Liraglutide: A human GLP-1 analogue for the treatment of type 2 diabetes

Key Points

Abstract

Liraglutide is the second glucagon-like peptide-1 (GLP-1) analogue in its class being considered for the treatment of type 2 diabetes mellitus. Liraglutide causes glucose-dependent increased insulin secretion, delayed glucagon secretion, and reduced appetite and gastric emptying. The use of liraglutide is also associated with enhanced pancreatic islet cell function. The addition of a C-16 fatty acid chain gives liraglutide a longer half-life than that of exenatide, allowing for once-daily dosing. Across the Liraglutide Effect and Action in Diabetes (LEAD) trials, liraglutide demonstrated significant reductions in hemoglobin A_1c (HbA_1c) levels compared with other antidiabetics when used as a monotherapy or in combination with other agents. Reductions in weight were also noted. The most common adverse events associated with liraglutide have been gastrointestinal in nature. Reports of major hypoglycemia and pancreatitis have been rare, but the potential effect of liraglutide on human C-cell tumors needs further evaluation. Additional studies are needed to determine liraglutide's full potential therapeutic role, but current trials show promising beneficial effects for this agent's use in type 2 diabetes. Liraglutide is currently under FDA review for the treatment of type 2 diabetes. (Formulary. 2009;44:136–142.)

In May 2008, an NDA for liraglutide (Novo Nordisk), the second GLP-1 analogue in its class, was submitted for review. In April 2009, the Endocrinologic and Metabolic Drugs Advisory Committee voted that liraglutide was approvable with regard to cardiovascular safety and risk of papillary thyroid cancer, but the committee delivered a split vote on whether the available data on C-cell tumors were sufficient to warrant approvability.⁷

CHEMISTRY AND PHARMACOLOGY

Liraglutide is a GLP-1 analogue that differs from endogenous human GLP-1 by the addition of a C16 fatty acid.⁸ By mimicking the actions of food-induced endogenous GLP-1 release, liraglutide causes glucose-dependent increased insulin secretion, decreased glucagon secretion, and reduced appetite and gastric emptying.⁹ In patients with type 2 diabetes, enhanced pancreatic islet cell function as assessed by homeostasis model assessment of beta-cell function (HOMA-B) has also been noted with liraglutide.^10,11

PHARMACOKINETICS

Upon subcutaneous (SC) injection, liraglutide binds to available albumin and is released slowly, exhibiting linear pharmacokinetics when administered in the upper arm, abdomen, and thigh.^12,13 Liraglutide is 51% bioavailable after SC injection, with maximum serum concentrations reached approximately 9 to 12 hours after dosing.^14,15 Liraglutide has a half-life of 11 to 15 hours with SC dosing and 8 hours with intravenous (IV) dosing.^12,14,15 Slight but statistically significant accumulation has been observed before steady-state attainment with doses greater than 7.5 mcg/kg.¹⁶ Studies analyzing the metabolism of liraglutide have demonstrated that the drug is metabolized into multiple minor metabolites, which are then excreted in the urine and feces.¹⁷ Excretion in the urine, however, is negligible.¹⁸

CLINICAL TRIALS

Six Liraglutide Effect and Action in Diabetes (LEAD) trials have been conducted; 4 of these studies have been published (LEAD-1, LEAD-2, LEAD-3, LEAD-4), and the remaining 2 have been presented as abstracts (LEAD-5, LEAD-6).^{10,11,19–22} Table 1 provides a summary of the study parameters for the LEAD trials, and the figure on page 139 provides absolute hemoglobin A_1c (HbA_1c) reductions with liraglutide 1.8 mg across the LEAD trials.

LEAD-2, a randomized, double-blind trial, compared liraglutide 0.6, 1.2, and 1.8 mg/d, glimepiride 4 mg, and placebo in combination with metformin 1 g twice daily in 1,091 patients with type 2 diabetes.¹¹ Patients had a mean age of approximately 57 years, had diabetes for a mean of 7.4 years, and had previously taken monotherapy or combination oral antidiabetic therapy. Baseline HbA_1c, body mass index (BMI), and weight were 8.4%, 31 kg/m² , and 88.6 kg, respectively, with no differences among groups.²³

LEAD-1 compared liraglutide 0.6, 1.2, and 1.8 mg/d, rosiglitazone 4 mg/d, and placebo in combination with glimepiride 2 to 4 mg in 1,041 patients with type 2 diabetes.¹⁰ Baseline parameters were well balanced among groups. At baseline, mean patient age was 56±10 years, mean weight was 82±17 kg, and mean HbA_1c was 8.4%±1.0%.

At 26 weeks, HbA_1c reductions from baseline were 0.6%, 1.1%, and 1.1% with liraglutide 0.6, 1.2, and 1.8 mg, respectively, and 0.4% with rosiglitazone (ITT analysis). Patients treated with placebo demonstrated an increase in HbA_1c of 0.2%. At all doses, liraglutide was superior in reducing HbA_1c levels compared with placebo (P<.0001 vs placebo), but liraglutide was only superior to rosiglitazone at the 2 higher doses (P<.0001 vs rosiglitazone). At the end of treatment, mean weight was increased in patients treated with liraglutide 0.6 mg (0.7 kg) or liraglutide 1.2 mg (0.3 kg) and in patients treated with rosiglitazone (2.1 kg). A reduction in weight of 0.2 kg and 0.1 kg was observed with liraglutide 1.8 mg and placebo, respectively. Although reductions in BP of 2.6 to 2.8 mmHg were observed with liraglutide 1.2 and 1.8 mg, these reductions were not statistically significant compared with the rosiglitazone and placebo arms (BP reductions, 0.9–2.3 mmHg).

LEAD-4 compared the effects of adding liraglutide (either 1.2 or 1.8 mg) or placebo to a regimen of metformin 1 g twice/d and rosiglitazone 4 mg twice/d in a 26-week, randomized, double-blind trial.²⁰ The mean age for the 533 enrolled patients was 55±10 years; baseline BMI was 33.5±5.2 kg/m² , and baseline HbA_1c was 8.3%±1.0%.

Liraglutide 1.2 and 1.8 mg decreased HbA_1c levels significantly compared with placebo (liraglutide 1.2 and 1.8 mg, 1.48%; placebo, 0.54%; P<.05). Liraglutide 1.2 and 1.8 mg doses were associated with weight reductions of 1.02±0.33 kg and 2.02±0.32 kg, whereas placebo was associated with a weight increase of 0.60±0.34 kg (P<.0001 vs placebo for both groups). Compared with placebo, liraglutide 1.2- and 1.8-mg doses were associated with a significant change in systolic BP only (placebo-corrected difference, –5.6 and –4.5 mmHg with liraglutide 1.2 and 1.8 mg, respectively; P<.001). Low-density lipoprotein cholesterol (LDL-C) and triglyceride levels were also reduced significantly in patients treated with liraglutide 1.2 mg versus those treated with placebo (P<.05). Free fatty acids decreased significantly in patients treated with liraglutide compared with placebo-treated patients (P<.05).

Liraglutide 1.8 mg, insulin glargine, and placebo used in combination with metformin (1 g twice/d) and glimepiride 2 to 4 mg were compared in the LEAD-5 trial.²¹ A total of 581 patients with mean age of 57.5±10 years, mean BMI of 30.5±5.3 kg/m² , and mean HbA_1c of 8.2%±0.9% were randomized to treatment.

Liraglutide 1.8 mg was associated with a significantly greater reduction in HbA_1c levels (1.33%) than were insulin glargine (1.09%) and placebo (0.24%; P<.0001). Weight was also decreased significantly among patients treated with liraglutide (1.81 kg) compared with those treated with placebo (reduction, 0.42 kg) and insulin glargine (increase, 1.62 kg).

LEAD-6, the only head-to-head trial completed, compared liraglutide 1.8 mg with exenatide 10 mcg twice/d in conjunction with metformin and/or sulfonylurea in a 26-week, randomized, open-label, multicenter study.²² The mean age of patients was 57 years; at baseline, mean BMI was 33 kg/m² , and mean HbA_1c was approximately 8.2% for the 464 included patients.

Compared with exenatide, liraglutide was associated with significantly greater reductions in HbA_1c (liraglutide, 1.12%; exenatide, 0.79%; P<.0001), whereas weight reductions from baseline were not significantly different between groups (liraglutide, 3.24 kg; exenatide, 2.87 kg). Minor hypoglycemia occurred less frequently in the liraglutide group (1.9 vs 2.6 events/patient/y in liraglutide and exenatide groups, respectively; P=.0131). Nausea occurred equally in both groups initially, but at 26 weeks, nausea was reported in 3% and 10% of the liraglutide- and exenatide-treated patients, respectively (P value not reported).

Studies comparing liraglutide with other agents such as sitagliptin are currently under way; investigators are also assessing the potential role of liraglutide in weight management.^24,25

ADVERSE EVENTS

Gastrointestinal adverse events were the most commonly reported side effects with liraglutide (incidence with liraglutide 1.8 mg in LEAD-4, 56%, leading to 11% of withdrawals).^{10,11,19–21} Table 2 summarizes commonly reported adverse events in the LEAD trials. However, the incidence of gastrointestinal adverse events tended to decrease to <10% after the first 4 weeks of drug administration.^11,19,22

Minor hypoglycemia was reported in 27.4% of patients treated with liraglutide, metformin, and glimepiride compared with 16.7% of patients treated with metformin and glimepiride alone.²¹ Incidence of major hypoglycemia has been low (0–1 patients) across the LEAD trials.

In LEAD-1, 1 patient treated with liraglutide 0.6 mg who had no previous history of pancreatitis developed chronic pancreatitis.¹⁰ A total of 4 other liraglutide-treated patients with a history of pancreatitis completed the study without reporting pancreatitis as an adverse event. Two liraglutide-treated patients developed pancreatitis in LEAD-3; both patients recovered, but only 1 remained in the study.¹⁹ One liraglutide-treated patient in LEAD-2 developed pancreatitis and subsequently recovered but was withdrawn from the study.¹¹

According to Novo Nordisk, in preclinical studies, C-cell hyperplasia was observed in rodents. In the LEAD trials, 6 cases of C-cell hyperplasia were documented, 4 in the liraglutide arms and 2 in the comparator arms. As the studies were randomized 2:1, it is uncertain if the adverse effect is associated with liraglutide, as was observed in rodents, or is due to the development of underlying comorbid pathophysiology.

Although a marginal increase in pulse rate has been reported with liraglutide treatment, further evaluation is needed to determine potential correlation and clinical significance.^11,19 In a study by Vilsboll et al,²⁶ B-type natriuretic peptide, plasminogen activator inhibitor-1 (marker of impaired fibrinolysis), and C-reactive protein (not significant) decreased with liraglutide therapy. Overall, the development of antibodies to liraglutide has been observed to occur at a rate of <15%.¹⁰ In a study of exenatide, antiexenatide antibodies were observed in 45% of the patients but were determined to have no biological relevance.²⁷ Headache, dizziness, and injection-related injection-site bruising have also been reported.^10,28

DRUG INTERACTIONS

Delayed gastric emptying with liraglutide may result in a reduction in the rate and extent of absorption of orally administered drugs. Since intragastric pH is not altered by liraglutide, drugs dependent on gastric pH for their actions should not be affected.²⁹

In 1 trial, delayed gastric emptying resulted in reduced peak concentrations and delayed time to peak concentrations of ethinylestradiol/levonorgestrel combination oral contraceptives; however, the overall exposure was not affected.³⁰ Reduced efficacy of oral contraceptives is not anticipated.

In another trial, when liraglutide was administered concurrently with lisinopril and digoxin, small reductions in area under the curve (AUC) were observed (lisinopril, 15% reduction; digoxin, 16% reduction).³¹ Overall exposure of acetaminophen was not altered, but peak concentration and time to peak concentration were reduced with coadministration of liraglutide.³² Exposure of griseofulvin and atorvastatin did not change when these agents were used concurrently with liraglutide.³¹

DOSAGE AND ADMINISTRATION

Liraglutide is administered once/d (24-hour interval) as an SC injection into the abdomen, thigh, or upper arm.³³ Specific doses have not yet been determined. However, most improvements in outcomes have been observed with doses ranging from 0.6 to 2 mg/d.^{10,11,19–22,33}

Dosage adjustment for renal dysfunction is not required, even in patients with significant impairment (creatinine clearance [CrCl] ≤30 mL/min); liraglutide has not been demonstrated to be significantly removed by dialysis.^18,34,35 In patients with hepatic function impairment, liraglutide exposure appears to be reduced.³⁶ Glycemic control-based dosing is recommended.

Ms Sakauye is a PharmD candidate at the TJ Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, California. Dr Shah is assistant professor of Pharmacy Practice and Regional Coordinator, Travis Air Force Base, TJ Long School of Pharmacy and Health Sciences, University of the Pacific.

Acknowledgment: The authors would like to thank Pooja Patel and Geoffrey G. Parker (PharmD candidates) for their comments on this paper.

Disclosure Information: The authors report no financial disclosures as related to products discussed in this article.

In each issue, the "Focus on" feature reviews a newly approved or investigational drug of interest to pharmacy and therapeutics committee members. The column is coordinated by Robert A. Quercia, MS, RPh, clinical manager and director of Drug Information, Department of Pharmacy Services, Hartford Hospital, Hartford, Conn, and adjunct associate professor, University of Connecticut School of Pharmacy, Storrs, Conn; and by Craig I. Coleman, PharmD, assistant professor of pharmacy practice, University of Connecticut School of Pharmacy, and director, Pharmacoeconomics and Outcomes Studies Group, Hartford Hospital.

EDITORS' NOTE: The clinical information provided in "Focus on" articles is as current as possible. Due to regularly emerging data on developmental or newly approved drug therapies, articles include information published or presented and available to the author up until the time of the manuscript submission.

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