Obesity Management: Clinical Review and Update of the Pharmacologic Treatment Options

The completer population showed 9.2% weight loss in the liraglutide group and 3.0% weight loss in the control group.39 Weight loss of ≥ 5% was seen in 63.2% and 27.1% of the liraglutide and placebo groups, respectively. Weight loss rates of ≥ 10% was seen by 33.1% and 10.6%, respectively. The most common AEs were nausea, diarrhea, and constipation. Nausea generally occurred early during the titration period and then diminished.

A second clinically relevant study was performed with liraglutide. Often patients are able to lose weight with diet and exercise and then plateau. This study examined participants who lost 5% percent of their initial body weight and then were randomized to liraglutide or placebo.40 Key inclusion criteria were people aged ≥ 18 years old with a BMI 30 kg/m² to 45 kg/m² or BMI 27 kg/m² to 45 kg/m² with dyslipidemia and/or hypertension. In order to be randomized, participants were required to lose at least 5% of their initial body weight on a 1,200 kcal to 1,400 kcal diet with increased physical activity during a 4 to 12 week run-in period.

Four hundred twenty-two participants were enrolled, 212 in the liraglutide group and 210 in the placebo group. Most of the participants were female (81%). The average BMI in the study was 35.6 kg/m². Subjects in the liraglutide group had a weekly titration regimen.

After an average weight loss of 6% using a low calorie diet and increased physical activity the participants were randomized to continue diet and increased activity alone (placebo) or with liraglutide. At week 56 the results showed an additional 6.2% weight loss in the liraglutide group and 0.2% weight gain in the placebo group. The liraglutide group had a greater number of participants with ≥ 5% weight loss compared to placebo, 50.5% vs 21.8% (P < .0001).40 In the pooled data set from the registration trials the 3 most common GI AEs were nausea, diarrhea, and constipation occurring in 39.3%, 20.9%, and 19.4% of participants respectively. Discontinuation due to nausea for liraglutide was 2.9%.⁴¹

Clinicians should be aware that medications that can cause hypoglycemia such as sulfonylureas and insulin must be tapered as patients lose weight with liraglutide. Documented symptomatic hypoglycemia in patients with T2DM and with sulfonylurea background therapy was 43.6% with liraglutide vs 27.3% with placebo.

In the setting of renal impairment, patients treated with GLP-1 receptor agonists, including liraglutide, have had reports of acute renal failure and worsening of chronic renal failure usually associated with nausea, vomiting, diarrhea, or dehydration. Liraglutide causes thyroid C-cell tumors at clinically relevant exposures in rats and mice. It is unknown whether liraglutide causes 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 liraglutide is contraindicated in patients with a personal or family history of MTC or in patients with multiple endocrine neoplasia syndrome type 2.

Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with liraglutide in postmarketing reports. After initiation of liraglutide, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting). If pancreatitis is suspected, liraglutide should promptly be discontinued.

Conclusion

The treatment of obesity and overweight with comorbidities has always been a challenge. In the past there were few FDA-approved drugs and many drugs had to be used off-label. The toolbox of medications available for medical weight management is more robust than ever. The medications have different MOAs and can be used in a variety of patients. There are differences in the classes and some are controlled substances. Phentermine, lorcaserin, and Qsymia (phentermine/topiramate) are controlled substances whereas orlistat, naltrexone/bupropion and liraglutide are not. Other differences exist including duration of use. The sympathomimetic drugs have a limited window of use whereas orlistat, Qsymia (phentermine/topiramate), lorcaserin, naltrexone/bupropion, and liraglutide do not.

The medications that are available have a wide variety of MOAs. Therefore, if a patient fails one medication, then it is very reasonable to try a medication with a different MOA. In addition, there is the potential for weight regain when weight reduction medications are discontinued. As people lose weight their metabolic rate decreases about 15 kcal per pound of weight reduction.⁴²

Another challenge of using these medications is managing patient expectations. The current metric used for FDA approval is a 5% weight loss that is greater in the study group compared with the diet and physical activity active control. However, many clinicians and patients do not find this weight reduction amount consistent with their expectations. In addition weight loss trajectory may also be too slow for patients and cause early discontinuation. Therefore, patient education and a discussion of reasonable expectations for weight reduction medications are necessary.

Clinicians must acknowledge that there are limitations to the use of these medications. Newer agents do have a higher cost and insurance reimbursement is somewhat limited. However, they offer the opportunity to prevent more expensive, protracted conditions such as diabetes and cardiovascular disease. In summary, clinicians now have a wider variety of medication options to be used with dietary and lifestyle changes in order to improve health and prevent chronic diseases.