Clearly, diet, exercise, and behavior modification are integral parts of weight loss therapy, rather than options. Recently multiple medications have been approved with indications for “chronic weight management” and these have emerged as truly novel new approaches. However, these weight loss medications are options with significant benefits, as well as known risks. This article will focus on the safety and tolerability profiles of the existing medications and how best to manage them clinically. These medications are listed in Table 1, along with the mechanisms of action, dosing recommendations, and response evaluation recommendations (1-5). Table 2 describes the safety, contraindications and tolerability (1-5). All physicians are aware of the troubled history of using medications for weight management; the historical perspective of these agents ranges from discovery of abuse potential with amphetamines, to identification of valvulopathy with fenfluramine and dexfenfluramine, and most recently, removal of sibutramine because of increased risk of cardiovascular events in those with pre-existing heart disease. Also, it is an unfortunate fact that some physicians do not practice appropriate prescribing, which is a concern of state medical boards. Therefore, it behooves all prescribers to be educated into the product labels and potential risks and adverse effects before prescribing. In this article, we will use product labels (1-5) as an authoritative source of information for prescribers. In the United States, the Food and Drug Administration (FDA) has approved medications (1-5) for “chronic weight management,” indicating that obesity is a chronic disease and should be treated like other chronic diseases. The FDA intends for these medications to be used not for cosmetic weight reduction, but for health improvement, so they are indicated for patients with a body mass index (BMI) of 30 kg/m2 or greater (obese) or 27 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbidity, such as hypertension, type 2 diabetes mellitus, or dyslipidemia. The message here relates to identifying those with higher health risks, as well as potential legal issues. All of the current weight loss medications were studied in patients who met these BMI criteria. The medications were not studied for safety or efficacy in patients with lower BMIs. Therefore, health care providers should not give these medications to patients with BMIs lower than the recommended threshholds. Unfortunately, we do not have additional guidance for ethnicities, such as Asians and Hispanic Americans, who may be at higher risk at lower BMI levels. However, prescribers are reminded that departing from the product label can create problems and prescribing weight loss medications to persons with a BMI below these levels is considered a “departure from the Standard of Care.” The newer weight loss medications all have labeling language (1-5) that clearly indicates that the effect of these medications on reduction in cardiovascular morbidity and mortality is unproven. The labels all warn that there are no studies of combinations of these agents with other weight loss medications or products. Thus the prescriber is warned of risks associated with prescribing a particular weight loss medication with other weight loss medications, including prescription and over-the-counter drugs and herbal preparations. There are simply no established data to support this practice and it should not be done. It has become the practice for the FDA to include recommendations for stopping medications for chronic weight management if they are ineffective after a certain time period. This approach is certainly foundational to good medical practice; for example, physicians would not prescribe a diabetes medication if it showed no evidence for efficacy. These recommendations are described in Table 1 (1-5). Table 2 discusses and summarizes the contraindications, safety, and tolerability issues for the medications approved for chronic weight management (1-5). Orlistat is a pancreatic lipase inhibitor that will block the absorption of about 30% of ingested fat, and is contraindicated in individuals with malabsorption (1). The label also notes that >2% of patients treated with orlistat developed gall bladder disease, so this is also a contraindication. Orlistat can impair absorption of cyclosporine and there are rare reports of liver failure with this medication. Orlistat is remarkable for its safety profile and the most important thing for prescribers to remember is to prescribe it with a multivitamin taken seperately, because absorption of fat soluble vitamins can be impaired. Lorcaserin has the best safety and tolerability profile of currently available medications, but some aspects of its safety profile deserve discussion (2). First, the medication contains a warning about “serotonin syndrome or neuroleptic malignant syndrome-like reactions.” While these adverse effects were not reported in the Phase 3 studies of lorcaserin, they are a theoretical possibility. Co-administration of lorcaserin with other serotonergic or antidopaminergic agents has not been studied. Many reported cases of serotonin syndrome are associated with giving two serotonergic agents together. Thus, the package insert states “use with extreme caution in combination with other drugs that may affect the serotonergic neurotransmitter systems.” The label for lorcaserin also carries a warning about valvular heart disease. Although there was no significant risk of valvulopathy in the echocardiogram studies during Phase III evaluation, there were not sufficient numbers to exclude the possibility. Lorcaserin is a specific agonist for the 5HT 2C receptors and has little affinity for other receptors. The 5HT 2B receptor has been implicated in valvulopathy. Therefore, it is not recommended that patients starting lorcaserin have echocardiograms. The lorcaserin label also discusses hypoglycemia. This is a common element in all medications approved for chronic weight management because when diabetic individuals lose weight, the sensitivity to insulin increases and those on insulin or insulin secretagogues, such as sulfonylureas, may develop hypoglycemia. To decrease this risk in a patient who is a well-controlled diabetic, one should lower the dose of insulin or sulfonylurea when starting a weight loss program. Of course, all weight loss medications are contraindicated in pregnancy and lorcaserin is no exception. In fact, any weight loss is contraindicated in pregnancy. That this medication is fairly well tolerated is evidenced by the rate of patients discontinuing lorcaserin due to adverse events. In the group receiving placebo, 6.7% of the patients stopped early due to “adverse events,” compared to 8.6% of patients in the lorcaserin group. This is a very low rate and very similar to the placebo group. The label of the combination phentermine and topiramate extended-release (ER) carries information from earlier labels of each drug, especially for topiramate, which has been used for epilepsy and for migraine prophylaxis (3). The fact that this agent includes 2 medications in one pill means the prescriber must deal with the risks of each agent. Topiramate has known teratogenicity effects on the fetus of pregnant women. Thus the medication comes with a REMS (Risk Evaluation Mitigation Strategy), a way to ensure that safeguards are put into place to educate the patient, the physician, and the pharmacist about risks and to inform the female patient not to get pregnant while taking this medication. If the patient were to get pregnant, then the drug should be stopped immediately. Before starting the medications, it is recommend that the patient have a pregnancy test, followed by monthly tests while on the medication. The other risks and adverse effects associated with topiramate are dose-dependent. Using a lower dose and dose titration helps minimize risks and adverse effects. See Table 1 for dose escalation recommendations. In the case of topiramate, which is associated with cognitive dysfunction at higher doses, slow dose escalation can minimize adverse effects. The starting dose is 3.75 mg/23 mg (phentermine 3.75 mg/topiramate 23 mg extended-release) and after 14 days it is increased to 7.5 mg/46 mg once daily. There are higher doses, but if one looks at the overall weight loss at the end of 2 years, the weight loss is very similar for the recommended dose of 7.5 mg/46 mg versus the highest dose of 15 mg/92 mg. This idea of using the lowest dose possible extends to the beginning titrations dose of 3.75 mg/23 mg. The package insert includes data on this lower dose and average weight loss was sufficient to meet FDA approval as a weight loss agent. As skilled clinicians know, patients are not all “average.” Thus, individuals can be responsive to this lower dose (3.75 mg/23 mg) and achieve beneficial weight loss with a much lower chance of adverse effects. Prescribers should not be afraid to titrate back down to this lower dose or simply stay at this lower dose. Topiramate is associated with metabolic acidosis at higher dose levels. For this reason, the label recommends blood chemistry evaluations when starting this medication. Similarly, it should be used with caution in persons who have a history of kidney stones. Topiramate is a carbonic anhydrase inhibitor and can cause altered taste sensation with carbonated beverages and is associated with perioral paresthesias. There is a rare idiosyncratic reaction with topiramate that causes acute glaucoma, and if this occurs the drug should be stopped immediately. The phentermine component of this medication is a sympathomimetic agent and can increase heart rate and blood pressure, especially at higher doses. For this reason this author cannot recommend usage in patients with pre-existing cardiovascular disease. This medication should not be used within 14 days of monoamine oxidase inhibitor (MAOI) use. Naltrexone SR/bupropion SR is another combination of 2 medications in one pill: 32 mg naltrexone and 90 mg bupropion (4). Thus aspects of each component need to be discussed. Naltrexone is an opioid antagonist and patients who require opioids for pain management should stop naltrexone in advance. Every antidepressant in the United States comes with a black box warning about suicidal thoughts and behaviors. Bupropion has been used for depression and smoking cessation and thus carries this warning. However, there was no evidence of suicidality in the Phase 3 studies for chronic weight management. The risk of seeing an increase of suicidal thoughts in patients starting an anti-depressant is only seen in patients 24 years of age or under. Bupropion also lowers seizure threshold. In the naltrexone/bupropion trials seizures occurred at a rate of about 1 per 1000. Obviously patients with a history of seizures are contraindicated for this medication, but there are a few situations where there is a known increased risk that may not be obvious. Patients that have an eating disorder and are actively purging are at increased risk for seizures. Similarly, those withdrawing from alcohol or drug abuse may be at increased risk for seizures. Bupropion is a mild uptake inhibitor of norepinephrine and dopamine and thus can increase pulse and blood pressure, especially early in the course of therapy. This drug should not be given to those with uncontrolled hypertension. In the Phase 3 trials, systolic blood pressure from 140 to 145 mm Hg was acceptable for inclusion in the study. The maximally acceptable diastolic blood pressure was from 90 to 95 mm Hg. Patients with blood pressures above these levels were not allowed to participate in the clinical trials. These threshholds can easily be applied to clinical practice. The other aspect of managing this risk is to check blood pressure regularly. In the clinical trials the most significant changes in blood pressure were noted in the first 3 months. Having the patient come back for regular monthly blood pressure checks is very reasonable; alternatively have the patient become involved in their own care and check at home. Bupropion is metabolized by the CYP2B6 pathway and drugs that compete for this pathway (ticlopidine or clopidogrel) will raise the level of bupropion. Thus, patients on these medications should reduce the dose of naltrexone/bupropion to one pill BID. The CYP2D6 pathway is inhibited by bupropion, so clinicians should also consider decreasing the dose of anti-depressants, antipsychotics, beta blockers, and Type 1C antiarrhythmic agents if naltrexone/bupropion is started. Most prescribers will find the tolerability of naltrexone/bupropion challenging. Nausea and vomiting are the chief adverse effects (due to naltrexone). However, because high-fat meals can increase the absorption of naltrexone/bupropion, a useful strategy is to encourage patients to take the medication with a high carbohydrate meal to slow absorption. Another useful strategy is to slow the dose titration (see Table 1). The good news is that nausea is a tolerability issue and less of a safety issue. In the vast majority of patients this adverse effect goes away with time. Patients can be advised to back titrate to a lower dose if they experience significant difficulty. Liraglutide is a GLP-1 receptor analog with 97% homology to native GLP-1 and is marketed for type 2 diabetes management at doses up to 1.5 mg. The medication is given by subcutaneous injection. The black box warning of risk of thyroid C-cell tumors that is in place for liraglutide when used for diabetes has carried over to the label for the weight management indication. Liraglutide causes C-cell tumors in rodents, although this effect in humans is unproven. Still prudence calls for contraindication of liraglutide in patients with a personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia. And of course the drug is contraindicated in pregnancy or if patients have hypersensitivity. There were increased rates of mild or moderate pancreatitis in the obesity clinical trials and if acute pancreatitis is suspected, the drug should be stopped and the symptoms investigated. There were also increased reports of cholecystitis and cholelithiasis during Phase 3 studies, but whether related to weight loss or drug is uncertain. If patients develop symptoms, gallbladder studies are indicated. Patients on insulin secretagogues had increased incidence of serious hypoglycemia in the weight loss studies. This is a well known complication of negative energy balance and weight loss in patients taking insulin or insulin secretagogues. Therefore, prescribers should consider reducing these medications before the weight loss effort with liraglutide 3.0 mg and the medication is not recommended in patients taking insulin. Post marketing reports of renal dysfuntion when liraglutide 3.0 mg has been used in type 2 diabetes mandates caution of use of this drug in patients with renal impairment. Liraglutide is associated with mean increases in heart rate of about 2 to 3 beats per minute in the clinical studies (but not blood pressure). In obesity clinical trials, 6 (0.2%) of 3384 Liraglutide 3.0 mg-treated patients and none of the 1941 placebo-treated patients reported suicidal ideation and prescribers should be aware of this caution. The final safety issue is hypersensitivity and prescribers should be aware that there are rare reports of serious reactions to this protein given by injection. In terms of drug interactions, the chief concern is the delay in gastric emptying associated with GLP-1 analogs which can delay the absorption of oral medications. The chief tolerability issues with liraglutide 3.0 mg are gastrointenstinal issues. In the weight management studies, nausea was reported by 39% of liraglutide-treated patients and 14% of those on placebo. Other drug-associated gastrointestinal side effects, albeit less prevalent were vomiting, diarrhea, constipation, dyspepsia and abdominal pain. The slow dose titration is the best way to manage these side effects and it should be noted that while 39% of obesity trial participants on liraglutide reported nausea, the discontinuation rates for gastrointestinal side effects were low, including for nausea (2.9% versus 0.2% for Saxenda® and placebo, respectively), vomiting (1.7% versus <.1%), and diarrhea (1.4% versus 0%). The dose titration recommendations are to begin at 0.6 mg and to increase weekly by 0.6 mg, until 3.0 mg dose in reached by week 5. In 2014 we have 4 new weight loss medications and one older medication with very different mechanisms of action – all approved for chronic weight management. Each medication has its own unique risk profile that makes patient selection important. Knowledge of the contraindications and safety issues can guide physicians to the most appropriate choice for a particular patient. Obesity medicine is entering a new era where our available options for prescribing have been very well studied. There should be no surprises, because bupropion, naltrexone, phentermine, topiramate and liraglutide have been prescribed for many years in millions of patients and lorcaserin has high specificity for a single receptor subtype. The FDA demanded very detailed risk-oriented studies to have these medications approved. In addition, the FDA has established REMS programs or risk management strategies to help ensure that the patients do not receive inapppropriate medications. These medications were approved by the US FDA after very thorough testing. The decision to approve these medications was based on the benefits out-weighing the risks. Thus, if following the appropriate guidelines according to package labels, the practitioner can feel safe in prescribing these medications.
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Ken Fujioka (2015) studied this question.