The impact of different study populations in glucose clamp studies

Over the last decade, the euglycemic clamp technique has evolved to the reference method for assessing time action profiles of insulins, and regulatory agencies require glucose clamp trials as part of the clinical development of novel and biosimilar insulin products [1, 2]. Of course the experimental set-up of glucose clamp trials can vary, depending for example on whether a long-acting or a rapid-acting insulin is tested. However, one of the most important decisions when planning glucose clamp trials is the choice of a suitable study population. The choice is between patients with type 1 diabetes, type 2 diabetes, or healthy people. Indeed, healthy volunteers can be the preferable option. Each of these groups comes with their own specific advantages and disadvantages.

People suffering from Diabetes Mellitus can develop both macrovascular and microvascular complications. Retinopathy, nephropathy and neuropathy are the main microvascular complications occurring in Diabetes Mellitus. Mechanisms include structural and functional alterations resulting from chronically elevated glucose concentrations. Therefore, assessment of the microvasculature is important for studies investigating new treatment modalities in diabetes.

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.