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Objective: To compare the treatment costs of insulin glargine (IG; Lantus®) to detemir (ID; Levemir®), both combined with bolus insulin aspart (NovoRapid®) in type 2 diabetes (T2D) in Germany. Methods: Cost comparison was based on data of a 1-year randomised controlled trial [1]. IG was administered once daily and ID once (57% of patients) or twice daily (43%) according to treatment response. At the end of the trial, mean daily basal insulin doses were 0.59 U/kg (IG) and 0.82 U/kg (ID). Aspart doses were 0.32 U/kg (IG) and 0.36 U/kg (ID). Costs were calculated from the German statutory health insurance (SHI) perspective using official 2008 prices. Sensitivity analyses were performed to test robustness of the results. Results: Annual basal and bolus insulin costs per patient were € 1,473 (IG) and € 1,940 (ID). The cost of lancets and blood glucose test strips were € 1,125 (IG) and € 1,286 (ID). Annual costs for needles were € 393 (IG) and € 449 (ID). The total annual cost per patient of administering IG was € 2,991 compared with € 3,675 for ID, translating into a 19% annual cost difference of € 684/patient. Base case results were robust to varying assumptions for insulin dose, insulin price, change in weight and proportion of ID once daily administrations. Conclusion: IG and ID basal-bolus regimes have comparative safety and efficacy, based on the Hollander study, IG however may represent a significantly more cost saving option for T2D patients in Germany requiring basal-bolus insulin analogue therapy with potential annual cost savings of € 684/patient compared to ID.

Abstract Background Bone morphogenic proteins (BMPs) play a key role in bone formation. Consequently, it was expected that topical application of recombinant human (rh)BMP-2 and rhBMP-7 would improve the healing of complex fractures. However, up to 36% of fracture patients do not respond to this therapy. There are hints that a systemic increase in transforming growth factor β1 (TGFβ1) interferes with beneficial BMP effects. Therefore, in the present work we investigated the influence of rhTGFβ1 on rhBMP signaling in primary human osteoblasts, with the aim of more specifically delineating the underlying regulatory mechanisms. Methods BMP signaling was detected by adenoviral Smad-binding-element-reporter assays. Gene expression was determined by reverse transcription polymerase chain reaction (RT-PCR) and confirmed at the protein level by western blot. Histone deacetylase (HDAC) activity was determined using a test kit. Data sets were compared by one-way analysis of variance. Results Our findings showed that Smad1/5/8-mediated rhBMP-2 and rhBMP-7 signaling is completely blocked by rhTGFβ1. We then investigated expression levels of genes involved in BMP signaling and regulation (for example, Smad1/5/8, TGFβ receptors type I and II, noggin, sclerostin, BMP and activin receptor membrane bound inhibitor (BAMBI), v-ski sarcoma viral oncogene homolog (Ski), Ski-related novel protein N (SnoN) and Smad ubiquitination regulatory factors (Smurfs)) and confirmed the expression of regulated genes at the protein level. Smad7 and SnoN were significantly induced by rhTGFβ1 treatment while expression of Smad1, Smad6, TGFβRII and activin receptor-like kinase 1 (Alk1) was reduced. Elevated SnoN expression was accompanied by increased HDAC activity. Addition of an HDAC inhibitor, namely valproic acid, fully abolished the inhibitory effect of rhTGFβ1 on rhBMP-2 and rhBMP-7 signaling. Conclusions rhTGFβ1 effectively blocks rhBMP signaling in osteoblasts. As possible mechanism, we postulate an induction of SnoN that increases HDAC activity and thereby reduces the expression of factors required for efficient BMP signaling. Thus, inhibition of HDAC activity may support bone healing during rhBMP therapy in patients with elevated TGFβ serum levels.

Background: The single-center, open-label, four-arm, exploratory study investigates the relation of different anti-diabetics to serum levels of active TGF-ß, a known pro-fibrotic stimulus, before and after a defined test meal. Findings: We investigated sera of patients with type 2 diabetes mellitus (T2DM) treated with metformin and sulfonylurea, insulin glargine or a DPP-4 inhibitor (DPP4i). Patients' sera were analyzed before and 5 h after a defined test meal at intervals of 30 min. The sulfonylurea/metformin group exhibited the highest basal levels of active TGF-ß (31.50 ± 3.58 ng/ml). The glargine/metformin group had active TGF-ß levels (24.98 ± 1.90 ng/ml) that were comparable to those of the healthy participants (22.12 ± 2.34 ng/ml). The lowest basal levels of active TGF-ß were detected in the DPP-4i/metformin group (12.28 ± 0.84 ng/ml). Following the intake of a standardized meal, active TGF-ß levels decreased (approx. 30%) in healthy subjects as well as in the sulfonylurea/metformin group and in the glargine/ metformin group. After 5 h, the active TGF-ß levels were normalized to basal levels. Active TGF-ß levels in the DPP-4i/metformin group did not change significantly after the test meal. Overall plasma levels of insulin and proinsulin were comparable between healthy participants, and T2DM patients in the glargin/metformin group and in the DPP4i/metformin group. However, no correlation between active TGF-ß levels, glucose, insulin or pro-insulin levels was detected. Conclusions: T2DM patients often exhibit elevated levels of pro-fibrotic active TGF-ß. Our results suggest that glargine/metformin and DPP4i/metformin treatment may more effectively reduce active TGF-ß serum levels than the sulfonylurea/metformin treatment. [ABSTRACT FROM AUTHOR]

Background: Patients with alcoholic liver disease (ALD) often suffer from high blood pressure and rely on antihypertensive treatment. Certain antihypertensives may influence progression of chronic liver disease. Therefore, the aim of this study is to investigate the impact of the commonly used antihypertensives amlodipine, captopril, furosemide, metoprolol, propranolol, and spironolactone on alcohol-induced damage toward human hepatocytes (hHeps). Methods: hHeps were isolated by collagenase perfusion. Reactive oxygen species (ROS) were measured by fluorescence-based assays. Cellular damage was determined by lactate-dehydrogenase (LDH)-leakage. Expression analysis was performed by reverse-transcription polymerase chain reaction and Western blot. Transforming growth factor (TGF)-β signaling was investigated by a Smad3/4-responsive luciferase-reporter assay. Results: Ethanol and TGF-β1 rapidly increased ROS in hHeps, causing a release of 40%-60% of total LDH after 72 hours. All antihypertensives dose dependently reduced ethanol-mediated oxidative stress and cellular damage. Similar results were observed for TGF-β1-dependent damage, except for furosemide, which had no effect. As a common mechanism, all antihypertensives increased heme-oxygenase-1 (HO-1) expression, and inhibition of HO-1 activity reversed the protective effect of the drugs. Interestingly, Smad3/4 signaling was reduced by all compounds except furosemide, which even enhanced this profibrotic signaling. This effect was mediated by expressional changes of Smad3 and/or Smad4. Conclusions: Our results suggest that antihypertensives may both positively and negatively influence chronic liver disease progression. Therefore, we propose that in future patients with ALD and high blood pressure, they could benefit from an adjusted antihypertensive therapy with additional antifibrotic effects. [ABSTRACT FROM AUTHOR]

Background: Bone morphogenic proteins (BMPs) play a key role in bone formation. Consequently, it was expected that topical application of recombinant human (rh)BMP-2 and rhBMP-7 would improve the healing of complex fractures. However, up to 36% of fracture patients do not respond to this therapy. There are hints that a systemic increase in transforming growth factor β1 (TGFβ1 ) interferes with beneficial BMP effects. Therefore, in the present work we investigated the influence of rhTGFβ1 on rhBMP signaling in primary human osteoblasts, with the aim of more specifically delineating the underlying regulatory mechanisms. Methods: BMP signaling was detected by adenoviral Smad-binding-element-reporter assays. Gene expression was determined by reverse transcription polymerase chain reaction (RT-PCR) and confirmed at the protein level by western blot. Histone deacetylase (HDAC) activity was determined using a test kit. Data sets were compared by one-way analysis of variance. Results: Our findings showed that Smad1/5/8-mediated rhBMP-2 and rhBMP-7 signaling is completely blocked by rhTGFβ1. We then investigated expression levels of genes involved in BMP signaling and regulation (for example, Smad1/5/8, TGFβ receptors type I and II, noggin, sclerostin, BMP and activin receptor membrane bound inhibitor (BAMBI), v-ski sarcoma viral oncogene homolog (Ski), Ski-related novel protein N (SnoN) and Smad ubiquitination regulatory factors (Smurfs)) and confirmed the expression of regulated genes at the protein level. Smad7 and SnoN were significantly induced by rhTGFβ1 treatment while expression of Smad1, Smad6, rhTGFβ11 and activin receptorlike kinase 1 (Alk1) was reduced. Elevated SnoN expression was accompanied by increased HDAC activity. Addition of an HDAC inhibitor, namely valproic acid, fully abolished the inhibitory effect of rhTGFβ1 on rhBMP-2 and rhBMP- 7 signaling. Conclusions: rhTGFβ1 effectively blocks rhBMP signaling in osteoblasts. As possible mechanism, we postulate an induction of SnoN that increases HDAC activity and thereby reduces the expression of factors required for efficient BMP signaling. Thus, inhibition of HDAC activity may support bone healing during rhBMP therapy in patients with elevated TGFβ serum levels. [ABSTRACT FROM AUTHOR]

Background: Due to the progressive nature of type 2 diabetes mellitus (T2DM), antidiabetic treatment needs to be continuously intensified to avoid long-term complications. In T2DM patients on either basal insulin-supported oral therapy (BOT) or supplementary insulin therapy (SIT) presenting with HbA1c values above individual targets for 3-6 months, therapy should be intensified. This study investigated effectiveness and tolerability of an intensification of BOT or SIT to a basal-bolus therapy (BBT) regimen in T2DM patients in daily clinical practice., Methods: This noninterventional, 8-month, prospective, multicenter study evaluated parameters of glucose control, occurrence of adverse events (eg, hypoglycemia), and acceptance of devices in daily clinical practice routine after 12 and 24 weeks of intensifying insulin therapy to a BBT regimen starting from either preexisting BOT with insulin glargine (pre-BOT) or preexisting SIT with ≥3 daily injections of insulin glulisine (pre-SIT)., Results: A total of 1,530 patients were documented in 258 German medical practices. A total of 1,301 patients were included in the full analysis set (55% male, 45% female; age median 64 years; body mass index median 30.8 kg/m(2); pre-BOT: n=1,072; pre-SIT: n=229), and 1,515 patients were evaluated for safety. After 12 weeks, HbA1c decreased versus baseline (pre-BOT 8.67%; pre-SIT 8.46%) to 7.73% and 7.66%, respectively (Δ mean -0.94% and -0.80%; P<0.0001). At week 24, HbA1c was further reduced to 7.38% and 7.30%, respectively (Δ mean -1.29% and -1.15%; P<0.0001), with a mean reduction of fasting blood glucose values in both treatment groups by more than 46 mg/dL. An HbA1c goal of ≤6.5% was reached by 17.9% (pre-BOT) and 18.6% (pre-SIT), and an HbA1c ≤7.0% by 46.1% (pre-BOT) and 43.0% (pre-SIT) of patients. During 24 weeks, severe as well as serious hypoglycemic events were rare (pre-BOT: n=5; pre-SIT: n=2; pretreated with both insulins: n=1)., Conclusion: Intensifying glargine-based BOT or glulisine-based SIT to a BBT regimen in poorly controlled T2DM patients in daily routine care led to marked improvements of glycemic control and was well tolerated.

Background: Patients with alcoholic liver disease (ALD) often suffer from high blood pressure and rely on antihypertensive treatment. Certain antihypertensives may influence progression of chronic liver disease. Therefore, the aim of this study is to investigate the impact of the commonly used antihypertensives amlodipine, captopril, furosemide, metoprolol, propranolol, and spironolactone on alcohol-induced damage toward human hepatocytes (hHeps)., Methods: hHeps were isolated by collagenase perfusion. Reactive oxygen species (ROS) were measured by fluorescence-based assays. Cellular damage was determined by lactate-dehydrogenase (LDH)-leakage. Expression analysis was performed by reverse-transcription polymerase chain reaction and Western blot. Transforming growth factor (TGF)-β signaling was investigated by a Smad3/4-responsive luciferase-reporter assay., Results: Ethanol and TGF-β1 rapidly increased ROS in hHeps, causing a release of 40%-60% of total LDH after 72 hours. All antihypertensives dose dependently reduced ethanol-mediated oxidative stress and cellular damage. Similar results were observed for TGF-β1-dependent damage, except for furosemide, which had no effect. As a common mechanism, all antihypertensives increased heme-oxygenase-1 (HO-1) expression, and inhibition of HO-1 activity reversed the protective effect of the drugs. Interestingly, Smad3/4 signaling was reduced by all compounds except furosemide, which even enhanced this profibrotic signaling. This effect was mediated by expressional changes of Smad3 and/or Smad4., Conclusions: Our results suggest that antihypertensives may both positively and negatively influence chronic liver disease progression. Therefore, we propose that in future patients with ALD and high blood pressure, they could benefit from an adjusted antihypertensive therapy with additional antifibrotic effects.

Objective: To compare the treatment costs of insulin glargine (IG; Lantus) to detemir (ID; Levemir), both combined with bolus insulin aspart (NovoRapid) in type 2 diabetes (T2D) in Germany., Methods: Cost comparison was based on data of a 1-year randomised controlled trial. IG was administered once daily and ID once (57% of patients) or twice daily (43%) according to treatment response. At the end of the trial, mean daily basal insulin doses were 0.59 U/kg (IG) and 0.82 U/kg (ID). Aspart doses were 0.32 U/kg (IG) and 0.36 U/kg (ID). Costs were calculated from the German statutory health insurance (SHI) perspective using official 2008 prices. Sensitivity analyses were performed to test robustness of the results., Results: Annual basal and bolus insulin costs per patient were euro 1,473 (IG) and euro 1,940 (ID). The cost of lancets and blood glucose test strips were euro 1,125 (IG) and euro 1,286 (ID). Annual costs for needles were euro 393 (IG) and euro 449 (ID). The total annual cost per patient of administering IG was euro 2,991 compared with euro 3,675 for ID, translating into a 19% annual cost difference of euro 684/patient. Base case results were robust to varying assumptions for insulin dose, insulin price, change in weight and proportion of ID once daily administrations., Conclusion: IG and ID basal-bolus regimes have comparative safety and efficacy, based on the Hollander study, IG however may represent a significantly more cost saving option for T2D patients in Germany requiring basal-bolus insulin analogue therapy with potential annual cost savings of euro 684/patient compared to ID.