Boehringer Ingelheim (Finland)

OBJECTIVE: To investigate the efficacy, safety, and tolerability of empagliflozin in patients with type 2 diabetes and hypertension. RESEARCH DESIGN AND METHODS: Patients (N = 825) with type 2 diabetes and hypertension (mean seated systolic blood pressure [SBP] 130-159 mmHg and diastolic blood pressure [DBP] 80-99 mmHg) were randomized (double blind) to 10 mg or 25 mg empagliflozin or placebo once daily for 12 weeks. RESULTS: At week 12, adjusted mean difference versus placebo in change from baseline in mean 24-h SBP (ambulatory blood pressure monitoring [ABPM]) was -3.44 mmHg (95% CI -4.78, -2.09) with 10 mg empagliflozin and -4.16 mmHg (-5.50, -2.83) with 25 mg empagliflozin (both P < 0.001). At week 12, adjusted mean difference versus placebo in change from baseline in mean 24-h DBP (ABPM) was -1.36 mmHg (95% CI -2.15, -0.56) with 10 mg empagliflozin and -1.72 mmHg (95% CI -2.51, -0.93) with 25 mg empagliflozin (both P < 0.001). Changes in office BP were consistent with ABPM. Adjusted mean difference versus placebo in change from baseline in HbA1c at week 12 was -0.62% (95% CI -0.72, -0.52) (-6.8 mmol/mol [95% CI -7.9, -5.7]) with 10 mg empagliflozin and -0.65% (95% CI -0.75, -0.55) (-7.1 mmol/mol [95% CI -8.2, -6.0]) with 25 mg empagliflozin (both P < 0.001). Empagliflozin was well tolerated. One patient on placebo and one patient on 10 mg empagliflozin reported events consistent with volume depletion. CONCLUSIONS: Empagliflozin was associated with significant and clinically meaningful reductions in BP and HbA1c versus placebo and was well tolerated in patients with type 2 diabetes and hypertension.

AIM: To evaluate the efficacy and safety of the potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin administered as add-on therapy to metformin in patients with type 2 diabetes with inadequate glycaemic control. METHODS: This 24-week, randomized, placebo-controlled, double-blind, parallel-group study was carried out in 82 centres in 10 countries. Patients with HbA1c levels of 7.0-10.0% on metformin and a maximum of one additional antidiabetes medication, which was discontinued at screening, continued on metformin ≥1500 mg/day for 6 weeks, including a placebo run-in period of 2 weeks, before being randomized to linagliptin 5 mg once daily (n = 524) or placebo (n = 177) add-on. The primary outcome was the change from baseline in HbA1c after 24 weeks of treatment, evaluated with an analysis of covariance (ANCOVA). RESULTS: Mean baseline HbA1c and fasting plasma glucose (FPG) were 8.1% and 9.4 mmol/l, respectively. Linagliptin showed significant reductions vs. placebo in adjusted mean changes from baseline of HbA1c (-0.49 vs. 0.15%), FPG (-0.59 vs. 0.58 mmol/l) and 2hPPG (-2.7 vs. 1.0 mmol/l); all p < 0.0001. Hypoglycaemia was rare, occurring in three patients (0.6%) treated with linagliptin and five patients (2.8%) in the placebo group. Body weight did not change significantly from baseline in both groups (-0.5 kg placebo, -0.4 kg linagliptin). CONCLUSIONS: The addition of linagliptin 5 mg once daily in patients with type 2 diabetes inadequately controlled on metformin resulted in a significant and clinically meaningful improvement in glycaemic control without weight gain or increased risk of hypoglycaemia.

Interaction of the basement-membrane binding O75X adhesin of uropathogenic Escherichia coli with various extracellular matrix proteins was studied. The adhesin showed strong binding to type IV collagen immobilized on microtitre plates, whereas other collagens, laminin and fibronectin, were only weakly recognized. Similarly, specific binding of [125I]-labelled type IV collagen to O75X-positive bacteria was shown. Interaction of the two proteins was also demonstrated by affinity chromatography of the O75X adhesin on immobilized type IV collagen. The adhesin bound strongly to the immobilized N-terminal 7S domain of type IV collagen, and the binding of [125I]-labelled type IV collagen to O75X-positive bacteria was inhibited by the soluble 7S domain. Binding of O75X to type IV collagen and to its 7S domain was specifically inhibited by chloramphenicol but was not affected by periodate or endoglycosidase-H treatment of the glycoproteins. Our results show that the 7S domain of type IV collagen is the basement membrane receptor for the O75X adhesin and suggest an interaction based on protein-protein recognition. Inhibition of the interaction by chloramphenicol favours the supposition that a modified tyrosine is involved in the binding site.

BACKGROUND: The purpose of this study was to identify early features of lamin A/C gene mutation related dilated cardiomyopathy (DCM) with cardiovascular magnetic resonance (CMR). We characterise myocardial and functional findings in carriers of lamin A/C mutation to facilitate the recognition of these patients using this method. We also investigated the connection between myocardial fibrosis and conduction abnormalities. METHODS: Seventeen lamin A/C mutation carriers underwent CMR. Late gadolinium enhancement (LGE) and cine images were performed to evaluate myocardial fibrosis, regional wall motion, longitudinal myocardial function, global function and volumetry of both ventricles. The location, pattern and extent of enhancement in the left ventricle (LV) myocardium were visually estimated. RESULTS: Patients had LV myocardial fibrosis in 88% of cases. Segmental wall motion abnormalities correlated strongly with the degree of enhancement. Myocardial enhancement was associated with conduction abnormalities. Sixty-nine percent of our asymptomatic or mildly symptomatic patients showed mild ventricular dilatation, systolic failure or both in global ventricular analysis. Decreased longitudinal systolic LV function was observed in 53% of patients. CONCLUSIONS: Cardiac conduction abnormalities, mildly dilated LV and depressed systolic dysfunction are common in DCM caused by a lamin A/C gene mutation. However, other cardiac diseases may produce similar symptoms. CMR is an accurate tool to determine the typical cardiac involvement in lamin A/C cardiomyopathy and may help to initiate early treatment in this malignant familiar form of DCM.

BACKGROUND AND PURPOSE: It is not yet known which end points are the most suitable for evaluation of the effects of acute stroke intervention. The European Cooperative Acute Stroke Study (ECASS) I study used 2 primary end points. The study was powered to detect a 15% improvement of the median of each primary end point. The study failed to show this effect and was negative in the intention-to-treat analysis. The National Institute of Neurological Disorders and Stroke (NINDS) study used 4 dichotomized end points and applied a global end-point analysis. This study was positive and led to FDA approval of thrombolytic therapy for acute ischemic stroke. This study was undertaken to answer the question of whether a different statistical design may have shown a positive results of the ECASS I trial. METHODS: We performed a retrospective analysis of the ECASS I intention-to-treat data set (615 randomized and treated patients, rtPA treatment versus placebo) and post hoc application of the NINDS trial statistical methodology (global end-point analysis). The scores of the modified Rankin Scale (mRS), Barthel Index (BI), and the National Institutes of Health Stroke Scale (NIHSS) were dichotomized according to the criteria used in the NINDS trial. Favorable outcome was defined as a score of 0 or 1 on mRS, a score of 95 or 100 on BI, and a score of 0 or 1 on NIHSS. RESULTS: The number of patients reaching favorable outcome were higher in all 3 end points in the rtPA-treated group. The effect sizes were 8% for mRS, 6% for BI, and 14% for NIHSS, respectively. The differences are statistically significant for the mRS (P=0.044; odds ratio [OR], 1. 4; 95% confidence interval [CI], 1.0 to 2.0) and the NIHSS (P=0.001; OR, 1.9; 95% CI, 1.4 to 2.8), while for the BI significance was missed (P=0.102; OR, 1.3; 95% CI, 0.9 to 1.8). The global end-point statistics, however, shows a significant increase (P=0.008; OR, 1.5; 95% CI, 1.1 to 2.0) of favorable outcome in the rtPA-treated patient group. CONCLUSIONS: Using the global end-point analysis, ECASS is positive in the intention-to-treat analysis. This may indicate that the time window for thrombolysis may be as long as 6 hours. Looking at the 3 dichotomized end points, the effect sizes for 2 end points, mRS and BI, are smaller in the ECASS 6-hour intention-to-treat population compared with the NINDS trial, whereas the effect size for the NIHSS is larger. While in the NINDS trial all 3 end points reveal statistically significant results, in ECASS only 2 of the 3 corresponding end points, mRS and NIHSS, were statistically significant. This finding underlines an important difference of a global end-point approach: it may show a positive overall result although one of the end points is not positive.

BACKGROUND: The overlap between asthma and chronic obstructive pulmonary disease (COPD) is an important clinical phenomenon. However, the prevalence of asthma-COPD overlap syndrome (ACOS) is not known. AIMS: To investigate the prevalence of ACOS among asthmatic patients with a smoking history, and evaluate the factors predicting ACOS in this patient group. METHODS: We investigated 190 primary care asthma patients with no previous diagnosis of COPD, but who were either current or ex-smokers, with a smoking history of at least 10 pack-years. Spirometry was performed on all the patients while they were taking their normal asthma medication. Patients were considered to have ACOS if their postbronchodilator forced expiratory volume in 1 s/forced vital capacity was < 0.70. RESULTS: Fifty-two (27.4%) of the patients were found to have ACOS. Age ⩾ 60 years and smoking for ⩾ 20 pack-years were the best predictors of ACOS. If both of these criteria were met, the odds ratio (95% confidence interval) for ACOS was 6.08 (2.11-17.49), compared with the situation where neither of these criteria were fulfilled. CONCLUSIONS: There is a high prevalence of ACOS among primary health care asthmatics with a positive smoking history but no previous diagnosis of COPD. In this population, age over 60 years and a smoking history of more than 20 pack-years were the best predictors of ACOS.

The present cost-of-illness study is focused on the costs of COPD in Germany. In a pre-study, data on 814 randomly selected patients were collected to achieve reliable figures for the distribution of COPD severity grades and the frequencies of exacerbations. The main study was performed on 321 randomly selected patients from the pre-study. Data on resource use were collected in a face-to-face interview with the respective physicians using the patient records as a basis. Costs associated with resource consumption were weighted with the frequencies of COPD severity grades as assessed in the pre-study to determine the costs of COPD. Annual COPD-related costs per patient were 3,027 from the societal perspective. Main cost components were hospitalisations (26 %), medication (23 %) and early retirement (17 %). Annual COPD-related costs from the perspective of the German health insurance system (GKV) were 1,944 euros per patient.

Idiopathic pulmonary fibrosis (IPF) is the most common type of idiopathic interstitial pneumonia and is characterized by a poor prognosis, with an estimated 5-year survival of approximately 20%. Progressive and irreversible lung functional impairment leads to chronic respiratory insufficiency with a severely impaired quality of life. In the last 2 decades, novel treatments for IPF have been developed as a consequence of an increasing understanding of disease pathogenesis and pathobiology. In IPF, injured dysfunctional alveolar epithelial cells promote fibroblast recruitment and proliferation, resulting in scarring of the lung tissue. Recently, pirfenidone and nintedanib have been approved for the treatment of IPF, having shown efficacy to slow functional decline and disease progression. This article focuses on the pharmacologic characteristics and clinical evidence supporting the use of nintedanib, a potent small-molecule tyrosine kinase inhibitor, as therapy for IPF. After introducing the mechanism of action and pharmacokinetics, an overview of the safety and efficacy results from the most recent clinical trials of nintedanib in IPF is presented.

Chronic kidney disease (CKD) is frequently comorbid with type 2 diabetes, and glucose-lowering treatment options are limited for such patients (1). We investigated the efficacy and safety of linagliptin, a dipeptidyl peptidase-4 inhibitor, in type 2 diabetic patients with moderate to severe renal impairment and insufficient glycemic control. This randomized, double-blind, parallel-group clinical trial comprised a 12-week, placebo-controlled phase followed by a 40-week, active-controlled extension. The study was conducted between 17 March 2010 and 18 June 2012 at 52 outpatient clinics in nine countries (ClinicalTrials.gov, NCT01087502). Patients with type 2 diabetes, HbA1c 7.0–10.0% (53–86 mmol/mol), and estimated glomerular filtration rate (eGFR) 110 mg/dL. The primary end point was change in HbA1c from baseline to week 12 in the full-analysis set (FAS; all randomized patients who received ≥1 dose of study drug and had a baseline and ≥1 postbaseline measurement of HbA1c); missing data were imputed using last observation carried forward. Secondary end points included change in HbA1c from baseline over time. The incidence of adverse events (AEs) was evaluated for the treated set (TS; all randomized patients who received ≥1 dose …

PURPOSE OF REVIEW: The majority of patients with type 2 diabetes mellitus (T2DM) have hypertension requiring combination therapy. Sodium glucose cotransporter 2 (SGLT2) inhibitors are novel glucose-lowering drugs with shared and potentially unique beneficial effects on cardiovascular risk beyond glycemic control. This review focuses on the potential role of SGLT2 inhibitors in the treatment of hypertension associated with T2DM. RECENT FINDINGS: SGLT2 inhibitors reduce office SBP by 3-5 mmHg and DBP by 2-3 mmHg across all class members. Corresponding clinically meaningful, significant blood pressure (BP) lowering effects have been confirmed using 24 h ambulatory BP monitoring. SGLT2 inhibitors reduce BP irrespective of the type of background antihypertensive medication. The antihypertensive actions of SGLT2 inhibitors involve several mechanisms including modest diuretic effects, weight loss, and direct vascular effects leading to decreased arterial stiffness and vascular resistance. The first-in class cardiovascular outcome trial with empagliflozin showed a significant reduction in a composite endpoint of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction in T2DM patients at high risk for cardiovascular events. SUMMARY: SGLT2 inhibitors have clinically significant antihypertensive effects. SGLT2 inhibition could be a potentially useful supplement to the BP-lowering treatment armamentarium in patients with T2DM.

Background: Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases.

: IPF is associated with a high burden of disease, and reimbursement restrictions are in conflict with early care. As there are antifibrotic treatment options for IPF patients, early diagnosis is important.

Background: Increasing age is associated with poor prognosis in patients with COPD. Objective: This analysis from the replicate Phase III OTEMTO ® and TONADO ® studies examined the efficacy and safety of tiotropium, a long-acting anticholinergic, combined with olodaterol, a long-acting β 2 -agonist, compared to monotherapies and placebo in patients with COPD aged 40 years to <65 years, 65 years to <75 years, 75 years to <85 years, and ≥85 years. Methods: In these double-blind, parallel-group, active-controlled, multicenter, randomized studies, patients received tiotropium + olodaterol 2.5/5 µg or 5/5 µg, tiotropium 5 µg or 2.5 µg (TONADO only), olodaterol 5 µg (TONADO only), or placebo (OTEMTO only). This analysis used the approved doses of tiotropium + olodaterol 5/5 µg, tiotropium 5 µg, and olodaterol 5 µg. Primary end points at 12 weeks (OTEMTO) or 24 weeks (TONADO) included St George’s Respiratory Questionnaire (SGRQ) total score, forced expiratory volume in 1 second (FEV 1 ) area under the curve from 0 hour to 3 hours (AUC 0–3 ) response, and trough FEV 1 response. Results: A total of 1,621 patients were randomized (40 years to <65 years, n=749; 65 years to <75 years, n=674; 75 years to <85 years, n=186; ≥85 years, n=12) in OTEMTO and 5,162 patients (40 years to <65 years, n=2,654; 65 years to <75 years, n=1,967; 75 to <85 years, n=528; ≥85 years, n=13) in TONADO. FEV 1 AUC 0–3 and trough FEV 1 responses improved with tiotropium + olodaterol 5/5 µg at 12 weeks and 24 weeks compared to monotherapies or placebo for all age groups. SGRQ scores generally improved with tiotropium + olodaterol 5/5 µg after 12 weeks in OTEMTO and improved after 24 weeks in all age groups in TONADO. In all age groups receiving tiotropium + olodaterol 5/5 µg compared to monotherapies or placebo, transition dyspnea index scores generally improved, while rescue medication usage improved. Conclusion: No differences were noted in relative responses to treatment or safety when using tiotropium + olodaterol 5/5 µg compared to monotherapies or placebo across all age groups. Keywords: FEV 1 , SGRQ, lung function, TDI, rescue medication

AIMS: To characterize clinical profiles, prevalence of chronic kidney disease (CKD), and treatment patterns in type 2 diabetes (T2D) and heart failure (HF) patients in Finnish primary care. METHODS: A total of 1385 patients (1196 with T2D, 50 with HF, and 139 with T2D and HF) in 60 Finnish primary care centers were recruited to this cross-sectional study. Data on demographic and clinical characteristics, laboratory measurements, and medications were collected retrospectively from medical records. T2D patients were classified according to their risk of cardiovascular (CV) events as very high-risk (62%) and other patients (38%). RESULTS: Of the T2D patients, 10% (139/1335) had a diagnosis of HF and 42% (457/1090) had stage 3-5 CKD and/or albuminuria based on laboratory measurement. Of the HF patients, 74% (139/189) had T2D and 78% (114/146) had stage 3-5 CKD and/or albuminuria. Metformin was the most frequently used medication in both very high-risk patients (74%) and other patients (86%). SGLT2 inhibitors and/or GLP-1 analogues were used by 37% of very high-risk patients compared to 42% in other patients. CONCLUSIONS: The majority of T2D patients in Finnish primary care are at very high risk of cardiovascular events. However, the implementation of treatments with proven cardioprotective effects in very high-risk patients is currently suboptimal.

Purpose: Sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin has recently been shown to improve the outcomes of heart failure (HF) patients regardless of patient's left ventricular ejection fraction by reducing the combined risk of cardiovascular death or hospitalization for worsening HF. The aim of this study was to assess the cost-effectiveness of adding empagliflozin to the standard care (SC) in comparison to SC only in the treatment of HF in Finland. Patients and Methods: The assessment was performed in the cost-utility framework using two Markov cohort state-transition models, one for HF with reduced ejection fraction (HFrEF) and one for HF with preserved ejection fraction (HFpEF). The models have been primarily developed based on the EMPEROR-Reduced and EMPEROR-Preserved trials which informed the modelled patient characteristics, efficacy of treatments in terms of associated risks for heart failure hospitalizations, cardiovascular (CV) and non-CV death, treatment related adverse events (AE), and state- and event-specific health-related quality of life weights (EQ-5D). Direct health care costs were estimated from Finnish published references. Cost-effectiveness was assessed from health care payer perspective based on incremental cost-effectiveness ratio (ICER; cost per quality adjusted life-year [QALY] gained) and probability of cost-effectiveness (at willingness-to-pay [WTP] of 35,000 euros/QALY). The ICER was reported as the weighted (HFrEF, 43.5%; HFpEF, 56.5%) average result of the two models. Results: Empagliflozin + SC treatment increased the average quality-adjusted life-expectancy, and treatment costs of HF patients by 0.15 QALYs and 1,594 euros, respectively, when compared to SC. An additional QALY with empagliflozin was thus gained at a cost of 10,621 euros. The probability of empagliflozin + SC being cost-effective compared to placebo + SC was 77.6% and 83.5% with WTP of 35,000 and 100,000 euros/QALY, respectively. Conclusion: Empagliflozin is a cost-effective treatment for patients with HF in the Finnish health care setting.

The efficacy and safety of nintedanib in patients with IPF were assessed in the two replicate Phase III placebo-controlled INPULSIS trials. In both trials, nintedanib reduced disease progression by reducing decline in forced vital capacity (FVC). The recommended dose of nintedanib was 150 mg twice daily (bid), but dose reductions to 100 mg bid and treatment interruptions were allowed for the management of adverse events. Following a dose reduction, the dose could be re-escalated to 150 mg bid. We assessed whether dose reductions and/or treatment interruptions influenced the effect of nintedanib on reducing FVC decline.

Abstract Background Surprisingly little is known about asthma control among asthmatics who smoke. The aim of this cross-sectional study was to investigate asthma symptom control according to the GINA guidelines among asthmatics with a clinically significant smoking history. Methods One hundred ninety asthmatics from primary care in Finland were investigated. The patients were current or previous cigarette smokers with a history of 10 or more pack-years. They completed a questionnaire including questions on asthma symptoms and reliever use so that their level of asthma symptom control (well controlled, partly controlled, or uncontrolled) according to GINA could be determined. Results Sixty-six (34.7%) patients had their asthma well controlled, 81 (42.6%) had their asthma partly controlled, and 43 (22.6%) had uncontrolled asthma. Current smokers had uncontrolled asthma more often than ex-smokers, OR 2.54 (95% CI 1.25–5.14, p = 0.01). Patients with moderate to severe asthma exacerbation during the previous year had uncontrolled asthma more often than patients without an exacerbation, OR 2.17 (95% CI 1.06–4.47, p = 0.04), and patients with FEV 1 &lt; 80% of predicted had uncontrolled asthma more often than patients with FEV 1 &gt; 80% of predicted, OR 2.04 (95% CI 1.02–4.08, p = 0.04). Conclusions Asthmatic patients with a clinically significant smoking history often do not have well controlled asthma. Poor asthma symptom control was associated with current smoking status, history of exacerbations and impaired lung function. Therefore, every attempt should be made to help asthmatics who smoke to quit smoking.

Background, methods: Efficacy, safety and tolerability of empagliflozin (EMPA) were investigated in patients with T2DM and hypertension in a randomized, double-blind Phase III trial. Patients received EMPA 10 mg (n = 276), 25 mg (n = 276) or placebo (PBO; n = 272) qd for 12 weeks. Co-primary endpoints were changes from baseline in HbA1c and mean 24-hour systolic blood pressure (SBP) by ambulatory BP monitoring (ABPM) at week 12. Key secondary endpoint was change from baseline in mean 24-hour diastolic BP (DBP) at week 12. Other secondary endpoints included changes from baseline in office SBP and DBP and proportions of patients reaching controlled BP (< 130/80 mmHg) at week 12.

The efficacy of 50 mg pirenzepine twice daily in the treatment of reflux oesophagitis was compared with that of placebo in 47 patients over a period of 12 weeks. The 23 patients receiving pirenzepine experienced decreases in symptoms after 4 weeks (p less than 0.001) and 12 weeks (p less than 0.02) of treatment significantly greater than those in the 24 patients receiving placebo. The decreases in symptoms were associated with significantly less use of antacids by the pirenzepine group (p less than 0.01) during the first 4 weeks. Endoscopically, oesophagitis was healed or improved in 54.5% of patients receiving pirenzepine and in 18.2% of patients receiving placebo (p less than 0.05) after 4 weeks of treatment. After 12 weeks of treatment healing or improvement was seen in 55.0% and 35.0% of patients, respectively (difference not significant). Histologic improvement did not differ significantly between the groups. Our results suggest that pirenzepine is useful in the management of reflux oesophagitis.

Background: Patient recruitment and retention are a challenge when conducting clinical trials in patients with pulmonary fibrosis, including idiopathic pulmonary fibrosis and other interstitial lung diseases. This study aimed to understand and address the barriers associated with trial participation for these populations. Methods: Nine patients, nine caregivers and three healthcare professionals participated in virtual simulations of planned phase III trials. During the simulations, participants received information about the trials and either tested a home spirometry device or watched a home spirometry demonstration, before providing their insights in debriefs. The findings were interpreted in advisory boards with representatives from patient organisations and expert investigators. Results: Regarding barriers to participation, patient fatigue and breathlessness were emphasised as posing challenges for travel, visit length and completion of onsite assessments. Lack of information, support and appreciation were also identified as factors that may exacerbate anxiety and negatively affect participant retention rates. Feedback on the home spirometry was mixed, with participants appreciating being able to complete the test at home but worrying about device handling. Based on the insights gained, patient-friendly adaptations were made to the trial protocol and conduct, including remote assessment of patient-reported outcomes, increased visit flexibility, travel support services, patient and caregiver information campaigns, and training of investigators on patients' needs. Conclusions: Participants identified important barriers to participation, which led to patient-friendly changes being made to the planned trials. As a result, participation in the planned trials should be less burdensome, with improved recruitment and retention rates, and ultimately, improved data quality.