Christoph Schindler

Improved Insulin Sensitivity With Angiotensin Receptor Neprilysin Inhibition in Individuals With Obesity and Hypertension.

Natriuretic peptide (NP) deficiency and sustained renin‐angiotensin system activation are associated with impaired oxidative metabolism and predispose to type‐2 diabetes. We hypothesized that sacubitril/valsartan (LCZ696), which augments NP through neprilysin inhibition while blocking angiotensin II type‐1 (AT1)‐receptors, improves insulin sensitivity, lipid mobilization, and oxidation. After 8 weeks of treatment of obese patients with hypertension, sacubitril/valsartan 400 mg q.d., but not amlodipine 10 mg q.d., was associated with a significant increase from baseline in the insulin sensitivity index (hyperinsulinemic‐euglycemic clamp), and tended to be higher in patients treated with sacubitril/valsartan compared to amlodipine. Abdominal adipose tissue interstitial glycerol concentrations increased with sacubitril/valsartan, but decreased with amlodipine. Whole‐body lipolysis and substrate oxidation did not change with either treatment. Results confirm that sacubitril/valsartan treatment leads to a metabolic benefit in the study population and supports the relevance of neprilysin inhibition along with AT1‐receptor blockade in the regulation of human glucose and lipid metabolism.

Clinically and pharmacologically relevant interactions of antidiabetic drugs

Patients with type 2 diabetes mellitus often require multifactorial pharmacological treatment due to different comorbidities. An increasing number of concomitantly taken medications elevate the risk of the patient experiencing adverse drug effects or drug interactions. Drug interactions can be divided into pharmacokinetic and pharmacodynamic interactions affecting cytochrome (CYP) enzymes, absorption properties, transporter activities and receptor affinities. Furthermore, nutrition, herbal supplements, patient’s age and gender are of clinical importance. Relevant drug interactions are predominantly related to sulfonylureas, thiazolidinediones and glinides. Although metformin has a very low interaction potential, caution is advised when drugs that impair renal function are used concomitantly. With the exception of saxagliptin, dipeptidyl peptidase-4 (DPP-4) inhibitors also show a low interaction potential, but all drugs affecting the drug transporter P-glycoprotein should be used with caution. Incretin mimetics and sodium–glucose cotransporter-2 (SGLT-2) inhibitors comprise a very low interaction potential and are therefore recommended as an ideal combination partner from the clinical–pharmacologic point of view.

Phase Ib study evaluating safety and clinical activity of the anti-HER3 antibody lumretuzumab combined with the anti-HER2 antibody pertuzumab and paclitaxel in HER3-positive, HER2-low metastatic breast cancer

SummaryPurpose To investigate the safety and clinical activity of comprehensive human epidermal growth factor receptor (HER) family receptor inhibition using lumretuzumab (anti-HER3) and pertuzumab (anti-HER2) in combination with paclitaxel in patients with metastatic breast cancer (MBC). Methods This phase Ib study enrolled 35 MBC patients (first line or higher) with HER3-positive and HER2-low (immunohistochemistry 1+ to 2+ and in-situ hybridization negative) tumors. Patients received lumretuzumab (1000xa0mg in Cohort 1; 500xa0mg in Cohorts 2 and 3) plus pertuzumab (840xa0mg loading dose [LD] followed by 420xa0mg in Cohorts 1 and 2; 420xa0mg without LD in Cohort 3) every 3xa0weeks, plus paclitaxel (80xa0mg/m2 weekly in all cohorts). Patients in Cohort 3 received prophylactic loperamide treatment. Results Diarrhea grade 3 was a dose-limiting toxicity of Cohort 1 defining the maximum tolerated dose of lumretuzumab when given in combination with pertuzumab and paclitaxel at 500xa0mg every three weeks. Grade 3 diarrhea decreased from 50% (Cohort 2) to 30.8% (Cohort 3) with prophylactic loperamide administration and omission of the pertuzumab LD, nonetheless, all patients still experienced diarrhea. In first-line MBC patients, the objective response rate in Cohorts 2 and 3 was 55% and 38.5%, respectively. No relationship between HER2 and HER3 expression or somatic mutations and clinical response was observed. Conclusions Combination treatment with lumretuzumab, pertuzumab and paclitaxel was associated with a high incidence of diarrhea. Despite the efforts to alter dosing, the therapeutic window remained too narrow to warrant further clinical development. Trial registration: on ClinicalTrials.gov with the identifier NCT01918254 first registered on 3rd July 2013.

Motivations for (non)participation in population-based health studies among the elderly – comparison of participants and nonparticipants of a prospective study on influenza vaccination

BackgroundParticipation in epidemiological studies has strongly declined in recent years. We examined the reasons for (non)participation in population-based health studies among participants and nonparticipants of a prospective study on influenza vaccination among the elderly.MethodsMales and females between 65 and 80xa0years of age (Nu2009=u20095582) were randomly selected from the residents’ registration office in Hannover, Germany, and were invited to participate in a study featuring vaccination with a seasonal adjuvanted influenza vaccine (Fluad™, Novartis) including five follow-up visits (day 0, 1/3, 7, 21, 70 with respect to vaccination). A 24-item nonresponder questionnaire, including 10 items on reasons for participating in a hypothetical health study, was mailed to 1500 randomly selected nonparticipants. The same 10 items were included in the end-of-study questionnaire administered to the participants in the vaccination study (nu2009=u2009200). Logistic regression analysis with backward elimination was used to identify the reasons most strongly associated with nonparticipation.ResultsFive hundred thirty-one (35%) nonparticipants and 200 participants (100%) returned the respective questionnaires. Nonparticipation was associated with a lower interest in obtaining personal health information (ORu2009=u20093.32) and a preference for less invasive (ORu2009=u20093.01) and less time-demanding (ORu2009=u20092.19) studies. Responses to other items, e.g. regarding altruistic motives, monetary compensation, general interest of the study, or study approval through ethics committee and data security authority, did not differ between participants and nonparticipants.ConclusionsParticipation rates in health studies among elderly individuals could potentially be improved by reducing interventions and time demand, for instance by implementing methods of self-sampling and remote data collection.Trial registrationNo. 1100359 (ClinicalTrials.gov, date of registration: 09.02.2015).

Usability of Functional MRI in Clinical Studies for Fast and Reliable Assessment of Renal Perfusion and Quantification of Hemodynamic Effects on the Kidney

The purpose of this study was to evaluate contrast‐media–free arterial spin labeling, a technique of functional magnetic resonance imaging (MRI), for assessment of kidney perfusion in a clinical study. We examined renal perfusion by arterial spin labeling in 15 healthy adults using a clinical 1.5‐T MRI system, twice under baseline conditions and 60 minutes after a single oral dose of 50 mg captopril. Data evaluation included assessment of interstudy and interrater reproducibility in addition to the pharmacological effect of captopril on kidney perfusion and a sample size calculation for potential application of the technique in pharmacological intervention studies. Interstudy reproducibility of cortical and medullary kidney perfusion was excellent (intraclass correlation coefficients 0.77 and 0.83, respectively). Interrater reproducibility was excellent in the cortex and good in the medulla (intraclass correlation coefficients 0.97 and 0.66, respectively). Ingestion of 50 mg captopril was associated with an 11% drop of systolic blood pressure and a rise in kidney perfusion by 22% in the cortex (369 ± 48 vs 452 ± 56 mL/[min·100 g], P < .001) and 26% in the medulla (157 ± 39 to 198 ± 45 ml/[min·100 g]; P < .01). Statistical power analysis revealed that a small sample size of only 6 participants is needed in a clinical trial to capture an equal change in kidney perfusion to the one induced by 50 mg captopril with a statistical power of 82% and an α error of 0.05. In conclusion, funtional MRI with arterial spin labeling is a reliable method for quantification of kidney perfusion and for fast assessment of pharmacologically induced renal perfusion changes, allowing low case numbers.

Editorial: Closing sale of innovative treatment options for the treatment of diabetes and metabolic disorders?

Within the past decade, considerable numbers of drugs for the treatment of diabetes and metabolic disorders have either not reached the market, having been stopped late in development, or having been withdrawn after initial approval soon after market authorization due to serious safety concerns. Many formerly promising drug candidates with block buster potential in their respective therapeutic area have foundered, often with high financial losses for the developing drug company (Table 1). A critical look back over the past 10 years leads me sceptically to ask if we are currently experiencing a closing sale of innovative treatment options for treating diabetes and metabolic disorders?

Establishment of a cohort for deep phenotyping of the immune response to influenza vaccination among elderly individuals recruited from the general population

ABSTRACT Elderly individuals have the highest burden of disease from influenza infection but also the lowest immune response to influenza vaccination. A better understanding of the host response to influenza vaccination in the elderly is therefore urgently needed. We conducted a biphasic prospective, population-based study from Dec. 2014 to May 2015 (pilot study) and Sept. 2015 to May 2016 (main study). Individuals 65–80 y of age were randomly selected from the residents registration office in Hannover, Germany, for the pilot (n = 34) and main study (n = 200). The pilot study tested recruitment for study arms featuring 2, 4, or 5 visits/blood draws. The 5-visit (day 0, 1/3, 7, 21, 70 with respect to vaccination) study arm was selected for the main study. Both studies featured vaccination with Fluad™ (Novartis, Italy), a detailed medical history, a physical exam, recording of adverse events, completion of a questionnaire on common infections and an end-of-study questionnaire, and blood samples. Response rates in the pilot and main studies were 3.7% and 4.0%, respectively. Willingness to participate did not differ among the study arms (Fishers exact test, p = 0.44). In both studies, there were no losses to follow-up. Compliance with study visits, blood sampling and completion of the questionnaires was very high (100%, >97%, 100%, respectively), as were participants acceptance of and satisfaction with both phases of the study. The low response rates indicate the need for optimized recruitment strategies if the study population is to be representative of the general population. Nonetheless, the complex prospective study design proved to be highly feasible.

New therapeutic efforts and upcoming developments in the field of diabetes medicine and endocrinology.

I welcome the readers to the newest issue of Therapeutic Advances in Endocrinology and Metabolism. In this issue, two important therapeutic fields are addressed: In the diabetes area the pharmacologic improvement of insulin therapy and a specific cellular therapy for treating severe foot ulcers as a treatment option in complicated and therapy-resistant cases; in the field of specific endocrine and metabolic disorders, the pharmacologic treatment of the syndrome of inappropriate antidiuretic hormone (SIADH) which is also called the Schwartz-Bartter-Syndrome is extensively reviewed. n nIt is a sobering statistic: in an online survey of 500 patients with types 1 and 2 diabetes mellitus, 57% reported intentionally omitting their insulin injections. From a patient’s perspective, avoiding hypoglycemia is a major concern and this is probably one of the main causes of non-adherence to this medication, resulting in poor glycemic control. A longer-acting basal insulin should, therefore, address this problem. The review by Ammar Wakil and Stephen Atkin in this issue looks at Degludec, a new long acting insulin with a longer half-life than others, a flat time-action profile (less likely to cause hypoglycemia) and less day-to-day variability, improving glycaemic control. Degludec is made by deleting a threonine residue from human insulin and adding an acyl side chain to a lysine residue, so that injection results in self-association and the formation of large soluble multi-hexamers – a subcutaneous depot. This promises better glycemic control compared with insulin glargine and patients have more choice as to the timing of their basal insulin dose. n nLower limb amputations as a result of non-healing foot ulcers in diabetic patients are regrettable, especially because they might have been avoided with more consequent and earlier treatment of the disease. In a letter to the Editor from the group of Matthias Weck, an emerging cellular therapy using platelet-rich plasma gel is described, and seems to provide previously unavailable ulcer management options to avoid limb loss. n nPhysicians haven’t had a specific therapy for hyponatremia until the recent arrival of vasopressin receptor antagonists, the vaptans. Peter Gross contributes to the issue with a comprehensive review focusing on SIADH, accounting for one third of hyponatremia and serving as a general model for the disease. Misdiagnosis is common, and the author discusses the importance of demonstrating reduced effective serum osmolality in a given hyponatremia to exclude the possibility of a normoosmolar or hyperosmolar hyponatremia. It must be considered that a common circumstance of hyperosmolar hyponatremia is hyperglycemia. The introduction of parenteral (conivaptan) and orally available (tolvaptan) renal V-2 vasopressin receptor antagonists – collectively called vaptans - for the specific, easily titratable treatment of SIADH has been considered a breakthrough. The author gives detailed practical expert advice on their therapeutic use.

Dedicated to evidence-based medicine and the evaluation of new therapeutic approaches in the field

I welcome you to the first issue of the journal Therapeutic Advances in Endocrinology and Metabolism under my editorship. I have taken over from Glenn Matfin beginning July 2011 and would first of all like to take the chance to thank him for the excellent work for the journal which has been done since its foundation in 2010. n nTherapeutic Advances in Endocrinology and Metabolism is aimed at clinicians and researchers from the field and will be a forum for all views and reviews relating to this diverse discipline. The Editorial Board, the Associate Editors and I are committed to developing this journal as a source for timely analysis of new therapies, the candid discussion of issues that impinge upon the translation of molecular mechanisms of metabolic regulation to the practice and prevention of diseases such as obesity, diabetes mellitus type I and II, metabolic bone disease, adrenal disorders, hyperlipidemia and endocrine hypertension, and the publication of original findings in the areas of metabolic epidemiology, physiology and clinical research. n nThe landscape in scientific publishing is changing very fast in times in which all kinds of information have been made easily available electronically via the World Wide Web. Print issues become increasingly less important and the younger generation of scientists and clinicians in particular often prefer to read articles on mobile phones or tablet computers. Therefore, this journal aims also to be an international communication platform especially for this younger generation working in the field of metabolic medicine. Still today, publishing remains the single most effective way of transferring important medical and scientific information. This journal is currently indexed at Chemical Abstract Service (CAS) and on Scopus, and will shortly be indexed on PubMed, guaranteeing worldwide visibility and recognition. All of the journals content will be freely accessible on PubMedCentral, as well as on Sage Journals Online and via Stanford Universitys High Wire platform. n nSage Publications, the international publisher of this journal, has been in existence for almost half a century, and they are a world leader in their chosen professional markets, currently with over 500 journal titles. I am very fortunate that Sage Publications, and the managing editor, Matthew Thorne with whom I already work very successfully together for the sister journal Therapeutic Advances in Cardiovascular Disease since its foundation in 2007, have decided to diversify into this important field of endocrinology and metabolism. n nI am convinced that there is still space in the scientific landscape for a journal that aspires to be a communication platform for evidence-based medical strategies in metabolic medicine, including the term ‘intelligence-based medicine’ which has been originally impressed by my colleague and friend Carlos M. Ferrario [Ferrarioet al. 2007]. This means the application of well-acquired and validated scientific knowledge to translational medicine. In concert with these considerations, we welcome all articles in the field of metabolic medicine, as well as commentaries, hypothesis-driven reviews, and position statements regarding therapeutic guidelines, treatment algorithms, and prevention measures. n nAs a clinical pharmacologist, my personal specific interest is dedicated to the evaluation of new drugs and optimal drug treatment. Clinical pharmacology is commonly accepted to be a bridging discipline between basic science observations and clinical practice. As such, it forms the core of clinical therapeutics and the basis for outcomes-based medicine [Schindler, 2008]. Drug development in the diabetes and metabolic field has been a ground-breaking and most active area during the last couple of years, but we must not forget that the metabolic and diabetologic drug development community has had to cope with several especially severe backslashes. For the indication of anti-obesity treatments, the selective CB1receptor antagonist rimonabant, initially celebrated as groundbreaking innovation, and the monoamine reuptake inhibitor sibutramine have had their market authorization suspended due to increased incidence of serious adverse events [Topolet al. 2010; Sayburn, 2010]. Approval applications for the combination phentermine/topiramat, the selective 5-HT2c receptor ligand lorcaserine and the combination bupropion/naltrexone have been recently rejected by the US Food and Drug Administration (FDA) due to safety concerns. Currently the lipase inhibitor orlistat is the only available drug licensed for long-term therapy of obesity in the USA. For the indication of diabetes, after withdrawal of rosiglitazone due to increased cardiovascular mortality, PPARg agonists as a major drug class in metabolic medicine teeter on the brink of collapse since a recent meta-analysis suggested an increased risk for bladder cancer in patients treated with piogitazone [Lewiset al. 2011; FDA, 2011]. Reflecting these disillusioning very recent developments, it is now time to call for a sustainable concept for effective risk management in drug development in order to guarantee drug safety even in the long run. n nThe hopes for new successful therapy approaches in the area currently rest on the further clinical development of synthetic analogues of gut hormones, such as pancreatic polypeptide, obinepitide, combined GLP-1 and glucagon agonists, peptide YY, pramlintide/metreleptin, oxyntomoduline and ghreline for the treatment of obesity [Schindleret al. 2011]. For the indication of diabetes and metabolic medicine, SGLT II-inhibitors [Abdul-Ghaniet al. 2011], bardoxolone [Pergolaet al. 2011], salsalate [Hotamisligil, 2006; Caiet al. 2005], PCSK9 inhibition for low-density lipoprotein (LDL) reduction [Asonet al. 2011] and the anti-IL-1 receptor antagonist anakinra [Larsenet al. 2007] have so far shown promising study results. Therapeutic Advances in Endocrinology and Metabolism will closely follow the development of these and other promising therapies. n nWe hope that you as readers support us to become a vehicle for the dissemination of new knowledge including critical comments and discussions in the area of diabetes and metabolic medicine and thanks to the authors-to-be for sending to us their best contributions. On behalf of the Editorial Board and staff of the journal we thank you for your interest in the journal and are looking forward to serving your knowledge needs.

Airway and systemic inflammatory responses to ultrafine carbon black particles and ozone in older healthy subjects

ABSTRACT Increased adverse health effects in older subjects due to exposure to ambient air pollutants may be related to the inflammatory response induced by these contaminants. The aim of this study was to assess airway and systemic inflammatory responses in older healthy subjects to a controlled experimental exposure with spark-generated elemental carbon black ultrafine particles (cbUFPs) and ozone (O3). Twenty healthy subjects, age 52–75 years, were exposed on three occasions separated by at least 8 weeks. The exposures to filtered air (FA), to cbUFP (50 μg/m3), or to cbUFP in combination with 250 ppb ozone (cbUFP + O3) for 3 h with intermittent exercise were performed double blind, and in random order. Sputum and blood samples were collected 3.5 h after each exposure. Exposure to cbUFP + O3 significantly increased plasma club cell protein 16 (CC16), the number of sputum cells, the number and percent of sputum neutrophils, and sputum interleukin 6 and matrix metalloproteinase 9. Exposure to cbUFP alone exerted no marked effect, except for an elevation in sputum neutrophils in a subgroup of 13 subjects that displayed less than 65% sputum neutrophils after FA exposure. None of the inflammatory markers was correlated with age, and serum cardiovascular risk markers were not markedly affected by cbUFP or cbUFP + O3. Exposure to cbUFP+O3 induced a significant airway and systemic inflammatory response in older healthy volunteer subjects. The effects induced by cbUFP alone suggest that the inflammation was predominantly mediated by O3, although one cannot rule out that the interaction of cbUFP and O3 played a role.