© Springer International Publishing Switzerland 2015
Andrea Lenzi, Silvia Migliaccio and Lorenzo Maria Donini (eds.)Multidisciplinary Approach to Obesity10.1007/978-3-319-09045-0_2323. Prescription Medications for the Treatment of Obesity
(1)
Division of Endocrinology, Department of Medical and Surgical Science, Centre for Applied Biomedical Research (C.R.B.A.), S. Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
(2)
Division of Endocrinology, Department of Medical and Surgical Science, S. Orsola-Malpighi Hospital, University Alma Mater Studiorum, Via Massarenti 9, 40138 Bologna, Italy
23.1 Introduction
Modifications in lifestyle remain the most important aid to effectively tackle obesity, but the low rate of success in most obese subjects and the need for continued intervention, not always accessible due to elevated health care costs, have limited the efficacy of this approach. On the other hand, bariatric surgery represents an alternative remedy with a high rate of stable and significant success in body weight reduction and consequent cardiometabolic parameter amelioration. However, it is hard to hypothesize that this option could be applied on a large scale due to the high costs, the inherent surgical risks, and the maladaptive postoperative compliance from some patients [1].
Taking into account the limitations provided by lifestyle changes and bariatric surgery mentioned above, one might conclude that there could be some room for the pharmacological approach to obesity. However, the last 30 years have produced poor results and limited success in generating drugs devoid of important side effects to tackle obesity and its comorbidities. This has caused pharmaceutical companies to substantially reduce investments in research and development in this field.
23.2 The Pharmacotherapy of Obesity Between Guidelines and Regulatory Agencies
Recently, new guidelines for the management of overweight and obesity in adults have been approved in the USA [1]. The concept has been reinforced that all patients for whom weight loss is recommended should be offered or referred for comprehensive lifestyle intervention. It has also been reestablished that if a patient presents with a body mass index (BMI) ≥30 or ≥27 with comorbidities and is unable to lose weight or to sustain weight loss with comprehensive lifestyle intervention, pharmacological therapy should be taken into account to help achieve targeted weight loss and to prevent diseases. However, it is clearly stated that medications should be approved by the regulatory agencies, and clinicians should know what the benefits and health risks of the prescribed medication are. Medications work to reinforce lifestyle change and should be prescribed only as an adjunct to a good quality lifestyle intervention [1]. This issue should be mandatory, but it is not always taken into account by the companies developing antiobesity drugs when the clinical trials are designed to obtain drug approval. With few exceptions, indeed, the majority of the phase 2 and 3 trials and most of the non-sponsored studies include lifestyle intervention at low level of priority.
The regulatory point of view in this issue varies between US and European agencies. According to the American Food and Drug Administration (FDA) draft guidance, the efficacy of a 1-year treatment with an antiobesity drug should meet one of these two conditions: (I) the difference in weight change from the baseline between the treatment group and placebo is 5 %, and (II) the number of patients in the treatment group that obtains this weight gain is at least 35 % and approximately double the number of subjects in the placebo group. On the other hand, European Medicines Agency (EMA) require antiobesity drugs to satisfy the following two criteria: (I) a weight loss of at least 10 % of baseline weight and (II) a magnitude of weight loss significantly different from the placebo group treated with lifestyle intervention. However, after the position statement regarding the antidiabetic drugs issued by the Endocrinologic and Metabolic Drugs Advisory Committee in 2008, the FDA Advisory Committee established in March 2012 that the evaluation of antiobesity drugs should be made after their effectiveness in reducing cardiovascular risk had been assessed. Briefly, a two-step process is required to establish the cardiovascular safety of any antiobesity drug, consisting of a randomized cardiovascular event-driven trial before approval and a longer and larger trial after approval. Moreover, preliminary trials in the highest risk population are required to consolidate the findings.
23.3 Drugs Approved for Short-Term Use
Amphetamines and their analogues (phentermine, benzphetamine, phendimetrazine, and diethylpropion) were approved long time ago by the FDA.
In September 1999, the EMA recommended their withdrawal from the market because of their unfavorable risk to benefit ratio. However, the FDA still allows these drugs to be marketed in the USA, limiting their use to only the short term (<12 weeks) due to the risk of abuse in obese patients who do not respond to lifestyle modifications [2].
Among the analogues of amphetamine, phentermine represents the most prescribed antiobesity drug in the USA, and a meta-analysis of many randomized control trials (RCTs) showed that subjects treated with phentermine alone lost 3.6 kg compared to placebo [3]. Its use is now showing a novel rapid revival due to the new combo formulation with topiramate recently approved by the FDA (see below). Phentermine is commercially available in the USA in different formulations (hydrochloride salt, resin, or disintegrating tablets), and the recommended daily doses are up to 30 mg/day for the orally disintegrated tablets.
The major side effects of this class of drugs are insomnia, dry mouth, and anxiety. These effects are usually transient, and they do not differ between subjects receiving continuous versus intermittent therapy. More serious uncommon complications in prolonged use include primary pulmonary hypertension and cardiovascular or cerebrovascular events, hyperthyroidism, and glaucoma. Obviously, due to their mechanism of action, they are also contraindicated in individuals with psychiatric disorders, including anorexia, depression, or in patients at risk of drug dependency [2].
23.4 Drugs Approved for Long-Term Use
23.4.1 Orlistat
Orlistat is a gastrointestinal lipase inhibitor approved for use in adults and adolescents aged 12–16 years. It does not act directly on appetite, but decreases fat absorption to approximately 30 % of intake.
Orlistat’s long-term efficacy (120 mg three times daily) was demonstrated in several RCTs of 2–4 years’ therapy [4]. The results of these studies appear similar: orlistat reduces weight about 2.9 % more than placebo and increases the absolute percentage of participants achieving 5 % weight loss by about 21 %. Furthermore, the XENDOS study, a 4-year RCT of 3,305 nondiabetic obese patients, showed that orlistat reduced the risk of developing T2DM by 37.3 % compared to only lifestyle modification [5]. Orlistat has demonstrated its efficacy also in diabetic subjects: in a multicenter 57-week RCT, 120 mg orlistat or placebo was administered to 391 obese subjects with T2DM. The orlistat group lost about 2 kg more than the placebo group and twice as many patients receiving orlistat lost > or = 5 % of their initial body weight. Orlistat treatment was also associated with significant decreases in HbA1c, fasting plasma glucose, total cholesterol, LDL cholesterol, LDL/HDL cholesterol ratio, and triglycerides. The most commonly experienced side effects of orlistat are due to its mechanism of action and include diarrhea, fecal incontinence, flatulence, and abdominal pain [5]. Recently, FDA undertook a review of orlistat treatment safety, which identified a total of 13 cases of serious liver injury [2].
23.4.2 Lorcaserin
Lorcaserin is a selective serotonin (5HT) 2C receptor agonist, sharing characteristics similar to fenfluramine. The tolerability and efficacy of lorcaserin for the treatment of obesity were evaluated in three large RCTs, which provided the basis for FDA approval in June 2012.
In the BLOSSOM RCT, 4,008 obese or overweight patients with obesity-related comorbid conditions were randomized to receive either lorcaserin 10 mg/die (QD), lorcaserin 10 mg twice daily (BID), or placebo for 52 weeks. Weight loss was 4.7, 5.8, and 2.9 kg, respectively, similar among males and females, but higher in Caucasian patients than African-American or Hispanic patients. The percentages of subjects achieving 5 % or greater weight loss were 47.2, 40.2, and 25 % for lorcaserin BID, lorcaserin QD, and placebo, respectively [6].
The BLOOM RCT evaluated 3,182 patients for 2 years with similar results [7]. The BLOOM-DM RCT evaluated the safety and efficacy of lorcaserin in 604 patients with T2DM. Weight loss was approximately 5 kg for lorcaserin and 1.6 kg for placebo. The study found that 45 % of lorcaserin QD achieved at least a 5 % weight loss (16 % in the placebo group). Approximately half of the patients in the lorcaserin treatment arm obtained an HbA1c level <7 %, almost twice the rate in the placebo group [8]. Lorcaserin is generally well tolerated: the most frequent adverse reactions are headache, dizziness, and nausea. There was no increase in cardiac valvulopathy rate after a 2-year treatment with lorcaserin [6–8]. Considering its mechanism of action, extreme caution should be used when prescribing lorcaserin to patients taking a selective 5HT reuptake inhibitor or 5HT-NA reuptake inhibitor due to the potential for 5HT syndrome [6–8]. Lorcaserin was approved by the FDA as an antiobesity drug (Belviq®), whereas a few months later the marketing authorization application of lorcaserin in Europe was rejected by the EMA; the manufacturer of this drug then withdrew its application in Europe [9].
23.4.3 Topiramate and Phentermine Combo
Topiramate is an anticonvulsant drug approved for adjunctive treatment of partial onset and generalized tonic-clonic seizures. Its mechanism of action is not fully understood: it may include blockage of voltage-activated sodium channels, glutamate-receptor antagonism, inhibition of high-voltage-activated calcium channels, inhibition of carbonic anhydrase, and enhancing of gamma-aminobutyric acid-evoked currents [10]. For many years, topiramate alone has been demonstrated to be able to determine weight loss. A meta-analysis of 10 RCTs (3,320 individuals overall) showed that patients treated with topiramate lost an average of 5.34 kg more than with placebo [10]. Topiramate is quite well tolerated, especially at doses of 192 mg/die or less. Paresthesias are frequently experienced by patients. Other adverse effects are fatigue, depression, and difficulty with memory [10]. Finally, topiramate is contraindicated in pregnancy for its teratogenic effects [10].
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