The purpose of this research study is to understand the long-term effects of the drug phentermine on weight, blood pressure, other health outcomes, and safety. Phentermine has been approved by the US Food and Drug Administration (FDA) for weight management since 1959, but it has not been approved for long-term use (i.e., treatment lasting more than 12 weeks). This trial is designed to learn about the long-term effects of phentermine for up to 2 years because obesity is a chronic disease and expert guidelines recommend long-term use of anti-obesity medications as one treatment option.

The Long-term Effectiveness of the Anti-obesity medication Phentermine (LEAP) trial, a placebo-controlled, randomized trial, will be conducted at 5 clinical sites across the United States. All participants will be provided with an evidence-based online lifestyle intervention, and participants receiving 24 mg/day of phentermine vs. a placebo for up to 24 months will be compared in an intent-to-treat fashion. The co-primary outcomes of percent weight loss and change in systolic blood pressure at 24 months will be examined. Also, between group changes in drivers of energy balance, including resting metabolic rate, caloric intake, physical activity and dietary composition will be compared. To explore the effects of weight loss on cardiometabolic health, changes in heart rate, hemoglobin A1c, lipids, waist circumference, atherosclerotic cardiovascular disease (ASCVD) risk score, and novel ECG markers of cardiac strain will be compared. Overall adverse event and serious adverse event rate, including rates of incident cardiovascular disease or death, will be measured.

Inclusion Criteria:

• BMI 30-44.9 kg/m2 or BMI 27-29.9 with weight related comorbidity (including hypertension, prediabetes, type 2 diabetes mellitus, dyslipidemia, nonalcoholic fatty liver disease, treated obstructive sleep apnea, osteoarthritis, low back pain, gastroesophageal reflux disease)
• English-speaking
• Has a smartphone or other device with regular internet access
• Interested in and willing to lose weight as a result of treatment
• Able to take oral medication and willing to adhere to the clinical visit schedule for the trial and lifestyle based treatment regimen throughout the study duration, as recommended by the study clinician
• For females of reproductive potential: use of effective contraception for at least 1 month prior to randomization and agreement to use such a method during study participation and for an additional 8 weeks after the end of study drug administration
• Provision of electronically-signed consent form
• Stated willingness to comply with all study procedures and availability for the duration of the study

Exclusion Criteria:

• History of coronary artery, cerebrovascular or peripheral arterial disease including myocardial infarction, unstable angina, revascularization, stroke/TIA, carotid intervention, claudication
• Poorly-controlled blood pressure (>149/94) or elevated heart rate (>110 bpm)
• History of cardiac arrhythmia
• Active / currently-treated hyperthyroidism
• History of glaucoma or been told by an ophthalmologist that you are at high risk for glaucoma
• Heavy alcohol use within the last 6 months (men: more than 4 drinks on any day or more than 14 drinks per week; women: more than 3 drinks on any day or more than 7 drinks per week)
• History of substance use disorder or active use of illicit substances within the last 12 months. Tetrahydrocannabinol (THC)-containing products will not be considered an illicit substance.
• Use of a drug in the monoamine oxidase inhibitor class, currently or within the last 14 days
• Currently pregnant or lactating/breastfeeding; intention to get pregnant in next 24 months; seeking or in active treatment for infertility
• End-stage renal disease on dialysis or CKD class IV or higher (eGFR <30)
• History of valvular heart disease
• Congestive heart failure (any history or current)
• Cirrhosis or symptoms of liver failure in the last 2 years
• Severe pulmonary disease requiring supplemental oxygen
• Quit using nicotine-containing products less than 6 months prior to baseline visit or intention to quit use in the next 2 years
• Use of oral corticosteroids more than 5 days/month in the last 3 months
• Elevated depressive symptoms
• Uncontrolled anxiety symptoms
• Hospitalization for mental illness in the last 24 months
• Diagnosis of dementia or serious mental illness (e.g., schizophrenia, bipolar disorder, severe depression)
• Binge Eating Disorder, Bulimia or Anorexia Nervosa diagnosis or treatment within the last 2 years
• Prior procedure for weight control (including bariatric surgery, devices)
• Use of phentermine, phentermine-containing medication, or anti-obesity medication with similar mechanism of action to phentermine (e.g., phendimetrazine or diethylpropion) in the previous 24 months
• Use of any non-phentermine-containing medications prescribed for weight loss in previous 12 months
• Unstable dose of weight-loss-promoting medications within the last 12 months. Weight-loss-promoting medications are medication prescribed for another condition, but are known to have weight loss effects. Examples would include use of a GLP1 agonist or SGLT2 inhibitor in patients with diabetes; use of topiramate among patients with migraine headaches.
• Use of any stimulant medications in previous 12 months
• Known allergy or intolerance to phentermine or phentermine-containing medication
• Documented or self-reported weight change (gain or loss) of more than 5% of current body weight in the past 3 months
• History of cancer other than non-melanoma skin cancer in the past 5 years
• History of organ transplantation
• Plan to move outside the area in the next two years
• Unable to make changes to diet (e.g., severe food allergies or intolerances; medically necessary aspects of diet incompatible with intervention)
• Already participating in another research study that includes lifestyle changes and/or study medication or has participated in such a study within the last 12 months
• Total body weight that exceeds 400 lbs., precluding use of the digital scale in the lifestyle intervention
• Upper arm circumference that exceeds 50 cm, precluding use of the OMRON HEM 907 XL to measure blood pressure
• Other concern or medical comorbidity that, per discretion of study clinician, would render the participant unfit or unable to safely take part in the 24-month intervention

Participants, study investigators and research staff, care providers, laboratory staff, and outcomes assessors will be blinded to treatment assignment.