Why, When & How to Add Prandial

Insulin after Basal Opitmization

(Focus on Basal Plus)
 BACKGROUND
FACTS ABOUT DIABETES

Diabetes mellitus is a chronic and progressive disease

with steadily worsening glycemia
Addition of medication is needed to maintain
treatment goals
Long term damage, dysfunction and failure of various
organ
Requires continuing medical care and ongoing patient
self-management education and support to prevent
acute complications and to reduce the risk of long-term
complications
 Beta Cell Function Deterioration
vs Insulin Resistance
100 Insulin resistance

75
(% of normal by HOMA)

DIAGNOSIS

undiagnosed
Beta-cell function

50
Pancreatic function
= 50% of normal

25 IGT Postprandial
Hyperglycemia

0
10 -2 0 2 6 10 14
HOMA, homeostasis model assessment Years from Diagnosis
Adapted from Holman1
1. Holman RR. Diabetes Res Clin Pract 1998;40(Suppl 1):S215

Lebovitz H. Diabetes Review 1999;7:139-53 (modified) 2. UKPDS Group. Diabetologia 1991; 34:87790
 350 DIAGNOSIS
300 Post-meal
250 glucose Fasting
Glucose glucose
200
(mg/dl)
150
100
50

250 Insulin resistance

Relative 200
-cell 150 Insulin
level
function 100
(%) 50 -cell failure
0
Obesity IGT T2DM Uncontrolled
hyperglycaemia

Clinical
features Risk for diabetes complications

Years 10 5 0 5 10 15 20 25 30
IGT = impaired glucose tolerance
Adapted from Bergenstal RM. In: Int. Textbook of Diabetes Mellitus, third edition: John Wiley & Sons; 2004:
p9951015.
Chronic Complications in Newly Diagnose Diabetes Mellitus
50% of patients had 1 complications

Stroke or TIA: 1%
Retinopathy: 21%
NEWLY
DIABETES
Hypertension: 35%

Plasma creatinine
>120mol/l: 3%
Abnormal ECG : 18%

Intermittent
Claudicasio: 3%
Erectal Dysfuntion : 20%

Foot skin ischemia : 6%

Pedal pulse (-) : 13%
UKPDS 6, Diabetes Res. 1990 Jan;13(1):1-11. J Hypertens 1993 Jun;11(6):681.
Acta Medica Iranica, 44(6): 415-419; 2006 International Journal of Diabetes Mellitus, 2010 April; 2(1):61-3
 Tertiary prevention

Secondary prevention

Primary prevention

Early
Early diagnosis isisimportant
intervention important! !
MANAGEMENT of TYPE 2 DM:
Early Intervention

Treatment target

HOW LOW SHOULD WE GO ?

 The benefits of early tight control:
UKPDS 10-year post-trial follow-up

1
2 2

Holman et al. N Engl J Med 2008;359:157789;

UKPDS Study Group. Lancet 1998;352:83753
 A1C
Blood pressure
<7%
Lipid
FPG
80 130
Blood glucose
mg/dL
Body weight
PPG
Others
< 180
mg/dL
Konsensus Perkeni 2015
MANAGEMENT of TYPE 2 DM :
Early Intervention

Reaching the target

WHEN and HOW SHOULD WE DO ?
 Physiologic Insulin Secretion:
24-hour Profile
Prandial insulin
50
Insulin
(U/mL) 25
Basal Insulin
0
Breakfast Lunch Dinner

Post Prandial Glucose

150
Glucose
(mg/dL) 100
50 Basal Glucose

0 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9
AM PM

Time of day
FIX FASTING FIRST:
Rationale for Basal Insulinization
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
Relative contribution (%)

70%
50
Fasting
30%

0
<7.3 7.38.4 8.59.2 9.310.2 >10.2
HbA1c (%) quintiles
ADA=American Diabetes Association; OHA=oral hypoglycaemic agent; PG=plasma glucose.
Adapted from Monnier L, et al. Diabetes Care 2003;26:8815.
 Treating fasting hyperglycaemia lowers the entire
24-hour plasma glucose profile

400
20

Plasma glucose (mmol/l)

Plasma glucose (mg/dl)

300 T2DM
15

200 Hyperglycaemia due to an increase in fasting glucose

10

100
5
Normal
Meal Meal Meal
0 0
6 10 14 18 22 2 6
Time of day (hours)

Comparison of 24-hour glucose levels in control subjects vs patients with diabetes (p<0.001).
Adapted from Polonsky K, et al. N Engl J Med 1988;318:12319.
A stepwise approach for the treatment of patients
with type 2 diabetes

A1C <7.0% Basal Bolus

Preprandial capillary PG 80130 mg/dl
Peak postprandial capillary PG <180 mg/dl Basal Plus
ADA-2015 Basal Plus Basal +
Two prandial three prandial
for largest
One prandial glucose
Basal Insulin for largest excursion
glucose
excursion
Once daily
OHA (optimized)
mono or
combination
therapy
Diet and
exercise
HbA1c HbA1c uncontrolled, FBG on target
uncontrolled PPBG>8.8 mmol/l (>160 mg/dl)
Time

Raccah D. Diabetes Ob Met 2008; 10: 76-82

Adapted from ADA. Diabetes Care 2015;38(Suppl.1)
 Basal Insulin
will cover fasting blood glucose & between
meals

Human Insulin
Humulin N, Insulatard HM
Analog Insulin:
Insulin Glargine (Lantus), Insulin Detemir (Levemir)
Bolus / Prandial / Mealtime Insulin
will cover prandial glucose

Insulin Human
Humulin R, Actrapid
Insulin Analog
Humalog, Novorapid, Apidra
 The simple way to add basal insulin
Initiate insulin with a single injection of a basal insulin
Bedtime or morning long-acting insulin OR
INITIATE Bedtime intermediate-acting insulin
Daily dose: 10 units or 0.2 units/kg

Check FBG Daily

In the event of hypoglycemia
Increase dose by 2 units every 3 days until or FBG level < 3.89 mmol/L (<
70 mg/dL)
FBG is 3.897.22 mmol/L (70130 mg/dL)
TITRATE Reduce bedtime insulin
If FBG is > 10 mmol/L (> 180 mg/dL), dose
increase dose by 4 units every 3 days by 4 units, or by 10% if >
60 units

Continue regimen and

MONITOR check HbA1c every 3 months

FBG, fasting blood glucose Adapted from Nathan DM, et al. Diabetologia 2006;49:171121
 Guidelines a new sense of urgency
Shorten delays in treatment changes
Achieve and maintain normal glycemic goals
Add medications, transition to new regimens
quickly
Whenever HbA1c levels are 7%

STEP 1: Lifestyle intervention + metformin

STEP 2: Add another agent basal insulin, SU or TZD
STEP 3: Intensify therapy
Timely basal insulin therapy for patients not meeting targets
Nathan DM, et al. Diabetologia 2006;49:171121
 Basal insulin limitations

When we add once-daily basal injection to existing OAD

regimen
Inadequate postprandial glycaemic control1
Significant postprandial hyperglycemia2 (case 2 and 3)
To overcome the above shortcomings, bolus therapy
(rapid acting insulin injections) added for prandial
hyperglycemia
More number of injections2
Increased self monitoring2
Patient motivation, educational-emotional support and good
cognitive function is needed increased burden on healthcare
resources2

1. Barnett A et al. Int J Clin Pract 2008; 62:1647-1653

2. Liebl A. Int J Clin Pract 2009; 63 (Suppl 164):1-5
 Matching treatment to disease progression using a
stepwise approach

Basal Plus: once-daily basal insulin glargine

plus once-daily* rapid-acting insulin glulisine
Basal Bolus
Add prandial insulin before each meal

Basal Plus
Add prandial insulin at main meal

Basal
Add basal insulin and titrate

Lifestyle changes plus metformin ( other agents)

Progressive deterioration of -cell function

*As the disease progresses, a second daily injection of glulisine may be added
Adapted from Raccah D, et al. Diabetes Metab Res Rev 2007;23:25764
 The Basal Plus strategy
using once-daily glargine + once-daily glulisine

Optimize fasting blood glucose

Titrate insulin glargine to control fasting BG to as close to normal
levels as possible
Add once-daily insulin glulisine at the main meal1
to control postprandial BG in candidates with:
HbA1c >7% to <9% despite optimal titration of glargine2
And FBG control close to or at target3

1Nathan DM, et al. Diabetes Care 2008;31:111; 2Del Prato S, et al. Diabetologia 2008;51 Suppl.
1:S452;
3Sanofi-aventis data on file. Glargine titration optimization: Using algorithms employed by clinical

studies for patients with type 2 diabetes, the target FPG should be 100 mg/dL (5.5 mmol/l)
 Straight to three bolus doses Sequential addition of bolus doses

Fix the FPG first using basal insulin (dose optimisation) Fix the FPG first using basal insulin (dose optimisation)
Goal: FPG 70-130 mg/dl Goal: FPG 70-130 mg/dl
Consider adding bolus insulin when: Consider adding bolus insulin when:
A1C >7% and FPG at goal or basal insulin dose >0.5 U/kg2 A1C >7% and FPG at goal or basal insulin dose >0.5 U/kg2

Add bolus 2U at each meal Add bolus 4U at the largest meal

Titrate to next pre-prandial goals (and bedtime) daily Titrate to next pre-prandial goals (and bedtime) goal daily

<70 mg/dl -1U If subsequent pre-meal sugars are:

70-130 mg/dl 0 <70 mg/dl -1U
>130 mg/dl +1U 70-130 mg/dl 0
>130 mg/dl +1U
Discontinues SU on addition of bolus insulin Discontinues SU on addition of bolus insulin
Patients need to monitor up to 4x per day Patients need to monitor up to 4x per day

If A1C >7% after 3 months despite titrating bolus dose, or bolus If A1C >7% after 3 months despite titrating bolus dose, or bolus
doses are more than 30 U per meal: dose is more than 30 U per meal:
Resume titration of basal insulin and/or consider performing a 7 Add 2nd bolus of 4U at 2nd largets meal and titrate as befor.
point profile Repeat for 3rd dose at final meal of the day

A. Pfu tzner, T. ForstInt. J Clin Pract, October 2009, 63 (Suppl. 164), 1114
 Insulin glulisine:
A novel rapid-acting insulin analogue
The two substitutions favour monomer formation and facilitate rapid
absorption from the tissue following subcutaneous injection
Human Rekombinan insulin analog Glu+ Lys=
Insulin glulisine:
Substitution of asparagine B3
Gluisine
with lysine, and of lysine B29
A chain with glutamic acid =substitution
Gly
S
1 S 20
Glu
B chain Gln Cys
Ala

Lys 5 Thr
Phe Gln Lys
Ile S Pro 30
1 Asn
S
10 15
His S S Phe
5 25
Gly
His
10 Leu 20
15
Qualitative composition

Unique Formula insulin glulisine Human Lispro Aspart Glulisine

Insulin
Components Function

Glycerol (85%) tonicity agent x x x ---

Zinc complexing agent x x x ---
Polysorbate 20 stabilising agent --- --- --- x

Becker RHA . Diabetes Ther & Tech 2007;9(1)109-21

 Insulin Glulisine has a more rapid time-action profile than RHI and
insulin lispro in non-diabetic
obese subjects
Insulin glulisine N=18 non-diabetic subjects; mean
Insulin lispro BMI: 34.7 kg/m2
RHI 6 (range: 3040); dose: 0.3 IU/kg

Glucose infusion rate (mg/kg/min)

200
Insulin concentration (mU/l)

150 4

100
2
50

0 0

0 120 240 360 480 600 0 120 240 360 480 600
Time (minutes) Time (minutes)

BMI=body mass index

Becker RH, et al. Exp Clin Endocrinol Diabetes 2005;113:43543. Reproduced with permission.
Insulin glulisine has a more rapid onset of action than insulin
lispro in lean to obese non-diabetic subjects

Insulin glulisine Insulin lispro

*p<0.05; **p<0.001 vs insulin lispro

10 Dose 0.2 U/kg 10 Dose 0.4 U/kg

(N=80) ** (N=80)
GIR AUC(0-1 h)/GIR AUC(0-10 h) (%)

GIR AUC(0-1 h)/GIR AUC(0-10 h) (%)

8 8
** **
6 6 ** **
*
4 * 4

2 2

0 0
All <25 2530 3035 35 All <25 2530 3035 35
BMI groups (kg/m2) BMI groups (kg/m2)

Heise T, et al. Diabetes Obes Metab 2007;9:74653.

Significantly greater improvement in HbA1c with insulin
glulisine compared with RHI

7.6

7.5
Insulin glulisine N=876 withT2DM;
7.4 RHI BMI=34.6 kg/m2 and
34.51kg/m2 in the insulin
HbA1c (%)

7.3
glulisine and RHI groups
7.2 respectively; NPH=basal
insulin
7.1

7.0
*
*p<0.05
6.9
*
Baseline 12 weeks 26 weeks

Similar incidence of symptomatic hypoglycaemia

NPH=neutral protein Hagedorn

Dailey G, et al. Diabetes Care 2004;27:23638. Reproduced with permission.
 POC study: adding glulisine to glargine further improves
glycemic control
Randomization
Endpoint
p=0.029*
40 9
% achieving HbA1c <7.0

p=0.0499
30
8

HbA1c (%)
8.0
20 7.8 7.8
22.4
7.5
7
10
8.8
0 6
Control Glargine Control Glargine
group + glulisine group + glulisine

*for difference in change in HbA1c

Sanofi-aventis data on file. Basal Plus (POC) study

 OPAL study: glargine + glulisine improves glycemic control
irrespective of whether glulisine is given with breakfast or the
main meal
Baseline
Endpoint
p=0.028 p=NS
60 9
% achieving HbA1c <7.0

p<0.0001 p<0.0001
52.2
40 8

HbA1c (%)
36.5

20 7 7.35 7.29
7.03
6.94

0 6
Breakfast Main meal Breakfast Main meal
group group group group

The main meal group also included subjects whose main meal was breakfast

Lankisch M, et al. Diabetes Obes Metab 2008;10:117885

 POC study: the Basal Plus approach is safe and
associated with only minor weight gain
0.6 10 0.3
p=NS p=NS p=NS

Severe symptomatic hypo

Mean body weight change

(event/patient-year)
(event/patient-year)
8

Symptomatic hypo
from baseline (kg)

0.5 8.19
0.4 7.68 0.2
6 0.2

4
0.2 0.1
0.2
2

0.0
0.0 0 0.0
Control Glargine Control Glargine Control Glargine
group + glulisine group + glulisine group + glulisine

Sanofi-aventis data on file. Basal Plus (POC) study

 OPAL study: the timing of glulisine addition to glargine
does not affect safety or weight gain

1.2 p=NS p=NS p=NS

4 0.05
Mean body weight change

1.0 3.69

(event/patient-year)
(event/patient-year)
0.04
from baseline (kg)

Confirmed hypo
1.0 0.04

Severe hypo
0.8 0.9
2.72 0.03
0.6 2
0.02
0.4
1
0.2 0.01
0.01
0.0 0 0.00
Breakfast Main Breakfast Main Breakfast Main
group meal group meal group meal

Lankisch M, et al. Diabetes Obes Metab 2008;10:117885

 Matching treatment to disease progression using a
stepwise approach
Basal Bolus: once-daily basal insulin glargine
plus 3 injections of rapid-acting insulin glulisine
(each injection before a meal)
The Gold Standard for advanced Basal Bolus
Add prandial insulin before each meal
type 2 diabetes

Basal Plus
Add prandial insulin at main meal

Basal
Add basal insulin and titrate

Lifestyle changes plus metformin ( other agents)

Progressive deterioration of -cell function

Adapted from Raccah D, et al. Diabetes Metab Res Rev 2007;23:25764

 In advanced type 2 diabetes, Basal Bolus therapy
reproduces physiological insulin secretion
Endogenous insulin secretion
Ideal basal insulin
Ideal prandial insulin

Breakfast Lunch Dinner

45
Insulin (mU/L)

30

15

0
06.00 12.00 18.00 24.00 06.00
Time (hours)

Adapted from Kruszynska YT, et al. Diabetologia 1987;30:1621

 Basal Bolus therapy delivers comparable good efficacy
whatever the titration algorithm used

100 8.5
8.16 Simple algorithm
% achieving HbA1c <7.0

p=NS
CHO counting
80 8.0
8.16
73

HbA1c (%)
60 69 7.5

40 7.0
ADA/EASD target 6.70
20 6.5
6.54
p=NS
0 6.0
Simple CHO Baseline 2 6 12 18 Endpoint
algorithm counting
Weeks

Bergenstal RM, et al. Diabetes Care 2008;31:130510

 The Basal Bolus strategy is safe and associated with
acceptable weight gain
p=NS p=0.02 p=NS

BG <50 mg/dL with symptoms

4 8 1.0
Mean body weight change

8.0

(event/patient-year)
(event/patient-year)
3.6 0.89
from baseline (kg)

0.8
3 6

Severe hypo
0.6 0.67
2 2.4 4 4.9
0.4
1 2
0.2

0 0 0.0
Simple CHO Simple CHO Simple CHO
algorithm counting algorithm counting algorithm counting

Bergenstal RM, et al. Diabetes Care 2008;31:130510

3.2 GINGER study

GINGER:
Basal Bolus provides superior glycemic control vs.
intensified premixed insulin therapy
Subjects:
310 with inadequately controlled type 2 diabetes (HbA1c 811%)
Pretreated with premixed insulin (mean of 5 years),
with some receiving metformin (continued during study)

Mean baseline values:

HbA1c (%): 8.5
Insulin glargine + three daily doses of insulin
BMI (kg/m2): 30.1 glulisine +/- metformin (n=153)
Diabetes duration (years): 13.0

Twice-daily premixed insulin +/- metformin (n=157)

Randomization 52 weeks

Fritsche A, et al. Diabetologia 2008;51 Suppl. 1:S83

3.2 GINGER study

GINGER:
Basal Bolus provides superior glycemic control vs.
intensified premixed insulin therapy
p=0.0004
50 9.0
8.6
% achieving HbA1c <7.0

47
40
8.5 p=0.0001
8.0

HbA1c (%)
30 7.7
28
20 7.3
7.0
10 Premixed insulin
Glargine + glulisine

0 6.0
Glargine Premixed 0 3 6 9 12
+ glulisine insulin Months

Fritsche A, et al. Diabetologia 2008;51 Suppl. 1:S83

3.2 GINGER study

GINGER: Basal Bolus has an acceptable safety profile in

late stage type 2 diabetes

p=0.007 p=NS p=NS

4 15 0.25
Mean body weight change

(event/patient-year)
(event/patient-year)
Symptomatic hypo
3.6 13.4 0.20
from baseline (kg)

3 0.2

Severe hypo
10
0.15
9.9
2
2.2
0.10
5 0.1
1
0.05

0 0 0.00
Glargine Premixed Glargine Premixed Glargine Premixed
+ glulisine insulin + glulisine insulin + glulisine insulin

Fritsche A, et al. Diabetologia 2008;51 Suppl. 1:S83

3.3 LACE study

LACE: insulin glargine + insulin glulisine in Basal Bolus

vs. premixed insulin in real-life conditions

Subjects:
197, mostly insulin treated, with type 2 diabetes (HbA1c 7%) and BMI 26 kg/m2
Prior to study, 88% on insulin and 70% on OHAs (continued during study)
Allowed to change treatment as needed, i.e. not following any specified protocol

Mean baseline values:

HbA1c (%): 9.25
BMI (kg/m2): 35.8 Insulin glargine + insulin glulisine +/- OHAs (n=106)
Diabetes duration (years): 13.0

Premixed insulin +/- OHAs (n=91)

Randomization 9 months

Lee F, et al. Diabetologia 2008;51 Suppl. 1:S406

3.3 LACE study

LACE: glargine + glulisine in Basal Bolus provides superior

glycemic control to premixed insulin in real-life
conditions
Baseline Baseline
Endpoint Endpoint
50 10
p=NS p=0.009
% achieving HbA1c <7.0

40
42 9
9.25 9.25

HbA1c (%)
30
30 8
20
7.52
7
10
6.93

0 6
Glargine Premixed Glargine Premixed
+ glulisine insulin + glulisine insulin

Lee F, et al. Diabetologia 2008;51 Suppl. 1:S406

3.3 LACE study

LACE: glargine + glulisine in Basal Bolus has the same

safety profile as premixed insulin therapy

0.4
p=NS
Hypoglycemia events

0.3
0.38
per month

0.2 0.24

0.1

0.0
Glargine + glulisine Premixed insulin

Lee F, et al. Diabetologia 2008;51 Suppl. 1:S406

 Conclusions (1/2)
Type 2 diabetes is a progressive disease that requires insulin intensification after
several years of evolution
Shorten delays in treatment changes to achieve and maintain normal glycemic
goals
A single daily injection of basal insulin glargine is a simple and effective way to
start insulin therapy
Maintains targets with a low risk of hypoglycemia
The dose of insulin glargine should be titrated for maximum and long-lasting
efficacy
If, despite adequate titration, the patient is still or no longer at target (HbA1c <7%),
addition of one shot of insulin glulisine at the main meal should be considered
The Basal Plus strategy, i.e. glargine once daily with glulisine once daily,
demonstrated combined efficacy with an acceptable safety profile
 Conclusions (2/2)
As the disease progresses, a second injection of prandial insulin at the second main meal
can be considered as a transition towards a Basal Bolus regimen
For patients with advanced type 2 diabetes who are still not at target, a Basal Bolus regimen
with insulin glargine and three daily doses of insulin glulisine should be considered
Insulin Glulisine has unique molecule structure and zinc-free formula. The unique molecular
structure of insulin Glulisine provides faster absorption and onset of action, plus stability
without the need for zinc
The Basal Bolus strategy reflects normal physiology of insulin secretion
The Basal Bolus strategy with once daily glargine and three times daily glulisine has an
acceptable safety profile, and has superior efficacy vs. premixed insulin regimens
Basal Bolus has superior efficacy compared with premixed insulin and an acceptable safety
profile:
In the GINGER study, significantly more subjects reached target HbA1c (47% vs. 28%)
In the real-life LACE study, HbA1c levels were significantly reduced
Basal-bolus strategy was associated with a lower incidence of hypoglycemia than
premix insulin, although not significant
Findings from a real life prospective study confirm the results of randomized controlled
clinical trials in terms of the superior efficacy of Basal-Bolus vs. premixed insulins
The Basal Bolus strategy is an optimized approach for patients with advanced type 2
diabetes
Thank you