Ueda2016 symposium - basal plus & basal bolus - lobna el toony

2. Stepwise intensification of insulin in T2DM management—
Exploring the concept of the basal-plus approach in clinical practice
LOBNA F ELTOONY
Head Of Internal Medicine Department
Faculty Of Medicine
Assiut University

6. HOMA=homeostasis model assessment
Adapted from Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21–5.
Decreasing -cell function as part of the
progression of T2DM
Normal -cell
function by
HOMA (%)
Time (years)
0
20
40
60
80
100
―10 ―8 ―6 ―4 ―2 0 2 4 6
Time of diagnosis?
Pancreatic function
~ 50% of normal

8. Clinical Inertia:
“Failure to Advance Therapy When Recommended”
MeanA1CatLastVisit*
(%)
8.2 Years
ADA Goal
Diet and
Exercise
Years Elapsed Since Initial Diagnosis
Initiation
of
insulin therapy
SU or
metformin
Combination
oral agents8.6%
8.9%
9.6%
7
8
9
10
2.5 Years 2.9 Years 2.8 Years
*Adapted from: Brown JB et al. Diabetes Care. 2004;27:1535-1540.

10. Insulin
The most powerful agent we
have
to control glucose

12. Patient J.L., December 15, 1922 February 15, 1923
The Miracle of Insulin

13. Indications of insulin
Continuous Use
* Type 1 Diabetes
* Type 2 Diabetes with OHA failure
- Primary - Secondary
Intermittent Use
* Type 2 diabetes during
- major surgery
- pregnancy, labour and delivery
- myocardial infarction
- acute infections
Life-saving in T1DM
Essential in T2DM

14. Starting dose of insulin
• T1DM: 1 -0.2-1 U/kg / day1
• T2DM: 0.2-0.3 U/kg / day
 In split mixed regimen- 2/3 as intermediate acting & 1/3 as
short- acting 2
 In basal bolus regimen: ½ basal at bed time and ½ bolus in 3
divided doses.
 Dosage is individualized and titrated soon
1Goodman & Gillman’s The pharmacological basis of therapeutics ed. 9th .pg. 1501
2 Harrison’s Principles of Internal Medicine (15th Edition) pg. 2131

16. HbA1C(%)
UKPDS: Long-term follow-up
Bailey CJ & Day C. Br J Diabetes Vasc Dis 2008; 8:242–247.
Holman RR, et al. N Engl J Med 2008; 359:1577–1589.
Differences in mean glycated
hemoglobin levels between the
intensive therapy group and the
conventional-therapy group
were lost by 1 year, with similar
glycated hemoglobin
improvements thereafter in all
groups (p= not significant)
P=0.71
Glucose similar
BUT CV events
now better
Metformin group 21% 33% 27%

17. A new paradigm
Del Prato S. Diabetologia 2009; 52:1219–1226.
Del Prato S. Diabetologia 2009; 52:1219–1226.

18. Why Early insulin initiation?
Clinical & Pharmacological Reasons(4)
Insulin
Improves beta-cell function
(reduces glucotoxicity &
lipotoxicity)
Reverses insulin resistance Improves Quality of Life
Beneficial effects on
lipids
Insulin provides
4 benefits beyond
glycemic control

19. LIFESTYLE MEASURES
Then at each step, if not to target (generally HbA1c <7.0%)
IDF Treatment algorithm for people with type 2 diabetes
or
oror
Metformin
Sulfonylurea or
α-Glucosidase inhibitor
Sulfonylurea
α-Glucosidase inhibitor
or DPP-4 inhibitor
or Thiazolidinedione
Basal insulin or
Pre-mix insulin
GLP-1 agonist
Basal + meal-time insulin
Metformin
(if not first line)
α-Glucosidase inhibitor
or DPP-4 inhibitor
or Thiazolidinedione
Basal insulin or
Pre-mix insulin
(later basal + meal-time)
Alternative approachUsual approach
Consider
first line
Consider
second line
Consider
third line
Consider
fourth line

20. Early Insulinization Is Recommended by the ADA/EASD
to Avoid Clinical Inertia
●If HbA1c targets are not achieved after ~3 months of initial treatment, alternative
therapy such as basal insulin should be initiated1,2
Monotherapy
Efficacy*
Hypo risk
Weight
Side effects
Costs
Metformin
High
Low risk
Neutral / loss
GI / lactic acidosis
Low
If HbA1c target not achieved after ̴3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific
preference - choice dependent on a variety of patient- and disease-specific factors):
Dual therapy†
Efficacy
Hypo risk
Weight
Side effects
Costs
Metformin +
Sulfonylurea Thiazolidinedione DPP-4 inhibitor SGLT 2 inhibitor GLP-1 receptor agonist
High
Moderate risk
Gain
Hypoglycemia
Low
High
Low risk
Gain
Edema, HF, fxs
Low
Intermediate
Low risk
Neutral
Rare
High
If HbA1c target not achieved after ̴3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific
preference - choice dependent on a variety of patient- and disease-specific factors):
Intermediate
Low risk
Loss
GU, dehydration
High
High
Low risk
Loss
GI
High
Insulin (basal)
Highest
High risk
Gain
Hypoglycemia
Variable
Healthy eating, weight
control, increased
physical activity,
and diabetes
education
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

21. AACE/ACE diabetes algorithm for glycemic control (A1c > 9.0%).

22. Rationale for initiating insulin therapy
with basal insulin

23. WHAT!?
Did you say
INSULIN?!
Barriers to
the Use of
Insulin

24. Patient Concerns About Insulin
• Fear of injections
• Worries that insulin
could worsen diabetes
• Concerns about
hypoglycemia
• Complexity of
regimens

27. Step One: Initiating Insulin
• Start with either…
– Bedtime intermediate-acting insulin or
– Bedtime or morning long-acting insulin
Insulin regimens should be designed taking
lifestyle and meal schedules into account
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

28. Basal insulin in type 2 diabetes
(e.g. LA 0.1-0.2 U/kg or 10U)
Non-insulin therapies
LA = Long-Acting insulin: Glargine, Detemir
Basal Insulin in Type 2 Diabetes

29. Basal Insulin Therapy
• Usual first step in beginning insulin therapy
• Continue oral agents and add basal insulin to optimize FPG
• A1C of up to 9.0% usually brought to goal (7%) by addition of
basal insulin therapy to oral agents
• Easy and generally safe: patient-directed treatment algorithms
with small risk of serious hypoglycemia
ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes.
ADA/EASD Management of hyperglycemia in type 2 diabetes: A patient-centered approach. Diabetologia (2012) 55:1577–1596

30. Starting With Basal Insulin in DM 2
Advantages
• 1 injection with no mixing
• Insulin pens for increased acceptance
• Slow, safe, and simple titration
• Low dosage
• Effective improvement in glycemic control
• Limited weight gain 6-37

32. 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. 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)
Why Basal insulin?
Hyperglycaemia due to an increase in fasting glucose
T2DM
Treating fasting hyperglycaemia lowers the entire 24-hour plasma glucose profile

33. A balanced approach for insulin therapy in T2DM
250
200
150
100
50
0
Plasmaglucose(mg/dL)
06:00 12:00 18:00 24:00 06:00
Time
T2DM
Normal
Mealtime hyperglycaemia
Fasting hyperglycaemia
60
40
20
0
Contribution(%)
80
1
(<7.3)
2
(7.3-8.4)
3
(8.5-9.2)
4
(9.3-10.2)
5
(>10.2)
HbA1c quintiles
Postmeal hyperglycaemia
Fasting hyperglycaemia
Diabetes Care 1990; 16: 676–686 Monnier L. Diabetes Care 2003;26:881

34. Fix Fasting First
Basal
Insulins
Normal Fasting Blood Glucose
Elevated Fasting Hyperglycemia and HGO
Hence need to fix fasting first

35. Look at all available basal insulins

36. Types of basal insulin
Intermediate-Acting
(e.g. NPH, lente)
Long-Acting
(e.g. ultralente)
Long-Acting Analogues
(glargine, detemir)
Onset 1-3 hr(s) 3-4 hrs 1.5-3 hrs
Peak 5-8 hrs 8-15 hrs
No peak with glargine, dose-
dependent peak with detemir
Duration Up to 18 hrs 22-26 hrs
9-24 hrs (detemir);
20-24 hrs (glargine)
Rossetti P, et al. Arch Physiol Biochem
2008;114(1): 3 – 10.

37. 37
Profile of Insulin Glargine vs NPH
Glargine
NPH

38. The quest for a better basal insulin… A “qualified A1c” by
hypoglycaemia
Hypoglycaemia
NPH
Glargine
A1c
~ 0.4–0.6% ?
The impact of hypoglycaemia on A1c

39. Addition of Glargine allows most patients with T2DM to reach glycemic targets
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
8.808.61
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

40. Basal Insulin Therapy in T2DM:
AACE/ACE Recommendations
• Initiate insulin treatment by adding a long-acting basal
formulation to existing noninsulin agents
40
Relatively peakless
time-action curves
Greater day-to-day
consistency
Lower risk of
hypoglycemia
• Start with 10 U or 0.1-0.2 U/kg per day at bedtime
• Slowly titrate by 1-3 U every 2-3 days until FPG reaches the desired target (<100
mg/dL for most patients)
• Decrease dosage if FPG declines below a threshold specified for individual patient
*Under FDA review as of October 2012.
Rodbard HW, et al. Endocr Pract. 2009;15:540-559.
Basal insulin analogues (detemir, degludec,* or glargine) are strongly preferred over
human NPH insulin

41. Schreiber SA, et al. Diabetes Technol Ther 2008; 10:121–7.
Insulin glargine + OADs provides sustained glycaemic control
Extension of an original 9-month, open-label, uncontrolled,
multi-centre, observational study (n = 12,216)
Months of treatment
6.5
7.0
7.5
8.0
8.5
9.0
3 9 32
8.6
7.2
7.0 7.0
MeanHbA1c(%)
n = 1,915 (extension)
Sustained Glycaemic Control with Basal Insulin in T2DM: ‘Real-life’ Data

42. 8.5
9.0
8.0
7.5
7.0
6.5
0 4 8 12 16 20 24
HbA1c(%)
NPH + OAD
Insulin glargine + OAD
Weeks
0
2
4
6
8
10
12
14
16 21% risk reduction
p <0.02
42% risk
reduction p <0.01
Overall Nocturnal
Hypoglycemia
Eventsperpatientperyear
Insulin Glargine vs. NPH in Treat-to-
Target Trial: HbA1c and Hypoglycemia
Riddle et al. Diabetes Care 2003;26:3080-6.
Randomized to NPH or Glargine +
OAD with target HbA1c <7%

43. Initiate & Titrate basal insulin
FPG, fasting plasma glucose
Nathan DM, et al. Diabetes Care 2009;32:193-203.
Initiate insulin with a single injection of a basal insulin (Glargine)
Check
FPG
daily
In the event of hypoglycemia or
FPG level <3.89 mmol/L
(<70 mg/dL)
Reduce bedtime insulin dose
by 4 units, or by 10% if >60
units
• Bedtime or morning long-acting insulin OR
• Bedtime intermediate-acting insulin
Daily dose: 10 units or 0.2 units/kg
INITIATE
• Increase dose by 2 units every 3 days until
FPG (70–130 mg/dL)
• If FPG is >180 mg/dL, increase dose by 4
units every 3 days
TITRATE
Continue regimen and
check HbA1c every 3 monthsMONITOR
• Continue regimen and check HbA1c every 3
months

44. • If HbA1c is <7%...
– Continue regimen and check HbA1c every 3 months
• If HbA1c is ≥7%...
– Move to Step Two…
After 2-3 Months…
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

45. Step-by-step approach
Even with optimal use of basal insulin, it is estimated that, using current treatment
paradigms, ~40% of people will not meet HbA1c recommendations of < 7%.
A well-considered step-by-step approach to the intensification of insulin therapy,
adding one, two or three prandial insulin injections to basal insulin according to
each individual’s prandial requirements, seems a logical way forward.
The current evidence underlying this concept of meal-driven insulin intensification
for the treatment of T2D, as well as the implications of adopting such an approach
in clinical practice.
D. R. Owens Diabet. Med. 30, 276–288 (2013

46. In spite of titrating basal insulin, the inability to achieve
glycemic control despite normal or near-normal
fasting glucose usually means that excessive glycemic
excursions may be occurring during postprandial
period

47. Step Two: Intensifying Insulin
If fasting blood glucose levels are in target range but HbA1c ≥7%,
check blood glucose before lunch, dinner, and bed and add a second
injection:
• If pre-lunch blood glucose is out of range,
add rapid-acting insulin at breakfast
• If pre-dinner blood glucose is out of range,
add NPH insulin at breakfast or rapid-acting insulin at lunch
• If pre-bed blood glucose is out of range,
add rapid-acting insulin at dinner
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

48. InsulinEffect
B DL HS
Bolus insulin
Basal insulin
Basal-Plus Insulin Therapy
Endogenous insulin
Adapted with permission from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY:
Marcel Dekker, Inc; 2002:193
Tuesday, February 16,
2016
48

49. Making Adjustments
• Can usually begin with ~4 units and
adjust by 2 units every 3 days until blood
glucose is in range
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
•When number of insulin Injections increase from 1-
2………..Stop or taper of insulin secretagogues (sulfonylureas).

50. Insulin Initiation & Intensification – AACE 2015
START BASAL
A1c <8% A1c >8%
TDD: 0.1-0.2U/Kg TDD: 0.2-0.3U/Kg
Insulin titration
every 2-3 days
to reach
glycaemic goal
 Fixed regimen: Increase TDD by 2U
 Adjustable regimen  FBG > 180 mg/dL: add 20% of TDD
 FBG 140-180 mg/dL: add 10% of TDD
 FBG 110-139 mg/dL: add 1 unit
 If hypoglycemia, reduce TDD by  BG < 70 mg/dL: 10% - 20%
 BG < 40 mg/dL: 20% - 40%
Glycemic control not at goal*
Intensify: Add prandial insulin
TDD:
0.3-0.5 U/Kg
 50% Basal Analog
 50% Prandial Analog
 Less desirable : NPH & regular/premixed insulin
Insulin titration
every 2-3 days
to reach
glycemic goals
 Increase prandial dose by 10% for any meal if the 2-hr PP or next
premeal glucose is > 180 mg/dl
 Premixed: Increase TDD by 10% if fasting/premeal BG > 180 mg/dL
 If fasting AM hypoglycemia, reduce basal insulin
 If nighttime hypoglycemia, reduce basal and/or pre-supper or pre-
evening snack short/rapid-acting insulin
 If between-meal daytime hypoglycemia, reduce previous premeal
short/rapid-acting insulin
* <7% for most patients with T2DM; fasting & premeal BG < 110 mg/dL; absence of hypoglycemia; ENDOCRINE PRACTICE Vol 21 No. 4 April 2015 e1

51. When to stop titrating basal insulin and add prandial insulin?
Current opinions
1 Skyler JS. In: Lebovitz HE, ed. Therapy for diabetes Mellitus and related disorders. Alexandria, VA: American Diabetes Association, Inc.; 2004:207-
223.
2 American Diabetes Association. Practical Insulin: A Handbook of Prescribing Providers. 3rd ed. 2011:1-68
The individual is not meeting glycemic targets on basal insulin1-4 and:
A1C still not at goal
with 0.5 U/kg/day
of daily basal
insulin3
Elevated A1C
despite normal FPG
with basal insulin2,3
FPG with basal
insulin is within
targeted range, but
PPG is persistently
above goal3,4
Further increases in
basal insulin result
in hypoglycemia3

52. Stepwise Intensification of Treatment for Continuity of Control
Progressive deterioration of -cell function
Lifestyle changes
Oral agents
Basal
Add basal insulin and titrate
Basal plus
Add prandial insulin at main meal
Basal bolus
Additional prandial doses as
needed
FBG above target
HbA1c above target
HbA1c above
target
FBG at target
HbA1c above target
Adapted from Raccah D et al. Diabetes Obes Metab 2008;10(2):76-82.
When glycaemic targets are not met:
– Treatment should be changed to the next ‘step’
– Currently, therapy change is often too late
– Earlier treatment modification is necessary

53. • If HbA1c is <7%...
– Continue regimen and check HbA1c every
3 months
• If HbA1c is ≥7%...
– Move to Step Three…
After 2-3 Months…
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

54. Advancing Basal/Bolus Insulin
 Indicated when FBG acceptable but
– A1C > 7% or > 6.5%
and/or
– SMBG before dinner > 140 mg/dL
 Insulin options
– To glargine or NPH, add mealtime aspart / lispro
– To suppertime 70/30, add morning 70/30
– Consider insulin pump therapy
 Oral agent options
– Usually stop sulfonylurea
– Continue metformin for weight control
– Continue glitazone for glycemic stability?

56. Isoglycemic clamp study
 Inadequate prandial insulin : Postprandial Hyperglycemia
 Excess inter-prandial supply: Increased risk of Hypoglycemia
Insulin Profiles: Premixed 30/70 Aspart
0
100
200
300
400
0 4 8 12 16 20 24 hrs
PlasmaInsulin(pM)
HYPER HYPER HYPER
Luzio S et al, Diabetologia 49:1163-8, 2006
risk
HYPO
risk
HYPO
The pre-mixes are NOT suitable to
Treat-to-target A1C <7.0%

57. Insulin Glargine is more suited for initiating insulin therapy than premixed insulin
analogues
Basal insulin
e.g. insulin Glargine
Premixed insulin
e.g. premixed insulin
aspart 30/70
Initial number of injections daily 1 21
Daily initial dose Insulin glargine: 10 U 6 U + 6 U1
Timing of injections Morning or evening
Breakfast
and dinner1
Monitoring for
titration targets
FPG
(once daily)
FBG and preprandial BG
(twice daily)1
Lifestyle
Flexible mealtimes
and meal content
Scheduled mealtimes
and set meal plans
Intensification
Addition of once-daily prandial insulin
(basal-plus) to basal bolus
Increase to 3 times daily
1. Summary of product characteristics for NovoMix 30, 50 and 70. Available at
www.emea.europa.eu/humandocs/Humans/EPAR/novomix/novomix.htm (last accessed 2 July 2008).

58. Clinical evidence for the
‘basal-plus’ / basal-bolus’ approach

59. Glulisine added to glargine further improves glycemic control
*For difference in change in HbA1c
Randomization
Proof of concept (POC) study: Basal Plus+1 therapy versus basal insulin
glargine alone
Control
group
Glargine
+ glulisine
p = 0.0499
0
10
20
30
40
%achievingHbA1c<7.0%
8.8
22.4
p = 0.029*
Control
group
Glargine
+ glulisine
6
7
8
9
HbA1c(%)
8.0
7.87.8
7.5
Endpoint
8.0
7.8 7.8
7.5
8.8
Owens DR, et al. Diabetes Obes and Metab 2011.

60. Control
group
Glargine
+ glulisine
p = ns
0.0
0.2
0.4
0.6
Meanbodyweightchange
frombaseline(kg)
0.5
0.2
Proof of concept (POC) study: Basal Plus+1 therapy versus basal insulin
glargine alone
Glargine
+ glulisine
Control
group
0
2
4
6
8 7.68
8.19
10
p = ns
Symptomatichypo
(event/patient-year)
Glargine
+ glulisine
0.0
Control
group
0.0
0.1
0.2
0.3
Severesymptomatichypo
(event/patient-year)
0.2
p = ns
Basal plus approach is safe with only minor weight gain
Randomization Endpoint
Owens DR, et al. Diabetes Obes and Metab 2011.

61. 1.2.3 study: Insulin glargine with addition of 1, 2 or 3
daily doses of glulisine
• Subjects:
– Insulin naïve (785 entered study, 343 randomized) with type 2 diabetes
(HbA1c ≥8.0%)
– Receiving 2 or 3 OHAs for ≥3 months (OHAs continued except sulfonylurea)
Randomization (subjects with
HbA1c >7.0%, n=434)
24 weeks
Insulin glargine
(n=785)
14 weeks
Additional insulin glulisine once daily (n=115)
Additional insulin glulisine twice daily (n=113)
Additional insulin glulisine three times daily (n=115)
(1.2.3 study)
Mean study entry values:
• HbA1c (%): 9.8
• BMI (kg/m2): 35.0
Davidson M, et al. Endocr Pract 2011;17:395–403.

62. Glargine plus glulisine
(patients with HbA1c >7%)
Responders (whole population; n=785)
0
20
40
60
80
%achievingHbA1c<7.0%
Additional
subjects
achieved
HbA1c <7.0%
with glulisine added to
glargine
23%
Run in Randomization Wk 8 Wk 16 Wk 24
7.40
7.0
10.19
10.19
10.16
7.44
7.29
8.0
9.0
10.0
Glulisine 1x
Glulisine 2x
Glulisine 3x
HbA1c (randomized population; n=343)
Glargine
(alone)
Subjects achieved
HbA1c <7.0% with
glargine during run
in
37%
Davidson M, et al. Endocr Pract 2011;17:395–403.
HbA1c(%)
Intensification with glulisine improves glycemic control
1.2.3 study: Insulin glargine with addition of one, two or three daily doses of glulisine

63. p = NS for all other pairwise comparisons
Hypoglycemia (event/patient-year)
0
0.25
0.50
0.75
1.0
Severeorserious‘hypos’
x1 x2 x3
Glulisine
0.28
0.89
p = 0.044
0.64
0
5
10
15
20
x1 x2 x3
Glulisine
Confirmedsymptomatic‘hypos’
12.3
10.6
15.9
x1 x2 x3
0
1
2
3
4
5
Meanchangefrombaseline(kg)
3.8 3.9
4.1
Glulisine
Body weight
Davidson M, et al. Endocr Pract 2011;17:395–403.
1.2.3 study: Insulin glargine with addition of one, two or three daily doses of
glulisine

64.  Randomization if A1c >7.0%
 Glimepiride stopped
 Glargine / Premix
 Other OADs maintained
All-To-Target: Study Design
Randomized Comparison of Premixed Insulin vs Either Basal-Plus or Basal-Bolus
Premix (70/30) 2 x daily + 2-3 OADs
N = 192
G+1: Glargine + upto 1 Glulisine + 2-3 OADs
N = 189
G+3: Glargine + upto 3 x Glulisine + 2-3 OADs
N = 191
Screening
* ** *
* Treatment in G+1 and G+3 groups intensified at weeks 12, 24, 36 or 48 if A1c>7%
Riddle, MC et al. Diabetes, Obesity and Metabolism 2014. 16: 396–402,
Inclusion Criteria
 T2DM≥2 years
 BMI<45kg/m2
 HbA1c>7.5%
 Use of 2-3 OADS
Run-in
Run-in (4 week) Randomized (60 weeks)
R

65. Hypoglycemia (event rate per patient-year)
*p < 0.01 vs premix ; **p < 0.001 vs premix
12.2
7.1* 7.2*
1.9
0.8** 0.9**
0.2 0.1* 0.2
Premix BID Basal Plus Basal Bolus
Δ HbA1c from baseline (%)
All-to-Target:
Stepwise intensification with glargine and glulisine vs premix
<70 mg/dL +
symptoms
<50 mg/dL +
symptoms
<36 mg/dL
*p =0.06 vs premix ; **p <0.01 vs premix
Mean baseline HbA1c = 9.4%
-1.8
-2.1* -2.2**
Premix BID Basal Plus Basal Bolus
Riddle, MC et al. Diabetes, Obesity and Metabolism 2014. 16: 396–402,

66. All-to-Target: A comparison of premixed, basal-plus and stepwise basal-bolus
regimens
• More patients achieve A1c < 7% using glargine and glulisine in basal-plus and stepwise basal-
bolus regimens compared with twice daily premixed insulin
Riddle M, et al. Diabetes 2011;60(Suppl.1):PP-0409.
HbA1c<7% at week 60
HbA1c<7% at week 60
without hypoglycemia
* vs premix
39%
49%
45%
14%
24% 24%
0%
10%
20%
30%
40%
50%
60%
%ofpatients(at
week60)
Premix BID
n=192
Glargine+glulisine
basal-plus
n=189
Glargine+glulisine
stepwise basal-bolus
n=191
p<0.025*
p<0.05*
p<0.05* p<0.01*
Riddle, MC et al. Diabetes, Obesity and Metabolism 2014. 16: 396–402,

68. 69

69. Proposed progressive insulin strategies in type 2
diabetes.
*Log = rapid-acting insulin analogues (lispro, aspart, glulisine

70. Initiating & Adjusting Insulin
Continue regimen; check
HbA1c every 3 months
If FBG in target range, check BG before lunch, dinner, & bed; depending
on BG results, add second injection
(can usually begin with ~4 units and adjust by 2 units every 3 days until BG in range)
Recheck pre-meal BG levels and if out of range, may need to add another
injection; if HbA1c continues to be out of range, check 2-hr postprandial levels
and adjust preprandial rapid-acting insulin
If HbA1c ≤7%...
Bedtime intermediate-acting insulin, or
bedtime or morning long-acting insulin
(initiate with 10 units or 0.2 units per kg)
Check FG and increase dose until in
target range
If HbA1c 7%...
Hypoglycemia
or FG >3.9 mmol/L (70 mg/dL):
Reduce bedtime dose by ≥4 units
(or 10% if dose >60 units)
Pre-lunch BG out of range: add
rapid-acting insulin at breakfast
Pre-dinner BG out of range: add NPH insulin at
breakfast or rapid-acting insulin at lunch
Pre-bed BG out of range: add
rapid-acting insulin at dinner
Continue regimen; check
HbA1c every 3 months
Target range:
3.9-7.2 mmol/L
(70-130 mg/dL)
If HbA1c ≤7%... If HbA1c 7%...
Nathan DM et al. Diabetes Care 2009;32(1):193-203.

71. Conclusions
In the early stages of insulin therapy,
most individuals seem to achieve
favorable glycaemic control with
basal insulin alone, or in
combination with a single prandial
insulin injection.
The addition of a single prandial
insulin injection at the largest meal is
well tolerated and associated with
significant improvements in (HbA1c),
low rates of hypoglycaemia & limited
weight gain.
More people achieve recommended
HbA1c targets with a basal-plus
strategy, compared with twice-daily
premixed insulin therapy, with lower
rates of hypoglycaemia.
Step-by-step approach with the
basal-plus strategy is a promising
alternative method of insulin
intensification that allows for
individualization of treatment and
may delay progression to a full
basal–bolus insulin replacement
therapy for many individuals.
Owens D. Diabet Med. 2013 Mar; 30(3): 276–288.

72. Stepwise Intensification of Treatment for Continuity of Control
Progressive deterioration of -cell function
Lifestyle changes
Oral agents
Basal
Add basal insulin and titrate
Basal plus
Add prandial insulin at main meal
Basal bolus
Additional prandial doses as
needed
FBG above target
HbA1c above target
HbA1c above
target
FBG at target
HbA1c above target
Adapted from Raccah D et al. Diabetes Obes Metab 2008;10(2):76-82.
When glycaemic targets are not met:
– Treatment should be changed to the next ‘step’
– Currently, therapy change is often too late
– Earlier treatment modification is necessary

73. THANK YOU
Thank you