Stepwise addition of prandial

insulin Glulisine after basal insulin

optimization
 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
Years from Diagnosis
HOMA, homeostasis model assessment
Adapted from Holman1 1. Holman RR. Diabetes Res Clin Pract 1998;40(Suppl 1):S21–5
Lebovitz H. Diabetes Review 1999;7:139-53 (modified) 2. UKPDS Group. Diabetologia 1991; 34:877–90
 T2DM is a progressive condition
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:
p995―1015.
Chronic Complications in Newly Diagnose Diabetes Mellitus
50% of patients had ≥ 1 complications

Stroke or TIA: 1% • Tertiary prevention

Retinopathy: 21%

NEWLY • Secondary prevention

DIABETES
Hypertension: 35%

• Primary prevention
Plasma creatinine
>120mol/l: 3%
Abnormal ECG : 18%

Intermittent
Claudicasio: 3% Early diagnosis is important !
Erectal Dysfuntion : 20% Early intervention is important !

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
 MANAGEMENT of TYPE 2 DM: Early Intervention

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

trial follow-up

Treatment target
HOW LOW SHOULD WE GO ?

Holman et al. N Engl J Med 2008;359:1577–89;

UKPDS Study Group. Lancet 1998;352:837–53
 A1C
Blood pressure
<7%
Lipid
FPG
Blood glucose 80 – 130
mg/dL
Body weight

Others
PPG
< 180
mg/dL
Konsensus Perkeni 2015
 MANAGEMENT of TYPE 2 DM :Early Intervention
Physiologic Insulin Secretion: 24-hour Profile

Prandial insulin
50
Insulin
(µU/mL) 25
Basal Insulin
0
Breakfast Lunch Dinner

Post Prandial Glucose

150
Glucose
(mg/dL) 100
50 Basal Glucose
Reaching the target
WHEN and HOW SHOULD WE 0 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9
DO ? 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 (%)

Treating fasting hyperglycaemia lowers the

70% entire 24-hour plasma glucose profile
50
Fasting
30% 400
20
0
<7. 7.3―8.4 8.5―9.2 9.3―10.2 >10.2

Plasma glucose (mmol/l)

Plasma glucose (mg/dl)
300 T2DM
3 HbA1c (%) quintiles
15
ADA=American Diabetes Association; OHA=oral
hypoglycaemic agent; PG=plasma glucose.
Adapted from Monnier L, et al. Diabetes Care 200 Hyperglycaemia due to an increase
2003;26:881―5. in fasting glucose 10

100
5
Normal
Meal Meal Meal
Comparison of 24-hour glucose levels in control subjects vs 0 0
patients with diabetes (p<0.001). 6 10 14 18 22 2 6
Adapted from Polonsky K, et al. N Engl J Med 1988;318:1231―9.
Time of day (hours)
 A stepwise approach for the treatment of
patients with type 2 diabetes

A1C <7.0% Basal Bolus

Preprandial capillary PG 80–130 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)
±16 hours

24 hours
 Long Acting Insulin Analog

Insulin Glargine
• Peakless
• Clear solution
• Basal Insulin
• Could be given 1 – 2
times a day
• Not for intravenous
use
 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 3.89–7.22 mmol/L (70–130 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;49:1711–21
 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;23:257–64
 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;31:1–11; 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), 11–14
 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: 30–40); 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;113:435–43. 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 Dose 0.4 U/kg

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

10

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

(N=80) ** (N=80)
8 8
**
** **
6 6 **
*
*
4 4

2 2

0 0
All <25 25–30 30–35 ≥35 All <25 25–30 30–35 ≥35
BMI groups (kg/m2) BMI groups (kg/m2)

Heise T, et al. Diabetes Obes Metab 2007;9:746−53.

Significantly greater improvement in HbA1c with insulin
glulisine compared with RHI
7.6

7.5
Insulin glulisine
7.4 RHI
HbA1c (%)

7.3
N=876 withT2DM;
BMI=34.6 kg/m2 and
7.2 34.51kg/m2 in the insulin
glulisine and RHI groups
7.1 respectively; NPH=basal
* insulin
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;27:2363–8. Reproduced with permission.
POC & OPAL study: adding glulisine to glargine further improves
glycemic control, whether glulisine is given with breakfast or the
main meal (OPAL Study)
*for difference in change in HbA1c Randomization
Endpoint p=0.029*
40 9
% achieving HbA1c <7.0

p=0.0499
30
8

HbA1c (%)
POC 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

p=0.028 p=NS
60 9
% achieving HbA1c <7.0

p<0.0001 p<0.0001
52.2
40 8
HbA1c (%)
OPAL
36.5
Baseline
20 7 7.35 7.29
7.03 Endpoint
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 Sanofi-aventis data on file. Basal Plus (POC) study
Lankisch M, et al. Diabetes Obes Metab 2008;10:1178–8
 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;10:1178–85

 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
type 2 diabetes 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

Adapted from Raccah D, et al. Diabetes Metab Res Rev 2007;23:257–64

 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;31:1305–10

 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;31:1305–10

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 8–11%)
• Pretreated with premixed insulin (mean of 5 years),
with some receiving metformin (continued during study)

Mean baseline values:

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

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
• Diabetes duration (years): 13.0 Insulin glargine + insulin glulisine +/- OHAs (n=106)

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 than premixed insulin and the same safety
profile as premixed insulin in real-life conditions
Baseline Baseline
Endpoint Endpoint
50 10 0.4
p=NS p=0.009 p=NS

Hypoglycemia events per month

40
% achieving HbA1c <7.0

42 9 0.3
9.2 9.25
5 0.3
30 8
HbA1c (%)

30 0.2 0.24
8
20

7.52
7 0.1
10
6.93

0 6 0.0
Glargine Premixed Glargine Premixed Glargine + Premixed
+ glulisine insulin + glulisine insulin glulisine insulin

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

 Conclusion
 T2DM: A progressive disease that requires insulin intensification
 A single daily injection of basal insulin glargine is a simple and effective way to start
insulin therapy
 Insulin Glulisine:
 Provides faster absorption and onset of action, plus stability without the need for zinc.
 Significantly greater improvement in HbA1c than RHI and insulin lispro.
 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
 POC & OPAL study: The Basal Plus strategy, i.e. glargine once daily with glulisine once daily,
demonstrated combined efficacy with an acceptable safety profile
 Basal Bolus: The Gold Standard for advanced type 2 diabetes
 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
Thank you