The Skinny on Weight Loss Drugs: The New Kids on the Block
Authors:
Thomas 'Judd' Ott, Student Pharmacist Mercer University, Kendra Manigault, Pharm.D., BCPS, BCACP, CDE, Clinical Assistant Professor, Mercer University, Amy Grimsley, Pharm.D. BCOP, Pharmacy Residency Coordinator and Pharmacy Educator, Cheyenne Regional Medical Center
Introduction
Obesity increases the risk of comorbidities, decreases quality of life, and increases overall mortality rates. Of note, greater than 60 comorbidities are associated with obesity including cardiovascular diseases, diabetes, pulmonary issues, and several types of cancers.
1
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2 Although patients seeking obesity treatment may be extremely overweight or obese, the expert panel of the 2013 American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society (AHA/ACC/TOS) Obesity Guidelines report that a modest sustained weight loss of 3%-5% can provide clinically meaningful reductions in triglycerides, blood glucose, glycated hemoglobin (HbA1C), and risk of developing type 2 diabetes. Furthermore, slightly greater weight loss (>5%) can lead to blood pressure reduction, improvement in low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), and reduction of medications.
3 Successful weight loss of 3%-5% can be achieved by non-pharmacological treatment but it may be difficult for most patients to continue the strict diets and regular exercise necessary to maintain their initial weight loss.
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As a result, drug therapy can provide patients with additional reduction which can potentially have considerable health benefits. The purpose of this second article of a three-part series is to look at additional options for weight loss therapy and briefly discuss some of the additional benefits associated with sustained weight loss due to pharmacological treatment.
GLP-1 agonist
Liraglutide (Saxenda®)
Liraglutide approved for weight loss under the brand name Saxenda®, is an agonist of the human glucagon-like peptide -1 (GLP-1) receptor. It is designed to mimic the endogenous human GLP-1, a physiological regulator of appetite and caloric intake. By mimicking this endogenous peptide sequence it activates the GLP-1 receptor leading to decreased body weight.
5
Liraglutide is also marketed under the brand name Victoza® as treatment for type 2 diabetes; however, Saxenda® is not indicated for and should not be used for the management of type 2 diabetes.
5 Liraglutide should be used in combination with a reduced-calorie diet and increased physical activity for the long term weight management in patients with an initial BMI ≥ 30 kg/m
2 or ≥27 kg/m
2 accompanied with other risk factors (hypertension, diabetes, and dyslipidemia).
5 Liraglutide is available as an 18 mg/3 mL prefilled multi-dose pen used for subcutaneous injections. Liraglutide should be initiated at 0.6 mg once daily at any time of the day without regards to meals. The dose should be increased in weekly intervals of 0.6 mg increments until a 3 mg per day dose is achieved at week five. If patients cannot tolerate the 3 mg dose or has not reached at least a 4% weight loss in a 16 week period, liraglutide should be discontinued.
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Clinical trials of liraglutide for weight loss confirmed liraglutide is significantly better than placebo in producing and maintaining weight loss.
6,7 A clinical trial of liraglutide 3 mg compared to placebo in weight management found that liraglutide resulted in greater weight loss than placebo. The liraglutide group achieved an average of 8.0±6.7% body weight lost and 63.2% of patients lost at least 5% of baseline body weight compared to an average of 2.6±5.7% of body weight lost and 27.1% of patients that lost at least 5% in the placebo group.
8 One clinical trial showed liraglutide 3 mg was responsible for a mean weight loss of 7.2 kg compared to 2.8 kg in placebo groups. A trial looking specifically at liraglutide's ability to maintain the lost weight showed patients lost an additional 6.2% of weight after obtaining a 5% weight loss from a low calorie diet (P < 0.0001), these patients not only lost additional weight but 81.4% were able to maintain the initial 5% weight loss compared to only 48.9% in the placebo group (P < 0.0001).
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Liraglutide's most common adverse effects are typically dose related and associated with nausea, vomiting, diarrhea, constipation, dyspepsia, and abdominal pain.
9 Liraglutide carries a black box warning for risk of thyroid C-cell tumors and is contraindicated in patients with a personal or family history of medullary thyroid carcinoma and in patients with Multiple Endocrine Neoplasia syndrome type 2. As a result, patients should be monitored accordingly while receiving therapy. Cases of acute pancreatitis have been reported in postmarked clinical trials as well. There also were reports of acute renal failure but a causal relationship between liraglutide use and renal failure has not been established.
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5-HT2C Receptor Agonist
Lorcaserin (Belviq®)
Lorcaserin, marketed as Belviq®, is approved for chronic weight management. It is a serotonin 2C (5-HT
2C) receptor agonist that possesses an unknown mechanism of action for weight loss. It is believed lorcaserin selectively activates 5-HT
2C receptors on anorexigenic pro-opiomelancortin neurons in the hypothalamus. These neurons are thought to decrease food consumption and promote a feeling of fullness, decreasing caloric intake.
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Lorcaserin is indicated for chronic weight management in conjunction with diet and exercise in adults with BMI ≥ 30 kg/m
2 or ≥27 kg/m
2 accompanied with other risk factors (hypertension, diabetes, and dyslipidemia). It is available as a 10 mg tablet and should be administered twice a day with or without food. Patients should be evaluated at 12 weeks for efficacy; if 5% of baseline body weight has not been achieved therapy should be discontinued.
Lorcaserin trials have proven to be significantly more effective than placebo (P < 0.001) in trials reviewed for this article.
11,12 A 2010 study showed at the end of 1 year, lorcaserin provided patients with a mean average of 5.8 kg weight loss versus just 2.2 kg for placebo group; and 47.5% of patients received greater than 5% loss from baseline body weight versus 20.3% in the placebo group.
11 Participants were also evaluated after 2 years to determine maintenance of weight loss. After the first year, patients who received placebo continued on placebo therapy while patients receiving lorcaserin continued lorcaserin or switched to placebo in a 2:1 ratio. Initial weight loss of ≥5% was maintained in 67.9% of the lorcaserin group compared to 50.3% in the placebo group (P < 0.001).
11 The lorcaserin study group in the one year BLOSSOM trial showed similar results as 47.2% of lorcaserin treated patients achieved a 5% loss from baseline body weight compared to 25% in the placebo group (P < 0.001). The lorcaserin groups mean change from baseline was 5.8 kg vs 2.9 kg for the placebo group (P<0.001).
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Clinical trial data identified the most common adverse reactions as headache, dizziness, fatigue, nausea, dry mouth, and constipation.
10 The risk of serotonin syndrome, a syndrome associated with all serotonergic drugs, is a potential concern with lorcaserin; therefore, an assessment of patients' medications for other serotonergic drugs should be completed to reduce this risk.
10 Other rare reactions that may occur includes cognitive impairment, psychiatric disorders, priapism, decreased heart rate, decreased white blood cell count, elevated prolactin levels, and pulmonary hypertension.
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Discussion:
Reports supporting the reduced severity of several comorbidities with sustained weight loss of 3-5% support the use of drug therapy in patients needing assistance to achieve a healthier weight. Overweight patients present with comorbidities such as hypertension, diabetes, and dyslipidemia which complicates the patient's quest to lose weight. Fortunately, many of the weight loss drugs demonstrated the ability to help improve these comorbidities in select clinical trials. Liraglutide was shown to improve blood pressure, fasting plasma glucose levels, HbA
1c and decrease the number of study participants with prediabetes.
6,7 Lorcaserin has shown improvements in HbA
1c and fasting blood glucose.
11-13 Naltrexone/bupropion was shown to improve triglycerides and HDL levels.
14-16Orlistat, discussed in part 1 of this series, has been seen to provide improvements in total cholesterol and HDL levels for most patients.
17-20 Phentermine/topiramate, which will be discussed in part 3 of this series, showed improvements in systolic and diastolic blood pressure, glycemic parameters, and lipid panels.
21-23 Additionally, the SEQUEL trial showed phentermine/topiramate decreased the number of medications needed to manage hypertension, dyslipidemia, and glycemic control while patients on placebo required more medications to manage these conditions.
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Regardless of the benefits of these drugs they are not without potential side effects. Comorbid conditions should be considered to decrease the potential for unwanted effects. For example, sympathomimetic amines would not be the drug of choice in patients at high risk for cardiovascular events. Of note, phentermine has not been shown to adversely affect blood pressure and heart rate, but more clinical observation is needed in this area.
24 In patients with higher baseline heart rates, it may be best to avoid the combination of phentermine/topiramate since its use has been linked to increases in heartrate of 20 beats per minute. Liraglutide may be a good choice for patients with diabetes, although not recommended to be used for glycemic control, since it has been shown to have favorable effects on HbA
1c and fasting blood glucose levels while providing weight loss.
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Patients on serotonergic drugs should possibly avoid lorcaserin due to the risk of serotonin syndrome. Physicians and other healthcare providers should do their due diligence in assessing the patient for potential disease state and drug contraindications.
Conclusion:
Comparison trials are needed to comprehensively evaluate the varying benefit of weight loss agents. Providers should evaluate the risk versus benefit of these medications when determining the best options for patients.
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