Andrea Marie Macabuag-Oliva, MD, FPCP, FPCEDM
Obesity, defined as a condition in which there is an excess of body fat, has reached epidemic proportions globally and this situation is likely to get worse. Rural versus urban comparisons as well as migration studies provide evidence that acculturation or modernization increases the prevalence of obesity. This effect has been attributed to the reduced physical activity and dietary changes that are associated with westernization. Studies worldwide have proven that obese individuals have elevated risk for all-cause mortality due largely to the increased risk of having diseases such as type 2 diabetes, cardiovascular disease, gallbladder disease, hormone-sensitive cancers and gastrointestinal cancers. Moreover, there is also an increased risk for non-fatal conditions such as back pain, arthritis, infertility and poor psychosocial functioning.
Many government agencies in the Asia-Pacific region haves initiated healthy lifestyle changes and universal prevention programs to address these concerns. Aside from a healthful diet, proper exercise and behavior modification, pharmacotherapy is an important tool to control weight gain. Unfortunately, older anti-obesity drugs that suppressed appetite by acting on the central nervous system via the serotoninergic or noradrenergic pathways had many cardiac side effects and were pulled out from the market.
In the past few years, however, newer weight loss agents have become available. One of these is liraglutide, which is injected subcutaneously on a daily basis and promises 5-10% weight loss in 56 weeks, based on trials that have compared this to placebo.
Liraglutide (Saxenda) is a glucagon-like peptide-1 (GLP-1) analogue. GLP-1 analogues exert its main effect by stimulating glucose-dependent insulin release from the pancreatic islets. It has also been shown to slow gastric emptying and to inhibit inappropriate post-meal glucagon release. It also stimulates the appetite centers of the hypothalamus to induce satiety. These factors all contribute to make one feel full or sated for a longer period of time.
How does Liraglutide fare with regards to weight loss?
The SCALE Maintenance trial was a randomized, double‐blind, placebo‐controlled study designed to determine the efficacy of liraglutide for weight maintenance. Patients with no comorbidities but with a body mass index (BMI) of ≥ 30 kg/m2, as well as patients with a comorbid condition and a BMI of ≥27 kg/m2, were enrolled in this study and randomized to liraglutide 3.0 mg or placebo for 56 weeks.
Participants (N=) 422 lost around 6% of their baseline body weight during the run-in period. After randomization, the liraglutide group had a significantly greater decrease in body weight than placebo (6.2% versus 0.2%, p < 0.0001). A significantly greater proportion of liraglutide‐treated patients achieved at least a 5% weight loss (50.5% versus 21.8%). Similarly, a significantly greater proportion of liraglutide‐treated patients achieved at least 10% weight loss (26.1% versus 6.3%) and maintained the 5% weight loss achieved during the run‐in (81.4% versus 48.9%) as compared to placebo‐treated patients (p < 0.0001 for all).
Is Liraglutide Safe?
Overall, liraglutide 3.0 mg per day is a well‐tolerated long‐term weight loss agent. The most common adverse events (AEs ) with a prevalence of greater than 5% are nausea, hypoglycemia, diarrhea, constipation, vomiting, headache, dyspepsia, fatigue, dizziness, abdominal pain, and increased lipase. Gastrointestinal intolerability is common and in clinical trials was noted to be the most common reason for drug discontinuation in patients with adverse events. Liraglutide should be used cautiously in patients with impaired kidney or liver function. Also, it is marketed with a black box warning about the risk of medullary thyroid carcinoma (MTC) as it has been shown to cause thyroid C‐cell tumors in rats and mice; however, with the evidence to date including over 6000 patients, no increased risk for MTC has been observed in humans. Nevertheless, liraglutide is contraindicated in patients with a personal or family history of MTC or MEN. Liraglutide is also contraindicated in pregnancy and is not recommended in nursing mothers, children, patients taking insulin or other GLP‐1 agonists.
The LEADER Trial, which is the cardiovascular outcome trial of Liraglutide, is a large, multicenter, double blind study involving 9340 patients with type 2 diabetes and high cardiovascular risk who were randomized to receive either liraglutide 1.8 mg daily or placebo. These patients were followed for 3.8 years. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. This primary outcome occurred in significantly fewer patients in the liraglutide group (13.0%) than in the placebo group (14.9%), HR 0.87, 95% CI 0.78 to 0.97); p < 0.001 for noninferiority and p = 0.01 for superiority). There were fewer deaths overall (HR 0.85, 95% CI 0.74 to 0.97) and fewer cardiovascular deaths (HR 0.78, 95% CI 0.66 to 0.93) in the liraglutide treated group compared with placebo. Importantly, there was no signal for increased hospitalization for heart failure in the liraglutide group and adverse events were similar to those seen in prior trials.
How does it compare with other available weight loss medications?
Currently there are other classes of drugs that are approved by the FDA for long‐term weight loss. These are orlistat and fixed‐dose combinations of phentermine/topiramate and naltrexone/bupropion. All of these have been shown to cause clinically significant weight loss of at least 5% of initial body weight when used individually as adjunct to lifestyle interventions. A recent network meta‐analysis comparing the effectiveness of these five medications demonstrated that liraglutide was one of two medications associated with the highest odds of achieving at least 5% weight loss as compared with placebo.
The new GLP1-RA: once weekly Semaglutide
In the Philippines, the therapeutic indication of Semaglutide (0zempic) at 0.25 mg, 0.5 mg and 1 mg is for control of hyperglycemia of people with type 2 diabetes. On the other hand, Liraglutide (Saxenda) 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg and 3 mg is approved for the management of weight loss in overweight or obese patients. These are both GLP-1 agonists that help maintain blood sugar levels and curb appetite. While semaglutide (Ozempic) is NOT indicated in the Philippines for weight loss, it may still help aid patients with diabetes to lose weight.
In other countries though, semaglutide, at doses of up to 2.4 mg, marketed as Wegovy, has it’s therapeutic indication to aid in achieving weight loss among adults and children aged ≥12 years with obesity, or some adults with excess weight (BMI ≥27) (overweight) who also have weight-related medical problems.
Obesity: a pandemic just like COVID….
Obesity, as a global epidemic, does not bring the same panic and fear that the height of the COVID pandemic brought. It may be because obesity is an insidious and silent killer. Knowing this, we should be vigilant and not be complacent in our fight against this disease. Now that we are equipped with the knowledge and tools to fight this problem, we can use these resources to create a healthier, leaner, more physically-fit population. Together, we look forward to the day when we can say veni, vidi, vici against obesity.
Sources:
- https://www.ncbi.nih.gov > “Semaglutide, a Glucagon like Peptide-1 receptor Agonist with Cardiovascular Benefits for Managemetn of type 2 Diabetes” Jan, 2022
- https://www.ncbi.nih.gov > “The GLP-1 agonist, Liraglutide, as a Pharmacotherapy for Obesity” Dec, 2015
- WHO, “The Asia-Pacific Perspective: Redefining Obesity and its Treatment.” February, 2020
- Victoza [package insert]. Novo Nordisk: Plainsboro, NJ, 2015. [Google Scholar]
- Saxenda [package insert]. Novo Nordisk: Plainsboro, NJ, 2015. [Google Scholar]
- Mehta, A, Marso, S.P. “Liraglutide for Weight Management: A Critical Review of the Evidence”, NIH, March 2017
