A Study to Identify Biomarkers of Hypoglycaemia in Patients With Type 2 Diabetes

Background information It is well recognised that patients with both type 1 and type 2 diabetes suffering repeated hypoglycaemia are at risk of death and significant morbidity (1). This is of major clinical importance as currently, only the recording of a low blood sugar at the time of hypoglycaemia gives confirmation that a hypoglycaemic event has taken place. There are many instances when the confirmation or exclusion of a hypoglycaemic event would be beneficial.

Landmark studies such as the Diabetes Control and Complications Trial (DCCT) )(2) in type 1 diabetes and the in numerous large studies (UKPDS, ACCORD, ADVANCE, VADT(1, 3-7)) designed to look at whether intensive diabetes control in type 2 diabetes reduced microvascular and macrovascular cardiovascular events, have helped in establishing glycaemic targets which will contribute to preventing the development or worsening of retinopathy, nephropathy and neuropathy. What these studies exemplified was that as glycaemic control became stricter, the risk of hypoglycaemia increased (defined as a blood glucose fall to less than 3.9mmol/l according to American Diabetes Association guidelines)(1, 6, 7). For many patients, the main barrier to achieving optimal glycaemic targets to prevent complications are their increased risks of hypoglycaemia that remains the most feared complication of intensifying diabetes therapy for both patients and their health care professional.

Although hypoglycaemia has traditionally been considered a complication of the treatment for type 1 diabetes, it has recently been recognised as a problem in people with type 2 diabetes particularly those on intensive insulin therapy (8). In type 1 diabetes, patients on average experience two symptomatic events per week and one severe event, the latter of which is responsible for 2-4% of deaths. In type 2 diabetes the risk of a severe hypoglycaemic event is about 7% in the first few years following diagnosis rising to 25% thereafter. There are multiple concerns on the impact that a hypoglycaemic event may have leading to pathological, social and economic consequences. In the ACCORD study, the risk of death was significantly increased in those with one or more episode of severe hypoglycaemia in both the intensive and standard study treatment arms (1, 9). As plasma glucose falls to below 4.0mmol/L, a series of defensive response mechanisms occur, at individualised glycaemic thresholds, to reverse hypoglycaemia including a rise in catecholamine, cortisol and glucagon levels (10). This may lead to hypokalemia, prolonged QT interval, and cardiac arrhythmias (11). It may also lead to increased oxidative stress (12); impaired cardiovascular autonomic function for up to 16 hours afterwards (13); increased inflammatory markers (14); platelet activation (15) and promote vascular damage. These changes might be clinically relevant as hypoglycaemia was associated with cardiac ischemia (chest pain) when 72-h continuous glucose monitoring along with simultaneous cardiac Holter monitoring were performed in people with ischemic heart disease and type 2 diabetes treated with insulin (16). A few studies, in people with type 1 diabetes and healthy controls, suggested an increase in platelet activation with hypoglycaemia (15, 17) emphasising the increased risk that hypoglycaemia may have on cardiovascular events.

All of these changes may therefore result in the generation of biomarkers that may be able to identify the occurrence of a hypoglycaemia event after the blood glucose has reversed to normal or rebound hyperglycaemic levels have resulted. This will be of particular value in hypoglycaemic unawareness, nocturnal hypoglycaemia and events of uncertain aetiology where hypoglycaemia is part of the differential diagnosis.

An ability to determine whether a hypoglycaemic event has occurred through measurement of a biomarker will be of major impact for the confidence of patients and their healthcare providers allowing glycaemic control to be optimised and glycaemic targets to be reached through more stringent diabetes therapeutic treatment regimens.