A governance structure was put in place to provide support for individual scientists, monitor progress and coordinate project activities. A website, twitter account and dissemination toolkit were established to create awareness of the project’s mission, vision and progress, whereas a short animated clip and podcast videos explained the project for a general audience. We constructed a large, sustainable Hypo-RESOLVE database with data on hypoglycaemia and other clinical parameters from 98 individual clinical trials involving >60,000 people with diabetes treated with insulin. One of its analyses showed that hypoglycaemia over a 6-week period predicts future hypoglycaemia at varying levels of severity. We also found strong associations for the cumulative exposure to hypoglycaemia with acute and chronic complications in both type 1 and type 2 diabetes, without a threshold level below which these risks suddenly emerge. The multicentre Hypoglycaemia Measurement ThResholds and ImpaCtS (Hypo-METRICS) study (n=602), which examined the clinical, psychological and health-economic impact of sensor-detected hypoglycaemia in people with diabetes, showed that more than half of all low sensor-glucose values are asymptomatic, but also that 40% of person-reported hypoglycaemia has no corresponding low sensor value. This study also showed that asymptomatic hypoglycaemia (i.e. only detected by the sensor) does not affect next-day functioning. The specifically developed Hypo-METRICS app with 3-daily entries on quality of life and related questions was well-tolerated and highly appreciated by participants, which holds promise for applying this tool in future studies and in daily clinical practice. A meta-analysis of stepped hypoglycaemic clamps showed glycaemic thresholds for counterregulatory hormone responses among people without diabetes to align with IHSG level 1 hypoglycaemia. In addition, experimental hypoglycaemia (using hyperinsulinaemic glucose clamps) showed cognitive decline at glucose levels below 3.0 mmol/l, consistently across groups with type 1 or type 2 diabetes, irrespective of clinical parameters, thus supporting IHSG level 2 hypoglycaemia. The hyperinsulinaemic hypoglycaemic clamp study also showed that hypoglycaemia causes long-term pro-inflammatory effects on multiple levels in all groups, with only very limited attenuation following exposure to antecedent hypoglycaemia, whether experimentally induced or based on sensor data. Animal studies further established the role of FGF15 neurons in the hypothalamus controlling glucagon secretion. Data also showed that cold exposure affected the counterregulatory hormone response to subsequent hypoglycaemia, whereas mouse models of impaired awareness of hypoglycaemia and of type 2 diabetes with defective glucagon secretion have been developed, which showed that repeated hypoglycaemia induced multiple defects affecting all hypothalamic cell types and their interactions. Systematic reviews revealed that few studies truly examined the impact of hypoglycaemia on quality of life among people with type 1 or type 2 diabetes. To fill these knowledge gaps, two studies were conducted, showing that hypoglycaemia affects multiple domains of quality of life in people with diabetes, as well as among family members. Finally, a novel conceptual model of hypoglycaemia-related health-related quality of life (HRQoL) was generated. This 14-item PROM showed good structural and convergent validity with related constructs, internal consistency, and test-retest reliability. After having held a stakeholder meeting with representatives from professional and patient organisations, HTA bodies, regulators and other stakeholders, and an Innovation Task Force (ITF) meeting with representatives from the European Medicines Agency (EMA), official Qualification Advice was obtained from EMA for this purpose.
