Early Initiation of Insulin:Basal Bolus versus Premixed by Dr Shahjada Selim, BSMMU

1. Early Initiation of Insulin:
Basal Bolus versus Premixed
Dr Shahjada Selim
Assistant Professor
Department of Endocrinology
Bangabandhu Sheikh Mujib Medical University, Dhaka
Email: selimshahjada@gmail.com

2. ADA Diabetes Management Algorithm 2015

4. ‘Modestly reduced macro-
vascular complication risk
while posed additional
complication’
Inzucchi et al., 2012; Skyler, Bergenstal, Bonow, et al., 2009, Stratton IM et al. BMJ 2000;321:405–412

5. AACE and the Canadian Diabetes Association
suggest considering insulin treatment at the
time of T2DM diagnosis if glycemic control is
very poor (HbA1c levels >9%)
ADA/EASD guidelines recommend insulin
therapy be considered for patients who
present for the first time with T2DM and an
HbA1c level >10%.
Handelsman, Y. et al. Endocr. Pract.17 (Suppl. 2), 1–53 (2011).
Bhattacharyya, O. K. Can. Fam. Physician. 55, 39–43 (2009).

6. ● If HbA1c targets are not achieved after ~3 months of initial treatment,
alternative therapy such as basal insulin should be initiated1,2
Early insulin therapy has the potential to achieve near-normal
glucose control & prevent progression of glucose intolerance3
1. Inzucchi SE, et al. Diabetologia 2012;55:1577–96
2. Nathan DM, et al. Diabetes Care 2009;32:193–203
3. ORIGIN Trial Investigators. N Engl J Med 2012;367:319–28
ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes

7. Treat-To-Target Concept has demonstrated the
role of basal insulin analogs in facilitating early
insulin replacement, lower risk of hypoglycemia
and becoming foundation of the therapy.
4T study also showed that, over the longer term
(3 years), a premixed insulin regimen was not as
effective as basal insulin at attaining glycemic
targets.
Diabetes Care in 2012: Current Trends and Future Directions

8. 4-T Study: Insulins Relative Changes over 3 Years and Hypoglycaemia
N Engl J Med 2009; 361: 1736-47

9. Biphasic Prandial Basal
Median HbA1c level achieved + + +
HbA1c targets achieved + ++ ++
Mean SMBG level achieved + ++ ++
Fewer hypoglycaemic episodes ++ + +++
Less weight gain + + ++
Less increase in waist
circumference
+ + ++

10. 1Riddle M, et al. Diabetes Care 2003;26:3080–6; 2Yki-Järvinen H, et al. Diabetologia 2006;49:442–51; 3Bretzel RG, et al. Lancet 2008;371:1073–84; 4Janka H,
et al. Diabetes Care 2005;28:254–9; 5Rosenstock J, et al. Diabetes Care 2006;29:554–9; 6Yki-Jarvinen H, et al. Diabetes 2006;55 Suppl. 1:A30
HbA1c(%)
APOLLO3 LAPTOP4 Triple
Therapy5
LANMET2Treat-To-
Target1
INITIATE6
7.147.15
6.96
7.14
6.80
8.71
8.85 8.80
9.5
8.80
8.61
6.96
Baseline
Study endpoint
58.0
Target HbA1c
≤7% (%) 49.4 48.057.0NA NA
7
8
9
10
6
The most studied basal insulin
With established CV safety,
10 million patients,
> 60 million patient-years,
>59,000 participants in clinical trials

11. 0
100
200
300
400
0 4 8 12 16 20 24 hrs
Isoglycemic clamp study
PlasmaInsulin(pM)
• Inadequate prandial insulin : Postprandial Hyperglycemia
• Excess inter-prandial supply: Increased risk of Hypoglycemia
risk
HYPOrisk
HYPO
HYPER
HYPER HYPER
Luzio S et al, Diabetologia 49:1163-8, 2006
pre-mixes
are NOT suitable to
Treat-to-target A1C <7.0%

12. Fixed ratio.2
Premix :
Less flexible.1
Less studied alternative.1
Less adaptable.2
Less desirable to intensify.3
More Hypos & weight gain
Unable to titrate individually
1. Diab Care 38; 38:140–149 Jan 2015. 2. Owens DR. Diabet. Med. 30, 276–288; 2013. 3. AACE Algorithm 2013
“The fixed-ratio nature of premixed formulations make them less flexible &
adaptable to the individual’s specific needs than a basal-plus strategy”.2

14. R
A
N
D
O
M
I
S
A
T
I
O
N
Patients with T2DM
HbA1c: 7.5% to 10.5%
and FBG: ≥6.7 mmol/L
(≥120 mg/dL) and
treated with OADs
(n = 364)
Insulin glargine + OADs (n = 177)
Initial dose: 10 IU once daily in the
morning
Human premixed insulin (70/30) (n =
187)
Initial dose: 10 IU before breakfast
and 10 IU before dinner
Treatment phaseScreening
24 weeks
Run-in phase
3–14 weeks
Subjects taking sulphonylurea and metformin for at least a month were enrolled. Sulphonylurea was
replaced with 3 or 4 mg glimepiride during run-in phase. OHA dose remained the same throughout the
study in the insulin glargine arm, while OHAs were discontinued in the premixed insulin arm.
Janka H, et al. Diabetes Care 2005;28:254–9.

15. 15
4
6
8
10
12
14
16
Endpoint
Fasting After
breakfast
Lunch After
lunch
Dinner After
dinner
Bedtime 03.00
*
*
*
*
*
Bloodglucose(mmol/L)
Baseline
Insulin glargine + OHAs
Premixed insulin twice daily
Time of day
*p < 0.05 for treatment comparison of
changes from baseline to endpoint
Janka H, et al. Diabetes Care 2005;28:254–9.

16. Premixed
insulin†
Insulin
glargine‡
0
-0.5
-1.0
-1.5
-2.0
-1.31
Premixed
insulin†
Insulin
glargine‡
Weightgain(kg)
1.4
2.1
2.5
2.0
1.5
1.0
0.5
0
-1.64
HbA1cchangefrombaseline(%)
Final daily dose:
Premixed insulin 64.5 IU
Insulin glargine 28.2 IU
p = 0.0003
p = NS
†Twice daily; ‡plus OHAs
Janka H, et al. Diabetes Care 2005;28:254–9.

17. 17
0.51
0
2
4
6
8
10
12
Eventsperpatientperyear
Premixed insulin
Insulin glargine*
All confirmed
hypoglycaemia
Confirmed
symptomatic
Confirmed
nocturnal
p < 0.0001
p = 0.0009
p = 0.0449
Hypoglycaemia confirmed by blood glucose <60 mg/dL (3.3 mmol/L)
Janka H, et al. Diabetes Care 2005;28:254–9.
*Plus ODAs
1,04
2,62
9.87
5.73
4.07

18. R
A
N
D
O
M
I
S
A
T
I
O
N
Insulin-naïve patients
with T2DM previously
treated with metformin
(>1,000 mg/day) alone
or plus other OADs
HbA1c ≥8%
(n = 222)
Insulin glargine + OADs
(n = 114): Initiated at 10–12 U
once daily at bedtime
Premixed insulin aspart (BIAsp
70/30) + OADs (n = 108)
Initiated at 5–6 U twice daily,
before breakfast and dinner
Treatment phaseScreening
28 weeks
Run-in phase
3–14 weeks
During run-in, metformin was optimised to 1,500–2,550 mg/day, secretagogues and -glucosidase
inhibitors were discontinued. Pioglitazone was continued (if taken pre-study) and subjects taking
rosiglitazone were changed to pioglitazone.
Raskin P, et al. Diabetes Care 2005;28:260–5.

19. 0
2
4
6
8
10
12
14
16
0
2
4
6
8
10
12
*FPG target of 80–110 mg/dL (4.4–6.1 mmol/L)
p < 0.01
p = NS
Target FPG* achieved by 57%
of insulin glargine group and
36% of premix group
HbA1c<7% achieved by 40%
of insulin glargine group and
66% of premix group
Premix
Insulin glargine
14,0
7,1
13,5
6,5
Baseline Study end
FPG(mmol/L)
9,7
6,9
9,8
7,4
Baseline Study end
HbA1c(%)
Raskin P, et al. Diabetes Care 2005;28:260–5.

20. 0
10
20
30
40
50
0
1
2
3
4
5
6
0
20
40
60
80
100
*Minor hypoglycaemia: <56 mg/dL (<3.1 mmol/L) with or without symptoms
p < 0.05p < 0.01
Raskin P, et al. Diabetes Care 2005;28:260–5.
Hypoglycaemia* Daily insulin doseWeight gain
p < 0.05
43
16
Premixed
insulin
Insulin
glargine
%patients
5,4
3,5
Premixed
insulin
Insulin
glargine
kg
78,5
51,3
Premixed
insulin
Insulin
glargineIUatstudyend

21. Subjects:
310 with inadequately controlled type 2 diabetes (HbA1c 8–11%)
Pretreated with premixed insulin (mean of 5 years),
with some receiving metformin (continued during study)
Fritsche A, et al. Diabetologia 2008;51 Suppl. 1:S83
Mean baseline values:
• HbA1c (%): 8.5
• BMI (kg/m2): 30.1
• Diabetes duration (years): 13.0
52 weeksRandomization
Insulin glargine + three daily doses of insulin
glulisine +/- metformin (n=153)
Twice-daily premixed insulin +/- metformin (n=157)

22. Fritsche A, et al. Diabetologia 2008;51 Suppl. 1:S83
p=0.0004
%achievingHbA1c<7.0
0
10
20
30
40
50
Glargine
+ glulisine
Premixed
insulin
47
28
Months
7.0
8.0
9.0
6.0
p=0.0001
0 3 6 9 12
8.5
8.6
7.7
7.3
HbA1c(%)
Premixed insulin
Glargine + glulisine

23. 0
1
2
3
4
Glargine
+ glulisine
Premixed
insulin
Meanbodyweightchange
frombaseline(kg)
3.6
2.2
p=0.007
Symptomatichypo
(event/patient-year)
0
5
10
15
Glargine
+ glulisine
Premixed
insulin
9.9
13.4
p=NS
Severehypo
(event/patient-year)
0.00
0.05
0.10
0.15
0.20
0.25
Glargine
+ glulisine
Premixed
insulin
0.1
0.2
p=NS
Fritsche A, et al. Diabetologia 2008;51 Suppl. 1:S83

25. 18
29
0
5
10
15
20
25
30
DTSQscore
p<0.0001
Schreiber S, et al. Diabetologia 2007;50(suppl 1):S410–1.
Baseline 12 weeks
Basal-plus and basal-bolus insulin therapy provided
better patient treatment satisfaction

26. p = 0.0012
Bradley C, et al. Diabetes 2005;54(Suppl):Abstract 1246-P.
0
5
10
15
Insulin glargine
+ OADs
Premixed human
insulin 30/70 BID
DTSQcscoreatendpoint
11.5
14.0
At 24 weeks insulin glargine was associated with a greater increase
in patient treatment satisfaction

27. Hammer H and Klinge A. Int J Clin Pract 2007;61:2009–18.
Efficacy Safety
Very good
Good
Satisfactory
Unsatisfactory
No response given
Most physicians rated the efficacy and safety
of insulin glargine as ‘very good’ or ‘good’
46%
41%
54%42%

28. Markers of glycemic variability were better in patients treated
with BB than in those treated with MIX in better control group.
Conclusion: These results suggest that BB therapy achieves
better glucose profiles than MIX therapy.

30. Banerjee S, Maji D, Baruah M. J Assoc Physicians India. 2013 Jan;61(1 Suppl):24-7.

31. Basal insulin alone is the most convenient initial insulin regimen, beginning at 10 U
or 0.1–0.2 U/kg, depending on the degree of hyperglycemia.
Basal insulin is usually prescribed in conjunction with metformin and possibly one
additional noninsulin agent.
A less studied alternative, transitioning from basal insulin to twice-daily premixed (or
biphasic) insulin analog (70/30 aspart mix, 75/25 or 50/50 lispro mix), could also be
considered.
Regular human insulin and human NPH-Regular premixed formulations (70/30) are
less costly alternatives to rapid-acting insulin analogs and premixed insulin analogs,
respectively, but their pharmacodynamic profiles make them suboptimal for the
coverage of postprandial glucose excursions.
ADA STANDARDS OF MEDICAL CARE IN DIABETES—2015

32. Basal Insulin strategy:
• Simple, flexible approach to intensifying a basal insulin regimen.
• Easily progressed to a basal-bolus regimen, if required.
• Premixed insulin regimens are less flexible & must be switched to
a more physiological basal-bolus regimen if further intensification
is required.
• Switching from premixed insulin regimens to basal ± boluses
improves patient satisfaction.
• The basal-bolus regimen offers patients flexible treatment that
responds to different needs and lifestyles and reduces glucose
variability

33. Laptop Study1 Initiate Study2
Hammer & Kingler3 AT-LANTUS Study5
. Janka H, et al. Diabetes Care 2005;28:254–9.
. 2. Raskin P, et al. Diabetes Care 2005;28:260–5.
. 3. Davies M, et al. Diabetes Res Clin Pract 2008;79:368–75.
. 4. Hammer H and Klinge A. Int J Clin Pract 2007;61:2009–
18
. 5. Diabetes Care 34:249–255, 2011.
DURABLE Study5