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 2 diabetes.3 Effective glycemic control reduces the risk
United States—approximately 9% of the US pop- for diabetes-related microvascular complications, in-
ulation.1 In addition, an estimated 86 million US cluding diabetic neuropathy, diabetic kidney disease, and
adults (more than 33% of the US population) have predi- retinopathy.3,7 However, a 2013 study estimated that
abetes, a condition that substantially increases the risk for 33% to 49% of patients with diabetes do not achieve
diabetes.1 Based on the current trends and the aging of the glycemic control.8
US population in the next few decades, the prevalence of Pharmacologic therapies for type 2 diabetes include
diabetes is projected to increase to 1 in 3 adults by 2050.2 metformin, sulfonylureas, meglitinides, thiazolidinedi-
However, appropriate intervention and management of ones, dipeptidyl peptidase-4 inhibitors, glucagon-like
diabetes can help reduce its rising prevalence.2 peptide-1 (GLP-1) receptor agonists, sodium-glucose
Type 2 diabetes accounts for 90% to 95% of all cases cotransporter-2 inhibitors, insulin, and insulin analogs.9
of diabetes and is characterized by insulin resistance and For patients with type 2 diabetes who are not achiev-
gradual decline in the ability of the pancreas to produce ing their target HbA1c levels despite the addition of basal
insulin.1 Type 1 diabetes accounts for 5% of all cases of insulin, the American Diabetes Association recom-
diabetes, and is characterized by the destruction of pan- mends advancing to a combination injectable therapy to
creatic beta cells and the insufficiency or the absence of cover postprandial glucose excursions, with options in-
insulin production by the pancreas.1 cluding the addition of a GLP-1 receptor agonist or a
Diabetes was the seventh leading cause of death in the mealtime insulin (ie, a rapid-acting insulin analog that is
United States in 2013, and is a major cause of stroke, heart administered immediately before eating).7
disease, kidney failure, blindness, and other serious condi-
tions.1 Furthermore, diabetes is associated with microvas- New Once-Daily Combination FDA Approved for
cular, macrovascular, and neuropathic complications that Type 2 Diabetes
can be disabling, life-threatening, and can have a pro- On November 21, 2016, the US Food and Drug Ad-
found impact on a patient’s health and quality of life.3,4 ministration (FDA) approved Soliqua 100/33 (insulin
In the United States, the annual healthcare costs at- glargine [Lantus] 100 units/mL and lixisenatide [Adlyx-
tributed to diabetes totaled $245 billion in 2012, includ- in] 33 mcg/mL; sanofi-aventis), as an adjunct to diet and
ing $176 billion in direct medical costs and $69 billion exercise, to improve glycemic control in adults with type
in indirect costs (ie, absenteeism, reduced/lost productiv- 2 diabetes that is inadequately controlled with basal in-
ity, and disability).5 Overall, the medical costs for pa- sulin (<60 units daily) or lixisenatide.10,11
tients with diabetes are 2.3 times higher than the costs Insulin glargine, the first once-daily, long-acting insu-
for individuals without diabetes, with more than 20% of lin analog, was initially approved by the FDA in 2000 to
all US healthcare dollars spent on diabetes care.5 improve glycemic control in adult and pediatric patients
Effective diabetes management includes lifestyle with type 1 diabetes and in adults with type 2 diabetes; it
changes and self-management strategies; appropriate has a prolonged duration of action without a pronounced
patient education; reducing the risk for weight gain and peak.12,13 Lixisenatide, a GLP-1 receptor agonist, received
hypoglycemia; and targeting the patient’s glycated he- FDA approval in July 2016 as an adjunct to diet and ex-
moglobin (HbA1c) goal based on several patient factors, ercise for the treatment of adults with type 2 diabetes.14
including age, comorbid conditions, disease duration, The safety and efficacy of lixisenatide as monotherapy
and adherence.6 Patients with diabetes require ongoing and in combination with other FDA-approved therapies,
monitoring to evaluate the effectiveness of their thera- including metformin, sulfonylureas, pioglitazone, and
pies toward achieving stable glycemic control.6 basal insulin, were evaluated in clinical studies involving
Improvements in glycemic control are associated 5400 patients with type 2 diabetes14 in which lixisena­
with improved outcomes for patients with type 1 or type tide was shown to improve HbA1c levels.15

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 blood glucose levels by increasing glucose-dependent
Table 1 Insulin Glargine plus Lixisenatide General Dosing insulin release, decreasing glucagon secretion, and slow-
Recommendations
ing gastric emptying.11,14
For patients with type 2 diabetes
that is inadequately controlled with: Starting dose of insulin glargine plus lixisenatide
Less than 30 units of basal insulin or 15 units (15 units insulin glargine/5 mcg lixisenatide)
Dosing and Administration
lixisenatide administered subcutaneously once daily Insulin glargine plus lixisenatide 100/33 is available in
30-60 units of basal insulin 30 units (30 units insulin glargine/10 mcg lixisenatide) a 3-mL prefilled, disposable, single-use pen for subcuta-
administered subcutaneously once daily neous injection.11
Other key dosage information The insulin glargine plus lixisenatide pen delivers
Maximum daily dosage 60 units (60 units insulin glargine/20 mcg lixisenatide) doses from 15 units to 60 units with each injection. For
Frequency and timing of Once daily within the hour before the first meal of the day patients requiring an insulin glargine plus lixisenatide
administration daily dose below 15 units or more than 60 units, an alter-
Method of administration Subcutaneous injection in the thigh, upper arm, or native antidiabetic treatment should be used.11
abdomen
(Insulin glargine plus lixisenatide should not be
Before starting treatment with insulin glargine plus
administered intravenously, intramuscularly, or by an lixisenatide, patients should discontinue therapy with
infusion pump; it should not be diluted or mixed with any
other insulin drugs or solutions)
basal insulin or lixisenatide.11 The general dosing recom-
mendations for insulin glargine plus lixisenatide are list-
Source: Soliqua 100/33 (insulin glargine and lixisenatide injection) prescribing information; November
2016. 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- lixisenatide treatment regimen may predispose patients
action in patients taking insulin or insulin-containing to hypoglycemia or to hyperglycemia. Treatment regi-
drugs. Hypoglycemia (severe, 0%-1.1%; documented men changes should be made cautiously and under close
symptomatic, 25.6%-40%) and allergic reactions (ana- medical supervision; furthermore, the patient’s blood
phylaxis, 0.2%; allergic reactions, such as anaphylactic glucose levels should be monitored more frequently.11
reaction, angioedema, and urticaria, 0.4%) have been re- Overdose because of medication error. Patients should
ported with insulin glargine plus lixisenatide therapy.11 be instructed to check the label before each injection to
avoid accidental mix-ups with insulin-containing drugs.
Contraindications The maximum dose of insulin glargine plus lixisenatide
Insulin glargine plus lixisenatide is contraindicated should not be exceeded. Insulin glargine plus lixisenatide
during episodes of hypoglycemia. It is also contraindicat- should not be used with other GLP-1 receptor agonists.11
ed in patients with a hypersensitivity to insulin glargine, Hypoglycemia. Hypoglycemia may be life-threatening.
lixisenatide, or to any of the drugs’ excipients.11 The frequency of glucose monitoring should be increased
in patients undergoing changes in insulin dosage, when
Drug Interactions insulin-containing drugs are coadministered with other
The dose of insulin glargine plus lixisenatide may re- glucose-lowering drugs, during changes to meal pattern
quire adjustment when administered concomitantly with and/or physical activity, and in patients with renal or he-
drugs that affect glucose metabolism; the patient’s blood patic impairment and hypoglycemia unawareness.11
glucose levels should be closely monitored.11 Acute kidney injury. Patients with renal impairment
Dose reductions of insulin glargine plus lixisenatide and those with severe gastrointestinal adverse reactions
and increased monitoring may be warranted when insu- should be monitored for renal function. Insulin glargine
lin glargine plus lixisenatide is administered with drugs plus lixisenatide should not be used in patients with end-
that increase the risk for hypoglycemia. Conversely, dose stage renal disease.11
increases and more frequent monitoring may be required Immunogenicity. Some patients may have antibodies
when insulin glargine plus lixisenatide is coadministered to insulin glargine plus lixisenatide. An alternative anti-
with drugs that decrease the blood glucose–lowering ef- diabetic treatment should be considered if glycemic
fects of insulin glargine plus lixisenatide.11 control worsens or if the patient is unable to achieve
Lixisenatide delays gastric emptying, which may af- targeted glycemic control, or if significant injection-site
fect the absorption of concomitantly administered oral reactions or allergic reactions occur.11
medications.11 Oral contraceptives should be taken at Hypokalemia. Hypokalemia may be life-threaten-
least 1 hour before the administration of insulin glargine ing. Patients at risk for hypokalemia should be moni-
plus lixisenatide. Antibiotics, acetaminophen, or other tored for potassium levels and should receive treatment
medications should be taken at least 1 hour before or if indicated.11
11 hours after the administration of insulin glargine Fluid retention and heart failure with thiazolidine-
plus lixisenatide.11 diones. Thiazolidinediones can cause dose-related fluid
retention, particularly when they are used in combina-
Warnings and Precautions tion with insulin-containing drugs. Patients should be
Anaphylaxis and serious hypersensitivity reactions. monitored for signs and symptoms of heart failure; dosage
Anaphylaxis and serious hypersensitivity reactions can reduction or the discontinuation of thiazolidinediones
occur with either of the components of insulin glargine should be considered if heart failure occurs.11
plus lixisenatide. Patients should be instructed to discon- Macrovascular outcomes. No clinical studies have
tinue treatment if a reaction occurs and to promptly seek shown a reduction of macrovascular risk with insulin
medical attention.11 glargine plus lixisenatide or with any other antidiabetic
Pancreatitis. Insulin glargine plus lixisenatide has drug.11
not been studied in patients with a history of pancreati-
tis. Insulin glargine plus lixisenatide should be discontin- Use in Specific Populations
ued if pancreatitis is suspected; treatment should not be Pregnancy. There may be risks to the fetus from expo-
restarted if pancreatitis is confirmed.11 sure to lixisenatide during pregnancy. Insulin glargine plus
Never share the prefilled pen. The insulin glargine lixisenatide should only be used during pregnancy if the
plus lixisenatide prefilled pen should never be shared potential benefit justifies the potential risk to the fetus.11
between patients, even if the needle is changed.11 Lactation. The developmental and health benefits of
Hyperglycemia or hypoglycemia with changes in breast-feeding should be considered in addition to the
treatment regimen. Changes to the insulin glargine plus mother’s clinical need for insulin glargine plus lixisena­

Vol 10 l Special Feature l March 2017 www.AHDBonline.com l American Health & Drug Benefits l 79
 tide and any potential adverse effects on the breast-fed publications/aag/pdf/2016/diabetes-aag.pdf. Accessed December 5, 2016.
2. Boyle JP, Thompson TJ, Gregg EW, et al. Projection of the year 2050 burden
child from insulin glargine plus lixisenatide.11 of diabetes in the US adult population: dynamic modeling of incidence, mortal-
Geriatric use. No overall differences were observed ity, and prediabetes prevalence. Popul Health Metr. 2010;8:29.
3. Centers for Disease Control and Prevention. National diabetes statistics re-
in the subgroup analyses of patients aged ≥65 years versus port: estimates of diabetes and its burden in the United States, 2014. www.cdc.
patients aged ≥75 years; however, caution should be ex- gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf. Accessed
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4. Mayo Clinic staff. Diseases and conditions: diabetes: complications. July 31,
isenatide to geriatric patients to avoid hypoglycemia, 2014. www.mayoclinic.org/diseases-conditions/diabetes/basics/complications/
which may be difficult to detect in geriatric patients.11 con-20033091. Accessed December 5, 2016.
5. American Diabetes Association. Economic costs of diabetes in the U.S. in
Renal and hepatic impairment. Frequent glucose 2012. Diabetes Care. 2013;36:1033-1046.
monitoring and dose adjustment may be necessary in 6. Garber AJ, Abrahamson MJ, Barzilay JI, et al; for the American Association
patients with renal or hepatic impairment.11 of Clinical Endocrinologists (AACE); American College of Endocrinology
(ACE). Consensus statement by the American Association of Clinical Endo-
Gastroparesis. Insulin glargine plus lixisenatide is not crinologists and American College of Endocrinology on the Comprehensive
recommended in patients with severe gastroparesis.11 Type 2 Diabetes Management Algorithm—2016 executive summary. Endocr
Pract. 2016;22:84-113.
7. American Diabetes Association. Standards of medical care in diabe-
Conclusion tes—2016. Diabetes Care. 2016;39(suppl 1):S1-S112. Erratum in: Diabetes
With the FDA approval of insulin glargine plus lix- Care. 2016;39:1653.
8. Ali MK, Bullard KM, Saaddine JB, et al. Achievement of goals in U.S. dia-
isenatide 100/33, a new, once-daily treatment option betes care, 1999-2010. N Engl J Med. 2013;368:1613-1624. Erratum in: N Engl
became available for adults with type 2 diabetes that is J Med. 2013;369:587.
9. Mayo Clinic staff. Diseases and conditions: diabetes: treatments and drugs.
inadequately controlled with basal insulin (<60 units July 31, 2014. www.mayoclinic.org/diseases-conditions/diabetes/basics/treatment/
daily) or with lixisenatide. Insulin glargine plus lix- con-20033091. Accessed December 5, 2016.
isenatide demonstrated significant mean reductions in 10. Sanofi. Sanofi receives FDA approval of Soliqua 100/33 for the treatment of
adults with type 2 diabetes. Press release. November 21, 2016. www.news.sanofi.
HbA1c levels compared with insulin glargine alone. us/2016-11-21-Sanofi-Receives-FDA-Approval-of-Soliqua-100-33-for-the-Treat
In addition, the proportion of patients who achieved ment-of-Adults-with-Type-2-Diabetes. Accessed November 30, 2016.
11. Soliqua 100/33 (insulin glargine and lixisenatide injection) [prescribing
an HbA1c <7% was significantly higher in the insulin information]. Bridgewater, NJ: sanofi-aventis US; November 2016.
glargine plus lixisenatide group versus the insulin 12. Hilgenfeld R, Seipke G, Berchtold H, Owens DR. The evolution of insulin
glargine group.11,16 glargine and its continuing contribution to diabetes care. Drugs. 2014;74:911-927.
13. Lantus (insulin glargine injection) solution [prescribing information].
Insulin glargine plus lixisenatide 100/33 provides pa- Bridgewater, NJ: sanofi-aventis US; July 2015.
tients with inadequately controlled type 2 diabetes with 14. US Food and Drug Administration. FDA approves Adlyxin to treat type 2
a titratable, fixed-ratio combination of insulin glargine diabetes. Press release. July 28, 2016. www.fda.gov/NewsEvents/Newsroom/
PressAnnouncements/ucm513602.htm. Accessed December 5, 2016.
plus lixisenatide in a single, prefilled injection pen for 15. Adlyxin (lixisenatide) injection [prescribing information]. Bridgewater, NJ:
once-daily dosing. n sanofi-aventis US; July 2016.
16. Aroda VR, Rosenstock J, Wysham C, et al; for the LixiLan-L Trial Investi-
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80 l American Health & Drug Benefits l www.AHDBonline.com Vol 10 l Special Feature l March 2017