125 subjects were randomized to simvastatin or pioglitazone plus placebo or a simvastatin/pioglitazone combination. We tested changes in hs-CRP by analysis of covariance. A subgroup analysis was performed in patients with and without the metabolic syndrome (MetS). The correlation between changes in hs-CRP and homeostasis model assessment (HOMA; a measure of insulin resistance) was calculated with the Spearman's rank test. RESULTS: At baseline, there were no significant between-group differences. At 12 weeks, pioglitazone and simvastatin monotherapies significantly reduced hs-CRP (3.64 +/- 2.42 mg/l to 2.48 +/- 1.77 mg/l and 3.26 +/- 2.02 mg/l to 2.81 +/- 2.11 mg/l) and the combination regimen had an additive effect (from 3.49 +/- 1.97 mg/l to 2.06 +/- 1.42 mg/l, p < 0.001). For subgroups, the difference between monotherapy and combination therapy was only significant for simvastatin versus simvastatin plus pioglitazone in patients without MetS. Homeostasis model assessment decreased in those receiving pioglitazone, and the correlation between changes in HOMA and hs-CRP was significant (r = 0.43; p < 0.05). The PAI-1 decreased significantly in the pioglitazone groups only, and MMP-9 was also significantly lowered in the pioglitazone groups. No treatment-related serious adverse events occurred in any group. CONCLUSIONS: Pioglitazone, probably by reducing insulin resistance, has additive anti-inflammatory effects to simvastatin in non-diabetic subjects with CVD and high hs-CRP.