Guide to Weight Management Medications

Preface: This paper is intended to be a practical guide to clinically useful prescription weight management medications in current use for bariatric practitioners and is not meant to be an academic review of all pharmaceutical agents used in weight management in the past, present or in the future. For a more academic discussion, one should consult Handbook of Obesity, Clinical Applications, in chapters 12 through 17. 1-6

“Off-label” Medication Use:

Many physicians are intimidated by the fact that much of what is good practice in the pharmacotherapy of obesity requires “off-label” use of the drugs. “Off label” use means any use which deviates in any way from the package insert and PDR entry both of which must be approved by the FDA when the drug is initially placed on the market. For example, any medication use in which the medication is used for an “indication” other than the ones which are listed in the Physicians’ Desk Reference is an “off-label” use. Use of dosages in excess of the doses recommended in the PDR is also “off-label,” as is usage of medications for durations longer than the PDR suggests is “off-label.” For those physicians who are hesitant to use medications in an “off-label” manner, I offer the following comments. For the majority of the drugs included in the PDR, no duration of treatment is suggested. The duration of use of a medication in any patient is a matter of clinical judgment in each individual case. It is self-evident that putting time limits on use of medications used in treating a chronic illness is inappropriate if the risk of taking the medication is less than the risk of leaving the illness untreated. In the case of chronic diseases, the FDA does not presume they must tell an endocrinologist how long he may use insulin in a diabetic, or how long an allergist may use an antihistaminic in a patient with allergies, or how long a cardiologist may use an anti-hypertensive in a patient with hypertension, or how long a gynecologist may use a medication for a patient with endometriosis, etc. Even more pertinent are the statements regarding long term use of drugs used in treating Attention Deficit Disorders in children. The 2011 PDR entry for Concerta, a newer methylphenidate, states “The effectiveness of Concerta for long-term use, i.e., for more than 7 weeks, has not been systematically evaluated in controlled trials. The physician who elects to use Concerta for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.” The PDR entry (2011 edition) for Dexedrine, (GlaxoSmithKline’s dexamphetamine) does not discuss duration of therapy except to state “When possible, drug administration should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued therapy.” The 2009 PDR entry for Adderall, another dextroamphetamine, has similar language. These are category II drugs! Obviously the FDA holds obesity drugs to an entirely different standard, a standard which some obesity experts feel is unrealistic. In fact, the PDR does not address limiting duration of medication usage for any chronic illnesses except for obesity. Each of the chronic conditions in the foregoing paragraph has known and finite risks and the risk of treatment with the medication is considered to be less than the risk of leaving the condition untreated – so continued use of the medication in question is considered an acceptable risk. However, the FDA obviously considers obesity to be free of risk because the FDA appears to deem any level of risk due to pharmacologic obesity therapy unacceptable. Universal clinical experience and hundreds of papers in the medical literature are available to confirm that

pharmacologic therapy for obesity carries acceptable risk which is lower than the risk of remaining obese or overweight. In order to comprehend what the FDA means by “off label” use, one must also understand the FDA process in considering new drugs for approval. When a pharmaceutical company finds a compound which holds promise as drug, the company first does preclinical research on animals. The FDA is not involved at this stage. Having favorable animal data in hand, the manufacturer must submit a detailed application to the FDA to begin human testing in the form of clinical trials. The FDA rigidly controls human testing and insists that each and every detail of the testing plan meet their approval. The pharmaceutical company must submit detailed progress reports to the FDA at specified intervals. Phase 1 clinical trials address the issue of safety of the drug in humans. If the FDA is satisfied with the data on safety, then the company is allowed to submit a plan for phase 2 clinical trials which address both effectiveness and dosage. If the drug passes phase 2 trials successfully, the company will apply to move on to phase 3 trials which are large scale, multiple center, randomized, double-blinded human trials to determine safety, dosage, and effectiveness. The process is lengthy and expensive unless the drug has been placed on a fast track for approval. Typically by the time phase 3 trials are completed 10 years have passed from the time of initial application for human trials and the applicant company has spent $ 1.6 to $ 2 billion. By the time phase 3 trials are over the answers to a number of questions about the new drug are evident. Efficacy, safety, dosage ranges, contraindications, and side-effects and how to use the new drug in general are pretty well known. Much of the information spreads by word of mouth or ends up in the medical literature along the way so that interested physicians may be very familiar with the characteristics of the new drug well before it ever gets to the market. Finally, after the drug company has digested all the voluminous information generated in this process, the company will apply to the FDA for “marketing approval.” This is the beginning of a whole new process in which the FDA reviews again the medical evidence, decides first whether the drug is medically useful and safe, and then decides whether the company can actually manufacture, market, and sell the new drug in the U.S. As a part of the application the company must identify which “indications” it is asking approval for. “Indications” meaning the medical conditions for which the new drug is intended. If the FDA agrees that the new drug is useful and safe it will grant “marketing approval” for the release of the drug to be used for the “indication” applied for. The printed drug package insert or “label,” and what is printed in the PDR will include the “indication.” Once the drug is in use, physicians often discover beneficial effects in illnesses or situations other than the ones for which the drug was originally intended. As continued clinical experience with the new drug accumulates, the clinical use of the drug will often drift from what is specified in the PDR. Although this information will appear in the medical literature and be accepted into standard therapy, it will never appear on the “label” unless the drug manufacturer applies to the FDA for permission to include it. The history of medicine and medical progress is replete with examples; a recent example is the discovery that topiramate, originally “approved” for marketing as a drug for treating epilepsy, is very useful for both pain management and weight management in certain clinical settings. Use of any drug for a purpose other than for which it originally received “marketing approval” is “off label.” Viewed in this perspective, the terms “approved” and “off label” are marketing terms and not medical terms. Manufacturers sometimes go back to the FDA and ask for “marketing approval” for newly discovered “indications,” but since the process is lengthy, expensive, and fraught with uncertainty because of the capricious bureaucracy within the FDA, they often do not. The longer a drug is in use, the more likely new “off label” uses will be discovered, incorporated into treatment regimens, and adopted into standard

medical practice. In regard to “off label” usage, the following is quoted from the Forward of the 2011 edition of the Physicians’ Desk Reference: “The FDA has also recognized that the FD&C Act does not, however, limit the manner in which a physician may use an approved drug. Once a product has been approved for marketing, a physician may choose to prescribe it for uses or in treatment regimens or patient populations that are not included in approved labeling. The FDA also observes that accepted medical practice includes drug use that is not included in approved labeling.” Thus we see the FDA’s final “approval” has to do with marketing and what the manufacturer may tell the physician, and while the “labeling” serves as an initial guideline for physicians in using the new drug, ultimately the “label” may only partially and incompletely describe how any drug is used in medical practice. “Off label” use of drugs is common in every medical specialty. In fact, “off label” use of medications is most often an indicator that a physician is knowledgeable and experienced in his specialty, rather than an indicator that a physician is engaging his patients in marginal or dubious therapies. Evaluation of a physician’s practice should be based on whether or not he is using medications in conformity with good medical practice, not whether he is using some medications in a manner different from what the FDA originally gave “marketing approval,” and which is therefore “off label.”

Introduction: The adverse medical consequences of obesity are well known and thoroughly documented in the medical literature.7 The beneficial effects of weight loss and maintenance of a lower weight are well known to clinicians but unproven in the view of some scientists.8 The recent publication of two reports providing clear evidence that weight loss following bariatric surgery prolongs life may partially silence these critics.10,

11 The safety and efficacy of the medications in use approved by the FDA for weight loss and weight maintenance is well established and thoroughly documented in the scientific medical literature.12 These include phentermine, diethylpropion, phendimetrazine, and orlistat. Large randomized placebo controlled clinical trials of one year duration have been accomplished and published for the newer drug, orlistat. Unfortunately, most of the trials for phentermine, diethylpropion, and phendimetrazine were performed before the FDA required that obesity drugs have two year trials in much larger groups of subjects. As a result, the trials were of shorter duration in smaller groups than are now required. Many obesity experts claim there is no long-term proof of safety of the older drugs notwithstanding of 50 years of widespread with no significant incidence of serious adverse effects. There is also medical literature substantiating the use of medications approved for other indications which are useful in treating obesity – these include topiramate,13-15 and ephedrine.16 In spite of the literature and despite the universal very favorable clinical experience with currently used anorectics, there is residual distrust of anorectics among many federal and state bureaucrats, many physicians, and many patients. The usage of anorectic medications remains controversial in the minds of many people 17 and must be thoroughly discussed with each patient before initiating therapy and at frequent intervals during therapy. The practitioner must always take time to be sure that the patient is well informed of the expected benefits and the potential risks and that “informed consent” is obtained either verbally or in written form, and that this is documented in the patient record. Verbal consent is acceptable if documented in some detail in the

medical record. Patients on anorectics must always be examined and questioned closely looking for side effects at every encounter; this should also be documented in the medical record. The pathophysiology and etiologies of obesity are still under intense investigation and are still controversial, but it is clear these are biochemical issues. Pharmacology is, and will continue to be in the future 18, a mainstay of medical weight management; good practice requires that the practitioner consider the use of weight management medications at every stage in the treatment of every obese patient. It has been clear for some time that these medications are even more important for weight maintenance after weight loss than they are for weight loss itself and that the current medications should be used long-term and not short-term. 19 An exhaustive review and analysis of prior studies and clinical trials on both pharmacological and surgical treatment of obesity was recently published by the Southern California-RAND Evidenced-Based Practice Center, Santa Monica, CA. 20 Drs. Frank Greenway and George Bray recently published an extensive review anorectic agents in Pharmacological Review entitled “The Pharmacological Treatment of the Overweight Patient.” 72 Another recent review includes a discussion of drugs in development. 21

Patient Selection:

Selection of patients for whom controlled substance anorectic medications can be prescribed has become increasingly controversial over the past decade since FDA approval of dexfenfluramine and the subsequent phen/fen crisis. Although the ASBP’s Overweight and Obesity Evaluation and Management document specifies that overweight patients may be treated with controlled substance anorectics, the FDA has adopted the NIH Guidelines which restrict these medications to patients with a BMI ≥ 30 or with a BMI ≥ 27 with certain co-morbidities. These guidelines have also been adopted by a variety of organizations including the Obesity Society (NAASO), the AMA, the American Association of Clinical Endocrinologists, the American Gastroenterology Association, and the American College of Physicians.22 The situation has been further complicated by the passage of federal National All Schedules Prescription Electronic Reporting (NASPER) Act of 2005 and the implementation of CURES (Controlled Substance Utilization Review and Evaluation System) which mandates that all controlled substance prescriptions be reported to state departments of justice within a week of the date the controlled substance is dispensed. These weekly reports must include patient and doctor names, diagnosis, dosage and amounts prescribed. Not every state has implemented a CURES program yet, but in states where it has been, physicians following the ASBP guidelines put the overweight patient and the prescribing physician at risk of being harassed for “misusing” a controlled substance. Some state medical boards specifically restrict prescribing controlled substance anorectic agent to patients at or above the “official” BMI thresholds. A physician who prescribes outside the commonly accepted guidelines by following the ASBP Guidelines may expose himself to an increased malpractice liability risk since the ASBP Guidelines are at odds with every other guideline. The ASBP’s Overweight and Obesity Evaluation and Management,23 although politically incorrect, are based on the assumption that treatment decisions are best made by a concerned and well informed physician after a careful medical appraisal of a patient’s health. On the other hand, the commonly accepted guidelines are based on assumptions which are patently false to any physician experienced in Bariatrics, to wit: all obesity drugs are high risk drugs and the risks of taking drugs for obesity exceed risks associated with weight gain until adiposity is severe and exceeds arbitrary thresholds.

A simplified version of the guidelines is given below. Anorectics may be used for: 1. Any adult who is overweight, or has an abnormal body fat percentage, or abnormal waist circumference, or abnormal BMI. 2. Any patient who has lost weight and is on maintenance.24 This is true even if they did not use an anorectic during weight loss. Patients who have lost weight after bariatric surgery, but have started regaining weight should be included in this group. 3. Any patient with obesity in their genetic background who has a tendency to gain weight easily (even if their weight is currently normal). 4. Obese children and adolescents. Although the use of anorectic medications in children is controversial, there have been controlled trials with anorectics in children which indicate both safety and efficacy.25-29 Prescribing an anorectic medication which assists in weight loss in obese children with metabolic syndrome is certainly preferable to the alternative of treating them with medications for diabetes and hypertension. Patients must be selected carefully using good clinical judgment using the CDC growth charts (http://www.cdc.gov/nchs/about/major/nhanes/growthcharts/clinical_charts. htm# Clin%201) appropriate to the patient’s age to determine if the patient’s weight is not appropriate for their height – e.g. weight is above the 95th percentile range but height is at the 50th percentile. Informed consent should be obtained from both parents, and the practitioner should be confident that the patient can and will follow instructions. Parents should always be told that their pediatrician will likely be opposed to using an anorectic.

Each physician will have to decide which of the guidelines to use in their own practice and how far they can stray “off schedule.” Although it will often not be in a given patient’s best interest, probably the safest course for a physician to follow is to prescribe controlled substance weight management medications only for those patients whose lifetime maximum BMI exceeded the politically correct thresholds. Such a patient can be kept on the medication chronically except in states where the medical board forbids it. We all look forward to the day when political correctness and bigotry vanish from the Bariatric scene and we have a broad spectrum of effective pharmacologic agents of known safety to prescribe for our patients.

Prescription Medications useful in weight management: 1. Phentermine 2. Diethylpropion 3. Ephedrine 4. Sibutramine (Withdrawn October 2010) 5. Orlistat 6. Phendimetrazine 7. Topiramate 8. Pindolol 9. 5HTP & Carbidopa 10. Spironolactone 11. Fluoxetine and Sertraline 12. Bupropion 13. Zonisamide 14. Metformin 15. Exenatide 16. Liraglutide 17. Pramlintide 18. Naltrexone and Bupropion 19. Zonisamide and Bupropion 20. Topiramate and Phentermine 21. Rimonabant

22. Tesofensine Phentermine: Phentermine is safe and effective for nearly every patient; if an anorectic is to be used phentermine should be the drug of choice unless there is some reason to avoid it. Contraindications and reasons to avoid phentermine include: 1. Absolute contraindications:

a. Pregnancy. Although this is true now, phentermine and other anorectics were widely used to prevent excessive weight gain during pregnancy in the 1960s without any adverse effects on either the gestation or the fetus. There are no known teratogenic effects. Patients can be advised to continue taking it while trying to get pregnant and then discontinue it once they become pregnant. b. Nursing an infant. c. Prior severe allergic reaction such as bullous eruption, or allergic reaction with challenge dose.

2. Relative contraindication – sometimes phentermine or another anorectic may be used with caution in these situations. This requires careful consideration and good judgment.

a. Epilepsy. Phentermine can be used with caution if the patient’s epilepsy is in good control on medications and other stimulants do not have an adverse effect on seizure control. The best approach is to discuss this with the patient and the patient’s neurologist. If either is opposed probably best to avoid phentermine. b. If the patient is opposed to using it for any reason. The practitioner should be very careful with informed consent with such patients. If the patient remains skeptical about anorectics after a thorough explanation of risks and benefits, then it is best to avoid them for the patient in question. In some cases where the patient’s primary physician has advised that the patient to avoid anorectic medications, the practitioner may be able to allay the patient’s concerns and use an anorectic if the primary physician’s opinion seems biased and not informed. In cases where a cardiologist, a neurologist, or other medical specialist has advised avoiding stimulants because of potential adverse effect on a specific medical condition it is usually best to avoid anorectics unless the practitioner confers with the specialist and the specialist agrees that a particular anorectic could be used. c. Mild allergic reaction (i.e. rash while on phentermine without confirmation rash was a phentermine reaction). Proceed with caution and use a very low first dose. d. Previous use with excessive stimulation. (see Pindolol below). e. Severe anticholenergic effects such as extreme dryness of mouth or extreme, unmanageable constipation. f. Episodic tachyarrhythmia especially in patients with irritable sinus node or ectopic node. g. Uncontrolled hypertension. h. History of substance abuse.

3. No contraindication:

a. Controlled hypertension. b. Glaucoma. c. Patients on virtually any other medication or combination of medicines including but not limited to anti-depressants, drugs for bipolar disorder, cardiac drugs, other anorectic medications. Although the PDR entry for phentermine cautions against use of phentermine with monoamine oxidase inhibitors there is “… no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses.” 30

Clinical Use: Phentermine has been used with good success to help patients lose weight since it was introduced in 1959. A reasonable guess is that several hundred million people have taken it at one time or another over the past 50 years.

Dosages: The lowest commercially available dose is 15mg daily, other doses include 30mg and 37.5mg. Many practitioners start with 18.75mg (1/2 a 37.5 mg tablet) in the morning then increasing to twice daily with the second dose before 3 P.M. If caution is advisable, then the starting dose should be 15mg daily. The starting dose for children and younger adolescents should be 15mg/day. Dose ranges: If initial doses are ineffective or become ineffective, the daily dose may be increased. Peak effectiveness for many adults is often at 60mg/day in my experience, but some patients can tolerate higher doses of up to 160mg/ day or even more. Dr. Richard Rothman, who has used phentermine extensively in his bariatric practice, has found that doses exceeding 160 mg per day do not provide additional benefit. Usually the stimulant effect of phentermine fades with time, but some patients have persistent excessive stimulation. Adult patients with attention deficient disorder very often can tolerate higher doses. Children and adolescents with ADD or ADHD can sometimes tolerate higher than usual doses. Combinations: Phentermine is a long acting anorectic with a half life of 18 to 24 hours. Some patients have insomnia if they take phentermine anytime other than morning but have hunger in the evening with a morning dose. Diethylpropion or Phendimetrazine (see below), a short acting anorectic with a half life of 4 to 6 hours may be combined with phentermine. Patients can generally tolerate 18.75 to 37.5mg phentermine in the morning combined with 25mg diethylpropion or phendimetrazine 17.75mg (1/2 a 35 mg tablet) or 35mg taken late afternoon or early evening. Pindolol and or 5HTP/Carbidopa may also be combined with phentermine (see below). The combination of 5HTP/Carbidopa often attenuates the stimulant effects of phentermine. Beneficial side effects: Phentermine has some side effects which the patients find beneficial.

a. Increased energy. Low energy is a frequent complaint of obese patients at initial evaluation. Weight reduction therapy in general improves energy level in these patients; phentermine often provides an added improvement. b. Altered mood. Some patients report their mood is improved on phentermine. c. Attention Deficit Disorder. Generally patients with ADD or ADHD who are not on medications for ADD see improvement on phentermine. d. Decreased gastro-intestinal motility. Some patients with chronic diarrhea or rapid transit time notice improvement on phentermine. e. Bladder neck sphincter contraction. Women with stress incontinence may see improvement due to phentermine. Adverse reactions/adverse side-effects: Since phentermine works by increasing noradrenaline release which then acts through beta-adrenergic receptors pervasive throughout the entire nervous system, it should not be surprising that it can produce a variety of diverse side effects. Some side effects may be beneficial, while others limit the effectiveness of the drug. Estimates of reactions are from my own experience with approximately 10,000 patients placed on phentermine. The incidences apply if the patient is taking the medication as directed. Incidences of all adverse reactions go up if the patient is taking more than advised. Practitioners should question the patient on each encounter on doses and timing of doses to verify that the patient is on an appropriate dose and schedule. a. Stimulation. Patient reaction to the stimulant effects of phentermine vary widely. Some patients notice “feeling speedy” with initial doses of phentermine, but most patients do not notice or complain of this. Other patients report being pleasantly energized. An occasional patient becomes so stimulated they cannot be persuaded to ever take phentermine again. Generally, stimulant effects occur early, are mild,

and disappear with continued exposure to the drug. Perhaps 20% of patients experience some stimulant effect and perhaps 1 in 100 has such severe stimulation that they won’t take it. b. Insomnia. Insomnia is pretty common in the population of patients presenting for obesity treatment so the clinician should always question patients complaining of insomnia about their sleep patterns before the initiation of phentermine. Insomnia where the patient cannot go to sleep occurs early on in phentermine therapy. This is a stimulant effect which, if it occurs at all, is generally mild and disappears if the patient continues the drug. Sleep deprivation symptoms are rare. The incidence of insomnia is perhaps 15% one week and 2 to 3% one month after initiation of phentermine therapy. There is a second form of insomnia which can occur after the patient has been on phentermine for months or years in which the patient goes to sleep easily but awakens after a few hours and cannot go back to sleep. Sleep deprivation symptoms can become problematic with this form of insomnia. The incidence of late appearing insomnia is generally less than one in a thousand patients. c. Dry mouth. Many patients complain of mild dry mouth – generally so mild it only serves to remind them to drink the 64 ounces of water daily we recommend. A rare patient will have such severe dry mouth that mucosal erosions may occur – the incidence is less than one in a thousand patients. d. Jaw Clenching. Jaw clenching and night-time teeth grinding are two stimulant effect variants which can occur but are uncommon. I estimate the incidence of each of these at about 1 in 500 patients. The addition of 5HTP/Carbidopa may ameliorate this side effect. The addition of bedtime Trazadone at a dose of 50mg can also be effective. e. Irritability. This is the most common mood change noted, occurring in perhaps one in a hundred patients or 1%. Usually this is mild and the patient can control it, but sometimes the patient becomes so irritable the drug must be discontinued. A beta-blocker can be an effective antidote. f. Mood changes. Such reactions are unusual. Occasional patients who have mild depression but are not on antidepressant medication report an improvement in mood. Rarely a patient will report unfavorable mood changes. g. Allergy. Allergic reactions generally present as typical allergic skin rashes or urticaria. These can occur early or late. The incidence is low, less than one in a thousand patients has an allergic reaction to phentermine. Of course, the most common cause of an allergic rash in our bariatric population is an allergy to a cosmetic or household product. Most of the time when patients develop an allergic rash when on phentermine it has been caused by something other than the phentermine. I have never seen a severe allergic reaction to phentermine. h. Changes in bowel motility. Very few patients notice this, but phentermine has anticholenergic effects and can slow down gastrointestinal transit time. Constipation may occur, perhaps one in a hundred patients, and is usually easily relieved with an increase in fiber intake. Unmanageable constipation requiring discontinuation of phentermine is very rare – on the order of one in 5,000 patients. Patients who have long standing constipation which is difficult to manage probably should avoid phentermine; diethylpropion is a better choice for these patients. Patients with a rapid transit time and diarrhea or very frequent bowel movements find that their frequency drops dramatically. We have seen a few of these patients who report that their life returns to normal when on phentermine. i. Bladder neck sphincter contraction. The urethral sphincter tightens on phentermine. Women with stress incontinence love this effect; men with prostatic hyperplasia are less enthusiastic. The former need no treatment; the latter do fine and often have no symptoms with tamsulosin hydrochloride (Flomax) 0.4 mg once or twice daily. j. Blood pressure changes. Blood pressure for most patients on phentermine goes down; in the rest blood pressure is unchanged. Blood pressure changes are generally due to the fact that patients on phentermine lose weight. The incidence of a real increase in blood pressure due to phentermine is 1:5000 or less. k. Pulse rate changes. In general, pulse rates do not increase when phentermine is started, but occasional patients have a mild increase in pulse rate in the first few days of phentermine therapy. Pulse rates generally slow down in response to losing weight and in response to an increase in frequency and duration of exercise. l. Neurological problems/Hand tremors. Patients with pre-existing hand tremors may note that their tremors are intensified. Patients with epilepsy could, in theory, experience an increase in seizures. I have

only given phentermine to a few patients with stable, quiescent epilepsy on anti-epileptic medication and have seen no seizures. m. ADD and ADHD. Patients with previously undiagnosed mild Attention Deficit Disorder or Attention Deficit Hyperactivity Disorder are sometimes surprised to find that they focus and think more clearly on phentermine. This effect is well known to bariatric physicians, but has been rarely mentioned in the medical literature.28 A recent New England Journal Clinical Practice Review on Attention Deficit-Hyperactivity Disorder does not include any discussion of phentermine.31 Phentermine may or may not be effective for patients who are already on medications for ADD. Generally phentermine can be safely added and should be given a trial. My experience has been that patients on atomxitine may respond to phentermine but patients on dextroamphetamine or methylphenidate may not. n. Addiction. In 50 years of world-wide use there has never been a case of phentermine addiction reported. When phentermine was approved by the FDA in 1959 it was classified as a Category IV drug with potential for addiction because of the close similarity in molecular structure to amphetamine. Phentermine in practice has proven to have no potential for addiction, however the prospect of having the FDA declassify it as a Category IV drug is low. Phentermine does not create cravings for illicit drugs or alcohol in patients with a history of substance abuse. It can be safely used in such patients provided the patient is stable and practitioner thoroughly discusses this issue before starting phentermine and repeatedly during the course of treatment. If the patient begins craving or using alcohol or drugs of abuse, then the phentermine should be immediately discontinued. Although there is nothing in the medical literature to support using phentermine or other category IV or III drugs in patients with substance o. Panic disorder. Phentermine does not cause panic, but any stimulant can lower the threshold at which panic occurs. I have seen two cases in which the patient experienced their first episode of panic during the first few days of phentermine therapy. Both were young women who afterwards admitted to occasional episodes of anxiety previously but no panic. One of the patients, convinced that the phentermine was causal, returned for a second visit and then never returned. The other remained my patient but did not use anorectants subsequently. Many patients with panic disorder or with anxiety can tolerate phentermine without adverse effects and benefit from it. Once such a patient understands that phentermine can lower the threshold at which anxiety can occur, they generally can manage on their own. p. Psychosis: There are rare case reports of phentermine induced psychosis in the medical literature. A PubMed search for “Phentermine AND Psychosis” limited to “Case Reports” on March 22, 2006 turned up 7 reports. Most of the reports are so old PubMed has no abstract. The only credible report in the last decade with an abstract reports that a schizophreniform-like psychotic disorder appeared in a young woman after she increased her phentermine to 150-180mg per day for a month. 33 q. Primary Pulmonary hypertension and/or regurgitant cardiac valvular disease: Valvulopathy has been associated with fenfluramine use but not with phentermine use. There are drugs which are known to increase risk for the onset of primary pulmonary hypertension (PPH); phentermine is not one them. 34 Chlorphentermine, a chlorinated form of phentermine is known to produce pulmonary toxicity in rats and is suspected to cause PPH 35, but chlorphentermine is a manufactured product and is not a phentermine metabolite. Aminorex, fenfluramine, and d-fenfluramine, each used for treating obesity in the past, are also thought to increase the risk for PPH. A widely cited paper from Europe published in the New England Journal of Medicine in 1996 reported an investigation of 95 cases of PPH and implicated fenfluramines as the chief drugs involved in the development of PPH. The paper cited phentermine in two cases but it’s likely these two patients took other anorectics as well 36. A similar investigation on patients with PPH in North America again mentioned phentermine but implicated fenfluramines as causal. A few other cases of pulmonary hypertension were reported in the medical literature in patients treated with a combination of phentermine and fenfluramine. 37, 38, 39 There is not a single case report of PPH implicating phentermine alone as the inciting agent. [PubMed searches on 4/4/2006: phentermine AND pulmonary hypertension; phentermine NOT fenfluramine AND pulmonary hypertension; phentermine NOT fenfluramine AND pulmonary hypertension limited to case reports]. In spite of a marked increase in use of phentermine and fenfluramine in the United States during the 1990s there was

no increase in the incidence of PPH during the same time period. 40 My conclusion: pulmonary hypertension is not caused by or associated with isolated phentermine use. Cardiac valvular lesions are not caused by or associated with isolated phentermine use. r. Impotence, changes in libido: These are rare, on the order of 1 in 5,000 patients. s. Idiosyncratic reactions can occur as with any drug.

Other concerns raised in the 2011 PDR include carcinogenesis and pregnancy effects. There is no known association of phentermine with either. Obstetricians once used diethylpropion and, to a lesser degree, phentermine, to prevent excessive weight gain during pregnancy. However, at present these are seldom used during pregnancy. Phentermine is a pregnancy category C drug. Patients who are trying to become pregnant can take it safely until pregnancy is confirmed. Management of adverse reactions/side-effects: During the course of anorectic therapy any number of health events can occur that are coincidental but not related to the anorectic, the diet, or anything else recommended for weight management in any way. Oftentimes, the patient’s first reaction is that this event is caused by phentermine (or other weight management medication). All too often, a poorly informed physician will blame an unrelated health event on the obesity therapy. I have found that the best strategy in such a case is to immediately agree that whatever the reaction or the event is, that it could be related to anorectic, and advise that the drug be discontinued. Later, should it become clear that the event is unrelated, the anorectic can be re-started or a different one selected.

a. Severe reactions. Phentermine should be discontinued immediately in any case if a severe side effect occurs. Patients who call because they think they are having a reaction should always be told to discontinue phentermine and any other medication we have dispensed or prescribed immediately and come to the office or see another physician as soon as possible for examination. The office staff should be trained to give this advice if they receive a phone call from a patient and the practitioner is not immediately available. This should be done even when the practitioner’s first thought is that the reaction is due to something other than phentermine. b. Less than severe reactions. Patients who call with any sort of reaction should be advised to discontinue the phentermine until they discuss the reaction with a practitioner. The safest way to conduct the discussion is face-to-face. If the reaction is mild, occurs early after starting phentermine, and is an expected reaction such as mild dry mouth, then the practitioner may be able to safely deal with it on the telephone. The easiest and safest thing to do with mild reactions is to discontinue the drug or reduce the dose until the stimulation is gone, then starting with a tiny amount, very gradually increase the dose, slowly increasing the dose to allow tachyphylaxis to occur, until the desired therapeutic effect is reached. Pindolol 5mg one to three times daily is often effective in dealing with mild side effects if the gradual approach fails. Another way to deal with stimulant effects is to skip doses either occasionally or on a scheduled basis. c. Allergic reactions. The possibility that an allergic reaction is due to phentermine should always be taken seriously and the drug discontinued. Then an investigation into the potential source of the allergen should be conducted by the practitioner or other physician. My experience has been that allergic reactions more often prove to be due to something else rather than the anorectic, but it is best to be conservative and avoid phentermine until the offending allergen is identified.

Clinical Utility: Highly useful in bariatric practice. Phentermine is the most widely used appetite suppressant.

Diethylpropion: Diethylpropion is safe and effective for nearly every patient; it should be the second choice to be considered if phentermine cannot be used. Diethylpropion hydrochloride in the immediate release form is a short acting drug with a ½ life of 4 to 6 hours. There is also a controlled release form in which the diethylpropion is dispersed in a hydrophilic matrix with a longer half life. In other respects diethylpropion is similar to phentermine. Diethylpropion has been associated with leukopenia or blood dyscrasias. Also, it can increase seizure thresholds, therefore should be used with caution in patients with seizure disorders. Otherwise, contraindications and reasons to avoid diethylpropion are the same as Phentermine. A recent study supports the safety and efficacy of long term use of diethylpropion.93 Dosages: The normal starting dose for adults is 25mg three times daily or 75mg of the long acting version once daily. Children should be started on either 12.5mg (1/2 a 25mg tablet) or 25 mg once or twice daily. Dose range: generally 25 to 75mg per day. Occasional patients tolerate 150mg per day. Combinations: Diethylpropion may be safely combined with other medications including phentermine, Pindolol, and 5HTP/Carbidopa (see phentermine above). Adverse reactions/side-effects: Diethylpropion is a sympathomimetic amine and has a pattern of adverse reactions and side-effects similar to phentermine. Stimulant side-effects tend to less severe and of shorter duration than observed with phentermine.

Management of adverse reactions/side-effects: Management is the same as with phentermine.

Clinical Utility: Very useful. Diethylpropion is second only to phentermine in clinical usefulness.

Ephedrine: Ephedrine is safe and effective although difficult to obtain due to intense government scrutiny.16, 41 Ephedrine has been around for two thousand years as a bronchodilator and as treatment for asthma. Although it is not a controlled substance, the FDA has given it bad publicity recently and forced it off the over-the-counter market. This ban on ephedra was struck down by a Federal Court in Utah in April 2005. The FDA didn’t give up and filed a successful appeal. Ephedrine was temporarily unavailable during the ban, became obtainable during 2006, but is now virtually impossible to obtain even though it is legal in applications other than dietary supplements. Ephedrine is a mild anorectic but in addition is useful because it temporarily raises metabolic rate by about 5% for 3 to 4 hours. This effect is doubled if 200mg caffeine (a cup of coffee or one maximum strength NoDoz tablet) is added. Lesser amounts of caffeine boost the effect to a lesser extent. Caffeine prevents ephedrine resistance.42 12.5mg ephedrine produces about 90% of the effect of 25mg.

In other respects ephedrine is similar to phentermine. Contraindications and reasons to avoid ephedrine are the same as phentermine. Dosages: The normal starting dose for adults is 25mg three times daily. Younger patients have more problems with the stimulant effects than older patients. For this reason I avoid using it in patients under age

30. Patients who have undesirable stimulant effects with the initial dose should be instructed to take either 6.25mg (1/4 a 25mg tablet) or a “crumb” of a crushed tablet once daily for a few days and then to very slowly increase the daily dose. Nearly everyone can tolerate ephedrine if the dose is kept low and only slowly increased. Dose range: generally 12.5 to 75mg per day. Occasional patients tolerate 100mg per day. Combinations: Ephedrine may be safely combined with other medications including phentermine, Pindolol, and 5HTP/Carbidopa. Adverse reactions/side-effects: Ephedrine is a sympathomimetic amine and has a pattern of adverse reactions and side-effects similar to phentermine. Stimulant side-effects tend to be of shorter duration than observed with phentermine. Management of adverse reactions/side-effects: Management is the same as with phentermine. Clinical Utility: Very useful especially in older patients. Ephedrine’s thermogenic effect can be a useful addition for patients who have stopped losing weight short of their goal.

Sibutramine: Sibutramine was voluntarily withdrawn on October 8, 2010. References 42-47may be obtained if further information pertaining to Sibutramine is desired.

Orlistat: Orlistat is a very safe but only modestly effective weight loss drug. It is an intestinal lipase inhibitor which will prevent absorption of some of the fat a patient consumes for a few hours after taking the drug. The absorption of fat soluble vitamins can also be impaired, therefore taking a multivitamin that includes the fat soluble vitamins is recommended. Its effectiveness is limited by its unpopularity with the vast majority of patients. Some patients find it useful for maintenance. Orlistat is available in an over the counter formulation, Alli. Alli comes in a 60mg dose that is recommended to be taken three times per day. Dosages: 120 mg three times per day. Adverse reactions/side-effects: The most common side-effects of Orlistat are abdominal discomfort, oily stools, oily diarrhea, and increased flatus. Also there is an increased risk of calcium oxylate neprolithiasis and changes in thyroid functions in those taking levothyroxine. Management of adverse reactions/side-effects: Severe adverse reactions are virtually unheard of, but the GI side effects are all too common. Most patients learn to skip the drug if they plan to eat a fatty meal. Clinical Utility: Orlistat is not very useful in bariatric practice especially as it is available over the counter. Orlistat is approved for use in adolescents and can be helpful for those “fast food junkies.” A few patients find it useful for help with weight maintenance.

Phendimetrazine: Phendimetrazine is another safe and effective older anorectic but because there actually is some potential for abuse (it is a category III controlled substance). Phendimetrazine in the immediate release form is an intermediate acting drug with a ½ life of 5 to 12 hours. There is also a controlled release form with a longer

half life. In other respects it is similar to phentermine. ntraindications and reasons to avoid phendimetrazine are the same as phentermine. Dosages: The normal starting dose for adults is 35mg three times daily. Dose range: generally 35 to 105mg per day. Occasional patients tolerate up to 210mg per day. Combinations: Phendimetrazine may be safely combined with other medications including phentermine, Diethylpropion, Pindolol, and 5HTP/Carbidopa (see phentermine above).

Adverse reactions/side-effects: Phendimetrazine is a sympathomimetic amine and has a pattern of adverse reactions and side-effects similar to Phentermine.

Management of adverse reactions/side-effects: Management is the same as with phentermine. : Clinical Utility:Useful in patients who do not respond well to other anorectics.

Topiramate: Topiramate is approved for the treatment of epilepsy and migraine headaches. Topiramate has been found to be very useful for the management of binge eating and drug induced weight gain.51 These two conditions respond to much lower doses that those required for treating epilepsy. Topiramate is also being used for the treatment of peripheral neuropathy. The drug is weak carbonic anhydrase inhibitor; early side effects such as paresthesias are related to this effect and generally fade with continued use. Topiramate’s mechanisms of action that produce its anti-epileptic effect are known however its mechanisms that reduce appetite are unknown. Topiramate has undergone clinical trials for use as a weight loss drug 14, 52 however concerns over psychiatric and central nervous system side effects have prevented further development as a weight loss drug. Contraindications: Allergy to sulfamate containing compounds or increased intraocular pressure. Dosages: The starting dose for weight management is 25mg at bedtime. Often this is effective to some degree, but generally the dose must be advanced to 50mg/day (25mg b.i.d.) to achieve good effect. Increases in dosage should be gradual, increasing by 25mg per day every 2 to 4 weeks. The occurrence of side-effects is minimized by slow titration. Generally the dose must be gradually increased with time to maintain effectiveness. 200mg per day is the maximum dose for weight management; generally it takes one or two years of therapy before the maximum dose is required. Combinations: Topiramate may used in combination with phentermine, diethylpropion, ephedrine, phendimetrazine, 5HTP, Carbidopa, or other medications. Adverse reactions/side-effects: The most common side effects are central nervous system events with paresthesia being the most frequent. Side-effects are dose-related, tend to be mild, and generally disappear with continuation of the drug. Difficulty with memory and concentration, psychomotor slowing, and somnolence are common with higher doses but uncommon at 25 or 50 mg per day. A very rare side effect is nephrolithiasis. The most serious potential adverse reaction to topiramate is a syndrome of acute myopia

and secondary angle closure glaucoma which tends to occur in the first month of therapy while the patient is still on a low dose.53, 54 Symptoms include acute onset of decreased visual acuity and/or ocular pain with or without mydriasis. The syndrome, if left untreated, can result in blindness. The syndrome is reversible if topiramate is discontinued immediately55 and the patient put on a loop diuretic such as furosemide to rapidly reduce intraocular pressure. Consultation with an ophthalmologist should be obtained immediately. Management of adverse reactions/side-effects: Patients started on topiramate should be watched carefully for eye symptoms. Patients continued on topiramate should have intra-ocular pressures checked periodically, at least quarterly. Always discontinue topiramate immediately if the patient complains of eye pain or any change in visual acuity. Patients who present with eye symptoms should be immediately referred to an ophthalmologist, since untreated secondary angle glaucoma can result in blindness. The practitioner should speak directly to the patient’s ophthalmologist stressing the acuteness of the situation and ask for an urgent consultation. If an ophthalmologist cannot be reached, then the practitioner should call the closest hospital emergency room and speak directly to the physician in charge. If for any reason the practitioner thinks there will be a delay in having the patient seen by an ophthalmologist, then the practitioner should prescribe furosemide 40 mg to be taken immediately and twice daily. Patients should be cautioned to watch for hypotension and should be seen in follow-up within 24 to 48 hours. Less than severe neurological reactions can often be alleviated with dose reductions. If a patient develops severe flank or groin pain, hematuria or other symptoms consistent with nephrolithiasis, the patient should be instructed to contact their health care practitioner immediately.

Clinical Utility: Very useful in selected patients including those who have experienced weight gain on anti-depressants. Somewhat useful in binge eating disorder.

Pindolol: Pindolol is a weak beta-blocker which may be used with phentermine, diethylpropion, ephedrine or phendimetrazine to block the stimulant effect without affecting the anorectic effect. Pindolol may be added when patients taking phentermine, or other sympathomimetic amine have trouble with over stimulation. Over stimulation can manifest itself as feeling “speedy,” intensification of feelings of anxiety, or insomnia. Beta blockers work by blocking beta receptors and typically are used to treat hypertension and angina. The Pindolol itself does not have any direct effect on weight management. Contraindications: Patients already on a beta blocker probably will not suffer from over stimulation. Such patients may not benefit from taking Pindolol and its addition could provoke transient hypotension. Patients taking thioridazine (Mellaril) should not be given Pindolol because of an increased risk of arrhythmia. Dosages: The dosage range for Pindolol is 1 to 15mg/day. 5mg at bedtime is the usual starting dose. Pindolol can also be added to compounded medications at any dose level. Combinations: Pindolol may be combined with phentermine, diethylpropion, ephedrine, phendimetrazine, 5HTP, Carbidopa, or other medications including anti hypertensives.

Adverse reactions/side-effects: Pindolol has the potential of causing any of the side effects of beta blockers including depression, lethargy, lack of energy, drowsiness, sleepiness, slow heart rate, and hypotension. Management of adverse reactions/side-effects: Always discontinue Pindolol immediately (and any other medication the bariatrician has prescribed) if the patient experiences a severe reaction. Less than severe reactions can often be alleviated with dose reductions. Clinical Utility: Very useful in a few patients.

5HTP/Carbidopa: This combination of an over-the-counter supplement (5HTP) and a prescription medication (Carbidopa) is a very useful anorectic medication. Any compounding pharmacy can provide it. Ordinarily 5HTP/Carbidopa (or 5HTP/C) is combined with phentermine. 5HTP/Carbidopa can be used alone but is less effective than when combined with phentermine. Induction of higher serotonin levels in certain brain areas are known to create the same feel-good sensation that eating sweet foods can produce. The two Fenfluramine drugs Pondimin and Redux, now withdrawn from the market, produced this effect and induced anorexia. Some patients treated with a fenfluramine drug reported significantly reduced carbohydrate cravings. Unfortunately these drugs also triggered heart valve 5-HT2B receptors as well, which in a few patients led to valvulopathy. Since serotonin doesn’t cross the blood-brain barrier, administration of serotonin itself does not induce higher brain serotonin levels. There is an extensive literature on serotonin and 5HTP in treating obesity and carbohydrate cravings. Chapter 17 in Handbook of Obesity, Clinical Applications 4 includes some of the pertinent literature citations as does a recent paper by Halladay. 56

5HTP or Hydroxytyptophan is the immediate precursor of serotonin (5 Hydroxytryptamine). 5HTP has long been known to have anorectic properties and to have the effect of relieving carbohydrate cravings. The 5HTP is converted to serotonin in the brain and activates the leptin-melanocortin anorexigenic signaling pathway 57. 5HTP works because it crosses the blood-brain barrier and is then converted to serotonin in the brain. However, because of rapid decarboxylation of 5HTP and conversion to serotonin in the gut, liver, and bloodstream, high oral doses of 5HTP are required to produce even small increases in brain serotonin. If 5HTP is given alone, high doses of up to 900 mg per day produce the best results. Many patients have nausea and other gastrointestinal side effects at such a high doses limiting the effectiveness of 5HTP alone. A few patients do well with 150 to 300 mg 5HTP per day but for most patients low doses are not effective. Carbidopa is a peripheral inhibitor of L-aromatic amino acid decarboxylation and inhibits premature decarboxylation of 5HTP to serotonin before the 5HTP can cross the blood-brain barrier. Carbidopa, at a 5 mg dose, has no other pharmacologic effect. L-dopa/ Carbidopa combinations are used in treating Parkinson’s disease. The Carbidopa inhibits decarboxylation of the L-dopa, increasing its effectiveness. Combining Carbidopa with 5HTP increases the effectiveness of the 5HTP dramatically. 5HTP/Carbidopa in combination has been used extensively in Europe as a treatment for depression, generally at higher doses of 5HTP than needed for anorectic use. 58

The only mention in the peer-reviewed medical literature to this combination is in reference to its use as a treatment for intention myoclonus.59 There are no citations to the use of this combination in alleviating carbohydrate cravings although there are numerous references to the use of 5HTP alone for carbohydrate

cravings and for weight loss.60,61 Richard B. Rothman, M.D., Ph.D., a researcher and chief of pharmacotherapy at NIDA, presented a talk at the 2001 ASBP spring meeting in Atlanta in which he discussed the use of 5HTP/Carbidopa for weight loss.62 Dr. Rothman confirmed, in a recent presentation,63 that he is still using 5HTP/Carbidopa combinations with phentermine in his weight management practice. He finds the combination especially useful in patients who have carbohydrate cravings. 93 Dosages: Starting dose 5mg 5HTP with 5mg Carbidopa, taken three times daily after meals. If the patient has a good response and no side effects, then the dose may be gradually increased first to 10mg, then 15mg and eventually up to 20mg or 25mg 5HTP, always with 5mg Carbidopa. Occasional patients benefit from a fourth, nighttime dose. Combinations: 5HTP/Carbidopa is absorbed readily and may be taken with or without food or other medications, however some patients experience nausea or epigastric pain if 5HTP is taken on an empty stomach. This usually will resolve spontaneously if the patient will persist in taking it but patient compliance is usually better if you warn them of this potential problem and advise taking 5HTP with food. Patients who susceptible to gastric irritation or with GERD should always be cautioned to take 5HTP/Carbidopa with food or a protein supplement. The adverse GI effects may be due in part to increased gastric motility and other effects due to the presence of high levels of serotonin in the gut after 5HTP doses. Adverse reactions/side-effects: 5HTP can cause gastrointestinal side effects in higher doses. Carbidopa is not used alone therapeutically and has no known side effects. Side effects for Carbidopa reported in the medical literature are those of the L-dopa with which the Carbidopa is compounded. The only adverse side-effects I have seen are gastric irritation or nausea when the medication is taken with an empty stomach. This is true for both the 10 mg 5HTP and the 20 mg 5HTP levels. Neither Serotonin syndrome nor cardiac valulopathy has ever been reported in patients on 5HTP at any dose level. A single case report of a scleroderma-like illness in a patient treated with 5HTP/Carbidopa for intention myoclonus appeared in 1980 64 but no other cases have been reported since. The eosinophilia-myalgia syndrome was associated with a single contaminated batch of L-tryptophan and has not been reported with 5-HTP. Because of its biochemical relationship to L-tryptophan, 5HTP has been under very close scrutiny since 1990 and is considered to be very safe. 65 Management of adverse reactions/side-effects: Always discontinue 5HTP/Carbidopa immediately (and any other medication we have prescribed) if the patient experiences a severe reaction. Minor reactions may occur if the patient is taking more than the prescribed dose. Reducing the dose is usually effective in such circumstances.

Clinical Utility: 5HTP/Carbidopa is highly useful as an anorectic particularly when combined with phentermine.

Spironolactone: Spironolactone can block some hormonal effects including the food cravings which commonly occur in some women prior to menses. 66 Aldactazide or the generic equivalent consisting of spironolactone 25mg. combined with hydrochlorthiazide 25mg. is less expensive than spironolactone alone (which is available as

50mg. tablets) and is equally effective. The combination produces a diuresis which typically lasts 6 to 8 hours. Contraindications: Patients with known allergic reactions to sulfa or thiazides should not take hydrochlorthiazide. Dosage: One tablet daily beginning when premenstrual symptoms begin and continuing until menstrual flow ceases. Combinations: Spironolactone may be used in patients taking any of the other medications useful in weight management.

Adverse reactions/side-effects: These include allergic reactions and side-effects common to diuretics in general.

Clinical Utility: Spironolactone is highly useful in patients who have pre menstrual carbohydrate craving.

Fluoxetine & Sertraline: Fluoxetine and Sertraline are both selective serotonin reuptake inhibitors that are approved for the treatment of depression. A meta-analysis of six studies with Fluoxetine revealed that weight loss was significant for the initial 6 months of the studies but during the second 6 months, there was regain of 50% of the lost weight. 73 Similar results were found in a study of Sertraline. 74 Adverse reactions/side-effects: Dry mouth, insomnia, nausea, tremor, headache, increased sweating, decreased libido, and rarely serotonin syndrome. Contraindications: MAO inhibitors Dosage: Fluoxetine 20-60 mg daily or Sertraline 50-200 mg daily Combinations: Fluoxetine and Sertraline can be combined with Phentermine, Diethypropion, and Phendimetrazine. Clinical Utility: Preferred over tricyclic antidepressants in the depressed overweight/obese patient.

Bupropion: Bupropion is a norepinephrine and dopamine reuptake inhibitor that is chemically similar to Diethylpropion. It is approved for the treatment of depression and smoking cessation. It comes in both an immediate and sustained release formulation. The sustained release formulation has been studied for weight loss. 75 Bupropion is useful in helping to decrease appetite and cravings along with improving overall mood. Nondepressed patients seem to have a better weight loss response than depressed patients. Adverse reactions/side-effects: dry mouth, weight loss, insomnia, constipation, nausea, tremor, dizziness, headache, agitation, and increased sweating. Bupropion may lower seizure threshold, therefore must be used with caution in those with seizure disorders.

Contraindications: concomitant administration of Zyban Dosage: Initially Bupropion SR 150mg daily but may increase up to 450mg daily Clinical Utility: Prevention of weight gain after smoking cessation, control of cravings, depressed patients that have experienced weight gain with selective serotonin reuptake inhibitors or tricyclic antidepressants.

Zonisamide: Zonisamide is an anti-epileptic drug that has serotonergic and dopaminergic activity in addition to blockade of sodium and calcium channels. Its mechanism for weight loss is unknown. Its action also as a weak carbonic anhydrase inhibitor produces an altered sense of taste which may also contribute to its weight loss properties. 76 Orexigen Therapeutics is currently investigating the combination of Zonisamide 400 mg and Bupropion SR 300 mg, which has been named Empatic. Phase II b clinical trials are currently underway.( www.orexigen.com) Adverse reactions/side-effects: drowsiness, loss of appetite, dizziness, headache, nausea, agitation/irritability, and metabolic acidosis. Contraindications: allergy to sulfur Dosage: Zonisamide 100mg and may increase up to 600mg per day Clinical Utility: Useful in selected patients.

Metformin: Metformin is a biguanide that is approved for the treatment of type 2 diabetes. This drug reduces hepatic glucose production, decreases intestinal absorption from the gastrointestinal tract, decreases fatty acid oxidation in liver and skeletal muscle, and enhances insulin sensitivity. Metformin has become the first drug of choice in treating insulin resistance and patients with polycystic ovarian disease. 77,78 Although Metformin does not produce enough weight loss to be FDA approved as a weight loss drug, studies have proven it to be effective in treating patients with diabetes and those who are at risk for developing diabetes. 79,80 Metformin comes in both an immediate and extended release formulation. Gastrointestinal side effects may improve or resolve by switching a patient to the extended release formulation. Adverse reactions/side-effects: nausea, diarrhea, vomiting, gas, rash, and lactic acidosis. Long term use may increase homocysteine levels and cause a malabsorption of vitamin B12 therefore administration of supplemental folic acid and vitamin B12 is advised. Contraindications: Acute or chronic metabolic acidosis and renal dysfunction. Dosage: 500mg or 500mg XR and may increase up to 2000mg or 2000mg XR daily

Clinical Utility: Those overweight/obese patients with type 2 diabetes who are on sulfonyureas, and thiazolidinediones, patients with PCOS, insulin resistance or metabolic syndrome patients.

Exenatide: Exenatide is a 39-amino acid peptide that is a synthetic version of a salivary protein found the Gila monster lizard. It has a >50% homology with glucagon-like peptide- 1(GLP-1), therefore it mimics many of the properties of GLP-1 such as: increases glucose dependent insulin secretion, decreases glucagon secretion which decreases hepatic glucose output, decreases the rate of nutrient absorption by regulating gastric emptying, decreases food intake, and reduces fasting and postprandial glucose levels24 along with improvements in Hemoblobin A1C. 81 Unlike GLP-1, Exenatide is resistant to the degradation by dipeptidyl peptidase-4 therefore Exenatide has a longer half-life. This drug which is FDA approved for the treatment of type 2 diabetics who are not adequately controlled with other oral agents. In several studies, Exenatide has produced weight loss without lifestyle changes or exercise. 82,83 Adverse reactions/side-effects: nausea, vomiting, diarrhea, dizziness, nervousness, headache, and dyspepsia. May increase INR if patient is on warfarin. Contraindications: type 1 diabetes and end-stage renal disease Dosage: 5 or 10 mcg subcutaneously twice a day within 60 minutes before meals Clinical Utility: same as Metformin

Pramlintide: Pramlintide, approved for the treatment of diabetes, is a synthetic analog of amylin that has a longer half-life. Amylin is a neuroendrocrine peptide that is cosecreted with insulin by pancreatic -cells in response to meals. Amylin binds to specific receptors in the hindbrain including the area postrema, an area known to regulate feeding behavior in animals. Pramlintide has the following actions: aids in the absorption of glucose by delaying gastric empyting, promotes satiety, decreases post-prandial glucagon secretion, and decreases food intake leading to potential weight loss. 84 It is approved as a treatment adjunct in patients with type 1 and 2 diabetes who use insulin. 85,86 Adverse reactions/side-effects: hypoglycemia (black box warning), anorexia, nausea, headache, vomiting, abdominal pain, joint pain, fatigue, and unexplained cough. Contraindications: Hypoglycemia unawareness and gastroparesis

Dosage: 15 mcg subcutaneously before major meals and may increase up to 120 mcg before major meals. Clinical Utility: Overweight or obese type 1 diabetics and insulin dependent 2 diabetics not adequately controlled on insulin. Remember, pramlintide is not a substitute for insulin.

Naltrexone & Bupropion(CONTRAVE): Naltrexone is an opioid receptor antagonist that is used primarily in the management of alcohol or opioid dependence. It inhibits μ- opioid receptors on the POMC (proopiomelanocotin) neurons which augments POMC release. This pharmacological property also enhances the weight loss of Bupropion. 87 Phase III clinical trials using the combination of Bupropion and Naltrexone, Contrave, are underway. (http://www.orexigen.com) Adverse reactions/side-effects: nausea, headache, and constipation Dosage: Initial proof of concept trial: Naltrexone 50mg and Bupropion SR 300mg, but subsequent trials have varied Contrave dosages. 93 Clinical Utility: Obesity, obese type 2 diabetics, and perhaps mildly depressed obese overeaters

Zonisamide & Bupropion(EMPATIC) Empatic is also being developed by Orexigen.(http://orexigen.com) In the most recent Phase IIB clinical trials, six different dosage combinations of Zonisamide and Bupropion were utilized. The most effective combination in the trials was Zonisamide 360mg and Bupropion 360mg. 93 Adverse reactions/side-effects: headache, nausea, insominia dry mouth, and anxiety Clinical Utility: Obesity and mildly depressed obese patients. Topiramate & Phentermine(QNEXA) Qnexa is being developed by Vivus. (http://vivus.com). Multiple Phase III clinical trials are nearing or actually have been completed. Variable dosages of both Topiramate and Phentermine were used in these multi-center trials, but the higher dosage combinations produced the greatest weight loss when compared to either Topiramate or Phentermine alone. 93 Adverse reactions/side effects: paresthesias, nausea, dizziness, dry mouth, constipation, and insomnia Clinical Utility: Obesity

Rimonabant: Rimonabant is a cannabinoid receptor-1 (CB-1) antagonist. CB-1 receptors are widely distributed in the central nervous system and modulate the release of GABA, dopamine, noradrenaline, glutamate, and serotonin. These receptors are also present on adipose tissue, GI tract, lung, and peripheral nervous system. Marijuana and tetrahydrocannabinol are two well know CB-1 stimulants which increase high fat and high sweet food intake. Rimonabant has been shown in a number of clinical trials to decrease weight, decrease waist circumference, improve cardiovascular risk factors, i.e., decrease triglycerides, increase HDL, increase LDL particle size, decrease C-reactive protein, increase Adiponectin, decrease glucose and insulin levels, decrease the risk of metabolic syndrome, and assist with smoking cessation. 88-91 Rimonabant was approved in Europe and marketed as Acomplia, however the October of 2008, the European Regulatory Authorities suspended sales. The FDA Advisory Committee did not recommend approval based upon concerns about potential mood and behavioral effects.

Adverse reactions/side-effects: depressed mood or mood changes, anxiety, dizziness, insomnia, nausea, viral gastroenteritis, upper respiratory tract infection, influenza, arthralgia, and fatigue.

Dosage: 5mg to 20mg daily. The most effective dose seems to be 20mg per day.

Clinical Utility: Overweight patients with cardiometabolic risk factors, those with metabolic syndrome or diabetes, or as a smoking cessation aid.

Tesofensine: Tesofensine was originally developed for the treatment of Parkison’s or Alzheimer’s disease. This investigational drug inhibits the presynaptic uptake of noradrenaline, dopamine, and serotonin but was noted to produce weight loss in obese patients with Parkinson’s or Alzheimer’s disease. Phase II trials have just concluded. Adverse reactions/side-effects: dry mouth, insomnia, tachycardia, constipation, nausea, diarrhea, high blood pressure. The highest dose of 1.0mg was associated with increased blood pressure, hostility, and anger. 92 Dosage: 0.25mg, 0.5mg, and 1.0mg Clinical Utility: Overweight and obese patients who may have anxiety or mood disorders. Practical Considerations : Pharmacotherapy is one mainstay of obesity treatment; dietary treatment, motivation, behavior modification, and exercise are the other four. The anorectics always work better for the patients who are working at all the mainstays. I generally prescribe a startup VLCD diet with 1.6 to 2 grams protein/Kg ideal body weight, 20 grams low glycemic carbohydrates, and 20 grams of fat. VLCD here means “very low carbohydrate diet.” The same protein intake should be maintained when the diet is changed to a low calorie diet or to maintenance. I also start them on vitamins and supplements including a multivitamin, calcium, carnitine, chromium and others. After three days on such a diet, hunger and carbohydrate cravings usually disappear 67 and the patient may discover that an anorectic medication is unnecessary. However, an anorectic can be very helpful during the initial three days. Phentermine should be the first choice at startup. Topiramate for patients with Binge Eating Disorder or drug induced weight gain should be started as soon as you make the diagnosis. The medications for carbohydrate cravings such as 5HTP/Carbidopa and Spironolactone usually aren’t necessary until the patient starts eating more than 20 grams of carbohydrates daily. In some patients carnitine will suppress carbohydrate cravings; best to verify the patient is taking or has tried carnitine before prescribing either 5HTP/Carbidopa or Spironolactone. Sooner or later the patient will begin eating more carbohydrates and an anorectic becomes more important. Many patients eventually experience a slow down with their weight loss or reach a plateau. It’s at this point that the addition of ephedrine, 5HTP/Carbidopa, and Spironolactone should be considered. One reason successful maintenance is difficult is that most patients enter a “weight reduced” metabolic state characterized by decreased metabolic rate, decreased sympathetic tone, and low circulating leptin, thyroxin, and tri iodothyronine levels. 68 Continued phentermine, or phentermine and 5HTP/Carbidopa, usually enables the patient to comfortably eat less. Free T3 and free T4 levels should be assayed and, if

either one is low, consideration should be given to treatment to bring the levels up to normal. Leibel and associates have shown that low dose Leptin reverses the syndrome. One day perhaps we’ll have Leptin for our maintenance patients. Bariatric physicians who are treating their patients according to this paper are using the medications “off schedule.” Physicians who prescribe rather than dispense these medications expose themselves to the risk that an over-zealous pharmacist will report the physician to the state medical board for over-prescribing a controlled substance. Some medical boards (including the California Medical Board), will accuse the physician of “indiscriminately prescribing controlled substances” which in their opinion, is grounds for suspending the offending physician’s license to practice.

Physicians who dispense controlled substances in their offices should make themselves aware of DEA regulations and follow them scrupulously. The DEA requires that every pill that come into and goes out of a physician’s office be accounted for. Dispensing logs, patient records, and patient accounts must be kept in exact correspondence. The DEA also expects a precise inventory which must be in exact agreement with invoices of drugs received and with the dispensing logs. The DEA will levy a $5,000 fine for each and every discrepancy their agents can find. If the DEA agents suspect that a physician is deviating from their rules or isn’t cooperative, they have the authority to shutter the physician’s office, seize every asset, and take the physician away in handcuffs. On the other hand, physicians who follow the rules, keep meticulous records, and are cooperative have nothing to fear if DEA agents arrive unexpectedly. The state medical boards vary in their regulation of office dispensing practices; practitioners who wish to dispense medications should be aware of local requirements. Nearly every state board requires a good faith examination of a patient before any medication is prescribed or dispensed. Patients on maintenance on any of the controlled medications should be seen at least once every three months.

Concluding Remarks: Obesity, a chronic metabolic illness with a strong genetic component, is now thought by some to be one of Garrod’s “inborn errors of metabolism.”69 As with any illness with a biochemical basis, pharmacology has been, and will continue to be a mainstay of scientifically driven medical treatment.18, 70, 71 Pharmacologic therapy of obesity, for a variety of reasons, is an emotionally and politically charged subject. Many who oppose the use of anorectic medications or any prescription medications for weight management are misinformed and are opposed for emotional or political reasons. The FDA, to its shame, has repeatedly contributed to the misinformation and has been and continues to be biased against obese patients and weight loss medications. In spite of this, patients with obesity deserve the best treatment modern medicine can offer and this includes any drug in the pharmacopoeia which clinical experience has shown to be useful in treating obesity. The clinician who treats overweight and obese with pharmacotherapy must be exceptionally well informed, be keenly observant, and use sound clinical judgment in prescribing these agents.

Written by Dr. Ed Hendricks, 2007 Revised by Dr. Denise Bruner, 2010

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Ed J. Hendricks, M.D. November 8, 2007