1. Comparison of Basal insulins, Initiation and titration of Lantus

2. How is insulin normally secreted ?
Basal
Serves to balance the rate
of hepatic glucose production
and peripheral uptake during
overnight and prolonged
periods between meals.
Bolus
Serves to control postprandial
hyperglycemia in response to
food intake.
Breakfast
Lunch
Dinner
Bolus
Basal
Time of day

3. What is basal-bolus therapy?
A combination of long- and short-acting insulins (injected separately) to mimic physiological insulin secretion and provide glycaemic control
Considered to be an intensive insulin regimen: 1 basal + a bolus with every meal
Allows for precise insulin dose adjustments (and independent control of FBG and PPBG levels) to achieve glycaemic targets with low risk of hypoglycaemia

4. Rationale for basal-bolus therapy
Basal-bolus should be the regimen of choice for maintaining overall glycaemic control1
An ideal basal insulin:
A peakless profile, prolonged duration of action and flexibility in dosing
An ideal bolus insulin (a bolus with every meal):
Rapid onset and short duration of action
Limits post-meal hyperglycaemia
Prevents post-prandial hypoglycaemia
The ideal insulin replacement therapy should consist of insulin preparations that reproduce both the normal basal and post-prandial secretion profiles. The basal-bolus strategy combines both the basal and meal-induced component of normal insulin secretion, thus mimicking normal physiological insulin secretion.1 Basal-bolus should therefore be the regimen of choice in type 1 diabetes mellitus.
An ideal basal insulin will have a nearly constant, i.e. peakless, day-long profile, and a prolonged duration of action.1
An ideal bolus, or mealtime, insulin should have a rapid onset of action and a sharp peak after an hour, limiting post-prandial hyperglycaemia.1 Because its peak should coincide with the post-prandial glucose peak, post-prandial hypoglycaemia should be limited.2
Clinical experience shows that for some patients, alternatives to the rapid-acting analogues, for example, regular human insulin, may need to be considered according to individual needs.3
References
1. Rosenstock J. Clin Cornerstone 2001;4:50–64.
2. Dave JA, Delport SV. S Afr Family Practice 2006;48:30–6.
3. Danne T, Ampudia-Blasco FJ . Data on file, 2007.

5. Duration of action (hrs)
Basal Insulins:
Intermediate :
NPH
Long (Analog):
Glargine:
Detemir:
Insulin preparation
Onset of action
(min)
Peak of action
(hrs)
Duration of action (hrs)
Intermediate (NPH)
1 - 2 h
4 - 8
Long (Detemir)
2 - 4 h
flat/ 6-8 *
14-20 *
Long (Glargine)
flat
UP TO 24
* Dose dependent
1) Rosenstock J, et al. Diabetologia 2008;51:408–16.
2) Mudaliar S et al. Endocrinol Metab Clin North Am. 2001;30:

6. 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

7. 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

8. 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

9. Insulin Glargine Vs NPH

10. Significantly greater HbA1c reduction and less hypoglycaemia with insulin glargine versus NPH
Randomised, non-blinded study of once-daily insulin glargine versus four-times-daily NPH (both + mealtime insulin lispro), 121 patients†
Mean HbA1c levels during study
Incidence of mild and nocturnal hypoglycaemia
p<0.05 2 4 6 8 10 12 14
7.6
Insulin glargine + insulin lispro
Insulin glargine + Insulin lispro
13.2
7.4
NPH + insulin lispro
NPH + insulin lispro
7.2
Mean HbA1c ± SEM (%)
7.0
Events/patient-month
7.2
6.8 * *
This 12-month study demonstrated for the first time the superiority of insulin glargine over NPH.
Patients previously receiving NPH four times daily plus mealtime insulin lispro were randomised to continue with either NPH or begin once-daily insulin glargine at dinner, both with mealtime insulin lispro.
Mean HbA1c decreased in the insulin glargine group, and remained significantly lower than in the NPH group throughout the study. Fasting and pre-prandial blood glucose levels were also lower with insulin glargine.
The frequency of mild, daytime and night-time hypoglycaemia was significantly lower in the insulin glargine group than in the NPH group.
Reference
Porcellati F, et al. Diabet Med 2004;21:1213–20.
p<0.05 * *
6.6 *
3.2
6.4
1.2
Time (months)
Mild
Nocturnal
Hypoglycaemia
*p<0.05 insulin glargine vs NPH; †HbA1c analysis values were not aligned with the Diabetes Control and Complications Trial
Porcellati F, et al. Diabet Med 2004;21:1213–20. Reproduced with permission.

11. Greater treatment satisfaction and confidence with insulin glargine versus NPH
Randomised, controlled study comparing once-daily insulin glargine with once- or multiple-daily NPH, 517 patients
−1.0
−0.5
0.0
0.5
1.0
1.5
Insulin glargine
NPH
p<0.001
Change from baseline to endpoint in DTSQ score
p=0.038
Patients in this randomised, controlled study comparing insulin glargine with NPH completed the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and the Well-Being Questionnaire at regular time points during the study.
There was a significant difference in the treatment satisfaction scores from baseline to endpoint between the two groups, with the insulin glargine group reporting an increase in treatment satisfaction and the NPH group reporting a slight deterioration in DTSQ score. In addition, patients reported better outcomes in the DTSQ items ‘Perceived Frequency of Hyperglycaemia and Hypoglycaemia’ with insulin glargine than with NPH.
There were no significant differences in psychological well-being scores between the two groups; mean scores increased in both groups.
Reference
Witthaus E, et al. Diabet Med 2001;18:619−25.
p=NS
Treatment satisfaction*
Perceived frequency of hyperglycaemia
Perceived frequency of hypoglycaemia
NS=not; p values are for between-group comparisons *Satisfaction Questionnaire (DTSQ)
NS=not significant; p values are for between-group comparisons *Treatment satisfaction was measured using the Diabetes Treatment Satisfaction Questionnaire (DTSQ) Witthaus E, et al. Diabet Med 2001;18:619–25.

12. Insulin Glargine Vs Detemir

13. Insulin Glargine has longer duration of action than insulin Detemir
216
Glargine 12
Detemir
SC insulin
180 10
0.35 U/kg
mmol/l
mg/dl
144 8
108 6 72 4 24
100
(Subjects with plasma glucose >150 mg/dl by time of study) 16
Subjects (n)
Subjects (%) 50 8
n = 24; mean ± SD 2 4 6 8 10 12 14 16 18 20 22 24
Time (hours)
Porcellati F, et al. Diabetes Care 2007;30:2447–52. 13 13

14. Similar HbA1c change with once-daily insulin glargine and with twice-daily insulin detemir
In this 26-week study, 320 patients with Type 1 diabetes (mean HbA1c 8.8–8.9%) were randomized to once-daily insulin glargine (at bedtime) or twice-daily insulin detemir. Insulin aspart was used at mealtimes in both groups
Baseline
Endpoint
8.7
8.8
8.2
6.0
6.5
7.0
7.5
8.0
8.5
9.0
9.5
10.0
Insulin glargine
Insulin detemir
HbA1c (%)
320 patients were randomized to receive either twice-daily insulin detemir or once-daily insulin glargine each in combination with premeal insulin aspart
At the study endpoint, HbA1c had decreased from 8.8 to 8.2% in the insulin detemir group and from 8.7 to 8.2% in the insulin glargine group
Pieber TR, et al. Diabet Med 2007; 24: 635–42
Change in HbA1c over 24 weeks treatment was similar with once-daily insulin glargine versus twice-daily insulin detemir
HbA1c=haemoglobin A1c
Pieber TR, et al. Diabet Med 2007; 24: 635–42.

15. Greater improvements in FBG with once-daily insulin glargine versus twice-daily insulin detemir after 24 weeks
In this 26-week study, 320 patients with Type 1 diabetes (mean HbA1c 8.8–8.9%) were randomized to once-daily insulin glargine or twice-daily insulin detemir (both in combination with insulin aspart)
Insulin glargine
Insulin detemir
7.01
7.71
Δ=0.70 (95% CI: 0.38, 1.02) p<0.001
0.0
2.0
4.0
6.0
8.0
10.0
FPG at endpoint (mmol/L)
320 patients were randomized to receive either twice-daily insulin detemir or once-daily insulin glargine each in combination with premeal insulin aspart
Self-monitored fasting plasma glucose was lower with insulin glargine than with insulin detemir (7.0 versus 7.7 mmol/L; p<0.001)
Within-subject variation in predinner plasma glucose was lower with insulin detemir than with insulin glargine (p<0.05)
Pieber TR, et al. Diabet Med 2007; 24: 635–42
FPG at endpoint was significantly lower with insulin glargine versus insulin detemir
CI=confidence interval; FPG=fasting plasma glucose;
HbA1c=haemoglobin A1c
Pieber TR, et al. Diabet Med 2007; 24: 635–42.

16. Lower insulin dose with insulin glargine versus insulin detemir
In this 26-week study, 320 patients with Type 1 diabetes (mean HbA1c 8.8–8.9%) were randomized to once-daily insulin glargine or twice-daily insulin detemir (both in combination with insulin aspart)
Basal insulin
Bolus insulin
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Insulin glargine
Insulin detemir
Daily insulin dose (U/kg)
0.35
0.39
0.47
0.36
320 patients were randomized to receive either twice-daily insulin detemir or once-daily insulin glargine each in combination with premeal insulin aspart
Daily insulin doses (total dose; basal insulin dose) at endpoint were lower in the insulin glargine arm compared with the insulin detemir arm, although significance testing was not performed
Body weight gain was not significantly different comparing insulin detemir and insulin glargine (0.52 versus 0.96 kg; p=0.193)
Pieber TR, et al. Diabet Med 2007; 24: 635–42.
HbA1c=haemoglobin A1c
Pieber TR, et al. Diabet Med 2007; 24: 635–42.

17. Initial Dosing Guidelines for Insulin Glargine
Type of Patient
Appropriate Glargine Dosage
40 – 50 % TDD titrate appropriately
Initiate at same dosage; titrate appropriately
Reduced total daily dose by 20%- 30% compared to NPH; titrate appropriately
Insulin-naïve
Switched from NPH once daily
Switched from NPH twice daily
When initiating Lantus® (insulin glargine) therapy in insulin-naïve patients with type 2 diabetes, an average dose of 10 IU once daily should be administered. Titration of Lantus to a final dose range of 2 to 100 IU is suggested1
Patients switching from NPH once daily to Lantus should initiate Lantus therapy at the same dose and titrate the dose based on patient response1
For patients switching from NPH twice daily, the initial dose of Lantus should be reduced by 20% to 30% to decrease the risk of hypoglycaemia. The Lantus dose should be titrated according to patient response1
1. Lantus® (insulin glargine) EMEA Summary of Product Characteristics. Bridgewater, NJ: Aventis Pharmaceuticals; 2002.

18. Titrate basal insulin as long as FPG > target
Bedtime or morning long-acting insulin OR
Bedtime intermediate-acting insulin
Daily dose: 10 units or 0.2 units/kg
INITIATE
Check FPG daily
In the event of hypoglycemia or FPG level < 70 mg/dL
Reduce bedtime insulin dose by 4 units, or by 10% if >60 units
Increase dose by 2 units every 3 days until FPG is (70–130 mg/dL)
If FPG is >180 mg/dL, increase dose by 4 units every 3 days
TITRATE
The introduction of basal insulin into the treatment regimen of a patient with type 2 diabetes can be done with a single daily injection. The availability of basal insulin analogs addresses fasting blood glucose levels and overall glycemic control and can be administered in one injection daily. This may help overcome patient anxiety over injections. The international consensus group recommends that basal insulin is administered either at bedtime or in the morning and should be started at a dose of 10 units per day or 0.2 units/kg. Then basal insulin needs to be titrated by monitoring fasting blood glucose levels daily. The dose should be increased by 2 units every 3 days until fasting blood glucose levels are in range (3.89–7.22 mmol/L; 70–130 mg/dL). If the fasting blood glucose value is > 10 mmol/L (> 180 mg/dL), 4 units of insulin may be used instead of 2 units. In the event of hypoglycemia or inappropriate fasting blood glucose levels, the insulin dose should be reduced by ≥ 4 units or 10% if the dose is > 60 units. The regimen should then be continued and HbA1c levels checked every 3 months.
MONITOR
Continue regimen and check HbA1c every 3 months

19. Summary – For the treatment of Type 1 diabetes…
An ideal exogenous insulin therapy should mimic the endogenous insulin profile.
Premixed insulins should not be used, as they are associated with:
Inadequate diurnal glycaemic control (particularly overnight)
Increased risk for hypoglycaemia
Limited treatment flexibility
An ideal basal insulin has a:
_ Peakless profile and prolonged duration of action (24-hour coverage)

20. Insulin glargine in type 1 diabetes mellitus: Key learning points
long-acting insulin analogues provide insulin profiles that better match endogenous insulin profiles versus human insulin-based products
NPH insulin should be administered twice daily
The peaked pharmacokinetic/pharmacodynamic characteristics of NPH insulin increases the risk of hypoglycaemia
Insulin glargine therapy provides better overall treatment satisfaction compared with NPH
Insulin detemir has a shorter duration of action compared with insulin glargine
Insulin detemir should be administered twice daily for 24-h cover in the majority of subjects
Insulin glargine offers:
significantly better control of fasting blood glucose and HbA1c after optimal titration
lower nocturnal hypoglycaemia
good control over 24 hours with just one injection
Low risk of hypoglycaemia

21. Thank you