What are Phentermine and Diethylpropion?

Phentermine and Diethylpropion: FDA-Approved Sympathomimetic Appetite Suppressants

Phentermine and diethylpropion are sympathomimetic amine medications FDA-approved for short-term (12 weeks) weight loss treatment in adults with obesity or overweight with weight-related complications, used adjunctively with lifestyle modifications including caloric restriction and increased physical activity. 1

Mechanism of Action

Phentermine

• Acts as a sympathomimetic amine with pharmacologic activity similar to amphetamines, though the exact mechanism remains incompletely understood. 2
• Promotes weight loss by activating the sympathetic nervous system, decreasing food intake and increasing resting energy expenditure. 3
• Works through central nervous system stimulation and elevation of blood pressure, though whether the primary action is purely appetite suppression versus other metabolic effects remains unclear. 2

Diethylpropion

• Functions as a sympathomimetic amine with CNS stimulant properties, but is chemically modified to limit CNS stimulation and blood pressure elevation compared to other amphetamine derivatives. 1
• Rapidly absorbed from the GI tract and extensively metabolized through N-dealkylation and reduction pathways. 4
• Active metabolites cross the blood-brain barrier and have plasma half-lives of 4-6 hours. 4

FDA Approval Status and Clinical Use

Approved Indications

• Both drugs are FDA-approved only for short-term use (12 weeks) in adults 18 years and older with obesity or overweight who have not responded adequately to lifestyle interventions alone. 1, 5
• Phentermine was approved in 1959; diethylpropion in 1959. 1, 6
• These drugs were approved when obesity was considered a curable condition—a concept now proven incorrect—which explains the short-term approval despite obesity being a chronic disease requiring long-term management. 1

Off-Label Long-Term Use

• Many practitioners use both medications longer than 12 weeks in an off-label fashion given the chronic nature of weight management. 1
• Phentermine is the most commonly used drug for treating obesity in the United States and has been used successfully off-label for long-term treatment since 1959. 6

Dosing

Phentermine

• Available as 15 mg or 30 mg capsules (equivalent to 12 mg and 24 mg phentermine base). 2
• Recommended dosage is 15-37.5 mg orally once daily in the morning, with dosage individualized to achieve adequate response with the lowest effective dose. 3
• Low-dose phentermine (8 mg) can be prescribed up to 3 times per day, and some clinicians use doses as low as 4 mg on an "as needed basis" before situations with high risk of hedonic food consumption. 1, 3

Diethylpropion

• Available as 25 mg immediate-release tablets (taken 3 times per day before meals) or 75 mg extended-release tablets (taken once daily in the morning). 1

Efficacy

Phentermine

• In clinical trials, adult obese subjects treated with anorectic drugs lost more weight on average than those treated with placebo and diet, though the magnitude of increased weight loss is only a fraction of a pound per week. 2
• Weight loss is greatest in the first weeks of therapy and tends to decrease in succeeding weeks. 2

Diethylpropion

• Mean difference for percent total body weight loss was 5.36% (95% CI, 3.50%-7.23%) favoring diethylpropion over placebo. 1
• Absolute weight loss showed a mean difference of 4.74 kg (95% CI, 3.08-6.40 kg) compared to placebo. 1
• Greater proportions achieved 5% total body weight loss (58.3% vs 42.3%) and 10% total body weight loss (27.4% vs 15%) with diethylpropion versus placebo. 1

Cardiovascular Considerations and Contraindications

Critical Safety Warnings

• Both phentermine and diethylpropion should be avoided in patients with a history of cardiovascular disease or uncontrolled hypertension. 1, 7
• Blood pressure and heart rate should be monitored periodically while taking either medication. 1
• Phentermine can cause mild increases in heart rate and blood pressure. 3

Important Distinction from Fenfluramine

• These drugs should not be confused with the previously available "fen-phen" combination (phentermine with fenfluramine), which was associated with valvular heart disease and pulmonary hypertension. 5
• Concerns about pulmonary hypertension with diethylpropion are largely based on cases where patients also used other anorectics including fenfluramine. 1

Additional Contraindications

• Should not be used in patients with untreated hyperthyroidism due to concerns for arrhythmias and seizures. 1
• Must be avoided in patients treated with, or within 14 days of, monoamine oxidase inhibitors. 1
• Should not be used with other sympathomimetic amines due to potential serious interactions. 3

Common Adverse Effects

Phentermine

• Constipation, dry mouth, palpitations, insomnia, and irritability. 1
• Restlessness, tremor, hyperreflexia, rapid respiration, confusion in overdose. 2

Diethylpropion

• Constipation, dry mouth, insomnia, headache, and irritability. 1
• Chemical modification results in less potential for CNS stimulation and blood pressure elevation compared to other amphetamine derivatives. 1

Abuse Potential

• Diethylpropion is classified as a Schedule IV controlled substance based on concerns for abuse and dependence. 1
• Both drugs have some potential for abuse, though less than amphetamines. 8
• Manifestations of chronic intoxication include severe dermatoses, marked insomnia, irritability, hyperactivity, personality changes, and in severe cases, psychosis clinically indistinguishable from schizophrenia. 2

Age Considerations

• Clinical trials for phentermine-topiramate extended-release enrolled subjects up to age 70, but high-quality data specifically guiding phentermine use in the geriatric population is limited. 5
• Guidelines consistently refer to use in adults 18 years of age or older. 5

Clinical Guideline Recommendations

AGA 2022 Guidelines

• The AGA conditionally suggests using phentermine with lifestyle modifications in adults with obesity or overweight with weight-related complications (conditional recommendation, low certainty evidence). 1
• The AGA conditionally suggests using diethylpropion with lifestyle modifications in adults with obesity or overweight with weight-related complications (conditional recommendation, low certainty evidence). 1
• The evidence was deemed low certainty due to lack of long-term data (most trials were 3-12 months duration). 1

Monitoring and Discontinuation

• Discontinue phentermine if 5% weight loss is not achieved after 12 weeks on maximum dose. 3
• If using long-term beyond FDA-approved duration, document specific benefits, tolerance, and adverse effects. 5
• Start with the lowest effective dose and titrate carefully. 3

Alternative Considerations

• Orlistat may be a safer alternative for patients with cardiovascular concerns as it works by inhibiting gastrointestinal lipases rather than affecting the sympathetic nervous system. 3
• Orlistat blocks absorption of approximately 30% of ingested fat. 3

Key Clinical Pitfalls

• Both drugs are generic and inexpensive, making them accessible options, but have been inappropriately maligned because their two-dimensional structure diagrams resemble amphetamine. 6
• The short-term FDA approval does not reflect current understanding of obesity as a chronic disease requiring long-term management. 1
• When used appropriately as part of a comprehensive weight-reducing program including regular dietary counseling, these appetite suppressants can provide real therapeutic benefit with little risk. 8