Obesity is a chronic condition that results from energy imbalance, whereby the patient's energy intake exceeds their total expenditure of energy, resulting in weight gain.¹⁾ Obesity is associated with an increased risk of developing chronic illnesses, including hypertension, type II diabetes mellitus, and hyperlipidemia.²⁾ Obesity is defined as a body mass index (BMI) of ≥ 25 kg/m² using the Asian-Pacific guidelines.³⁾ Due to the worldwide, rapid increase in obesity, 32% of the Korean population is considered obese with a BMI ≥ 25.⁴⁾ Therefore, obesity has become a serious public health problem that carries important healthcare-related consequences, including increased costs.

Treatments for obesity typically include diet modification, exercise, medication, and cognitive behavioral therapy. Because people typically become obese due to overconsumption that results from an individual's sensitivity to food stimuli and the pleasure derived from eating, appetite suppressants can be used to control eating behavior, food intake, and, thereby, body weight.⁵⁾ Phentermine is one such appetite regulator. Phentermine is an adrenergic reuptake inhibitor that stimulates the peripheral tissues to secrete noradrenalin. Increased noradrenaline stimulates the β-adrenergic receptors in the hypothalamus to refrain from food intake and activates the sympathetic nervous system to increase resting energy expenditure. The consequence is weight loss. In addition, this medication increases the effects of serotonin (5-hydroxytryptamine, 5-HT) by suppressing monoamine oxidase and preventing 5-HT from being removed by the lungs. Compared to amphetamine, which has a similar chemical structure to phentermine, phentermine does not affect the secretion and resorption of dopamine, so it has been reported that phentermine has a very low chance of substance abuse or misuse.^5-8)

Phentermine was approved in 1959. In the 1990s, combination therapy with fenfluramine was reported as effective for regulating weight loss and metabolism, and thus many combined presubscriptions have been administered by doctors. However, this therapy subsequently demonstrated serious side effects, such as cardiac valve disease, and was pushed out of the market.^9,10) Also, the Committee of the European Agency for the Evaluation of Medicinal Products decided to temporarily prohibit the use of central appetite suppressants because they demonstrated more risks than benefits.^6,10) However, it was also claimed that the assessment of such high risks also included the side effects of fenfluramine (e.g., pulmonary hypertension) and did not exclude the benefits of phentermine. Therefore, it was suggested that research on separate medications was necessary for comparison with long-term research data. It has been reported that the exclusive use of phentermine hardly raises the risk of valvular heart disease or primary pulmonary hypertension.¹¹⁾ There is little data from large-scale studies on the long-term efficacy or safety of phentermine, especially when used as monotherapy. Moreover, there are very few reports on the safety and efficacy of phentermine available on Korean populations. Accordingly, we performed postmarketing surveillance (PMS) research on obese patients who visited hospitals for primary care in order to assess the safety and efficacy of phentermine.

The findings of this study show that more than 45% of the patients who took phentermine lost ≥ 5% of their body weight, demonstrating a mean weight loss of 3.8 kg, which confirms that the medication is significantly effective for weight loss. On the other hand, more than 30% of the patients who took the medication complained of AEs. Although the frequency of AEs was high, only 9.0% stopped taking the medication and no serious AEs were reported.

In this study, 62.0% of patients completed the 12-week phentermine treatment. This completion rate is similar to that reported in an observational study by Kim et al.,¹¹⁾ in which the patients showed a 57.4% completion rate for phendimetrazine, which is also a sympathomimetic drug. In 2005, the Korean Food and Drug Administration (KFDA) recommended short-term (e.g., 4-week) phentermine therapy, which could be followed by an additional 8 weeks following consultation with the patient as long as efficacy was proven. According to this study, only 50% (or possibly more) of first-time patients wanted additional medication after 4 weeks of treatment, and good efficacy was reported. This shows that the recommendations of the KFDA are appropriate, to some extent.

In our study, 45.6% of patients lost ≥ 5% of their total body weight, which was slightly lower than previously reported data (range, 53.9% to 73.6%) by Choi et al.,¹²⁾ and Park et al.,¹³⁾ and who assessed the efficacy of phentermine under similar study conditions. However, the mean weight reduction was 3.8 ± 4.0 kg (5.2% ± 5.0%) in our study, and 559 patients (82.0%) achieved more than 1.8 kg weight reduction. Thus, short-term phentermine therapy is considered relatively safe and effective.

There are several problems with prescribing phentermine continuously. The most troublesome aspect is the possibility of abuse or misuse of these kinds of psychotropic appetite suppressants. Although phentermine does not affect the secretion and reuptake of dopamine, negative viewpoints on central appetite suppressants originate from the addictive qualities of amphetamines. Some patients who experienced desirable results demanded that their physicians extend the application of the medication to > 3 months or repeat the same treatment protocol, which made the physicians uncomfortable. Some patients visit many hospitals in order to receive duplicate prescriptions and take those medications at their discretion. Because these medications are not covered by insurance, the current medical system cannot trace or control such discreet abuse or misuse. Therefore, both the physicians (who prescribe phentermine) and the pharmacists (who compound it) should clearly educate their patients not to abuse or misuse this medication.

AEs of phentermine were very common-about 30% incidence rate-in this study, but in most cases they were mild. Only 9% of patients discontinued the use of this medication due to AEs. Therefore, it can be said that, on the whole, patients demonstrated relatively good tolerance of the medication. The most frequent AEs reported in this study included insomnia (11.0%) and dry mouth (5.6%). Some domestic studies have reported that dry mouth is the most commonly observed AE, while foreign studies often cite headache as the most common.^12,14) Although pulmonary hypertension,¹⁵⁾ hypertrophic cardiomyopathy,¹⁶⁾ and ischemic stroke have been reported as serious AEs following the administration of amphetamine-like analogues, such as phendimetrazine, these rare AEs were not reported in this study. We expected a rise in blood pressure following the administration of this medication, but no significant difference in blood pressure was noted. This could be explained by the fact that any increase in blood pressure may have been offset by the loss of weight. However, phentermine could still result in habitual intake and trigger withdrawal symptoms such as depression, fatigue, anxiety, tremors, and gastralgia when patients suddenly stop taking the medication.

This study found that good compliance and higher BMI were associated with better efficacy and older age was associated with poor efficacy. These findings are different from other studies,¹⁷⁾ one of which reported that patients who demonstrated the best compliance included older patients with chronic diseases and a long history of medications. This discrepancy is believed to originate from the fact that young female patients, and patients with higher social status and income, have a keen interest in obesity treatment and will demonstrate a high level of compliance. It also turned out that combination treatment with other obesity medications reduced body weight. However, it is dangerous to accept these justifications alone because PMS research has its own limitations. Therefore, the efficacy of combination treatments should be compared with those of single medications after the completion of a well-planned clinical trial.

This study is the largest PMS study ever conducted, included almost 800 obese patients, and provides useful data that could be used in the further study of the safety and efficacy of phentermine. Also, our large PMS study is meaningful in the context of the lack of reliable studies done on phentermine. The limitations of this study include the following. First, as we observed the participants for only three months, the efficacy of phentermine could be overestimated in our study. Second, this study did not enroll a control group and demonstrates a low efficacy assessment due to some failure in tracing the enrolled patients. However, regarding the assessment of the AEs and the physical measurement of the patients, only those who participated in the educational sessions were allowed to join this research study, in order to minimize evaluation errors and standardize assessments among the researchers. Finally, we cannot exclude the possibility of underestimating the incidence of mild AEs; patients might not have reported AEs due to lack of awareness. However, if those AEs were too minor to report, it would not affect to compliance or discontinuation of phentermine.

In conclusion, we found that phentermine is significantly effective for weight loss. Although patients complained of insomnia and dry mouth, they demonstrated relatively good tolerance to the medication during this period. However, in order to conquer obesity, which is a chronic disease, obesity medications should be evaluated in terms of their safety and efficacy over the long-term. Therefore, better designed and longer clinical research studies will be necessary in the future.