AHFS Class:

• Long-acting Insulins 68:20.08.16

Generic Name(s):

• Insulin Glargine

• Insulin Glargine and Lixisenatide

Chemical Name:

• 21^A-Glycine-30^Ba-l-arginine-30^Bb-l-arginine insulin (human)

Molecular Formula:

• C₂₆₇H₄₀₄N₇₂O₇₈S₆

Insulin glargine is a biosynthetic (rDNA origin), long-acting human insulin analog.1,2,3,30,31

Insulin glargine is commercially available as Lantus^® (100 units/mL), a “follow-on” preparation (Basaglar^®; 100 units/mL), and a concentrated preparation (Toujeo^®; 300 units/mL).1,30,31

Lantus^® and Basaglar^® are structurally and pharmacologically similar drugs that contain a related drug substance.1,30 Basaglar^® was licensed by the US Food and Drug Administration (FDA) through an abbreviated approval pathway [505(b)(2)] that relies in part on FDA's finding of safety and effectiveness for Lantus^®.41,42,44 Comparative studies have found no substantial differences between the pharmacokinetics, immunogenicity, or toxicity of Lantus^® and Basaglar^®.42,45,48 Although Basaglar^® is highly similar to Lantus^® in terms of composition, strength, presentation, structure, and physicochemical and biological properties, it was not approved as a biosimilar or an interchangeable biologic product.42,44 Insulin is classified by FDA as a chemical, not a biologic product, so there is no biologic reference product for insulin glargine; thus, biosimilarity to insulin glargine cannot be established.42,44 Instead, Basaglar^® is referred to as a “follow-on” insulin glargine preparation; FDA determined that there was no need to use a different nonproprietary name (insulin glargine) for Basaglar^® at this time.42,44

Diabetes Mellitus

Insulin glargine 100-unit/mL preparations (Basaglar^® and Lantus^®) are used for the treatment of type 1 diabetes mellitus in adults and pediatric patients or type 2 diabetes mellitus in adults who require long-acting insulin for control of hyperglycemia.1,30 The 300-unit/mL preparation of insulin glargine (Toujeo^®) is used for the treatment of type 1 or type 2 diabetes mellitus in adults who require long-acting insulin for control of hyperglycemia.31

Insulin glargine in fixed combination with lixisenatide (Soliqua^® 100/33) is used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus inadequately controlled on lixisenatide or on less than 60 units daily of basal insulin.49,50,52

For additional information on the management of diabetes mellitus, see Uses in the Insulins General Statement 68:20.08.

Insulin Glargine

Efficacy of insulin glargine administered once daily at bedtime (as Lantus^®) in patients with type 1 diabetes mellitus has been demonstrated in comparisons with isophane (NPH) insulin human administered once or twice daily in 3 open-label, randomized studies of up to 28 weeks' duration in adults and one study in pediatric patients 6-15 years of a patients also received regular insulin or insulin lispro before meals during these studies.1,3,7 Glycemic control (as determined by glycosylated hemoglobin [hemoglobin A_1c, HbA_1c]) was similar in patients receiving insulin glargine or isophane insulin human.1,2,3

Efficacy of insulin glargine administered once daily at bedtime (as Lantus^®) in adults with type 2 diabetes mellitus has been established in 2 open-label, randomized clinical studies comparing insulin glargine with isophane insulin human administered once or twice daily; patients continued to receive regular insulin or oral antidiabetic agents during these studies.1,8,9 Insulin glargine achieved a level of glycemic control similar to that of isophane insulin human as measured by HbA_1c.1,2,8,9

Glycemic control with insulin glargine appears to be similar regardless of which meal it is administered before during the day.1,12 In a 24-week, open-label, randomized clinical study in adults with type 1 diabetes mellitus, insulin glargine (as Lantus^®) was administered prior to breakfast, dinner, or bedtime; patients received supplemental insulin lispro at mealtimes.1,12 Glycemic control (as determined by HbA_1c values at the end of the study, the primary end point) was not significantly different among the 3 treatment groups; only minor reductions in HbA_1c occurred.1,12 Symptomatic and documented nocturnal hypoglycemia occurred in fewer patients receiving insulin glargine before breakfast than in the other 2 groups.12 However, 5% of patients in the before-breakfast group discontinued treatment because of lack of efficacy.1

In another open-label, randomized, 24-week clinical study in patients with type 2 diabetes mellitus poorly controlled on oral antidiabetic agents, insulin glargine (as Lantus^®) given prior to breakfast was more effective in reducing HbA_1c than insulin glargine or isophane (NPH) insulin human given at bedtime.1,11 All patients were switched to or continued to receive glimepiride (3 mg daily in the morning) for 4 weeks prior to the addition of insulin therapy, and glimepiride therapy was continued throughout the remainder of the study.1,11 The incidence of hypoglycemia (primary safety end point) was similar across all treatment groups.11

In an open-label study of 5 years' duration comparing therapy with once-daily insulin glargine (as Lantus^®) to twice-daily NPH insulin in patients with type 2 diabetes mellitus, the progression of diabetic retinopathy was similar between the 2 treatment groups.1,32

In a study evaluating the cardiovascular safety of insulin glargine (Outcome Reduction with Initial Glargine Intervention [ORIGIN]), the early use of insulin glargine to achieve normal plasma glucose concentrations in patients with dysglycemia neither reduced nor increased adverse cardiovascular outcomes as compared with guideline-suggested glycemic control.33 In this study, approximately 12,500 adults with cardiovascular risk factors in addition to impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes mellitus received treatment with insulin glargine (as Lantus^®, median dosage: 0.45 units/kg daily) or standard care (antidiabetic drugs other than insulin glargine in patients with a diagnosis of type 2 diabetes mellitus) for a median duration of 6 years.1,33 Patients who received standard care were not able to receive insulin therapy until maximal dosages of 2 different oral antidiabetic drugs had been used.33 There were 2 coprimary composite end points in this study: the composite of death from cardiovascular causes, nonfatal myocardial infarction [MI], and nonfatal stroke, and a composite of any of the previously mentioned cardiovascular adverse events, a revascularization procedure, or hospitalization due to heart failure.1,33 At a median follow-up of 6.2 years, there was no substantial difference between the 2 treatment groups in terms of major adverse cardiovascular outcomes or all-cause mortality.1,33 Additionally, the incidence of cancer or death from cancer was similar between treatment groups.1,33 Therapy with insulin glargine reduced the incidence of diabetes mellitus; however, the long-term clinical benefits of this reduction is unknown.33

Safety and efficacy of the “follow-on” 100-unit/mL preparation of insulin glargine (Basaglar^®) have been established by studies demonstrating its similarity to Lantus^®45 and by the clinical trials that established the safety and efficacy of Lantus^®, as well as by 2 clinical trials conducted using Basaglar^® in patients with type 1 or type 2 diabetes mellitus.30,46,47 In these studies, Basaglar^® was deemed sufficiently similar to Lantus^® in terms of pharmacokinetics, toxicity, and immunogenicity and provided comparable glycemic control.42,45,46,47

Safety and efficacy of the 300-unit/mL preparation of insulin glargine (Toujeo^®) administered once daily in adults with type 1 or type 2 diabetes mellitus have been established in 4 open-label, controlled trials comparing a 100-unit/mL insulin glargine preparation (Lantus^®) to Toujeo^®.31,35,36,37,38 In these trials, the 300-unit/mL preparation of insulin glargine provided similar glycemic control as the 100-unit/mL preparation (as assessed by reductions in HbA_1c).31,35,36,37,38 Patients treated with insulin glargine 300 unit/mL required approximately 11-17.5% higher insulin dosages after 6 months of therapy compared with those receiving the 100-unit/mL preparation.31 Additionally, there were no clinically important differences in weight gain between the 2 insulin groups.31

Insulin glargine is not the insulin of choice for treatment of diabetic ketoacidosis; a short-acting insulin (e.g., insulin regular) is the preferred agent.1,13,30,31

Insulin Glargine/Lixisenatide Fixed-combination Therapy

Current data indicate that treatment with the fixed combination of insulin glargine and lixisenatide (insulin glargine/lixisenatide) is more effective than monotherapy with either drug in improving glycemic control (as determined by reductions in HbA_1c) in patients with type 2 diabetes mellitus.49,51,52 Additionally, therapy with insulin glargine/lixisenatide was associated with weight loss while weight gain was observed with insulin glargine monotherapy.51,52 Safety and efficacy of insulin glargine/lixisenatide have been established in an open-label trial in approximately 740 patients with type 2 diabetes mellitus inadequately controlled on basal insulin (e.g., insulin glargine, NPH insulin, insulin detemir) alone or in conjunction with 1 or 2 oral antidiabetic agents (e.g., metformin, a sulfonylurea, a meglitinide, a sodium-glucose cotransporter 2 [SGLT2] inhibitor, a dipeptidyl peptidase-4 [DPP-4] inhibitor).49,50 Patients underwent a 6-week run-in period in which all oral antidiabetic drugs (except metformin) were discontinued and therapy with insulin glargine was initiated and titrated prior to randomization.49,50 Patients then received treatment with insulin glargine/lixisenatide or continued insulin glargine therapy.49,50 The dosages of insulin glargine or insulin glargine/lixisenatide were titrated once weekly based upon fasting plasma glucose concentrations (mean final dosages of insulin glargine/lixisenatide or insulin glargine were equivalent at week 30 [46.7 units]).49,50 At week 30, there was a substantially greater reduction in HbA_1c with insulin glargine/lixisenatide than with insulin glargine alone (reduction of 1.1 versus 0.6%, respectively).49,50 Patients receiving insulin glargine/lixisenatide had an average weight loss of 0.7 kg while those receiving insulin glargine monotherapy gained an average of 0.7 kg.50

In another open-label trial of 30 weeks' duration, approximately 1170 patients with type 2 diabetes mellitus inadequately controlled on metformin with or without another antidiabetic agent (e.g., a sulfonylurea, a meglitinide, an SGLT2 inhibitor, a DPP-4 inhibitor) received therapy with insulin glargine/lixisenatide, insulin glargine, or lixisenatide, all in conjunction with metformin.51,52 Greater reductions in HbA_1c were observed with insulin glargine/lixisenatide than with either component alone (reduction of 1.6, 1.3, or 0.9% with insulin glargine/lixisenatide, insulin glargine, or lixisenatide therapy, respectively).51,52 Mean body weight was reduced by 0.3 or 2.3 kg in patients receiving insulin glargine/lixisenatide or lixisenatide, respectively.51,52 Mean body weight was increased by 1.1 kg in patients receiving insulin glargine monotherapy.51,52

The manufacturer states that insulin glargine/lixisenatide should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.49 The safety and efficacy of insulin glargine/lixisenatide in conjunction with short-acting (e.g., prandial) insulin have not been established, and such concomitant use is not recommended.49 Insulin glargine/lixisenatide is not recommended for use with any other drug preparations containing lixisenatide or another glucagon-like peptide-1 (GLP-1) receptor agonist.49

General

The dosage of insulin glargine is expressed in units.1,30,31 Each unit of insulin glargine is approximately equal to 0.036 mg of the drug.1 The dosage of the fixed combination of insulin glargine and lixisenatide (insulin glargine/lixisenatide) has been expressed in terms of the insulin glargine component; however, each mL of insulin glargine/lixisenatide contains 100 units of insulin glargine and 33 mcg of lixisenatide.49

Therapy with lixisenatide or basal insulin should be discontinued prior to initiating therapy with insulin glargine/lixisenatide.49

Administration

Insulin glargine is administered by subcutaneous injection once daily into the abdomen, thigh, or upper arm at the same time each day using a conventional insulin syringe or the appropriate injection pen (e.g., SoloStar^®, KwikPen^®).1,10,30,31

Insulin glargine/lixisenatide is administered by subcutaneous injection once daily using a prefilled injection pen.49 Insulin glargine/lixisenatide should be administered within 1 hour before the first meal of the day.49 If a dose of insulin glargine/lixisenatide is missed, the patient should resume the once-daily regimen with the next scheduled dose.49

Insulin glargine or insulin glargine/lixisenatide should not be administered IV, IM, or via an infusion pump.1,30,31,49 A planned rotation of sites within an area should be followed so that any one site is not injected more than once every 1-2 weeks to reduce the risk of lipodystrophy.1,6,30,31 Clinical studies have not indicated important differences in absorption of insulin glargine from the various injection areas (e.g., abdomen, thigh, upper arm).1 It is not necessary to shake the vial of insulin glargine prior to measuring the dosage.1 Insulin glargine or insulin glargine/lixisenatide should not be mixed with other insulins, other drugs, or diluted with other solutions.1,30,31,49

Insulin glargine injection should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.1,30,31 Insulin glargine or insulin glargine/lixisenatide should be administered only if the solution is clear, colorless, and without particulates.1,30,31,49

Unopened injection pens and vials containing insulin glargine 100 units/mL should be stored at 2-8°C and protected from direct heat and light until the expiration date; the drug should not be frozen.1,30 Alternatively, unopened injection pens and vials containing insulin glargine 100 units/mL may be stored at room temperature (below 30°C) and away from direct heat and light for up to 28 days.1,30 Opened (in-use) vials containing insulin glargine 100 units/mL should be stored at 2-8°C for up to 28 days.1 Alternatively, such in-use vials may be stored at room temperature away from direct heat and light for up to 28 days.1 In-use injection pens of insulin glargine 100 units/mL (Kwikpen^®, SoloStar^®) should be stored at room temperature away from heat and direct light for up to 28 days; in-use injection pens should not be refrigerated.1,30

Unopened injection pens of insulin glargine 300 units/mL (Toujeo^®) should be stored at 2-8°C and protected from light until the expiration date; the drug should not be frozen.31 In-use injection pens of insulin glargine 300 units/mL should be stored at room temperature away from heat and direct light for up to 42 days; such in-use injection pens should not be refrigerated.31

Injection pens containing insulin glargine/lixisenatide should be stored at 2-8°C in the original carton and protected from light before first use; after first use, the injection pens should be stored at room temperature below 25°C.49 The injection pens should not be frozen; they should not be used if freezing has occurred.49 Injection pens of insulin glargine/lixisenatide should be discarded 28 days after first use, even if some drug remains in the pen.49

The accompanying labeling should be consulted for additional details about the administration of insulin glargine or insulin glargine/lixisenatide.1,30,31,49

Dosage

Insulin Glargine Therapy

In patients with type 1 diabetes mellitus, insulin glargine must be used concomitantly with short-acting (e.g., prandial) insulin.1,30 In general, an initial total daily insulin dosage of 0.2-0.4 units/kg may be used in insulin-naive patients with type 1 diabetes mellitus.31 When used in conjunction with short-acting insulin, the manufacturers state that an initial insulin glargine dosage should be approximately one-third or one-third to one-half of the total daily insulin dosage for the 100- or 300-unit/mL preparations, respectively.1,30,31 The remainder of the daily insulin dosage should be given preprandially as rapid- or short-acting insulin.1,30,31

In insulin-naive patients with type 2 diabetes mellitus, the recommended initial dosage of the 100-unit/mL preparation of insulin glargine is 0.2 unit/kg or up to 10 units given once daily.1,30 The recommended initial dosage of the 300-unit/mL preparation of insulin glargine in insulin-naive patients with type 2 diabetes mellitus is 0.2 units/kg once daily.31 The dosage of insulin glargine should be titrated based upon a patient's metabolic needs, blood glucose concentrations, and glycemic control goal.1,30,31

The dosage of the 300-unit/mL preparation of insulin glargine should be increased no more frequently than every 3-4 days to minimize the risk of hypoglycemia.31 The maximum glucose-lowering effect of a dose of insulin glargine 300 units/mL may take 5 days to fully manifest, and the first dose of the 300-unit/mL preparation may not be able to fulfill the metabolic needs of the patient in the first 24 hours of use.31 Therefore, blood glucose concentrations should be monitored and dosages of coadministered antidiabetic drugs should be adjusted per the standard of care.31

The dosage and timing of concurrent short- or rapid-acting insulins or other concomitant antidiabetic agents may need to be adjusted in patients receiving insulin glargine.1,30,31 Insulin requirements may be altered with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), or during illness, emotional disturbances, or other stresses.1,30,31

Transferring from Therapy with Other Insulins

When insulin glargine is substituted for another intermediate- or long-acting insulin in patients with diabetes mellitus, a change in the dosage of the basal insulin may be required.1,30 The dosage and timing of concurrent short- or rapid-acting insulin or other concomitant antidiabetic agents may also need to be adjusted.1,30,31

In patients transferring from another 100-unit/mL preparation of insulin glargine (e.g., Lantus^®) to Basaglar^®, the dosage of Basaglar^® should be the same as the other preparation, and the administration time should be determined by the clinician.30 In patients currently receiving once-daily isophane (NPH) insulin, the 100-unit/mL preparation of insulin glargine administered once daily may be substituted on a unit-for-unit basis for NPH insulin.1 In patients currently receiving twice-daily NPH insulin, the recommended initial dosage of the 100-unit/mL preparation of insulin glargine once daily is 80% of the total daily NPH insulin dosage that is being discontinued.1,30 For patients transferring from the 300-unit/mL preparation of insulin glargine to the 100-unit/mL preparation of insulin glargine, the recommended initial dosage of the 100-unit/mL insulin glargine preparation is 80% of the insulin glargine 300-unit/mL preparation dosage.1,30

On a unit-for-unit basis, the 300-unit/mL preparation of insulin glargine has less of a glucose-lowering effect than the 100-unit/mL preparation.31 In patients currently receiving once-daily insulin glargine (100 units/mL) or an intermediate-acting insulin preparation, the recommended initial dosage of the 300-unit/mL preparation of insulin glargine is the same as the current long-acting insulin dosage.31 For patients controlled on the 100-unit/mL preparation of insulin glargine, a higher daily dose of the 300-unit/mL preparation of insulin glargine will be needed to maintain the current level of glycemic control.31 Patients transferring from other basal insulins to the 300-unit/mL preparation of insulin glargine may experience higher average fasting plasma glucose concentrations during the first weeks of therapy.31 In patients currently receiving twice-daily NPH insulin, the recommended initial dosage of the 300-unit/mL preparation of insulin glargine once daily is 80% of the total daily NPH insulin dosage that is being discontinued.31 Close monitoring of blood glucose concentrations is recommended during the transition to insulin glargine and in the initial weeks thereafter.31

For patients with type 1 diabetes mellitus transitioning from IV insulin to the 300-unit/mL preparation of insulin glargine, the longer onset of action of the 300-unit/mL preparation of insulin glargine (onset of action develops over 6 hours) should be considered before stopping IV insulin.31 The full glucose-lowering effect of the 300-unit/mL preparation of insulin glargine may not be apparent for at least 5 days.31

Insulin Glargine/Lixisenatide Fixed-combination Therapy

The recommended initial dosage of insulin glargine/lixisenatide for patients with type 2 diabetes mellitus inadequately controlled on less than 30 units of basal insulin or on lixisenatide is 15 units (15 units insulin glargine/5 mcg lixisenatide) subcutaneously once daily.49 For patients inadequately controlled on 30-60 units of basal insulin, the recommended initial dosage of insulin glargine/lixisenatide is 30 units (30 units insulin glargine/10 mcg lixisenatide) subcutaneously once daily.49 The dosage should be titrated by 2-4 units every week based on the patient's metabolic needs, blood glucose concentrations, and glycemic control goal.49 The recommended daily dosage of insulin glargine/lixisenatide is 15-60 units (15-60 units insulin glargine/5-20 mcg lixisenatide) once daily.49 Alternative antidiabetic therapy should be used if the patient requires a daily dosage of insulin glargine/lixisenatide of less than 15 units (15 units insulin glargine/5 mcg lixisenatide) or exceeding 60 units (60 units insulin glargine/20 mcg lixisenatide) daily.49

Special Populations

Hepatic Impairment

Data regarding the effects of hepatic impairment on the pharmacokinetics of insulin glargine in patients with diabetes mellitus are lacking.1,30,31 Careful monitoring of blood glucose and adjustment of insulin glargine or insulin glargine/lixisenatide dosage may be necessary in such patients.1,30,31,49

Renal Impairment

Data regarding the effects of renal impairment on the pharmacokinetics of insulin glargine in patients with diabetes mellitus are lacking.1,30,31 However, increased circulating concentrations of insulin have been observed in patients with renal impairment who were receiving insulin human; therefore, insulin glargine requirements may be reduced in these patients.1,30,31 Careful monitoring of blood glucose and adjustment of insulin glargine or insulin glargine/lixisenatide dosage may be necessary in such patients.1,30,31,49 Safety and efficacy of insulin glargine/lixisenatide have not been established in patients with end-stage renal disease (estimated glomerular filtration rate [eGFR] less than 15 mL/minute per 1.73 m²); the fixed combination is not recommended for use in such patients.49

Geriatric Patients

In geriatric patients, the initial dosage, dose increments, and maintenance dosage of insulin glargine or insulin glargine/lixisenatide should be conservative in order to avoid hypoglycemia.1,30,31,49

Contraindications

Known hypersensitivity to insulin glargine or any ingredient in the preparation.1,30,31,49 Contraindicated during episodes of hypoglycemia.1,30,31,49

Warnings/Precautions

Hypoglycemia

Hypoglycemia is the most common adverse effect of insulins, including insulin glargine, and monitoring of blood glucose concentrations is recommended for all patients with diabetes mellitus.1,2,4,5,30,31 The prolonged effect of subcutaneous insulin glargine may delay recovery from hypoglycemia.1,30 Severe hypoglycemia requiring the assistance of another person, IV glucose infusions, or glucagon administration has occurred with insulin therapy, including insulin glargine.1 As with all insulin preparations, the time course of the glucose-lowering effect of insulin glargine or insulin glargine/lixisenatide may vary among different individuals or at different times in the same individual and depends on many factors (e.g., area of injection, injection site blood supply, temperature).1,31,49 The risk of hypoglycemia generally increases with the intensity of glycemic control.30 Other factors that may increase a patient's risk of hypoglycemia include changes in meal patterns (e.g., macronutrient content, timing of meals), level of physical activity, and concomitant drug therapy.1,30,31 Patients with renal or hepatic impairment may be at a higher risk of hypoglycemia.1,30,31 In comparative studies, the overall rate of hypoglycemic reactions with insulin glargine was similar to that with isophane insulin human.1,2,3 For more information on the symptoms associated with hypoglycemia, See Hypoglycemia under Cautions: Endocrine and Metabolic Effects, in the Insulins General Statement 68:20.08.

Hypoglycemia Due to Medication Errors

Confusion between basal insulin preparations and other insulins, particularly rapid-acting insulins, has caused medication errors.1,30,31 To avoid such errors, patients should be advised to check the label on all insulin preparations to confirm the correct preparation and strength prior to administration.1,30,31

Formulation Considerations

Any change in insulin should be made cautiously and only under medical supervision.1,30,31 Insulin glargine should not be diluted or mixed with any other insulin.1,30,31 Patients previously receiving insulin may require a change in dosage if insulin therapy is changed to insulin glargine.1,31 Likewise, adjustment of oral antidiabetic dosage may be necessary in patients receiving concomitant therapy with insulin glargine.1,30,31 Changes in insulin strength, manufacturer, type, and/or method of administration may necessitate a change in insulin dosage.1,31

On a unit-for-unit basis, the 300-unit/mL preparation of insulin glargine has less of a glucose lowering effect than the 100-unit/mL preparation.31 To minimize the risk of hyperglycemia when initiating insulin glargine 300 unit/mL, blood glucose concentrations should be monitored daily, the dosage of the 300-unit/mL insulin glargine preparation should be titrated appropriately, and dosage of coadministered antidiabetic drugs should be adjusted per the standard of care.31 (See Transferring from Therapy with Other Insulins under Dosage: Insulin Glargine Therapy, in Dosage and Administration.)

Sharing of Injection Pens

Injection pens containing insulin glargine or insulin glargine/lixisenatide must never be shared among patients, even if the needle has been changed.1,30,31,49 Sharing of injection pens poses a risk for transmission of blood-borne pathogens.1,30,31,49

Hypokalemia

All insulin preparations, including insulin glargine, cause a shift in potassium from the extracellular to the intracellular space, possibly leading to hypokalemia.1,30,31 Untreated hypokalemia can lead to respiratory paralysis, ventricular arrhythmias, and death.1,30,31 Serum potassium concentrations should be monitored in patients at risk for hypokalemia (e.g., patients receiving potassium-lowering drugs, patients taking drugs with effects sensitive to serum potassium concentrations).1,30,31

Metabolic Effects

Insulin may cause sodium retention and edema, particularly if metabolic control is improved by intensive insulin therapy.1,30,31 Insulin therapy, including insulin glargine, also may cause weight gain attributable to the anabolic effects of insulin and the decrease in glucosuria.1,30,31

Heart Failure

Peroxisome proliferator-activated receptor (PPAR)-γ agonists (e.g., thiazolidinediones) can cause dose-related fluid retention, particularly when used in conjunction with insulin.1,30,31 Fluid retention may lead to or exacerbate heart failure.1,30,31 Patients treated with insulin, including insulin glargine, and a PPAR-γ agonist should be observed for manifestations of heart failure (e.g., excessive/rapid weight gain, shortness of breath, edema).1,30,31 If heart failure develops, it should be managed according to current standards of care, and discontinuance or reduction of the dosage of the PPAR-γ agonist must be considered.1,30,31 Concomitant use of rosiglitazone and insulin therapy is not recommended.54

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity with insulin glargine or insulin glargine/lixisenatide.1,30,31,49 Insulin antibodies may increase or decrease the efficacy of insulin, and insulin dosage adjustments may be required.1 During phase 3 clinical trials of insulin glargine (as Lantus^®), the incidence of insulin antibody development with insulin glargine therapy was similar to the incidence observed with isophane (NPH) insulin.1 Insulin antibodies have also been detected in patients receiving other insulin glargine preparations (Basaglar^® or Toujeo^®).30,31

Potential Carcinogenicity

FDA has notified healthcare professionals and patients about the results of several observational studies suggesting an increased risk of cancer in patients with diabetes receiving insulin glargine;14,15,16,17,18,20,21 however, upon further analysis, FDA states that the results of these studies are inconclusive due to limitations in how the studies were designed and carried out and in the data available for analysis.24 At this time, FDA states that it has not concluded that insulin glargine increases the risk of cancer.24

In a health insurance database cohort of over 127,000 diabetic patients in Germany, a positive, dose-related association was found between diagnosis of a malignant neoplasm and use of insulin human or an insulin analog (insulin glargine, insulin aspart, insulin lispro) over a mean follow-up period of 1.63 years.15,20 After adjusting for insulin dosage, patients who had received insulin glargine dosages of 10, 30, or 50 units daily had a 9, 19, or 31% increase, respectively, in cancer risk compared with that for insulin human; no such increased risk was found for insulin aspart or insulin lispro.15,20 The results of this study prompted similar reviews of patient databases in Sweden and Scotland, both of which also suggested a positive association between cancer (e.g., of the breast) and use of insulin glargine.16,17,20 Review of a third database of patients in the United Kingdom18 and post hoc analysis of data from a controlled trial in patients with type 2 diabetes mellitus receiving insulin glargine or isophane (NPH) insulin human for a mean cumulative period exceeding 4 years did not reveal such an association.19 Potentially confounding factors (e.g., patient age, blood pressure, weight, concomitant antidiabetic therapy) and other limitations of retrospective analyses prevent firm conclusions based on these data.15,22 However, in vitro studies indicating that insulin promotes the growth of cancer cells and that insulin glargine is more mitogenic than insulin human support the concerns raised by these observations.15,20,21,23 and additional epidemiologic analyses worldwide have been called for to further examine any association between insulin analogs such as insulin glargine and cancer.20,22,23 In a study evaluating the cardiovascular safety of insulin glargine (Outcomes Reduction with Initial Glargine Intervention [ORIGIN]), the overall incidence of cancer or death from cancer was similar among patients who received insulin glargine and those who received other antidiabetic drugs (e.g., oral antidiabetic agents, insulin other than insulin glargine).1,33

Based on currently available data, FDA recommends that patients not stop taking their insulin therapy without consulting a clinician, since uncontrolled hyperglycemia can have both immediate and long-term serious adverse effects.14,24 Some clinicians suggest that use of a long-acting human insulin (e.g., isophane [NPH] insulin human) or a combination of a long- and short-acting insulin twice daily may be considered as an alternative to insulin glargine therapy.22,23 FDA is continuing to evaluate the long-term risk, if any, for cancer associated with the use of insulin glargine.24 FDA encourages both healthcare professionals and patients to report adverse effects with the use of insulin glargine to the FDA's MedWatch Adverse Event Reporting Program14,24 ([Web]).

Use of Fixed Combinations

When insulin glargine is used in fixed combination with lixisenatide or other drugs, the cautions, precautions, contraindications, and interactions associated with the concomitant agent(s) should be considered in addition to those associated with insulin glargine.1,49

Sensitivity Reactions

Dermatologic and Sensitivity Reactions

As with any insulin therapy, lipodystrophy may occur at sites of insulin injections and may affect insulin absorption.1,30,31 Injection site rotation within an area may reduce or prevent these effects.1 Pain at the injection site was reported among 2.7% of patients receiving insulin glargine (as Lantus^®) compared with 0.7% of those receiving isophane insulin human in clinical studies.1 Other adverse local reactions reported with insulin glargine include redness, itching, urticaria, edema, and inflammation.1

Hypersensitivity characterized by generalized skin reactions, angioedema, anaphylaxis, bronchospasm, hypotension, or shock may occur with insulin glargine therapy and may be life-threatening.1,30,31 If hypersensitivity reactions occur, insulin glargine or insulin glargine/lixisenatide should be discontinued and the patient should be treated per standard of care until hypersensitivity manifestations resolve.1,30,31,49

Specific Populations

Pregnancy

Data are lacking on the use of insulin glargine or insulin glargine/lixisenatide in pregnant women.1,30,31,49 In animal reproduction studies in rats and rabbits, insulin glargine (100 units/mL) administered during pregnancy at dosages 2-7 times the human dose of 10 units daily did not cause any effects different than those seen with insulin human (regular).1 However, dilation of the cerebral ventricles was observed in some rabbit fetuses.1 Insulin glargine or insulin glargine/lixisenatide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.1,30,31,49

Lactation

It is unknown whether insulin glargine is distributed into milk; caution is advised if used in nursing women.1,30,31 Use of insulin glargine is compatible with breast-feeding; however, women who are lactating may require adjustments of their insulin dose.1,30,31

Pediatric Use

Safety and efficacy of the 100-unit/mL preparations of insulin glargine (Lantus^®, Basaglar^®) have not been established in children younger than 6 years of age with type 1 diabetes mellitus or in pediatric patients with type 2 diabetes mellitus.1,30 Safety and efficacy of the 300-unit/mL preparation of insulin glargine (Toujeo^®) or of insulin glargine/lixisenatide have not been established in pediatric patients.31,49

Geriatric Use

Initial dosage, dose increments, and maintenance dosage of insulin glargine or insulin glargine/lixisenatide should be conservative to avoid hypoglycemia.1,30,31,49

Common Adverse Effects

Common adverse effects associated with insulin glargine therapy during clinical trials include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, edema, and weight gain.1,30,31

Adverse effects occurring in at least 5% patients receiving insulin glargine/lixisenatide in clinical trials include hypoglycemia, nausea, nasopharyngitis, diarrhea, upper respiratory tract infection, and headache.49

Drugs Affecting Glycemic Control

Drugs That May Potentiate Hypoglycemic Effects

Drug interactions are possible with drugs that may potentiate hypoglycemic effects of insulin glargine (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, disopyramide, fibrate derivatives, fluoxetine, monoamine oxidase [MAO] inhibitors, oral antidiabetic agents, pentoxifylline, pramlintide, propoxyphene [no longer commercially available in the US], salicylates, somatostatin derivatives [e.g., octreotide], sulfonamide anti-infectives).1,30,31 Dosage reductions and increased frequency of glucose monitoring may be required if insulin glargine is used concomitantly with these drugs.1,30,31

Drugs That May Antagonize Hypoglycemic Effects

Drug interactions are possible with drugs that may antagonize hypoglycemic effects such as atypical antipsychotics (e.g., olanzapine, clozapine), corticosteroids, danazol, diuretics, estrogens and progestins (e.g., oral contraceptives), glucagon, isoniazid, niacin, phenothiazines, protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones.1,30,31 Dosage increases and increased frequency of glucose monitoring may be required if insulin glargine is used concomitantly with these drugs.1,30,31

Drugs That May Have a Variable Effect on Glycemic Control

Drug interactions are possible with drugs that may have a variable effect on glycemic control (e.g., alcohol, β-adrenergic blocking agents, clonidine, lithium salts, pentamidine).1,30,31 Dosage adjustments and increased frequency of glucose monitoring may be required if insulin glargine is used concomitantly with these drugs.1,30,31

Sympatholytic Agents

Sympatholytic agents (e.g., β-adrenergic blocking agents, clonidine, guanethidine, reserpine) may decrease or eliminate the signs of hypoglycemia.1,30,31 Increased frequency of glucose monitoring may be required when insulin glargine is used concomitantly with these drugs.1,30,31

Pharmacokinetics

Absorption

Bioavailability

Following injection into subcutaneous tissue, neutralization of insulin glargine solution results in formation of microprecipitates from which the drug is slowly released.1,30,31

Following subcutaneous injection, absorption of insulin glargine is slower and more prolonged compared with that of isophane (NPH) insulin human; the serum concentration-time profile for the 100- or 300-unit/mL preparation of insulin glargine is relatively constant over 24 or 36 hours, respectively.1,55

The absorption of the 300-unit/mL preparation of insulin glargine is more prolonged than that of the 100-unit/mL preparation.40

Onset

Following subcutaneous injection of the 100-unit/mL preparation of insulin glargine, onset of hypoglycemic action is 1.1 hours. Following subcutaneous injection of the 300-unit/mL preparation of insulin glargine, the onset of glucose-lowering action develops over 6 hours.31 Substantial interindividual and intraindividual variation may occur based on tissue blood supply, temperature, exercise, and/or interindividual and intraindividual differences in response.1

Duration

Following subcutaneous injection of the 100- or 300-unit/mL preparation of insulin glargine, duration of hypoglycemic action is approximately 24 or 36 hours, respectively.1,30,40 Duration of action is similar following subcutaneous injection at abdominal, deltoid, or thigh sites.1,30 Substantial interindividual and intraindividual variation in duration may occur based on tissue blood supply, temperature, exercise, and/or interindividual and intraindividual differences in response.1

Elimination

Metabolism

In the subcutaneous tissue depot, insulin glargine is partially metabolized to form 2 metabolites with activity similar to that of insulin.1,30,31 There are no differences in metabolism of insulin glargine when administered as the 100- or 300-unit/mL preparation.40

Description

Insulin glargine is a biosynthetic (rDNA origin), long-acting human insulin analog that is prepared using recombinant DNA technology and a special laboratory strain of nonpathogenic Escherichia coli (K12).1,2,3,30,31 Insulin glargine differs structurally from insulin human by the replacement of asparagine at position A21 with glycine and the addition of 2 arginines to the C-terminus of the B-chain.1,2,3,30,31 Insulin glargine has pharmacologic effects comparable to those of insulin human. 1,2 (See the Insulins General Statement 68:20.08.) In clinical studies, the glucose-lowering effect of the 100-unit/mL preparation of insulin glargine was approximately the same as insulin human on a molar basis.1

Insulin glargine is commercially available as an acidic solution with a pH of approximately 4.1,2,30,31 Neutralization of the acidic insulin glargine solution following injection into subcutaneous tissue results in the formation of microprecipitates of the drug from which small amounts of insulin glargine are slowly released.1,2,3,31 This results in a relatively constant concentration-time profile over 24-36 hours (dependent upon insulin concentration) with no pronounced peak.1,2,3,30,31,40,55 Compared with the 100-unit/mL preparation of insulin glargine, the pharmacokinetic and pharmacodynamic profiles of the 300-unit/mL preparation of insulin glargine demonstrate a less variable response and a longer duration of action (36 versus 24 hours).1,40

Advice to Patients

Provide copy of manufacturer's patient information.1,25,26,30,31,49

Importance of not mixing or diluting insulin glargine or the fixed combination of insulin glargine and lixisenatide (insulin glargine/lixisenatide) with any other insulin or solution.1,25,30,31,49 Importance of using insulin glargine or insulin glargine/lixisenatide only if solution is clear and colorless with no particles visible.1,25,26,31,49

Provide instructions regarding proper glucose monitoring, injection technique, and management of hyperglycemia or hypoglycemia.1,4,5,25,30,31,49 Discuss insulin requirements in special situations such as intercurrent conditions (illness, stress, emotional disturbances), missed doses, or inadvertent administration of incorrect doses.1,25,30,31,49 Risk of inadequate, or variable timing of, food intake.1,25

Importance of advising patients to refer to patient information for additional information about the potential adverse effects of insulin therapy, including lipodystrophy (and the need to rotate injection sites within the same body region), weight gain, allergic reactions, and hypoglycemia.1,25,30,31

Provide instructions to patient regarding use of the subcutaneous insulin glargine devices.1,26,30,31 Patients should be cautioned against reuse of needles.25,26,30,31 Importance of advising patients to never use a syringe to remove insulin glargine from the SoloStar^® injection pen.31

Importance of informing patients that they should never share injection pens containing insulin glargine or insulin glargine/lixisenatide with another person, even if the needle has been changed; sharing of the pen may pose a risk of transmission of infection.1,25,26,30,31,49

Importance of informing patients that changes to insulin regimens should be made cautiously and only under medical supervision.1,25,30,31 Importance of advising patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia.1,25,30,31

Importance of informing patients that their ability to concentrate and react may be impaired as a result of hypoglycemia, which may pose a risk in situations where these abilities are especially important (e.g., driving, operating machinery).1,25,30,31,49 Importance of advising patients who experience frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery.1,25,30,31,49

Importance of advising patients to always check the insulin label prior to each injection; medication errors involving confusion between insulins, particularly long- and short-acting insulins, have occurred.1,25,30,31

Importance of informing patients that the 300-unit/mL preparation of insulin glargine (Toujeo^®) contains 3 times as much insulin in 1 mL as standard insulin preparations (100 units/mL).31

Importance of informing patients that the dose counter of the Toujeo^® SoloStar^® injection pen displays the number of units to be injected; no recalculation of the dose is required to convert between different concentrations of insulin glargine.31

Importance of informing patients that if they are transitioned to the 300-unit/mL preparation of insulin glargine (Toujeo^®) from other basal insulins, they may experience higher average fasting plasma glucose concentrations during the first weeks of therapy.31 Importance of advising patients to monitor glucose concentrations daily when initiating insulin glargine.31

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1,25,30,31,49

Importance of women informing clinicians if they are or plan to become pregnant or breast-feed.1,4,25,30,31,49

Importance of informing patients of other important precautionary information.1,25,30,31,49 (See Cautions.)

Additional Information

Overview (see Users Guide). For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Sanofi-Aventis. Lantus^® (insulin glargine) injection prescribing information. Bridgewater, NJ; 2015 Jul.

2. Gillies PS, Figgitt DP, Lamb HM. Insulin glargine. Drugs . 2000; 59:253-60. [PubMed 10730548]

3. Ratner RE, Hirsch IB, Neifing JL et al. Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes. Diabetes Care . 2000; 23:639-43. [PubMed 10834423]

4. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care . 2000; 23(Suppl 1):S32.

5. American Diabetes Association. Insulin administration. Diabetes Care . 2000; 23(Suppl 1):S86.

6. Aventis Pharmaceuticals, Kansas City, MO: Personal communication.

7. Ratner RE, Hirsch IB, Mecca TE et al. Efficacy and safety of insulin glargine in subjects with type 1 diabetes: a 28-week randomized, NPH insulin-controlled trial. Diabetes . 1999; 48(Suppl 1):A120.

8. Rosenstock J, Schwartz S, Clark C et al. Efficacy and safety of HOE 901 (insulin glargine) in subjects with type 2 DM: a 28-week randomized, NPH insulin-controlled trial. Diabetes . 1999; 48(Suppl 1):A100.

9. Yki-Jarvinen H, Dressler A, Ziemen M et al. Comparison of insulin glargine (HOE901) vs NPH insulin during 1 year of insulin combination therapy in type 2 diabetes. Paper presented at the sixtieth Scientific Sessions of the American Diabetes Association. San Antonio, TX, 2000 June 9-13: Abstract No. 529. From web site. [Web]

10. Sanofi Aventis. Lantus^® (insulin glargine) injection patient information. Bridgewater, NJ; 2016 Apr.

11. Fritsche A, Schweitzer MA, Haring HU et al. Glimepiride combinated with morning insulin glargine, bedtime neutral protamine hagedorn insulin, or bedtime insulin glargine in patients with type 2 diabetes: a randomized controlled trial. Ann Intern Med . 2003; 138:952-9. [PubMed 12809451]

12. Hamann A, Matthaei S, Rosak C et al. A randomized clinical trial comparing breakfast, dinner, or bedtime administration of insulin glargine in patients with type 1 diabetes. Diabetes Care . 2003; 26:1738-44. [PubMed 12766103]

13. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care . 2005; 28(Suppl 1):S4-36.

14. Food and Drug Administration. Early communication about safety of Lantus (insulin glargine). 2009 Jul 1. Available from website. Accessed 2009 Nov 18. [Web]

15. Hemkens LG, Grouven U, Bender R et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia [serial online] . 2009; doi: 10.1007/s00125-009-1418-4.

16. Jonasson JM, Ljung R, Talbäck M et al. Insulin glargine use and short-term incidence of malignancies—a population-based follow-up study in Sweden. Diabetologia [serial online] . 2009; doi: 10.1007/s00125-009-1444-2.

17. Colhoun HM and the SDRN Epidemiology Group. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia [serial online] . 2009; doi: 10.1007/s00125-009-1453-1.

18. Currie CJ, Poole CD, Gale EAM. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia [serial online] . July 2, 2009; doi: 10.1007/s00125-009-1440-6.

19. Rosenstock J, Fonseca V, McGill JB et al. Similar risk of malignancy with insulin glargine and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes: findings from a 5 year randomised, open-label study. Diabetologia [serial online] . July 2, 2009; doi: 10.1007/s00125-009-1452-2.

20. Smith U, Gale EAM. Does diabetes therapy influence the risk of cancer? Diabetologia [serial online] . 2009; doi: 10.1007/s00125-009-1441-5.

21. Stumvoll M, Nawroth PP. The insulin glargine dilemma: an opportunity for the diabetes community? Diabetologia . 2009; 52: 1987-9. Commentary.

22. European Association for the Study of Diabetes. Possible link between insulin glargine and cancer prompts urgent call for more research. 2009 Oct. 3. Press release.

23. Hemkens LG, Bender R, Grouven U et al. Insulin glargine and cancer. Lancet . 2009; 374;1743-4. Letter. [PubMed 19932352]

24. Food and Drug Administration. Drug Safety Communication: Update to ongoing safety reviews of Lantus (insulin glargine) and possible risk of cancer. 2011 Jan 12. Available from website. Accessed 2017 Sep 18. [Web]

25. Eli Lilly and Company. Basaglar^® (insulin glargine) injection patient information. Indianapolis, IN; 2015 Dec.

26. Eli Lilly and Company. Basaglar^® (insulin glargine) injection instructions for use. Indianapolis, IN; 2015 Dec.

30. Eli Lilly and Company. Basaglar^® (insulin glargine) injection prescribing information. Indianapolis, IN; 2015 Dec.

31. Sanofi-Aventis.Toujeo^® (insulin glargine) injection prescribing information. Bridgewater, NJ; 2015 Sep.

32. Rosenstock J, Fonseca V, McGill JB et al. Similar progression of diabetic retinopathy with insulin glargine and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes: a long-term, randomised, open-label study. Diabetologia . 2009; 52:1778-88. [PubMed 19526210]

33. ORIGIN Trial Investigators, Gerstein HC, Bosch J et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med . 2012; 367:319-28. [PubMed 22686416]

35. Riddle MC, Bolli GB, Ziemen M et al. New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 2 diabetes using basal and mealtime insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 1). Diabetes Care . 2014; 37:2755-62. [PubMed 25078900]

36. Yki-Järvinen H, Bergenstal R, Ziemen M et al. New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 2 diabetes using oral agents and basal insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 2). Diabetes Care . 2014; 37:3235-43. [PubMed 25193531]

37. Bolli GB, Riddle MC, Bergenstal RM et al. New insulin glargine 300 U/ml compared with glargine 100 U/ml in insulin-naïve people with type 2 diabetes on oral glucose-lowering drugs: a randomized controlled trial (EDITION 3). Diabetes Obes Metab . 2015; 17:386-94. [PubMed 25641260]

38. Home PD, Bergenstal RM, Bolli GB et al. New Insulin Glargine 300 Units/mL Versus Glargine 100 Units/mL in People With Type 1 Diabetes: A Randomized, Phase 3a, Open-Label Clinical Trial (EDITION 4). Diabetes Care . 2015; 38:2217-25. [PubMed 26084341]

39. Goldman J, White JR. New Insulin Glargine 300 U/mL for the Treatment of Type 1 and Type 2 Diabetes Mellitus. Ann Pharmacother . 2015; 49:1153-61. [PubMed 26238470]

40. Clements JN, Threatt T, Ward E et al. Clinical Pharmacokinetics and Pharmacodynamics of Insulin Glargine 300 U/mL. Clin Pharmacokinet . 2017; 56:449-458. [PubMed 27699623]

41. US Food and Drug Administration. Center for Drug Evaluation and Research: Application number 205692Orig1s000: Summary review. From FDA website. [Web]

42. . Another insulin glargine (Basaglar) for diabetes. Med Lett Drugs Ther . 2017; 59:3-4. [PubMed 28026834]

43. . Concentrated insulin glargine (Toujeo) for diabetes. Med Lett Drugs Ther . 2015; 57:69-70. [PubMed 25941955]

44. Food and Drug Administration. FDA News Release: FDA approves Basaglar, the first “follow-on” insulin glargine product to treat diabetes. 2015 Dec 16. From FDA website. [Web]

45. Linnebjerg H, Lam EC, Seger ME et al. Comparison of the Pharmacokinetics and Pharmacodynamics of LY2963016 Insulin Glargine and EU- and US-Approved Versions of Lantus Insulin Glargine in Healthy Subjects: Three Randomized Euglycemic Clamp Studies. Diabetes Care . 2015; 38:2226-33. [PubMed 26307603]

46. Blevins TC, Dahl D, Rosenstock J et al. Efficacy and safety of LY2963016 insulin glargine compared with insulin glargine (Lantus®) in patients with type 1 diabetes in a randomized controlled trial: the ELEMENT 1 study. Diabetes Obes Metab . 2015; 17:726-33. [PubMed 25974640]

47. Rosenstock J, Hollander P, Bhargava A et al. Similar efficacy and safety of LY2963016 insulin glargine and insulin glargine (Lantus®) in patients with type 2 diabetes who were insulin-naïve or previously treated with insulin glargine: a randomized, double-blind controlled trial (the ELEMENT 2 study). Diabetes Obes Metab . 2015; 17:734-41. [PubMed 25931141]

48. Ilag LL, Deeg MA, Costigan T et al. Evaluation of immunogenicity of LY2963016 insulin glargine compared with Lantus® insulin glargine in patients with type 1 or type 2 diabetes mellitus. Diabetes Obes Metab . 2016; 18:159-68. [PubMed 26434665]

49. Sanofi-Aventis. Soliqua^® 100/33 (insulin glargine and lixisenatide) injection, for subcutaneous use prescribing information. Bridgewater, NJ; 2017 Aug.

50. Aroda VR, Rosenstock J, Wysham C et al. Efficacy and Safety of LixiLan, a Titratable Fixed-Ratio Combination of Insulin Glargine Plus Lixisenatide in Type 2 Diabetes Inadequately Controlled on Basal Insulin and Metformin: The LixiLan-L Randomized Trial. Diabetes Care . 2016; 39:1972-1980. [PubMed 27650977]

51. . Lixisenatide for type 2 diabetes. Med Lett Drugs Ther . 2017; 59:19-21. [PubMed 28118649]

52. Rosenstock J, Aronson R, Grunberger G et al. Benefits of LixiLan, a Titratable Fixed-Ratio Combination of Insulin Glargine Plus Lixisenatide, Versus Insulin Glargine and Lixisenatide Monocomponents in Type 2 Diabetes Inadequately Controlled on Oral Agents: The LixiLan-O Randomized Trial. Diabetes Care . 2016; 39:2026-2035. [PubMed 27527848]

54. GlaxoSmithKline. Avandia^® (rosiglitazone maleate) tablets prescribing information. Research Triangle Park, NC; 2016 Sep.

55. US Food and Drug Administration. Center for Drug Evaluation and Research: Application number 205692Orig1s000: clinical pharmacology and biopharmaceutics review. From FDA website. [Web]