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INSULIN AND INCRETINS:
THE PERFECT PARTNERSHIP?
Moderator
Stephen Colagiuri, MD
Professor of Metabolic Health
Boden Institute of Obesity,
Nutrition and Exercise
University of Sydney
Sydney, Australia
Panelists
Stephen C. Bain, MD
Luc Martinez, MD
Professor of Medicine (Diabetes)
Institute of Life Science
Swansea University Medical School
Swansea, United Kingdom
Former Professor of Family Medicine
University Pierre et Marie Curie
Vice President, French Society of
General Medicine
Executive Member, Primary Care
Diabetes Europe
Paris, France
Andreas Liebl, MD
Medical Director
Center for Diabetes and Metabolism
Fachklinik Bad Heilbrunn
Bad Heilbrunn, Germany
Intensification of Insulin Therapy in T2DM
• Delays in the intensification of insulin therapy
• Treatment options for patients uncontrolled on basal
insulin
• Practical aspects of how to intensify basal insulin
therapy with a GLP-1 RA
Fewer T2DM Patients at Target When Treated With
Insulin/Injectables: PANORAMA Study
Diet/Exercise
HbA1c <7%
1 OAD
12.1%
HbA1c ≥7%
23.9%
76.1%
87.9%
2 OADs
Insulin/Injectables*
≥3 OADs
36.1%
38.6%
50.1%
61.4%
de Pablos-Velasco P, et al. Clin Endocrinol. 2014;80:47-56.
49.9%
63.9%
*Insulin or GLP-1 RA
Insulin Therapy Needs to Control Both
FPG and PPG Total Hyperglycemia, %
Treated With OADs[a]
80%
60%
Treated With Basal Insulin[b]
80%
70%
60%
60%
40%
20%
48%
52%
40%
42%
43%
48%
0%
<7.3
7.3-8.4
8.5-9.2
9.3-10.2
<6.5
≥10.2
6.5-<7.0 7.0-<7.5 7.5-<8.0
≥8
80%
80%
60%
70%
58%
40%
59%
58%
57%
40%
50%
42%
52%
40%
20%
30%
20%
0%
0%
<7.3
n = 290
42%
20%
30%
0%
60%
41%
7.3-8.4
8.5-9.2
9.3-10.2
FPG (basal hyperglycemia)
≥10.2
<6.5
6.5-<7.0 7.0-<7.5 7.5-<8.0
Postprandial hyperglycemia
a. Monnier L, et al. Diabetes Care. 2003;3:881-885; b. Riddle M, et al. Diabetes Care. 2011;34:2508-2514.
≥8
n = 1699
Why Does Intensification of Insulin Therapy
Not Happen in Many Patients With T2DM?
• Clinical inertia
– Physician barriers
• Inexperience with using insulin; lack of resources/training
• Fear of hypoglycemia
• Not buying into HbA1c targets; don’t want to be too aggressive
– Patient barriers
• Insulin carries “baggage” (eg, negative family experience, “end of
the road” perception)
• Educational issues about insulin dose increases
• Progressive nature of disease
 Higher doses of insulin and/or addition of other therapies
will be needed
Intensification Options for T2DM Patients
Uncontrolled on Basal Insulin
• Add an OAD
– DPP-4 or SGLT2 inhibitor  limited glucose-lowering potency
• Add a short-acting insulin at mealtime
– Stepwise addition: small dose with largest meal, uptitration, add to 3
meals/day  up to 4 injections, weight increase and hypoglycemia
risk
• Switch to premixed insulins
– Only 2 injections  limited flexibility
• Novel insulin combinations
– Modern short-acting plus long-acting insulin analog combination
• Basal insulin/GLP-1 RA combinations
IDegAsp Fixed-Ratio Combination vs
Basal Bolus: HbA1c Reduction
IDegAsp twice a day (n=138)
IDeg once daily + IAsp (n=136)
9.0
Mean HbA1c, %
8.5
Treatment difference:
0.18%-points (–0.04; 0.41)
8.0
7.5
7.0%
6.8%
7.0
6.5
6.0
0.0
0
10
14
18
22
26
Time, weeks
•
•
•
Mean HbA1c decreased by 1.31% in the IDegAsp group and by 1.50% in the basal bolus group
Noninferiority of IDegAsp vs basal bolus (IDeg + IAsp) not confirmed
Proportion of patients achieving HbA1c <7.0% (53 mmol/mol) after 26 weeks was similar for
IDegAsp and basal bolus (56.5% and 59.6%, respectively)
Calculated, not measured; Data are mean (SEM) in the FAS (LOCF); Comparisons: estimates adjusted for multiple covariates.
Rodbard HW, et al. Diabetes Obes Metab. 2015;18:274-280.
Lower Total Daily Dose of IDegAsp vs Basal Bolus
Estimated ratio: 0.88
Total Daily Insulin Dose Over Time
140
IDegAsp twice a day (n=136)
(95% CI: 0.78, 1.00) P<.05
Ideg once daily + IAsp (n=135)
Insulin Dose, U
120
100
80
60
40
20
0
2
4
6
8
10
12
14
Time, weeks
IDegAsp twice a day vs IDeg
once daily + IAsp
•
•
16
18
20
Mean Ratio (U/kg)
Basal insulin dose
1.05
Bolus insulin dose
0.55
Total insulin dose
0.83
IDegAsp twice a day, 70% of IDegAsp dose is basal and 30% is bolus
IDeg once daily + IAsp, sum of single IDeg dose and all IAsp doses
Comparisons: estimates adjusted for multiple covariates; SAS; LOCF
Cooper J, et al. EASD 2014. Abstract 147.
22
24
26
Rationale for Basal Insulin/GLP-1 RA
Combination
• Basal insulin improves FPG levels
• GLP-1 RA reduces PPG levels
• Complementary efficacy and mitigated side effects
when combined
• Now available as titratable fixed-ratio combinations
Complementary Effects of Basal Insulin
and GLP-1 RA Therapy
Increased
+
Side effects
Efficacy
Decreased
GLP-1 RA monotherapy
Basal insulin
GLP-1 RA/insulin combined
-
HbA1c
FPG
PPG
Weight
Hypoglycemia
Nausea
For illustrative purposes only; not meant to quantify or imply magnitude of change in either direction
Fixed-Ratio Combinations of
Basal Insulin and GLP-1 RAs
GLP-1 RA
GLP-1 RA
Liraglutide
Lixisenatide
Insulin
Glargine
Insulin
Degludec
IDegLira
IGlarLixi
Fixed Ratio Basal Insulin/GLP-1 RA Combinations
iGlarLixi
Components
Basal insulin glargine
GLP-1 RA lixisenatide
Ratio
2 U insulin glargine/1 µg lixisenatide
3 U insulin glargine/1 µg lixisenatide
Maximum dose
40 U insulin glargine/20 µg lixisenatide
60 U insulin glargine/20 µg lixisenatide
Development
studies
Regulatory
status
Phase 2: Proof of concept randomised trial[a]
Phase 3: LixiLan-O[b] and LixiLan-L[c]
LixiLan-G (upcoming)[d]
Approved for use in the US
Submitted for approval in EU
a. Rosenstock J, et al. Diabetes Care. 2016;39:1579-86; b. Rosenstock J, et al. Diabetes Care. 2016 Aug 15. [Epub ahead
of print]; c. Aroda VR, et al. Diabetes Care. 2016 Sep 20. [Epub ahead of print]; d. Clinicaltrials.gov. NCT02787551;
LixiLan-L Trial: Patients Uncontrolled on Insulin
Key Clinical Findings
HbA1c
Weight
Change in HbA1c, %
0
-0.2
n = 367
n = 369
-0.4
-0.62
-0.6
-0.8
-1
EOT HbA1c
*Max.
n = 367
6.94%
n = 369
1.5
0.7
1
0.5
0
-1
P<.0001
IGlar U100*
2
-0.5
-1.13
-1.2
iGlarLixi
Hypoglycaemia
-0.7
P<.0001
7.48%
dose 60 U. Documented symptomatic hypoglycemia (PG ≤70 mg/dL).
Aroda VR, et al. Diabetes Care. 2016 Sep 20. [Epub ahead of print].
Hypoglycaemia Rate,
events/patient-year
IGlar U100*
Change in Weight, kg
IGlarLixi
Documented symptomatic
IGlarLixi
IGlar U100*
n = 367
n = 369
6
5
4
3
2
4.22
3.03
1
0
Severe hypoglycaemia in
4 IGlarLixi subjects and
1 Gla-100 subject
LixiLan-L Trial: Patients Uncontrolled on Insulin
Mean Daily IGlar U100 Dose ±SE, Units
Insulin Dose Over Time
45
40
IGlarLixi
IGlar U100 *
35
n = 367
n = 369
30
25
20
15
10
5
0
0
3
5
7
9
11
15
18
21
24
27
30
LOCF
Study Week
The HbA1c-over-time plot includes all scheduled measurements obtained during the study, including those obtained
after study drug discontinuation or introduction of rescue therapy
*Max. dose 60 U
Aroda VR, et al. Diabetes Care. 2016 Sep 20. [Epub ahead of print]
Fixed Ratio Basal Insulin/GLP-1 RA Combinations
IDegLira
Components
Basal insulin degludec
GLP-1 RA liraglutide
Ratio
1 U insulin degludec/
0.036 mg liraglutide
Maximum dose
50 dose steps
(50 U IDeg and 1.8 mg Lira)[a]
Development
studies
Regulatory
status
Phase 3 complete:
DUAL I, II, III, IV, V, VI[b]
Phase 3 ongoing: DUAL VII, VIII, IX[b]
Approved in EU, US and Switzerland
a. Gough et al. Lancet Diabetes Endocrinol 2014;2:885–93; b. Clinicaltrials.gov; NCT01336023, NCT01392573,
NCT01676116, NCT01952145, NCT02501161, NCT02298192, NCT02100475, NCT02911948, NCT02607306
DUAL V Trial: Patients Uncontrolled on Insulin
HbA1c Over Time
IDegLira (n=278)
9.0
Difference
–0.59%
IGlar U100 (n=279)
8.5
[–0.74; –0.28] 95% CI
P<.001
HbA1c, %
8.0
∆HbA1c
7.5
EOT
7.0
7.1% –1.13%
6.5
6.6% –1.81%
6.0
5.5
0.0
0
4
8
12
Time, weeks
Lingvay I, et al. JAMA. 2016;315:898-907.
16
20
26
DUAL V Trial: Patients Uncontrolled on Insulin
Key Clinical Findings
0.0
n = 278
n = 279
-0.5
–1.13
-1.0
-1.5
–1.81
2.0
1.8
1.0
n = 278
n = 279
0.0
-1.0
–1.4
6.6%
7.1%
p<0.001
6
5
5.05
4
3
2
1
0
p<0.001
p<0.001
Hypoglycaemia*
IGlar U100
(no max.)
-2.0
-2.0
EOT
HbA1c
IDegLira
IGlar U100
(no max.)
Change in Weight, kg
Change in HbA1c, %
IDegLira
Confirmed
Weight
Hypoglycaemia Rate,
events/patient-year
HbA1c
2.23
n = 278
n = 279
IDegLira
IGlar U100
(no max.)
Severe hypoglycaemia in
one IGlar U100 subject‡
*Hypoglycemia was defined as severe or <3.1 mmol/L.
†Severe: An episode requiring assistance from another person to actively administer carbohydrate, glucagon, or other resuscitative actions
Lingvay I, et al. JAMA. 2016;315:898-907.
DUAL V Trial: Patients Uncontrolled on Insulin
Daily Insulin Dose Over Time
80
Difference: –25.5 U,
IDegLira (n=278)
IGlar U100 (n=279)
P<.001
70
66 U
Dose, Units
60
50
40
41 U
30
20
10
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
Time, weeks
IDegLira dose capped at 50 dose steps; there was no maximum dose for IGlar U100.
Lingvay I, et al. JAMA. 2016;315:898-907.
P
GI Adverse Events
Post hoc analysis of nausea in blinded studies (DUAL II and IV)
12
• Liraglutide arm from
DUAL I included for visual
comparison only
• Non-GLP-1 RA
comparator arms were
pooled for analysis
10
Patients With Nausea, %
• Post hoc analysis of two
double-blinded, Phase 3,
26-week trials
8
6
4
2
0
1 2 4 6 8 10 12 14 16 18 20 22 24 26
n = 415
Liraglutide 1.8 mg (DUAL I)
Non-GLP-1 RA comparators (DUAL II+IV Ideg+placebo) n = 345
IDegLira (DUAL II)
IDegLira (DUAL IV)
Adapted from Aroda et al. Diabetes 2015;64(Suppl. 1):A257
n = 199
n = 289
Utility of Fixed-Ratio Basal Insulin/GLP-1
RA Combinations in Clinical Practice
High percentage of patients achieving HbA1c target with
– Lower risk for hypoglycemia (compared with insulin alone)
– Weight loss (vs weight gain with insulin)
– Reduced frequency of GI side effects due to slow titration with
low initial dose of GLP-1 RA
– Increased patient acceptability
T2DM Patients Suitable for a Fixed-Ratio Basal
Insulin/GLP-1 RA Combination
• HbA1c above 7% or even 8%
• Advanced T2DM, some complications already
• Insulin therapy delayed for some time
• At higher risk for hypoglycemia
• Overweight
T2DM Patients Suitable for a Fixed-Ratio Basal
Insulin/GLP-1 RA Combination (cont)
Patients not at HbA1c target treated with:
1. Basal insulin—FPG controlled but suboptimal
postprandial control
2. GLP-1 RA
3. Oral glucose-lowering medications (single/dual)
IDegLira Titration
Titration Algorithm in Clinical Trials[a]
MEAN PREBREAKFAST PG
mmol/L
(mg/dL)
DOSE CHANGE
dose steps or U
Titrated twice weekly based on the mean
of 3 measurements
>5.0
(>90)
4.0-5.0
(72-90)
<4.0
(<72)
+2
TARGET*
0
–2
*DUAL IV target was 4-6 mmol/L as add-on to sulfonylurea
a. Lingvay I, et al. JAMA. 2016;315:898-907.
b. Xultophy® Summary of Product Characteristics.
EU Label[b]
IDegLira is to be dosed in
accordance with the individual
patient’s needs.
It is recommended to optimize
glycemic control via dose
adjustment based on FPG
DUAL VI Study: Once- vs Twice-Weekly Titration
Titration Algorithm
Mean Prebreakfast (Fasting) SMPG*†
Dose Change
mmol/L
mg/dL
Dose steps
<4.0
<72
–2
4.0-5.0
72-90
0
>5.0
>90
+2
*IDegLira once-weekly titration: titrated once weekly based on the mean of 2 consecutive
prebreakfast SMPGs
†IDegLira twice-weekly titration: titrated twice weekly based on the mean of 3 consecutive
prebreakfast SMPGs
1 IDegLira dose step = 1 U IDeg/0.036 mg liraglutide
Harris SB, et al. EASD 2016. Abstract P-908.
Patient and Physician Perspectives
• Patient
1. Simplicity—1 injection per day, easy to self-titrate
2. Weight loss
3. Improved glycemic control
4. Well tolerated
• Physician: easy to manage and explain to patient
Conclusions
• Novel fixed-ratio basal insulin/GLP-1 RA combinations provide
an opportunity for
– Poorly controlled T2DM patients on insulin
– Those in whom it is difficult to escalate/intensify insulin therapy
• Higher percentages of patients achieving Hb1Ac targets with
– A lower risk for hypoglycemia (vs insulin alone)
– Potential for weight loss
– Lower doses of insulin
– Fewer GI side effects due to slow titration with low initial doses
of GLP-1 RA
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