The American Heart Association has adopted body mass index (BMI) as the accepted measurement for adiposity. BMI is calculated by taking a patient’s weight in kilograms and dividing by their height in meters squared (kg/m²). Individuals with a BMI of 30 or greater are considered obese [1] . As of 2014, 34.9% of the United States (US) adult population was defined as obese. Although obesity rates do not appear to have significantly increased overall in the past decade, the rate of obesity in women over the age of 60 has increased significantly [2] . This increased rate of obesity in older women corresponds to the two-fold increase in diabetes in persons aged 65 or older since 1980 [3] . The association between obesity and diabetes has been well studied, with obese men having a seven times greater chance of developing diabetes and obese women having a twelve fold increased risk [4] . However, other comorbidities such as hypertension, hyperlipidemia, asthma, arthritis and general poor health have also been associated with obesity [5] making it one of leading causes of preventable death [6] .

Limited options exist for the treatment of obesity. This is due in part to weight loss medications being removed from the market. For example, sibutramine was removed due to the increased risk of cardiovascular events discovered in the SCOUT (Effect of Sibutramine on Cardiovascular Outcomes in Overweight and Obese Subjects) trial [7] . Saxenda (liraglutide) was approved in December 2014 for the treatment of obesity. Prior to its approval, liraglutide was used exclusively for diabetes at a lower dose (1.2 to 1.8 mg daily) and under a different brand name, Victoza^®. To gain approval for weight loss, medications must produce a weight loss of ≥5% from baseline; this requirement was met in early clinical trials with liraglutide [8] .

With the large number of individuals in the U.S. who are diabetic as well as obese, having a medication which could potentially treat both conditions is crucial. This article will explore the use of liraglutide as a weight loss medication including its mechanism of action, safety profile, and clinical evidence of efficacy.

Research connecting the gastrointestinal system and insulin secretion dates back to the 1960s stemming from an observation that oral glucose administration produced a greater insulin response compared to an intravenous glucose infusion [9] [10] . This was later termed the incretin effect. The incretin effect is primarily mediated by two insulinotropic gut hormones, glucagon-like peptide (GLP-1) and gastric inhibitory polypeptide (GIP), and accounts for approximately 50% - 70% of the total insulin secreted following oral glucose administration [11] . GLP-1 is a peptide released from L-cells in the intestine in response to nutrient ingestion and subsequently enhances glucose-stimulated insulin secretion. Circulating GLP-1 and GIP are found within minutes post meal ingestion, suggesting both neuronal and endocrine signals are responsible for the release of the hormone [12] . The incretin effect is greatly impaired in patients with type 2 diabetes (T2DM) and GLP-1 secretion is noticeably deficient.

Liraglutide is a GLP-1 analogue, produced by recombinant DNA technology, which shares 97% amino acid sequence homology to endogenous human GLP-1 [13] [14] . Native GLP-1 is rapidly degraded by endogenous DPP-4 enzyme promoting a short half-life of 1.5 - 2 minutes. Liraglutide is stable against DPP-4 degradation and has a prolonged plasma half-life of 13 hours [15] [16] . Similar to endogenous GLP-1, liraglutide binds to and activates the GLP-1 receptor. GLP-1 receptors are found in the pancreas, stomach, intestine, heart, kidney, peripheral and central nervous system [16] [17] . Once activated, several responses occur including glucose-dependent stimulation of pancreatic insulin secretion and inhibition of inappropriately high glucagon secretion.

In addition to its glucoregulatory mechanisms, activation of GLP-1 receptors regulates appetite and caloric intake, slow gastric emptying and promote weight loss [13] . This has promoted further research with GLP-1 receptor agonists in the treatment of obesity. In clinical trials, subjects taking liraglutide with a BMI between 30 - 40 kg/m² with or without diabetes, observed short term reduction in body weight by decreasing calorie intake and improving eating behaviors without an increase in 24-h energy expenditure [18] [19] . Mean estimated energy intake during a meal was significantly reduced in liraglutide 1.8 and 3 mg subjects when compared to placebo (p < 0.003). This reduction translated into improved appetite rating scores consisting of reduced appetite, satiety, and fullness in both liraglutide arms compared with placebo. Gastric emptying rates were similar between the three groups during a 5-h meal test. The 1-h gastric emptying rates, however, were 23% lower in the liraglutide 3 mg arm and 13% lower in the 1.8 mg arm when compared to placebo (p = 0.007, p = 0.14, respectively). The clinical significance of this finding is unknown [19] .

Liraglutide’s effect on cardiac repolarization was tested in a QTc trial. A randomized, placebo-controlled, cross-over study, found no clinically relevant prolongation in the QTc interval after daily doses up to 1.8 mg were given [20] . The maximum plasma concentrations (Cmax) in overweight and obese subjects treated with liraglutide 3 mg was similar to the Cmax observed in healthy volunteers.

The pharmacokinetic properties of liraglutide (outlined in Table 1) do not differ to a clinically relevant extent when comparing various subcutaneous injection sites (abdomen, upper arm, and thigh) [13] . Liraglutide is highly

protein bound (98%), and has reduced susceptibility from DPP4 degradation [21] . Liraglutide demonstrates a relatively slow rate of absorption, with maximum concentrations observed at 9 - 14 hours [22] . Absolute bioavailability is approximately 55% upon subcutaneous administration with a mean apparent volume of distribution of 20 - 25 L (100 kg person) [13] .

Liraglutide is metabolized in a manner similar to large proteins; no specific route has been identified as a major route of elimination [13] . Intact liraglutide is not found in feces or urine and only low levels of liraglutide related metabolites are detected during the first 6 - 8 days [17] [23] . The elimination half-life is approximately 13 hours, allowing for once daily administration. Although renal elimination does not appear significant, liraglutide area under the curve (AUC) was lower in patients with mild to severe renal impairment. There have been reports of acute renal failure with GLP-1 receptor agonists including liraglutide, however some of these reports were in patients with underlying renal disease and the majority occurred in volume depleted patients [13] . Data in hepatic impairment is limited. Caution should be utilized in patients with renal or hepatic impairment.

Race, ethnicity and gender have no effect on the pharmacokinetics of liraglutide and no dose adjustment is necessary [13] . This drug demonstrated little to no inhibition of cytochrome P450 enzymes thus indicating low potential for pharmacokinetic cytochrome P450 mediated and plasma protein binding drug-drug interactions [24] . No clinically significant drug interaction has been identified with oral contraceptives, digoxin, lisinopril, atorvastatin, acetaminophen, griseofulvin, and insulin detemir with coadministration of steady state liraglutide 1.8 mg/day [13] .

Several clinical trials have investigated the efficacy of liraglutide on weight loss in non-diabetic as well as diabetic patients (Table 2).

The efficacy of liraglutide as a weight loss agent was evaluated in a 56-week randomized, controlled clinical trial [25] . Patients without diabetes were enrolled in the trial if BMI was ≥30 (or ≥27 with other comorbidities). In a 2:1 ratio, patients were randomized to receive liraglutide (n = 2487) or placebo (n = 1244). The dose of liraglutide was initiated at 0.6 mg subcutaneously daily and titrated up 0.6 mg weekly to the target dose of 3.0 mg daily. Both groups received counseling on lifestyle modifications. The primary endpoints in this trial were weight change from baseline, the proportion of patients who lost at least 5% of their weight from baseline, and the proportion of patients who lost more than 10% of their baseline body weight. After 56 weeks, patients in the liraglutide group lost 8.4 kg ± 7.3 kg while patients in the placebo group lost 2.8 kg ± 6.5 kg from baseline (p < 0.001 vs placebo). The percentage of patients who lost at least 5% of their body weight from baseline was 63.2% in the liraglutide group vs. 27.1% in the placebo group (p < 0.001 vs placebo). Likewise, 33.1% of patients in the liraglutide group vs 10.6% of patients in the placebo group lost at least 10% of their body weight from baseline (p < 0.001). Patients in the liraglutide group most commonly reported gastrointestinal related adverse events; with nausea and vomiting reported primarily within the first 4 - 8 weeks of treatment. Based on the results of this trial, the authors concluded liraglutide 3.0 mg once daily, in combination with diet and exercise, produced clinically meaningful weight loss in obese patients without diabetes.

A small trial involving 44 obese binge-eaters aimed to evaluate the efficacy of liraglutide 1.8 mg daily for 12 weeks [26] . Subjects were randomized to receive liraglutide 1.8 mg plus diet and exercise or diet and exercise alone. Subjects were excluded if they were taking medications which affect weight or appetite and if they had diabetes, impaired glucose tolerance, or cardiovascular disease. Among the primary endpoints were changes in