Obesity Pharmacotherapy

Donna H. Ryan

Rekha Kumar

CASE STUDY 1

A 44-year-old woman presents to her healthcare professional (HCP) for an annual wellness visit. She denies any new complaints, but her provider notes a 15 lb weight gain since the prior visit. She has a past medical history of depression, irritable bowel syndrome with diarrhea (IBS-D), and migraine headaches. Her medications are a low-dose combination oral contraceptive pill, sertraline 150 mg daily, and sumatriptan 50 mg as needed for migraines. Weight history is notable for successfully losing weight several times in the past through self-directed diet and exercise; however, she always regains the weight. She is very frustrated and does not understand why she is unable to maintain the weight loss. On examination, weight is 198 lb, height 5′6″, blood pressure (BP) 118/72, heart rate (HR) 86, body mass index (BMI) 32 kg/m², and waist circumference 99 cm. The remainder of her physical examination is unremarkable. Her laboratory data are notable for blood glucose 92 mg/dL, high-density lipoprotein (HDL) 35 mg/dL, low-density lipoprotein (LDL) 180 mg/dL, triglycerides 210 mg/dL, and thyroid-stimulating hormone (TSH) 1.2 µIL/mL.

Using Shared Decision-Making

Here is a sample conversation about introducing medications in the weight management conversation. The topics to be covered are mechanisms of action, potential efficacy, cost and reimbursement issues, and need for long-term therapy.

HCP: “You have been successful in losing weight in the past but like many patients, weight regain seems to be an issue.”
Patient: “Losing weight is the easy part! The hard part is keeping it off. I am frustrated and don’t want to live the rest of my life on a diet. I eat healthy food, but the weight comes back anyway.”
HCP: “You haven’t tried medications. Some of our newer medications have been extensively studied and are safe. Taking one can make it more likely that you will lose significant weight—5% or 10%, but importantly, as long as you take the medication, the more likely you are to sustain that hard-won weight loss. What is your initial reaction to taking a medication?”
Patient: “Aren’t medications cheating? I guess I want to hear more….”
HCP: “These medications don’t work on their own. They reinforce your body’s biology and help with hunger and fullness. There is one that doesn’t affect appetite, but helps you stay on a low-fat diet. If you are not making an effort with diet and increased physical activity, you will not get optimal results. I am going to give you a handout that describes the medications (See additional resources, below, for a handout, ‘Medications for Weight Loss’) and I want you to go home and do some internet research. The meds all have slightly different profiles. And you will need to check with your insurance company to see which ones you have coverage for. I will see you back, answer your questions and we can decide on the one that is right for you. When we choose one, we will need to monitor you monthly over the first 3 months to make sure it is working and to deal with side effects. How does this sound?”
Patient: “I have a friend at work who lost 40 pounds when her diabetes medications were changed, so I know medications can make a difference in weight. It sounds like a good plan to me. Can we meet in a month?”

The patient returned to the office in a month and expressed a preference for phentermine/topiramate because of her history of migraine headaches. She is started on phentermine/topiramate ER 3.75/23 mg daily and instructed to increase to 7.5/46 mg daily after 2 weeks. She schedules appointments with a registered dietitian nutritionist every 4 weeks between visits with her HCP. At the visit at 12 weeks, she is found to have lost 14 lb (7% of her total body weight).

CLINICAL SIGNIFICANCE

With nearly 40% of US adults having a BMI ≥30 kg/m², and unsuccessful following lifestyle modification changes alone, many of these individuals would benefit from intensifying therapy with an antiobesity medication (AOM)¹ to help them adhere to lifestyle changes in order to lose enough weight to achieve health benefits and to sustain weight loss. On the other hand, some medications promote unintentional weight gain and providers also need to avoid prescribing certain drugs which would worsen obesity.

Since 2012, four new medications have been approved by the US Food and Drug Administration (US FDA) with an indication for chronic weight management, although one was voluntarily withdrawn in February 2020. In addition, one capsule that is considered a device was marketed in 2020. Moreover, there are several companies with active obesity drug discovery programs and promising compounds in development that appear to produce twice the amount of weight loss achievable with current medications. Thus, we are entering a period where prescribers have access to safe and increasingly effective tools to help patients with complications of excess abnormal body fat to regularly achieve enough weight loss to prevent and control obesity-driven chronic diseases. This chapter will review current best practices and context regarding using medications for patients with obesity (including avoiding medications that promote weight gain), the safety and efficacy of currently available medications (both with a weight management indication and those commonly used “off-label” to aid weight management), and the most promising AOMs on the horizon.

INDICATIONS, RATIONALE, AND CONTEXT FOR OBESITY PHARMACOTHERAPY

In the National Institutes of Health (NIH)-supported Obesity Guidelines released in 2014,² obesity pharmacotherapy was allowed for individuals who are unresponsive to lifestyle interventions after 6 months of treatment, have a BMI of ≥30 kg/m², or a BMI of ≥27 kg/m² with a weight-induced comorbidity where weight-loss medication may be added to the treatment plan. At the time those recommendations were drafted, orlistat was the only medication available for obesity management. In 2015, the US Endocrine Society produced the first guidelines³ that recommended pharmacologic treatment of obesity. These evidence statements and recommendations were based on a systematic evidence review encompassing all available approved AOMs. This guidance was also notable for including recommendations for management of drug-induced weight gain.³ The Endocrine Society guidelines review the existing evidence for the FDA-approved medicines for weight management, and the recommendations contained in them are not just permissive of medication use (as in earlier guidelines), but also directive of medication use to help patients achieve weight loss in order to attain health benefits.³ Taking this a step further, the AACE/ACE Guidelines⁴ from 2016 indicate that initial pharmacotherapy added to lifestyle intervention is appropriate if patients present with one or more severe comorbidities and would benefit from weight loss of 10% or more.⁴,⁵

CLINICAL HIGHLIGHTS

The 2013 American Heart Association/American College of Cardiology/The Obesity Society (AHA/ACC/TOS) Guidelines for the Management of Overweight and Obesity in Adults² recommends that patients with obesity or overweight with cardiovascular risk factors should be counseled on diet, physical activity, and other lifestyle modifications. Unfortunately, behavioral interventions alone do not lead to sustained weight loss for many patients because adaptive physiologic responses reduce energy expenditure and increase appetite. Patients have measurable changes in resting metabolic rate, burn fewer calories with the same exercise, and have more hunger and cravings and reduced satiety at a lower weight. These phenomena, known as metabolic adaptation or adaptive thermogenesis, counteract weight loss and lead to weight regain.
Healthcare professionals should consider prescribing AOMs along with diet and physical activity to help patients achieve health goals through weight loss, especially when comorbidities are compromising health.³,⁴,⁵
The Endocrine Society’s systematic evidence review of common medications that promote weight gain and use of alternative approaches is a valuable resource; this knowledge base should be a standard of care for adult HCPs. Wherever possible, for patients with overweight and obesity, using medications that are weight neutral or associated with weight loss is advisable. See Table 8.1.
The rationale for using AOMs is to help achieve and sustain more weight loss that can be achieved with lifestyle intervention alone, thus benefitting the health of patients who need to lose weight for health reasons.
Prescribers need to be knowledgeable about ALL medications, because there is no one medication that works in every patient. If patients do not respond in the first 12 to 16 weeks with at least 4% to 5% weight loss, the drug should be discontinued, and another medication tried.
Obesity is a chronic disease. AOMs should be used long term, just like antihypertensive and lipid-lowering agents.

As shown in Table 8.1, there are currently four medications approved for chronic weight management by the US FDA in addition to phentermine and a few related compounds which are approved for short-term use. Although their abuse potential is low, some of these medications are scheduled by the US Drug Enforcement Agency and regulated by the states. Of note is the fact that three medications have been approved since 2012 and are approved for long-term use (reinforcing the concept that obesity is a chronic disease). The mechanism of action of FDA-approved AOMs is also shown in Table 8.1. These medications (except orlistat) work biologically to suppress appetite, affecting hunger, satiety, and response to highly rewarding foods, thus making it easier for patients to follow their dietary intentions to restrict caloric intake. The rationale for using medications to aid in weight loss and weight loss maintenance is based on an advanced understanding of the biologic regulation of body weight and food intake. Knowledge has emerged regarding the biologic basis of eating, e.g., the gut-brain axis of the homeostatic regulation of hunger and satiety, and of the reward circuitry that governs the response to foods of high hedonic value.⁶ Patients who struggle losing weight with lifestyle alone do not have weak “will power.” Rather, the biologic forces opposing weight loss are very powerful. Furthermore, once weight loss occurs, metabolic adaptations reduce metabolism, adding to the forces opposing weight loss and driving regain.

TABLE 8.1 Current Antiobesity Medications Approved in the United States and How They Work^a

AGENT	ACTION	APPROVAL	SCHEDULED DRUG
Phentermine	Sympathomimetic amine; norepinephrine release and to lesser extent releases other monoamines	Approved 1959	Yes
Orlistat	Pancreatic lipase inhibitor; blocks absorption of 30% of ingested dietary fat	Approved 1999 OTC Approved 2007	No
Phentermine/Topiramate ER	Sympathomimetic Anticonvulsant (GABA receptor modulator carbonic anhydrase inhibitor, glutamate antagonist)	Approved 2012	Yes
Naltrexone SR/Bupropion SR	Opioid receptor antagonist Dopamine/norepinephrine reuptake inhibitor	Approved 2014	No
Liraglutide 3.0 mg	GLP-1 receptor agonist	Approved 2014	No
GABA, gamma aminobutyric acid.
^aInformation from product labels of prescribing information, except where noted.

Even with our most intensive lifestyle interventions, some patients are unsuccessful at achieving adequate weight loss. In the “gold standard” Look AHEAD intensive lifestyle intervention, despite a minimum of 24 counseling sessions in the first year and the use of meal replacements, 30% of patients did not achieve 5% weight loss from baseline.⁷ Furthermore, weight regain occurred even though intervention continued through year 4. At that time, there was only 3.6% difference in weight between the intensive lifestyle intervention group and control.⁸ Clearly, HCPs cannot duplicate this degree of intensity of effort at the intervention deployed in Look
AHEAD. In primary care efforts at lifestyle intervention, average weight loss is on the order of 0.9 to 2.0 kg in 6 months.⁹ For the many patients who are unable to achieve and sustain weight loss with lifestyle intervention alone, AOMs are needed to help achieve enough weight loss to produce improved health benefits. Additionally, for patients with more severe complications of obesity, such as type 2 diabetes (T2D) or obstructive sleep apnea, weight loss of >10% is needed to maximize health benefits. Despite the limitations of lifestyle intervention for weight loss, high-intensity behavioral treatment of obesity (≥14 visits in the first 6 months, followed by at least monthly contact for maintenance of weight loss) is recommended as a standard of care for treatment of obesity and should produce a 5% to 10% weight loss during the first 6 months of treatment. Several randomized trials using different medications have reported that the combination of intensive behavioral treatment and pharmacotherapy is additive in terms of weight loss.

How much weight does a patient need to lose? Health benefits can be achieved without normalizing body weight or achieving a BMI <25 or <30 kg/m². One begins to see improvement in glycemic measures, triglycerides, and HDL-cholesterol with small amounts of weight loss (3% to 5%), but there appears to be a further dose response benefit with greater levels of weight loss.² Modest weight loss (5% to 10%) is also associated with improvement in systolic and diastolic blood pressure.2 There are graded improvements in measures of quality of life, depression, mobility, sexual dysfunction, and urinary stress incontinence that are demonstrable with modest weight loss (5% to 10%) and continue to improve with further weight loss.¹⁰ Additionally, for patients with higher BMI levels (≥40 kg/m²), the ability to lose the same proportion of weight with lifestyle intervention is equal to that of those with lower BMI levels, and there is equal benefit in terms of risk factor improvement with modest weight loss.¹⁰ For some comorbid conditions, more weight loss is needed, i.e., 10% to 15%, to translate into clinical improvement. This is observed for obstructive sleep apnea and nonalcoholic steatohepatitis.¹⁰

Lifestyle Counseling

All patients who have obesity or overweight and abnormal cardiovascular risk factors should be counseled on diet, physical activity, and other lifestyle modifications. Specifically, patients should be advised to pursue high-intensity lifestyle modification, as defined in the 2013 AHA/ACC/TOS guideline on management of obesity. The HCP should counsel patients that the combination of pharmacotherapy and intensive lifestyle modification nearly doubles weight loss, compared to either therapy alone.

Table 8.2 shows the proportion of patients who achieved 5% or 10% weight loss at 1 year in the clinical studies which were performed for FDA approval. All medications are included except phentermine. There are no long-term studies with phentermine, and its efficacy is discussed below. It should be noted that in all cases there is a greater proportion of medication-treated subjects who achieve the 5% and 10% benchmark, compared to placebo. Also noteworthy is the wide range of success that is achieved with placebo alone. This is because the components, delivery, and intensity of the lifestyle intervention varied between the studies.

In terms of context, the studies that led to the approval of AOMs were all conducted along with a lifestyle intervention of diet and physical activity counseling. In any study where the medication was stopped, weight regain was demonstrated. Therefore, the labels state they are “indicated as an adjunct to reduced calorie diet and increased physical activity for chronic weight management in adults.” As discussed later, the medication could be given after patients lose weight on a strict diet to produce more weight loss and advance maintenance. Furthermore, this chapter will later discuss the use of medications in the setting of bariatric procedures, where AOMs are used as an adjunct to the surgical procedure to treat insufficient weight loss or weight regain or to improve weight-related comorbidities.

BEST PRACTICES IN PRESCRIBING MEDICATIONS APPROVED FOR WEIGHT MANAGEMENT

Qualifications for Prescription

The FDA labels for AOMs provide the indications of BMI ≥30 kg/m² or BMI ≥27 kg/m² with a weight-related comorbidity. It is not necessary for patients to fail a weight loss attempt while under the care of an HCP for the patient to be prescribed a medication; the history of failure to maintain successful weight loss is enough. For patients with more severe complications (T2D, hypertension, and sleep apnea), practitioners should be more proactive about using medications and follow the AACE recommendations.⁴,⁵ Those patients would benefit from 10% or more loss and should be prescribed medications to augment the weight loss effort.

Choosing an Individual Medication

The Endocrine Society guideline³ indicates that contraindications and warnings should be the first step to match the patient to the medication profile, excluding medications from consideration if they are contraindicated or associated with serious warnings. See Table 8.3
for a description of contraindications and safety issues with AOMs. Choosing a medication requires matching the patient profile to the medication profile. If patients describe difficulty controlling their appetite, then common sense dictates that one of the medications that affect appetite should be chosen, rather than orlistat. Also, one should consider dual benefits: orlistat can enforce a low-fat diet and lower plasma LDL cholesterol.¹⁵ Liraglutide 3.0 mg can lower glycemic measures and, at a dose of 1.8 mg in patients with T2D, is associated with reduction in cardiovascular events in addition to affecting appetite and body weight.¹⁶ See Table 8.4 for a description of dual benefits of AOMs.

TABLE 8.2 Antiobesity Medications Approved in the United States: Dosing and Route of Administration; Efficacy (Proportion of Treated Individuals Who Achieve >5% and >10% During Phase 3 Clinical Trials)^a

DRUG, GENERIC NAME	DOSE AND ROUTE OF ADMINISTRATION	PROPORTION ACHIEVING >5% WEIGHT LOSS AT ONE YEAR^A	PROPORTION ACHIEVING >10% WEIGHT LOSS AT ONE YEAR^A
Phentermine	8 mg up to tid, before meals Or 15 mg, 30 mg, or 37.5 mg once daily	In a 6-month study¹¹ Phentermine 7 mg = 43.3% Phentermine 15 mg = 46.2% Placebo = 15.5%	Not described
Orlistat	120 mg tid, before meals Or 60 mg tid before meals Oral	In five studies, Orlistat = 35.5%-54.8% vs. Placebo = 16%-27.4%	In five studies, Orlistat = 16.4%-25.8% vs. Placebo = 3.8%-9.9%
Phentermine/Topiramate ER (Phen/TPM)	7.5 mg/46 mg qid 15 mg/92 mg qid, indicated as rescue Oral, once daily dosing (requires titration)	In two studies, Phen/TPM (3 doses) = 45% − 70%; vs. Placebo = 17% − 21% Difference from placebo = 27.6% − 49.4%	In two studies, Phen/TPM (3 doses) = 19% − 48%; vs. Placebo = 7% Difference from placebo = 11.4% − 40.3%
Naltrexone SR/Bupropion SR (NB)	32 mg/360 mg Oral; bid dosing (requires titration)	In three studies, NB = 44.2% − 62.3%; vs. Placebo = 17% − 43% Difference from placebo = 14% − 25%	In three studies, NB = 15% − 35%; vs. Placebo = 5% − 21% Difference from placebo = 10% − 14%
Liraglutide	3.0 mg Injection; once daily dosing (requires titration)	In two studies, Liraglutide = 62%¹² and 49%¹³; vs. Placebo = 34.4%¹² and 16.4%¹³ Difference from placebo = 32.6%¹⁴ and 22.6%¹²	In two studies, Liraglutide = 22.4%¹³ and 33.9%¹²; vs. Placebo = 5.5%¹³ and 15.4%¹² Difference from placebo = 16.9%¹² and 18.5%¹⁴
^aInformation from product labels of prescribing information, except where noted.