Poorly controlled glycaemia in type 1 (T1DM) and type 2 (T2DM) diabetes mellitus can result in macro- and microvascular complications. Traditionally, management efforts have focused on meeting HbA1_c goals (<7%) by targeting fasting plasma glucose.^2,3,4,5,6,7,

However, over recent years, evidence has emerged that targeting post-prandial glucose (PPG), a contributor to HbA1_c and the main driver of glycaemic variability, can prevent diabetes-related complications, according to Prof Joel Dave, Head of the Division of Endocrinology at Groote Schuur Hospital and University of Cape Town.²

The primary factors determining PPG profile are: insulin secretion, insulin action in stimulating glucose uptake and suppressing glucose production, glucagon suppression, glucose effectiveness in stimulating its own uptake and production, and gastric emptying as well as incretin hormones. ^2,8,9

Normal insulin secretion happens in two phases, explained Prof Dave:^2,9

1. Phase 1: occurs within five minutes of eating
2. Phase 2: occurs about 90 minutes after eating.

To effectively manage diabetes, clinicians need to stimulate the normal physiology of insulin secretion and target PPG, which is possible with new agents. These agents mimic the physiologic action of endogenously secreted insulin more closely, resulting in improved PPG control, stressed Prof Dave.²

Optimal timing of mealtime insulin dosing key to controlling PPG

Optimal timing of mealtime insulin dosing is a key factor in controlling PPG levels, but timely and accurate mealtime insulin dosing are often challenging for people with diabetes, said Dr Landi Lombard, an endocrinologist based in the Western Cape.^2,10

Lane et al conducted a multinational, online study to explore attitudes and behaviours around mealtime insulin dosing and the impact of mealtime dose timing (particularly with regard to premeal dosing [15–20 minutes before a meal]) in patients with T1DM.¹⁰

The team found that 91% of adults with diabetes experience at least one of the following challenges:¹¹

• Not sure what to eat (either type of meal or amount of carbohydrate) to dose accurately
• Not sure when to eat to dose at the right time
• Interruptions after dosing causing delays to eat
• Forgetting to take insulin in timeframe needed (and having to delay eating)
• Missing social events due to concerns around dosing and food intake
• Dosing after start of a meal to be more certain of when and what to eat
• Having to inject more insulin after eating due to eating more/different food than expected
• Having to eat extra food after end of the meal, due to eating less/different food than expected
• Completely forgetting to take the mealtime insulin
• Not sure how much to eat to dose accurately.

The vast majority of adult patients (82%) felt that having to administer insulin 15–20 minutes before their meals, negatively affected their lifestyle greatly or to some extent.¹⁰

Most patients (91%) worry about PPG levels after a meal, because it increases the risk of hypoglycaemia.Furthermore, 67% of adult patients claim that having the freedom to administer insulin at mealtime either immediately before or after the start of a meal, would have a positive impact on their lives.¹⁰

According to Dr Landi Lombard, taking cognisance of the challenges that patients with diabetes face, there is little doubt that better and faster meal-time insulin was needed. Faster insulin aspart is a big step towards achieving this goal, giving us an ultra-fast mealtime insulin, he added.²

He explained that the main aims of ultra-fast analogues are to:²

1. Improve PPG control
2. Allow for more flexible mealtime dosing, resulting in improved quality of life (QoL)
3. Be effective for use in insulin pump therapy
4. Improve absorption after injection
5. Improve onset of action
6. Ensure greater potential for early glucose lowering without late postprandial or nocturnal hypoglycaemia.

One of the biggest benefits of faster insulin aspart is the flexibility to inject just before having a meal, five minutes before or even after a meal (the latter is not ideal), which meet patient requirements, thus resulting in improved QoL, concluded Dr Lombard.²

Faster insulin aspart – the clinical evidence

The safety profile of faster insulin aspart is similar to conventional insulin aspart, with respect to hypoglycaemia and treatment emergent adverse events, said Prof Thomas Danne, Director of the Department of General Paediatrics and Endocrinology/Diabetology at the Auf der Bult Children’s Hospital in Hannover, Germany, and President of the International Society for Paediatric and Adolescent Diabetes.²

The efficacy and safety of faster insulin aspart in adult and paediatric patients with T1DM and T2DM have been confirmed repeatedly in the ONSET phase 3 clinical trial programme, and can be used as pump or injection therapy, he added.^12,13,14,15

In the ONSET 1 trial, faster insulin aspart administered 20 minutes after the start of the meal was non‐inferior (0.4% margin) to mealtime insulin aspart regarding change in HbA1_c after 26 weeks of treatment.¹²

In the ONSET 8 trial, mealtime faster insulin aspart was superior to insulin aspart for one‐hour PPG increment using a meal test (estimated treatment difference [ETD] −0.90mmol/L). Self‐monitored one‐hour PPG increment favoured faster insulin aspart at breakfast (ETD, −0.58mmol/L) and across all meals (−0.48mmol/L).¹³

ONSET 5 showed that faster aspart was superior to insulin aspart in change from baseline in one-hour PPG increment after a meal test with, statistically significant reductions also at 30 minutes and two hours.¹⁴

ONSET 7 showed that in children and adolescents with T1DM, mealtime and postmeal faster insulin aspart with insulin degludec provided effective glycaemic control, with no additional safety risks versus insulin aspart. Mealtime faster insulin aspart provided superior HbA1_c control compared with insulin aspart.¹⁵

Faster insulin aspart – in clinical practice

In T1DM, the recommended starting dose of faster insulin aspart is about 50% of the total daily insulin dose, and in T2DM the recommended initial dose is four (4) units at one or more meals, noted Prof Danne.²

Individual doses should be based on the carbohydrate content of the meal and the number of injections, and titration will depend on individual glycaemic targets and carbohydrate consumption.²

Patients already on a mealtime insulin can be converted to faster insulin aspart on a unit-to-unit basis. Close glucose monitoring (CGM) is recommended during the transfer from other mealtime insulins and in the initial weeks thereafter. Patients switching from other insulins will require training on dose timing, he stressed.²

Prof Danne cautioned that there may be a need for a change in dosage when switching to faster insulin aspart. Dose adjustment may be considered daily based on mealtime and bedtime self-measured plasma glucose and meal carbohydrate content.²

Case study

Prof Thomas Pieber, Head of the Division of Endocrinology and Metabolism and Chairman of the Department of Internal Medicine at the Medical University of Graz (Austria), cited a case study to demonstrate the efficacy of faster insulin aspart in clinical practice.

Sophia* (20) was diagnosed with T1DM at the age of 11. She was successfully managed on multiple daily injection therapy during the first few years following her diagnosis. During puberty, she gained weight and her body mass index (BMI) was 29.5, and she did not meet her recommended HbA1_c targets. She is currently a university student and decided to implement lifestyle changes to include regular physical activity (cross-country skiing) in order to manage her disease better.²

She has lost weight and her current BMI is 26.1. She uses CGM to avoid hypoglycaemia – especially when she is engaged in physical activity. However, she expressed frustration because her PPG measures 12 mmol/L following a meal after exercise.²

She was referred for treatment optimisation. Her objectives were to improve her blood glucose levels and control PPG excursions following exercise. She was offered pump therapy but preferred CGM and multiple-daily injection therapy.²

Her current treatment includes insulin degludec 18 IU at bedtime and insulin aspart 15 IU. The treatment team decided to switch her to faster insulin aspart for one month and a more flexible insulin/carb ratio (IU/12-25 carb) when exercising. On resting days, she uses more insulin.²

Before switching, Sophia experienced hypoglycaemic events and PPG excursions following a meal after exercising. Post-switching, she manages to meet her targets most of the time, and currently her HbA1_c is 6.9%. She has indicated that she prefers to remain on faster insulin aspart.²

Moving beyond HbA1c to reduce complications

Apart from targeting PPG, another key concept that has emerged over recent years is time in range (TIR), said Prof Dave. The introduction of CGM has resulted in a move away from HbA1_c as the definite target for the effective management of diabetes.²

Unlike HbA1_c measurement, the use of CGM allows for the direct observation of glycaemic excursions and daily profiles, which can inform on immediate therapy decisions and/or lifestyle modifications. CGM also provides the ability to assess glucose variability and identify patterns of hypo- and hyperglycaemia.¹⁶

CGM has heralded different glycaemic metrics (TIR, below target range, above target range) that can be used to help patients reduce their risk of developing micro- and macrovascular complications.^2,16

TIR is the percentage of time that a patient spends with their blood  glucose levels in a specific target glucose range. Every 10% increase in TIR can lower HbA1_c by 0.5% to 0.8%, which is as effective as any drug therapy, added Prof Dave.^2,16

Beck et al showed that on average, a TIR of 70% and 50% corresponded with an HbA1_c of about 7% and 8%, respectively. Therefore, to achieve the ‘magical’ target of <7%, a patient will need to spend TIR ≥70%, said Prof Dave.^2,17

The Impact of Fast-Acting Insulin Aspart on Glycaemic Control in Patients with Type 1 Diabetes Using Intermittent-Scanning Continuous Glucose Monitoring Within a Real-World Setting: The GoBolus Study by Danne et al showed that real-world switching to faster aspart in adults with T1DM on multiple daily injections improved HbA_1c, increased TIR, and decreased time in hyperglycaemia without affecting time in hypoglycaemia.¹⁸

By week 24, HbA_1c had decreased by 0.19% (-2.1mmol/L) with no mean change in insulin doses or basal/bolus insulin ratios. For patients with sufficient available CGM data, TIR increased from 46.9% to 50.1%, corresponding to an increase of 46.1 min/day. Time in hyperglycaemia decreased from 49.1% to 46.1% and from 20.4% to 17.9% (>13.9mmol/L), corresponding to 43.5 and 35.6 fewer minutes per day on average spent in these ranges, respectively. Mean interstitial and PPG improved from 10.4 mmol/L to 10.1mmol/L and 11.9 mmol/L to 11.0 mmol/L, respectively.¹⁸

*Patient’s name has been changed to protect her identity

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