Introduction
Challenges of the Pediatric Population with T1D
PK Profile of Degludec
Peak action, h | Minimal peak | 2–3a | 8–12b | Minimal peak | 5 |
Mean half-life, h | 24–27 | 5.0–7c | 12–14 | 19 | 4.0 |
Duration of action, h | > 42 | 20–23a | 20–26d | 30–36 | 13a |
Recommended dosing interval | Once per day | Once or twice per day | Once per day | Once per day | Once or twice per day |
Guidance and Clinical Cases
Broad Guidance for Clinicians
Case 1: How to Initiate a Patient on Degludec/Starting Dose
Name: Olivia | A1C: 13.0% (118.9 mmol/mol) |
Age: 13.3 years | |
Body weight: 48.6 kg | |
Previous dose: None | |
Case history Olivia has a new diagnosis of diabetes. She has hyperglycemia (18.1 mmol/L [326 mg/dL]), and ketosis, but is not acidotic. She does lots of sport. Olivia is in puberty, and had menarche 2 months ago | |
Guidance Olivia was initiated on degludec 14 units (0.29 units/kg) daily with insulin aspart as bolus insulin, with an ICR of 1 unit to 15 g carbohydrate, with a correction factor of 1 unit to 3 mmol/L (55 mg/dL), aiming for fasting plasma glucose of 5.0–7.4 mmol/L (90–130 mg/dL) |
Broad Guidance for Clinicians
Case 2: How to Switch a Patient to Degludec from Other Basal Insulins
Name: Alice | A1C: 8.0% (63.9 mmol/mol) |
Age: 7 years | ICR: 1 unit per 15 g at breakfast; 1 unit per 20 g at other meals |
Body weight: 22.8 kg | |
Previous dose: Glargine U100 8 units/day (0.35 units/kg); insulin aspart 12 units across 3 meals | |
Case history Alice was diagnosed 6 months ago and started on a basal–bolus injection regimen with glargine U100. Alice is very distressed by her current insulin injections, with complaints about painful injections. Her basal injections are at bedtime, and this is leading to huge anxiety and proving very disruptive to family life and the daily routine. In particular, there is a high burden on Alice’s mother, as she is the only person Alice will allow to give the injection. Alice is apprehensive, but okay with her bolus injections | |
Guidance The more neutral pH of degludec (degludec; pH 7.6) compared with that of glargine U100 (pH 4.0) [6, 26] may help alleviate the negative association with daily basal insulin injections On the basis of her case notes and the lower dose requirement with degludec, a dose reduction of 1 unit was made making Alice’s first dose with degludec 7 units/day In addition, Alice’s previous bolus insulin dose was also reduced Following the switch, Alice’s fasting BG testing was used to inform further adjustments in degludec dose. As this information may often be lacking in older children/troubled adolescents, use of CGM or flash glucose monitoring is invaluable As degludec reaches steady state over a 2- to 3-day period, care was taken to emphasize that doses need to be taken at the same time each day during this period. If this is not possible, the variability in glucose exposure may be corrected for by giving a slightly higher dose of degludec on the first day of switch, or simply correcting with additional bolus insulin over this period |
Broad Guidance for Clinicians
Common reasons for switching to degludec |
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To reduce the risk of hypoglycemia |
To permit setting of lower glycemic targets considering the risk of hypoglycemia |
To provide more stable overnight glucose control because of variable and unpredictable fasting plasma glucose levels, or other indications of glucose variability with a previous basal insulin |
To address issues with adherence because of the inflexibility of a previous regimen or the injection process/device |
To reduce number of basal injections to simplify the lives of children and caregivers |
Allergic reactions to other basal analogs |
Case 3: How to Switch a Patient to Degludec Previously Using Pump Therapy
Name: Miguel | A1C: 9.8% (83.6 mmol/mol) |
Age: 15 years | ICR: 1 unit per 10 g |
Body weight: 65 kg | |
Previous basal dose: 28 units/day (0.43 units/kg) | |
Total daily dose: 44 units/day | |
Case history Miguel recently had a hospital admission with DKA. His adherence to bolus insulin dosing is not optimal (1–2 boluses per day) and his glucose testing is inadequate (0–2 tests daily), hence he did not recognize his pump had failed as a result of cannula occlusion. Miguel agreed that a pump was not the best option for him at present | |
Guidance As Miguel has had issues with adherence, particularly with self-measuring of BG, his basal insulin requirement was recalculated and he received appropriate psychological support and education to help him meet his glycemic targets. As there is often limited information available from non-adherent patients, the added complexity often makes it advisable to start afresh with weight-based insulin dosing (e.g., 40% of body weight for the basal insulin dose). Miguel has a high proportion of his total daily dose determined by his basal insulin (> 60% when it should optimally be 40–50% of total); likely increased to make up for skipped bolus injections As Miguel was on too much basal insulin, he was started on 25 units/day (0.38 units/kg) of insulin degludec 100 units/mL and 1 unit insulin aspart per 10 g carbohydrate. Flash glucose monitoring was used to facilitate titration of his insulin doses |
Name: Anna | A1C: 8.0% (63.9 mmol/mol) |
Age: 17 years | ICR: 1 unit per 8 g with breakfast, 1 unit per 10 g with other meals; 1 unit per 12 g before or after exercise |
Body weight: 57 kg | |
Previous basal dose: 24 units/day | |
Case history Anna is an active teenager and has been living with diabetes for 8 years. She has been on a pump most of that time, but is keen to have a less “visible” therapy. In general, she is moderately adherent to her diabetes care, performing 3–4 SMBG measurements daily. She remembers insulin boluses, unless she is on a night out with friends, when she will tend to skip boluses, because of anxiety about possible hypoglycemia. Although Anna has suboptimal glycemic control, she changes pump catheter regularly and does not interrupt basal rate. Therefore, the switch to degludec can be based on her previous daily basal dose | |
Guidance Although pump therapy has been reported to improve glycemic control and reduce the risk of hypoglycemia and hospitalization for DKA [31, 32], Anna is not in good control as a result of skipped boluses. Instead of using frequent prandial and correction bolus doses, which is associated with better HbA1c, she applies infrequent large corrections. Consequently, Anna still has marked hypo- and hyperglycemia, and potentially DKA. Her fasting glucose was usually satisfactory. Switching to degludec was advised Anna was commenced on degludec 24 units once daily (0.42 units/kg) (no dose reduction because of still pubertal high insulin need) with the same ICR She was strongly encouraged not to skip bolus doses She was educated about alcohol and diabetes, and also counseled regarding pregnancy and diabetes |
Clinical Perspective and Rationale for Switching
Broad Guidance for Clinicians
Case 4: How to Titrate Degludec in Patients Initiated or Switched from Another Insulin
Name: Michael | A1C: 8.5% (69.4 mmol/mol) |
Age: 4 years | |
Body weight: 14 kg | |
Previous MDIs: Biphasic lispro and neutral protamine Hagedorn (NPH) insulin (25:75) given as 7 U (am) and 4 U (pm) | |
Case history Michael was diagnosed with T1D when he was 3 years old and has been treated with biphasic lispro (25:75 for insulin lispro/insulin lispro protamine) twice daily. Initially, he was very well controlled with a low insulin requirement, but over the last year his control has deteriorated, partly because his parents were unwilling to consider a more intensive insulin regimen. However, he recently experienced an episode of severe nocturnal hypoglycemia and professional CGM documented previously unsuspected nocturnal hypoglycemia, persuading his parents that for their son’s safety, a change was required. Additionally, he consistently had elevated fasting glucose potentially due to previously unrecognized nocturnal hypoglycemia and rebound morning hyperglycemia (Somogyi phenomenon) or the “dawn phenomenon” [42]. CGM confirmed that he was experiencing reactive hyperglycemia secondary to unsuspected hypoglycemia, demonstrating that the basal insulin component within his fixed biphasic insulin mixture was too high | |
Guidance | |
Michael’s parents were advised to increase the frequency of BG monitoring, especially at bedtime and overnight (3–4 h after bedtime) to minimize risk of nocturnal hypoglycemia and a switch to degludec was proposed The initial dose of degludec (based on his total daily requirement) was reduced from the level used with NPH insulin and set to 30% of his daily dose (0.3 U/kg) Beginning on 4 U/day (0.29 units/kg) of degludec, the titration algorithm of the BEGIN: Young 1 was applied [8] and on the basis of his lowest pre-breakfast fasting plasma glucose of 10.9 mmol/L (196 mg/dL), his first dose adjustment was an increase of 1 U to 5 U/day Over the course of 2 weeks, Michael reached his new target of 4–8 mmol/L (70–145 mg/dL), achieved with 4.5 U (0.32 units/day) of degludec and he experienced no recurrence of nocturnal severe hypoglycemia |
Glycemic Targets
Insulin dose | Basal dose | Bolus dose | |||
---|---|---|---|---|---|
< 5 U | 5–15 U | > 15 U | ≤ 5 U | > 5 U | |
Pre-breakfast or pre-dinner BG, mmol/L (mg/dL) | Dose adjustment | Dose adjustment | |||
< 5.0 (< 90) | − 0.5 | − 1 | − 2 | − 1 | − 2 |
5.0–8.0 (90–145) | 0 | 0 | 0 | 0 | 0 |
8.1–10.0 (146–180) | + 0.5 | + 1 | + 2 | + 0.5 | + 1 |
10.1–15.0 (181–270) | + 1 | + 2 | + 4 | + 1 | + 2 |
15.0 (> 270) | + 1.5 | + 3 | + 6 | + 1.5 | + 3 |
Treat-to-Target Titration of Degludec
Case 5: How to Use Degludec in Patients Who Have Unpredictable Levels of Physical Activity That May Impact Glycemic Control
Name: Thomas | A1C: 7.1% (54.1 mmol/mol) |
Age: 14 years | ICR: 1 unit per 10 g and 1 unit per 15 g (pre- and post-exercise) |
Body weight: 53 kg | |
Current MDIs: Degludec with insulin aspart (18 U and 26 U) | |
Case history Thomas is an avid footballer, and in addition to physical education classes, he has football practice once a week (ca. 90 min) and on most weeks, a 60-min match. Recently his team was invited to participate in an overseas football tournament. He would be away from home for 4 days. During this time he will play approximately 5–7 h of football a day. While his parents are keen that Thomas participates in the tournament, they are concerned he may neglect his diabetes care and are particularly concerned regarding possible hypoglycemia. Should hypoglycemia happen while he is away, his parents are concerned that this may lead to a reluctance to participate in future tournaments or sport in general. This would likely impact his physical and mental well-being | |
Guidance While Thomas is experienced with taking responsibility for his BG levels and the adults responsible for his care on the trip are familiar with his condition, given the combination of travel, higher levels of exercise, and potentially unregulated diet necessitate consideration and careful planning Adequate provision of BG test strips, high glycemic index snacks, and hypoglycemia remedies (e.g., glucose tablets) is essential [48] As the week includes some periods of moderate- to high-intensity exercise, it is recommended that 3 days before the tournament his degludec dose is reduced by 30%, with any hyperglycemia managed by bolus corrections Flash glucose monitoring was recommended to facilitate timely glucose checks |
Guidance with Insulin Prior to and During Exercise
Bolus Dose
Basal Dose
Exercise and Degludec
Case 6: How to Maintain Treatment with Degludec in Patients Following an Episode of DKA
Name: Matthew | A1C: 11.3% (100 mmol/mol) |
Age: 10 years | |
Body weight: 28 kg | |
Current MDIs: NPH insulin with insulin aspart | |
Case history Matthew was been raised under difficult social circumstances and had a troubled relationship with his family. He lived with his mother, step-father, and five half-siblings; despite his young age, he was entrusted with management of his diabetes, with no adult supervision. He experienced an episode of very severe DKA (pH 6.88). Management included standard therapy with IV fluids and insulin and in addition degludec was commenced within 6 h of admission His DKA episode resulted in him being placed in foster care. It was clear that he was severely neglected, being grossly underweight. His parents had not collected diabetes supplies, including insulin, for several months | |
Guidance The PK properties of degludec, described previously, mean that the circulating concentration will not drop quickly and will not drop to zero even if a dose is missed. In fact, a patient would likely have to miss two to three daily doses of degludec to be at any risk of DKA. In addition, in a trial of children with T1D treated with IDet or degludec, degludec resulted in significantly lower rates of hyperglycemia with ketosis [8] Since degludec is more forgiving regarding missed injections and carries a lower risk of hypoglycemia with ketosis when compared with insulins such as IDet [8], Matthew was switched from NPH insulin to degludec It was emphasized that his diabetes care be appropriately supervised by a responsible adult |
Case 7: How to Use Degludec When There May Be Multiple Demands on a Patient’s Care Resulting in Unpredictable Variations in BG
Name: Angela | A1C: 7.8% (61.7 mmol/mol) |
Age: 17 years | ICR: 1 unit per 8 g |
Body weight: 65 kg | |
Current MDIs: Degludec with insulin aspart | |
Case history Angela has been using degludec and managing her diabetes for a few years and has grown quite independent and confident in managing her diabetes. Recently she has attended some pop concerts and would like to go away for a 3-day music festival. Her parents are concerned and have sought advice because it will be her first time away and they are concerned that she may experience episodes of hypoglycemia due to alcohol consumption, increased physical activity, and more unpredictable eating | |
Guidance She was advised that during the festival, to limit consumption of alcohol, increased physical activity and erratic timing of meals could be handled by ensuring that her BG is monitored regularly; that alcohol is only consumed with carbohydrates and bolus insulin is adjusted to smooth hyper- and hypoglycemic fluctuations in BG (particularly pre-breakfast). Angela was advised not to compromise her good glucose control by lowering her dose of degludec. She was further counseled regarding contraception/safe sex and effects of illicit drugs on glycemia |