Glycaemic Variability in Acute Stroke

NCT ID: NCT04521634

Last Updated: 2023-10-19

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 77 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2020-09-30
• Study Completion Date: 2022-12-31

Brief Summary

Increased glycaemic variability is associated with worse outcome in patients with diabetes after acute stroke.

Detailed Description

People with diabetes who have a stroke have worse outcomes (Burton JK et al. 2019; Muir KW et al. 2011; Masrur S et al. 2015). Evidence for tight glycaemic control (e.g. maintaining blood glucose between 4.0 and ~7.5mmol/L) on the days immediately after stroke is lacking; studies have not shown improved outcomes and have noted higher rates of hypoglycaemia in intensively treated patients (Bellolio MF et al. 2014; American Heart Association. 2019). However the National Institute for Health and Care Excellence Guidance states that, 'People with acute stroke should be treated to maintain a blood glucose concentration between 4 and 11mmol/L and hyperglycaemia (determined by both admission blood glucose and HbA1c) is associated with adverse outcomes (National Institute for Health and Care Excellence. 2017). In practice, maintaining blood glucose levels below 12mmol/L in people with acute stroke can be challenging, in particular when parental feeding is required.

Intermittent glucose measurement and measures of protein glycation provide limited information on the dynamic changes in glucose over time and do not take into account variability in glucose concentrations. Glycaemic variability (GV) is the consequence of multiple endogenous and exogenous factors and is a measurable variable.

To measure GV a data series of glucose values is required. These may be derived from continuous glucose monitoring and may be from within one time period (such as a day) or over several periods, allowing comparisons between periods. Initial methodologies for GV calculation were defined for self-monitoring data and newer methodologies have been expressly designed for continuous monitoring data.

There is no minimum length of time defined for satisfactory glycaemic variability calculation but, as with all statistical measures, the larger the dataset the more robust the metrics. Glucose concentration is not normally distributed about the mean. There is a long 'tail' to the glucose distribution extending into the hyperglycaemic range. Measures such as standard deviation do not take into account this asymmetric distribution and are thus relatively insensitive to hypoglycaemia. Hypoglycaemia is a significant barrier to improving glycaemic control and is a source of anxiety to people with diabetes. Not only that, it is unpleasant, is associated with morbidity and mortality and contributes to the global healthcare and financial burden of diabetes.

In vitro data has suggested that GV is more deleterious than consistent hyperglycaemia. Human umbilical vein endothelial cells exposed to a glucose concentration alternating between 5 and 20mmol/L every 24 hours show significantly more apoptosis than cells exposed to a constant concentration of 5mmol/L or 20mmol/L over 14 days (Risso A, et al. 2001). Using the same constant and alternating glucose concentrations in human umbilical vein endothelial cells overproduction of reactive oxygen species is highest with oscillating glucose concentrations (Quagliaro L, et al. 2003). In the same sequence of studies expression of the cytokine IL-6 was highest with oscillating glucose concentrations (Piconi L, et al. 2004).

In human proximal tubular cells exposed to increased glucose concentrations (25mmol/L), cell growth, collagen synthesis and cytokine production are elevated, and this is increased further by oscillating the glucose concentration between 25mmol/L and 6.1mmol/L (Jones SC, et al. 1999).

In the critical care scenario, where glucose control is considered important, even in people without diabetes, variability is associated with mortality. In 7049 critically ill subjects the SD of blood glucose concentrations was a significant independent predictor of mortality in the intensive care unit and in hospital (Egi M, et al. 2006). These data have been confirmed by other authors in 3250 subjects with a five-fold mortality increase between the lowest and highest quartiles of standard deviation (Calles-Escandon J, et al. 2010) and in 5728 patients in a study which demonstrated that high variability accompanied by a high mean glucose conferred the highest mortality (Hermanides J, et al. 2010). These data have also been shown in a paediatric intensive care unit where a retrospective review of 1094 patients showed that those in the highest quintile of glycaemic variability had a longer length of stay and significantly elevated mortality (Wintergerst KA, et al. 2006).

In people with stroke, GV has been investigated in people with and without diabetes using finger-prick glucose testing. Increased GV on day 1 after acute ischaemic stroke has been associated with poor functional outcome on hospital discharge but this effect was lost at 3 months follow-up (Camara-Lemarroy et al. 2016.). Early neurological deterioration in acute ischaemic stroke has also been associated with GV (Hui et al. 2018) In people without diabetes, more pronounced stress hyperglycaemic responses measured by continuous glucose monitoring over the initial 72 hours after acute stroke were associated with death or dependency at 3 months (Wada et al. 2018).

Conditions

Diabetes Mellitus, Type 1; Acute Stroke

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: CROSS_SECTIONAL

Study Groups

Acute Stroke + Diabetes

People who have experienced and acute stroke and also have diabetes

No interventions assigned to this group

Acute stroke

People without diabetes who have experienced and acute stroke

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

• Known Diabetes or HbA1c >42 or no known diabetes
• Clinically suspected ischaemic stroke (NIHSS score >6) within 12 hours of symptoms
• Adults ≥18 years of age

Exclusion Criteria

• Haemorrhagic stroke
• Unable to participate due to other factors, as assessed by the Chief Investigators
• Pregnancy
• Premorbid MRS >2
• Adult over 80 years of age
• Known to have a terminal condition or conditions that suggest a life expectancy less than 1 year

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Imperial College London

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Neil Hill

Role: PRINCIPAL_INVESTIGATOR

Imperial College London Healthcare NHS Trust

Locations

Imperial College London

London, , United Kingdom

Countries

United Kingdom

References

Preechasuk L, Rilstone S, Tang WX, Man J, Yang M, Zhao E, Hoque L, Tuncay E, Wilding P, Godsland I, Halse O, Banerjee S, Oliver N, Hill NE. Glycaemic level and glycaemic variability in acute ischaemic stroke and functional outcome: An observational continuous glucose monitoring study. PLoS One. 2025 May 30;20(5):e0318456. doi: 10.1371/journal.pone.0318456. eCollection 2025.

Reference Type: DERIVED

PMID: 40445939 (View on PubMed)

Other Identifiers

20CX5808

Identifier Type: -

Identifier Source: org_study_id