The basal plus strategy

Denis Raccah, MD, PhDProfessor of Medicine

University Hospital Sainte MargueriteMarseilleFRANCE

7

Check A1C every3 months until <7%. Change treatment if

A1C is ? 7%

Step 3

ADA/EASD guidelines recommend use of basal insulin as early as the second step in type 2 diabetes management

a Sulfonylureas other than glybenclamide or chlorpropamide.b Insufficient clinical safety data; CHF, congestive heart failure

Tier 1: Well-validated core therapies

At diagnosis:

Lifestyle+

Metformin

Lifestyle + Metforminplus

Basal Insulin

Lifestyle + Metforminplus

Sulfonylureaa

Lifestyle + Metforminplus

Intensive Insulin

Step 1 Step 2

Lifestyle + Metforminplus

PioglitazoneNo hypoglycemia

Oedema / CHFBone Loss

Lifestyle + Metforminplus

GLP-1 agonistbNo hypoglycemia

Weight lossNausea / vomiting

Tier 2: Less well-validated therapiesLifestyle + Metformin

plusPioglitazone

plusSulfonylureaa

Lifestyle + Metforminplus

Basal Insulin

ADA/EASD Guidelines. Diabetes Care 2008;31(12):1–11

The concept of basal insulin therapy

Postprandial hyperglycemia persists despite treatment of FBG using basal insulin

Yki-Järvinen H, et al. Diabetologia 2006;49:442-51.

Bloo

d gl

ucos

e (m

mol

/l)

4

12

8

16

Baseline

Weeks 25-36

Insulin glargine + metformin

Beforebreakfast

22:00 04:00Afterbreakfast

Beforelunch

Afterlunch

Beforedinner

Afterdinner

Basal insulin therapy reduces the entire 24-hour blood glucose profile, but postprandial hyperglycaemia persists — LANMET study data

Decline of β-cell function determines the progressive nature of T2DM

HOMA=homeostasis model assessment.UKPDS Group. Diabetes 1995;44:1249―58. Adapted from Holman RR Diabetes Res Clin Pract 1998;40(suppl 1):S21 5

β-ce

ll fu

ncti

on (

% o

f no

rmal

by

HO

MA

)

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

Insufficiency of basal insulin + OAD

Definition

– FBG < 100mg/dl,

– with HbA1c > 7% and/or PPG > 140-160 mg/dl,

– Suggesting that OAD (insulin secretagogues) loose their capability to control PPG, and that prandial insulin supplementation must be considered.

Insufficiency of basal insulin + OADdifferent situations

• 30 to 50% of patients treated by basal insulin do not reach theHbA1c target, at initiation, and despite optimisation of the dose (basal insulin is not enough)

Riddle M et al. Treat To Target. Diabetes Care 2005

• Natural history of the pancreatic disease in type 2 diabetes (basal insulin is no longer enough with time)

• Hypoglycemic risk during the titration of basal insulin making difficult to reach the FBG target

• Very high dose of basal insulin without significant effect on FBG, and weight gain ( severe insulin resistance)

Monnier et coll. Diab Metab 2006

What options are available when basal insulin therapyis no longer sufficient for glycemic control ?

Insulin intensification

1- Premix insulin

2- Basal Bolus regimen

3- The Basal Plus strategy

23

Lifestyle changes plus metformin (± other agents)

BasalAdd basal insulin and titrate

Basal PlusAdd prandial insulin at main meal

Basal BolusAdd prandial insulin before each meal

Progressive deterioration of β-cell function

Adapted from Raccah D, et al. Diabetes Metab Res Rev 2007; 23(4):257? 64

Type 2 diabetes: matching treatment to disease progression using a stepwise approach

Basal Plus: once-daily basal insulin plus once daily* rapid-acting insulin

*As the disease progresses, a second daily injection of prandial insulin may be added

• PPG is correlated to HbA1c

• The PPG is not the same according to the meals of the day, and vary from one patient to another, and from one country to another ( the highest being after breakfast in France, and after dinner in USA)

• The control of the highest PPG could influence the rest of the day.

Rationale for the « basal plus » strategy

Glycemic profile according to the country

1] Monnier J et coll. Diabetes Care 2002;25:737-41[2]Rosenstock J et coll. Chapter 9. In:CADRE Handbook of diabetes management.New York:Medical information press;2004:pp145-68

Raccah D et al. Diabetes Metab Res Rev 2007

« Basal Plus »

Basal insulin + prandial insulin at the main meal

Basal Plus: general considerations for treatment with once-daily basal insulin plus once daily rapid

prandial insulin

• Fix fasting first• Titrate basal insulin to control fasting BG

• For some patient candidates, basal will not be enough• Intensify treatment

• Add prandial insulin to control postprandial BG for efficacy and safety in patient candidates with: • HbA1c >7% to <9% despite optimal titration of basal insulin1

• And FBG control close to or at target2

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

POC: comparing Basal Plus therapy with insulin glargine alone

Patients:• Previously received basal insulin for ≥3 months• Previously received metformin, and continued to receive OHAs during the study

Design:

Randomization (patients with HbA1c

≥7.0%)

Patients with type 2 diabetes and HbA1c 7.5-9.5% receiving basal insulin and metformin for ≥3 months

3 months

Insulin glargine

3 months

Insulin glargine + OHAs (n=57)

Insulin glargine + once-daily insulin glulisine + OHAs (n=49)

Mean baseline values:• HbA1c (%): 8.5

• BMI (kg/m2): 33.1

• Duration of diabetes (years): 11.5

Open-label, multinational trial

POC: adding glulisine to glargine increases efficacy and improves glycemic control

Glargine Glargine + glulisine6.06.57.07.58.08.59.09.5

10.0Randomisation

Endpoint

HbA

1c (%

)

Glargine Glargine + glulisine0

10

20

30

40

Patie

nts

achi

evin

g H

bA1c

<7

(%)

7.8

24.4

p=0.025

8.07.87.8

7.4

p=0.024

POC: the Basal Plus approach is safe and associated with only minor weight gain and hypoglycemic risk

Insulin glargine (n=57) Insulin glargine + insulin glulisine (n=49)

BW change from baseline (kg) +0.2 ± 1.8 +0.5 ± 2.5

Symptomatic hypoglycemia (event/pt.yr)

7.68 ± 14.00 8.19 ± 14.60

Severe symptomatic hypoglycemia (event/pt.yr)

0.20 ± 0.10 0

OPAL study: assessment of Basal Plus efficacy comparing glulisine added at breakfast or main meal

Subjects:• 316 insulin treated with poorly controlled type 2 diabetes

(HbA1c >6.5–9.0%) • Previously received basal insulin glargine for ≥3 months

(OHAs continued during the study)

Mean baseline values:• HbA1c (%): 7.3• BMI (kg/m2): 31.3• Diabetes duration (years): 10.5

24 weeksRandomization

Insulin glulisine once daily at breakfast + basal insulin glargine (n=162)

Lankisch M, et al. Diabetes Obes Metab 2008;10:1178–85

OPAL study: glargine + glulisine improves glycemic control irrespective of whether glulisine is given with

breakfast or the main meal

2.2 OPAL study

BaselineEndpoint

Breakfastgroup

Main mealgroup

0

20

40

60

% a

chie

ving

HbA

1c<7

.0

36.5

52.2

p=0.028 p=NS

p<0.0001

HbA

1c (%

)6

7

8

9

7.357.03

7.296.94

Breakfastgroup

Main mealgroup

p<0.0001

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

Lankisch M, et al. Diabetes Obes Metab 2008;10:1178–85

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

2.2 OPAL study

p=NS

Breakfastgroup

Mainmeal

0.0

0.2

0.4

0.6

0.8

1.0

1.2

Mea

n bo

dy w

eigh

t cha

nge

from

bas

elin

e (k

g)

1.00.9

0

1

2

3

4

2.72

3.69

Con

firm

ed h

ypo

(eve

nt/p

atie

nt-y

ear)

Breakfastgroup

Mainmeal

p=NS

0.00

0.01

0.02

0.03

0.04

0.05

Breakfastgroup

Mainmeal

Seve

re h

ypo

(eve

nt/p

atie

nt-y

ear)

0.01

0.04

p=NS

Lankisch M, et al. Diabetes Obes Metab 2008;10:1178–85

Results: 8-point blood glucose profile injection at breakfast

Calculated for the per-protocol analysis set (N=316); data are mean; *p<0.05; †p<0.0001

2h-postbreakfast

2h-postlunch

2h-postdinner

3:00 a.m. Fasting Pre-lunch Pre-dinner Bedtime

100

120

140

160

180

Blo

od g

luco

se (m

g/dL

)

5.6

6.7

7.8

8.9

10.0

11.1

Blood glucose (m

mol/L)

BaselineEndpoint

time of injection

†

*†

†

†*

Results: 8-point blood glucose profile injection at lunch

Calculated for the per-protocol analysis set (N=316); data are mean; *p<0.05; †p<0.0001

2h-postbreakfast

2h-postlunch

2h-postdinner

3:00 a.m. Fasting Pre-lunch Pre-dinner Bedtime

100

120

140

160

180

Blo

od g

luco

se (m

g/dL

)

5.6

6.7

7.8

8.9

10.0

11.1

Blood glucose (m

mol/L)

BaselineEndpoint

time of injection

†

*

*

Results: 8-point blood glucose profile injection at dinner

Calculated for the per-protocol analysis set (N=316); data are mean; *p<0.05; †p<0.0001

2h-postbreakfast

2h-postlunch

2h-postdinner

3:00 a.m. Fasting Pre-lunch Pre-dinner Bedtime

100

120

140

160

180

Blo

od g

luco

se (m

g/dL

)

5.6

6.7

7.8

8.9

10.0

11.1

Blood glucose (m

mol/L)

BaselineEndpoint

time of injection

†

*

*†

ELEONOR: evaluating glycemic control with Basal Plus using two dose adjustment methods

Subjects:• 200 insulin naïve with poorly controlled type 2 diabetes • Receiving ≥1 OHA (metformin continued, other OHAs stopped)

Randomization to self-monitoring of BG or Telecare program

Glargine + once-daily glulisine

8–16 weeks

Insulin glargine

Standard-monitoring of BG (n=109)

Telecare program (n=91)

Run in

2.3 ELEONOR study

Del Prato S, et al. Diabetologia 2008;51 Suppl. 1:S452

Mean baseline values:• HbA1c (%): 8.9• BMI (kg/m2): 29.9• Diabetes duration (years): 10.9

24 weeks

ELEONOR: efficacy of Basal Plus approach is unaffected by the method of dose adjustment used

2.3 ELEONOR study

SMBG = self monitoring of blood glucoseDel Prato S, et al. Diabetologia 2008;51 Suppl. 1:S452

20

40

60

80

100

51 55

0% a

chie

ving

HbA

1c<7

.0

Telecare SMBG

p=NS

Baseline Start glulisine Endpoint

8.9

8.8

7.17.0

Basal

Basal plus

TelecareSMBG

6

7

8

9

10

11

HbA

1c (%

)

ELEONOR: the Basal Plus approach is associated with only minor weight gain and few hypoglycemic events

2.3 ELEONOR study

SMBG = self monitoring of blood glucoseDel Prato S, et al. Diabetologia 2008;51 Suppl. 1:S452

0.0

0.1

0.2

0.3

0.4

0.5

Mea

n bo

dy w

eigh

t cha

nge

from

bas

elin

e (k

g)

0.4

0.1

Telecare SMBG

p=NS

0.00

0.02

0.04

0.06

Rat

es o

f sev

ere

hypo

eve

nts

per p

atie

nt-y

ear 0.05

0.03

Telecare SMBG

p=NS

1.2.3 study: insulin glargine with addition of one, two or three 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=343)

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)

2.4 1.2.3 study

Sanofi-aventis data on file (1.2.3 study)

Mean study entry values:• HbA1c (%): 10.1• BMI (kg/m2): 35.0

1.2.3 study: intensification of Basal insulinwith mealtime glulisine injections

improves glycemic control

2.4 1.2.3 study

Sanofi-aventis data on file (1.2.3 study)

Run in Randomization Wk 8 Wk 16 Wk 24

7.40

7.0

HbA

1c (%

)

10.1910.19

10.16

7.44

7.29

8.0

9.0

10.0Glulisine 1xGlulisine 2xGlulisine 3x

Responders in the whole population (n=785)

Evolution of HbA1c in the randomized population (n=343)

0

20

40

60

80

Subjects who achieved HbA1c<7.0% with glargine during run in

Additional subjects who achievedHbA1c <7.0%with glulisine added toglargine

All subjects(n=785)

% a

chie

ving

HbA

1c<7

.0

23%

37%

Glargine(alone)

Glargine plus glulisine(patients with HbA1c >7%)

1.2.3 study: The Basal Plus strategy is associated with a reduced level of hypoglycaemia

p=NS for all other pairwise comparisons

2.4 1.2.3 study

Sanofi-aventis data on file (1.2.3 study)

x1 x2 x30

1

2

3

4

5

Mea

n bo

dy w

eigh

t cha

nge

from

bas

elin

e (k

g)

3.7 3.8 3.9

Glulisine

0

5

10

15

20

x1 x2 x3Glulisine

Con

firm

ed s

ympt

omat

ic h

ypo

(eve

nt/p

atie

nt-y

ear)

12.2 12.9

17.1

p=0.043

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

Seve

re o

r ser

ious

hyp

o(e

vent

/pat

ient

-yea

r)

x1 x2 x3Glulisine

0.10

0.300.26

« Basal Plus » in clinical practice

Initiation • 6 point glycemic profile during 3 consecutive days• Identification of the main meal ( highest PPG, greatest glycemic delta)• Add one injection of rapid-acting insulin analog at this main meal: initial dose:0,05 U / Kg

Titration

What’s about the OAD?• Some patients may stop or decrease the insulin-secretagogues (based on glycemic profile)• Continuation of metforminWhat’s about the basal insulin dose?• No change

Mean PPG> 140 mg/dl Increase 2 U

Mean PPG between 100 and 140 mg/dl No changeMean value of PPG at this meal for the two previous days

Mean PPG < 100 mg/dl Decrease 2 U

2. La stratégie "basale plus" : résumé

1Del Prato S et coll. Diabetologia 2008 ; 51 Suppl. 1 : S452, et Sanofi-aventis, données internes ; 2Nathan DM et coll. Diabetes Care 2008 ; 31 : 1–11 ; 3Raccah D et coll. Diabetes Metab Res Rev 2007 ; 23 : 257–64 ; 4Halbron M et coll. Diabetes Metab 2007 ; 33 : 316–20

Basal Plus – Conclusion 1

• Basal Plus is once-daily basal insulin plus once-daily rapid-acting insulin (before the main meal)

• Adding once-daily rapid insulin to basal insulin gives a significant improvement in HbA1c

• Further reductions in HbA1c concentrations• Additional patients able to achieve HbA1c <7.0% goal

(between 30 and 50 % according to the studies)

• When added to once-daily basal insulin, giving prandial insulin before breakfast is as effective as giving it before the main meal

• Basal Plus is the first intensification step to consider after optimization of the basal insulin dose

• Basal plus strategy is safe in terms of hypoglycemic risk

Basal Plus – Conclusion 2

When basal insulin is no longer enough

• Basal Plus will be compared to premix insulin ( ALL TO TARGET study)

• Stepwise addition of rapid acting insulin will be compared to full basal-bolus regimen (OSIRIS study)

The basal plus strategy

Denis Raccah, MD, PhDProfessor of Medicine

University Hospital Sainte MargueriteMarseilleFRANCE