By: Emily Humphrey, PharmD; PGY1 Pharmacy ResidentMentor: Brandi Bowers, PharmD, BCACP; Clinical Assistant Professor, UMKC School of Pharmacy at MSU
Program Number: 2021-07-02Approved Dates: August 1, 2021 – February 1, 2022Approved Contact Hours: One Hour(s) (1) CE(s) per session
BackgroundObesity is a serious chronic disease affecting millions of people worldwide, and the prevalence of obesity continues to increase in the United States. This common condition has grown to epidemic proportions with 1.9 billion adults worldwide being overweight and 650 million obese in 2016.1 The global burden of obesity has continued to rise with over 4 million people dying each year as a result of being overweight or obese.1 Obesity and being overweight are major risk factors for several chronic disease such as cardiovascular disease, diabetes, musculoskeletal issues like osteoarthritis, and some cancers.1,2 Despite the growing risks and substantial burdens associated with obesity, less than five percent of eligible patients with obesity are treated with behavioral, pharmacological, or surgical interventions.3 With the advances over the last decade to improve the safety, efficacy, and availability of these modalities, now is the time to work towards reducing the obesity epidemic.4
Although anti-obesity agents can help patients achieve clinically significant weight loss, these medications are underutilized. This is may be due to providers not counseling on weight management, recommending lifestyle modifications alone, and the potential barriers to using these medications such as safety concerns, monitoring requirements, and cost.5,6 Understanding when it is appropriate to initiate weight loss medications, what medications are appropriate based on patient characteristics, and when medications should be discontinued is important to provide optimized patient care.
Patients that may benefit from weight loss should receive counseling on diet, exercise, and patient-specific goals for weight loss. The main focus for treatment of obesity should be to improve overall health of the patient by preventing or treating weight-related complications through weight loss versus focusing on weight loss alone.7 A weight loss of five to ten percent of baseline body weight within six months is a common initial weight loss goal, and weight loss of more than five percent is associated with numerous health benefits.8 In the Look AHEAD trial, patients with type II diabetes and body mass index (BMI) greater than 25 kg/m2 who participated in an intensive lifestyle intervention that aimed at and maintained a loss of at least seven percent body weight had more weight loss and improved glycemic control compared to standard of care.9 Patients achieving weight loss of at least ten percent within the first year had a reduced risk of fatal and nonfatal cardiovascular events at ten years.10 Setting SMART (Specific, Measurable, Achievable, Reasonable, and Time-bound) goals specifically related to behavior, dietary, and exercise changes will help patients achieve their overall weight loss goal of five percent.7,8 Weight loss can be extremely challenging for patients, especially if they are trying to manage implementing dietary, behavioral, and exercise changes all on their own. A multidisciplinary team approach involving physicians, pharmacists, registered dietitians, exercise specialists, and behavioral specialists can provide the patient with the support they need to achieve and maintain weight loss.11
TreatmentNonpharmacologicalSuccessful weight management requires realistic and sustainable treatment strategies. Lifestyle management should incorporate three key components: physical activity, meal plan, and behavior.7 The recommended amount of physical activity is 150 minutes of moderate intensity exercise per week which can decrease risk of all-cause mortality by 33% compared to no physical activity.12 Most Americans do not get enough physical activity, and reaching 150 minutes of moderate intensity activity starting out would be unrealistic goal for most patients. Exercise specialists as part of the multidisciplinary team can educate patients on practical ways to integrate physical activity into their day-to-day life.11 Patients should be encouraged to make small, manageable changes in physical activity that will be sustainable as they gradually increase activity as they are able to achieve at least 150 minutes of physical activity per week.
The goal of meal planning or dietary therapy is to reduce the total number of calories consumed. An average calorie deficit of 500 to 700 calories per day will result in approximately 0.5 kg/week weight loss initially.7 With the vast array of diet types and fad diets available, it can be difficult to choose a sustainable option. Conventional diets include balanced low-calorie diets, low-calorie versions of healthy diets (Mediterranean and Dietary Approaches to Stop Hypertension [DASH] diets), low-fat diets, low-carbohydrate and low glycemic index diets, high-protein diets, and very low-calorie diets. No single diet type fits all patients, and a variety of dietary interventions can help reduce calorie intake and promote weight loss. In a meta-analysis of 48 randomized clinical trials that compared different dietary programs with a comparator (no diet or competing dietary program), all diet programs showed significant weight loss (6 to 8 kg by six months) compared with no diet.13 This is why having a registered dietitian (RD) as part of the multidisciplinary team is so important. The RD can help patients determine which diet will best fit their needs and help the patient make simple, effective strategies to improve their diet and decrease overall caloric intake.11
PharmacologicalLifestyle interventions may not be enough for all patients. For patients who have already committed to lifestyle modifications but are still not achieving clinically meaningful weight loss of at least five percent at three to six months, it is appropriate to initiate anti-obesity medications in patients with BMI > 30 kg/m3 or BMI > 27 kg/m3 and a weight-related comorbidity such as diabetes, hypertension, hyperlipidemia, heart failure, cholelithiasis, osteoarthritis, gastroesophageal reflux disease, or obstructive sleep apnea.7 Medications currently approved for weight loss include phentermine and other sympathomimetics, orlistat, liraglutide, phentermine-topiramate, and bupropion-naltrexone. Sympathomimetic drugs should only be used for short-term management, while all other medications can be continued for chronic treatment. Lorcaserin (Belviq®) was previously recommended for long-term weight loss management but was removed from the market in early 2020 due to clinical trial data showing an increased occurrence of cancer.14
The sympathomimetic drugs (phentermine, diethylpropion, benzphetamine, and phendimetrazine) are only approved by the FDA for short-term use for up to 12 weeks in treatment of obesity due to their potential side effects and their high risk for abuse. These medications work for weight loss by stimulating the release of norepinephrine from the hypothalamus to reduce appetite. Although it is only approved for short-term use, phentermine is the most commonly prescribed weight loss medication in the US.15 Phentermine was originally approved in 1959 for short-term use for weight loss, and only one clinical trial from that period is available. This trial showed that phentermine given continuously or intermittently achieved greater weight loss than placebo (12.2 kg vs 4.8 kg).16 Though efficacious at reducing weight with short-term use, sympathomimetic drugs have several safety concerns with their use. Common side effects include increased heart rate and blood pressure, insomnia, and nervousness.7 Due to their effect on cardiovascular system, these medications are contraindicated in patients with cardiovascular disease (e.g., arrhythmias, heart failure, coronary artery disease, stroke, uncontrolled hypertension).7 Other contraindications include hyperthyroidism, glaucoma, history of drug abuse, and pregnancy.7
Orlistat is available via prescription (Xenical®) and at a lower dose over-the-counter (Alli®). Orlistat works by altering fat digestion through inhibition of pancreatic enzymes, thus inhibiting absorption of dietary fats by 30%. Due to its mechanism of action, orlistat should be taken during or up to one hour after each main meal containing fat and separated by at least two hours from multivitamins containing fat-soluble vitamins. When added to lifestyle intervention, orlistat helps patients achieve clinically significant weight loss of up to 10% of baseline body weight, maintain weight loss, and prevent weight regain. The XENDOS study was one of the longest trials evaluating the efficacy of orlistat. It showed significantly greater weight loss with orlistat versus lifestyle changes alone (5.8 kg vs 3 kg, p<0.001) and a lower cumulative incidence of diabetes with orlistat compared to lifestyle changes alone (6.2% vs 9%, p=0.0032) after four years.17 Contraindications associated with orlistat include pregnancy, chronic malabsorption syndrome, and cholestasis.18 Most common side effects associated with orlistat are gastrointestinal in nature, including cramps, flatus, fecal incontinence, anal leakage, oily spotting, and flatus with discharge.18 These side effects can be minimized by avoiding high-fat diets and following the recommended intake of no more than 30% total daily calories from fat.18
Liraglutide (Saxenda®) is a glucagon-like peptide-1 (GLP-1) agonist FDA-approved for weight loss and at a lower dose (max 1.8 mg daily) for treatment of diabetes under the brand name Victoza®. GLP-1 is an incretin hormone that increases glucose-dependent insulin secretion, decreases inappropriate glucagon secretion, slows gastric emptying, and decreases food intake. The efficacy of liraglutide for weight loss has been studied in patients with and without diabetes. In the SCALE trial, patients treated with 3 mg dose of liraglutide in combination with diet and exercise, achieved mean weight loss of 8.4 kg compared to 2.8 kg with diet and exercise alone (95% CI, -6 to -5.1; p<0.001).19 The SCALE-DM trial showed that overweight and obese participants with type II diabetes achieved greater weight loss with 3 mg dose of liraglutide compared to 1.8 mg dose and placebo over 56 weeks of treatment (6% vs 4.7% vs 2%, p<0.001).20 Contraindications associated with liraglutide include pregnancy, family or personal history of medullary thyroid cancer, or multiple endocrine neoplasia 2A or 2B. Acute pancreatitis has been observed with liraglutide in clinical trials and post-marketing reports; if pancreatitis is suspected, stop liraglutide and do not restart if pancreatitis is confirmed.21 Most common side effects include nausea, vomiting, diarrhea, and early satiety. Liraglutide is administered as a daily subcutaneous injection and should be titrated on a weekly basis or as tolerated from starting dose of 0.6 mg to a max of 3 mg for weight management.21
Phentermine-topiramate extended release (Qsymia®) combines the weight loss effects of a sympathomimetic agent with topiramate, which helps with weight loss by causing appetite suppression and enhancing satiety. The CONQUER study showed that the combination of phentermine-topiramate was efficacious in achieving clinically significant weight loss after 56 weeks at doses of phentermine/topiramate 15 mg/92 mg and 7.5 mg/46 mg compared to lifestyle interventions alone (-10.2 kg vs -8.1 kg vs -1.4 kg, p<0.0001).22 The SEQUEL study was an extension trial to CONQUER and showed sustained weight loss over 108 weeks with both doses of phentermine-topiramate compared to placebo, with the 15 mg/92 mg dose achieving greater weight loss than the 7.5 mg/46 mg dose (-10.5% vs -9.3% vs placebo -1.8%, p<0.0001).23 Additional side effects associated with topiramate in the combination product include cognitive dysfunction, dry mouth, paresthesia, and dysgeusia.24 Phentermine-topiramate is only available through a REMS program due to increased risk of fetal harm, specifically, risk of causing orofacial clefts in infants exposed to the combination drug during first trimester of pregnancy.25 While all anti-obesity medications are contraindicated in pregnancy, extra caution should be taken due to the risk for fetal harm with this medication. All women of reproductive potential should take a pregnancy test prior to starting the medication and monthly while on it and should use a reliable form of contraception.25
Bupropion-naltrexone extended release (Contrave®) is a combination product containing two drugs FDA-approved for other indications. The exact mechanism of the combination bupropion-naltrexone for weight loss is not fully understood but is thought to result from effect on areas of the brain involved in regulating food intake. The COR-I trial demonstrated efficacy of bupropion-naltrexone for weight loss management with average weight loss of 5% versus 1.3% with lifestyle intervention alone (p<0.0001).26 The most common side effects associated with bupropion-naltrexone are nausea, headache, and constipation. Other side effects include insomnia, vomiting, dizziness, and dry mouth.27 Bupropion-naltrexone carries a Black Box Warning due to the increased risk of suicidal thoughts and behavior in young adults (18 – 24 years old) associated with antidepressants such as bupropion.27 Bupropion-naltrexone is contraindicated in patients with uncontrolled hypertension, on chronic opioids/opiate agonists/partial agonists, prescribed other bupropion containing products, with a history of seizures or seizure disorders, with eating disorders, and with severe hepatic dysfunction.27 Bupropion-naltrexone should be used with caution in patients with cardiovascular disease as it can cause increase in blood pressure and heart rate and the cardiovascular safety outcomes associated with bupropion-naltrexone have not been established.27
All anti-obesity medications are efficacious in facilitating weight loss in combination with lifestyle interventions. Choice of anti-obesity drug should be based upon patient-specific comorbidities, presence of contraindications to medications, and side effects of the medications. Table 1 summarizes the information described above. Table 2 lists preferred weight loss medications based on clinical characteristics and comorbidities. Patients should be involved in the decision-making process. Thorough education and counseling about the medications available and safety concerns associated with each is necessary so patients can make an informed decision as to which agent is best for them.
The benefits of anti-obesity medications are typically lost when the treatment is discontinued. The efficacy and safety of the anti-obesity medications should be assessed at least monthly for the first three months of treatment and frequently reassessed thereafter. Efficacy and tolerability of anti-obesity medications can vary from patient to patient. In general, if a patient’s response to a weight-loss medication is < 5% weight loss after three months on a maximal dose of the medication or if the patient experiences significant adverse effects to the medication, the risk-to-benefit ratio should be reassessed and discontinuation of the medication should be considered.8 The exception to this rule is the lower dose of phentermine-topiramate. If a patient is on 7.5 mg/46 mg dose of phentermine-topiramate and has not lost at least 3% of their baseline body weight after 12 weeks, either discontinue or continue titration schedule to maximum dose of 15 mg/92 mg once daily.24 If using the maximum dose of 15 mg/92 mg daily of phentermine-topiramate and patient has not lost at least 5% after 12 weeks, then gradually discontinue therapy.24
SurgicalAnother option to manage obesity is bariatric surgery. Patients considered candidates for bariatric surgery include adults with a BMI >40 kg/m2, or a BMI of 35 to 39.9 kg/m2 with at least one serious comorbidity such as type 2 diabetes mellitus, poorly controlled hypertension, obstructive sleep apnea, osteoarthritis and nonalcoholic fatty liver disease.7,29 Bariatric surgery encompasses several surgical interventions and depending on the method used, patients can achieve weight loss ranging from 20 to 45 percent at 12 to 18 months post-procedure.29 Although not required, patients usually attempt lifestyle interventions with or without pharmacological agents before bariatric surgery is considered. It is important, however, that prior to bariatric surgery patients are be evaluated on their ability to incorporate nutritional and behavioral changes to ensure patients will be able to maintain weight management long-term after surgical intervention.29
A Look to the Future:With the growing need for aid in combating the obesity epidemic, drug manufacturers have been looking for new and safer options for managing weight loss. Since the publication of the 2016 AACE/ACE and 2013 AHA/ACC/TOS guidelines two prospective agents have surfaced for weight loss management: cellulose and citric acid hydrogeland semaglutide.
Cellulose and citric acid hydrogel, brand name Plenity®, is an FDA approved medical device for weight management in adults with a BMI of 25 to 40 kg/m2. It is currently only available through a telehealth consult on the drug manufacturer website, but it should be widely available by the end of 2021.30 Plenity® works by forming a three-dimensional matrix that occupies volume in the stomach and small intestine, creating a sensation of fullness and increased satiety.31 Unlike many of the other weight-loss agents available, Plenity® is very well tolerated with minimal side effects, making it an intriguing treatment option for most patients. Most common side effects associated with its use include gastrointestinal effects such as diarrhea, abdominal distention, flatulence, and abdominal pain. It has also shown to be an effective treatment option for a wider range of patients with weight loss of at least five percent in most patients with a BMI from 25 to 40 kg/m2 in conjunction with diet and exercise. This is unique to Plenity®, as the other anti-obesity agents currently on the market are only approved for weight loss for patients with a BMI of at least 27 kg/m2. The GLOW trial not only showed a greater average weight loss over lifestyle intervention alone, but it also demonstrated that patients treated with Plenity® have twice the odds of achieving at least 5% and 10% weight loss compared to lifestyle intervention alone.32 Plenity® is administered as three capsules twice a day with 16 ounces of water 20 minutes before lunch and dinner to work effectively.31
Semaglutide is another GLP-1 agonist, similar to liraglutide, that is currently FDA- approved for treatment of type II diabetes. While not currently FDA-approved for weight loss management, recent data has shown that it may be an effective treatment option weight loss in patients with and without diabetes. The STEP 1 trial showed average weight loss of 15.3 kg with semaglutide 2.4 mg given via subcutaneous injection once weekly compared to 2.6 kg with lifestyle interventions alone (estimated difference -12.7 kg; 95% CI, -13.7 to -11.7).33 In the STEP 4 trial, patients who continued on semaglutide 2.4 mg once weekly after a 20 week run-in period continued to sustain weight loss of 7.9% 48 weeks later whereas the patients who stopped semaglutide after 20 week run-in period saw an increase in weight of 6.9% at 48 weeks (difference -14.8% [95% CI, -16% to -13.5%]; p<0.001).34 Like liraglutide, the most common side effects associated with semaglutide are gastrointestinal in nature, it should be discontinued if pancreatitis is suspected, and it should not be used in patients that are pregnant or have a family or personal history of medullary thyroid cancer or multiple endocrine neoplasia 2A or 2B.
With the prospects of cellulose and citric acid hydrogeland semagultide being widely available on the market soon for weight loss, managing obesity is becoming safer and more reliable. This area is continuing to grow with numerous clinical studies for weight loss management underway investigating new medications such as tirzepatide and setmelanotide to name a few.35
Conclusion:Obesity is a chronic condition affecting millions of people. With obesity being a major risk factor for several chronic disease states such as cardiovascular disease and type II diabetes, it is ever more important to start managing obesity appropriately. Anti-obesity medications can have a benefit in increasing weight loss when added to lifestyle modifications, but these medications are often underutilized. Pharmacist involvement within the multidisciplinary approach to weight loss can improve the appropriate use of anti-obesity medications in combination with lifestyle interventions to provide additional weight loss benefits. Understanding which medications can be used for weight loss management, when it is appropriate to start, efficacy of these medications, and the safety concerns associated with their use can help optimize utilization of these agents in combating the obesity epidemic.
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