Effects of phentermine on the brain

Phentermine/Topiramate

Low-dose, controlled-release phentermine plus topiramate (as 1 capsule) was approved by the FDA in 2012 as a long-term treatment for obesity. Phentermine is an adrenergic agonist that promotes weight loss by activation of the sympathetic nervous system with a subsequent decrease in food intake and increased resting energy expenditure. The combination has been shown to have additive weight loss efficacy.97 Phentermine/topiramate is available in 4 doses: 3.75/23 mg (starting dose), 7.5/46 mg (lowest treatment dose), 11.25/69 mg, or 15/92 mg. The majority of patients start on 3.75/23 mg and progress to 7.5/46 mg, with higher doses used if the medication is well-tolerated and maximal efficacy is required; the highest dose is 15/92 mg.

The FDA requires a Risk Evaluation and Mitigation Strategy to inform prescribers and females of reproductive potential about the increased risk of congenital malformation, specifically orofacial clefts, in infants exposed to phentermine/topiramate during the first trimester of pregnancy.98 The most common adverse events (AEs) with phentermine/topiramate ER include: paresthesias, dizziness, dysgeusia, insomnia, constipation, and dry mouth. Medication interactions include an increased risk of malignant hypertension with MAO inhibitors and increased probability of rise in heart rate and blood pressure if used with other sympathomimetic amines.

The 52-week controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER) trial randomized 2487 patients who were obese with a mean BMI of 36.6 kg/m2 and comorbidities including hypertension, dyslipidemia, diabetes or prediabetes, or abdominal obesity to either placebo, mid-treatment dose (7.5/46 mg), or maximum treatment dose (15/92 mg); results showed 6.6% and 8.6% placebo-subtracted weight loss in the lower dose and maximum dose arms, respectively.99 Improvement in systolic and diastolic blood pressure, TGs, and greater increases in HDL were seen in obese and overweight subjects treated with phentermine plus topiramate compared with placebo in 2 phase 3 trials, the Controlled-Release Phentermine/Topiramate in Severely Obese Adults: A Randomized Controlled Trial and CONQUER trials. Improvements in fasting glucose and insulin levels were seen in the SEQUEL study, the 52-week extension of CONQUER, and a 54% and 76% reduction in progression to type 2 diabetes in the 2 treatment groups was noted in subjects without diabetes at baseline.100,101

Urinary tract

Phentermine can cause allergic interstitial nephritis [7].

A 47-year-old mildly obese woman began a weight reduction program that included anorectic therapy with phentermine and phendimetrazine. She had normal renal function at the start of therapy. After 3 weeks of treatment she fell ill and discontinued treatment. She was subsequently found to have leukocyturia, a rash on her face and chest, and a rise in serum creatinine from 67 to 175 μmol/l (0.8–2.1 mg/dl). Renal biopsy confirmed the diagnosis of acute interstitial nephritis. She was treated with corticosteroids, and her renal function returned to normal.

Cardiovascular

In a systematic review of 1279 patients taking fenfluramine, dexfenfluramine, or phentermine, evaluated in seven uncontrolled cohort studies, 236 (18%) and 60 (5%) had aortic and mitral regurgitation respectively [2]. Pooled data from six controlled cohort studies yielded, for aortic regurgitation, a relative risk ratio of 2.32 (95% CI = 1.79, 3.01) and an attributable rate of 4.9% and, for mitral regurgitation, a relative risk ratio of 1.55 (95% CI = 1.06, 2.25) with an attributable rate of 1.0%. Only one case of valvular heart disease was detected in 57 randomized controlled trials, but this was judged unrelated to drug therapy. The authors concluded that the risk of valvular heart disease is significantly increased by the appetite suppressants. Nevertheless, valvulopathy is much less common than suggested by previous less methodologically rigorous studies.

Spontaneous rupture of a retroperitoneal aneurysm occurred in a 70-year-old woman who had been taking phentermine hydrochloride, 30 mg/day, for about 1 month [3]. Other long-term medications included fluoxetine and amitriptyline, and she had no history of coronary artery disease, hypertension, diabetes, or complications of pregnancy. Although it is plausible that phentermine could have contributed to the ruptured aneurysm, other possibilities should be considered, particularly rupture of an anomalous retroperitoneal blood vessel.

Fatal pulmonary hypertension occurred in a 32-year-old man who had been taking phentermine in unknown doses for 4 months [4].

Combined use of fenfluramine and phentermine (“Fen-Phen”) has been associated with varying degrees of valvular regurgitation and pulmonary hypertension. In 57 men and women (30 taking Fen-Phen and 27 controls matched for BMI) chamber dimensions, wall motion, diastolic function, valvular abnormalities, left ventricular ejection fraction, and pulmonary artery pressures were measured [5]. Those taking Fen-Phen were studied shortly after they stopped taking it and again 6–12 months later. The results in these subjects were then compared with the findings in 660 randomly selected cardiac patients with heart disease that was not caused by Fen-Phen. Valvular regurgitation was greatest among patients who had recently stopped taking Fen-Phen, 57% of all valves having regurgitation, 88% of which were “mild”; they also had the largest left ventricles at end diastole (5.03 cm) and systole and higher pulmonary artery pressures (29 mmHg), associated with a lower incidence (14%) of pulmonic regurgitation. The number of people with aortic regurgitation fell with time after the withdrawal of Fen-Phen. However, among those who continued to have aortic regurgitation, there was an increase in the number of those who progressed from mild to moderate regurgitation, with an associated increase in left ventricular end-diastolic and end-systolic dimensions and left ventricular ejection fraction. There was an increase in the incidence of pulmonic regurgitation with time and a fall in pulmonary artery pressure from 29 to 14 mmHg. The incidence of tricuspid and mitral regurgitation fell with time, while pulmonic and aortic regurgitation tended to increase or become more severe when present. Dilatation of the pulmonary ring, resulting from raised pulmonic pressures, with subsequent pulmonary regurgitation and reduced pulmonary artery pressures, appears to be a functional change in the hearts of these individuals with unknown long-term consequences.

Pre-Clinical Research

Phentermine potentiates synaptic 5-HT function in rat predominantly by enhancing the release of this neurotransmitter Tao et al (2002). Until recently, phentermine was widely used in combination with fenfluramine to suppress appetite suppression and enhance weight loss. However, the withdrawal of fenfluramine from the market has led to combining phentermine with fluoxetine, a serotonin reuptake inhibitor. In combination with fluoxetine, phentermine produces greater reductions in food intake and body weight when it is used alone. Long-term reductions in brain dopamine levels were also observed with this combination, possibly reflecting dopamine neurotoxicity. Fluoxetine potentiates both the anorectic and dopamine neurotoxic effects of phentermine, probably by increasing phentermine brain levels Callahan et al (2000).

Pharmacotherapy

Most medications currently available to treat obesity are associated with relatively modest weight loss (Table 40.4). Furthermore, nonresponder rates can be high so that for any agent, only a minority of individuals who initiate therapy in a standard outpatient setting will lose weight. It is uncertain if patients who fail one therapy are more likely to succeed with other class agents.

To date, the most tolerated and effective class of medications for weight loss are GLP1 receptor agonists. These were developed for the treatment of type 2 diabetes mellitus and fortuitously were found to have meaningful effects in reducing appetite and body weight. Effects on appetite with continuous infusion were reported early, and when the first agonist, exenetide, came to market for glucose control in type 2 diabetes mellitus, modest weight loss was noted in many patients. Subsequent studies found that weight loss effects could be extended to obese individuals without diabetes and, further, that it was possible to stratify subjects as responders or nonresponders based on weight loss after 8 weeks of treatment.141 The GLP1-R agonist liraglutide, also used in type 2 diabetes mellitus (marketed as Victoza), and in a higher-dose formulation (Saxenda) has now been approved for obesity management in the United States, Europe, and Japan. Liraglutide provides benefit in terms of reduced rates of nonfatal myocardial infarction and stroke and cardiovascular death in patients with diabetes and established or at high risk for cardiovascular disease.142 Semaglutide has also been recently approved for management of type 2 diabetes mellitus with once-weekly dosing. Semaglutide may also reduce the rate of nonfatal myocardial infarction or stroke or cardiovascular death in patients with type 2 diabetes mellitus at high cardiovascular risk.143 Whether these agents will provide similar cardiovascular benefits in reducing cardiovascular risk in obese individuals is unclear. When administered at lower daily doses, it leads to weight loss in obese nondiabetic individuals. In a direct comparison of semaglutide and liraglutide, weight loss at 0.3 mg of semaglutide daily resulted in mean weight loss of 12.3% compared with mean weight loss of 8.3% in those randomized to 3.0 mg of liraglutide.144 Currently, most GLP1 receptor agonists are administered by subcutaneous injection. Headache and gastrointestinal events such as nausea, vomiting, diarrhea, or constipation represent the major side effects that limit use of GLP1 receptor agonists.

Phentermine is a sympathomimetic that was approved for obesity treatment in 1959. It stimulates the release of norepinephrine, and to a lesser extent serotonin (5-hydroxytryptamine [5HT]) and dopamine. Weight loss with phentermine is approximately 5% at 8 to 12 weeks, and typically is administered at 15 mg to 37.5 mg orally three times daily with meals as a short-term adjunct (a few weeks) to behavioral weight loss approaches. A lower 8-mgdose for longer-term use is available, but durability has not been reported. The clinical effect of phentermine is to diminish appetite, and it appears to work better in individuals who start with greater hunger and less cognitive restraint on their eating behavior.145 Side effects of phentermine can include pulmonary hypertension, valvular heart disease, palpitations, increased heart rate or blood pressure, insomnia, restlessness, dry mouth, diarrhea, constipation, and changes in sexual drive.

Phentermine

Phentermine stimulates the release of norepinephrine, and to a lesser extent serotonin (5-HT, 5-hydroxytryptamine) and dopamine, from nerve terminals. Only one RCT, published in 1968, evaluated the effect of at least 8 months of phentermine therapy on body weight.334 In that study, 108 obese women were randomized to receive an LCD and treatment with either daily phentermine (30 mg/day), daily phentermine every other month alternating with daily placebo every other month, or daily placebo for 36 weeks. Of the 64 subjects who completed the study, those randomized to either continuous or every-other-month phentermine therapy achieved the same 13% weight loss, which was greater than the 5% weight loss observed in the placebo group. In a more recent trial, subjects who completed 28 weeks of therapy with one half (15 mg/day) or one fourth (7.5 mg/day) the usual dose of phentermine had a 7.4% and 6.7% weight loss, respectively, compared with 2.3% weight loss in the placebo group.335 The most common side effects of phentermine are dry mouth, insomnia, and constipation. Although all sympathomimetic agents can increase blood pressure and heart rate, these abnormalities usually do not occur with phentermine therapy in the presence of weight loss.

Phentermine

Phentermine is a medication structurally similar to amphetamine that has been approved for years for short-term weight loss. Phentermine was first introduced in 1959 and is by far the oldest prescription medication approved for weight loss that is still available by prescription on the US market. Phentermine is a sympathomimetic amine that works on the central nervous system to suppress appetite.14 It has been shown to stimulate the release of norepinephrine in the hypothalamus, with no effects on serotonin.15 It is dosed up to 37.5 mg/day for short-term obesity treatment. Clinical trials performed in the 1970s and 1980s demonstrated around a 6.3-kg weight loss affect with phentermine, compared with 2.8 kg with placebo.16 As mentioned, it was combined with fenfluramine in the 1990s but was found not to be implicated in the severe valvular dysfunction and pulmonary hypertension that patients experienced with Fen-Phen use. While older trials did not include the same benchmarks for weight loss, a more recent 12-week trial conducted in Korea evaluated a novel release form of phentermine compared with placebo for short-term weight loss. They showed an overall body weight reduction of 8.1 ± 3.9 kg with 30 mg of phentermine compared to 1.7 ± 2.9 kg in placebo.17 In that study, 95.8% of subjects attained ≥ 5% weight loss compared with 20.8% of placebo, and 62.5% attained ≥ 10% weight loss compared with 4.7% in placebo (P < .001).17 It should be noted, however, that there were only 37 subjects in each treatment group, which greatly influenced these percentages. While phentermine was determined not to have caused the severe cardiac effects of Fen-Phen, the package insert still warns of the risk of cardiomyopathy, and anyone with a history of heart problems should not take phentermine. Side effects associated with phentermine include dry mouth, insomnia, dizziness, and increased heart rate. Phentermine's use is contraindicated in patients with glaucoma, hyperthyroidism, cardiovascular disease, including uncontrolled hypertension, and patients with a history of drug abuse.14 There is a drug interaction between phentermine and monoamine oxidase inhibitors (MAOIs), and these should not be used concurrently. Phentermine may also decrease the efficacy of adrenergic blocking drugs. It has abuse potential and is classified as a schedule 4 controlled substance. Due to the FDA approving phentermine for short-term treatment, patients should only be using it for 12 weeks or less.

6.18.6.2.3.2 Indications

Phentermine is approved as a short-term (a few weeks) adjunct in a regimen of weight reduction based on exercise, behavioral modification, and caloric restriction in the management of exogenous obesity for patients with an initial BMI≥30 kg m−2, or ≥27 kg m−2 in the presence of other risk factors (e.g., hypertension, diabetes, hyperlipidemia).

Phentermine received a great deal of attention as the result of a comprehensive study published in 1992 that was supported by the National Heart, Lung and Blood Institute of the National Institutes of Health.7 This study, which combined phentermine with the drug fenfluramine, showed the clear benefit of this drug combination on significant long-term weight loss, and the drug combination became known as phen-fen. This spurred a tremendous increase in the prescribing of phentermine to be used in combination with fenfluramine until fenfluramine's removal from the market in 1997.

Clinical data on the potential long-term effectiveness of phentermine alone are sparse. Yet, in studies ranging from 6 to 9 months, phentermine appears to retain its efficacy and may actually have better efficacy than fenfluramine9 over the treatment periods studied.

Phentermine and Diethylpropion

Phentermine and diethylpropion are noradrenergic sympathomimetic agents, but unlike amphetamine, they are not dopaminergic [17]. It has been shown in a meta-analysis that both resulted in modest weight loss in combination with lifestyle modifications. The mean weight loss at 6 months was 3.6 kg (95% CI 0.6–6.0) and 3.0 kg (95% CI −1.6 to 11.5) for phentermine and diethylpropion, respectively [18]. Common side effects include tachycardia, headache, raised blood pressure, insomnia and irritability. They should be used with caution in hypertensive patients. Phentermine is approved by the US FDA as an anti-obesity drug only for short term (up to 12 weeks) [4,5]. The recommended dose for phentermine is 15–37.5 mg daily before breakfast or 10–14 h before bedtime.

Phentermine/Topiramate

Phentermine/Extended-Release Topiramate (PHEN/ER TOP), Qnexa®, was the first combination of central acting drugs approved by FDA in 2012 for long-term treatment of overweight/obesity in adults (Yanovski and Yanovski, 2014). Topiramate is an anticonvulsant drug, used also for bipolar disease and in migraine-prophylaxis (Food and Drug Administration (FDA), 2012). It is known to inhibit carbonic anhydrase activity, block voltage-dependent sodium channel, and antagonize kinate subtype glutamate receptors (Kramer et al., 2011). The exact mechanisms associated with topiramate-induced BW loss are still unclear, although an anorectic action has been postulated following carbonic-anhydrase inhibition on taste and the activation of γ-aminobutyric acid (GABA)-A receptor in the lateral hypothalamus known to interact with leptin pathway (Turenius et al., 2009). The observation of BW loss following administration of topiramate, led to its evaluation as a possible antiobesity agent (Bray et al., 2003; Astrup et al., 2004). A meta-analysis of 10 RCTs reported a significant weight loss in overweight-obese patients treated with topiramate versus placebo, furthermore patients losing ≥ 5% and ≥ 10% were significantly more in the topiramate group; interestingly, the weight-losing effect of topiramate increased with dosage and duration of treatment, while it resulted independent of the presence of diabetes (Kramer et al., 2011). In diabetic subjects, topiramate monotherapy 96–192 mg compared to placebo (alone or in combination with lifestyle interventions and/or metformin or sulfonylurea), showed a significantly higher BW and BMI reduction associated to a significant reduction of HbA1c (Paravattil et al., 2016). Weight-loss treatment with topiramate resulted associated to a twofold incidence of side effects (paresthesia, taste perversion, psychomotor disturbances, and hypoesthesia, memory/attentional difficulties, dizziness), especially with higher doses (greater than 96 mg/day) (Kramer et al., 2011; Paravattil et al., 2016). Both topiramate and phentermine were proved to reduce BW, but their use was limited by the activation of biological compensatory mechanisms and the high incidence of side effects and adverse events reported at efficient doses. Clinical studies comparing the efficacy of the two single molecules versus their combination highlighted the superiority of the association on weight reduction (Singh and Kumar, 2015). The latter achieved results at lower doses of each component (because of their complementary and synergic effect on appetite regulation and energy balance) (Bays, 2010). The authorization of PHEN/ER TOP followed a RCT conducted on 2487 overweight-obese patients with BMI 27–45 kg/m2 and at least two metabolic comorbidities (CONQUER) (Gadde et al., 2011). Diabetic subjects were included, without lower BMI limit, treated with lifestyle or metformin monotherapy. Participants were randomized at PHEN/ER TOP 15/92 mg once daily, PHEN/ER TOP 7.5/46 mg once daily or placebo, in addition to standardized counseling on diet (− 500 kcal/day) and lifestyle modifications. After 56 weeks both PHEN/ER TOP groups showed significantly greater weight loss (− 12.4% for PHEN/ER TOP 15/92, − 9.6% for PHEN/ER TOP 7.5/46 mg, − 1.6% or placebo) with a significantly higher proportion of patients achieving ≥ 5% and ≥ 10% weight reduction compared to placebo (70% in PHEN/ER TOP 15/92 mg, 62% in PHEN/ER TOP 7.5/46 mg, 21% in placebo group); a subanalysis restricted to diabetic patients showed even greater results on weight loss (Garvey et al., 2014). Results on BW after 56 weeks, were confirmed in the EQUIP study, conducted on higher-BMI subjects (BMI ≥ 35 kg/m2, mean BMI 42.0 kg/m2), in whom the administration of PHEN/ER TOP 15/92 mg once daily induced significantly higher body reduction compared to PHEN/ER TOP 3.75/23 mg once daily and placebo (PHEN/ER TOP 15/92 > PHEN/ER TOP 3.75/23 mg > placebo). Furthermore, results were independent by baseline BMI (Allison et al., 2012). In the CONQUER trial, the superiority of PHEN/ER TOP versus placebo concerned also significant improvements in cardiovascular risk factors (blood pressure/hypertensive treatments, waist circumference, lipid profile/lipid lowering medications, blood glucose, inflammatory biomarkers) (Gadde et al., 2011); this difference was confirmed in higher-BMI subjects between PHEN/ER TOP 15/92 mg and placebo, but not always between PHEN/ER TOP 3.75/23 mg and placebo (Allison et al., 2012). Both the RCTs reported a slight improve in heart rate in PHEN/ER TOP patients compared to placebo (Gadde et al., 2011; Garvey et al., 2014; Allison et al., 2012; Vorsanger et al., 2016). Phentermine/ER Topiramate has been proved to improve glycemic control in diabetic patients: after 56 weeks, patients taking PHEN/ER TOP 15/92 mg daily exhibited greater reduction in HbA1c and greater reduction in antidiabetic medications compared to placebo; furthermore a greater portion of PHEN/ER TOP-treated subjects achieved HbA1c targets (Gadde et al., 2011; Allison et al., 2012; Davidson et al., 2013). Concerning OSA, a RCT was conducted on 45 subjects with BMI 30–40 kg/m2 diagnosed with moderate/severe OSA but unable or unwilling to comply with CPAP treatment, treated with PHEN/ER TOP or placebo: PHEN/ER TOP patients experienced a significant improve in apnea/hypopnea index (AHI) already at 8 weeks and further at 28 weeks, as well as in additional OSA parameters and self-assessed quality of sleep (Winslow et al., 2012). Durability of Phentermine/ER Topiramate was analyzed in the SEQUEL study (an extension of the Conquer trial): after 108 weeks, the significant difference between placebo and both PHEN/ER TOP groups with respect to weight loss and cardiovascular risk factors was sustained (− 1.8% for placebo, − 9.3% for 7.5/46 PHEN/ER TOP, and − 10.5% for 15/92 mg PHEN/ER TOP). A higher percentage of subjects treated with both doses of PHEN/ER TOP experienced weight losses of 5%, 10%, 15%, and 20% when compared with placebo-treated subjects. As seen at 56 weeks, PHEN/ER TOP resulted effective in all BMI categories; interestingly, both the 7.5/46 and 15/92 mg doses were statistically similar in their effectiveness in the lower baseline BMI, whereas, for BMI 40–45 kg/m2, the 15/92 mg group showed a significantly greater weight loss than the 7.5/46 mg group (Garvey et al., 2012). Among cardiovascular risk factors: blood pressure reduction was similar between treatment arms, but PHEN/ER TOP experienced a reduction in hypertensive medications; fasting glucose, insulin concentrations, incidence of diabetes and diabetes progression rate were significantly reduced in PHEN/ER TOP groups; also, triglycerides decreased and HDL cholesterol increased more in PHEN/ER TOP groups than placebo. Phentermine/ER Topiramate is currently approved at doses of 3.75/23, 7.5/46, and 15 mg/92 mg (recommended dose) for long-term overweight/obesity management. The side effects are due to both components of the drug. The most frequently reported are dry mouth, paraesthesia (sometimes causing drug discontinuation), constipation, upper respiratory tract infection/nasopharyngitis, dysgeusia (at higher doses), depression (Gadde et al., 2011; Garvey et al., 2014, 2012; Allison et al., 2012). Phentermine/ER Topiramate is contraindicated in pregnancy (for fetal toxicity by topiramate) (Hernández-Díaz et al., 2017), glaucoma, hyperthyroidism, during or within 14 days of taking monoamine oxidase inhibitors. Heart rate, mood disorders, and suicidal ideation must be monitored during treatment (Food and Drug Administration (FDA), 2017). With regards to cardiovascular safety, the RCTs conducted so far have shown a reduction in cardiovascular risk factors with no cardiovascular events reported in treated patients. Given the previous reports of palpitation, blood pressure elevation, and cardiac injuries due to phentermine (and its consequent limitation), data on blood pressure after Phentermine/ER Topiramate indicate that the metabolic benefit overcomes the sympathomimetic effect (Vorsanger et al., 2016).