The Hypo-RESOLVE project wants to single out the risk factors for severe hypoglycaemic episodes
Although there are certain widely recognised risk factors for hypoglycaemia like exercise, skipped meals or insulin dosing errors, hypoglycaemic episodes very often also occur quite unexpectedly. If a “hypo” occurs, you have to act quickly to bring your glucose levels back to normal and make sure you’re not a threat to yourself.
Needless to say, this often interferes directly with daily activities. Episodes can even occur without causing any symptoms, and sometimes recovery is spontaneous. Not uncommonly, a partner or family member recognises it before the patient does. “In the long term,” says Bastiaan de Galan, coordinator of IMI diabetes project Hypo-RESOLVE, “hypo events can cause fear and avoidant behaviour, which makes overall glucose control even more difficult. Severe episodes can increase the risk of cardiovascular disease, although we don’t know yet whether this relation is causal.”
The Hypo-RESOLVE project wants to find out more about the mechanisms of hypoglycaemic episodes beyond what is already known, including their effect on the psychosocial well-being of people who experience them. A Q&A with Bastiaan de Galan, associate professor at the Radboud University Medical Centre in Nijmegen, and Jill Carlton, senior research fellow at the University of Sheffield.
Q. What do people need to know about hypoglycaemia?
Bastiaan de Galan: Because it happens quite frequently, particularly in people with diabetes who are treated with insulin, it is a continuous threat which also affects their family members. Parents of children with type 1 diabetes have severe sleeping problems because they fear that their child might develop night-time hypoglycaemia and not wake up the next morning. The wider public isn’t aware of this, which could explain why glucose control is less than optimal in 80% of the people living with diabetes.
Q. What is the main objective of this project?
Bastiaan de Galan: We have constructed a large database of patient data from 96 individual trials from various sources involving more than 58,000 individual participants on hypoglycaemia and other outcomes, as well as lab results and “patient reported outcomes” (PROs). The analysis of the database aims to answer two questions: firstly, what are the risk factors for (severe) hypoglycaemia in people with type 1 or type 2 diabetes, apart from what we already know? This information is important for people with diabetes and healthcare providers, in order to know who runs the highest risk, how hypos can best be avoided and to guide decisions on treatment strategies.
Secondly, we want to know: what are the clinical, psychological and health-economic consequences of hypoglycaemia? This info is particularly relevant for regulators and payers, but also for people with diabetes and healthcare providers, as well as for the industry and those who design clinical trials.
I am proud of the sites in Denmark and the Netherlands where over 60 people with type 1, type 2 or no diabetes (out of 112 in total) have been subjected to experimental hypo with the aim of studying its effect on inflammation, epigenetics, heart and cognitive function. Experimental hypo is a process by which we administer insulin by a continuous infusion in the vein and simultaneously administer glucose so that we can titrate the blood glucose level quite precisely. It is a safe and well-established method to study effects and consequences of hypoglycaemia.
Although the corona crisis has put this on hold, we have now been able to restart and, if things go as planned, this study will be completed in January next year.
Q. What has surprised you most about the research so far?
Bastiaan de Galan: We have found that there is very little agreement on how guidelines across the world define and/or classify hypoglycaemia. This is not really a surprise, yet to see that this is indeed the case was a bit astonishing.
Q. How do continuous glucose monitoring devices work, and how effective are they?
Bastiaan de Galan: Continuous glucose monitoring, or CGM, happens in the tissue under the skin, so not directly in the blood. Glucose trends are highly informative for people using such a device, yet there is a delay of 10-15 min compared to blood glucose measurement by finger pricks. Also, the accuracy in the hypo range remains an issue.
They are being used by a growing number of people with type 1 and type 2 diabetes treated with insulin; yet mostly in higher-income countries, where they are being reimbursed. They are often too expensive for use in countries with fewer resources or for people who have to pay for such a device themselves.
One issue with CGM is that they appear to detect a lot of asymptomatic low glucose values with unknown clinical meaning. One of the objectives of Hypo-RESOLVE is to learn more about this clinical meaning and how such a hypo compares to a hypo measured by finger pricks (Hypo-METRICS study).
Q. Can you tell me a bit about your interaction with regulators so far?
Bastiaan de Galan: We had a very constructive meeting with the European Medicines Agency (EMA) last year. They are very interested in our project, particularly in our aim to define what a clinically meaningful hypo is and how to improve the health and wellbeing of people with diabetes. Also, they payed special attention to the hypo-specific Patient Reported Outcome (PRO) that we are about to develop for use in daily practice and future clinical trials, and potentially also in treatment recommendations and guidelines. We are currently seeking official qualification advice for this purpose.
Q. You’re developing patient reported outcomes (PROs), measures that will help assess the psychological impact of hypoglycaemia on patients, for use in clinical trials. What can you tell us about this part of the research?
Jill Carlton: The development of the new patient reported outcome (PRO) hinges upon capturing what it is that matters to people living with diabetes. Traditionally PROs were developed using a top-down approach, with items or questions in the PRO generated from either the literature, and/or clinicians, where they were asking about what they thought was important for an individual's quality of life. Nowadays, many instrument developers use a "bottom-up" methodology. Here, items are generated from what it is that people with that health condition say is important to them.
We are interviewing people with diabetes to find out how hypoglycaemia affects their quality of life. We have a topic guide where we list all the possible themes. Then we code the qualitative data from the interviews against this framework. We look for terms and phrases that people actually use, and this adds to the content validity of the PRO. We make every effort to try and use terms and phrases that are used in the interviews, and we use the same approach when thinking about the framing of the items (i.e. in the last week, in the last month etc..) and also response options (be that frequency, severity, agreement and the number and naming of the response options themselves). Content validity is arguably the most important aspect in a PRO. If it does not ask about the right things, then essentially we are only getting half the story.