A large-scale research project is being launched this winter in Quebec. University researchers, healthcare professionals (physicians, dietitians, kinesiologists, and psychologists) working in the main diabetes centers of the province, along with patient partners, have joined forces to establish the BETTER program (BEhaviors, Therapies, TEchnologies, and hypoglycemic Risk in Type 1 diabetes). This program includes the establishment of a registry of individuals with type 1 diabetes. Registry participants will be invited to complete questionnaires to better understand the causes, consequences, and experiences surrounding episodes of hypoglycemia. From this registry, a significant database will be created. The BETTER program also includes clinical studies to optimize the use of technology (insulin pump, continuous glucose monitor, and artificial pancreas) and new therapies (insulin and glucagon) with the aim of reducing the risk of hypoglycemia.

Define hypoglycemia in order to study it better

Hypoglycemia refers to a decrease in blood glucose levels and occurs when there is an excess of circulating insulin compared to the body’s needs at a specific time. Possible causes include errors in the insulin dose administered, overestimation of carbohydrate intake, engaging in physical activity, and more. Hypoglycemia can lead to a range of symptoms, with the intensity and onset varying from individual to individual. Listed symptoms include hunger, sweating, trembling, nausea, and can even affect the ability to concentrate and result in loss of consciousness.

In order to conduct research on hypoglycemia, it is important to start by defining it accurately. Various international entities have recently revised the definitions of hypoglycemia, especially in terms of its severity levels. Diabetes Canada, in its 2018 Clinical Practice Guidelines, maintains the usual classification, distinguishing mild, moderate, and severe hypoglycemia. Severe hypoglycemia is described as a blood glucose level below 2.8 mmol/L with an inability to self-treat. On the other hand, the American Diabetes Association prefers not to define a glycemic threshold, emphasizing that any abnormal blood glucose level can be harmful. Furthermore, a recent joint position statement by the American Diabetes Association and the European Association for the Study of Diabetes suggests classifying hypoglycemia into three levels (see Table 1) and avoids specifying a blood glucose value for the third level, corresponding to severe hypoglycemia. Nevertheless, the primary criterion for defining severe hypoglycemia is the need for assistance from another person to resolve it.

Table I. Glycemic levels proposed by the American Diabetes Association et l’European Association for the Study of Diabetes, 2017

Level 1 Blood glucose of 3.9 mmol/L or less.
Level 2 Blood glucose below 3.0 mmol/L, sufficiently low to describe it as a serious hypoglycemia, which is clinically significant.
Level 3 Severe hypoglycemia with cognitive impairment that requires assistance from others for treatment.

Studies report that, each year, 10% of people with type 1 diabetes have an episode of severe hypoglycemia. Severe hypoglycaemia greatly affects the quality of life of patients and their relatives.

Some factors that can increase the risk of severe hypoglycemia include:

  • Recent episode of severe hypoglycemia
  • Low glycated hemoglobin (HbA1C) levels
  • Inability to recognize hypoglycemia symptoms
  • Long-standing diabetes

Hypoglycemia in real-life context

Although we aim to define hypoglycemia from a scientific perspective, these definitions may not always resonate with individuals living with type 1 diabetes on a daily basis. The significance of a hypoglycemic episode can vary depending on the context in which it occurs, regardless of the actual blood glucose value at that time. For example, an episode of hypoglycemia may be more significant if it happens in a professional setting or while driving a car.

On average, individuals with type 1 diabetes report experiencing 3 to 4 episodes of mild or moderate hypoglycemia each week. This number may be even higher as some people may not feel all their hypoglycemic episodes. The fear of hypoglycemia represents one of the main barriers to achieving optimal glycemic control in individuals with type 1 diabetes.

The potential of technology to reduce the risk of hypoglycemia

Certain technological breakthroughs have provided individuals with type 1 diabetes with more flexibility and freedom in managing their condition. The introduction of continuous glucose monitoring systems (such as Dexcom® and Enlite®) and more recently, the FreeStyle Libre (also known as flash glucose monitoring system), has revolutionized the way blood glucose is measured. These devices allow for non-invasive and more frequent glucose monitoring, providing trend curves that help users better understand glycemic variations and adjust their treatment accordingly. Continuous glucose monitoring systems and flash glucose monitoring system can help improve glycemic control (HbA1C) while reducing time spent in hypoglycemia. For instance, studies on the FreeStyle Libre have shown a 46% reduction in time spent in hypoglycemia, particularly among those who initially had poorer glycemic control.

In addition, the use of insulin pumps can also be a useful tool in reducing hypoglycemia and preventing certain severe episodes. Insulin pumps allow for the programming of different basal insulin infusion rates throughout the day. The pump also has a function to assist in calculating bolus insulin doses for meals. It can even estimate the amount of active insulin still in circulation to help determine the appropriate doses to administer. Moreover, when coupled with a continuous glucose monitor (such as the system from Medtronic), insulin infusion can be automatically suspended in case of a drop in blood glucose.

Despite their demonstrated benefits, these new technologies are not accessible to everyone, primarily due to their cost and existing reimbursement policies. Furthermore, to be used to their full potential, they require initial and periodic education from healthcare professionals. For example, one must learn to adjust pump settings to prevent certain hypoglycemic events. Unfortunately, some patients lack support, and healthcare professionals may not always have the time or feel comfortable recommending these technologies and providing the necessary education.

Pharmacological Advances for Hypoglycemia Reduction

Since its first therapeutic use in 1921, insulin used for diabetes treatment has undergone significant pharmacological advances. Now, there are available ultra-rapid insulin analogs that take less than 5 minutes to act, as well as long-acting basal insulins with increasingly flat action profiles. These advancements allow for a closer imitation of the action of the pancreas in individuals without diabetes and potentially reduce the risk of hypoglycemia.
In contrast to insulin, there is glucagon. Used as an emergency medication in cases of severe hypoglycemia, glucagon is also undergoing pharmacological advancements that could benefit individuals with type 1 diabetes. Typically, in the event of severe hypoglycemia, glucagon is injected into a muscle by a third person to rapidly raise blood glucose levels. However, a new nasal administration method is currently being studied. This simpler-to-use formulation may potentially reduce emergency room visits resulting from severe hypoglycemia.

Towards Hypoglycemia Reduction

On one hand, the technological and pharmacological advancements with the potential to reduce the risk of hypoglycemia are encouraging. On the other hand, the BETTER program team believes that defining hypoglycemia accurately, understanding patients’ experiences with therapy, technology, and hypoglycemia, as well as facilitating education about these products, are essential.