1. Insulin therapy in Type 2 Diabetes

2. Agenda: Initiation of Insulin therapy
Evidence for Basal Insulin Selection
Intensification of Insulin therapy
Introduction of Insulin Glargine
Introduction of Insulin Glulisine

3. Agenda: Initiation of Insulin therapy
Evidence for Basal Insulin Selection
Intensification of Insulin therapy
Introduction of Insulin Glargine
Introduction of Insulin Glulisine

4. Relative contribution (%)
In T2DM contribution of fasting hyperglycaemia to overall glycaemia increases with worsening diabetes
290 patients with T2DM treated with diet or OHAs
Baseline (normal) PG defined as 6.1 mmol/l (110 mg/dl) ― threshold defined by ADA as the upper limit of normal PG at fasting or preprandial times
100
70%
Relative contribution (%) 50
This study analysed the diurnal glycaemic profiles of 290 patients with T2DM investigated at different levels of HbA1c. The patients were treated with diet or oral hypoglycaemic agents (not acarbose).
Plasma glucose (PG) concentrations were determined at fasting and during postprandial and post absorptive periods.
The areas under the curve above fasting PG concentrations and >6.1 mmol/l (110 mg/dl) were calculated for further evaluation of the relative contributions of postprandial and fasting PG increments to the overall diurnal hyperglycaemia. The value of 6.1 mmol/l (110 mg/dl) was chosen because this threshold has been defined as the upper limit of normal PG at fasting or preprandial times by the American Diabetes Association. The data were compared over quintiles of HbA1c.
The main contributor to overall hyperglycaemia in patients with poorly controlled T2DM was found to be fasting hyperglycaemia. Fasting hyperglycaemia was the dominant factor in patients who were furthest from HbA1c target.
Monnier L, et al. Diabetes Care 2003;26:881―5
Fasting
30%
<7.3
7.3―8.4
8.5―9.2
9.3―10.2
>10.2
HbA1c (%) quintiles
ADA=American Diabetes Association; OHA=oral hypoglycaemic agent; PG=plasma glucose. Adapted from Monnier L, et al. Diabetes Care 2003;26:881―5.

5. Treating fasting hyperglycaemia lowers the entire 24-hour plasma glucose profile
400
Type 2
diabetes 20
300 15
Plasma Glucose (mg/dL)
200
Hyperglycaemia due to increase in fasting glucose
Plasma Glucose (mmol/L) 10
100 5
Normal
Meal
Meal
Meal 6 10 14 18 22 2 6
Time of Day (h)
Comparison of 24-hour glucose levels in control subjects vs patients with diabetes (p<0.001). Adapted from Hirsch I, et al. Clin Diabetes 2005;23:78–86.

6. To Initiate Insulin With A Basal Insulin Regimen
In All Guidelines, It Is Recommended
To Initiate Insulin With A Basal Insulin Regimen
Start with basal insulin
Basal-Plus or Basal-Bolus, Premix insulins are not for initiation,
only for intensification (if needed) in a 2nd step
Diabetes Care 2015;38:140–149

7. The Ideal Basal Insulin
1 injection daily covers 24 hours
No peaks
Low incidence of hypoglycaemia
Good glycaemic control
Less weight gain
Safe
Predictable
Easy handling
Injection at different sites
Injection at different times
No mixing necessary/clear solution
High treatment satisfaction and acceptance
The ideal long-acting insulin should safely provide a 24-hour, peakless profile, thereby mimicking the normal physiologic basal insulin profile
The ideal long-acting insulin should help patients achieve target A1C levels with:
Low incidence of hypoglycaemia
Predictable
Simple, once-daily injection
High treatment satisfaction and acceptance

8. Basal Insulin Options Glargine and Detemir: Lasts up to 24 hours
>50% of detemir patients need BID injections to reach glycemic targets
Decreases risk of hypoglycemia (especially nocturnal)
Less weight gain
Less variability in effect
Neutral Protamine Hagedorn (NPH):
Lasts 10–16 hours
Peaks 8–10 hours
Less expensive
May partly cover meal (e.g., breakfast if taken in morning) but can result in later hypoglycemia (e.g., early afternoon)
Riddle et al. Diabetes Care. 26: ; 2003
Raskin et al Diabetes Care. 28: ; 2005

9. Agenda: Initiation of Insulin therapy
Evidence for Basal Insulin Selection
Intensification of Insulin therapy
Introduction of Insulin Glargine
Introduction of Insulin Glulisine

10. Glargine vs NPH Insulin
Title
Subtitle
Glargine vs NPH Insulin 6
NPH 5
Glargine 4
Glucose utilization rate (mg/kg/h) 3 2 1 10 20 30
Time (h) after SC injection
End of observation period
Lepore, et al. Diabetes. 1999;48(suppl 1):A97. 10

11. Insulin Glargine vs. NPH in Treat-to-Target Trial: HbA1c and Hypoglycemia
21% risk reduction p <0.02 16
9.0 14
NPH + OAD
8.5
Insulin glargine + OAD 12
8.0
Events per patient per year 10
42% risk reduction p <0.01
HbA1c (%) 8
7.5 6
7.0 4
This slide illustrates that in normal individuals, glucose excursions following meals are modest and kept within a very narrow range. Therefore, defense against hyperglycemia is very aggressive.
In patients with type 2 diabetes who have established fasting hyperglycemia, postprandial glycemic excursions are exaggerated.
The NPH in this study was given at bedtime, and the difference in hypoglycemia very well could be due to variable absorption
6.5 2 4 8 12 16 20 24
Overall
Nocturnal
Weeks
Hypoglycemia
Riddle et al. Diabetes Care 2003;26:

12. Summary Real-life studies with insulin glargine have shown:
Significantly lower risk of hypoglycemia vs NPH
Significantly greater reduction in HbA1c vs NPH and detemir
Significantly better persistency with treatment vs NPH and detemir
Sustained long-term glycemic control
Significantly reduced risk of MI vs NPH
These data confirm the importance of verifying RCTs in a real-life clinical setting.

13. To reach the high level of Lantus® efficacy, 55% of insulin detemir patients needed twice daily injections
n=275
n=268
p=ns
Rosenstock J, et al. Diabetologia 2008;51:408–16.
Rosenstock J, et al. Diabetologia ;51(3):
For internal use only

14. 77% higher insulin detemir dose was required to achieve the high level of Lantus® efficacy
0.44
0.78
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9 1
Mean daily dose (U/kg)
Lantus®
Insulin detemir QD or BID
+77%
IU/kg
U/kg
n=248
n=227
Rosenstock J, et al. Diabetologia ;51(3):

15. 3-fold increase in injection site reactions with insulin detemir
Overall safety: The only between-drug difference was more cutaneous adverse reactions with insulin detemir
3-fold increase in injection site reactions with insulin detemir
3-fold
increase
n=4
n=13
Allergic reactions and skin disorders were also more frequent in insulin detemir patients.
Rosenstock J, et al. Diabetologia ;51(3):

16. T2D Patients inadequately controlled with insulin Detemir benefit from switching to Glargine
Prospective multinational study in T2D Patients not controlled with insulin Detemir+OAD
Change in mean HbA1c in T2D Patients treated with glargine consisted of patients previously treated with Detemir once daily or twice daily
A.G Lievers et al. Diabetes Stoffw Herz 2013; 22:

17. T2D Patients inadequately controlled with insulin Detemir benefit from switching to Glargine
Prospective multinational study in T2D Patients not controlled with insulin Detemir+OAD
Change in mean FBG in T2D Patients treated with glargine consisted of patients previously treated with Detemir once daily or twice daily
A.G Lievers et al. Diabetes Stoffw Herz 2013; 22:

18. Patients with ≥1 hypoglycaemia event (%)
Hypoglycemia in The Last Month under Glargine
Patients with ≥1 hypoglycaemia event (%)
Incidence rate of hypoglycaemia reported during the last 4 weeks of previous insulin detemir treatment and for the last 4 weeks of insulin glargine treatment, respectively.
A.G Lievers et al. Diabetes Stoffw Herz 2013; 22:

19. Agenda: Initiation of Insulin therapy
Evidence for Basal Insulin Selection
Intensification of Insulin therapy
Introduction of Insulin Glargine
Introduction of Insulin Glulisine

20. Time To Intensify: Failing Basal Insulin How To Define It
1st step for everybody
Insulin titration on FPG
Fix fasting first
FPG at target
despite a well titrated basal insulin
HbA1c > 7.5 to 8%
Post-prandial glucose increments
from pre-prandial are not addressed on basal insulin.
A « PRANDIAL ISSUE »
may explain why HbA1c remains high despite a good titration

21. How To Intensify: Failing Basal Insulin Prandial Issue
1st step for everybody
Insulin titration on FPG
Fix fasting first
HbA1c remains above target
despite a good titration of basal insulin
The“prandial” issue
Intensification of insulin therapy usually consists of additional prandial injections:
at each meal (basal-bolus)
or at the main meal ( the “basal +” concept)

22. How to intensify: the guidelines
After basal insulin,
How to intensify: the guidelines
Updated 2015
HbA1c > target
The ADA/EASD position statement
endorsed the addition of 1 to 3 injections
of a rapid-acting insulin analog before meals.
As an alternative, the statement mentioned premixed insulins.

23. Agenda: Initiation of Insulin therapy
Evidence for Basal Insulin Selection
Intensification of Insulin therapy
Introduction of Insulin Glargine
Introduction of Insulin Glulisine

24. A Long-Acting Basal Insulin Analogue
Insulin Glargine
A Long-Acting Basal Insulin Analogue
Insulin glargine is an insulin analogue. It is a B31-B32-Di-Arg human insulin with further substitution of asparagine in position A21 by glycine.
These changes result in a shift of the electronic point from 5.4 in native insulin toward a pH of 4.0 in insulin glargine. As a result, insulin glargine precipitates at physiological pH in SC tissue after injection, which delays its absorption. G l y A s n -
A-Chain 1 5 2 3 r g
B-Chain
Extension
Substitution

25. Mechanism of Action Injection of an acidic solution (pH 4.0)
Clear Solution pH4
pH 7.4
Precipitation
Dissolution
Capillary Membrane
Insulin in Blood
Hexamers
Dimers
Monomers
10-3 M
10-5M
10-8 M
Injection of an acidic solution (pH 4.0)
Precipitation of insulin glargine in subcutaneous tissue (pH 7.4)
Slow dissolution of free insulin glargin hexamers from micro precipitates (stabilized aggregates)
Protracted action

26. PHARMACOKINETICS : Slow dissolution of the Glargine
hexamers at the injection site
results in a relatively constant
release with no pronounced
peak over a period of up to
24 hours.
Onset of action = 2 hours
Peak = flat
Duration = 24 hours

27. Figure 3. Approach to starting & adjusting insulin in T2DM
Start: 10U/day or U/Kg/day
Adjust: 10-15% or 2-4 U 0nce-twice weekly to reach FBG target.
For hypo: Determine & address cause; ↓dose by 4 units or 10-20%
Basal insulin alone is usually the optimal initial regimen, beginning at U/kg body weight, depending on the degree of hyperglycemia. It is usually prescribed in conjunction with 1-2 non-insulin agents, although insulin secretagogues (sulfonylureas, meglitinides) are typically stopped once more complex regimens beyond basal insulin are utilized.
In patients still not at target after basal insulin has been adequately titrated, and the patient is willing to take >1 injections, there are several options. First, consider GLP-1 receptor agonists (see Fig. 2). The combination of basal insulin + GLP-1RA is becoming well established after several studies confirmed its efficacy on par with more complex multi-dose insulin regimens, but with less hypoglycemia and with weight loss instead of weight gain. If such an approach is not possible or has been tried and proven unsuccessful, there are 3 possible advanced insulin regimens:
Adding 1 injection of a rapid acting insulin analogue before the largest meal,
Adding 2-3 injections of a rapid acting insulin analogue before 2-3 meals, or
Using premixed insulin BID
Each approach has its advantages and disadvantages. The figure describes the number of injections required at each stage, together with the relative complexity and flexibility.
Once a strategy is initiated, titration of the insulin dose is important, with dose adjustments made based on the prevailing BG levels as reported by the patient.
Comprehensive education regarding self-monitoring of BG, diet, exercise, and the avoidance of, and response to, hypoglycemia are critical in any patient on insulin therapy.
Diabetes Care 2015;38:140;
Diabetologia 2015; /s

28. Dosing

29. Titration

30. Insulin Glargine Injection in Special Populations
Desired blood glucose levels, as well as the doses and timing of antidiabetic medications, must be determined individually
Pediatric safe for 2 years old type 1 patients
Elderly Initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemic reaction
Obese patients No differences in safety and efficacy between insulin glargine and NPH human insulin
Renal or hepatic Careful glucose monitoring and dose impairment adjustments of insulins may be necessary
Safety and effectiveness of Lantus® (insulin glargine) have been established in patients with type 1 diabetes aged 6 to 15 years. Administration to paediatric patients aged <6 years has not been studied.1,2 Based on the results of a study in paediatric patients, the dose recommendations for changeover to Lantus are the same as described for adults1
In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycaemic reactions1
Subgroup analyses based on patients with a body mass index up to 49.6 kg/m2 did not show any differences in safety and efficacy between Lantus and NPH human insulin1
Although studies have not been performed in patients with diabetes and renal or hepatic impairment, Lantus requirements may be diminished because of a reduced capacity for gluconeogenesis and reduced insulin metabolism, similar to observations found with other insulins.1,2 Some studies with human insulin have shown increased circulating levels of insulin in patients with renal or liver failure. Careful glucose monitoring and dose adjustments of insulin, including Lantus, may be necessary in patients with renal or hepatic dysfunction1
Insulin requirements may be altered during intercurrent conditions such as illness, emotional disturbances, or stress. Dose adjustments of Lantus and other insulins or oral hypoglycaemic agents may be required if the patient’s weight or lifestyle changes or other circumstances arise that increase susceptibility to hypoglycaemia or hyperglycaemia1,2
Lantus® (insulin glargine) EMEA Summary of Product Characteristics
1. Lantus® (insulin glargine) US Prescribing Information. Bridgewater, NJ: Aventis Pharmaceuticals; 2002.
2. Lantus® (insulin glargine) EMEA Summary of Product Characteristics. Bridgewater, NJ: Aventis Pharmaceuticals; 2002.

31. Agenda: Initiation of Insulin therapy
Evidence for Basal Insulin Selection
Intensification of Insulin therapy
Introduction of Insulin Glargine
Introduction of Insulin Glulisine

32. Molecular structure of insulin Glulisine (Apidra®)
Becker RH. Diabetes Technol Ther 2007;9:109–21.
A chain
Human 3BLys-29BGlu-insulin
B chain
Gly 1 5 10 15 20 S
Gln
Ile
Cys
Phe
His
Leu 25 30
Pro
Lys
Thr
Ala
Glu
= substitution
Asn x
--- --
stabilising agent
Polysorbate 20
complexing agent
Zinc
Function
Components
GLU
ASP
Qualitative composition
buffering agent
Trometamol
LIS
RHI
Zinc-free formulation
Insulin glulisine is a modified version of endogenous human insulin produced by recombinant DNA technology using Escherichia coli.
Insulin glulisine differs from endogenous human insulin by two amino acid substitutions on the B chain:
asparagine in position B3 replaced with lysine
lysine at position B29 replaced with glutamic acid.
The two amino acid substitutions discourage self-association (no formation of hexamers in solution) and enhance the solubility of insulin glulisine at physiologic pH, which allows rapid absorption of monomers from the tissue after subcutaneous injection.
Reference
Becker RH. Diabetes Technol Ther 2007;9:109–21.

33. RA-insulins uptake from subcutaneous tissue
Zn2+
RA-insulin analogues:
LIS
ASP T T T T T T T T T
Phenol
Phenolic residues ( ) , Zn2+ atoms ( )
Phenolic residues ( ) Zn2+ atoms ( )
Structures
R-format
Hexamers
T-format
Dimer
Monomer
RA-insulin analogue:
GLU
No added zinc
Polysorbate 20 (Tween 20)
Capillary
Brange J, et al. Diabetes Care 1990:13;923–54.
Becker RH. Diabetes Technol Ther 2007;9:109–21.

36. Apidra® offers convenience tailored to fit a patient’s lifestyle.
Apidra® is an ideal partner for Lantus
Apidra® offers convenience tailored to fit a patient’s lifestyle.

37. Take home massage:
Insulin may be initiated after failure of mono or combination non-insulin therapies, when symptomatic, glucose toxicity, or at the request of the individual with diabetes.
Basal Insulin alone, is the best option for Insulin initiation.
The Basal Plus strategy is a flexible, ‘patient friendly’, stepwise approach to managing progressive diabetes in clinical practice.

38. Apidra® is an ideal partner for Lantus
Take home massage:
Lantus: The once daily peakless basal Insulin, easy to initiate and titrate.
Apidra® offers convenience tailored to fit a patient’s lifestyle.
Apidra® is an ideal partner for Lantus

39. +
Thank you for your attention!