Here are the steps I would take to switch Alin from glargine U100 to degludec: 1. Calculate Alin's total daily insulin dose (TDD) as glargine 8 units + aspart 12 units = 20 units or 0.88 units/kg 2. Start degludec at 30-50% of the TDD, which is 0.26-0.44 units/kg. For Alin, this would be 6-10 units. 3. Start degludec at 6 units once daily, any time of the day. 4. Continue aspart doses with meals. 5. Adjust doses based on BG levels over next 1

1. Novo Nordisk®
azad82d@gmail.com
azad.haleem@uod.ac
Dr.Azad A Haleem AL.Mezori
MRCPCH,DCH, FIBMS
Assistant Professor
University Of Duhok
College of Medicine
Pediatrics Department
Degludec Insulin therapy in children
Scan
For
Contac
t

2. What is type 1 diabetes?
T1D, type 1 diabetes
1. World Health Organization. Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia:
2. American Diabetes Association. Classification and diagnosis of diabetes: standards of medical care in diabetes—2022
• It’s a chronic metabolic disorder characterized by hyperglycemia as a cardinal
biochemical feature, caused by deficiency of insulin or its action, manifested
by abnormal metabolism of carbohydrates, protein and fat.
• Diagnosis of diabetes is made when:
• Symptoms +
• random BGL ≥ 11.1 mmol/L (≥200 mg/dl) (or)
• Fasting BGL ≥ 7mmol/L (≥ 126 mg/dl)
Type I diabetes: (β-cell destruction, usually leading to absolute insulin deficiency)
-Immune mediated. Idiopathic.
Type 2 diabetes: (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with
insulin resistance).
Genetic defects of β-cell function:Chromosome 7, glucokinase (MODY2)
Genetic defects in insulin action:Rabson-Mendenhall syndrome
Diseases of the exocrine pancreas: Pancreatitis
Endocrinopathies: Cushing disease
Drug- or chemical-induced : Glucocorticoids , Infections:Cytomegalovirus , genetic syndromes :Down syndrome
Gestational diabetes mellitus
Neonatal diabetes mellitus
Classification

3. What is type 1 diabetes?
T1D, type 1 diabetes
1. World Health Organization. Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia:
2. American Diabetes Association. Classification and diagnosis of diabetes: standards of medical care in diabetes—2022
• T1D is the most common form of diabetes in children and adolescents,
• accounting for >90% of childhood diabetes.
• Peaks of presentation occur in 2 age groups: at 5-7 yr of age (infectious) and at
the time of puberty (gonadal steroids ).
• Girls and boys are almost equally affected
• There is no apparent correlation with socioeconomic status.
Epidemiology

4. Physiology
• The main function of insulin are:
• 1. Reduce glucose by:
• ↓ gluconeogenesis
• ↓ glycogenolysis
• ↑ uptake of glucose by cell
• 2. Inhibit fat breakdown (lipolysis)
• 3. Inhibit protein breakdown (proteolysis)
Insulin deficiency will lead to:
1. Hyperglycemia: increase glucose→ osmotic diuresis → polyuria → dehydration →
compensatory polydepsia.
2. Proteolysis: → weight loss → Polyphagia.
3. Lipolysis: ↑ free fatty acids and accumulation of acetyl Co-A → Liver → keton bodies →
ketonemia → ketonuria & Metabolic acidosis.

5. Presentation & Investigations:
Presentation:
• Although most symptoms are nonspecific
• polyuria , polydepsia, Polyphagia & weight loss.
• Recurrent infection: skin or UTI.
• Diabetic Ketoacidosis
• Investigations:
• Blood glucose : Fasting glucose > 126 mg/dl & Random > 200 mg/dl.
• HbA1c: (glycated haemoglobin) average over the last 2-3 months. Measures amount of
glucose that attaches to haemoglobin.
• Ketone testing: either urine strips, or blood.
• Urine: glucosuria & Ketonuria if DKA suspected.

6. Management
• Need team & Special diabetic Clinic?
• Medical: specialist
• Insulin
• Specialist Nurses:
• Dietitian.
• Psychologist
• Equipments: insulin, glucometer, Ketones meter and good maintenance.
• Good follow up.
Insulin
Nutrition

7. Insulin
• Insulin has revolutionized management of type 1 diabetes mellitus (DM) which was invariably fatal before
the discovery of Insulin in 1922 by Banting & Best.
• Despite technological advances & Different types of Insulin there are difficulties in management of type 1
DM in children.

8. Rapid acting analogues:
• Three rapid acting analogues are approved and available for use in children.
• Insulin lispro (Humalog, Eglucent)
• Insulin aspart (Novorapid)
• Insulin glulisine (Apidra)
• Recently, faster aspart (f Aspart) is also approved in adults which starts its action in 5-10 minutes
after injection.
• The rapid-acting insulin analogs lead to less postprandial hyperglycemia and less late
postprandial hypoglycemia and less fasting hypoglycemia.
• Injection of rapid-acting insulin analogs 15-20 minutes pre-meal leads to maximal
reduction of postprandial glucose excursions as compared to 30 or more minutes pre-
meal for regular insulin.

9. Long acting insulin (glargine):
• Insulin glargine contains two modifications to human insulin so that the isoelectric point of the insulin is shifted from
a pH of 5.4 to 6.7.
• This change makes the insulin more soluble at an acidic pH of 4.0.
• When insulin glargine is injected into subcutaneous tissue, which is at physiologic pH of 7, the acidic solution is
precipitated, from which small amounts of insulin are released throughout a 24-hour period like that of basal insulin.
• It has very small peak at around 2 hours; followed by stable levels and weaning effect around 20 hours.
• It is to be given once daily , though early morning dose is preferred to reduce risk of midnight hypoglycemia.
• It is the backbone of basal bolus regimen across the world.
• Due to acidic nature of glargine, it should not be mixed in the same syringe with any another insulin or solution.

10. Degludec:
• Insulin degludec is an ultra-long-acting insulin.
• Degludec forms multi-hexamers after subcutaneous injection, leading to a very slow release of
insulin into the bloodstream and a prolonged duration of action.
• It is peak less, The half-life of degludec is about 25 hours and its duration of action more than 42
hours.
• Its long duration of action makes it suitable for anytime once daily injection.
• The PK properties of degludec are not affected by increasing age, renal impairment or
hepatic impairment
• It is approved in children above one year of age.

11. Insulin degludec mode of protraction
Di-hexamers
Insulin degludec exists as
di-hexamers in the pen to allow
for subcutaneous injection
Multi-hexamers
Immediately after injection, insulin
degludec forms stable, long-multi-
hexamer chains
1 nm
Monomers
Individual monomers slowly
dissociate from the ends of the
chains over time, resulting in the
flat and stable glucose-lowering
effect of insulin degludec
1 nm [ Zn2+]
Pen contains
300 total units
Delivers up to 80 units
in a single injection
Dial exact dose
(1-unit dose adjustments)
100 U/mL
formulation
80-unit
maximum-dose pen
No push-button extension
Less pressure for injection
U100

12. Insulin requirements: dose calculation;
Calculations serves a s starting point and should be adjusted according to patient-
specific needs.
Start with 0.5 IU/kg/day non DKA
Post DKA 2-2.5 IU/kg/day
honeymoon phase 0.2-0.5 IU/kg/day or single long acting insulin
Pre-pubertal 0.7-1.0 IU/kg/day.
During puberty 1-1.5 IU/kg/day and even up to 2 U/kg/day.
After completion of puberty 0.8-1 IU/kg/day
Basal insulin is generally kept at 40% of total dose while 60% dose is divided into boluses.
The correct dose of insulin is that which achieves the best glycaemic control

13. Insulin therapy in T1D
Classifying insulin regimens – difficulties and proposal for comprehensive new definitions. Pediatr Diabetes
ISPAD Clinical Practice Consensus Guidelines 2022
GUIDELINE ON INSULIN DOSAGE
Insulin dosing may be dependent on many factors such as:
• Age , Weight
• Stage of puberty
• Duration and phase of diabetes
• State of injection sites
• Nutritional intake and distribution
• Exercise patterns
• Daily routine
• Results of BG monitoring and glycated hemoglobin
• Intercurrent illness
• Menstrual cycles

14. • Injection sites:
• Insulin can be injected subcutaneously in the anterolateral thigh, the anterior abdominal wall (leaving out
2 inches from all sides of the umbilicus) and the upper outer region of the buttocks.
• The arm is not ideal for the pediatric patient because of little subcutaneous fat in this region.
• Insulin is absorbed fastest from the abdomen, then from the upper arms, followed by the thigh region and
slowest from the buttocks.
• Storage:
• Insulin Vials should be refrigerated at 2-8 C.
• Vials should never be frozen and frozen vials should be discarded.
• In use insulin Vials should not be used beyond three months if refrigerated and one month if kept in room
temperature of 25 C.
• Insulin pens which are open need not be refrigerated but should be kept in a cool, dry place.

15. Insulin regimens
A. Conventional Insulin therapy: Twice daily mixed Insulin.
B. Intensive Insulin therapy:
1. Basal – Bolus(3 Injections):
o 2 bolus of short acting before breakfast and lunch +
o Mixture of short acting and Intermediate acting at evening meal.
2. Basal – Bolus(3 +1 Injections):
o 3 bolus of short acting before breakfast + lunch + evening meal +
o Intermediate acting before bedtime.
3. Basal – Bolus(3 +1 Injections):
o 3 bolus of Rapid acting before breakfast + lunch + evening meal +
o Long acting before bedtime.
4. Basal – Bolus(3 +1 Injections):
o Long acting before bedtime.
o Rapid acting before meal according to Carbohydrate Counting and Insulin Correction
• Basal bolus regimen:
• This is by far more physiological then previous Regimens.
• Basal and bolus insulins are given separately to mimic physiological secretion.
• Single dose of long acting is given as basal while Three doses of rapid acting insulin is given as bolus insulin.
• It is flexible as bolus insulin can be given just before meal and can be shifted according to need.
• Basal insulin is generally kept at 40% of total dose while 60% dose is divided into boluses.
Insulin regimens
60% of the
total daily
dose
Rapid -acting
insulin
(NovoRapid Pen)
divided up
between 3
pre-meal
boluses
40 % of
the total
daily dose
long-acting insulin
(Lantus® (insulin
glargine Pen) or
degludec
single evening
injection

16. Glycemic control:
• Dose adjustment:
• In basal bolus regimen, fating sugars are adjusted by changing basal insulin dose while post meal sugars are adjusted
by changing pre-meal insulin.
• Insulin sensitivity factor and insulin to carbohydrate ratio:
• Insulin to carbohydrate ratio represents the amount of carbohydrate (in grams) covered by 1 unit of insulin.
• This is estimated by dividing 500 by the total daily dose of insulin.
• Insulin sensitivity provides information about the amount of blood glucose (in mg/dL) lowered by 1 unit of insulin.
.

17. Glycaemic targets in T1D
CVD, cardiovascular disease; *Reassess glycaemic targets over time
+More or less stringent glycemic goals may be appropriate for individual patients
#Postprandial glucose may be targeted if A1C goals are not met despite reaching preprandial glucose goals
1. ADA. Diabetes Care 2019; 42(suppl 1):S61–S70
<7% (53 mmol/mol)
is recommended for all
young people with diabetes
<6.5% (48mmol/mol) for selected
individuals, eg: is recommended
during the remission phase or early
stage diabetes “honeymoon.
<8% (64mmol/mol) for patients
with: history of severe
hypoglycaemia, limited life
expectancy, advanced
complications, extensive
comorbidities, or long-standing
diabetes
HbA1c targets
Glycemic targets for young people with diabetes are needed as optimizing
glycemia reduces short and long-term complications

18. • Fear of needles and painful injections is always a problem in children
• Adherence
• Forgetting or omitting doses of insulin may lead to a deterioration of metabolic control and increasing
levels of HbA1C
• The pen is more convenient than syringes and can deliver very small dose accurately.
• Insulin pen devices improve compliance
• Accuracy
• Insulin pens were more accurate than syringes at delivering insulin A half unit pen is also available.
• Different size needles are also available from 4mm to 8mm.
• 4 mm and 6 mm is useful in lean children as chances of deep intramuscular injection are very less.
Delivery of insulin (pen device): overcoming
barriers
Pen contains
300 total units
Delivers up to 80 units
in a single injection
Dial exact dose
(1-unit dose adjustments)
100 U/mL
formulation
80-unit
maximum-dose pen
No push-button extension
Less pressure for injection
U100

19. • Hypoglycaemia is the most common acute complication of T1D1
• Risk of recurrent and severe hypoglycaemia causes significant anxiety and emotional
morbidity for patients1
• Hypoglycaemia is a major limiting factor in achieving optimal glycaemic control1
Hypoglycaemia in children
T1D, type 1 diabetes
1. Ly et al. Pediatr Diabetes 2014:15(Suppl. 20):180–92; 2. Davis et al. Diabetes Care 1997;20:22–5
Risk factors:
• Younger age, <6 years
• Hypoglycaemia unawareness
• Previous severe hypoglycaemia
• Longer duration of diabetes

20. Case 1: How to Initiate a Patient on Degludec & NOVORAPID
Name: Dilnaz HA1C: 13.0%
Age: 13 years
Body weight: 48.6 kg
Previous dose: None
Case history
Dilnaz has a new diagnosis of diabetes. She has hyperglycemia 326 mg/dL, and ketosis, but is not acidotic. She does
lots of sport. Dilnaz is in puberty, and had menarche 2 months ago.
Guidance: Dilnaz was initiated on degludec 14 units (0.29 units/kg) daily with insulin aspart as bolus insulin, aiming for
fasting plasma glucose of 90–130 mg/dL.
Now she is stable on follow up
Insulin requirements: dose calculation;
Start with 0.5 IU/kg/day non DKA
Post DKA 2-2.5 IU/kg/day
honeymoon phase 0.2-0.5 IU/kg/day or single long acting insulin
Pre-pubertal 0.7-1.0 IU/kg/day.
During puberty 1-1.5 IU/kg/day and even up to 2
After completion of puberty 0.8-1 IU/kg/day
Basal insulin is generally kept at 40% of total dose while 60% dose is divided into
boluses.

21. • The insulin requirement following diagnosis is highly variable depending on the age of child, BMI,
puberty status, mode of presentation (e.g., DKA versus no DKA), etc.
• For example, a thin, young child without DKA and HA1C of 7% may need a total daily insulin dose of at
most 0.25 units/kg per day, whereas an overweight adolescent who presents with DKA may need at least
1 unit/kg per day.
• In practice, degludec should be initiated at 30–50% of the predicted total daily dose (basal + bolus). Once a
dose is selected, it is important to dose degludec every 24 h for the first 2–3 days, without unduly varying
the timing until steady state is achieved.
Guidance

22. Case 2: How to Switch a Patient to Degludec from Other Basal Insulins
Name: Alin A1C: 8.0%
Age: 7 years
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
• Alin was diagnosed 6 months ago and started on a basal–bolus injection regimen with glargine U100.
• Alin 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 Alin’s mother, as she is the only person Alin will allow to give the
injection. Alin is apprehensive, but okay with her bolus injections.

23. Guidance
• The more neutral pH of degludec (degludec; pH 7.6) compared with that of glargine U100 (pH 4.0) 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 Alin’s first
dose with degludec 7 units/day.
• In addition, Alin’s previous bolus insulin dose was also reduced Following the switch, Alins fasting BG testing was used to inform
further adjustments in degludec dose.
• 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.
• Patients may be switched to degludec from another basal insulin for a variety of reasons , and initially a dose reduction of up to
20% of their daily basal insulin dose is advised.

24. Case 3: How to Titrate Degludec in Patients Initiated or Switched from Another Insulin
Name: Deyar A1C: 8.5% (69.4 mmol/mol)
Age: 4 years
Body weight: 14 kg
Previous on: Biphasic lispro and neutral protamine Hagedorn (NPH) insulin (25:75) given as
7 U (9 am) and 4 U (9 pm)
Case history
• Deyar 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, 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.
• Glucose Monitoring 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

25. • Deyar 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)
• Over the course of 2 weeks, Deyar 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
Guidance

26. Case 4: How to Maintain Treatment with Degludec in Patients Following an Episode of DKA
Name: Mateen A1C: 11.3% (100 mmol/mol)
Age: 10 years
Body weight: 28 kg
Current MDIs: NPH insulin with insulin aspart
• Case history
• Mateen was been raised under difficult social circumstances and had a troubled relationship
with his family.
• 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.

27. • 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 degludec, degludec resulted in
significantly lower rates of hyperglycemia with ketosis.
8/14/2023
27
Guidance

28. Common reasons for switching to degludec
• 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
• Reduce pain & used when Allergic reactions to other basal analogs
Pen contains
300 total units
Delivers up to 80 units
in a single injection
Dial exact dose
(1-unit dose adjustments)
100 U/mL
formulation
80-unit
maximum-dose pen
No push-button extension
Less pressure for injection
U100

29. Insulin degludec OD + insulin aspart provides effective long-
term improvements in glycaemic control when compared
with insulin glargine + insulin aspart in children with T1D
Insulin degludec in combination with bolus insulin aspart is
safe and effective in children and adolescents with T1D
starting from 1 year age and above
Conclusion
Combination of insulin degludec and bolus insulin aspart in children
OD, once daily; T1D, type 1 diabetes
Thalange et al. Pediatr Diabetes 2015;16:164–76

30. Thank You