And why does this matter in drug development?

Statistical analytical methods are often taken for granted. In a recent crowdsourcing data analysis project, Nosek and co-workers found 29 research teams willing to analyze the same dataset [1]. The results varied from positive to neutral. How is this possible and what are the consequences? 

Putting effects of SGLT2 inhibitors into perspective

The DECLARE-TIMI 58 trial [1] investigated the effects of treatment with dapagliflozin on cardiovascular outcomes in people with type 2 diabetes in a double blind randomized placebo controlled manner. It is the third published trial investigating cardiovascular outcomes of SGLT2 inhibitors, following EMPA-REG (for empagliflozin) [2] in 2015 and CANVAS (canagliflozin) [3] in 2017. Of these three trials, DECLARE-TIMI 58 has been the largest by a fair margin, including more than 17000 patients with type 2 diabetes who either had multiple risk factors for atherosclerotic cardiovascular disease or established cardiovascular disease.

The first idea [1] for a glucose-responsive insulin (GRI, commonly referred to as smart insulin) was pitched almost 40 years ago, but to our knowledge only one compound has since undergone clinical evaluation. It seems a little surprising that it takes such a long time to develop a functioning GRI because its concept is actually relatively simple: At normal glucose concentrations, small amounts of insulin are released to keep blood glucose (BG) fairly constant. In response to rising glucose concentrations, for example after a meal, more insulin is released to limit the glucose rise and to return glucose concentrations back to normal. This closed-loop insulin release should limit BG variability and because insulin is only released when it is needed, it should also reduce the risk of over- and underdosing insulin. Two key elements are needed for a GRI: (1) A component that can ‘sense’ glucose and (2) a component that can respond and control the release of insulin. The concept may be simple, suggested solutions are complex and diverse [2].

The annual meeting of the European Association for the Study of Diabetes (EASD) took place this year in Berlin, Germany. The present text offers a selection of topics relevant for the field of type 2 diabetes mellitus (T2DM) discussed during that meeting.

Profil will be present at the 18th Annual Diabetes Technology Meeting with two posters and a presentation as invited speaker. The Annual DTM will take place from November 8 to November 10, 2018, in North Bethesda, Maryland. We are looking forward to this exciting event.

Introduction

The actual Medical Device Directive (MDD) 93/42/EEC [1]and the Active Implantable Medical Device Directive (AIMDD) 90/385/ECC [2]are the basic directives for all kinds of medical devices in Europe. These directives are mandatory for all member states and have to be put into national legislation by the national parliaments within a given time limit. It is not allowed to reduce or change the requirements of the directive but the parliaments can implement additional requirements like the German “Medizinprodukteberater” (consultant for medical devices) in §31 of the German medical device law. 

In contrast to the Medical Device Directive the Medical Device Regulation (MDR) [3]comes directly from the European Commission in Brussels without any approval by the national parliaments and has to be applied as European, supranational law within a given time limit. Additional national requirements resolved by the national parliaments are possible.

One of the reasons for the new MDR was the PIP-scandal: One manufacturer used the cheaper industrial silicon for breast implants instead of the ultra-pure medical silicon. Once this scandal had been made known publicly the Commission decided to tighten up the directive to prevent this kind of criminal process.

For the determination of pharmacokinetic and pharmacodynamic (PK/PD) effects of new insulins and other anti-diabetic drugs exists a gold standard: the euglycemic, hyperinsulinemic glucose clamp. In a typical glucose clamp experiment is infused glucose at a variable rate, so that BG is "clamped" at a pre-determined target level. Thereby a drug-induced decline in blood glucose (BG) concentrations is prevented.

Thus, the glucose clamp is designed as a closed-loop system where BG is measured frequently. The two major factors for determining glucose infusion rates (GIR) are considered as the changes in BG and deviation of BG from the target level.

Figure 1

In the field of metabolic disease pathology, nutritional aspects often play a key role in clinical studies . Our metabolic ward enables us to control the impact of environmental conditions in our clinical trials. Through high standardization of food components we are able to minimize the impact of nutrients, thus reducing variability of study results and increasing the potential to further optimize the subject sample size. Our long standing experience of many years enables us to specify nutritional requirements according to objectives and rationale of the trial, varying from mixed meal tolerance test to individually adapted diets.

Why FMD?

Endothelial dysfunction plays a pivotal role in the pathogenesis of progression of atherosclerotic disease. While in the past invasive cardiac catheterization in the coronary arteries was used for the quantification of endothelial function, a non-invasive technique would of course be much more appealing. Flow-mediated (vaso)dilation (FMD) of the brachial artery is such a technique and has shown prognostic value when it comes to cardiovascular (CV) disease.  Several meta-analyses have found that there is a significant inverse association between FMD and future CV events: A 1% decrease in FMD was associated with 13% increase in risk of future CV events and similarly a decrease of 1% standard deviation caused an increase of CV event risk of 22 %. FMD has proven to be a powerful research tool as well as a tool for risk stratification with a prognostic value that is difficult to ignore.

Profil uses transient elastography with controlled attenuation parameter in order to pre-identify potential trial participants for the presence of liver fat and/or the presence of an intermediate state of liver fibrosis. Dependent on the outcome subsequently MR (magnetic resonance)-based methods and liver biopsy are available for further substantiating the findings. The great advantage of this non-invasive and quick approach is economising trial conduct by reducing the number of more elaborate examinations and controlling the sample size required for a meaningful trial design. This blog text describes the transient elastography method in the context of the increasing interest in treating subjects with NAFLD (non-alcoholic fatty liver disease).