Types of Insulin Different Insulin Regimens? Insulin dose initiation & adjustment Limitations of current insulin's. New basal insulins

1. Insulin Therapy for Type 2
Diabetes: Update
Nasser Al-Juhani, MD,FRCP (U.K),ArBIM.SBIM,PHMD
Consultant of Endocrinology & Metabolic diseases
KSA,Jeddah

2. • Types of Insulin
• Different Insulin Regimens?
• Insulin dose initiation & adjustment
• Limitations of current insulin's.
• New basal insulins
Presentation Outline

3. • Insulin is life saving in type1 DM
• Insulin is the most effective glucose lowering agent
• Add insulin early in patients who do not meet A1C
targets in DM2
• Most patients with DM2 will eventually need insulin
Facts about INSULIN

4. 0
10
20
30
40
50
0 2 4 6 8 10 12 14 16 18 20 22 24
Physiological Insulin Secretion
24 Hour Profile
Seruminsulin(mU/L)
Time (Hours)
Basal insulin needs
Bolus insulin needs
Breakfast Lunch Evening Meal Sleep
•Basal insulin Suppresses glucose production between meals and overnight
•Bolus insulin (mealtime): Limits hyperglycemia after meals
Bergenstal R. Endocr Pract 2000;6:93-7.

5. TYPES OF SINSULIN
*Not all agents may be available in all countries; **pre-mixed insulins combine specific amounts of intermediate-acting and short-acting
insulin in one bottle or insulin pen
Basal insulin
Prandial/meal-time
insulins (rapid acting
analogues) Pre-mixed insulins**
NPH insulin Regular human insulin Biphasic human insulin 30/70
Insulin glargine (100
and 300 U/ml)
Insulin lispro Biphasic insulin aspart 30/70
Insulin detemir Insulin glulisine Biphasic insulin lispro 25/75 or
50/50
Insulin degludec Insulin aspart
Faster-acting insulin
aspart
IDegAsp 30/70 (degludec/aspart)
1. Home PD. Diabetes Obes Metab 2015;17:1011‒1020.

6. Which insulin regimen to start with?
What oral agents can be continued?

7. Different Insulin Regimens
Q2 :What insulin Regimen we use?
1-Basal insulin +OHA
2- Premixed Insulin BID/TID
3- Basal/Bolus Insulin
4- GLP-1 RA +basal insulin

8.  May be enough to control glucose if HbA1c < 9
 Can use if patient is reluctant to starting insulin
to overcome insulin fear
• Advantage:
• 1 injection a day (usually given at night)-
• Better compliance
• Simple titration
• Limited weight gain
• Drawback:
• Patients may require prandial insulin to reach
HbA1c targets
OPTION 1 :
Basal Insulin + Oral Agents

9.  Glargine 100 or 300, Detemir or Degludec ,NPH
 10 u (or 0.2 u/kg) usually at bedtime (10-12pm),
 Will need ~0.5 U/kg
 Can keep DPP-4i, SGLT-2i (but consider cost). May later
reduce SU
 Monitoring : daily FBG
 Increase basal dose 2 units every 3 days to keep FBG
target 80-130 mg/dl (<7.2 mmol) -Patient algorithm
5-18
OPTION 1 :
Basal Insulin + Oral Agents
ADA/EASD 2018

10. FPG at or below target; A1C target notmet
Nocturnal hypoglycemia
>0.5-0.7 U/kg/d on basal insulin
• 1. Inzucchi SE et al. Diabetes Care. 2012;35:1364–1379.
2. ADA. Practical Insulin: A Handbook for Prescribing Providers. 3rd ed. 2011:1–68.
When may it be time to stop titrating basal insulin
therapy in T2DM?
The need for prandial insulin becomes more likely as the
daily insulin dose exceeds 0.5 U/kg/d

11. Option 2:
Basal-Bolus Insulin Regimen

12. Option 2:
Basal/Bolus Insulin Regimen
Most closely simulate normal physiology
• Advantages:
• Like T1DM
• more flexibility in meal content
,timing
• lower A1C
• Less hypoglycemia
• Improved lipid profile
• Drawbacks:
• Requires motivated patient and
physician
• More frequent monitoring,
(minimum 3X -before meals/2hPP
and bedtime )
• more injections (may need to
inject 4 times)
• Training in carb counting and
insulin adjustment

13. Calculating Basal + Mealtime Insulin
Dose:
Calculate insulin dose
Weight in kg ______ x units/kg _____ = _____units long-acting (LA)
x units/kg _____ = _____units rapid-acting (RA)
Example: T2DM Patient (80 kg) with A1C of 9.6% on
metformin and insulin secretagogue
80 0.25 20
0.25 20
Total starting dose = 0.5 units/kg

14. Option 3:
Premixed analog or human Insulin
70/30,75/25,50/50

15. Role for pre-mixed insulin
Advantages
• Simple,Both basal and prandial components in a single insulin preparation
• Can cover insulin requirements through most of the day
Disadvantages
• Requires consistent meal and exercise pattern
• Cannot separately titrate individual insulin compononents1
•  risk for nocturnal hypoglycaemia2,3
• Often requires accepting higher HbA1c goal of <7.5% or ≤8% 2,3
Meals must be on time
1. Inzucchi SE et al. ADA, EASD Position Statement. Diabetes Care. 2012;35:1364–
1379.
2. Janka HU et al. Diabetes Care. 2005;28:254–259.
3. Fritsche A et al. Diab Obes Metab. 2010;12:115–123.

16. Premixed insulin TWICE daily
 Start dose 10 units bid before breakfast and dinner
 If on basal insulin ,divide current basal dose into 1/2 AM,
1/2 PM
 Continue metformin for weight control.D/C SU
 Monitoring X 2: fasting & predinner
 Titrate insulin by 2 units every 3 days to reach target
BG 80-130mg/dl.
ADA Position Statement: use of pre-mix insulin

17. Premixed insulin NOT preferred in:
• Type 1 DM
• Diabetes in pregnancy
• Many patients with chronic kidney disease
• Hospitalized patients
• Erratic life style/inconsistent meals

18. Which insulin regimen is the BEST?

19. Holman RR et al. N Engl J Med 2009;361:1736–1747.
Outcome Initial
Biphasic
Initial
Prandial
Initial
Basal
Median HbA1c level achieved + + +
HbA1c targets achieved + ++ ++
Fewer hypoglycaemic episodes ++ + +++
Less weight gain + + ++
Exploring different ways of initiating insulin T2DM:
Treating-To-Target in T2DM (4-T Study): Efficacy
These findings provide evidence in people with Type 2 diabetes to support
starting insulin therapy with a once-a-day basal insulin, and then adding a
mealtime insulin if glycaemic targets are not met

20. Exploring different ways of initiating insulin T2DM:
(4-T Study): Summary
• 70 % of patients added a second insulin
• Patients commencing therapy with basal insulin had fewer
hypoglycaemic episodes and less weight gain
• Those commencing therapy with a basal or prandial insulin achieved
glycaemic targets more often than patients commencing with a
biphasic insulin
Holman RR et al. N Engl J Med 2009;361:1736–1747.

21. Premix vs. basal bolus??
CHOICE

22. Factor Premix Regimen Basal Bolus Regimen
Injection frequency Prefers fewer injections
No problem with more
injections
SMBG Unwilling to self monitor Willing to self monitor
Daily routine
Fixed
2 meals or evening main meal
Variable
High variability in eating habits
Ability to follow regimen
Limited cognitive function
(Need assistance e.g elderly)
Motivated ,compliant with good
cognitive function e.g young
Support-education and
emotional
Essential Extremely essential
Adapted from: Liebl, et al. Int J Clin Pract, 2009;63(Suppl 164):1-5.
IT’S ALL ABOUT PATENT’S LIFE STYLE
Choice of insulin intensification regimen
Premix vs. basal bolus

23. Option 4:
GLP-1 receptor agonists + basal insulin

24. Combination :GLP-1RA+ Basal Insulin
compared to basal insulin only
Meta-analysis

25. GLP-1 RA in Combination With Basal insulin
• Exenatide BID, lixisenatide, liraglutide, albiglutide, Dulaglutide are indicated to use
with insulin
• Fixed-dose combinations: FDA approved 11/2016
• Insulin glargine and lixisenatide(Soliqua®)
• Insulin degludec and liraglutide (Xultophy®)
Moghisi ES.J Am Osteopath Assoc,2014,114(5supp2):S22-S29

26. Limitations of current
insulin's.

27. What is about insulin therapy in T2D.M?
•Side Effects
- Hypoglycemia
- weight gain
Hypoglycemia not a barrier to achieve glycemic targets

28. Classification of severity:
Non-severe versus severe symptomatic:
• Non-severe: Patient has symptoms but can
self-treat and cognitive function is mildly
impaired
• Severe: Patient has impaired cognitive
function sufficient to require external help
to recover (Level 3)
Reclassification of hypoglycaemia1–3
1. Seaquist ER et al. Diabetes Care 2013;36:1384‒1395.
2. International Hypoglycaemia Study Group. Diabetes Care 2017;40:155‒157.
3. Frier BM. Nat Rev Endocrinol 2014;10:711‒722.
Alert value for
hypoglycemia
Plasma glucose
3.9 mmol/L (< 70
mg/dl) and no
symptoms
Serious clinically
important
biochemical
hypoglycemia
Plasma glucose
3.1 mmol/l
(55 mg/dl)
Level 1 Level 2

29. I would treat my
patients more
aggressively if there
was no concern about
hypoglycemia
P<0.05
Specialists
Primary
care physicians
Proportion of healthcare professionals, %
T1DM, type 1 diabetes mellitus
Adapted from Peyrot M et al. Diabet Med. 2012;29:682-689
• These findings suggest that:
Insulins with less risk of hypoglycemia could be used more appropriately, potentially leading
to improvements in glycemic control and reductions in complications that result from
suboptimal glucose control
International internet GAPP survey involving 1,250 physicians who treat patients with T1DM and T2DM
29
The possibility of hypoglycemia limits
treatment intensification

30. Basal insulin analogues (Glargine, Detemir) : potential
advantages
•Compared with NPH insulin, basal insulin
analogues offer:
⎯ Decreased variation in blood glucose-lowering effect
⎯ Reduced rates of nocturnal hypoglycaemia
⎯ Once-daily dosing
Heise et al. Diabetes 2004;53:1614–20; Riddle et al. Diabetes Care 2003;26:3080-6; Hermansen et al. Diabetes Care 2006;29:1269-74; Philis-Tsimikas et al. Clin Ther
2006;28:1569–81

31. Time
Basal
Insulin
Hypoglycemia by Time of Day
HypoglycemiaEpisodes
(PG≤72mg/dL)
Riddle MC, et al. Diabetes Care. 2003;26:3080-3086.
*P <.05 (between treatment).
Insulin glargine
NPH insulin
0
50
100
150
200
250
300
350
20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00
B L D
20:00
*
**
*
*
*
*
Treat-to-Target Trial: Timing and Frequency of
Hypoglycemia

32. Limitations of current basal insulin analogues
• Variability
- Current basal insulin analogues are not truly peakless
• Duration of action
- ≤24 hours: leads to a lack of flexibility in dosing regimens
• Fear of hypoglycaemia
- Current insulin analogues do not have a completely flat
pharmacodynamic profile
Heise et al. Diabetes2004;53:1614–20

33. Hypoglycaemia zone
Target zone
Average
FPG
1 42 3 65 87 109 11 1412 13 1615 1817 2019 21 2422 23 2625 2827 3029
Day
54
90
36
18
14
4
10
8
12
6
16
2
18
0
19
8
21
6
72
FPG(mmol/L)
FPG(mg/dL)
3.0
5.0
2.0
1.0
8.0
4.0
6.0
7.0
9.0
10.
0
11.
0
12.
0
• FPG, fasting plasma glucose
• Adapted from Kovatchev et al. Diabetes Care 2006;29:2433–8
NEW GENERATION BASAL INSULIN
Glucose variability predict future risk of hypoglycemia

34. • FPG, fasting plasma glucose
• Adapted from Kovatchev et al. Diabetes Care 2006;29:2433–8
1 42 3 65 87 109 11 1412 13 1615 1817 2019 21 2422 23 2625 2827 3029
Day
Average
FPG
54
90
36
18
14
4
10
8
12
6
16
2
18
0
19
8
21
6
72
FPG(mmol/L)
FPG(mg/dL)
Hypoglycaemia zone
Target zone
3.0
5.0
2.0
1.0
8.0
4.0
6.0
7.0
9.0
10.
0
11.
0
12.
0
NEW GENERATION BASAL INSULIN
Glucose variability predict future risk of hypoglycemia
↓ within-day and within-subject variability with
glargine U-300 & Degludec basal insulins

35. 2ND Generation New Basal Insulins
The challenge in reducing nocturnal hypoglycaemia

36. Basal Insulin Glargine U-300
(Toujeo®
2015

37. insulin glargine U-300 (Toujeo®)
• Insulin glargine (300 units/mL)
• Less volume administered
• Forms smaller depot when injected
• Smaller depot alters kinetics
• prolongs duration: 30+ hour duration of
action
Reduction of volume by 2/3
Gla-100 Gla-300
Smaller surface area,1/2 less
Gla-100
Gla-300
• Gla-300 has the same molecular structure, mode of protraction
(forming precipitates) and metabolism (main circulating moiety
is M1) as Gla-100

38. Toujeo® is associated with less glucose
fluctuation compared to Gla-1001
With its prolonged activity, Toujeo® shows a flatter glucose profile than Lantus® in the last 4 hours before the next regular dose1
T1DM: type 1 diabetes mellitus; CGM: continuous glucose monitoring; SE: standard error. Shaded area represents the 4 hours immediately before the mean injection time, pooled over participants.
1. Bergenstal R, et al. Diabetes care 2017; 40: 554-560.
The objective was to compare glucose control in participants with type 1 diabetes receiving insulin glargine 300 units/mL or glargine 100 units/mL in the morning or evening, in combination with mealtime insulin. 16-week, open-label, parallel-group, two-period crossover study, 59
adults with type 1 diabetes were randomized (1:1:1:1) to once-daily Gla-300 or Gla-100 given in the morning or evening (with crossover in the injection schedule). The primary efficacy end point was the mean percentage of time in the target glucose range as measured using CGM

39. Switching to Toujeo® results in significant less
risk of hypoglycemia
* Confirmed ≤ 70 mg/dL (≤ 3,9 mmol/L) or severe hypoglycemic events.
RR: relative risk; T2DM: type 2 diabetes mellitus.
Aim: To compare the efficacy and safety of insulin glargine 300 units/mL with glargine 100 units/mL in people with T2DM using basal insulin (‡42 units/day) plus OADs. a multicenter, open-label, two-arm study. Adults receiving basal insulin
plus OADs were randomized to Gla-300 or Gla-100 once daily for 6 months. The primary end point was change in HbA1c.

40. 1. Bergenstal RM et al. Diabetes care 2017. 40:554-560.
2. Adapted from Jeandidier N et al. Abstract at 50th Annual Meeting of the European Association for the Study of Diabetes 2014. Poster presentation, abstract 961.
3. Peyrot M et al. Diabetes Med 2012;29:682–689;
4. Toujeo® European Summary of Product Characteristics. December 2015.
Aim: To investigate the efficacy and safety of Gla-300 when there is greater variability in the timing of injections. Eligible participants completing 6 months of optimized treatment with Gla-300 in EDITION 1 (n = 109) and EDITION 2 (n =
89), having a mean hemoglobin A1c level of 7.3 %, were randomized (1:1) to groups advised to increase variability of between-injection intervals to 24 – up to 3 h or to maintain fixed 24-h intervals for 3 months. Changes of HbA1c level
and other efficacy and safety measures were assessed.
Toujeo®: Flexibility of six hours window (±3 hr) of administration
Toujeo® offers more constant glucose profile regardless time of injection; morning or evening1

41. Basal Insulin Degludec
Tresiba®
2015

42. insulin degludec (Tresiba®)
2015
• 42+ hour duration of action
• Available in 100 units/mL or 200 units/mL
– No PK difference between U-100 and U-200
• Versus detemir or glargine U-100 :
– Similar A1C reduction
– ↓ within-day and within-subject variability
– ↓ hypoglycemia and ↓nocturnal hypoglycemia

43. Half-life of IDeg is twice as long as that of IGlar U100
*IGlar U100 was undectable after 48 hours. Results from 66 patients with T1D
IDeg, insulin degludec; IGlar U100, insulin glargine U100; T1D, type 1 diabetes
Heise et al. Diabetes 2011;60(Suppl. 1):LB11; Heise et al. Diabetologia 2011;54(Suppl. 1):S425; Heise et al. Expert Opin Drug Metab Toxicol 2015;11:1193–201
*
IDeg 0.8 U/kg
IGlar U100 0.8 U/kg
IDeg IGlar U100
0.4 U/kg 0.6 U/kg 0.8 U/kg 0.4 U/kg 0.6 U/kg 0.8 U/kg
Half-life (hours) 25.9 27.0 23.6 11.5 12.9 11.9
Mean half-life 25.4 12.1

44. Insulin degludec flexible dosing
Flex study concept: forcing flexible dosing
morning
Mon Tue Wed Thu Fri Sat Sun
morning morning
evening evening evening evening40h 40h
8h
24h
8h
40h
Meneghini et al. Diabetes Care 2013;36:858–64; Mathieu et al. J Clin Endocrinol Metab 2013;98:1154–62
Insulin glargine was administered according to the label: “Administered once
daily at any time but at the same time each day”

45. Ideal andidates for
Low Volume Insulin
Condition May Consider
 Nocturnal hypoglycemia
 Require more flexibility in timing of
dosing
 High basal insulin needs
(> 80 units per injection)
Glargine U‐300
Degludec U‐100,
U‐200

46. Head to head RCT
Gla-300 VS Degludec
Conflicting results
• BRIGHT
• Showed that Gla-300 provides similar glycemic control to IDeg-100, with less or
comparable hypoglycemia, in previously inadequately controlled, insulin-naïve adults
with T2DM.
Alicy Y.Y eta al Diabetes 2018 Jul; 67(Supplement 1)
• CONCLUDE:
• A trial comparing the efficacy and safety of insulin degludec U-200 and insulin
glargine 300 units/mL in subjects with type 2 diabetes mellitus inadequately treated
with basal insulin and oral antidiabetic drugs.
• Hypo may be less with degludec (issue with glucometers used)
• inconclusive on hypoglycemia risk for degludec vs. glargine
Pieber TR, et al. ,Diabetologia (https://doi.org/10.1007/s00125-019-05080-9)

47. Conclusions
Insulin Treatment in Type 2 Diabetes
• Basal treatment NPH or (glargine100 or 300) , detemir, degludec
Start 10 U and titrate
• Bolus treatment premeal (Lispro/glulisine/aspart)
Start at 4 U premeal and titrate;
• Premixed therapy
• Start at 10 U BID and titrate
• Basal bolus therapy
• Start at 0.5 U/kg, 40-50% basal, 20% bolus each meal