1. 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

2. Stephen C. Bain, MD Andreas Liebl, MD Luc Martinez, MD Panelists
Professor of Medicine (Diabetes)
Institute of Life Science
Swansea University Medical School
Swansea, United Kingdom
Andreas Liebl, MD
Medical Director
Center for Diabetes and Metabolism Fachklinik Bad Heilbrunn
Bad Heilbrunn, Germany
Luc Martinez, MD
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

3. 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
T2DM = type 2 diabetes mellitus
GLP-1 RA = glucagon-like peptide-1 receptor agonist

4. Fewer T2DM Patients at Target When Treated With Insulin/Injectables: PANORAMA Study
de Pablos-Velasco P, et al. Clin Endocrinol. 2014;80:47-56.
*Insulin or GLP-1 RA

5. Insulin Therapy Needs to Control Both FPG and PPG
Total Hyperglycemia, %
Treated With OADs[a]
Treated With Basal Insulin[b]
n = 290
FPG (basal hyperglycemia)
Postprandial hyperglycemia
n = 1699
a. Monnier L, et al. Diabetes Care. 2003;3: ; b. Riddle M, et al. Diabetes Care. 2011;34:

6. 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

7. 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

8. IDegAsp Fixed-Ratio Combination vs Basal Bolus: HbA1c Reduction
IDegAsp twice a day (n=138)
IDeg once daily + IAsp (n=136)
0.0
Time, weeks
Treatment difference:
0.18%-points (–0.04; 0.41)
7.0%
6.8%
IDegAsp = insulin degludec plus insulin aspart fixed-ratio combination
IDeg = insulin degludec
IAsp = insulin aspart
OD = once daily; BID = twice daily; FAS = full analysis set; LOCF = last observation carried forwards; ns = not significant; SEM = standard error of the mean
Results
After 26 weeks, HbA1c levels were reduced from 8.3% (67.2 mmol/mol) to 7.0% (53 mmol/mol) with [IDegAsp] and from 8.3% (67.2 mmol/mol) to 6.8% (51 mmol/mol) with [IDeg+IAsp]
Mean HbA1c decreased by 1.31% in the [IDegAsp] group and by 1.50% in the [IDeg+IAsp] group
After 26 weeks, the estimated treatment difference (ETD) between groups ([IDegAsp] – [IDeg+IAsp]) was 0.18% (95% CI –0.04, 0.41; p=non-significant [ns]). Therefore, the non-inferiority of [IDegAsp] versus [IDeg+IAsp] was not confirmed. All sensitivity analyses showed an upper confidence limit below 0.4 (ETD 0.16%, 95% CI −0.06, 0.38 for the per-protocol set; and 0.14%, 95% CI −0.08, 0.36 for the completers). Results from the FAS were 0.16% (95% CI −0.06, 0.39) using the simple model and 0.16% (95% CI −0.06, 0.38) using the repeated-measures model
The proportion of patients achieving HbA1c <7.0% (53 mmol/mol) after 26 weeks was similar for [IDegAsp] and [IDeg+IAsp] (56.5% and 59.6%, respectively). Based on the estimated odds ratio for [IDegAsp] versus [IDeg+IAsp], the difference in the proportion of patients achieving HbA1c <7.0% (53 mmol/mol) after 26 weeks was not significant (0.83; 95% CI 0.50, 1.38)
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:

9. Lower Total Daily Dose of IDegAsp vs Basal Bolus
Total Daily Insulin Dose Over Time
Estimated ratio: 0.88
(95% CI: 0.78, 1.00) P<.05
Insulin Dose, U
Time, weeks
IDegAsp twice a day vs IDeg once daily + IAsp
Mean Ratio (U/kg)
Basal insulin dose
1.05
Bolus insulin dose
0.55
Total insulin dose
0.83
CI, confidence interval; EOT, end of trial; IAsp, insulin aspart; IDeg, insulin degludec; IDegAsp, insulin degludec/aspart; LOCF, last observation carried forward; SAS, safety analysis set; U, units
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 Abstract 147.

10. 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

11. Complementary Effects of Basal Insulin and GLP-1 RA Therapy+
Efficacy
Side effects
Increased
GLP-1 RA monotherapy
Basal insulin
Decreased
FPG = fasting plasma glucose
PPG = postprandial glucose
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

12. Fixed-Ratio Combinations of Basal Insulin and GLP-1 RAs
GLP-1 RA Liraglutide
GLP-1 RA Lixisenatide
Insulin
Degludec
Insulin Glargine
IDeg = insulin degludec
IDegLira = insulin degludec plus liraglutide
IGlarLixi = insulin glargine plus lixisenatide
IDegLira
IGlarLixi

13. 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
Phase 2: Proof of concept randomised trial[a] Phase 3: LixiLan-O[b] and LixiLan-L[c]
LixiLan-G (upcoming)[d]
d. LixiLan-G trial information:
(accessed October 2016)
FDA, US Food and Drug Administration; IGlarLixi, insulin glargine/lixisenatide
Regulatory status
Approved for use in the US
Submitted for approval in EU
a. Rosenstock J, et al. Diabetes Care. 2016;39: ; b. Rosenstock J, et al. Diabetes Care Aug 15. [Epub ahead of print]; c. Aroda VR, et al. Diabetes Care Sep 20. [Epub ahead of print]; d. Clinicaltrials.gov. NCT ;

14. LixiLan-L Trial: Patients Uncontrolled on Insulin Key Clinical Findings
HbA1c
Weight
Documented symptomatic Hypoglycaemia
n = 367
n = 369
n = 367
n = 369
n = 367
n = 369
Change in Weight, kg
Hypoglycaemia Rate, events/patient-year
Change in HbA1c, %
EOT, end-of-trial; iGlarLixi, insulin glargine/lixisenatide; IGlar U100, insulin glargine 100 units/mL
P<.0001
P<.0001
Severe hypoglycaemia in 4 IGlarLixi subjects and 1 Gla-100 subject
EOT HbA1c
6.94%
7.48%
*Max. dose 60 U. Documented symptomatic hypoglycemia (PG ≤70 mg/dL).
Aroda VR, et al. Diabetes Care Sep 20. [Epub ahead of print].

15. Mean Daily IGlar U100 Dose ±SE, Units
LixiLan-L Trial: Patients Uncontrolled on Insulin Insulin Dose Over Time *
n = 367
n = 369
Mean Daily IGlar U100 Dose ±SE, Units
CI, confidence interval; iGlarLixi, insulin glargine/lixisenatide; IGlar U100, insulin glargine 100 units/mL; Lixi, lixisenatide
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 Sep 20. [Epub ahead of print]

16. Fixed Ratio Basal Insulin/GLP-1 RA Combinations
IDegLira
Components
Basal insulin degludec GLP-1 RA liraglutide
Ratio
1 U insulin degludec/ mg liraglutide
Maximum dose
50 dose steps (50 U IDeg and 1.8 mg Lira)[a]
Development studies
Phase 3 complete:
DUAL I, II, III, IV, V, VI[b]
Phase 3 ongoing: DUAL VII, VIII, IX[b]
Regulatory status
Approved in EU, US and Switzerland
a. Gough et al. Lancet Diabetes Endocrinol 2014;2:885–93; b. Clinicaltrials.gov; NCT , NCT , NCT , NCT , NCT , NCT , NCT , NCT , NCT

17. DUAL V Trial: Patients Uncontrolled on Insulin HbA1c Over Time
Difference
–0.59% [–0.74; –0.28] 95% CI P<.001
EOT
∆HbA1c
HbA1c, %
7.1%
–1.13%
6.6%
–1.81%
0.0
Time, weeks
Lingvay I, et al. JAMA. 2016;315:

18. DUAL V Trial: Patients Uncontrolled on Insulin Key Clinical Findings
HbA1c
Weight
Confirmed Hypoglycaemia*
IGlar U100 (no max.)
IDegLira
IGlar U100 (no max.)
IDegLira
p<0.001
n = 278
n = 279
1.8
5.05
Hypoglycaemia Rate, events/patient-year
n = 278
n = 279
Change in HbA1c, %
–1.13
Change in Weight, kg
–1.4
2.23
n = 278
n = 279
EOT, end of trial; IDegLira, insulin degludec/liraglutide; IGlar U100, insulin glargine U100
p<0.001
IDegLira
IGlar U100 (no max.)
p<0.001
EOT HbA1c
6.6%
7.1%
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:

19. DUAL V Trial: Patients Uncontrolled on Insulin Daily Insulin Dose Over Time
Difference: –25.5 U, P<.001
66 U
Dose, Units
41 U
Treatment difference was estimated from an ANCOVA analysis based on FAS. ANCOVA, analysis of covariance; CI, confidence interval; EOT, end of treatment; FAS, full analysis set; IDegLira, insulin degludec/liraglutide combination; IGlar U100, insulin glargine U100; LOCF, last observation carried forward; SAS, safety analysis set
Time, weeks
IDegLira dose capped at 50 dose steps; there was no maximum dose for IGlar U100.
Lingvay I, et al. JAMA. 2016;315:

20. P
GI Adverse Events Post hoc analysis of nausea in blinded studies (DUAL II and IV)
Post hoc analysis of two double-blinded, Phase 3, 26-week trials
Liraglutide arm from DUAL I included for visual comparison only
Non-GLP-1 RA comparator arms were pooled for analysis
Patients With Nausea, %
IDeg, insulin degludec; IDegLira, insulin degludec/liraglutide; GLP-1 RA, glucagon-like peptide-1 receptor agonist
n = 415
n = 345
n = 199
n = 289
Adapted from Aroda et al. Diabetes 2015;64(Suppl. 1):A257

21. 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

22. 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

23. T2DM Patients Suitable for a Fixed-Ratio Basal Insulin/GLP-1 RA Combination (cont)
Patients not at HbA1c target treated with:
Basal insulin—FPG controlled but suboptimal postprandial control
GLP-1 RA
Oral glucose-lowering medications (single/dual)

24. Titration Algorithm in Clinical Trials[a]
IDegLira Titration
Titration Algorithm in Clinical Trials[a]
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
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) +2
(72-90)
PG, plasma glucose; U, units
TARGET*
<4.0 (<72) –2
*DUAL IV target was 4-6 mmol/L as add-on to sulfonylurea
a. Lingvay I, et al. JAMA. 2016;315:
b. Xultophy® Summary of Product Characteristics.

25. 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
72-90
>5.0
>90 +2
1WT, once-weekly titration; 2WT, twice-weekly titration; SMPG, self-measured plasma glucose
*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 Abstract P-908.

26. Patient and Physician Perspectives
Simplicity—1 injection per day, easy to self-titrate
Weight loss
Improved glycemic control
Well tolerated
Physician: easy to manage and explain to patient

27. 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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