Profil Institute for Clinical Research

Pharmacotherapy directed toward reducing body weight may provide benefits for both curbing obesity and lowering the risk of obesity-associated comorbidities; however, many weight loss medications have been withdrawn from the market because of serious adverse effects. Examples include pulmonary hypertension (aminorex), cardiovascular toxicity, e.g. flenfluramine-induced valvopathy, stroke [phenylpropanolamine (PPA)], excess non-fatal cardiovascular events (sibutramine), and neuro-psychiatric issues (rimonabant; approved in Europe, but not in the USA). This negative experience has helped mould the current drug development and approval process for new anti-obesity drugs. Differences between the US Food and Drug Administration (FDA) and the European Medicines Agency, however, in perceptions of risk-benefit considerations for individual drugs have resulted in discrepancies in approval and/or withdrawal of weight-reducing medications. Thus, two drugs recently approved by the FDA, i.e. lorcaserin and phentermine + topiramate extended release, are not available in Europe. In contrast, naltrexone sustained release (SR)/bupropion SR received FDA approval, and liraglutide 3.0 mg was recently approved in both the USA and Europe. Regulatory strategies adopted by the FDA to manage the potential for uncommon but potentially serious post-marketing toxicity include: (i) risk evaluation and mitigation strategy programmes; (ii) stipulating post-marketing safety trials; (iii) considering responder rates and limiting cumulative exposure by discontinuation if weight loss is not attained within a reasonable timeframe; and (iv) requiring large cardiovascular outcome trials before or after approval. We chronicle the adverse effects of anti-obesity pharmacotherapy and consider how the history of high-profile toxicity issues has shaped the current regulatory landscape for new and future weight-reducing drugs.

Obesity, while recognized as a pressing global public health issue, does not present an immediate threat to life. Accordingly, weight-reducing medication is required to be exceptionally safe [1]. Since the 1960s, several agents have been withdrawn in the USA or Europe because of toxicity issues (Table 1) [2]. Two events in particular helped change the regulatory and marketing landscape concerning the development, registration, and commercialization of weight-reducing drugs. The first was the suspension in 2008 by the European Medicines Agency (EMA) of marketing authorization for the cannabinoid receptor type 1 inverse agonist rimonabant following reports of psychiatric adverse events including suicidal ideation [3]. The second was the demise of sibutramine, a serotonin–norepinephrine reuptake inhibitor, in 2010 in response to the results of a post-marketing safety trial that demonstrated an increased risk of non-fatal myocardial infarction and stroke in patients with pre-existing cardiovascular disease [4]. The regulatory environment in the USA and Europe for new anti-obesity drugs has become increasingly challenging in recent years [5]. Key points of current US FDA guidance include the need to demonstrate weight control over 1 year [6]. Required placebo-subtracted weight loss is C5 % and/or the percentage of subjects losing C5 % of baseline bodyweight has to be C35 % and double the percentage observed with placebo [7]. To satisfy safety requirements, a minimum of 3000 subjects would have to be assigned to the experimental drug, with no fewer than 1500 subjects assigned to placebo for a 1-year period [6, 8]. The EMA requires a 10 % reduction from baseline body weight at 1 year that must also be at least 5 % greater than that achieved with placebo [9]. If weight loss at the end of 1 year is 10 % or more, the proportions of responders in different treatment arms can be considered as an alternative primary efficacy criterion. The aforementioned safety issues have helped created a risk-averse regulatory environment that has become more pronounced in Europe than in the USA [2]. The resulting transatlantic divide in availability of weight-reducing drugs, which has only very recently started to narrow, has generated concern among European obesity experts [10]. Four drugs have recently been approved by the FDA: lorcaserin (2012), phentermine/topiramate extended release (ER) (2012), naltrexone hydrochloride/bupropion hydrochloride ER (2014), and liraglutide 3.0 mg (2014). Of these, only naltrexone hydrochloride/bupropion hydrochloride ER and liraglutide have received a positive recommendation by the EMA’s Committee for Medicinal Products for human use (CHMP). Some of the recent approvals represent something of a volte face by the FDA. Phentermine/topiramate was originally rejected because of safety concerns, with approval finally coming with a Risk Evaluation and Mitigation Strategy (REMS). The latter highlighted the possible increased risk of congenital malformation, specifically orofacial clefts, in infants exposed to the drug during the first trimester of pregnancy. Furthermore, the FDA required the manufacturer to perform ten post-marketing studies, including a long-term cardiovascular outcomes trial. The selective 5-HT2c receptor agonist lorcaserin was also initially rejected by the FDA due to concerns about tumour growth in rodents. As a & Andrew J. Krentz andrew.krentz@profilinstitute.com

FigureEndocrinologists can justly claim to have made many significant contributions to our knowledge of the pathogenesis and treatment of vascular disease. Classic examples that spring to mind include the hypertension of corticosteroid excess, the cardiovascular implications of thyroid hormone hypersecretion or deficiency, and characterization of the heightened vascular risk associated with diabetes mellitus. These achievements, along with numerous other examples, provide the inspiration for Cardiovascular Endocrinology – a new peer-reviewed journal for clinicians and scientists. Important strides have been made in our understanding of the pathogenesis of vascular disease in recent years. These advances have been accompanied by the discovery of hormones and cytokines whose importance to metabolic regulation and implications for vascular disease has rapidly become apparent. Light has also been cast on novel pathways, obesity-associated inflammation for example, that may mediate some of the adverse vascular effects of common endocrine disorders. The emergence of genomics, proteomics, transcriptomics, and metabolomics as powerful new research tools augurs well for continued progress. However, the complex adverse cardiovascular effects of thiazolidinediones provide a stark reminder of how the manipulation of intermediary metabolism may not always have predictable consequences for vascular biology. Similarly, the wisdom of sex steroid replacement therapy for the prevention of cardiovascular events has come under close scrutiny in the light of clinical trial data. Opportunities for productive collaboration between those working in endocrinology and cardiovascular medicine have never been greater. With a global explosion of obesity-associated diabetes, hypertension and dyslipidemia upon us, the need for effective collaboration to stem the threatened tide of vascular disease is clear. Accordingly, we believe that the time is right for a journal focused on bringing these specialties together. Cardiovascular Endocrinology aspires to be a valuable resource for the vascular and endocrinology clinical and research communities. Our aim is to create a forum that facilitates the exchange of information and ideas across these disciplines. To this end it is envisioned that state-of-the art reviews and editorials will feature prominently. In addition, invited expert commentaries will position original papers within the existing wider literature for readers whose primary interests may lie in another discipline. In this launch issue Jens Peter Goetze offers a personal opinion of how the term ‘cardiovascular endocrinology’ might be defined. Others may wish to contribute their own definitions. Opportunities for authors to explore areas of scientific or clinical controversy and to offer their hypotheses will be available. Submissions are invited on all aspects of vascular–endocrine associations. Particularly welcome are studies that illuminate the mechanisms responsible for physiological and pathological interactions between hormones and the vasculature. Papers that assist the translation of research finding from the bench to clinical practice, such as, novel biomarkers and new therapies, are also warmly encouraged. On behalf of the editorial board I invite you to share your research findings and clinical experiences with a readership united by a shared interest in endocrinology and vascular medicine. Let us know your thoughts as we progress; feedback from authors and readers will inform the journal’s development. Also, please encourage junior members of your practice or laboratory to become involved in the peer review process. We hope that you enjoy Cardiovascular Endocrinology and will consider actively contributing to its success. Acknowledgements Conflicts of interest None declared.

Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor that is being investigated for the treatment of type 2 diabetes mellitus (T2DM). This was a randomized, double-blind, placebo-controlled, parallel-group, 28-day study conducted at two sites, in 29 subjects with T2DM not optimally controlled on insulin and up to one oral antihyperglycaemic agent. Subjects were treated with canagliflozin 100 mg QD or 300 mg twice daily (BID) or placebo. Safety, tolerability, pharmacokinetic characteristics and pharmacodynamic effects of canagliflozin were examined. Glucose malabsorption following a 75-g oral glucose challenge was also examined. Canagliflozin pharmacokinetics were dose-dependent, and the elimination half-life ranged from 12 to 15 h. After 28 days, the renal threshold for glucose excretion was reduced; urinary glucose excretion was increased; and A1C, fasting plasma glucose and body weight decreased in subjects administered canagliflozin (A1C reductions: 0.19% with placebo, 0.73% with 100 mg QD, 0.92% with 300 mg BID; body weight changes: 0.03 kg increase with placebo, 0.73 kg reduction with 100 mg QD, 1.19 kg reduction with 300 mg BID). Glucose malabsorption was not observed with canagliflozin treatment. There were no deaths, serious adverse events or severe hypoglycaemic episodes. The incidence of adverse events was similar across groups. There were no clinically meaningful changes in routine laboratory safety tests, vital signs or electrocardiograms. In subjects receiving insulin and oral antihyperglycaemic therapy, canagliflozin was well tolerated without evidence for glucose malabsorption, had pharmacokinetic characteristics consistent with once-daily dosing, and improved glycaemic control.

This article provides a perspective on the challenges of appropriate glucose measurement in the context of glucose clamp experiments. In a first step, the core outcome parameters of a clamp experiment, the blood glucose target level, and the glucose infusion rate will be identified. The relation of these core parameters to glucose measurement are discussed. From there, the core quality parameters of glucose measurement within a clinical research setting are identified and assessed in light of their practical implications, with a specific consideration of the work presented by Cohen et al. in this issue of the Journal of Diabetes Science and Technology.

VIAJECT (VJ) ist eine neuartige Formulierung von Normalinsulin mit generischen Zusatzstoffen, die sich im Vergleich zu üblichen Normalinsulin durch bessere pharmakologische Eigenschaften auszeichnet. Dazu wurde eine klinisch-experimentelle Glucose-Clamp-Studie mit 10 gesunden Probanden durchgeführt (Alter (MW±STD: 40±8 Jahre; BMI: 22,5±2,5kg/m2). An 5 verschiedenen Studientagen erhielten die Probanden mit einer Spritze subkutane abdominale Injektionen von 12 IU Normalinsulin, 12 U Insulin Lispro oder 3, 6 und 12 IU VJ. Die Serum-Insulinkonzentrationen nach Injektion von Normalinsulin und VJ wurden mit einem Chemolumineszenz-Test bestimmt (MLT). Die Insulin Lispro-Konzentrationen wurden mit einem spezifischen ELISA (Linco) gemessen. Im Vergleich zu Insulin Lispro und Normalinsulin steigen die Serum-Insulinkonzentrationen nach Injektion von VJ schneller auf halb-maximale und maximale Konzentrationen an (TCmax-50/TCmax: 3 IU: 12±13/54±44min, 6 IU: 7±3/51±48min, 12 IU: 18±18/60±43min vs. Lispro 26±10/66±34min, p<0.05/N.S. vs. 12 IU VJ und Normalinsulin 37±22/120±70min, p<0.05/p<0.001 vs. 12 IU VJ). Die Serum-Insulinkonzentrationen nach Injektion von VJ sanken rascher ab als Normalinsulin. Bedingt durch diese pharmakokinetischen Eigenschaften war die relative Bioverfügbarkeit (Verhältnis der AUCs korrigiert für die applizierten Dosen bezogen auf Insulin Lispro) von VJ gut (AUC0–360min: 3U: 166%. 6 U: 163%, 12 U: 146%). Die beschriebenen pharmakokinetischen Eigenschaften führten zu entsprechenden pharmakodynamischen Wirkungen. Diese Studie zeigt, dass diese Formulierung von Normalinsulin durch eine schnelle Insulinabsorption charakterisiert ist, die mindestens so rasch ist wie die von kurzwirkenden Insulinanaloga und deutlich schneller als die von handelsüblichem Normalinsulin. Das rasche Abfluten von Viaject und die gute relative Bioverfügbarkeit machen diese Insulinformulierung zu einem attraktiven Kandidaten für die prandiale Insulintherapie.