Insulin types update ; Diabetes Mellitus Update ; Endocrinology and Diabetes Degludec ; Ryzodeg ;Basal Insulin ;PEG-Lispro Prescribing insulin safely

1. Insulin Therapy
What is New ?
Dr. Mohammad Daoud
Consultant Endocrinologist-ABIM Certified
KAMC/ NGHA - Jeddah –Saudi Arabia

3. Question?
Is Glycemic Control Better
With New Novel Insulins in
comparison to older ones?

4. Objectives
Introduction
Insulin :Choices and Profiles
Guidelines
Sequential addition/ titration of Insulin

11. Over time, glycaemic control deteriorates
*Diet initially then sulphonylureas, insulin and/or metformin if FPG>15 mmol/L
†ADA clinical practice recommendations. UKPDS 34, n=1704
UKPDS 34. Lancet 1998:352:854–65; Kahn et al. (ADOPT). N Engl J Med 2006;355:2427–43
6.2% – upper limit of normal range
Conventional*
Glibenclamide
Metformin
Insulin
UKPDSMedianHbA1c(%)
6.0
7.0
8.0
9.0
Years from randomisation
2 4 6 8 100
7.5
8.5
6.5
Recommended
treatment
target <7.0%†
ADOPT Glibenclamide
Metformin
Rosiglitazone
8.0
6.0
7.5
7.0
6.5
Time (years)
0 2 3 4 51

12. ADA-2015

13. Correlation of A1C with
estimated Average Glucose
A1C (%) Mean plasma glucose mg/dl
6 ̴ 120
7 ̴ 150
8 ̴ 180
9 ̴ 210
10 ̴ 240
11 ̴ 270
12 ̴ 300
ADA. V. Diabetes Care. Diabetes Care 2014;37(suppl 1):S23; Table 8

14. GlycemicControl
Recommendations
EMPOWER the Patient
Should be able to
Use data
Adjust Therapy
Avoid / Manage hypoglycemia
(E)
ADA. V. Diabetes Care. Diabetes Care 2014;37(suppl 1):S21–S22

19. B DL HS
InsulinEffect
Bolus Insulin
Basal Insulin
Endogenous Insulin
B, breakfast; L, lunch; D, dinner; HS, bedtime.
Adapted from:
1. Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.
2. Bolli GB et al. Diabetologia. 1999;42:1151-1167.
Normal Insulin Secretion
Time of Administration

20. Subcutaneous Insulin Administration

22. Basal Insulin: Pharmacokinetics
Suppress hepatic glucose production
Maintain near normo-glycemia in the fasting state
*

23. Basal Insulin: Pharmacokinetics
U-500-R 30-45 min 2-4 hrs 8-24
Glargine -300 1-2 hrs ------ 24 hrs
Degludec (IDeg) 30-90 minutes ------ >42 hrs
PEG-Lispro t ½ 2-3 days ------ > 36 hrs
Suppress hepatic glucose production
Maintain near normo-glycemia in the fasting state

24. The New –Old
U-500 regular insulin
-U-500 is a concentrated form of regular insulin
-Can be used to control hyperglycemia in severely
insulin resistant patients usually requiring > 200 u
daily
-U-500 insulin has been used successfully in patients
with
1. Obesity
2. Immune-mediated insulin resistance,
3. Genetic abnormalities of the insulin receptor

26. U500 R Insulin
Volume
(ml of Insulin)
Actual units of
U500 Insulin
0.1 ml 50 units
0.11 ml 55 units
0.12 ml 60 units

27. Toujeo SoloStar:
300 units/mL (1.5 mL)
Cannot be mixed with rapid-acting insulins.

32. Insulin Degludec (Tresiba)
100 u nits/ml and 200 units/ml

33. Insulin Degludec (Tresiba)
Long-acting insulin analog indicated to improve glycemic
control in adults with type 1 and 2 diabetes mellitus .
Almost human ; B-chainetion of last amino
Soluble multi-hexamer …slowly ..to monomers
For most patients, changing the basal insulin to Tresiba
can be done unit-to-unit based on the previous basal
insulin dose .

34. Basal Insulin: Pharmacokinetics
Degludec (Ideg) t ½ 25 hrs Duration >42 hrs
(100 or 200 unit/ml)
Insulin Degludec (Ideg):
Give as short as (8–12 h) and as long as (36–40 h) intervals between doses

Suppress hepatic glucose production
Maintain near normo-glycemia in the fasting state

35. http://www.thelancet.com/journals/landia/article/PIIS2213-8587(13)70013-5/abstract
Degludec OD vs 3TW

37. PEG: Ploy Ethylene Glycol

41. PEG-Lispro Vs Glargine
Better HbA1c and FPG reduction
Less Nocturnal Hypoglycemia and Glycemia variability
Less body weight / Weight loss
Higher liver fat content ,TAG and Transaminases levels
PEG: Ploy Ethylene Glycol

42. IDeg , Detemir
Glargine ,PEG-Lispro

45. SA- GLA-11-11-04
Less hypoglycemia and less weight gain with once daily Insulin
Glargine versus three times daily premix Lispro 25/75 & 50/50
• The cross-over ,Sixty insulin-naïve patients T2DM receiving at least two OHAs were
randomised to receive either once-daily insulin glargine + OAD, or premixed insulin lispro
25/75 before breakfast and lunch and 50/50 before dinner for 4 months
• Despite being sub-optimally titrated, Insulin Glargine was associated with
fewer hypoglycaemia events and less weight gain, compared with premix
Malone J, et al. Clin Ther 2004;26(12):2034–2044
The cross-over IONW trial was conducted in the USA. Sixty insulin-naïve patients with T2DM receiving at least two OHAs were randomised to receive either
once-daily insulin glargine, or premixed insulin lispro 25/75 before breakfast and lunch and 50/50 before dinner, for 4 months. Patients continued to receive
their existing OHAs
TID

46. Nutritional Insulin:
Meal related=Prandial
Control postprandial hyperglycemia
Inhaled Insulin Rapid absorption / elimination
(Afrezza)

48. Less Hypoglycemia
Better matches
Fast onset and Short duration

50. RAARAA RAA
RAA=

51. RAA RAA RAA
RAA=

52. Inhaled insulin
Afrezza
• Afrezza (insulin human) inhalation powder is a
rapid-acting Techno-sphere insulin (TI)
administered via a breath-powered oral inhaler
to patients with diabetes requiring
prandial insulin.
• Pre-meal time insulin for Type 1 and 2 diabetics.
• Type 1 diabetics must use in combination with
long-acting agent.
• FDA approved June 2014.

55. Afrezza
Limitations
•Contraindicated In patients who have chronic lung
disease .
•Smoker / Stopped less than 6 months
? Not recommended
•Caution in patients at risk for lung cancer
•PFT /Spirometry : Needed for all at baseline, after
the first 6 months of therapy and yearly thereafter
even in absence of pulmonary symptoms.

56. Afrezza DOSE
• Insulin-naive patients: ( 4 units at each meal)
• Patients previously on SubQ mealtime (prandial) insulin

57. Novo-Mix -30/70:
Aspart /Aspart protamine
Ryzodeg 70/30 ;Degludec /Aspart
Humilin 70/30 or Mixtard
70% NPH , 30 % RI
Lispro-Mix 25/75 , 50/50
Lispro /Lispro protamine
Basal Insulin+ GLP-1 RA:
Ideg-Lira
Lixi-Lan
Mixed Insulin

59. Mixed Insulin - ADA Guidelines
Not recommended for Type 1 DM patients
Type 2 DM patient: If well controlled …continue
Don’t mix Glargine / Detemir with other insulin : Different
PH
NPH + RI mixing …Use immediately
RAI (ex: Lispro / Aspart / Glulisine) + NPH ….
use within 15 minutes

60. Post-prandial
hyperglycaemia
Post-prandial
hyperglycaemia
contributes HbA1c ~1%
B=breakfast; L=lunch; D=dinner.
Adapted from Riddle MC. Diabetes Care. 1990;13:676-686.
Plasmaglucose(mg/dL)
300
200
100
0
Time of day (h)
6 12 18 24 6
Uncontrolled Diabetes HbA1c 8.5%

B

L

D
Normal
HbA1c ~5%
Basal Hyperglycaemia Contributes More to Increased
HbA1c Levels Than Does Post-prandial Hyperglycaemia
Basal hyperglycaemia
contributes ~2%
Fasting
hyperglycaemia

62. SA- GLA-11-11-04
62
In T2DM ‘Fix fasting first’ –will lower the entire plasma
glucose through 24 hr
Adapted from Polonsky K. N Engl J Med 1988;318:1231–9 and Hirsch I, et al. Clin Diabetes 2005;23:78–86.
Theoretical simulation of diurnal blood glucose profile
Time of day (hours)
400
300
200
100
0
06:00 06:0010:00 14:00 18:00 22:00 02:00
Plasmaglucose(mg/dL)
Normal
Meal Meal Meal
20
15
10
5
0
Plasmaglucose(mmol/L)
Hyperglycaemia due to an increase in fasting glucose
T2DM

64. ADA 2015

65. SA- GLA-11-11-04
65
When basal insulin is not enough
• Step 1: Think first of titrating the basal insulin dose till
reaching FBG target (Often under-dosage)
• Step 2: Shift to Basal Plus or Basal-bolus (MDI) regimen :
• Number of daily injections up to 4 (1+3)
• Inconvenience
• Risk of hypoglycemia & Weight gain
Add prandial insulin dose (s) as per guidelines
Sequential addition /Titration

66. Basal +
ADA 2015

68. Mixed Insulins
ADA 2015

70. Ryzodeg 70/30
Degludec/Aspart
• It is available as a solution for injection in a cartridge (100 units/ml)
and in a prefilled pen (100 units/ml)
• It is not known if RYZODEG 70/30 is safe and effective in children
under 18 years of age.

71. Ryzodeg 70/30
Degludec/Aspart
• Can be used once or twice daily with any main meal(s)
• Administer a rapid- or a short-acting insulin at other meals
if needed.
• Adjust the RYZODEG 70/30 dose according to blood glucose
measurements before breakfast (fasting).
• The recommended time between dose increases is 3 to 4
days.

72. Shifting to Ryzodeg
From Once /Twice Daily Basal Insulin alone
Or MDI Regimen
From Once Or Twice Daily Premix Or Self-mix Insulin Alone
Start RYZODEG 70/30 at the same unit dose and injection schedule.
Monitor blood glucose after starting therapy due to the rapid-acting insulin
component.
Continue the short- or rapid-acting insulin at the same dose for meals NOT
covered by RYZODEG 70/30; ex Type 1DM
If a dose of RYZODEG is missed, take the next dose as scheduled on that day
;then resume the usual dosing schedule.
Patients should not take an extra dose to make up for a missed dose

73. To Conclude…

75. Summary(continue)
Basal Insulin alone …Break the Ice
0.1-0.3 u /kg or fixed 10 u and adjust
Early on , Don’t switch ….Add
(esp. insulin secretagogues; SU /Glinides)
Metformin: Keep unless CI
( Lower insulin doses and less weight gain)
TZDs …decrease or stop
(Less risk of fluid retention /heart failure)

76. Summary(continue)
Basal –Bolus Insulin
TDD = 0.3-0.5 u /kg
Basal Insulin 40-50 %
Meal related :50-60 %
Insulin secretagogues (SU /Glinides): No need
Keep Metformin / maybe TZDs

77. Summary(continue)
Premixed / Bi-Phasic
TDD = 0.3-0.5 u /kg
2/3 am and 1/3 pm OR
2-3 doses (premixed analogues)
10% adjustment role
Drawbacks:
Hypo /Weight gain/ Larger doses
Insulin secretagogues (SU /Glinides): No need
Keep Metformin / maybe TZDs

78. Start Low …and Go Slow …
monitor and adjust
Based on a “Trend”
Stepwise (sequential) initiation and titration =
low rate of severe hypoglycemia
Stepwise (sequential) addition of prandial insulin
(start with the main meal) to basal insulin is recommended by
both AACE/Ace and ADA/EASD
Basal + vs MDI
Avoid hypoglycemia
Patient teaching …Core part of the team