Liraglutide Drug Information
Generic name: LIRAGLUTIDE
GLP-1 Receptor Agonist [EPC]
Uses of Liraglutide
- Liraglutide injection is indicated: as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus Limitations of Use: Liraglutide injection contains liraglutide. Coadministration with other liraglutide-containing products is not recommended. Liraglutide injection is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated: as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus.
- Limitations of Use: Coadministration with other liraglutide-containing products is not recommended.
Dosage & Administration of Liraglutide
Recommended Dosage Adult Patients
The recommended starting dosage of liraglutide injection is 0.6 mg injected subcutaneously once daily for one week. The 0.6 mg once daily dosage is intended to reduce the risk of gastrointestinal adverse reactions during initial titration and is not effective for glycemic control in adults. After one week at the 0.6 mg once daily dosage, increase the dosage to 1.2 mg injected subcutaneously once daily.
If additional glycemic control is required, increase the dosage to the maximum recommended dosage of 1.8 mg injected subcutaneously once daily after at least one week of treatment with the 1.2 mg once daily dosage. Pediatric Patients Aged 10 Years and Older The recommended starting dosage of liraglutide injection is 0.6 mg injected subcutaneously once daily. If additional glycemic control is required, increase the dosage in 0.6 mg increments after at least one week on the current dosage, to reduce the risk of gastrointestinal adverse reactions . The maximum recommended dosage is 1.8 mg injected subcutaneously once daily.
Recommendations Regarding Missed Dose Instruct patients who miss a dose of liraglutide
injection to resume the once -daily dosage regimen as prescribed with the next scheduled dose. Do not administer an extra dose or increase the dose to make up for the missed dose. If more than 3 days have elapsed since the last liraglutide injection dose, reinitiate liraglutide injection at 0.6 mg once daily to reduce the risk of gastrointestinal adverse reactions associated with reinitiation of treatment.
Upon reinitiation, liraglutide injection should be titrated at the discretion of the healthcare provider.
Important
Administration Instructions Inspect visually prior to each injection. Only use if solution is clear, colorless, and contains no particles. Inject liraglutide injection subcutaneously once daily at any time of day, independently of meals.
Inject liraglutide injection subcutaneously in the abdomen, thigh or upper arm. No dosage adjustment is needed if changing the injection site and/or timing. Rotate injection sites within the same region in order to reduce the risk of cutaneous amyloidosis . When using liraglutide injection with insulin, administer as separate injections.
Never mix. It is acceptable to inject liraglutide injection and insulin in the same body region but the injections should not be adjacent to each other.
Side Effects of Liraglutide
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Common Adverse Reactions The safety of liraglutide injection in patients with type 2 diabetes mellitus was evaluated in 5 glycemic control, placebo-controlled trials in adults and one trial of 52 weeks duration in pediatric patients 10 years of age and older . The data in Table 1 reflect exposure of 1,673 adult patients to liraglutide injection and a mean duration of exposure to liraglutide injection of 37.3 weeks. The mean age of adult patients was 58 years, 4% were 75 years or older and 54% were male.
The population was 79% White, 6% Black or African American, 13% Asian; 4% were of Hispanic or Latino ethnicity. At baseline the population had diabetes for an average of 9 years and a mean HbA 1c of 8.4%. Baseline estimated renal function was normal or mildly impaired in 88% and moderately impaired in 12% of the pooled population. Table 1 shows common adverse reactions in adults, excluding hypoglycemia, associated with the use of liraglutide injection for the treatment of type 2 diabetes mellitus.
These adverse reactions occurred more commonly on liraglutide injection than on placebo and occurred in at least 5% of patients treated with liraglutide injection. Overall, the type, and severity of adverse reactions in pediatric patients 10 years of age and older and above were comparable to that observed in the adult population. Table 1: Adverse reactions reported in ≥ 5% of Adult Patients Treated with Liraglutide Injection for Type 2 Diabetes Mellitus Cumulative proportions were calculated combining studies using Cochran-Mantel-Haenszel weights.
Placebo N=661 Liraglutide 1.2 mg N= 645 Liraglutide 1.8 mg N= 1024 Adverse Reaction (%) (%) (%) Nausea 5 18 20 Diarrhea 4 10 12 Headache 7 11 10 Nasopharyngitis 8 9 10 Vomiting 2 6 9 Decreased appetite 1 10 9 Dyspepsia 1 4 7 Upper Respiratory Tract Infection 6 7 6 Constipation 1 5 5 Back Pain 3 4 5 In an analysis of placebo- and active-controlled trials, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in Table 1. Other Adverse Reactions Gastrointestinal Adverse Reactions: In the pool of 5 glycemic control, placebo-controlled adult clinical trials, withdrawals due to gastrointestinal adverse reactions, occurred in 4.3% of liraglutide injection-treated patients and 0.5% of placebo-treated patients. Severe gastrointestinal adverse reactions were reported more frequently among patients receiving liraglutide injection (1.2 mg 4.4 %, 1.8 mg 4.2 %) than placebo (1.1 %). Withdrawal due to gastrointestinal adverse events mainly occurred during the first 2 to 3 months of the trials. Injection site reactions: Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of liraglutide injection-treated adult patients in the five double-blind, glycemic control trials of at least 26 weeks duration.
Less than 0.2% of liraglutide injection-treated patients discontinued due to injection site reactions. Hypoglycemia: In 5 adult glycemic control, placebo-controlled clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 8 liraglutide injection-treated patients (7.5 events per 1,000 patient-years). Of these 8 liraglutide injection-treated patients, 7 patients were concomitantly using a sulfonylurea. Table 2: Adult Incidence (%) and Rate (episodes/patient year) of Hypoglycemia in 26-Week Combination Therapy Placebo- controlled Trials "Patient not able to self-treat" is defined as an event requiring the assistance of another person for treatment.
Placebo Comparator Liraglutide Injection Treatment Add-on to Metformin Placebo + Metformin (N = 121) Liraglutide Injection + Metformin (N = 724) Patient not able to self-treat 0
Patient able to self-treat 2.5 3.6 Add-on to Glimepiride Placebo + Glimepiride
(N = 114) Liraglutide Injection + Glimepiride (N = 695) Patient not able to self-treat 0
Patient able to self-treat 2.6 7.5 Not classified 0 0.9 Add-on to
Metformin + Rosiglitazone Placebo + Metformin + Rosiglitazone (N = 175) Liraglutide Injection + Metformin + Rosiglitazone (N = 355) Patient not able to self-treat 0 0 Patient able to self-treat 4.6
Not classified 1.1 0.6 Add-on to Metformin + Glimepiride Placebo + Metformin
+ Glimepiride (N = 114) Liraglutide Injection + Metformin + Glimepiride (N = 230) Patient not able to self-treat 0
Patient able to self-treat 16.7 27.4 Not classified 0 0
In a 26-week placebo-controlled clinical trial in pediatric patients 10 years of age and older with a 26-week open-label extension, 21.2% of liraglutide injection-treated patients (mean age 14.6 years) with type 2 diabetes mellitus, had hypoglycemia with a blood glucose <54 mg/dL with or without symptoms (335 events per 1,000 patient years). No severe hypoglycemic episodes occurred in the liraglutide injection treatment group (severe hypoglycemia was defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions). Papillary thyroid carcinoma: In adult glycemic control trials of liraglutide injection, there were 7 reported cases of papillary thyroid carcinoma in patients treated with liraglutide injection and 1 case in a comparator-treated patient (1.5 vs. 0.5 cases per 1,000 patient- years). Most of these papillary thyroid carcinomas were <1 cm in greatest diameter and were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings on protocol-specified screening with serum calcitonin or thyroid ultrasound. Pancreatitis In glycemic control trials of liraglutide injection, there have been 13 cases of pancreatitis among liraglutide injection -treated patients and 1 case in a comparator (glimepiride) treated patient (2.7 vs. 0.5 cases per 1,000 patient-years). Nine of the 13 cases with liraglutide injection were reported as acute pancreatitis and four were reported as chronic pancreatitis. In one case in a liraglutide injection-treated patient, pancreatitis, with necrosis, was observed and led to death; however clinical causality could not be established.
Some patients had other risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse. Cholelithiasis and cholecystitis: In adult glycemic control trials of liraglutide injection, the incidence of cholelithiasis was 0.3% in both liraglutide injection- treated and placebo-treated patients. The incidence of cholecystitis was 0.2% in both liraglutide injection-treated and placebo-treated patients.
Laboratory Tests Bilirubin: In the five adult glycemic control trials of at least 26 weeks duration, mildly elevated serum bilirubin concentrations (elevations to no more than twice the upper limit of the reference range) occurred in 4% of liraglutide injection-treated patients, 2.1% of placebo-treated patients and 3.5% of active-comparator-treated patients. This finding was not accompanied by abnormalities in other liver tests. The significance of this isolated finding is unknown.
Calcitonin: Calcitonin, a biological marker of MTC, was measured throughout the clinical development program. At the end of the adult glycemic control trials, adjusted mean serum calcitonin concentrations were higher in liraglutide injection-treated patients compared to placebo-treated patients but not compared to patients receiving active comparator. Between group differences in adjusted mean serum calcitonin values were approximately 0.1 ng/L or less.
Among adult patients with pretreatment calcitonin <20 ng/L, calcitonin elevations to >20 ng/L occurred in 0.7% of liraglutide injection-treated patients, 0.3% of placebo-treated patients, and 0.5% of active-comparator-treated patients. The clinical significance of these findings is unknown. Lipase and Amylase: In one adult glycemic control trial in renal impairment patients, a mean increase of 33% for lipase and 15% for amylase from baseline was observed for liraglutide injection-treated patients while placebo-treated patients had a mean decrease in lipase of 3% and a mean increase in amylase of 1%. The clinical significance of elevations in lipase or amylase with liraglutide injection is unknown in the absence of other signs and symptoms of pancreatitis.
Vital signs Liraglutide injection did not have adverse effects on blood pressure. Mean increases from baseline in heart rate of 2 to 3 beats per minute have been observed in adult patients treated with liraglutide injection compared to placebo.
Postmarketing Experience
The following additional adverse reactions have been reported during post-approval use of liraglutide injection. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. G astrointestinal: Acute pancreatitis; hemorrhagic and necrotizing pancreatitis sometimes resulting in death; ileus, intestinal obstruction, severe constipation including fecal impaction, nausea, vomiting and diarrhea leading to dehydration H epatobiliary: Elevations of liver enzymes, hyperbilirubinemia, cholestasis, cholecystitis, cholelithiasis requiring cholecystectomy, hepatitis Hypersensitivity: Angioedema, anaphylactic reactions, pruritus N eoplasms: Medullary thyroid carcinoma Neurologic: Dysgeusia, dizziness, dysesthesia P ulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation.
Renal : Acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis; and increased serum creatinine Skin and subcutaneous tissue: Cutaneous amyloidosis, alopecia
Warnings & Cautions for Liraglutide
Risk of Thyroid C-cell Tumors Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell
tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice . Malignant thyroid C-cell carcinomas were detected in rats and mice. It is unknown whether liraglutide injection will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients treated with liraglutide injection have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide injection use in humans.
Liraglutide injection is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of liraglutide injection and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with liraglutide injection. Such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated.
Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.
Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis
has been observed in patients treated with GLP-1 receptor agonists, including liraglutide . After initiation of liraglutide injection, observe patients carefully for signs and symptoms of acute pancreatitis which may include persistent or severe abdominal pain (sometimes radiating to the back) and which may or may not be accompanied by nausea or vomiting. If pancreatitis is suspected, discontinue liraglutide injection and initiate appropriate management.
Never Share a Liraglutide Injection Pen Between Patients Liraglutide injection pens must
never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens.
Hypoglycemia Adult patients receiving liraglutide injection in combination with an insulin secretagogue
(e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. In pediatric patients 10 years of age and older, the risk of hypoglycemia was higher with liraglutide injection regardless of insulin and/or metformin use. . The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin. Inform patients using these concomitant medications and pediatric patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.
Acute Kidney Injury Due to Volume Depletion
There have been postmarketing reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with liraglutide injection . The majority of the reported events occurred in patients who experienced gastrointestinal reactions leading to dehydration such as nausea, vomiting, or diarrhea . Monitor renal function in patients reporting adverse reactions to liraglutide injection that could lead to volume depletion, especially during dosage initiation and escalation of liraglutide injection .
Severe Gastrointestinal Adverse Reactions Use of
GLP-1 receptor agonists, including liraglutide, has been associated with gastrointestinal adverse reactions, sometimes severe . In liraglutide injection clinical trials, severe gastrointestinal adverse reactions were reported more frequently among patients receiving liraglutide injection (1.2 mg 4.4 %, 1.8 mg 4.2 %) than placebo (1.1 %). Severe gastrointestinal adverse reactions have also been reported postmarketing with GLP-1 receptor agonists. Liraglutide injection is not recommended in patients with severe gastroparesis.
Hypersensitivity Reactions
There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) in patients treated with liraglutide injection . If a hypersensitivity reaction occurs, discontinue liraglutide injection; treat promptly per standard of care, and monitor until signs and symptoms resolve. Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a patient with a history of anaphylaxis or angioedema with another GLP-receptor agonist because it is unknown whether such patients will be predisposed to these reactions with liraglutide injection.
Liraglutide injection is contraindicated in patients who have had a serious hypersensitivity reaction to liraglutide or any of the excipients in liraglutide injection .
Acute Gallbladder Disease Acute events of gallbladder disease such as cholelithiasis or
cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.
Pulmonary Aspiration During General Anesthesia or Deep Sedation Liraglutide injection delays gastric
emptying . There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations. Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking liraglutide injection, including whether modifying preoperative fasting recommendations or temporarily discontinuing liraglutide injection could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking liraglutide injection.
Drug Interactions with Liraglutide
Effects of Delayed Gastric Emptying on Oral Medications Liraglutide injection causes a
delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, liraglutide injection did not affect the absorption of the tested orally administered medications to any clinically relevant degree . Nonetheless, caution should be exercised when oral medications are concomitantly administered with liraglutide injection.
Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin Liraglutide
injection stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving liraglutide injection in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia.When initiating liraglutide injection, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia.
Pregnancy Safety for Liraglutide
Pregnancy Risk Summary Based on animal reproduction studies, there may be risks to the fetus from exposure to liraglutide injection during pregnancy. Liraglutide injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal reproduction studies identified increased adverse developmental outcomes from exposure during pregnancy.
Liraglutide exposure was associated with early embryonic deaths and an imbalance in some fetal abnormalities in pregnant rats administered liraglutide during organogenesis at doses that approximate clinical exposures at the maximum recommended human dose (MRHD) of 1.8 mg/day. In pregnant rabbits administered liraglutide during organogenesis, decreased fetal weight and an increased incidence of major fetal abnormalities were seen at exposures below the human exposures at the MRHD (see Animal Data). The estimated background risk of major birth defects for women with uncontrolled pre-gestational diabetes (Hemoglobin A 1C >7) is 6 to 10%. The major birth defect rate has been reported to be as high as 20 to 25% in women with a Hemoglobin A 1C >10. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk: Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications.
Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. Animal Data Female rats given subcutaneous doses of 0.1, 0.25 and 1 mg/kg/day liraglutide beginning 2 weeks before mating through gestation day 17 had estimated systemic exposures 0.8-, 3-, and 11-times the human exposure at the MRHD based on plasma AUC comparison. The number of early embryonic deaths in the 1 mg/kg/day group increased slightly.
Fetal abnormalities and variations in kidneys and blood vessels, irregular ossification of the skull, and a more complete state of ossification occurred at all doses. Mottled liver and minimally kinked ribs occurred at the highest dose. The incidence of fetal malformations in liraglutide-treated groups exceeding concurrent and historical controls were misshapen oropharynx and/or narrowed opening into larynx at 0.1 mg/kg/day and umbilical hernia at 0.1 and 0.25 mg/kg/day.
Pregnant rabbits given subcutaneous doses of 0.01, 0.025 and 0.05 mg/kg/day liraglutide from gestation day 6 through day 18 inclusive, had estimated systemic exposures less than the human exposure at the MRHD of 1.8 mg/day at all doses, based on plasma AUC. Liraglutide decreased fetal weight and dose-dependently increased the incidence of total major fetal abnormalities at all doses. The incidence of malformations exceeded concurrent and historical controls at 0.01 mg/kg/day (kidneys, scapula), ≥ 0.01 mg/kg/day (eyes, forelimb), 0.025 mg/kg/day (brain, tail and sacral vertebrae, major blood vessels and heart, umbilicus), ≥ 0.025 mg/kg/day (sternum) and at 0.05 mg/kg/day (parietal bones, major blood vessels). Irregular ossification and/or skeletal abnormalities occurred in the skull and jaw, vertebrae and ribs, sternum, pelvis, tail, and scapula; and dose-dependent minor skeletal variations were observed. Visceral abnormalities occurred in blood vessels, lung, liver, and esophagus.
Bilobed or bifurcated gallbladder was seen in all treatment groups, but not in the control group. In pregnant female rats given subcutaneous doses of 0.1, 0.25 and 1 mg/kg/day liraglutide from gestation day 6 through weaning or termination of nursing on lactation day 24, estimated systemic exposures were 0.8-, 3-, and 11-times human exposure at the MRHD of 1.8 mg/day, based on plasma AUC. A slight delay in parturition was observed in the majority of treated rats. Group mean body weight of neonatal rats from liraglutide-treated dams was lower than neonatal rats from control group dams.
Bloody scabs and agitated behavior occurred in male rats descended from dams treated with 1 mg/kg/day liraglutide. Group mean body weight from birth to postpartum day 14 trended lower in F 2 generation rats descended from liraglutide-treated rats compared to F 2 generation rats descended from controls, but differences did not reach statistical significance for any group.
Pediatric Use of Liraglutide
Pediatric Use The safety and effectiveness of liraglutide injection as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus have been established in pediatric patients 10 years of age and older. Use of liraglutide injection for this indication is supported by a 26-week placebo-controlled clinical trial and a 26-week open-label extension in 134 pediatric patients 10 to 17 years of age with type 2 diabetes mellitus, a pediatric pharmacokinetic study, and studies in adults with type 2 diabetes mellitus . The risk of hypoglycemia was higher with liraglutide injection in pediatric patients regardless of insulin and/or metformin use . The safety and effectiveness of liraglutide injection have not been established in pediatric patients less than 10 years of age.
Contraindications for Liraglutide
Liraglutide injection is contraindicated in patients with a: personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) . serious hypersensitivity reaction to liraglutide or to any of the excipients in liraglutide injection. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with liraglutide injection. Patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2. Patients with a serious hypersensitivity reaction to liraglutide or any of the excipients in liraglutide injection.
Overdosage Information for Liraglutide
Overdoses have been reported in clinical trials and post-marketing use of liraglutide injection. Observed effects have included severe nausea, severe vomiting, and severe hypoglycemia. In the event of overdosage, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.
Initiate appropriate supportive treatment according to the patient's clinical signs and symptoms.
Clinical Studies of Liraglutide
Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus
In glycemic control trials in adults, liraglutide injection has been studied as monotherapy and in combination with one or two oral anti-diabetic medications or basal insulin. In each of the placebo controlled trials, treatment with liraglutide injection produced clinically and statistically significant improvements in hemoglobin A 1c and fasting plasma glucose (FPG) compared to placebo. All liraglutide injection-treated patients started at 0.6 mg/day.
The dose was increased in weekly intervals by 0.6 mg to reach 1.2 mg or 1.8 mg for patients randomized to these higher doses. Liraglutide injection 0.6 mg is not effective for glycemic control and is intended only as a starting dose to reduce gastrointestinal intolerance . Monotherapy In this 52-week trial, 746 adult patients with type 2 diabetes mellitus were randomized to liraglutide injection 1.2 mg, liraglutide injection 1.8 mg, or glimepiride 8 mg. Patients who were randomized to glimepiride were initially treated with 2 mg daily for two weeks, increasing to 4 mg daily for another two weeks, and finally increasing to 8 mg daily.
Treatment with liraglutide injection 1.8 mg and 1.2 mg resulted in a statistically significant reduction in HbA 1c compared to glimepiride ( Table 3 ). The percentage of patients who discontinued due to ineffective therapy was 3.6% in the liraglutide injection 1.8 mg treatment group, 6% in the liraglutide injection 1.2 mg treatment group, and 10.1% in the glimepiride-treatment group. The mean age of participants was 53 years, and the mean duration of diabetes was 5 years. Participants were 49.7% male, 77.5% White, 12.6% Black or African American and 35% of Hispanic or Latino ethnicity.
The mean BMI was 33.1 kg/m 2. Table 3: Results of a 52-week Monotherapy Trial in Adults with Type 2 Diabetes Mellitus Intent-to-treat population using last observation on study Liraglutide Injection 1.8 mg Liraglutide Injection 1.2 mg Glimepiride 8 mg Intent-to-Treat Population (N) 246 251 248 HbA 1c (%) (Mean) Baseline Change from baseline (adjusted mean) Least squares mean adjusted for baseline value Difference from glimepiride arm (adjusted mean) 95% Confidence Interval 8.2 -1.1 -0.6 p-value <0.0001 (-0.8, -0.4) 8.2 -0.8 -0.3 p-value <0.05 (-0.5, -0.1) 8.2 -
Percentage of patients achieving HbA 1c <7% 51 43 28 Fasting Plasma
Glucose (mg/dL) (Mean) Baseline Change from baseline (adjusted mean) Difference from glimepiride arm (adjusted mean) 95% Confidence Interval 172 -26 -20 (-29, -12) 168 -15 -10 (-19, -1) 172 -5 Body Weight (kg) (Mean) Baseline Change from baseline (adjusted mean) Difference from glimepiride arm (adjusted mean) 95% Confidence Interval 92.6 -2.5 -3.6 (-4.3, -2.9) 92.1 -2.1 -3.2 (-3.9, -2.5) 93.3 +
Figure 3: Mean HbA 1c for Adult Patients with Type 2 Diabetes
Mellitus who Completed the 52-week Trial and for the Last Observation Carried Forward (LOCF, intent-to-treat) data at Week 52 (Monotherapy) Combination Therapy Add-on to Metformin: In this 26-week trial, 1,091 adult patients with type 2 diabetes mellitus were randomized to liraglutide injection 0.6 mg, liraglutide injection 1.2 mg, liraglutide injection 1.8 mg, placebo, or glimepiride 4 mg (one-half of the maximal approved dose in the United States), all as add-on to metformin. Randomization occurred after a 6-week run-in period consisting of a 3-week initial forced metformin titration period followed by a maintenance period of another 3 weeks. During the titration period, doses of metformin were increased up to 2,000 mg/day.
Treatment with liraglutide injection 1.2 mg and 1.8 mg as add-on to metformin resulted in a significant mean HbA 1c reduction relative to placebo add-on to metformin and resulted in a similar mean HbA 1c reduction relative to glimepiride 4 mg add-on to metformin ( Table 4 ). The percentage of patients who discontinued due to ineffective therapy was 5.4% in the liraglutide injection 1.8 mg + metformin treatment group, 3.3% in the liraglutide injection 1.2 mg + metformin treatment group, 23.8% in the placebo + metformin treatment group, and 3.7% in the glimepiride + metformin treated group. The mean age of participants was 57 years, and the mean duration of diabetes was 7 years. Participants were 58.2% male, 87.1% White and 2.4% Black or African American.
The mean BMI was 31 kg/m 2. Table 4: Results of a 26-week Trial of liraglutide injection as Add-on to Metformin in Adults with Type 2 Diabetes Mellitus Intent-to-treat population using last observation on study Liraglutide Injection 1.8 mg + Metformin Liraglutide Injection 1.2 mg + Metformin Placebo + Metformin Glimepiride 4 mg For glimepiride, one-half of the maximal approved United States dose. + Metformin Intent-to-Treat Population (N) 242 240 121 242 HbA 1c (%) (Mean) Baseline Change from baseline (adjusted mean) Least squares mean adjusted for baseline value Difference from placebo + metformin arm (adjusted mean) 95% Confidence Interval Difference from glimepiride + metformin arm (adjusted mean) 95% Confidence Interval 8.4 -1 -1.1 p-value <0.0001 (-1.3, -0.9) 0 (-0.2, 0.2) 8.3 -1 -1.1 (-1.3, -0.9) 0 (-0.2, 0.2) 8.4 +0.1 8.4 -1 Percentage of patients achieving HbA 1c <7% 42 35 11 36 Fasting Plasma Glucose (mg/dL) (Mean) Baseline Change from baseline (adjusted mean) Difference from placebo + metformin arm (adjusted mean) 95% Confidence Interval Difference from glimepiride + metformin arm (adjusted mean) 95% Confidence Interval 181 -30 -38 (-48, -27) -7 (-16, 2) 179 -30 -37 (-47, -26) -6 (-15, 3) 182 +7 180 -24 Body Weight (kg) (Mean) Baseline Change from baseline (adjusted mean) Difference from placebo + metformin arm (adjusted mean) 95% Confidence Interval Difference from glimepiride + metformin arm (adjusted mean) 95% Confidence Interval 88 -2.8 -1.3 p-value <0.05 (-2.2, -0.4) -3.8 (-4.5, -3) 88.5 -2.6 -1.1 (-2, -0.2) -3.5 (-4.3, -2.8) 91 -1.5 89 +1 Liraglutide Injection Compared to Sitagliptin, Both as Add-on to Metformin: In this 26–week, open-label trial, 665 adult patients with type 2 diabetes mellitus on a background of metformin ≥1,500 mg per day were randomized to liraglutide injection 1.2 mg once daily, liraglutide injection 1.8 mg once daily or sitagliptin 100 mg once daily, all dosed according to approved labeling. Patients were to continue their current treatment on metformin at a stable, pre-trial dose level and dosing frequency. The mean age of participants was 56 years, and the mean duration of diabetes was 6 years.
Participants were 52.9% male, 86.6% White, 7.2% Black or African American and 16.2% of Hispanic or Latino ethnicity. The mean BMI was 32.8 kg/m 2. The primary endpoint was the change in HbA 1c from baseline to Week 26. Treatment with liraglutide injection 1.2 mg and liraglutide injection 1.8 mg resulted in statistically significant reductions in HbA 1c relative to sitagliptin 100 mg ( Table 5 ). The percentage of patients who discontinued due to ineffective therapy was 3.1% in the liraglutide injection 1.2 mg group, 0.5% in the liraglutide injection 1.8 mg treatment group, and 4.1% in the sitagliptin 100 mg treatment group. From a mean baseline body weight of 94 kg, there was a mean reduction of 2.7 kg for liraglutide injection 1.2 mg, 3.3 kg for liraglutide injection 1.8 mg, and 0.8 kg for sitagliptin 100 mg.
Table 5: Results of a 26-week Open-Label Trial of Liraglutide Injection Compared to Sitagliptin (both in combination with metformin) in Adults with Type 2 Diabetes Mellitus Intent-to-treat population using last observation on study Liraglutide Injection 1.8 mg + Metformin Liraglutide Injection 1.2 mg + Metformin Sitagliptin 100 mg + Metformin Intent-to-Treat Population (N) 218 221 219 HbA 1c (%) (Mean) Baseline Change from baseline (adjusted mean) Difference from sitagliptin arm (adjusted mean) Least squares mean adjusted for baseline value 95% Confidence Interval 8.4 -1.5 -0.6 p-value <0.0001 (-0.8, -0.4) 8.4 -1.2 -0.3 (-0.5, -0.2) 8.5 -
Percentage of patients achieving HbA 1c <7% 56 44 22 Fasting Plasma
Glucose (mg/dL) (Mean) Baseline Change from baseline (adjusted mean) Difference from sitagliptin arm (adjusted mean) 95% Confidence Interval 179 -39 -24 (-31, -16) 182 -34 -19 (-26, -12) 180 -15 Figure 4: Mean HbA 1c for Adult Patients with Type 2 Diabetes Mellitus who Completed the 26-week Trial and for the Last Observation Carried Forward (LOCF, intent-to-treat) data at Week 26 Combination Therapy with Metformin and Insulin: This 26-week open-label trial enrolled 988 adult patients with type 2 diabetes mellitus with inadequate glycemic control (HbA 1c 7% to 10%) on metformin (≥1,500 mg/day) alone or inadequate glycemic control (HbA 1c 7% to 8.5%) on metformin (≥1,500 mg/day) and a sulfonylurea. Patients who were on metformin and a sulfonylurea discontinued the sulfonylurea then all patients entered a 12-week run-in period during which they received add- on therapy with liraglutide injection titrated to 1.8 mg once-daily. At the end of the run-in period, 498 patients (50%) achieved HbA 1c <7% with liraglutide injection 1.8 mg and metformin and continued treatment in a non-randomized, observational arm.
Another 167 patients (17%) withdrew from the trial during the run-in period with approximately one-half of these patients doing so because of gastrointestinal adverse reactions . The remaining 323 patients with HbA 1c ≥7% (33% of those who entered the run-in period) were randomized to 26 weeks of once-daily insulin detemir administered in the evening as add-on therapy (N=162) or to continued, unchanged treatment with liraglutide injection 1.8 mg and metformin (N=161). The starting dose of insulin detemir was 10 units/day and the mean dose at the end of the 26-week randomized period was 39 units/day. During the 26 week randomized treatment period, the percentage of patients who discontinued due to ineffective therapy was 11.2% in the group randomized to continued treatment with liraglutide injection 1.8 mg and metformin and 1.2% in the group randomized to add-on therapy with insulin detemir. The mean age of participants was 57 years, and the mean duration of diabetes was 8 years.
Participants were 55.7% male, 91.3% White, 5.6% Black or African American and 12.5% of Hispanic or Latino ethnicity. The mean BMI was 34 kg/m 2. Treatment with insulin detemir as add-on to liraglutide injection 1.8 mg + metformin resulted in statistically significant reductions in HbA 1c and FPG compared to continued, unchanged treatment with liraglutide injection 1.8 mg + metformin alone ( Table 6 ). From a mean baseline body weight of 96 kg after randomization, there was a mean reduction of 0.3 kg in the patients who received insulin detemir add-on therapy compared to a mean reduction of 1.1 kg in the patients who continued on unchanged treatment with liraglutide injection 1.8 mg + metformin alone. Table 6: Results of a 26-week Open Label Trial of Insulin detemir as add on to Liraglutide Injection + Metformin Compared to Continued Treatment with Liraglutide Injection + Metformin alone in Adult Patients with Type 2 Diabetes Mellitus not Achieving HbA 1c < 7% after 12 weeks of Metformin and Liraglutide Injection Intent-to-treat population using last observation on study Insulin detemir + Liraglutide Injection + Metformin Liraglutide Injection + Metformin Intent-to-Treat Population (N) 162 157 HbA 1c (%) (Mean) Baseline (week 0) Change from baseline (adjusted mean) Difference from liraglutide injection + metformin arm (LS mean) Least squares mean adjusted for baseline value 95% Confidence Interval 7.6 -0.5 -0.5 p-value <0.0001 (-0.7, -0.4) 7.6 0 Percentage of patients achieving HbA 1c <7% 43 17 Fasting Plasma Glucose (mg/dL) (Mean) Baseline (week 0) Change from baseline (adjusted mean) Difference from liraglutide injection + metformin arm (LS mean) 95% Confidence Interval 166 -39 -31 (-39, -23) 159 -7 Add-on to Sulfonylurea: In this 26-week trial, 1,041 adult patients with type 2 diabetes mellitus were randomized to liraglutide injection 0.6 mg, liraglutide injection 1.2 mg, liraglutide injection 1.8 mg, placebo, or rosiglitazone 4 mg (one-half of the maximal approved dose in the United States), all as add-on to glimepiride.
Randomization occurred after a 4-week run-in period consisting of an initial, 2-week, forced-glimepiride titration period followed by a maintenance period of another 2 weeks. During the titration period, doses of glimepiride were increased to 4 mg/day. The doses of glimepiride could be reduced (at the discretion of the investigator) from 4 mg/day to 3 mg/day or 2 mg/day (minimum) after randomization, in the event of unacceptable hypoglycemia or other adverse events.
The mean age of participants was 56 years, and the mean duration of diabetes was 8 years. Participants were 49.4% male, 64.4% White and 2.8% Black or African American. The mean BMI was 29.9 kg/m 2. Treatment with liraglutide injection 1.2 mg and 1.8 mg as add-on to glimepiride resulted in a statistically significant reduction in mean HbA 1c compared to placebo add-on to glimepiride (Table 7). The percentage of patients who discontinued due to ineffective therapy was 3% in the liraglutide injection 1.8 mg + glimepiride treatment group, 3.5% in the liraglutide injection 1.2 mg + glimepiride treatment group, 17.5% in the placebo + glimepiride treatment group, and 6.9% in the rosiglitazone + glimepiride treatment group.
Table 7: Results of a 26-week Trial of liraglutide injection as add-on to Sulfonylurea in Adult Patients with Type 2 Diabetes Mellitus Intent-to-treat population using last observation on study Liraglutide injection 1.8 mg + Glimepiride Liraglutide injection 1.2 mg + Glimepiride Placebo + Glimepiride Rosiglitazone 4 mg For rosiglitazone, one-half of the maximal approved United States dose. + Glimepiride Intent-to-Treat Population (N) 234 228 114 231 HbA 1c (%) (Mean) Baseline 8.5 -1.1 -1.4 p-value <0.0001 8.5 -1.1 -1.3 8.4 +0.2 8.4 -
Change from baseline (adjusted mean) Least squares mean adjusted for baseline value
Difference from placebo + glimepiride arm (adjusted mean) 95% Confidence Interval (-1.6, -1.1) (-1.5, -1.1) Percentage of patients achieving HbA 1c <7% 42 35 7 22 Fasting Plasma Glucose (mg/dL) (Mean) Baseline Change from baseline (adjusted mean) Difference from placebo + glimepiride arm (adjusted mean) 174 -29 -47 177 -28 -46 171 +18 179 -16 95% Confidence Interval (-58, -35) (-58, -35) Body Weight (kg) (Mean) Baseline Change from baseline (adjusted mean) Difference from placebo + glimepiride arm (adjusted mean) 83 -0.2 -0.1 80 +0.3 0.4 81.9 -0.1 80.6 +2.1 95% Confidence Interval (-0.9, 0.6) (-0.4, 1.2) Add-on to Metformin and Sulfonylurea: In this 26-week trial, 581 adult patients with type 2 diabetes mellitus were randomized to liraglutide injection 1.8 mg, placebo, or insulin glargine, all as add-on to metformin and glimepiride. Randomization took place after a 6-week run-in period consisting of a 3-week forced metformin and glimepiride titration period followed by a maintenance period of another 3 weeks. During the titration period, doses of metformin and glimepiride were to be increased up to 2,000 mg/day and 4 mg/day, respectively.
After randomization, patients randomized to liraglutide injection 1.8 mg underwent a 2 week period of titration with liraglutide injection. During the trial, the liraglutide injection and metformin doses were fixed, although glimepiride and insulin glargine doses could be adjusted. Patients titrated glargine twice-weekly during the first 8 weeks of treatment based on self-measured fasting plasma glucose on the day of titration.
After Week 8, the frequency of insulin glargine titration was left to the discretion of the investigator, but, at a minimum, the glargine dose was to be revised, if necessary, at Weeks 12 and 18. Only 20% of glargine-treated patients achieved the pre-specified target fasting plasma glucose of ≤100 mg/dL. Therefore, optimal titration of the insulin glargine dose was not achieved in most patients. The mean age of participants was 58 years, and the mean duration of diabetes was 9 years. Participants were 56.5% male, 75.0% White and 3.6% Black or African American.
The mean BMI was 30.5 kg/m 2. Treatment with liraglutide injection as add-on to glimepiride and metformin resulted in a statistically significant mean reduction in HbA 1c compared to placebo add-on to glimepiride and metformin ( Table 8 ). The percentage of patients who discontinued due to ineffective therapy was 0.9% in the liraglutide injection 1.8 mg + metformin + glimepiride treatment group, 0.4% in the insulin glargine + metformin + glimepiride treatment group, and 11.3% in the placebo + metformin + glimepiride treatment group. Table 8: Results of a 26-week Trial of Liraglutide Injection as Add-on to Metformin and Sulfonylurea in Adult Patients with Type 2 Diabetes Mellitus Intent-to-treat population using last observation on study Liraglutide Injection 1.8 mg + Metformin + Glimepiride Placebo + Metformin + Glimepiride Insulin glargine For insulin glargine, optimal titration regimen was not achieved for 80% of patients. + Metformin + Glimepiride Intent-to-Treat Population (N) 230 114 232 HbA 1c (%) (Mean) Baseline Change from baseline (adjusted mean) Least squares mean adjusted for baseline value Difference from placebo + metformin + glimepiride arm (adjusted mean) 95% Confidence Interval 8.3 -1.3 -1.1 p-value <0.0001 (-1.3, -0.9) 8.3 -0.2 8.1 -
Percentage of patients achieving HbA 1c <7% 53 15 46 Fasting Plasma
Glucose (mg/dL) (Mean) Baseline Change from baseline (adjusted mean) Difference from placebo + metformin + glimepiride arm (adjusted mean) 95% Confidence Interval 165 -28 -38 (-46, -30) 170 +10 164 -32 Body Weight (kg) (Mean) Baseline Change from baseline (adjusted mean) Difference from placebo + metformin + glimepiride arm (adjusted mean) 95% Confidence Interval 85.8 -1.8 -1.4 p-value <0.05 (-2.1, -0.7) 85.4 -0.4 85.2
Liraglutide Injection Compared to Exenatide, Both as Add-on to Metformin and/or Sulfonylurea
Therapy: In this 26–week, open-label trial, 464 adult patients with type 2 diabetes mellitus on a background of metformin monotherapy, sulfonylurea monotherapy or a combination of metformin and sulfonylurea were randomized to once daily liraglutide injection 1.8 mg or exenatide 10 mcg twice daily. Maximally tolerated doses of background therapy were to remain unchanged for the duration of the trial. Patients randomized to exenatide started on a dose of 5 mcg twice-daily for 4 weeks and then were escalated to 10 mcg twice-daily.
The mean age of participants was 57 years, and the mean duration of diabetes was 8 years. Participants were 51.9% male, 91.8% White, 5.4% Black or African American and 12.3% of Hispanic or Latino ethnicity. The mean BMI was 32.9 kg/m 2. Treatment with liraglutide injection 1.8 mg resulted in statistically significant reductions in HbA 1c and FPG relative to exenatide ( Table 9 ). The percentage of patients who discontinued for ineffective therapy was 0.4% in the liraglutide injection treatment group and 0% in the exenatide treatment group.
Both treatment groups had a mean decrease from baseline in body weight of approximately 3 kg. Table 9: Results of a 26-week Open-Label trial of liraglutide injection versus Exenatide (both in combination with metformin and/or sulfonylurea) in Adult Patients with Type 2 Diabetes Mellitus Intent-to-treat population using last observation carried forward Liraglutide injection 1.8 mg once daily + metformin and/or sulfonylurea Exenatide 10 mcg twice daily + metformin and/or sulfonylurea Intent-to-Treat Population (N) 233 231 HbA 1c (%) (Mean) Baseline Change from baseline (adjusted mean) Least squares mean adjusted for baseline value Difference from exenatide arm (adjusted mean) 95% Confidence Interval 8.2 -1.1 -0.3 p-value <0.0001 (-0.5, -0.2) 8.1 -
Percentage of patients achieving HbA 1c <7% 54 43 Fasting Plasma Glucose
(mg/dL) (Mean) Baseline Change from baseline (adjusted mean) Difference from exenatide arm (adjusted mean) 95% Confidence Interval 176 -29 -18 (-25, -12) 171 -11 Add-on to Metformin and Thiazolidinedione: In this 26-week trial, 533 adult patients with type 2 diabetes mellitus were randomized to liraglutide injection 1.2 mg, liraglutide injection 1.8 mg or placebo, all as add-on to rosiglitazone (8 mg) plus metformin (2,000 mg). Patients underwent a 9 week run-in period (3-week forced dose escalation followed by a 6-week dose maintenance phase) with rosiglitazone (starting at 4 mg and increasing to 8 mg/day within 2 weeks) and metformin (starting at 500 mg with increasing weekly increments of 500 mg to a final dose of 2,000 mg/day). Only patients who tolerated the final dose of rosiglitazone (8 mg/day) and metformin (2000 mg/day) and completed the 6-week dose maintenance phase were eligible for randomization into the trial. The mean age of participants was 55 years, and the mean duration of diabetes was 9 years. Participants were 61.6% male, 84.2% White, 10.2% Black or African American and 16.4% of Hispanic or Latino ethnicity.
The mean BMI was 33.9 kg/m 2. Treatment with liraglutide injection as add-on to metformin and rosiglitazone produced a statistically significant reduction in mean HbA 1c compared to placebo add-on to metformin and rosiglitazone ( Table 10 ). The percentage of patients who discontinued due to ineffective therapy was 1.7% in the liraglutide injection 1.8 mg + metformin + rosiglitazone treatment group, 1.7% in the liraglutide injection 1.2 mg + metformin + rosiglitazone treatment group, and 16.4% in the placebo + metformin + rosiglitazone treatment group. Table 10: Results of a 26-week Trial of liraglutide injection as Add-on to Metformin and Thiazolidinedione in Adult Patients with Type 2 Diabetes Mellitus Intent-to-treat population using last observation on study Liraglutide Injection 1.8 mg + Metformin + Rosiglitazone Liraglutide Injection 1.2 mg + Metformin + Rosiglitazone Placebo + Metformin + Rosiglitazone Intent-to-Treat Population (N) 178 177 175 HbA 1c (%) (Mean) Baseline Change from baseline (adjusted mean) Least squares mean adjusted for baseline value Difference from placebo + metformin + rosiglitazone arm (adjusted mean) 8.6 -1.5 -0.9 p-value <0.0001 8.5 -1.5 -0.9 8.4 -0.5 95% Confidence Interval (-1.1, -0.8) (-1.1, -0.8) Percentage of patients achieving HbA 1c <7% 54 57 28 Fasting Plasma Glucose (mg/dL) (Mean) Baseline Change from baseline (adjusted mean) Difference from placebo + metformin + rosiglitazone arm (adjusted mean) 185 -44 -36 181 -40 -32 179 -8 95% Confidence Interval (-44, -27) (-41, -23) Body Weight (kg) (Mean) Baseline Change from baseline (adjusted mean) Difference from placebo + metformin + rosiglitazone arm (adjusted mean) 94.9 -2 -2.6 95.3 -1 -1.6 98.5 +0.6 95% Confidence Interval (-3.4, -1.8) (-2.4, -1.0) Liraglutide Injection Compared to Placebo Both With or Without metformin and/or Sulfonylurea and/or Pioglitazone and/or Basal or Premix insulin in Patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment: In this 26-week, double-blind, randomized, placebo-controlled, parallel-group trial in adult patients with type 2 diabetes mellitus, 279 patients with moderate renal impairment, as per MDRD formula (eGFR 30−59 mL/min/1.73 m 2 ), were randomized to liraglutide injection or placebo once daily. Liraglutide injection was added to the patient's stable pre-trial antidiabetic regimen (insulin therapy and/or metformin, pioglitazone, or sulfonylurea). The dose of liraglutide injection was escalated according to approved labeling to achieve a dose of 1.8 mg per day.
The insulin dose was reduced by 20% at randomization for patients with baseline HbA 1c ≤ 8% and fixed until liraglutide dose escalation was complete. Dose reduction of insulin and SU was allowed in case of hypoglycemia; up titration of insulin was allowed but not beyond the pre-trial dose. The mean age of participants was 67 years, and the mean duration of diabetes was 15 years.
Participants were 50.5% male, 92.3% White, 6.6% Black or African American, and 7.2% of Hispanic or Latino ethnicity. The mean BMI was 33.9 kg/m 2. Approximately half of patients had an eGFR between 30 and < 45mL/min/1.73 m 2. Treatment with liraglutide injection resulted in a statistically significant reduction in HbA 1c from baseline at Week 26 compared to placebo (see Table 11 ). 123 patients reached the 1.8 mg dose of liraglutide injection. Table 11: Results of a 26-week Trial of Liraglutide Injection Compared to Placebo in Adult Patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment Intent-to-treat population Liraglutide Injection 1.8 mg + insulin and/or OAD Placebo + insulin and/or OAD Intent to Treat Population (N) 140 137 HbA 1c (%) Baseline (mean) Change from baseline (estimated mean) b,c Difference from placebob Early treatment discontinuation, before week 26, occurred in 25% and 22% of liraglutide injection and placebo patients, respectively. 95% Confidence Interval 8.1 -0.9 -0.6 p-value <0.0001 (-0.8, -0.3) 8 -
Proportion achieving HbA 1c < 7%
Based on the known number of subjects achieving HbA 1c < 7%. When applying the multiple imputation method described in b) above, the estimated percents achieving HbA 1c < 7% are 47.6% and 24.9% for liraglutide injection and placebo, respectively. 39.3
FPG (mg/dL) Baseline (mean) Change from baseline (estimated mean) Estimated using a
mixed model for repeated measurement with treatment, country, stratification groups as factors and baseline as a covariate, all nested within visit. Difference from placebo 95% Confidence Interval 171 -22 -12 p-value <0.05 (-23, -0.8) 167 -10
Glycemic Control Trial in Pediatric Patients Aged 10 Years and Older with
Type 2 Diabetes Mellitus Liraglutide injection was evaluated in a 26-week, double-blind, randomized, parallel group, placebo controlled multi-center trial (NCT01541215), in 134 pediatric patients with type 2 diabetes mellitus aged 10 years and older. Patients were randomized to liraglutide injection once-daily or placebo once-daily in combination with metformin with or without basal insulin treatment. All patients were on a metformin dose of 1000 to 2000 mg prior to randomization.
The basal insulin dose was decreased by 20% at randomization and liraglutide injection was titrated weekly by 0.6 mg for 2 to 3 weeks based on tolerability and an average fasting plasma glucose goal of ≤110 mg/dL. The mean age was 14.6 years: 29.9% were ages 10 to 14 years, and 70.1% were greater than 14 years of age. 38.1% were male, 64.9% were White, 13.4% were Asian, 11.9% were Black or African American; 29.1% were of Hispanic or Latino ethnicity. The mean BMI was 33.9 kg/m 2 and the mean BMI SDS was 2.9. 18.7% of patients were using basal insulin at baseline. The mean duration of diabetes was 1.9 years and the mean HbA 1c was 7.8%. At week 26, treatment with liraglutide injection was superior in reducing HbA 1c from baseline versus placebo.
The estimated treatment difference in HbA 1c reduction from baseline between liraglutide injection and placebo was -1.06% with a 95% confidence interval of (see Table 12 ). Table 12: Results at week 26 in a trial comparing Liraglutide Injection in combination with metformin with or without basal insulin versus Placebo in combination with metformin with or without basal insulin in Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus Liraglutide injection +metformin±basal insulin Placebo+metformin±basal insulin N 66 68 HbA 1c (%) Baseline End of 26 weeks Adjusted mean change from baseline after 26 weeks The change from baseline to end of treatment visit in HbA1c and FPG was analyzed using a pattern mixture model with multiple imputation. Missing observations (10.6% in the liraglutide injection, 14.5% in the placebo) were imputed from the placebo arm based on multiple (x10,000) imputations. The data for week 26 was then analyzed with an ANCOVA model containing treatment, sex and age group as fixed effects and baseline value as covariate. 7.9 7.1 -0.64 7.7 8.2 0.42 Treatment difference Liraglutide Injection vs Placebo -1.06 p-value <0.001 Percentage of patients achieving HbA 1c <7% Categories are derived from continuous measurements of HbA 1c using a pattern mixture model with multiple imputation for missing observations. 63.7
FPG (mg/dL) Baseline End of 26 weeks Adjusted mean change from baseline
after 26 weeks 157 132 -19.4 147 166
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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