Basal Insulin and GLP-1RA Combination Therapy for Type 2 Diabetes

Learning Objectives
• Describe unmet needs of patients with type 2 diabetes
• Outline the role of basal insulin and GLP-1RAs as described in current
guidelines
• Compare the benefits and limitations of GLP-1RA vs prandial insulin as add-on
to basal insulin
• Describe the glycemic and non-glycemic outcomes observed with fixed-ratio
basal insulin/GLP-1RA combination products
• Initiate and titrate fixed-ratio basal insulin/GLP-1RA combination products

Case Scenario #1
61-year-old man diagnosed with type 2 diabetes mellitus 3 months ago (A1c 8.7%)
Weight: 187 lb
BMI: 28.8 kg/m2
BP: 126/78 mm Hg
A1c: 7.6%
FPG: 128 mg/dL
PPG: 196 mg/dL
eGFR: 92 mL/min/1.73 m2
Vital Signs and
Laboratory Results
• Lifestyle management
• Metformin 1000 mg BID
Current
Management
Has had some success in
modifying diet and increasing
physical activity
Notes

Diabetes Mellitus as a Cardiovascular Risk Factor
Kannel WB, et al. JAMA. 1979;241:2035-2038.
0 5 10 15 20 25 30 35 40 45
Coronary Heart Disease
Atherothrombotic Brain Infarction
Intermittent Claudication
Congestive Heart Failure
Cardiovascular Death
Cardiovascular Disease
Annual age-adjusted event rate per 1000 patient-years
Framingham Heart Study
Men with Diabetes Men without Diabetes Women with Diabetes Women without Diabetes

UKPDS: 1% A1c Decrease and Reduced Risk of
Complications
Stratton IM, et al. BMJ. 2000;321:405-412.
UKPDS, United Kingdom Prospective Diabetes Study.
Lower-extremity
amputation or fatal
peripheral
vascular disease
(P<0.0001)
Microvascular
disease
(P<0.0001)
Cataract
extraction
(P<0.0001)
Heart failure
(P<0.05)
Myocardial
infarction
(P<0.0001)
Stroke
(P<0.05)
Cardiovascular complications
43% 37% 19% 16% 14% 12%

Prevalence of Persons with Diabetes Achieving
Cardiovascular Targets: NHANES 2011-2014
Sun X, et al. BMC Public Health. 2017;17:893.
78.8%
67.0%
56.8% 55.8%
76.7%
77.2%
67.3%
57.3% 56.0%
78.4%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Achieving A1c <7.0% Achieving BP <130/80 mmHg Achieving LDL-C <100 mg/dL
Percent
of
Survey
Respondents
Women w/o Diabetes Women w/Diabetes Men w/o Diabetes Men w/Diabetes

The Disconnect Between Clinical Trial and
Real-world Results
1. Pratley RE, et al. Lancet. 2010;375:1447-1456. 2. Singhal M, et al. ISPOR Annual International Meeting. May 16-20, 2015; Poster PDB10.
3. Garber A, et al. Lancet. 2009;373:473-481.
†Quintiles EMR database, N=1474 patients with T2D who were prescribed liraglutide or exenatide once weekly.
–1.2%
–1.5%
–0.9%
CLINICAL TRIALS
REAL WORLD†
–0.8%
–1.1%
–0.7%
0
–1.2
–0.4
–0.8
–0.2
Change
in
A1c
(%)
–1.0
–0.6
–1.4
–1.6
1.2 mg 1.8 mg
N=251 N=247
8.3%
Liraglutide3
N=225
Reduction in A1c
(6 Months)
1.2 mg 1.8 mg
GLP-1 RAs in the REAL WORLD2†
N=221
8.4%
Liraglutide1
N=1474
8.6%
N=902
8.6%
Baseline A1c
Reduction in A1c
(12 Months)

Patient Adherence with Medications for T2DM
Is Suboptimal
Farr AM, et al. Adv Ther. 2014;31(12):1287-1305. Zhou FL, et al. Diabetes Obes Metab. 2018;20:1298-1301.
Adherence defined as: SU, TZD, DPP-4i: patients who maintained proportion of days covered ≥0.80 over 1 year
Basal insulin: patients with refill gap ≤90 days over 18 months
41%
37%
47%
43%
0%
20%
40%
60%
80%
100%
Sulfonylurea (n=134,961) Thiazolidinedione (n=42,012) Dipeptidyl peptidase-4
inhibitor (n=61,399)
Basal Insulin (N=3993)
Percent
Adherent

Depression and Distress are Common in
Patients with Diabetes
• Meta-analysis of 39 studies (N=20,218) showed1
 Odds of depression doubled (2x) in diabetes group
 Point prevalence: women 28%; men 18%
• In T2DM, depression is more common in those
 Treated with insulin vs lifestyle or OADs2
 Who experience recurrent hypoglycemia and poor glycemic control3
 With diabetes distress4
1.Anderson RJ, et al. Diabetes Care. 2001;24:1069-1078.
2.Hermanns N, et al. Diabet Med. 2005;22(3):293-300
3.Holt RIG, et al. Curr Diabetes Rep. 2014;14(6):491.
4.Perrin NE, et al. Diabet Med. 2017;34:1508-1520.

Strategies to Identify and Address
Patient Concerns
• Active listening
• Motivational interviewing
• Ask open-ended questions
• Involve patient in decision-making process

Resources for Patient Education
• American Diabetes Association
http://www.diabetes.org/diabetes-basics/type-2/?loc=util-header_type2
• American Association of Clinical Endocrinologists
http://outpatient.aace.com/
• National Diabetes Education Program
https://www.niddk.nih.gov/health-information/professionals/clinical-tools-
patient-education-outreach?cs=ndep

Case Scenario #2
53-year-old woman newly diagnosed with type 2 diabetes mellitus
Weight: 198 lb
BMI: 32.9 kg/m2
BP: 132/86 mm Hg
A1c: 8.4%
FPG: 156 mg/dL
Vital Signs and
Laboratory Results
• Lifestyle management in
consultation with dietitian
• Atorvastatin 40 mg/d
• Ramipril 10 mg/d
• NTG 0.3 mg SL prn
• Aspirin 81 mg/d
Current
Management
• PMH: hyperlipidemia, angina,
obesity
• She is upset with being
diagnosed with ‘yet another
disease’
• Adherence with current
treatment has been
challenging
Notes

Why Is It Difficult to Achieve and Maintain
Glycemic Targets?
CNS: Delayed satiety
Neurotransmitter dysfunction Kidney:  Glucose
reabsorption
Liver:  Hepatic glucose secretion
Pancreas:
 Insulin secretion
 Glucagon secretion
Muscle and adipose tissue:
 Glucose uptake
Adipose tissue:
 Lipolysis
Gut: Diminished incretin effect
Altered intestinal glucose absorption
HYPERGLYCEMIA

American Diabetes Association. Diabetes Care. 2018;41(Suppl 1):S73-S85.

Characteristics of Key Medications for
Type 2 Diabetes Mellitus
Bolen S, et al. https://www.effectivehealthcare.ahrq.gov/ehc/products/607/2215/diabetes-update-2016-report.pdf
American Diabetes Association. Diabetes Care. 2018;41(Suppl 1):S73-S85.
Garber AJ, et al. Endocr Pract. 2018;24:91-120.
†When added to metformin
↑, decrease; ↔, no change; ↓, increase
Magnitude of
A1c Lowering†
Adverse Events Risk of
Hypoglycemia
Weight
Effect
Cost
DPP-4i 0.4% to 0.5% Rare Low  High
GLP-1RA 0.5% to 1.3% GI Low  High
Insulin
(basal analog)
Theoretically
unlimited
Hypoglycemia
High  High
SGLT-2i 0.5% to 1% GU, dehydration,
fracture
Low  High
Sulfonylurea 1% Hypoglycemia Moderate  Low
TZD 0.4% to 0.9% Edema, HF, fracture Low  Low

GLP-1 Receptor Agonists: Benefits
• Low risk of hypoglycemia
• Increase insulin secretion in a glucose-dependent manner
• Improvements in cardiovascular markers
 Blood pressure, triglycerides, low-density lipoprotein cholesterol
• Use as an alternative to metformin
• Promote modest weight loss
Balena R, et al. Diabetes Obes Metab. 2013;15:485-502.

Cardiovascular Safety and Benefit for
GLP-1 RAs in Patients With T2DM
1.Holman R, et al. N Engl J Med. 2017;377(13):1228-1239.
2.Marso SP, et al. N Engl J Med. 2016;375(4):311-322.
3.Pfeffer MA, et al. N Engl J Med. 2015;373(23):2247-2257.
CV, cardiovascular; F/U, follow-up; MI, myocardial infarction; UA, unstable angina.
a Composite of CV death, nonfatal MI, nonfatal stroke
b Composite of CV death, nonfatal MI, nonfatal stroke, hospitalization for UA
c Composite of CV death, nonfatal MI, nonfatal ischemic stroke
GLP-1 Receoptor Agonist Primary endpoint
Heart failure
hospitalization
All-cause death
Exenatide1
(N=14,752; 3.2 y median F/U)
0.91a
(0.83-1.00)
0.94
(0.78-1.13)
0.86
(0.77-0.97)
Liraglutide2
(N=9340; 3.8 y median F/U)
0.87a
(0.78-0.97)
0.87
(0.73-1.05)
0.85
(0.74-0.97)
Lixisenatide3
(N=6068; 2.1 median F/U)
1.02b
(0.89-1.17)
0.96
(0.75-1.23)
0.94
(0.78-1.13)
Semaglutide4
(N=3297; 2.1 y median F/U)
0.74c
(0.58-0.95)
1.11
(0.77-1.61)
1.05
(0.74-1.50)

Cardiovascular Safety and Benefit for
SGLT-2is in Patients With T2DM
1.Neal B, et al. N Engl J Med. 2017;377(7):644-657.
2.Zinman B, et al. N Engl J Med. 2015;373(22):2117-2128.
CV, cardiovascular; F/U, follow-up; MI, myocardial infarction.
†Composite of CV death, nonfatal MI, nonfatal stroke
SGLT-2 Inhibitor
Primary
endpoint
Heart failure
hospitalization
All-cause death
Canagliflozin1
(N=10,142; 2.4 y median F/U)
0.86†
(0.75-0.97)
0.67
(0.52-0.87)
0.87
(0.74-1.01)
Empagliflozin2
(N=7020; 3.1 median F/U)
0.86†
(0.74-0.99)
0.65
(0.50-0.85)
0.68
(0.57-0.82)

Cardiovascular Safety of Basal Insulin
1.ORIGIN Investigators. N Engl J Med. 2012;367(4):319-328.
Nonfatal Myocardial Infarction, Nonfatal Stroke, Death From Cardiovascular Causes
ORIGIN Trial DEVOTE Trial

Case Scenario #3
64-year-old woman with type 2 diabetes mellitus for 7 years
Weight: 204 lb
BMI: 33.6 kg/m2
BP: 136/82 mm Hg
A1c: 8.2%
FPG: 118 mg/dL
PPG: 218 mg/dL
LDL-C: 86 mg/dL
Triglycerides: 160 mg/dL
Vital Signs and
Laboratory Results
• Insulin detemir 68 units (0.73
units/kg) at bedtime
• HCTZ 25 mg/d
• Lisinopril 20 mg/d
Current
Management
• PMH: hypertension, dyslipidemia,
obesity
• A1c 13 mos ago: 7.2%
• Has experienced several episodes
of symptomatic hypoglycemia over
past few months
• Episode early yesterday
morning required treatment in
emergency department
(blood glucose 52 mg/dL)
Notes

Uptitrating Basal Insulin May Not Achieve A1c Target
and May Increase Risk of Hypoglycemia
Reid T, et al. Int J Clin Pract. 2016;70:56–65.
-1.61 -1.59 -1.57
-1.49
-1.43
-1.26
-1.8
-1.6
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
0.5 IU/kg 0.7 IU/kg 1.0 IU/kg
A1c
change
from
baseline
(%)
At or below cut-off Exceeding cut-off
1.55
1.12
0.71
4.49
3.90
2.85
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
0.5 IU/kg 0.7 IU/kg Dose
cut-off
1.0 IU/kg
Overall
hypoglycemia
event
rate
(events
per
patient-year)
Prior to exceeding cut off dose After exceeding cut-off
Pooled analysis of glycemic profiles from 15 treat-to-target trials
in which insulin-naïve T2DM patients were treated with insulin glargine and OADs for ≥24 weeks (N=2837)

Combination of Basal Insulin with a GLP-1 RA
Has a Scientific Basis
Little S, et al. Diabetes Technol Ther. 2011:13(suppl 1):S53-S64.
Cohen ND, et al. Med J Aust. 2013;199(4):246-249.
Carris NW, et al. Drugs. 2014;74(18):2141-2152.
Basal insulin analogs†
• Control nocturnal and FPG
• Simple to initiate
• Achieve A1c targets in ~50-60%
• Hypoglycemia remains a concern
• Modest weight increase (1 to 3 kg)
GLP-1 RAs
• Pronounced PPG control
(especially short-acting agents)
• Simple to initiate
• Achieve A1c targets in ~40-60%
• Low risk of hypoglycemia
• Weight lowering/neutral effects
Complementary
actions
Additive
actions
†Note: NPH insulin is an alternative for use in combination with a GLP-1RA but has not been studied

Adding a GLP-1 RA vs Prandial Insulin† to
Basal Insulin– Systematic Review
Maiorino MI, et al. Diabetes Care. 2017;40(4):614-624.
†Results reported from 2 basal-plus and 7 basal-bolus studies including at least 60 patients/arm with T2DM
-0.11%
P=0.031
-4.1 kg
P<0.001
-5
-4
-3
-2
-1
0
1
2
Favors
Basal
Insulin
+
GLP-1RA
Favors
Basal
Insulin
+
Prandial
Insulin
Change
in Weight
Change
in A1c
1.09
P=0.076
0.68
P=0.005
-1
-0.5
0
0.5
1
1.5
A1C ≤7% Risk of Hypoglycemia
Favors
Basal
Insulin
+
GLP-1RA
Favors
Basal
Insulin
+
Prandial
Insulin
Weighted Mean
Difference vs Placebo
Relative Risk

Adding a GLP-1 RA to Basal Insulin Is Equally
Effective Compared to Adding Prandial Insulin
Diamant M, et al. Diabetes Care. 2014;37:2763-2773. Balena R, et al. Diab Obes Metab. 2013;15:485-502.
Carris NW, et al. Drugs. 2014;74(18):2141-2152. Holst JJ, Vilsbøll T. Diabetes Obes Metab. 2013;15(1):3-14.
Vora J, et al. Diabetes Care. 2013;36(suppl 2):s226-S232.
• Fewer injections
• Improved adherence?
• Less glucose monitoring required
• Lower insulin dose
• Weight benefit
• Less hypoglycemia
• More (GI) side effects
• Cost/Affordability
And… But…

Case Scenario #4
69-year-old man with type 2 diabetes for 12 years
Weight: 187 lb
BMI: 29.5 kg/m2
BP: 128/84 mm Hg
A1c: 6.9%
FPG: 106 mg/dL
PPG: 176 mg/dL
LDL-C: 68 mg/dL
Vital Signs and
Laboratory Results
• Insulin glargine 46 units (0.54
• Exenatide 10 mcg BID
• HCTZ 25 mg/d
• Valsartan 320 mg/d
• Pravastatin 40 mg/d
• Aspirin 81 mg/d
Current
Management
• Treatment has been modified
through the years to maintain
A1c 7%
• PMH: hypertension,
dyslipidemia, myocardial
infarction (3 years ago)
• Has found it increasingly difficult
to adhere to treatment; exhibiting
distress
Notes

Rationale for Co-Formulation of Basal Insulin/GLP-1RA:
Barriers to Concomitant Use of Individual Products
• More injections  clinical inertia
 Decreased adherence
 Reduced satisfaction
 Compromised self-management
• Uncertainty of choosing starting dose, adding therapies, titration
of each drug
Peyrot M, et al. Diabet Med. 2012;29(5):682-689. Peyrot M, et al. Diabetes Care. 2010;33(2):240-245.

Rationale for Co-Formulation of Basal
Insulin/GLP-1RA: Benefits
• Provides pathophysiologic-based treatment
• Targets both fasting and postprandial glucose
• Single injection
 May reduce out-of-pocket cost
• Safe, effective initiation and titration algorithm
• Avoids uncertainty regarding titrating individual components
• Minimizes delays in achieving glycemic control

Insulin Degludec/Liraglutide
(Xultophy® 100/3.6)
Insulin Glargine/Lixisenatide
(Soliqua 100/33)
Administration Subcutaneous Subcutaneous
Dose timing Once daily at same time each day
with/without food
Once daily within the hour prior to the first
meal of the day
Maximum daily dose 50 units degludec, 1.8 mg liraglutide 60 units glargine, 20 mcg lixisenatide
Dosing Based on degludec Based on glargine
Fixed-Ratio Basal Insulin/GLP-1 RA
Combinations
XULTOPHY® 100/3.6 (insulin degludec and liraglutide injection). Prescribing Information, Novo Nordisk. November 2016.
SOLIQUA™ 100/33 (insulin glargine and lixisenatide injection) [package insert]. Sanofi-Aventis U.S.; March 2018.

Fasting Plasma Glucose (mg/dL)
A1c
IDegLira in Insulin-Naïve Patients with T2DM not
Controlled on OADs: DUAL I
Gough SCL, et al. Diabetes Obes Metab. 2015;17:965-973.
FPG, fasting plasma glucose; A1c, glycated hemoglobin; OADs, metformin ±pioglitazone; LIRA, liraglutide; IDeg, insulin degludec; IDegLira, fixed-ratio
insulin degludec/liraglutide.

Change in A1c by Baseline BMI
Controlled on OADs: DUAL I (cont)
% of Patients Achieving A1c Targets

Change in Body Weight
Daily Insulin Dose

% of Patients with Nausea

IDegLira in Patients with T2DM Not Controlled
on Basal Insulin†: DUAL II
Buse JB, et al. Diabetes Care. 2014;37:2926-2933.
†Patients withT2DM not controlled on basal insulin + metformin ± SU or glinides
Time (weeks)
A1c
(%)
9.5
0
8.5
7.5
10 22
12 26
6.5
IDegLira (N=199) IDeg (N=199)
∆ = -1.05%,
p<0.0001
9.0
8.0
7.0
0 4 16
8 20
2 14
6 18 24
A1c
Mean final basal insulin dose/day: IDegLira, 45 units; degludec 45 units
-50
-10
Mean
Change
from
Baseline
in
FPG
(mg/dL)
-70
-30
0
-46.4
-60
P=0.0019
-40
-20
-62.4
Change in Fasting Plasma Glucose

IDegLira in Patients with T2DM Not Controlled on
GLP-1RA + OAD†: DUAL III
Linjawi S, et al. Diabetes Ther. 2017;8:101-114.
†Maximum-dose exenatide twice daily or liraglutide once daily plus metformin ± pioglitazone ± sulfonylurea
A1c (%)

Plasma Glucose
Fasting Plasma Glucose
GLP-1RA + OAD†: DUAL III (cont)
Linjawi S, et al. Diabetes Ther. 2017;8:101-114.
†Maximum-dose exenatide twice daily or liraglutide once daily plus metformin ± pioglitazone ± sulfonylurea

Change in A1c by
Baseline A1c
Change in A1c by
Baseline Fasting Plasma
Change in A1c by
Baseline Body Mass Index
Insulin Glargine + OAD†: DUAL V
Lingvay I, et al. Diabetes Obes Metab. 2018;20:200-205.
†Insulin glargine + metformin

Insulin Glargine + OAD†: DUAL VII (cont)
Billings LK, et al. Diabetes Care. 2018;41:1009-1016.
†Insulin glargine + metformin

IDegLira: Other Safety Events†
1. Gough SCL, et al. Diabetes Obes Metab. 2015;17:965-973. 2. Buse JB, et al. Diabetes Care. 2014;37:2926-2933. 3. Linjawi S, et al.
Diabetes Ther. 2017;8:101-114. 4. Lingvay I, et al. JAMA. 2016;315:898-907. 5. Billings LK, et al. Diabetes Care. 2018;41:1009-1016.
†Positively adjudicated by a blinded monitoring committee and judged by the investigator as treatment-related
DEG, insulin degludec; GLAR, insulin glargine; IDegLira, fixed-ratio insulin degludec/liraglutide; LIRA, liraglutide; NR, not reported.
DUAL I1 DUAL II2 DUAL III3 DUAL V4 DUAL VII5
Major adverse
CV event
IDegLira 4/833
DEG 1/413
LIRA 1/414
IDegLira 1/199
DEG 2/199
IDegLira 2/292
GLP-1RA 0/146
IDegLira 1/278
GLAR 1/279
IDegLira 0/252
GLAR+ASP 0/254
Pancreatitis IDegLira 0/833
DEG 0/413
LIRA 1/414
IDegLira 0/199
DEG 0/199
IDegLira 0/292
GLP-1RA 0/146
IDegLira 0/278
GLAR 0/279
IDegLira 0/252
GLAR+ASP 0/254
Pancreatic
cancer
NR IDegLira 0/199
DEG 1/199
NR IDegLira 0/278
GLAR 0/279
IDegLira 0/252
GLAR+ASP 0/254
Medullary
thyroid cancer
IDegLira 0/833
DEG 0/413
LIRA 0/414
IDegLira 0/199
DEG 0/199
IDegLira 0/292
GLP-1RA 0/146
IDegLira 0/278
GLAR 0/279
IDegLira 0/252
GLAR+ASP 0/254

IGlarLixi in Insulin-Naïve Patients with T2DM:
LixiLan-O
Patients with T2DM not controlled on Metformin ± second OAD
Rosenstock J, et al. Diabetes Care. 2016;39:2026-2035.
†P<0.05. ‡P<0.0001.
iGlarLixi, fixed-ratio insulin glargine/lixisenatide; OAD, oral antidiabetic agent.
Mean
A1c
(%)
8.5
6.5
6.0
8.0
7.5
8
Baseline
24
12 30
Week
7.0
Screening
iGlarLixi (N = 469)
Mean
Difference
P-value
vs Lixi (N = 234) -0.78% <0.0001
vs Glargine (N = 467) -0.29% <0.0001
Lixi Glargine iGlarLixi
6.5%
iGlarLixi Glargine Lixi
6.8%
7.3%
8.1%
8.2%

LixiLan-O (cont)
†PPG changes are mean for all 3 meals.
Patients with T2DM not controlled on Metformin ± second OAD
FPG
-60
-20
Mean
Change
from
Baseline
(mg/dL)
-80
-40
0
2-h PPG Excursions†
-27.0
P<0.0001
-60
-20
-80
-40
0
-58.1
P<0.0001
iGlarLixi (N = 468) Glargine (N = 466) Lixi (N = 233)
-59.0
-62.4
-3.2
-41.7
2
-2.3
P<0.0001
1.1
-0.3
1
0
-1
-2
-3
Weight Change (kg)
Mean final basal insulin dose/day: IGlarLixi, 39.8 units; glargine 40.3 units

LixiLan-O (cont)
iGlarLixi Glargine Lixisenatide
Adverse event leading to discontinuation 2.6% 1.9% 9%
GI adverse event
Nausea
21.7%
9.6%
12.6%
3.6%
36.9%
24.0%
Symptomatic hypoglycemia,
events/patient-year
1.4 1.2 0.3
Cardiovascular event 0.4% 1.5% 0.9%
Allergic reaction 1.3% 0.6% 0.9%
Pancreatitis 0% 0% 0%
Pancreatic cancer 0% 0.2% 0%

Efficacy of IGlarLixi in Patients with T2DM Not
Controlled on Basal Insulin: LixiLan-L
Patients with T2DM not controlled on basal insulin + Metformin ± second OAD
Aroda VR, et al. Diabetes Care. 2016;39:1972-1980.
iGlarLixi (N = 366)
Mean
Difference
P-value
vs Glargine (N = 365) -0.52% <0.0001
Mean
A1c
(%)
8.5
6.5
6.0
8.0
7.5
8
Baseline
24
12 30
Week
7.0
Screening
Glargine iGlarLixi
6.9%
7.5%
8.1%
8.5%
iGlarLixi Glargine
(%)
40
10
20
0
60
30
50
% Patients with
A1c < 7.0% at Week 30
55%
30%
Percent
Patients
(%)
40
10
20
0
A1c < 7.0% with No Wt
Gain and No Symptomatic
Hypoglycemia
30
20%
9%

Efficacy of IGlarLixi in Patients with T2DM Not Controlled
on Basal Insulin: LixiLan-L (cont)
†PPG changes are mean for all 3 meals.
Mean final basal insulin dose/day: iGlarLixi, 46.7 units; glargine 46.7 units
iGlarLixi (N = 366)
FPG
-60
-20
Mean
Change
from
Baseline
(mg/dL)
-100
-40
0
-8.3
2-h PPG Excursions†
Glargine (N = 365)
-80
P=NS
-60
-20
-100
-40
0
-8.4
-80
P<0.0001
-70.2
-6.3
-2
0
-1
1 0.7
P<0.0001
-0.7
Weight Change (kg)

Safety of IGlarLixi in Patients with T2DM Not Controlled on
Basal Insulin: LixiLan-L
IGlarLixi Glargine
Adverse event leading to
discontinuation
2.7% 0.8%
GI adverse event
Nausea
17.0%
10.4%
7.9%
0.5%
Symptomatic hypoglycemia,
events/patient-year
3.03 4.22

Case Scenario #5
52-year-old woman with T2DM for 7 years and obesity who started basal insulin
1 year ago
Height: 5 ft 4 in
Weight: 187 lb
BMI: 32.1 kg/m2
BP: 127/82 mm Hg
FPG: 149 mg/dL
A1c: 8.0%
Vital Signs and
Laboratory Results
• Insulin glargine 22 units/d
• Losartan/HCTZ 50/12.5 mg/d
• Simvastatin 20 mg/d
Current
Management
• Adherent to medication and
lifestyle management
• She’s very busy working full time
as a nurse and taking care of her
husband who recently had a stroke
• She says that she feels
overwhelmed
• …and she’s frustrated that she’s
gained 10 lbs since starting insulin
1 year ago
Notes

(Soliqua® 100/33)
Dose range delivered per injection 10 to 50 units 15 to 60 units
Prior to initiating Discontinue basal insulin, GLP-1RA
Initial dose 16 units 15 units: if inadequately controlled
with <30 units basal insulin or
lixisenatide
30 units: if inadequately controlled
with 30-60 units basal insulin
Dose timing Once daily at same time each day
with/without food
Once daily within the hour prior to
the first meal of the day
Initiating Fixed-Ratio Basal Insulin/GLP-1 RA
Combinations

(Soliqua® 100/33)
Dosing Based on degludec Based on glargine
Titration Every 3-4 days
Above target: +2 units
Within target: no change
Below target: -2 units
Weekly
Above target: +2 to +4 units
Within target: no change
Below target: -2 to -4 units
Maximum daily dose 50 units degludec,
1.8 mg liraglutide
60 units glargine,
20 mcg lixisenatide
Combinations (cont)

Case Scenario #6
73-year-old man with previously well-controlled type 2 diabetes mellitus whose
adherence has declined over the past year
Weight: 164 lb
BMI: 27.6 kg/m2
BP: 136/92 mm Hg
FPG: 132 mg/dL
PPG: 196 mg/dL
A1c: 7.7%
Vital Signs and
Laboratory Results
• Insulin detemir 34 units
(0.46 units/kg) at bedtime
• Liraglutide 1.2 mg/d
• HCTZ 12.5 mg/d
• Aspirin 81 mg/d
• Fluticasone nasal spray each
nostril once daily in spring
Current
Management
• PMH: grade 2 retinopathy;
hypertension; seasonal
allergies; mild cognitive
impairment
• Wife diagnosed with stage 3
breast cancer 1 year ago
Notes

(Soliqua® 100/33)
Initial dose 16 units 15 units: if inadequately controlled with
<30 units basal insulin or lixisenatide
30 units: if inadequately controlled with
30-60 units basal insulin
Combinations (cont)

Case Scenario #3
64-year-old woman with type 2 diabetes mellitus for 7 years
Weight: 204 lb
BMI: 35.6 kg/m2
BP: 136/82 mm Hg
A1c: 8.2%
FPG: 118 mg/dL
PPG: 218 mg/dL
LDL-C: 86 mg/dL
Vital Signs and
Laboratory Results
• Insulin detemir 68 units (0.73
• HCTZ 25 mg/d
• Lisinopril 20 mg/d
Current
Management
• PMH: hypertension, dyslipidemia,
obesity
• A1c 13 mos ago: 7.2%
• Has experienced several episodes
of symptomatic hypoglycemia over
past few months
• Episode early yesterday
morning required treatment in
emergency department
(BG 52 mg/dL)
Notes

Basal Insulin and GLP-1RA Combination Therapy for Type 2 Diabetes

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