Soliqua 100/33 (Insulin Glargine plus
Lixisenatide) Receives FDA Approval for
Adults with Type 2 Diabetes
By Loretta Fala, Medical Writer
D
iabetes affects more than 29 million people in the
United States—approximately 9% of the US pop-
ulation.1 In addition, an estimated 86 million US
adults (more than 33% of the US population) have predi-
abetes, a condition that substantially increases the risk for
diabetes.1 Based on the current trends and the aging of the
US population in the next few decades, the prevalence of
diabetes is projected to increase to 1 in 3 adults by 2050.2
However, appropriate intervention and management of
diabetes can help reduce its rising prevalence.2
Type 2 diabetes accounts for 90% to 95% of all cases
of diabetes and is characterized by insulin resistance and
gradual decline in the ability of the pancreas to produce
insulin.1 Type 1 diabetes accounts for 5% of all cases of
diabetes, and is characterized by the destruction of pan-
creatic beta cells and the insufficiency or the absence of
insulin production by the pancreas.1
Diabetes was the seventh leading cause of death in the
United States in 2013, and is a major cause of stroke, heart
disease, kidney failure, blindness, and other serious condi-
tions.1 Furthermore, diabetes is associated with microvas-
cular, macrovascular, and neuropathic complications that
can be disabling, life-threatening, and can have a pro-
found impact on a patient’s health and quality of life.3,4
In the United States, the annual healthcare costs at-
tributed to diabetes totaled $245 billion in 2012, includ-
ing $176 billion in direct medical costs and $69 billion
in indirect costs (ie, absenteeism, reduced/lost productiv-
ity, and disability).5 Overall, the medical costs for pa-
tients with diabetes are 2.3 times higher than the costs
for individuals without diabetes, with more than 20% of
all US healthcare dollars spent on diabetes care.5
Effective diabetes management includes lifestyle
changes and self-management strategies; appropriate
patient education; reducing the risk for weight gain and
hypoglycemia; and targeting the patient’s glycated he-
moglobin (HbA1c) goal based on several patient factors,
including age, comorbid conditions, disease duration,
and adherence.6 Patients with diabetes require ongoing
monitoring to evaluate the effectiveness of their thera-
pies toward achieving stable glycemic control.6
Improvements in glycemic control are associated
with improved outcomes for patients with type 1 or type
Vol 10 l Special Feature l March 2017 www.AHDBonline.com
2 diabetes.3 Effective glycemic control reduces the risk
for diabetes-related microvascular complications, in-
cluding diabetic neuropathy, diabetic kidney disease, and
retinopathy.3,7 However, a 2013 study estimated that
33% to 49% of patients with diabetes do not achieve
glycemic control.8
Pharmacologic therapies for type 2 diabetes include
metformin, sulfonylureas, meglitinides, thiazolidinedi-
ones, dipeptidyl peptidase-4 inhibitors, glucagon-like
peptide-1 (GLP-1) receptor agonists, sodium-glucose
cotransporter-2 inhibitors, insulin, and insulin analogs.9
For patients with type 2 diabetes who are not achiev-
ing their target HbA1c levels despite the addition of basal
insulin, the American Diabetes Association recom-
mends advancing to a combination injectable therapy to
cover postprandial glucose excursions, with options in-
cluding the addition of a GLP-1 receptor agonist or a
mealtime insulin (ie, a rapid-acting insulin analog that is
administered immediately before eating).7
New Once-Daily Combination FDA Approved for
Type 2 Diabetes
On November 21, 2016, the US Food and Drug Ad-
ministration (FDA) approved Soliqua 100/33 (insulin
glargine [Lantus] 100 units/mL and lixisenatide [Adlyx-
in] 33 mcg/mL; sanofi-aventis), as an adjunct to diet and
exercise, to improve glycemic control in adults with type
2 diabetes that is inadequately controlled with basal in-
sulin (<60 units daily) or lixisenatide.10,11
Insulin glargine, the first once-daily, long-acting insu-
lin analog, was initially approved by the FDA in 2000 to
improve glycemic control in adult and pediatric patients
with type 1 diabetes and in adults with type 2 diabetes; it
has a prolonged duration of action without a pronounced
peak.12,13 Lixisenatide, a GLP-1 receptor agonist, received
FDA approval in July 2016 as an adjunct to diet and ex-
ercise for the treatment of adults with type 2 diabetes.14
The safety and efficacy of lixisenatide as monotherapy
and in combination with other FDA-approved therapies,
including metformin, sulfonylureas, pioglitazone, and
basal insulin, were evaluated in clinical studies involving
5400 patients with type 2 diabetes14 in which lixisena­
tide was shown to improve HbA1c levels.15
l American Health & Drug Benefits l 77

Table 1 Insulin Glargine plus Lixisenatide General Dosing
Recommendations
For patients with type 2 diabetes
that is inadequately controlled with:
Less than 30 units of basal insulin or
lixisenatide
30-60 units of basal insulin
Other key dosage information
Maximum daily dosage
Frequency and timing of
administration
Method of administration
Source: Soliqua 100/33 (insulin glargine and lixisenatide injection) prescribing information; November
2016.
Starting dose of insulin glargine plus lixisenatide
15 units (15 units insulin glargine/5 mcg lixisenatide)
administered subcutaneously once daily
30 units (30 units insulin glargine/10 mcg lixisenatide)
administered subcutaneously once daily
60 units (60 units insulin glargine/20 mcg lixisenatide)
Once daily within the hour before the first meal of the day
Subcutaneous injection in the thigh, upper arm, or
abdomen
(Insulin glargine plus lixisenatide should not be
administered intravenously, intramuscularly, or by an
infusion pump; it should not be diluted or mixed with any
other insulin drugs or solutions)
blood glucose levels by increasing glucose-dependent
insulin release, decreasing glucagon secretion, and slow-
ing gastric emptying.11,14
Dosing and Administration
Insulin glargine plus lixisenatide 100/33 is available in
a 3-mL prefilled, disposable, single-use pen for subcuta-
neous injection.11
The insulin glargine plus lixisenatide pen delivers
doses from 15 units to 60 units with each injection. For
patients requiring an insulin glargine plus lixisenatide
daily dose below 15 units or more than 60 units, an alter-
native antidiabetic treatment should be used.11
Before starting treatment with insulin glargine plus
lixisenatide, patients should discontinue therapy with
basal insulin or lixisenatide.11 The general dosing recom-
mendations for insulin glargine plus lixisenatide are list-
ed in Table 1.

The Pivotal LixiLan-L Clinical Trial

Table 2 Insulin Glargine plus Lixisenatide 100/33 versus Insulin The FDA approval of insulin glargine plus lixisena­
Glargine in Patients with Type 2 Diabetes
tide was based on the LixiLan-L clinical trial, a random-
Insulin glargine
100 units/mL plus
ized, 30-week, active-controlled, open-label study that
lixisenatide Insulin glargine included 736 patients with type 2 diabetes.10,11,16 In this
33 mcg/mL 100 units/mL
Efficacy outcomes (N = 365) (N = 365)
insulin-intensification study, the efficacy and safety of
HbA1c
insulin glargine plus lixisenatide 100/33 were compared
with that of insulin glargine 100 units/mL.10,11
Baseline, mean post run-in phase, % 8.1 8.1
Patients with type 2 diabetes received a stable daily
End of study, mean, % 6.9 7.5
dose of 15 units to 40 units of basal insulin, alone or
LS change from baseline, mean,a % –1.1 –0.6 combined with 1 or 2 oral antidiabetic drugs, for at least
Difference vs insulin glargine,b % –0.5 (95% CI, –0.6 to –0.4; P <.01) 6 months. The patients’ mean age was 60 years, and the
Patients reaching HbA1c <7% at week 30, N (%)
c
201 (55.1) 108 (29.6) mean duration of diabetes was approximately 12 years.
Fasting plasma glucose At the end of a 6-week run-in phase, patients with
Baseline, mean, mg/dL 132.3 132.0
HbA1c levels between 7% and 10% and fasting plasma
glucose levels ≤140 mg/dL who received an insulin
End of study, mean, mg/dL 121.9 120.5
glargine dose of 20 units to 50 units (mean, 35 units)
LS change from baseline, mean, mg/dL –5.7 –7.0
were randomized to receive insulin glargine plus lix-
a
Estimated using an ANCOVA with treatment, randomization strata, and country as fixed factors and
baseline HbA1c levels as covariate. Overall, 20 patients in the insulin glargine plus lixisenatide group
isenatide 100/33 or insulin glargine 100 units/mL.11
and 10 patients in the insulin glargine 100 units/mL group had missing HbA1c measurements at week Insulin glargine plus lixisenatide demonstrated a sig-
30; these missing measurements were imputed via multiple imputations with respect to the patient’s
baseline HbA1c value.
nificant mean reduction in HbA1c levels (–1.1) from
b
The differences in effect observed in the clinical trial may not necessarily reflect the effect in care baseline compared with insulin glargine (–0.6; Table 2).
settings in which an alternative insulin glargine dosage can be used. At the end of the study, the doses of insulin glargine were
c
Patients with missing HbA1c measurement at week 30 were considered nonresponders.
ANCOVA indicates analysis of covariance; CI, confidence interval; HbA1c, glycated hemoglobin; LS,
equivalent between the treatment arms. Furthermore,
least square. 55.1% of patients who received insulin glargine plus
Source: Soliqua 100/33 (insulin glargine and lixisenatide injection) prescribing information; November 2016. lixisenatide achieved an HbA1c <7% at week 30 com-
pared with 29.6% of patients who received insulin
Mechanism of Action glargine alone (Table 2).11,16
Insulin glargine plus lixisenatide 100/33 is a combina-
tion of insulin glargine 100 units/mL and lixisenatide 33 Adverse Reactions
mcg/mL. Insulin glargine regulates glucose metabolism The most common (≥5% incidence) adverse reactions
by stimulating peripheral glucose uptake and inhibiting associated with insulin glargine plus lixisenatide therapy
hepatic glucose production.11 Lixisenatide, a GLP-1 re- were nausea (10%), nasopharyngitis (7%), diarrhea (7%),
ceptor agonist, is a hormone that helps to normalize upper respiratory tract infection (5.5%), and headache

78 l American Health & Drug Benefits l www.AHDBonline.com Vol 10 l Special Feature l March 2017
(5.4%).11 Hypoglycemia is the most common adverse re-
action in patients taking insulin or insulin-containing
drugs. Hypoglycemia (severe, 0%-1.1%; documented
symptomatic, 25.6%-40%) and allergic reactions (ana-
phylaxis, 0.2%; allergic reactions, such as anaphylactic
reaction, angioedema, and urticaria, 0.4%) have been re-
ported with insulin glargine plus lixisenatide therapy.11
Contraindications
Insulin glargine plus lixisenatide is contraindicated
during episodes of hypoglycemia. It is also contraindicat-
ed in patients with a hypersensitivity to insulin glargine,
lixisenatide, or to any of the drugs’ excipients.11
Drug Interactions
The dose of insulin glargine plus lixisenatide may re-
quire adjustment when administered concomitantly with
drugs that affect glucose metabolism; the patient’s blood
glucose levels should be closely monitored.11
Dose reductions of insulin glargine plus lixisenatide
and increased monitoring may be warranted when insu-
lin glargine plus lixisenatide is administered with drugs
that increase the risk for hypoglycemia. Conversely, dose
increases and more frequent monitoring may be required
when insulin glargine plus lixisenatide is coadministered
with drugs that decrease the blood glucose–lowering ef-
fects of insulin glargine plus lixisenatide.11
Lixisenatide delays gastric emptying, which may af-
fect the absorption of concomitantly administered oral
medications.11 Oral contraceptives should be taken at
least 1 hour before the administration of insulin glargine
plus lixisenatide. Antibiotics, acetaminophen, or other
medications should be taken at least 1 hour before or
11 hours after the administration of insulin glargine
plus lixisenatide.11
Warnings and Precautions
Anaphylaxis and serious hypersensitivity reactions.
Anaphylaxis and serious hypersensitivity reactions can
occur with either of the components of insulin glargine
plus lixisenatide. Patients should be instructed to discon-
tinue treatment if a reaction occurs and to promptly seek
medical attention.11
Pancreatitis. Insulin glargine plus lixisenatide has
not been studied in patients with a history of pancreati-
tis. Insulin glargine plus lixisenatide should be discontin-
ued if pancreatitis is suspected; treatment should not be
restarted if pancreatitis is confirmed.11
Never share the prefilled pen. The insulin glargine
plus lixisenatide prefilled pen should never be shared
between patients, even if the needle is changed.11
Hyperglycemia or hypoglycemia with changes in
treatment regimen. Changes to the insulin glargine plus
Vol 10 l Special Feature l March 2017 www.AHDBonline.com
lixisenatide treatment regimen may predispose patients
to hypoglycemia or to hyperglycemia. Treatment regi-
men changes should be made cautiously and under close
medical supervision; furthermore, the patient’s blood
glucose levels should be monitored more frequently.11
Overdose because of medication error. Patients should
be instructed to check the label before each injection to
avoid accidental mix-ups with insulin-containing drugs.
The maximum dose of insulin glargine plus lixisenatide
should not be exceeded. Insulin glargine plus lixisenatide
should not be used with other GLP-1 receptor agonists.11
Hypoglycemia. Hypoglycemia may be life-threatening.
The frequency of glucose monitoring should be increased
in patients undergoing changes in insulin dosage, when
insulin-containing drugs are coadministered with other
glucose-lowering drugs, during changes to meal pattern
and/or physical activity, and in patients with renal or he-
patic impairment and hypoglycemia unawareness.11
Acute kidney injury. Patients with renal impairment
and those with severe gastrointestinal adverse reactions
should be monitored for renal function. Insulin glargine
plus lixisenatide should not be used in patients with end-
stage renal disease.11
Immunogenicity. Some patients may have antibodies
to insulin glargine plus lixisenatide. An alternative anti-
diabetic treatment should be considered if glycemic
control worsens or if the patient is unable to achieve
targeted glycemic control, or if significant injection-site
reactions or allergic reactions occur.11
Hypokalemia. Hypokalemia may be life-threaten-
ing. Patients at risk for hypokalemia should be moni-
tored for potassium levels and should receive treatment
if indicated.11
Fluid retention and heart failure with thiazolidine-
diones. Thiazolidinediones can cause dose-related fluid
retention, particularly when they are used in combina-
tion with insulin-containing drugs. Patients should be
monitored for signs and symptoms of heart failure; dosage
reduction or the discontinuation of thiazolidinediones
should be considered if heart failure occurs.11
Macrovascular outcomes. No clinical studies have
shown a reduction of macrovascular risk with insulin
glargine plus lixisenatide or with any other antidiabetic
drug.11
Use in Specific Populations
Pregnancy. There may be risks to the fetus from expo-
sure to lixisenatide during pregnancy. Insulin glargine plus
lixisenatide should only be used during pregnancy if the
potential benefit justifies the potential risk to the fetus.11
Lactation. The developmental and health benefits of
breast-feeding should be considered in addition to the
mother’s clinical need for insulin glargine plus lixisena­
l American Health & Drug Benefits l 79
 tide and any potential adverse effects on the breast-fed
child from insulin glargine plus lixisenatide.11
Geriatric use. No overall differences were observed
in the subgroup analyses of patients aged ≥65 years versus
patients aged ≥75 years; however, caution should be ex-
ercised when administering insulin glargine plus lix-
isenatide to geriatric patients to avoid hypoglycemia,
which may be difficult to detect in geriatric patients.11
Renal and hepatic impairment. Frequent glucose
monitoring and dose adjustment may be necessary in
patients with renal or hepatic impairment.11
Gastroparesis. Insulin glargine plus lixisenatide is not
recommended in patients with severe gastroparesis.11
Conclusion
With the FDA approval of insulin glargine plus lix-
isenatide 100/33, a new, once-daily treatment option
became available for adults with type 2 diabetes that is
inadequately controlled with basal insulin (<60 units
daily) or with lixisenatide. Insulin glargine plus lix-
isenatide demonstrated significant mean reductions in
HbA1c levels compared with insulin glargine alone.
In addition, the proportion of patients who achieved
an HbA1c <7% was significantly higher in the insulin
glargine plus lixisenatide group versus the insulin
glargine group.11,16
Insulin glargine plus lixisenatide 100/33 provides pa-
tients with inadequately controlled type 2 diabetes with
a titratable, fixed-ratio combination of insulin glargine
plus lixisenatide in a single, prefilled injection pen for
once-daily dosing. n
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