Study Overview
Objective. To evaluate the efficacy of liraglutide for weight loss in a group of nondiabetic patients with obesity.
Design. Randomized double-blind placebo-controlled trial.
Setting and participants . This trial took place across 27 countries in Europe, North America, South America, Asia, Africa and Australia. It was funded by NovoNordisk, the pharmaceutical company that manufactures liraglutide. Participants were 18 years or older, with a BMI of 30 kg/m 2 (or 27 kg/m 2 with hypertension or dyslipidemia). Patients with diabetes, those on medications known to induce weight gain (or loss), those with history of bariatric surgery, and those with psychiatric illness were excluded from participating. Patients with prediabetes were not excluded.
Intervention. Participants were randomized (2:1 in favor of study drug) to liraglutide or placebo, stratified according to BMI category and pre-diabetes status. They were started at a 0.6–mg dose of medication and up-titrated as tolerated to a dose of 3.0 mg over several weeks. All received counseling on behavioral changes to promote weight loss. Participants were then followed for 56 weeks. A small subgroup in the liraglutide arm was randomly assigned to switch to placebo after 12 weeks on medication to examine for durability of effect of medication, and to evaluate for safety issues that might occur on drug discontinuation.
Main outcome measures . This study focused on 3 primary outcomes: individual-level weight change from baseline, group-level percentage of participants achieving at least 5% weight loss, and percentage of participants with at least 10% weight loss, all assessed at 56 weeks.
Secondary outcomes included change in BMI, waist circumference, markers of glycemia (hemoglobin A1c, insulin level), markers of cardiometabolic health (blood pressure, lipids, CRP), and health-related quality of life (using several validated survey measures). Adverse events were also assessed.
The investigators used an intention-to-treat analysis, comparing outcomes among all patients who were randomized and received at least 1 dose of liraglutide or placebo. For patients with missing values (eg, due to dropout), outcome values were imputed using the last-observation-carried-forward method. A multivariable analysis of covariance model was used to analyze changes in the primary outcomes and included a covariate for the baseline measure of the outcome in question. Sensitivity analyses were conducted in which the investigators used different imputation techniques (multiple imputation, repeated measures) to account for missing data.
Results. The trial enrolled 3731 participants, 2487 of whom were randomized to receive liraglutide and 1244 of whom received placebo. The groups were similar on measured baseline characteristics, with a mean age of 45 years, mostly female participants (78.7% in liraglutide arm, 78.1% in placebo), and the vast majority of participants identified as “white” race/ethnicity (84.7% in liraglutide, 85.3% in placebo). Mean baseline BMI was 38.3 kg/m 2 in both groups. Although overweight patients with BMI 27 kg/m 2 or greater were included, they represented a small fraction of all participants (2.7% in liraglutide group and 3.5% in placebo group). Furthermore, although patients with overt diabetes were excluded from participating, over half of the participants qualified as having prediabetes (61.4% in liraglutide group, 60.9% in placebo group). Just over one-third (34.2% of liraglutide group, 35.9% placebo) had hypertension diagnosed at baseline. Study withdrawal was relatively substantial in both groups – 71.9% remained enrolled at 56 weeks in the liraglutide group, and 64.4% remained in the placebo arm. The investigators note that withdrawal due to adverse events was more common in the liraglutide group (9.9% of withdrawals vs. 3.8% in placebo), while other reasons for withdrawing (ineffective therapy, withdrawal of consent) were more common among placebo participants.
Liraglutide participants lost significantly more weight than placebo participants at 56 weeks (mean [SD] 8.0 [6.7] kg vs. 2.6 [5.7] kg). Similarly, more patients in the liraglutide group achieved at least 5% weight loss (63% vs. 27%), and 10% weight loss (33.1% vs. 10.6%) than those taking placebo. When subgroups of patients were examined according to baseline BMI, the investigators suggested that liraglutide appeared to be more effective at promoting weight loss among patients starting below 40 kg/m 2.
Hemoglobin A1c dropped significantly more (–0.23 points, P < 0.001) among liraglutide participants than among placebo participants. Similarly, fasting insulin levels dropped by 8% more ( P < 0.001) in the liraglutide group at 56 weeks. In keeping with the greater weight loss, markers of cardiometabolic health also improved to a greater extent among liraglutide participants, with larger decreases in blood pressure (SBP –2.8 mm Hg lower in liraglutide, P < 0.001), and LDL (–2.4% difference, P = 0.002), and a larger increase in HDL (1.9% difference, P = 0.001). By week 56, 14% of prediabetic patients in the placebo arm had received a new diagnosis of diabetes, compared to just 4% in the liraglutide group ( P < 0.001).
Quality of life scores were higher for liraglutide participants on all included measures except those related to side effects of treatment, where placebo participants reported lower levels of side effects. The most common side effects reported by liraglutide participants related to GI upset, including nausea (40%), diarrhea (21%), and vomiting (16%). More serious events, including cholelithiasis (0.8%), cholecystitis (0.5%), and pancreatitis (0.2%), were also reported. Somewhat surprisingly, although liraglutide is also used to improve glycemic control in diabetics, rates of reported spontaneous hypoglycemia were fairly low in the liraglutide group (1.3% vs. 1.0% in placebo).
Conclusion. Liraglutide given at a dose of 3.0 mg daily, along with lifestyle advice, produces clinically significant weight loss and improvement in glycemic and cardiometabolic parameters that is sustained after 1 full year of treatment.
Commentary
Over the past few years, the FDA has approved a growing list of medications for the treatment of obesity [1,2]. Unlike the prior mainstay for prescription weight management, phentermine, which can only be used for a few months at a time due to concerns about abuse, many of these newer medications are approved for long-term use, aligning well with the growing recognition of obesity as a chronic illness. Interestingly, most of the drugs that have emerged onto the market do not represent novel compounds, but rather are existing drugs that have been repurposed and repackaged for the indication of weight management. These “recycled” medications include Qsymia (a mix of phentermine and topiramate) [1], Contrave (naltrexone and buproprion) [2], and now, Saxenda (liraglutide, also marketed as Victoza for treatment of type 2 diabetes). Liraglutide is a glucagon-like-peptide 1 (GLP-1) analogue, meaning it has an effect similar to that of GLP-1, a gut hormone that stimulates insulin secretion, inhibits pancreatic beta cell apoptosis, inhibits gastric emptying, and decreases appetite by acting on the brain’s satiety centers [3]. For several years, endocrinologists and some internists have been using liraglutide (Victoza) to help with glycemic control in diabetics, with the known benefit that, unlike some other diabetes medications, it tends to promote modest weight loss [4].
In this large multicenter trial, Pi-Sunyer et al evaluated the efficacy of liraglutide at a 3.0 mg daily dose (almost twice the dose used for diabetes) for weight management. The trial utilized a strong study design, with double blinding, randomization of a subgroup for early discontinuation (to evaluate for weight regain and stopping-related side effects), and, importantly, the intervention for both groups also included a behavior change component (albeit one of relatively low intensity, based on the limited description). Patients were followed for 56 weeks on the medication, making the “intervention” phase of the study longer than what has been done in many diet trials. Testing for a long-lasting impact on weight, and at the same time attempting to quantify risks associated with longer-term use of a medication, was an important contribution for this study given that liraglutide is being marketed for long-term use.
After a year on liraglutide, participants in that group had lost around 12 lb more, on average, than those using placebo, and had achieved greater improvements cardiometabolic risk markers, with a much lower risk of developing diabetes. While these findings are promising from a clinical standpoint, it is not clear whether the moderate health impacts of this drug will be sufficient to outweigh several issues that may impede its widespread use in practice. The rate of GI side effects (nausea, vomiting, diarrhea) in liraglutide participants was fairly high, and it is worth considering whether the side effects themselves could have been driving some of the weight loss observed in that group. Furthermore, the out of pocket cost of this medication, when used for weight loss in nondiabetics, is likely to be around $1000 per month. For most patients, this high price will prohibit longer-term use of liraglutide. Even in the setting of a trial where participants faced no out of pocket costs, almost one-third in the liraglutide arm did not complete a year of treatment. On a related note, the primary analysis for this trial used a “last observation carried forward” approach—somewhat concerning given that patients are likely to regain weight after stopping any weight loss intervention, pharmaceutical or otherwise. The authors do report that a range of sensitivity analyses with varying imputation techniques were conducted and did not change the main conclusions of the trial.
Despite the promising findings from this trial, several important clinical questions remain. What is the durability of health effects for patients who discontinue the medication after a year? What safety concerns may arise in those who can afford to continue using liraglutide at this higher dose for several years? A 2-year follow-up study on participants from the current trial has been completed and those results are expected soon, which may help to shed light on some of these issues [5]. Cost-effectiveness evaluations, and head-to-head comparisons of liraglutide with lower cost weight management options would also be very helpful for clinicians presenting a range of treatment options to patients with obesity.
Applications for Clinical Practice
Liraglutide at a daily dose of 3.0 mg represents a new option for treatment of patients with obesity. It should be used in conjunction with behavioral interventions that promote a more healthful diet and increased physical activity, and may result in clinically meaningful weight loss and decreased risk of diabetes. On the other hand, the medication is costly and associated with some unpleasant GI side effects, both important factors that may limit patients’ ability to use it in the long-term. More studies are needed to establish durability of effects and safety beyond a year and that offer direct comparisons with other evidence-based weight loss tools, pharmaceutical and otherwise.
—Kristina Lewis, MD, MPH