New findings on the impact of hypoglycaemia

The Hypo-RESOLVE consortium is dedicated to developing new tools to investigate the impact of hypos and to find solutions to improve the lives of people with diabetes. New Hypo-RESOLVE studies on the psychosocial impact of hypos and preclinical work on how they affect the immune system were presented at the recent Advanced Technologies & Treatments for Diabetes (ATTD) conference. Dr Susan Aldridge reports.

Hypoglycaemia can have a profound effect on physical, emotional and mental health. Frans Pouwer, Professor of Medical Psychology at the University of Southern Denmark and the Steno Diabetes Centre, has been looking at what people with diabetes have to say about their lived experience of hypoglycaemia. “After using insulin therapy for more than 100 years, hypoglycaemia is still a problem for people with type 1 and type 2 diabetes,” he said. “In a recent study, 83% of those with type 1 diabetes and 47% of those with type 2 had experienced a hypo in the last four weeks.” The unpleasant physical and emotional symptoms of hypoglycaemia they report include loss of consciousness, falls, interference with daily tasks, social embarrassment, low self-esteem, poor sleep quality and worry about the future.  

Hypo-RESOLVE research will now address these issues in depth. It’s a consortium of industry, academic and other partners, including people with diabetes, and was set up in 2018. Professor Jane Speight, Foundation Director of the Australian Centre for Behavioural Research in Diabetes, leads Work Package 6, the objective of which is to provide a comprehensive assessment of the psychosocial impact of hypoglycaemia on people with diabetes and their family members, and to identify and address knowledge gaps. 

Literature survey – findings and gaps

Professor Pouwer reviewed the progress of Work Package 6 so far, which began with a review of the current literature. Analysis of the impact of hypoglycaemia on quality of life found that in type 1 diabetes, severe hypos are associated with increased fear of hypoglycaemia and decreased quality of life for younger people; for adults, both self-treated and severe hypos are associated with increased fear, higher diabetes distress and a decrease in general wellbeing. 

There is, however, conflicting evidence on the impact of severe hypos on depression, anxiety, disordered eating and post-traumatic stress disorder (PTSD) in type 1 diabetes. 

Meanwhile, for adults with type 2 diabetes, severe hypos are associated with reduced confidence in diabetes self-management and a lower rating of perceived health over time. Frequent hypos are associated with reduced energy levels and diminished emotional wellbeing. Evidence of the impact of hypoglycaemia on sleep quality, depression, social support and diabetes-related quality of life is mixed. 

A number of themes emerged on the impact of hypos on family members of those with type 1 diabetes. Hypoglycaemia alters their everyday life, reducing freedom, increasing disruption and has an adverse impact on sleep. It leads to negative changes in their relationship with the person with diabetes and has a negative impact on emotional wellbeing. Furthermore, the detection, prevention and treatment of hypoglycaemia consumes both time and energy. Finally, family members report unmet needs for emotional and informational support for hypoglycaemia. 

“A key advantage of a systematic review is you can critically appraise the quality of studies that have been done,” said Professor Pouwer. For instance, only a few of the studies assess all aspects of quality of life, so a holistic picture is lacking, and there is also variation in the definition and measurement of hypoglycaemia. “We need studies where we use CGM, like the Hypo-METRICS study, where hypoglycaemia is measured to the highest standard,” he said.

The Hypo-RESOLVE survey

The Hypo-RESOLVE team has carried out a multinational, qualitative study to explore the impact of hypoglycaemia on care and support needs and quality of life. More than 200 people with type 1 and type 2 diabetes and their families, from the UK, Denmark, the Netherlands and Germany, took part. The study used the Wheel of Life activity in which the wheel is divided into sections, each of which is a domain important to someone’s current quality of life. This gives the holistic view needed to fully assess the impact of hypoglycaemia. Participants were also asked questions such as: “What do you wish other people understood about hypos?” and “What would you tell a close friend it’s like living with the risk of hypoglycaemia?”. 

Many different domains were impacted by hypoglycaemia, including work and study, relationships and social life, leisure and exercise, everyday activities, sleep, mental health, sex life and general health. Participants made statements such as: “It’s annoying when sport has to be interrupted all the time and you cannot, like healthy people, do what you want for as long as you want”; “I get so nervous about going low that I check all the time at work and I worry about what my employer thinks of me” and “To do something spontaneously, at short notice, is impossible because I have to prepare for all scenarios and drag luggage along with me.” 

New tools

“If we look back in the literature, there are key gaps,” said Professor Pouwer. “For instance, many studies are not done in real time or in the real world. And the tools used are not really sensitive enough to capture hypoglycaemia.” 

Hypo-RESOLVE has therefore been developing new tools that will hopefully lead to more meaningful findings. For instance, there is the Your SAY (Self-management And You) hypoglycaemia survey, which uses the 12-item Hypoglycaemia Impact Profile (HIP12), a new validated self-report tool for assessing the impact of hypoglycaemia on quality of life in type 1 diabetes.  

Professor Pouwer and colleagues are also currently working on a paper that taps into the psychometrics of the Hypo-METRICS tool. “The Hypo-METRICS app is an innovative, valid and reliable self-report instrument for the day-to-day impact of hypos,” he said. “The study will provide us with new data regarding the impact of self-reported and sensor hypos with high ecological validity.”   

To conclude, he cited a new paper that he contributed to in Diabetic Medicine. “This meta-analysis shows that we can significantly reduce hypo worry with blood-glucose awareness training or cognitive behavioural therapy,” he said. “So it’s good news that there are interventions available that can reduce the fear of hypoglycaemia.” However, none of these studies include those with high fear of hypoglycaemia, so Professor Pouwer would like to see the impact of interventions studied in this group, thus filling another of those hypoglycaemia research gaps.  

Hypos and inflammation

Bastiaan de Gaalen, Professor of Medicine at Maastricht University, discussed some of Hypo-RESOLVE’s pre-clinical work. Severe hypoglycaemia is already known to be associated with cardiovascular events, all-cause mortality and hospitalisation in people with type 2 diabetes. That has recently also been found to be the case for those with type 1 diabetes as well. And a recent post-hoc analysis of the LEADER cardiovascular outcome trial in type 2 diabetes (from Simon Heller and colleagues) found that having more than 12 non-severe hypos a year is associated with three-point MACE (a composite of major adverse cardiovascular events – cardiovascular death, non-fatal myocardial infarction and non-fatal stroke), cardiovascular death and all-cause mortality. 

What is the explanation? “Hypoglycaemia has an effect on the immune system,” said Professor de Gaalen. “Immune cells are activated and produce more cytokines, and this leads to inflamed cells in vessel walls and cardiovascular events. So we wanted to look at the effects of hypoglycaemia on the inflammatory response.” 

They conducted a hypoglycaemic clamp study in 100 people with type 1 and type 2 diabetes, as well as people without diabetes as controls. They were exposed to hypoglycaemia for one hour and blood samples were taken just after this and also three and seven days later. The researchers looked at the quantity of immune cells, monocyte phenotype and function – such as stimulated cytokine production – and presence of inflammatory proteins. “We saw an instant increase in the number of monocytes and then a fall, but they don’t go back to baseline levels and stay elevated for a week,” he said. “Also, in people with diabetes, we see a change from normal monocytes to more pro-inflammatory monocytes, along with an increase in inflammatory proteins.”  

They then looked at the impact of having a previous hypo. The adrenaline response is lowered if there is a previous hypo (also delivered via the clamp) and there is also a blunted granulocyte response and a slightly blunted inflammatory protein response. However, lymphocyte and monocyte responses were the same. 

The final question was whether having a sensor-detected hypo affects this inflammatory response following the clamp experiment. The adrenaline response was lower, which is what you’d expect, and there were also fewer immune cells, although no impact on inflammatory proteins. “We now want to look at the effect of spontaneous hypos as reported on Hypo-METRICS on the inflammatory response,” said Professor de Gaalen. “There will also be animal studies to replicate the inflammatory effect in different tissues. And we will look at the effect of hypos on cardiac function using echocardiography.” 

In summary, this pre-clinical work shows that International Hypoglycaemia Study Group (IHSG) Level 2 hypoglycaemia produces an inflammatory response at several levels that lasts for at least a week. This response is universal, irrespective of type or presence of diabetes and hypoglycaemia awareness. Prior hypoglycaemia may ameliorate the inflammatory response, potentially mediated through adrenaline. “These data provide considerable support for the IHSG classification of hypoglycaemia and underline the importance of avoiding level 2 and level 3 hypoglycaemia in people with diabetes,” concluded Professor de Gaalen.  

To learn more about hypoglycaemia, enrol on the EASD e-Learning courses ‘Hypoglycaemia’ and ‘Management of type 1 diabetes in adults’.

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.