Periodic Reporting for period 5 - Hypo-RESOLVE (Hypoglycaemia - REdefining SOLutions for better liVEs)
Período documentado: 2022-05-01 hasta 2023-10-31
Diabetes is a major non-communicable threat to global health that imposes an increasing burden on global health care resources. Lowering glucose levels to those in the non-diabetic range reduces the risk of vascular complications and mortality, but is associated with increased risk of hypoglycaemia (low blood sugar), when insulin treatment is needed. Hypoglycaemia causes profound physical and mental stress, and is associated with adverse clinical consequences, including death, psychological stress, poor quality of life and elevated costs, both for the individual and for society. The objective of the Hypo-RESOLVE project was to increase the understanding of hypoglycaemia in diabetes, using a comprehensive multi-level approach, in which academia, industry and people affected by or living with diabetes closely collaborated. The work performed in Hypo-RESOLVE included the construction of a large database of hypoglycaemia reported by clinical trials, basic and applied research to explain mechanisms underlying the link with cardiovascular disease and hypoglycaemia sensing, a study to establish the impact of sensor-detected hypoglycaemia, qualitative and quantitative research to assess psychological effects, the development of a hypoglycaemia-specific patient-reported outcome, and health-economic analyses. Collectively, the Hypo-RESOLVE project established that hypoglycaemia, whether measured in capillary blood or in the interstitium, has extensive and potentially long-term consequences for the individual with diabetes, ranging from clinical to psychological outcomes, with repercussions for their family members and society. The project provided important evidence to support the current classification of hypoglycaemia as proposed by the International Hypoglycaemia Study Group (IHSG) in 2017, in particular for the clinical significance of level 2 hypoglycaemia, and indicate that hypoglycaemic events captured by glucose sensors or through self-report are complementary rather than interchangeable.
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.
Data coming out of this project have considerably advanced our understanding of hypoglycaemia. The project has contributed to explain mechanisms underlying the association of hypoglycaemia with long-term (cardiovascular) consequences and of IAH. The project has provided data on the clinical relevance and psychological impact of low glucose measured by CGM. These data fill the gap in evidence to support the current classification of hypoglycaemia in people with diabetes at risk of medication-associated hypoglycaemia, facilitating its adoption by many national and international guidelines, as well as by EMA and the FDA. This is important so that all stakeholders in the diabetes community, whether they are people with diabetes, HCPs, regulators, scientists or industry, agree on the definition of hypoglycaemia, including this being an efficacy outcome for future clinical trials. Such trials may choose to use the Hypo-METRICS app and the Hypo-RESOLVE hypoglycaemia-specific PRO. Also. data from the Hypo-METRICS study and the consolidated Hypo-RESOLVE database are open for future analyses by researchers with an interest in hypoglycaemia.