The Physiological Basis for A1C Goal

Attainment with Basal Insulins in

Type 2 Diabetes

SAAS.GLA.16.09.0028b
menù
• Why is diabetes important
• How to improve prognosis of diabetes
• The role of basal insulin
menù
• Why is diabetes important
• How to improve prognosis of diabetes
• The role of basal insulin
THE GLOBAL DIABETES EPIDEMIC
Type 2 Diabetes ~90% 300 total
300
280 T2
200 150 total
Millions

140 T2

100
“Diabetes
will double 0
in 1995 2000 2010 2025
25 years”
Financial Times
6th Nov 2000
McCarthy and Zimmet, 1997 King et al 1998; Green, 1998 SAAS.GLA.16.09.0028b
 Estimated Yrs of Life Lost from DM

Emerging Risk Factors Collaboration. NEJM 2011; 364:829

 DIABETES IS A MICRO- and
MACRO-VASCULAR DISEASE

Eyes
(retinopathy) Brain and
cerebral
Heart and circulation
coronary
circulation (cerebrovascular
Kidney
disease)
(nephropathy)

Peripheral nervous
Lower limbs (system neuropathy)
(peripheral
vascular disease) Diabetic foot
(ulceration and
amputation)

70-80% of people with diabetes die of cardiovascular disease

International Diabetes Federation. Diabetes Atlas. Second Edition, 2003 SAAS.GLA.16.09.0028b
Effect of Complications on the Cost of Treating Diabetes

10000 Euros/pt/year
8000
8402
6000
6476
4000

2000 345 3308

0
Additional costs Type 2 Additional cost of Type 1
n = 7882 3532 1545 779
No complications Complications
SAAS.GLA.16.09.0028b
the DCCT-EDIC, UKPDS, STENO 2… messages
years 1993, 1998, 2008

be aggressive with
GLUCOSE CONTROL in T1 & T2 DM
at diabetes onset, or shortly after
to prevent long-term complications!

keep A1C <7.0%

• since clinical onset of diabetes, life-long…
• primarily in young, middle-age subjects free of
vascular complications
 Proportion of Type 2 Diabetic Patients
at HbA1c Goal in USA and Europe
USA Europe
100 100

80 80
69%
Patients (%)

Patients (%)
64%
60 60

40 36% 40 31%
20 20

0 0
< 7% ≥ 7% ≤ 6.5% > 6.5%
HbA1c (%) HbA1c (%)

(Koro et al., 2004; Liebl, 2002)

SAAS.GLA.16.09.0028b
 Too much time elapses between steps of intensification of oral
therapy – result: A1C remains HIGH over time and complications
develop
Prospective study: following 7,208 courses of treatment in patients with T2DM (1994-2002)
60 Glycaemic burden Last HbA1c (%) on treatment
9.6
Cumulative months HbA1c >7.0%

50

9.2
40

HbA1c (%)
30 8.8

20
8.4
10

0 8.0
D/E MF SU SU+MF D/E MF SU SU+MF
D/E=diet/exercise;MF=metformin;SU=sulphonylurea
Brown J, et al. Diabetes Care 2004;27:1535–1540 SAAS.GLA.16.09.0028b
 Mos A1C

Eli Lilly, EASD 2016

SAAS.GLA.16.09.0028b
 Mos A1C

Eli Lilly, EASD 2016

SAAS.GLA.16.09.0028b
 Characteristics of 57.920 T2DM patients initiating basal
insulin in Italy Years 2004-2011

Caratteristiche Media±ds
o%
Età (anni) Age (years) 62.1±11.2
Maschi (%) 53.4%
Durata diabete (anni) Diabetes 10.9±8.3
duration (years)
BMI (Kg/m2) 29.3±5.4
HbA1c (%) 8.9±1.6
HbA1c <=7% (%) 11.5%
HbA1c >8% (%) 68.6%
Pressione sistolica (mmHg) 140±20
Pressione diastolica (mmHg) 79±10
Colesterolo totale (mg/dl) 186±43
Colesterolo HDL (mg/dl) 48±13
Colesterolo LDL (mg/dl) 106±35
Trigliceridi (mg/dl) 166±129

Annali AMD, 2012

SAAS.GLA.16.09.0028b
Question 1: What is the average HbA1c level of T2DM
patients in your practice when they start on insulin?
1. ≥8% (≥ 64 mmol/mol)

2. ≥9% (≥ 75 mmol/mol)

3. ≥10% (≥ 86 mmol/mol)

4. ≥12% (≥ 108 mmol/mol)

SAAS.GLA.16.09.0028b
menù
• Why is diabetes important
• How to improve prognosis of diabetes
• The role of basal insulin
 Healthy eating, weight control, increased physical activity & diabetes education
Mono-
therapy Metformin
Efficacy* high
Hypo risk low risk
Weight neutral/loss
Side effects GI / lactic acidosis
Costs 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- & disease-specific factors):
Metformin Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Dual Sulfonylurea Thiazolidine- DPP-4 SGLT2 GLP-1 receptor Insulin (basal)
therapy† dione inhibitor inhibitor agonist
Efficacy* high high intermediate intermediate high highest
Hypo risk moderate risk low risk low risk low risk low risk high risk
Weight gain gain neutral loss loss gain
Side effects hypoglycemia edema, HF, fxs rare GU, dehydration GI hypoglycemia
Costs low low high high high variable

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- & disease-specific factors):
Metformin Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Triple Sulfonylurea Thiazolidine- DPP-4 SGLT-2 GLP-1 receptor Insulin (basal)
dione Inhibitor Inhibitor agonist
therapy + + + + + +
TZD SU SU SU SU TZD

or DPP-4-i or DPP-4-i or TZD or TZD or TZD or DPP-4-i

or SGLT2-i or SGLT2-i or SGLT2-i or DPP-4-i or Insulin§ or SGLT2-i

or GLP-1-RA or GLP-1-RA or Insulin§ or Insulin§ or GLP-1-RA

or Insulin§ or Insulin§

If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Metformin
+
Combination
injectable Basal Insulin + Mealtime Insulin or GLP-1-RA
therapy‡ Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 SAAS.GLA.16.09.0028b
 Healthy eating, weight control, increased physical activity & diabetes education
Mono-
therapy Metformin
Efficacy* high
Hypo risk low risk
Weight neutral/loss
Side effects GI / lactic acidosis
Costs 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- & disease-specific factors):
Metformin Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Dual Sulfonylurea Thiazolidine- DPP-4 SGLT2 GLP-1 receptor Insulin (basal)
therapy†
Efficacy*
Hypo risk
Weight
Side effects
high
moderate risk
gain
hypoglycemia
dione
high
low risk
gain
edema, HF, fxs
inhibitor
intermediate
low risk
neutral
rare
inhibitor
intermediate
low risk
loss
?
GU, dehydration
agonist
high
low risk
loss
GI
highest
high risk
gain
hypoglycemia
Costs low low high high high variable

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- & disease-specific factors):
Metformin Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Triple Sulfonylurea Thiazolidine- DPP-4 SGLT-2 GLP-1 receptor Insulin (basal)
dione Inhibitor Inhibitor agonist
therapy + + + + + +
TZD SU SU SU SU TZD

or DPP-4-i or DPP-4-i or TZD or TZD or TZD or DPP-4-i

or SGLT2-i or SGLT2-i or SGLT2-i or DPP-4-i or Insulin§ or SGLT2-i

or GLP-1-RA or GLP-1-RA or Insulin§ or Insulin§ or GLP-1-RA

or Insulin§ or Insulin§

If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Metformin
+
Combination
injectable Basal Insulin + Mealtime Insulin or GLP-1-RA
therapy‡ Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 SAAS.GLA.16.09.0028b
 Healthy eating, weight control, increased physical activity & diabetes education
Mono-
therapy Metformin
Efficacy* high
Hypo risk low risk
Weight neutral/loss
Side effects GI / lactic acidosis
Costs 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- & disease-specific factors):
Metformin Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Dual Sulfonylurea Thiazolidine- DPP-4 SGLT2 GLP-1 receptor Insulin (basal)
therapy†
Efficacy*
Hypo risk
Weight
Side effects
high
moderate risk
gain
hypoglycemia
dione
high
low risk
gain
edema, HF, fxs
inhibitor
intermediate
low risk
neutral
rare
inhibitor
intermediate
low risk
loss
?
GU, dehydration
agonist
high
low risk
loss
GI
highest
high risk
gain
hypoglycemia
Costs low low high high high variable

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- & disease-specific factors):
Metformin Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Triple Sulfonylurea Thiazolidine- DPP-4 SGLT-2 GLP-1 receptor Insulin (basal)
dione Inhibitor Inhibitor agonist
therapy + + + + + +
TZD SU SU SU SU TZD

or DPP-4-i or DPP-4-i or TZD or TZD or TZD or DPP-4-i

or SGLT2-i or SGLT2-i or SGLT2-i or DPP-4-i or Insulin§ or SGLT2-i

or GLP-1-RA or GLP-1-RA or Insulin§ or Insulin§ or GLP-1-RA

or Insulin§ or Insulin§

If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Metformin
+
Combination
injectable Basal Insulin + Mealtime Insulin or GLP-1-RA
therapy‡ Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 SAAS.GLA.16.09.0028b
 Natural history of Type 2 DM

NGT IGT/IFG T2D

Diet OHGAs OHGAs
+ Insulin

Insulin sensitivity remains low

Time (years)
IFG: Impaired fasting glucose; IGT: Impaired glucose tolerance;
NGT: Normal glucose tolerance; OHGA: Oral hypoglycaemic agent.
 ADA-EASD 2015
\

???

SAAS.GLA.16.09.0028b
Question 2: What do you consider to be the greatest
barrier to insulin initiation for your patients?
1. Fear or experience of hypoglycemia

2. They do not perceive sufficient

benefit

3. Complex titration algorithm

4. Interference with activities of daily

living

5. Fear of weight gain

6. Fear of injecting

SAAS.GLA.16.09.0028b
B year 2016
Menu
• Why is diabetes important
• How to improve prognosis of diabetes
• The role of basal insulin
 24-Hour Plasma Glucose in failure to OHA

22.2

Diabetic
16.6 T2

Glucose
(mmol/L) 11.1

5.5

Normal
0
0600 1000 1400 1800 2200 0200 0600

Time of Day
courtesy of Jay Skyler
adapted from Polonsky et al, N Engl J Med 1988 SAAS.GLA.16.09.0028b
 Physiology of Glucose Homeostasis known
9.0
only since 1980

Glucose (mmol/l)
Meals
7.0

5.0

480
Insulin (pmol/l)

320 Normal Subjects

Mean ± 2SD
160

0700 1200 1800 2400 0600 hrs

Ciofetta M. et al., DIabetes Care 22:795-800, 1999 SAAS.GLA.16.09.0028b
 Physiology of Glucose Homeostasis known only since 1980
Meals
9.0

Glucose (mmol/l)
∼4 h ∼5 h ∼9 h

7.0 total ∼18 h

PG control
by basal
insulin
5.0

480
Insulin (pmol/l)

Normal Subjects
320 Mean ± 2SD

160

0700 1200 1800 2400 0600 hrs

Ciofetta M. et al., DIabetes Care 22:795-800, 1999 SAAS.GLA.16.09.0028b
 24-Hour Plasma Glucose in failure to OHA

Effect of treatment with basal insulin

22.2

Diabetic
16.6 T2

Glucose
(mmol/L) 11.1

5.5

Normal
0
0600 1000 1400 1800 2200 0200 0600

Time of Day
courtesy of Jay Skyler
adapted from Polonsky et al, N Engl J Med 1988 SAAS.GLA.16.09.0028b
 9.0

Glucose (mmol/l)
Meals
7.0

5.0

480
Normal Subjects
Insulin (pmol/l)

Mean ± 2SD
320

30-60 pmol/l
160 5-10 mU/L

0700 1200 1800 2400 0600 hrs

SAAS.GLA.16.09.0028b
Take home message #1

• Basal insulin should be initiated early, when A1C is no

longer controlled <7.0% by 1-2 drugs

• Basal insulin must be titrated

 9.0

Glucose (mmol/l)
Meals
7.0

5.0

480
Normal Subjects
Insulin (pmol/l)

Mean ± 2SD
320

30-60 pmol/l
160 5-10 mU/L

0700 1200 1800 2400 0600 hrs

 Ideal Basal Insulin
• safety and tolerability profile

• Flat PK/PD, long (24 h and a little beyond) –

mimicking CSII*

• Low within-subject variability

• Flexible dosing

• Available to all patients at a sustainable price

*CSII: continuous subcutaneous insulin infusion

 Year 2000
Long-acting Analogues Post-NPH Era
basal insulin
s.c. injection
Plasma Glucose

205 205
mg/dl

150 150
NPH
Gla-100
95 95

Subjects with Type 1 DM

Mean±SE
4
Glucose Infusion Rate

NPH
3
INSULIN ACTION
mg/Kg/min

1 Gla-100
0

0 2 4 6 8 10 12 14 16 18 20 22 24
Rossetti P. et al., Arch. Physiol. Biochem., 114:3-10, 2008 Time (hours)
 Year 2000
Long-acting Analogues Post-NPH Era
basal insulin
s.c. injection
detemir
Plasma Glucose

205 205
mg/dl

150 150
NPH
Gla-100
95 95

Subjects with Type 1 DM

Mean±SE
4
Glucose Infusion Rate

NPH
3
INSULIN ACTION
mg/Kg/min

1 Gla-100
0
detemir
0 2 4 6 8 10 12 14 16 18 20 22 24
Rossetti P. et al., Arch. Physiol. Biochem., 114:3-10, 2008 Time (hours)
 Consistent achievement of A1C ∼7.0%
with basal insulin

Baseline Study endpoint (after insulin glargine 100 U/mL treatment)

HbA1c changes (%)

TTT1 LANMET2 APOLLO3 LAPTOP4 Triple Therapy5 INITIATE6

1. Riddle M, et al. Diabetes Care 2003;26:3080–6. 2. Yki-Järvinen H, et al. Diabetes Care 2006;49:442–51.
3. Bretzel RG, et al. Lancet 2008;371:1073−84. 4. Janka H, et al. Diabetes Care 2005;28:254−9.
5. Rosenstock J, et al. Diabetes Care 2006;29:554–9. 6. Yki-Järvinen H, et al. Diabetes Care 2007;30:1364–69.
SAAS.GLA.16.09.0028b
 Proof of Concept: Initial Report on the Treat To Target Study
Combination Oral Agents + Gla-100 vs NPH

FBG HbA1c
mmol/l %
50 11 Both Treatment Groups 0.4-0.5 units/Kg 45
11.1 9.0
Total Daily Dose (units)

40 8.6
8.3 8.5
6.5
30
8.0
5.5
20 7.5
10 2.7
6.9 7.0
10
Units : Starting dose 10 units
0
6.5
0
0 2 4 6 8 12 18 24 weeks

Rosenstock J, et al. Diabetes. 2001;50(suppl 2):A520.

SAAS.GLA.16.09.0028b
 Self-adjustment of the insulin dose

FASTING PLASMA GLUCOSE

3 TIMES > 5.5 mmol/l (> 100 mg/dl):

ADD 2 UNITS OF BASAL INSULIN

SAAS.GLA.16.09.0028b
 Patient driven algorithms
• Simplified patient-directed titration algorithms may as effective, if not
more, than titration conducted by clinicians1–3
• Allowing patients to self-adjust insulin doses can empower them to
manage their disease and give them the confidence to become more
involved in their treatment2
• At the same time, education is important and patient empowerment
through education for successful self-management may play a key role
in optimizing metabolic and risk factor control as well as quality of life4

1. Garg SK, et al. Endocr Pract 2015;21:143–57;

2. Khunti K, et al. Diabetes Obes Metab 2013; 5: 690–700.
3. Davies M, et al. Diabetes Care 2005;28:1282–8;
4. Gagliardino JJ, et al. Diabetes Metab 2012;38:128–34. SAAS.GLA.16.09.0028b
Question 3: What percentage of your patients self-
titrate their insulin doses?
1. 0–20%

2. 21–40%

3. 41–60%

4. 61–80%

5. 81–100%

SAAS.GLA.16.09.0028b
 Healthy eating, weight control, increased physical activity & diabetes education
Mono-
therapy Metformin
Efficacy* high
Hypo risk low risk
Weight neutral/loss
Side effects GI / lactic acidosis
Costs 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- & disease-specific factors):
Metformin Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Dual Sulfonylurea Thiazolidine- DPP-4 SGLT2 GLP-1 receptor Insulin (basal)
therapy†
Efficacy*
Hypo risk
Weight
Side effects
high
moderate risk
gain
hypoglycemia
dione
high
low risk
gain
edema, HF, fxs
inhibitor
intermediate
low risk
neutral
rare
inhibitor
intermediate
low risk
loss
?
GU, dehydration
agonist
high
low risk
loss
GI
highest
high risk
gain
hypoglycemia
Costs low low high high high variable

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- & disease-specific factors):
Metformin Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Triple Sulfonylurea Thiazolidine- DPP-4 SGLT-2 GLP-1 receptor Insulin (basal)
dione Inhibitor Inhibitor agonist
therapy + + + + + +
TZD SU SU SU SU TZD

or DPP-4-i or DPP-4-i or TZD or TZD or TZD or DPP-4-i

or SGLT2-i or SGLT2-i or SGLT2-i or DPP-4-i or Insulin§ or SGLT2-i

or GLP-1-RA or GLP-1-RA or Insulin§ or Insulin§ or GLP-1-RA

or Insulin§ or Insulin§

If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Metformin
+
Combination
injectable Basal Insulin + Mealtime Insulin or GLP-1-RA
therapy‡ Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 SAAS.GLA.16.09.0028b
 Initiation and progression of
insulin treatment in T2DM

Basal -plus

ADA, EASD
Diabetes Care, Diabetologia 2012 SAAS.GLA.16.09.0028b
 Healthy eating, weight control, increased physical activity & diabetes education
Mono-
therapy Metformin
Efficacy* high
Hypo risk low risk
Weight neutral/loss
Side effects GI / lactic acidosis
Costs 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- & disease-specific factors):
Metformin Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Dual Sulfonylurea Thiazolidine- DPP-4 SGLT2 GLP-1 receptor Insulin (basal)
therapy†
Efficacy*
Hypo risk
Weight
Side effects
high
moderate risk
gain
hypoglycemia
dione
high
low risk
gain
edema, HF, fxs
inhibitor
intermediate
low risk
neutral
rare
inhibitor
intermediate
low risk
loss
?
GU, dehydration
agonist
high
low risk
loss
GI
highest
high risk
gain
hypoglycemia
Costs low low high high high variable

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- & disease-specific factors):
Metformin Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Triple Sulfonylurea Thiazolidine- DPP-4 SGLT-2 GLP-1 receptor Insulin (basal)
dione Inhibitor Inhibitor agonist
therapy + + + + + +
TZD SU SU SU SU TZD

or DPP-4-i or DPP-4-i or TZD or TZD or TZD or DPP-4-i

or SGLT2-i or SGLT2-i or SGLT2-i or DPP-4-i or Insulin§ or SGLT2-i

or GLP-1-RA or GLP-1-RA or Insulin§ or Insulin§ or GLP-1-RA

or Insulin§ or Insulin§

If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Metformin
+
Combination
injectable Basal Insulin + Mealtime Insulin or GLP-1-RA
therapy‡ Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 SAAS.GLA.16.09.0028b
Summary
• Type 1 DM should be treated by dedicated doctor
• Type 2 DM treated by doctor:
early diagnosis
early aggressive treatment with A1C <7.0%
NEVER use SU/glinides (SGLT2: wait and see)
love insulin (basal)

SAAS.GLA.16.09.0028b
IN T2 DM, USE INSULIN…

…according to the rule of the

5M
SAAS.GLA.16.09.0028b
IN T2 DM, USE INSULIN…
• MORE (in more patients)
• MORE EARLY (at diagnosis, or shortly
after)
• MORE PHYSIOLOGICALLY (prefer basal
insulin first, add prandial later as
needed – do not mix…)
• MORE AGGRESSIVELY (treat to target)
and
• MORE SAFELY (minimize hypoglycaemia)

SAAS.GLA.16.09.0028b
 INSULIN…

…a natural hormone
created by Nature, not
by drug companies !!!

…exactly what it is missing

in people with diabetes!!!
SAAS.GLA.16.09.0028b
Basal Insulin Dose Optimization:
Current evidence and clinical perspectives
 Objectives
• Understand the reasons for suboptimal glycemic control in Asian
T2DM patients
• Understand the benefits of early basal insulin initiation and subsequent
dose titration for achieving optimal glycemic control in T2DM patients

OAD, oral antidiabetic drug; T2DM, type 2 diabetes mellitus.

Content

Basal insulin: Asian perspective

Basal insulin: dose titration strategies

Basal insulin: dose optimization

Content

Basal insulin: Asian perspective

Basal insulin: dose titration strategies

Basal insulin: dose optimization

Question 1:

Approximately, what percentage of patients in your clinical practice

have reached adequate glycemic control (i.e. HbA1c<7%)?

1. 0–20%

2. 21–40%

3. 41–60%

4. 61–80%

5. 81–100%
 Majority of T2DM patients in Asia-Pacific region fail to achieve
glycemic targets (HbA1c<7%)
HbA1c above target HbA1c at or below target*
Australia Thailand Singapore India Indonesia
(St Vincent’s1) 2
(Diab Registry ) 3
(Diabcare ) (DEDICOM4) (DiabCare5)

30.0% 26.3% 33.0% 32.1%

37.8%
70.0% 67.0% 62.2% 67.9%
69.8%

Hong Kong China S. Korea Malaysia Philippines

(Diab Registry6) (Diabcare7) (KNHANES8†) (DiabCare9) (DiabCare10)

15.0%
39.7% 41.1% 43.5% 22.0%

60.3% 58.9% 56.5% 78.0% 85.0%

DEDICOM, Delhi Diabetes Community; HbA1c, glycated hemoglobin; KNHANES, Korea National Health and Nutrition Examination Survey; T2DM, type 2 diabetes mellitus;
* An HbA1c ≤7% or <7%; † Both type 1 and 2 diabetic patients.

1. Bryant W, et al. MJA 2006; 185:305–9; 2. Kosachunhanun N, et al. J Med Assoc Thai 2006; 89:S66–71; 3. Lee WRW, et al. Singapore Med J 2001; 42:501–7; 4. Nagpal J &
Bhartia A. Diabetes Care 2006; 29:2341–8; 5. Soewondo P, et al. Med J Indones 2010; 19:235–44; 6. Tong PC, et al. Diabetes Res Clin Pract 2008; 82:346–52; 7. Pan C, et al.
Curr Med Res Opin 2009; 25:39–45; 8. Choi YJ, et al. Diabetes Care 2009; 32:2016–20;
9. Mafauzy M, et al. Med J Malaysia 2011; 66:175–81; 10. Jimeno CA, et al. Phil. J Int Med 2012; 50:15–22.
 Majority of T2DM patients in Asia fail to achieve glycemic targets
(HbA1c <7%)
• The JADE program
– Significant proportion of patients with diabetes do not achieve any target
Total HK India Korea Philippines Singapore Taiwan Thailand
(n=3687) (n=832) (n=788) (n=295) (n=1186) (n=256) (n=55) (n=275)

HbA1C <7% 35.3 61.8 13.8 40.7 31.3 35.2 25.5 29.8

No targets 32.6 14.3 38.3 28.1 42.2 42.8 40.0 23.3

1 target 38.7 37.1 40.6 36.6 39.2 37.9 43.6 37.5

2 targets 23.4 36.3 19.2 29.8 16.2 15.2 12.7 29.8

3 targets 5.4 12.3 1.9 5.4 2.5 3.1 3.6 9.5

HK, Hong Kong; JADE, Joint Asia Diabetes Evaluation; T2DM, type 2 diabetes mellitus.

So WY, et al. J Diabetes 2011; 3:109–18.

 Initiation of basal insulin is often delayed in Asia
• International guidelines recommend considering initiation of basal
insulin soon after the failure of monotherapy;3 despite this, evidence
suggests that insulin initiation in Asia is often delayed
• FINE Asia study2
– T2DM patients were poorly controlled, with a diabetes duration of 9.3 years and an
HbA1c level of 9.8% at basal insulin initiation in the FINE Asia study

• CREDIT study3
– T2DM patients were also poorly controlled, with a diabetes duration of 9 years and
an HbA1c level of 9.2% at insulin initiation in the CREDIT study

The average time to initiation of insulin is ≥9 years1,2

CREDIT, Cardiovascular Risk Evaluation in people withType 2 Diabetes on Insulin Therapy;

FINE, First Basal Insulin Evaluation; T2DM, type 2 diabetes mellitus.

1. Inzucchi SE, et al. Diabetes Care 2015; 38:140–9; 2. Tsai ST, et al. J Diabetes 2011; 3:208–16;
3. Balkau B, et al. Diabetes Res Clin Pract 2015; 108:432–40.
 Clinical inertia: failure to advance therapy
Mean in HbA1c at last visit (%)

Time to insulin initiation >9 years1–3

HbA1c levels are higher at each step or addition of a new medication
and show that late initiation of insulin contributes to a worsening
pattern of failure to achieve glucose control targets
ADA, American Diabetes Association; CREDIT, Cardiovascular Risk Evaluation in People with Type 2 Diabetes on Insulin Therapy;
EASD, European Association for the Study of Diabetes; SU, sulfonylurea.

Brown JB, et al. Diabetes Care 2004; 27:1535–40.

 Contributions of basal and postprandial hyperglycemia in
insulin-naïve T2DM patients
• On OAD therapy, fasting (basal) hyperglycemia dominates over a wide range
of HbA1c*
Postprandial hyperglycemia Basal hyperglycemia
100

80

60 76% 78% 79% 79% 80%

40

20
24% 22% 21% 21% 20%
0
<8.0 8.0–<8.5 8.5–<9.0 9.0–<9.5 ≥9.5
Baseline HbA1c ranges
OAD, oral antidiabetic drug; T2DM, type 2 diabetes mellitus; *Pooled baseline data from six treat-to-target studies (n=1699 T2DM patients
on diet ± OADs). Mean HbA1 8.69%, FPG 10.8 mmol/L (194 mg/dL); Calculations assume hyperglycemia is >5.6 mmol/L (100 mg/dL).

Riddle M, et al. Diabetes Care 2011; 34:2508–14.

 Early intervention with basal insulin maintains glycemic control in
the long term
Clinical inertia
OAD OAD
OAD monotherapy OAD OAD + multiple daily
DietIntervention!
monotherapy uptitration combination + basal insulin insulin injections
HbA1c (%)
Intervention!
10 Basal insulin

9 Intervention!
Intervention!
8
Intervention!

OAD, oral antidiabetic drug. Duration of diabetes (years)

Del Prato S, et al. Int J Clin Pract 2005; 59:1345–55.

Question 2

When do you usually recommend the initiation of basal

insulin for your T2DM patients?
1. After failure to reach glycemic targets
on monotherapy with metformin

2. After failure to reach glycemic targets

on dual therapy with two OADs

3. When a patient presents with a

HbA1c>9%

4. When a patient presents with

symptomatic hyperglycemia
 ADA/EASD position statement 2015

• ADA/EASD guidelines recommend that if target HbA1c (<7%) is

not achieved “within 3 months of monotherapy with metformin
along with healthy eating, weight control, increased physical
activity and diabetes education” treatment intensification with a
“two-drug combination” should be initiated.

• Among the different options for dual therapy with metformin, the
guidelines state that basal insulin is of the “highest efficacy”

ADA, American Diabetes Association; EASD, European Association for the Study of Diabetes.

Inzucchi SE, et al. Diabetes Care 2015; 38:140–9.

 Insulin glargine is an extensively studied basal
insulin used for diabetes treatment

Indication
• Insulin glargine (Lantus) is a long-acting insulin analog
indicated to improve glycemic control in adults and pediatric
patients with type 1 diabetes mellitus and in adults with T2DM.

• Insulin glargine can be administered at any time of the day but

should be administered once a day at the same time every day1

Insulin glargine offers flexible dose adjustments to meet individual patients’ needs2,3

T2DM, type 2 diabetes mellitus.

1. Sanofi. LANTUS® (Insulin Glargine) Prescribing Information. USA, 2015;

2. Strange P. J Diabetes Sci Technol 2007; 1;540–8; 3. Barnett A. Clin Ther 2007; 29:987–99.
 Outcomes from treat-to-target studies with basal
insulin (insulin glargine)
• HbA1c<7% can often be attained1–3
• Basal insulin is well tolerated
– Nocturnal hypoglycemia is reduced1
– Rates of daytime hypoglycemia are low1
– Severe hypoglycemia is infrequent1,4
• Treatment with basal insulin before HbA1c reaches >8% increases the
chance of achieving glycemic control1,2

1. Riddle MC, et al. Diabetes Care 2003; 26:3080–6; 2. Banerji MA, et al. Postgrad Med 2014; 126:111–25;
3. Gerstein HC, et al. Diabet Med 2006; 23: 736–42; 4. Yki-Järvinen H, et al. Diabetes Care 2007; 30:1364–9.
 ORIGIN: insulin provides long-term near-normal glycemic control
Patients on insulin glargine
ORIGIN study achieved and maintained low HbA1c
• Patients with IGT, IFG or early
7.0
T2DM at high CV risk† 6.5 6.5 6.5
6.4 6.4

HbA1c, %
• N=12,537 6.5
6.4
6.2
6.3
• Randomized to insulin glargine 6.4
6.0 6.3
(with a target FPG ≤95 mg/dL 6.1
6.2 6.2
6 6
[5.3 mmol/L]) vs standard care 5.5
5.9
• Median follow-up of 6.2 years 0 1 2 3 4 5 6 7
Years
Gla Standard care

• When used to target normal FPG levels for more than 6 years, insulin glargine had a
neutral effect on the primary CV endpoints and cancers vs standard care*
• Rates of severe hypoglycemia were 1.00 versus 0.31 per 100 person-years
• Median weight increased by 1.6 kg in the insulin glargine group and fell by 0.5 kg in the
standard-care group
CV, cardiovascular; FPG, fasting plasma glucose; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; ORIGIN, Outcome Reduction with an Initial Glargine Intervention;
T2DM, type 2 diabetes mellitus; * Co-primary outcomes were nonfatal myocardial infarction, nonfatal stroke, or death from CV causes, and these events plus revascularization or
hospitalization for heart failure; † The enrolled population in ORIGIN is broader than the population indicated for Lantus®.

ORIGIN Investigators. N Engl J Med. 2012; 367:319–28.

Content

Basal insulin: Asian perspective

Basal insulin: dose titration strategies

Basal insulin: dose optimization

 ADA/EASD 2015: approach to starting and adjusting
insulin in T2DM

• Basal insulin alone convenient initial regimen (10 U or 0.1–

0.2 U/kg), depending on the degree of hyperglycemia.

• Usually prescribed in conjunction with metformin and

possibly one additional non-insulin agent.

• Once insulin is initiated, dose titration is important

ADA, American Diabetes Association; EASD, European Association for the Study of Diabetes; T2DM, type 2 diabetes mellitus.

Inzucchi SE, et al. Diabetes Care 2015;38:140–9.

 Insulin titration according to the guidelines
• Once initiated, basal insulin is ideally titrated from a low starting dose (usually 10 U/day)
to achieve therapeutic efficacy using various titration algorithms
ADA/
EASD 20151 AACE/ACE 20162 IDF 20123

10 U/day or HbA1c <8%: 0.1–0.2 U/kg Starting doses of insulin for

Initial dose per day
0.1–0.2/kg/day HbA1c >8%: 0.2–0.3 U/kg safety reasons should be low

Titration increase dose Fixed regimen: Increase TDD of basal insulin Self-titration regimen: insulin
2–4 U once or by 2 U every 2–3 days dose increases of 2 U every 3
twice weekly Adjustable regimen: days
Titrate insulin every 2–3 days according to: Physician led: biweekly or
FBG> 180 mg/dL: add 20% of TDD with more frequent contact with
FBG 140–180 mg/dL: add 10% of TDD a health-care professional
FBG 110–139 mg/dL: increase dose by 1 U
Target FPG, mg/dL
– <110 (6.1) <117 (6.5)
(mmol/L)
Target HbA1c, % <7 <7 <7
Down titration-
Decrease dose BG <70 mg/dL: decrease TDD by 10–20%
dealing with –
by 4 U BG <40 mg/dL: decrease TDD by 20–40%
hypoglycemia

FPG, fasting plasma glucose; FBG, fasting blood glucose;TDD, total daily dose.

1. Inzucchi SE, et al. Diabetes Care 2015;38:140–9; 2. Garber AJ, et al. Endocr Pract 2016;22:84–113;
3. International Diabetes Federation. Global Guideline for Type 2 Diabetes. 2012;
Available at: http://www.idf.org/sites/default/files/IDF-Guideline-for-Type-2-Diabetes.pdf (accessed September 2016).
 Dose titration of insulin glargine
• The dose of insulin glargine should be adjusted according to an
individual’s metabolic needs and blood glucose measurements to
reach their glycemic control goal

• The dosage of insulin glargine should be individualized under the

supervision of a treating healthcare professional

Sanofi. LANTUS® (Insulin Glargine) Prescribing Information. USA, 2015.

 Simple up/down treat-to-target titration algorithms with insulin
glargine for individual dose adjustments
• Different titration algorithms based on FPG values have proven to be effective
in numerous clinical studies
Frequency of Down titration-
Study FPG (mmol/L) Dose titration dose titration dealing with hypoglycemia
INSIGHT1 Until ≤5.5 Add 1 unit Daily Doses were reduced at the discretion
of the investigator in response to
biochemical or clinical hypoglycaemia
LANMET2 • >10 • Add 4 units Every 3 days
• >5.5 • Add 2 units

TTT3 • ≥10 • Add 8 units Weekly Severe hypoglycaemia: decrease in

• 7.8–10 • Add 6 units insulin dose 2–4 U/day per
• 6.7–7.8 • Add 4 units adjustment
• 5.6–6.7 • Add 2 units

FPG, fasting plasma glucose; INSIGHT, Implementing New Strategies with Insulin Glargine for Hyperglycaemia Treatment; LANMET, Insulin glargine or NPH
combined with metformin in type 2 diabetes; TTT, Treat-to-Target Trial.

1.Gerstein HC, et al. Diabetes Med 2006; 23:736–42; 2. Yki-Järvinen H, et al. Diabetologia 2006; 49:442–51;
3. Riddle MC, et al. Diabetes Care 2003; 26:3080–6.
 HbA1c goals are attained with insulin glargine using simple titration
algorithms
Mean HbA1c attained in various Treat-to-Target trials
Baseline Study end
9 8.7 8.8 8.7
8.6 8.6

–1.6 –1.6 –1.7 –2.0 –1.7

8
HbA1c%

7.0 7.0 7.0 7.0

7 6.8

5
1 2 3 4 5
Study name TTT INSIGHT APOLLO INITIATE Observational
Patient population n=367 n=206 n=174 n=58 n=11,511
Study duration 24 weeks 24 weeks 44 weeks 24 weeks 9 months

Typically ~50% of patients attain HbA1c<7%1–5

APOLLO, Once-daily basal insulin glargine versus thrice-daily prandial insulin lispro in people with type 2 diabetes on oral hypoglycaemic agents; INITIATE, Initiate Insulin by Aggressive Titration and Education; TTT,
Treat-to-Target Trial; INSIGHT, Implementing New Strategies with Insulin Glargine for Hyperglycaemia Treatment; Observational, Insulin glargine benefits patients with type 2 diabetes inadequately controlled on oral
antidiabetic treatment.

1. Riddle MC, et al. Diabetes Care 2003; 26:3080–6;2. Gerstein HC, et al. Diabetes Med 2006; 23:736–42;3. Bretzel RG, et
al. Lancet 2008; 371:1073–84;4. Yki-Järvinen H, et al. Diabetes Care 2007; 30:1364–9;5. Schreiber SA & Haak T. Diabetes
Obes Metab 2007; 9:31–8.
Question 3

In general, how often are you able to review your T2DM patients’ BG
levels and titrate their doses?
1. More than once per week

2. Once per week

3. Every 2 weeks

4. Every month

5. Every 3 months
 AT-LANTUS study: comparison of physician-driven versus patient-
driven titration algorithms
• Results for physician-driven (weekly) versus patient-driven (every 3 days) dose
titration
50
170

45
150
FBG (mg/dL)

Insulin dose (U)

40

130 35

30
110
25

*P<0.003 and †P<0.001 between algorithms at 24 weeks

90 20
0 4 8 12 16 20 24
Time since randomization (weeks)
FBG, fasting blood glucose.

Davies M, et al. Diabetes Care 2005; 28:1282–8.

 ATLAS study: Asian patients up-titrated their insulin
dose effectively when guided
• Although the large majority of Asian patients have little experience with
self-titration or SMBG, Asian patients in the ATLAS study up-titrated
their insulin dose effectively when guided
– Patient-led titration resulted in a significantly higher drop in HbA1c value at
24 weeks when compared with physician-led titration (−1.40% vs. −1.25%)
– Mean decrease in FBG was greatest in the patient led group
(−2.85 mmol/L vs. −2.48 mmol/L)
– Mean daily insulin dose was higher in the patient-led group
(28.9 units vs. 22.2 units)
– Incidence of severe hypoglycemia was rare in both treatment groups

ATLAS, Asian Treat to Target Lantus Study; FBG, fasting blood glucose;
SMBG, self-monitoring of blood glucose.

Garg SK, et al. Endocr Pract 2015; 21:143–57.

 ATLAS study: HbA1c levels in response to patient-led versus
physician-led titration
• The study indicated patient-led insulin glargine titration is non-inferior to
physician-led titration

Patient-led Physician-led
titration titration
(n=275) (n=277)

HbA1c
7.32 7.49
[8.70 at baseline] [8.76 at baseline]
-1.21% FBG
-1.25%
6.10 6.50
(mmol/L) [9.00 at baseline] [9.00 at baseline]

PPG 10.30 10.50

-1.4% (mmol/L) [12.30 at baseline] [12.30 at baseline]
-1.32%

For patients in group A (physician-led), titration was performed by the physician at each visit (representing
common practice in Asia); in group B (the patient-led group), patients were guided to adjust their own insulin dose
twice each week

ATLAS, The Asian Treat to Target Lantus Study;

FBG, fasting blood glucose;
PPG, postprandial glucose. Garg SK, et al. Endocr Pract 2015;21:143–57.
 Optimized titration can lead to effective glycemic control

Once insulin is initiated, dose titration is important1,2

Dose titration is patient-specific and should be done

in order to achieve target fasting blood glucose3

Adequate titration of the insulin dose, either by physicians

or by patients, can help patients reach treatment goals,
including HbA1c <7% and FBG <5.5 mmol/L (<100 mg/dL)2

The choice between algorithms may depend on

clinical circumstances and a patient’s willingness and ability
to become more involved in management of therapy2

FBG, fasting blood glucose.

1.Inzucchi SE, et al. Diabetes Care 2015; 38:140–9; 2. Barnett A. Clin Ther 2007; 29:987–99;
3. Agarwal SK, et al. J Indian Med Assoc 2013; 111:626–8.
Question 4

What percentage of your T2DM patients have reached glycemic

control with basal insulin (either alone or in combination with OADs)
1. 0–20%

2. 21–40%

3. 41–60%

4. 61–80%

5. 81–100%
 Barriers to basal insulin titration in Asia (i)
• Inadequate dose titration remains a barrier to optimal insulin1–3
– Poor target achievement suggests suboptimal titration by patients and/or
their physicians3

• Barriers to physician-led titration4

– Fear of hypoglycemia
– Presumed unwillingness and/or inability of the patient to inject insulin
– Complexity of insulin therapy considered too difficult to be managed in a
busy practice
– Uncertainties regarding insulin titration
– Difficulties communicating with patients during/after insulin titration

1. Garber AJ. Diabetes Obes Metab 2009; 11 (suppl. 5):10–13; 2. Riddle MC, et al. Diabetes Care 2003; 26:3080–6;
3. Baser O, et al. Clinicoecon Outcomes Res 2013; 5:497–505; 4. Arnolds S, et al. J Diabetes Sci Technol 2013; 7:771–88.
 Barriers to basal insulin titration in Asia (ii)
• Barriers to self-titration
– Physicians’ perception is that Asian patients are unable to take control of
their condition and will not effectively self-titrate their insulin dose1,2
– Differences in the provision of diabetes-related healthcare services across
Asian countries in terms of treatment settings (e.g. hospital-based in China)1
– Time limitations make it challenging for a busy doctor3,4
• to manage and assess the large amount of clinical information to make
individualized treatment decisions
• to educate a patient toward self-care

1. Garg SK, et al. Endocr Pract 2015; 21:143–57; 2. Arnolds S, et al. J Diabetes Sci Technol 2013;7:771–88;
3. Chan JC, et al. Curr Cardiovasc Risk Rep 2011; 5:230–9; 4. Yki-Järvinen H, et al. Diab Care 2007; 30:1364–9.
 Clinical impact of patient education
• Patient empowerment through education for successful self-management may
play a key role in optimizing metabolic and risk factor control as well as quality of life1

• Important due to increasing number of T2DM patients and economic burden2

• Impact of diabetes education, study using data from the IDMPS1

– Educated patients compared with those who did not receive diabetes education had:
• Significantly lower mean HbA1c (7.8 ± 1.9 vs 7.9 ± 1.9)
• Higher number of patients with HbA1c values <7% (38.1% vs 35.8%)
• Increased annual number of visits to specialists (7.18 ± 7.00 vs 5.91 ± 5.49)
• Higher percentage of performance of fasting and postprandial SMBG (51.4% vs 39.6%)
• Greater percentage of patients treated with insulin (34.9% vs 25%)
• Lower cardiovascular risk factors (healthier BMI, BP, and lipid profiles)

Patient empowerment through education enables patients to be actively involved in the

control and treatment of their T2DM and may lead to improvement in treatment outcomes

BMI, body mass index; BP, blood pressure;IDMPS, International Diabetes Management Practice Study;
SMBG, self-monitoring of blood glucose;T2DM, type 2 diabetes mellitus.

1. Gagliardino JJ, et al. Diabetes Metab 2012;38:128–34;

2. International Diabetes Federation 2015.
 A patient-centric approach to optimize insulin therapy
in Asia
• A patient‐centric approach for diabetes care
is recommended by the ADA/EASD
• Given the prolonged and progressive
nature of diabetes, patients must contribute
to constantly adapting his/her care rather
than just being the recipient
• A physician must adopt the role of an
‘educator’ and ‘partner’ rather than being
solely a ‘decision maker’

Adopting a patient-centric approach in Asia, may help alleviate some of the

challenges in initiating timely and appropriate insulin therapy

Goh SY, et al. J Diabetes Complications 2016; 30:973–80.

Content

Basal insulin: Asian perspective

Basal insulin: dose titration strategies

Basal insulin: dose optimization

 2014 meta-analyses conducted by DeVries H, et al. and
Owens DR, et al.
• Fifteen studies included in meta-analyses (N=2,837 patient level data)
– EAGLE, LANCELOT, GALAPAGOS not included, as not completed at time
of analysis
– treat-to-target trials in insulin-naïve T2DM patients treated with insulin
glargine
– ≥6 months’ duration
– FPG target <100 mg/dL
• Used standardized top-level methodology across studies to assess
key parameters
– Efficacy (HbA1c, FPG), hypoglycemia, insulin dose, weight, background
medication

EAGLE, Efficacy Assessment of Insulin Glargine Versus LiraglutidE After Oral Agents Failure; FPG, fasting plasma glucose; LANCELOT, Least One Oral Antidiabetic Drug Treatment;
GALAPAGOS, Insulin glargine compared with premixed insulin for management of insulin-naïve type 2 diabetes patients uncontrolled on oral antidiabetic drugs.

DeVries H, et al. Eur Endocrinol 2014; 10:23–30; Owens DR, et al. Diabetes Res Clin Pract 2014; 106:264–74.
 Key characteristics of studies included
Study Phase Treatment Patients Treatment period Insulin titration
(n) (wk) schedule
EASIE IIIb/IV Gla + MET vs sitagliptin + MET 515 24 Twice weekly
4020 IIIb Gla + SU or MET vs pioglitazone + SU or MET 389 24 extended to 48 Weekly
4022 IIIb Gla + SU or MET vs TZD + SU + MET 337 24 extended to 48 Weekly
L2T3 IV Gla + OADs vs ID + OADs 973 24 Every 2 days
INSIGHT IIIb Gla + current OAD(s) vs current OADs 405 24 Daily
4001 IIIb Gla morning or bedtime + glime vs NPH glime 695 24 Weekly
4009 IIIb Morning vs bedtime Gla + morning glimepiride 624 24 Weekly
4013 IIIb Gla + glimepiride vs NPH + glimepiride 481 24 Weekly
4002 IIIb Gla + OADs vs NPH insulin + OADs 764 24 Weekly
(TTT)
TRIPLE IIIb Gla + SU + MET vs rosiglitazone + SU + MET 219 24 Weekly
4021 IIIb Gla + SU + MET vs Lispro 75/25 + SU + MET 212 24 Weekly
LAPTOP IIIb Gla + glimepiride + MET vs premixed 30/70 371 24 First 8 wks weekly,
then 2-wk intervals
APOLLO IV Gla + OADs vs insulin lispro + OADs 415 44 Weekly
INITIATE IV Gla with group education + OADs vs Gla individual 121 24 Self-titration
education + OADs
TULIP IV Gla + OADs vs hygienic and dietary measures + 215 40 Every 2 days
OADs
Gla, insulin glargine; MET, metformin; NPH, Neutral Protamine Hagedorn; TZD, thiazolidinedione; OAD, oral antidiabetic drug ; SU, sulfonylurea.

DeVries H, et al. Eur Endocrinol 2014; 10:23–30; Owens DR, et al. Diabetes Res Clin Pract 2014; 106:264–74.
 Mean HbA1c reduction with insulin glargine in T2DM
Glycemic control in insulin-naïve T2DM on OADs
10

9.0
9 8.7 8.7 8.8
Mean HbA1c (%)

–1.4%
8 –1.6%
–1.7% –1.6%
7.6
7.1 7.2
7.0
7

6
Baseline 24 weeks Baseline 24 weeks Baseline 24 weeks Baseline 24 weeks
Gla + MET Gla + SU Gla + MET + SU Overall
(n=593) (n=867) (n=1,268) (n=2,728)

Gla, insulin glargine; MET, metformin; OADs, oral antidiabetic drugs; T2DM, type 2 diabetes mellitus; SU, sulfonylurea.

DeVries H, et al. Eur Endocrinol 2014; 10:23–30.

 Proportion of patients achieving target HbA1c at Week 24
Responder rates for glargine/OAD pools and overall
50
44.6
Patients (%) achieving HbA1c

45
39.8
endpoint at 24 weeks

40
35.4 34
35
30 26.4
24.1 24.3
25
20 15.9
15
10
HbA1c HbA1c HbA1c HbA1c HbA1c HbA1c HbA1c HbA1c
5 <7% <7.5% <7% <7.5% <7% <7.5% <7% <7.5%
0
Gla + MET Gla + SU Gla + MET + SU Overall
(n=634) (n=906) (n=1,297) (n=2,837)

Gla, insulin glargine; Met, metformin;

OAD, oral antidiabetic drug; SU, sulfonylurea.

Owens DR, et al. Diabetes Res Clin Pract 2014; 106:264–74 (suppl).
 Rates of hypoglycemia with insulin glargine during titration and
maintenance period
• Insulin glargine therapy is well tolerated during up-titration and maintenance
PG-cutoff
<3.9 <3.1 <3.9 <3.1 <2.0 <3.9 <3.1 <3.9 <3.1 <2.0 <3.9 <3.1 <3.9 <3.1 <2.0
(mmol/L):

7.0
Episodes per patient-year

6.0
5.0
4.1 3.9
4.0 3.6

3.0 \\\\\\

2.0 1.4
1.1 1.3
1.0 0.5 0.7 0.6
0.2 0.3 0.3
0.00 0.005 0.005
0.0
Overall Nocturnal Severe Overall Nocturnal Severe Overall Nocturnal Severe
0–12 weeks1 12–24 weeks1 0–24 weeks2
(titration) (maintenance) (n=2,837)
PG, plasma glucose; Insulin glargine therapy is well tolerated during up-titration and maintenance.

1. Owens DR, et al. Diabetes Res Clin Pract 2014; 106:264–74 (suppl);
2. DeVries H, et al. Endocrinol 2014; 10:23–30.
 Hypoglycemia with insulin glargine versus premixed insulin (BIAsp 30)
• At similar glycemic control, insulin glargine therapy was well tolerated, with
lower rates of overall hypoglycemia, less weight gain –1.7 kg, lower insulin
dose, and convenient with fewer injections needed
Glycemic control Hypoglycemia
10.0 25.0
Baseline 24 weeks Gla BIAsp 30
P<0.05 P<0.05 P=NS

Episodes/patient-yr
8.9 9.0 20.0
9.0
Mean HbA1c (%)

15.9
–1.2% –1.3% 15.0
8.0 7.7 7.7 10.9
10.0
6.5
7.0 3.6 4.3
0.57 U/kg* 1.17 U/kg* 5.0 3.4
0.36 0.42
6.0 0.0
QD (n=143) BID (n=137) Overall Minor Nocturnal
Gla + MET + BIAsp 30 + MET (<3.1
secretagogues mmol/L)
Gla, insulin glargine; BIAsp 30, biphasic insulin aspart 70/30; MET, metformin; Randomized, controlled study in T2DM patients uncontrolled (mean HbA1c:
9.0%; mean FBG: 9.9mmol/L) on previous treatment with basal insulin (glargine or NPH OD-BD + OADs) for at least 3 months.
* Median end-of-study total daily insulin dose

Ligthelm RJ, et al. Endocr Pract 2011; 17:41–50.

 There is a need to better understand basal insulin dose titration in
the Asian population
• Asia is characterized by a relatively young onset of T2DM and low BMI1
• Asian individuals show a higher percentage of body fat and greater
abdominal obesity compared with Western patients with an equivalent
BMI1
• A recent pooled analysis demonstrated that, at similar doses of Gla-100,
non-Asian patients were able to achieve better HbA1c control in
comparison to Asian patients2
– Higher daily basal insulin doses may be required by Asian patients for
them to achieve adequate glycemic control

BMI, body mass index; Gla-100, insulin glargine 100 U/mL; MET, metformin; SU, sulfonylurea; T2DM, type 2 diabetes mellitus.

1. Tsai ST, et al. J Diabetes 2011;3:208–16;

2. Chan JC, et al. ADA 2016: 980-P.
 Summary
Insulin glargine is ideally titrated from a low starting dose to an appropriate
dose/kg/day to achieve glycemic goals with various titration algorithms
• Starting dose at 10 U/day or 0.1–0.2/kg/day1
• In patients on Gla + MET* a 1.7% HbA1c reduction has been demonstrated and
56.8% reached target HbA1c <7%2* with dose titration to 0.52 U/kg2,3 from
15 Treat-to-Target studies pooled patient level analysis
• With Treat-to-Target titration algorithms: by Week 12, >80% of the maximum
treatment effect (in terms of reductions in HbA1c) had been achieved compared
with glycemic control at Week 24 for each concomitant OAD treatment regimen
with insulin glargine

No increased hypoglycemia risk with insulin glargine during titration period

compared with maintenance period2,3

* At Week 24;
Gla, insulin glargine; MET, metformin; OAD, oral antidiabetic drug.

1. Inzucchi SE, et al. Diabetes Care 2015; 38:140–9; 2. DeVries H, et al. Eur Endocrinol 2014; 10:23–30;
3. Owens DR, et al. Diabetes Res Clin Pract 2014; 106:264–74 (suupl).
Q & A– submit your questions on the
cards provided or request for the mic

Prof. Geremia Bolli and Dr Elizabeth Paz-Pacheco

Considerations for Basal Insulin
Intensification Strategies

Dr Sunil M. Jain
Consultant endocrinologist and Managing Director
TOTALL Diabetes Hormone Institute, India
Presentation overview
• Evidence for combination of basal insulin with a rapid-acting insulin
• Evidence for combination of basal insulin with a GLP-1 RA
• Clinical evidence comparing short-acting GLP-1 RAs + basal insulin vs.
rapid-acting insulins + basal insulin
• When to administer short-acting GLP-1 RAs and rapid-acting insulin in
relation to meals
• Fixed-dose combinations of rapid acting insulins and basal insulins

GLP1-RA: Glucagon-like peptide-1 receptor agonists

 T2DM treatment gaps and desirable characteristics
for new therapies
Increase % patients reaching
target and maintain patients at
Achieve and goal
maintain
glucose control Reduce
New therapies with complementary Combination hypoglycemia Demonstrate reduced rate of
modes of action to control therapy and weight hypoglycemia and weight
FPG and PPG gain neutrality or weight loss

Demonstrate ability to Target Treatment Reduce

Reduce frequency of dosing and
monitoring, and simplify
preserve or restore
beta-cell function
diabetes
pathophysiology
gaps in treatment
complexity
education requirements (may
improve adherence)
T2DM
Effective and safe in most Demonstrate long-term
patients including difficult to Applicable to Reduce benefits on micro- and
treat populations broad patient long-term macrovascular outcomes
(e.g. elderly, renally impaired) population complications
Positive
metabolic profile Demonstrate benefits on
non-glycemic targets (e.g. serum
lipids and blood pressure)

FPG, fasting plasma glucose; PPG, postprandial plasma glucose

1. Inzucchi SE, et al. Diabetes Care 2015;38:140–9; 2. Saisho Y, et al. J Clin Med 2014;3:923–43 3. Davies MJ, et al. Diabet Med 2013;30:512–24
4. Azim S, et al. Curr Cardiol Rep 2014;16:541; 5. Mathur S, et al. Drug Saf 2015;38:17–32; 6. Owens DR, et al. Diabetes Metab 2013;39:485–96
 Postprandial hyperglycemia is a major obstacle to
achieving better glycemic control
Pooled analyses of glycemic profile data from six similarly designed RCTs in which
patients with poorly controlled T2DM were treated with basal insulin (N=1,699)

100
Total hyperglycemia (%)

80
58 59 58 57 52
Postprandial
60 hyperglycemia

40 Basal
hyperglycemia
42 42 43 48
20 41

0
<6.5 6.5–<7.0 7.0–<7.5 7.5–<8.0 ≥8.0

HbA1c (%)

Data represent relative contributions of basal and postprandial hyperglycemia to overall hyperglycemia by
HbA1c category at Week 24–28 of insulin treatment
Riddle et al. Diabetes Care 2011;34:2508–14
Question 1:
What option do you prefer when basal insulin does not
provide adequate control?
1. Switch to another basal insulin

2. Intensify therapy with a GLP-1

RA

3. Intensify therapy with a prandial

insulin

4. Transition to a pre-mixed insulin

formulation

5. I am often unsure of the best

treatment strategy to take
ADA/EASD recommendations for intensifying
therapy for PPG Control
Options for intensification of insulin therapy

Intensification of
insulin therapy

Combination of Combination of
basal insulin with a basal insulin with a
GLP-1 RA rapid-acting insulin

Basal-bolus
Basal-plus therapy Premixed insulin
therapy
Options for intensification of insulin therapy

Intensification of
insulin therapy

Combination of Combination of
basal insulin with a basal insulin with a
GLP-1 RA rapid-acting insulin

Basal-bolus
Basal-plus therapy Premixed insulin
therapy
Question 2:
What percentage of your patients prefer premixed insulin over
basal-plus or basal-bolus insulin therapy?

1. 0–25%

2. 25–50%

3. 50–75%

4. 75–100%
 Insulin glulisine vs. RHI: better glycemic control and
similar rate of symptomatic hypoglycemia
Insulin glulisine RHI
better better

Hypoglycemia
Twice-daily
(symptomatic):
p=0.0029
"rapid-acting"
Overall, nocturnal,
n=876, 26 weeks
insulin glulisine
or severe
BMI=34.5 kg/m² with NPH
No difference
is slightly better
than RHI in obese
Weight gain
persons with T2D
comparable

-0.3 -0.2 -0.1 0 0.1 0.2 0.3

Baseline-end point change in (HbA1c)

Adapted from Dailey G, et al. Diabetes Care 2004;27:2363–8.

Question 3:
What percentage of your patients, on a basal-plus or basal-bolus
insulin therapy, have achieved adequate glycemic control?

1. 0–25%

2. 25–50%

3. 50–75%

4. 75–100%
 Basal-bolus and basal-plus

Insulin glargine + glulisine vs. premixed insulin in T2D: Improved glycemic

control and fewer discontinuations (All-to-Target study)
Insulin-naive T2D patients (baseline HbA1c 9.4 ± 1.6%) were randomized to once-daily
glargine + 0–1 glulisine (G+1, n=194), glargine + 0–3 glulisine (G+3, n=194) or
twice-daily premixed protamine-aspart/aspart (PM-2, n=194) for 60 weeks
FPG change over 60 weeks Discontinuations
*p<0.05; **p<0.01; ***p<0.001 G+1 vs. PM-2
12.2 #p<0.05; ##p<0.01; ###p<0.001 G+3 vs. PM- p=0.07
2 p=0.29
11.1

% with discontinuation
30 27.0
FPG (mmol/L)

10
# 23
8.9 20
***
### ***
20
###
*** **
**
##
PM-2
7.8 **
### ### #

G+3 10
6.7 G+1
5.5
0
BL Wk 6 Wk 12 Wk 24 Wk 36 Wk 48Wk 60 LOCF Premixed Glargine + Glargine +
insulin 0–1 glulisine 0–3 glulisine
Adapted from Riddle MC, et al. Diabetes Obes Metab 2014;16:396-402. Adapted from Riddle MC, et al. Diabetes Obes Metab 2014;16:396-402.

Basal insulin plus a single prandial injection was as effective in improving glycemic control as premixed
insulin. Full basal-prandial therapy (glargine + 0–3 glulisine) was only slightly more effective than
twice-daily premixed insulin with less hypoglycemia, but with a similar rate of severe hypoglycemia

BL: Baseline; LOCF: Last observation carried forward.

 Basal-bolus and basal-plus

Insulin glargine + glulisine vs. premixed insulin in T2D:

Improved glycemic control (All-to-Target study)
Insulin-naive T2D patients (baseline HbA1c 9.4 ± 1.6%) were randomized to once-daily
glargine + 0–1 glulisine (G+1, n=194), glargine + 0–3 glulisine (G+3, n=194) or twice-
daily premixed protamine-aspart/aspart (PM-2, n=194) for 60 weeks
HbA1c change over 60 weeks Proportion reaching HbA1c <7% over 60 weeks
Baseline 60 weeks
p=0.0309
*
p=0.025

9.3 9.4 50 49
10
* 9.4 45

Percentage with
7.2 7.1 40 39
8 7

HbA1c <7%
HbA1c (%)

6 30

4 20

2 10

0 0
Premixed Glargine + Glargine + Premixed Glargine + Glargine +
insulin 0–1 glulisine 0–3 glulisine insulin 0–1 glulisine 0–3 glulisine
Adapted from Riddle MC, et al. Diabetes Obes Metab 2014;16:396-402. Adapted from Riddle MC, et al. Diabetes Obes Metab 2014;16:396-402.

Basal insulin plus a single prandial injection was as effective in improving glycemic control as premixed
insulin. Full basal-prandial therapy (glargine + 0-3 glulisine) was only slightly more effective than
twice-daily premixed insulin with less hypoglycemia, but with a similar rate of severe hypoglycemia

*Absolute mean difference in HbA1c change with G+1 and

PM-2 = -0.34 (95% CI -0.82 to +0.15, p=0.0359), non-inferiority confirmed.
 Basal-bolus

Insulin glargine + glulisine vs. premix: improved

glycemic control
Insulin-treated patients (82 T1D, 306 T2D, HbA1c 7.8 ± 0.7%) cross-over (2x12 week)
were randomized to glargine + glulisine or premixed insulin
Primary end point was patient satisfaction and quality of life
HbA1c <7% target at end point Change in fasting blood glucose

Baseline
% of pts with HbA1c <7% at end

60 55 16 Endpoint

FBG concentration (mmol/L)

p<0.0001
50 14

40 36 12
9.7 9.4 9.2
30 10
8.2
20 8

10 6

0 4

Glargine/glulisine Premix Insulin glargine/glulisine Premix insulin

insulin
Adapted from Testa MA, et al. J Clin Endocrinol Metab 2012;97: 3504–3514. Adapted from Testa MA, et al. J Clin Endocrinol Metab 2012;97: 3504–3514.
 Basal-bolus

Insulin glargine/glulisine provides significantly better

glycemic control vs. intensified premixed insulin
52-week study comparing insulin glargine and glulisine (basal-bolus) with optimized
premix analog insulin (70% NPH/30% aspart or 70% NPH/30% regular) in 310 patients
with inadequately controlled T2D on conventional premix insulin*

p=0.0004
9 50

Pts achieving HbA1c <7%

p=0.0001

7.7
40
47%
HbA1c (%)

8
30

7
20 28%
Insulin glargine/glulisine
7.3 10
Premix
6 0

0 3 6 9 12 Insulin glargine + Premix

insulin glulisine
Months

Adapted from Fritsche A, et al. GINGER Study, Diabetes Obes Metab 2010;12:115-23. Adapted from Fritsche A, et al. GINGER Study, Diabetes Obes Metab 2010;12:115-23.

Comparable rates of hypoglycemic episodes

*Additional long-term studies are needed to confirm these results.

Summary: Combination of basal insulin with a rapid-acting insulin

• Basal bolus therapy with insulin glargine + glulisine provides superior glycemic
control in comparison to premixed insulin
– Greater reduction in FBG with insulin glargine + glulisine
– Greater number of patients reaching target HbA1c with insulin glargine + glulisine
– Superior glycemic control is obtained with insulin glargine + glulisine even when
premixed insulin is intensified/optimized
• Insulin glargine + glulisine also provides improved treatment satisfaction and
quality of life in comparison to premixed insulin
• Basal-plus therapy of insulin glargine + glulisine is as effective at improving
glycemic control as premixed insulin in T2DM patients
• Hypoglycemia is more frequent with twice-daily premixed insulin than with
basal-bolus or basal-plus therapy of insulin glargine + insulin glulisine in
T2DM patients
 Options for intensification of insulin therapy

Intensification of
insulin therapy

Combination of Combination of
basal insulin with a basal insulin with a
GLP-1 RA rapid-acting insulin

Basal-bolus
Basal-plus therapy Premixed insulin
therapy

Lankisch MR, et al. Prim Care Diabetes 2016 Feb;10:51–9.

Question 4:

If available, which of the following treatment options

would you prescribe to your patients uncontrolled on
basal insulin?
1. GLP-1 RA
2. SGLT2
3. Switch to premixed insulin
4. Basal plus therapy
5. Basal bolus therapy
 The complementary modes of action of basal insulins
and GLP-1 RAs provide control of both FPG and PPG

↑ Glucose-dependent insulin release

Targets hepatic glucose over production
↓ glucagon secretion
by decreasing gluconeogenesis
delayed gastric emptying,
↓ fasting blood glucose
↓ post-prandial glucose excursions

Complimentary
approach to
HbA1c
control

Basal insulin GLP-1 RA

Result: Result:
fasting blood post-prandial blood
glucose control glucose control

1. Balena R, et al. Diab Obes Metab 2013;15:485–502; 2. Baggio LL and Drucker DJ. Gastroenterol 2007;132: 2131–57
3. Wang Z, et al. Diab Care 2010;33:1555–60; 4. Holst JJ, et al. Physiol Rev 2007;87:1409–39
 Use of twice-daily exenatide in basal insulin-treated patients with
type 2 diabetes: a randomized, controlled trial

Data are LS mean ± CI; *p< 0.001; †p< 0.01

for between group comparison

Buse JB, et al. Ann Intern Med 2011;154: 103–12.

 Lixisenatide effects in patients on basal insulin:
change in HbA1c at 24 weeks: primary endpoint

*p < 0.0001 vs placebo; **p < 0.001 vs placebo

1. Riddle MC, et al. Diabetes Care 2013;36:2489–96.

2. Seino Y, et al. Diabetes Obes Metab 2012;14:910–7.
3. Riddle MC, et al. Diabetes Care 2013;36:2497–503
 Lixisenatide effects in patients on basal insulin:
change in 2-hr PPG at 24 weeks: secondary endpoint

1. Riddle MC, et al. Diabetes Care 2013;36:2489–96.

2. Seino Y, et al. Diabetes Obes Metab 2012;14:910–7.
3. Riddle MC, et al. Diabetes Care 2013;36:2497–503
 Lixisenatide effects in patients on basal insulin:
change in body weight at 24 weeks: secondary endpoint

1. Riddle MC, et al. Diabetes Care 2013;36:2489–96.

2. Seino Y, et al. Diabetes Obes Metab 2012;14:910–7.
3. Riddle MC, et al. Diabetes Care 2013;36:2497–503.
Summary: Combination of basal insulin with a GLP-1 RA
• The complementary modes of action of basal insulins and GLP-1 RAs
provide control of both FPG and PPG
• GLP-1 RAs provide an alternative treatment intensification option for
patients who are at risk of euglycemic diabetic ketoacidosis
• Adding twice-daily exenatide injections can improve glycemic control
without increased hypoglycemia or weight gain in T2DM patients
previously on insulin glargine
– Significant decrease in HbA1c with twice-daily exenatide plus insulin
glargine compared with insulin glargine alone
• Addition of lixisenatide to insulin glargine and OADs in T2DM patients
previously on insulin glargine alone provides greater glycemic control
than insulin glargine and OADS alone
– Significant decrease in HbA1c and 2hr-PPG with lixisenatide plus insulin
glargine and OADs compared with insulin glargine and OADs alone
COMPARISON OF SHORT-ACTING GLP-1
RAS PLUS BASAL INSULIN WITH RAPID-
ACTING INSULINS PLUS BASAL INSULIN
 Addition of exenatide BID vs insulin lispro TID to
basal insulin glargine: change in HbA1c
(n =247)
(n =263)

Please note that the article reports

1. HbA1c (%) values at randomization
and end-points and
2. Least-squares (LS) mean change
(SE) in HbA1c values
Therefore, the HbA1c values at each
week in between could not be verified.

• Reduction in HbA1c with exenatide BID was non-inferior to

insulin lispro

Values are LS Mean ± SE calculated using MM8M Diamant M, et al. Diabetes Care 2014 Oct; 37(10): 2763-2773.
 GET GOAL DUO 2: Comparison of lixisenatide QD, insulin glulisine
QD and insulin glulisine TID in combination with insulin glargine
and metformin
Co-primary endpoints:
• Non-inferiority of lixisenatide versus insulin glulisine QD in HbA1c reduction AND either
• Non-inferiority of lixisenatide versus insulin glulisine TID in HbA1c reduction OR
• Superiority of lixisenatide versus insulin glulisine TID in body weight change

All co-primary endpoints were met

Rosenstock J, et al. Diabetes Care 2016;39:1318–28.

 GET GOAL DUO 2: secondary endpoints- composite endpoints

• A larger proportion of patients treated with lixisenatide achieved the composite endpoints
compared with insulin glulisine QD and TID
• Patients receiving lixisenatide were twice as likely to achieve the triple composite
outcome of HbA1c <7.0% without weight gain or documented symptomatic hypoglycemia

Rosenstock J, et al. Diabetes Care 2016;39:1318–28.

Summary
• Addition of a GLP-1 RA to basal insulin in comparison to the addition of
a rapid-acting insulin to basal insulin, offers:
– Similar glycemic control
– Fewer hypoglycemic events
– No weight gain

Short-acting GLP-1 RAs as add-on to basal insulin offers an

alternative treatment intensification option, attaining meaningful
glycemic targets with fewer hypoglycemic events without
weight gain versus basal-plus or basal-bolus in
uncontrolled basal insulin-treated T2DM
WHEN TO ADMINISTER SHORT-ACTING
GLP-1 RAS AND RAPID-ACTING INSULIN
IN RELATION TO MEALS
Question 5:

Are you reluctant to add a short acting GLP-1 RA to

a basal insulin due to concerns over injection
frequency/timing?

1. Yes
2. No
 Does timing of injection of GLP-1 RA matter?
The lixisenatide main meal study

*The main meal was determined by asking patients:

“On most days, at which meal do you eat the largest amount of food?”
A dietary consultation was also performed to confirm the patient’s assessment

FPG: fasting plasma glucose.

Ahrén B, et al. J Diabetes Complications. 2014;28(5):735-41 .
 The lixisenatide main meal study
Primary endpoint: HbA1c change over time

Flexibility of timing of administration and of use according to patients’ needs

mITT population with LOCF

Ahrén B, et al. J Diabetes Complications. 2014;28(5):735-41 .
 Does the timing of injection of a basal bolus regimen matter?

HbA1c at baseline HbA1c at Week 24

† p <0.0001 within each group vs. baseline.

A single bolus of glulisine, added to glargine and OADs, resulted in significantly

improved HbA1c levels, irrespective of whether glulisine was administered at
breakfast or at main mealtime

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

FIXED-DOSE COMBINATIONS OF GLP-1 RAS
AND BASAL INSULINS
Question 6:

Of your patients who prefer premixed insulin over

basal-bolus/basal-plus therapy, how many do so
because it is a simple regimen?
1. 0–25%
2. 25–50%
3. 50–75%
4. 75–100%
Fixed-ratio formulation of once-daily insulin
glargine/lixisenatide
Benefits of an “All-in-one“ Therapeutic Strategy

Gla-100 Lixisenatide
• 1 injection • 1 injection
• Predominant FPG lowering • Predominant PPG lowering
• Significant HbA1c reduction • HbA1c reduction on top of Lantus
• Potential Weight gain • Weight loss
• Hypoglycemia • Low risk of hypoglycemia
• GetGoal program

IGlarLixi
• 1 injection, 2 therapies
• FPG + PPG control
• Greater HbA1c reduction
• More patients with controlled HbA1c
• Potential Weight loss
• No additional risk of hypos vs. basal
 LixiLan-O: Patients with T2DM not controlled on OADs
- key results
HbA1c Reduction PPG Reduction
0.0 2-hour PPG (mmol/L) Excursion PPG (mmol/L)
0
-0.2
–0.2
LS mean change (%)

-0.4 -1

LS mean change
-0.6 -2 –2.3

(mmol/L)
-0.8 –0.9 –3.2
-3 –3.3
-1.0
-4 –2.1*
-1.2 –1.3 –4.6 95% CI: –2.5, –1.8

-1.4 -5 –5.7 +0.9

–1.6 iGlarLixi 95% CI: 0.5, 1.4
-1.6
iGlar -6 –2.4
-1.8 95% CI: –2.8, –2.0
p<0.0001 Lixisenatide
–1.1
p<0.0001 95% CI: –1.6, –0.6

Patients at target HbA1c Weight change Hypoglycemia‡§

iGlarLixi Baseline† 89.4 89.8 90.8 Patients with No. of events
Proportion of patients (%)

100 iGlar events (%) per patient

40.6* 2.0
LS mean change (kg)

Lixisenatide 50 5.0 year

80 14.3*
36.4* 1.0 45 4.5
74 16.4* 1.1 40 4.0
60 35 3.5
0.0
59 56 30 3.0
40 –0.3 25 2.5
-1.0
40 20 25.
23. 2.0
20 33 6
-2.0 –2.3 15 6 1.5
19 –1.4* 10 6.4 1.0
0 -3.0
95% CI: –1.9, –0.9 5 0.5 1.4 0.3
1.2
HbA1c <7% HbA1c ≤6.5% –2.0 0 0.0
95% CI: 1.4, 2.6

*p<0.0001; †Mean body weight (kg) at baseline; ‡Documented symptomatic hypoglycemia, defined as plasma glucose ≤70 mg/dL
§One event of severe hypoglycemia was reported during the study and occurred in the iGlar group;

Sanofi data on file – LixiLan-O CSR pages 86-115, 124-127

 LixiLan-L: Patients with T2DM not controlled on basal
insulin - key results
HbA1c Reduction PPG Reduction
0.0 2-hour PPG (mmol/L) Excursion PPG (mmol/L)
0.0
LS mean change (%)

-0.2

LS mean change
-1.0 –1.4 –0.5
-0.4

(mmol/L)
–0.6 -2.0
-0.6
-0.8 -3.0
–3.9
-1.0 -4.0
–1.1 –4.7
–3.4
-1.2 iGlarLixi -5.0 95% CI: –3.9, –2.9
–0.5 –3.3
95% CI: –0.6, –0.4 iGlar p<0.0001
95% CI: –3.9, –2.8
p<0.0001 p=NS

100
Patients at target HbA1c Weight change Hypoglycemia‡§
Proportion of patients (%)

iGlarLixi Patients with No. of events

Baseline† 87.8 87.1
80 iGlar 1.0 events (%) per patient
25.5
LS mean change (kg)

95% CI: 18.9, 32.1

50 5.0 year
0.7 45 4.5
60 p<0.0001
19.8 0.0 40 42. 4.0
55 95% CI: 13.9, 25.6 35 40. 3.5
5 4.2
40 0
p<0.0001 –0.7 30 3.0
25 2.5
34 -1.0 3.0
20 30 20 2.0
–1.4 15 1.5
14 10 1.0
0 95% CI: –1.8, –0.9
5 0.5
HbA1c <7% HbA1c ≤6.5% -2.0 p<0.0001
0 0.0

†Mean body weight (kg) at baseline; ‡Documented symptomatic hypoglycemia, defined as plasma glucose ≤70 mg/dL
§Severe hypoglycemia was reported in 4 (1.1%) patients in the iGlarLixi group and 1 (0.3%) patient in the iGlar group;
Sanofi data on file – LixiLan-L CSR pages 86-112, 120-124
 DUAL studies: fixed-ratio combination of insulin
degludec and liraglutide (IDegLira)
DUAL I: Primary Endpoint- HbA1c Reduction
• HbA1c decreased by 1.9% with IDegLira
• HbA1c decrease was significantly greater with IDegLira* compared to:
– Insulin degludec arm: HbA1c reduction of 1.44%, p<0.0001
– Liraglutide arm: HbA1c reduction of 1.28%, p<0.0001

Adapted from: Gough S, et al. Lancet Diab Endocrinol 2014;2:885–93.

 DUAL II: Primary outcome- HbA1c reduction
HbA1c over time Insulin dose over time

IDegLira (n=199) IDeg (n=199)

∆ HbA1c
End of trial IDeg dose:

Daily dose (U)

EOT: 8.0% IDegLira: 45 U
HbA1c (%)

Degludec: 45 U
-0.89%
ETD: -1.1%
p<0.0001 End of trial Liraglutide dose:
6.9% IDegLira: 1.8 mg
Start: 16 U
-1.90% Prior: 29 U

Weeks Weeks
Mean values (+SEM) based on FAS and LOCF imputed data; The dose was limited to a maximum of 50 U of degludec
estimated treatment difference (ETD) and p-value is from ANCOVA or 50 dose steps of IDegLira

Adapted from: Buse JB, et al. Diabetes Care 2014;37:2926–2933.

Conclusion
• A substantial proportion of patients on basal insulin do not reach their HbA1c
goal
• Addition of rapid-acting insulins is one option to target PPG
• Basal insulin/GLP-1 RAs combination therapy may provide a good
intensification option for those uncontrolled on basal insulin alone
• T2DM treatment recommendations (e.g., ADA/EASD, AACE) endorse the
addition of GLP-1 RAs to basal insulin
• The short-acting GLP-1 RAs lixisenatide QD and exenatide BID have been
best validated as add-on therapies to basal insulin (glargine)
• Addition of short-acting GLP-1 RAs that preferentially target PPG is a good
alternative to rapid-acting prandial insulins/premixed insulins