Glucagon: Use in Emergency Treatment and Prevention of Mild Hypoglycaemia
Glucagon is used for the urgent treatment of severe hypoglycaemia. Patients are advised to carry an intramuscular injection pen in an ‘emergency kit’ for this purpose. Alternatively, and more recently, nasal powder formulations have been developed [48], with Baqsimi® receiving FDA approval in 2019 as the first non-injectable glucagon therapy for severe hypoglycaemia. Intranasal glucagon is a safe and effective alternative to intramuscular glucagon and oral glucose for treating hypoglycaemia in both adults and children [48-51].
Beyond emergencies, the potential for glucagon to be used to prevent mild hypoglycaemia has been investigated, for instance, before exercise or in other situations where there is a risk of hypoglycaemia due to reduced food intake or delayed meals. Smaller doses of glucagon (micro- or mini-dosing) may provide an alternative to carbohydrate intake to treat mild hypoglycaemia. Studies have shown that treatment with mini-dose glucagon may offer a means to assist in maintaining a healthy weight due to reduced calorie intake to treat mild to moderate hypoglycaemia [52].
Research has also shown that mini-dose glucagon is effective in treating impending episodes of hypoglycaemia in children with T1D [53]. However, the need to reconstitute the glucagon preparation before injection and its limited shelf life once reconstituted can limit its use for treating non-severe hypoglycaemia. Scientists remain interested in applying mini-dose glucagon to further develop a dual-hormone closed-loop artificial pancreas system [54].
Adjuvant Pharmacological Therapies for Glycaemic Management
Currently, pramlintide is the only non-insulin medication that has been approved by the FDA for assisting in blood glucose management in T1D [44]. It works by slowing gastric emptying, promoting satiety, and inhibiting glucagon secretion. However, it is not available in most European countries and hence is not commonly prescribed. Other medications such as metformin, glucagon-like peptide 1 (GLP-1) receptor agonists, and sodium-glucose cotransporter 2 (SGLT-2) inhibitors have been used off-label until now [55]. However, there is increasing (research) interest also in T1D.
Monitoring and Managing Glycaemia: The Constant Challenge
People with T1D face daily challenges managing their glucose levels, which can significantly reduce their quality of life [56]. Effective glycaemic management is crucial to protecting the cardiovascular system, as maintaining near-normal blood glucose levels minimises the risk of vascular complications. Chronic hyperglycaemia remains the main predictor of these complications.
The Diabetes Control and Complications Trial (DCCT) clearly showed the importance of intensive insulin therapy in reducing the risk of diabetes-related vascular complications [57]. The DCCT, which involved over 1,400 patients with T1D for 6.5 years, demonstrated that aiming for near-normal glycaemic control significantly reduced the risk of complications such as retinopathy, nephropathy, and neuropathy compared to conventional insulin therapy. Additionally, follow-up studies, such as the Epidemiology of Diabetes Interventions and Complications (EDIC) study, showed that intensive diabetes therapy during the DCCT resulted in long-term (up to 30 years) benefits on cardiovascular health [58] and all-cause mortality [59].
However, achieving and maintaining near-normal glucose levels is a complex and challenging task. It requires a combination of insulin therapy, dietary management, physical activity, and frequent blood glucose monitoring. Advanced technologies, such as CGM systems and insulin pumps, can help reduce the risk of dysglycaemia. Nevertheless, these technologies require ongoing education, support, and self-management skills.
Blood Glucose Targets for People Living with T1D: What Are They and How Are They Measured?
The latest guidelines recommend an HbA1c target of less than 7.0% for non-pregnant adults; however, this should be personalised based on the individual’s age, risk factors, and other health conditions [23, 60]. For daily blood glucose levels, the guidelines suggest:
● Pre-meal blood glucose between 80-130 mg/dL (4.4-7.2 mmol/L) [60]
● Peak postprandial glucose not above 180 mg/dL (10.0 mmol/L) [23, 60]
To achieve an HbA1c below 6.5%, the following targets are advised:
● Fasting plasma glucose below 110 mg/dL (6.1 mmol/L)
● 2-hour post-meal glucose not above 140 mg/dL (7.8 mmol/L) [61].
Achieving these targets can be challenging, so people with T1D should work closely with their healthcare team to develop a personalised treatment plan that considers their individual needs and circumstances.
HbA1c - The Trusty Standard for Evaluating Blood Glucose Management
For decades, glycated haemoglobin (HbA1c) has been the gold standard for evaluating glycaemic management [62]. Haemoglobin is the protein in red blood cells that binds and transports oxygen throughout the bloodstream. It also has an affinity for circulating glucose, resulting in glycation.
Here’s how it works:
1. Glucose enters the red blood cell and binds to haemoglobin, quickly and reversibly forming ‘labile HbA1c’ [63].
2. Labile HbA1c then slowly rearranges to form ‘stable HbA1c’, which accumulates in the red blood cell throughout its lifespan of about three months [64].
3. Higher formation rates of this glucose-haemoglobin binding indicate the presence of excessive glucose in the bloodstream.
HbA1c is expressed in percentage (%) or mmol/mol and reflects average blood glucose levels over the last 90-120 days, with the last 2-4 weeks being the most important [65, 66]. HbA1c is still considered a robust and easy-to-use parameter, and therapies often focus on lowering HbA1c to prevent diabetes-related complications based on the convincing results from the DCCT [57].
However, while HbA1c has been considered the gold standard for evaluating glycaemia, it has its limitations:
● It cannot reflect short-term glucose fluctuations, hypoglycaemia, or time spent in specific blood glucose ranges [36, 67-69]
● It is less likely to capture the impact of acute interventions
● It cannot be used in certain patient populations (e.g., in patients with certain haemoglobinopathies or end-stage kidney disease) [69]
● Patients with the same HbA1c can have markedly different mean glucose levels [67]
Optimal glucose levels should consider multiple aspects, including maximising time in the target range, minimising hypoglycaemic events, managing post-meal glucose peaks, and limiting glucose variability [70, 71]. In 2018, a “Beyond HbA1c writing group” pointed to the need to incorporate glycaemic metrics beyond HbA1c [72].
Continuous Glucose Monitoring (CGM)
Recent years have seen major advancements in glycaemic management for people with T1D, thanks to the increasing availability of CGM [73]. CGM is now considered the standard of care to monitor daily glucose profiles [23], with the latest American Diabetes Association (ADA) Standards of Medical Care (2024) recommending that real-time CGM (rtCGM) or intermittently scanned CGM (isCGM) “should be offered for diabetes management in adults with diabetes on multiple daily injections or continuous subcutaneous insulin infusion who are capable of using the devices safely”. rtCGM devices should be used as close to daily as possible for maximum benefits [74].