Does My Drug Cause Weight Loss or Weight Gain?

Chronic weight management (BMI ≥30, or ≥27 with comorbidity)

−10.2 kg / −9.8% at the 15/92 dose at 56 weeks (CONQUER); sustained −12.1% at 108 weeks (SEQUEL); 78.7% reduction in incident T2D (SEQUEL)

Phentermine appetite suppression (sympathomimetic) + topiramate appetite suppression

No PK interaction; off-label combination used cautiously by obesity-medicine specialists with CV monitoring.

REMS-required for women of childbearing age (cleft palate risk from topiramate). Phentermine CV warnings still apply. Discontinuation rule: <5% loss at 12 weeks at 15/92 dose.

Epilepsy; Migraine prophylaxis

−6.3% body weight at 192-384 mg/day over 6 months (Bray 2003); −16.5% from baseline at 192 mg with low-calorie diet maintenance (Astrup 2004); off-label monotherapy for weight loss

Appetite suppression via GABA-A modulation; altered taste perception; carbonic anhydrase inhibition

No documented PK interaction. Off-label combination occasionally used by obesity-medicine specialists.

Cognitive effects ('dopamax'); 10.7% kidney stones in long-term users (Maalouf 2010); metabolic acidosis (40-71%); cleft palate teratogenicity (RR 5.16 at >100 mg) — REMS in pregnancy.

Major depressive disorder; Smoking cessation

−7.2% at 300 mg/day and −10.1% at 400 mg/day at 24 weeks (Anderson 2002); 7.5-8.6% sustained at 48 weeks. Off-label for weight; on-label for depression.

NDRI; dopamine and norepinephrine effects on appetite and reward

No PK interaction. Effects on weight are additive with GLP-1s in the same direction.

Seizure risk (dose-dependent). Contraindicated in seizure disorder and eating disorders. Common: insomnia, dry mouth.

Chronic weight management (BMI ≥30, or ≥27 with comorbidity)

−6.1% with NB 32/360 vs −1.3% placebo at 56 weeks (COR-I); 48% achieved ≥5% loss vs 16% placebo

Bupropion (NDRI) reduces appetite via dopamine; naltrexone blocks opioid-mediated reward eating

No PK interaction documented. Combinations exist clinically but are off-label.

Bupropion seizure risk (~0.1%). Contraindicated in seizure disorder, eating disorders, abrupt sedative withdrawal. Common nausea (~30%).

ADHD; Moderate-severe binge-eating disorder (adults, since 2015)

−4.9 kg as secondary outcome at 50-70 mg/day in BED trials over 11 weeks (McElroy 2015). Hudson 2017 maintenance trial: 3.7% relapse on Vyvanse vs 32.1% placebo over 6 months.

Catecholamine release; appetite suppression

No PK interaction documented. Theoretical additive cardiovascular and appetite-suppression concerns. Combination not RCT-tested.

DEA Schedule II. Boxed warning for sudden death, MI, stroke. Psychiatric: psychosis, mania risk. Avoid in CV disease.

Type 2 diabetes

−3.1 kg at 1.5 mg, −4.0 kg at 3.0 mg, −4.7 kg at 4.5 mg in T2D patients (AWARD-11). Smallest weight effect of the modern GLP-1s.

GLP-1 receptor agonist (same class as semaglutide)

Don't combine — same drug class.

Same boxed warning for thyroid C-cell tumors as other GLP-1s. GI side effects.

Short-term (≤12 weeks) weight management since 1959

Approximately −3.6 kg over 12 weeks at 15-37.5 mg/day in pooled trials. FDA approval is short-term only; long-term use is off-label.

Releases norepinephrine and dopamine; appetite suppression

Off-label combination with GLP-1s is used clinically but has no RCT data. CV monitoring warranted.

Increases heart rate and blood pressure; contraindicated in cardiovascular disease, hyperthyroidism, glaucoma, MAOI use. DEA Schedule IV.

Type 2 diabetes; Prediabetes (DPP indication)

−2.1 kg over 2.8 years in DPP; −5.8 kg over 6 months in non-diabetic obese (Seifarth 2013); −6.2% sustained at 15 years in metformin responders (DPPOS Apolzan 2019)

Improves insulin sensitivity, reduces hepatic glucose production, modest appetite suppression

No PK interaction. Standard of care to combine in T2D.

Excellent long-term safety record (60+ years). Contraindicated in severe renal impairment. Hold around contrast imaging due to lactic acidosis risk.

Type 2 diabetes; Heart failure (HFrEF and HFpEF); CKD progression

Approximately 2-3 kg from urinary glucose excretion (~70 g/day → ~280 kcal/day deficit). Major value is the cardiovascular and kidney outcome benefits, not weight.

Blocks SGLT2 in proximal renal tubule → glucose excretion in urine

Combination is now first-line in T2D + obesity + cardio-renal risk per ADA 2025.

Genital mycotic infections (~6% vs 2% placebo). Rare DKA, Fournier's gangrene. Volume depletion in elderly.

Type 2 diabetes; Heart failure; CKD progression

~2-3 kg via urinary glucose excretion. Major indications are heart failure (DAPA-HF, DELIVER) and CKD (DAPA-CKD), not weight.

Blocks SGLT2 in proximal renal tubule

Combination first-line in T2D + obesity + cardio-renal risk per ADA 2025.

Same class effects as Jardiance.

ADHD; Narcolepsy

No RCT specifically for weight loss in adults. Pediatric ADHD literature documents 1-2 kg weight effect from chronic stimulant treatment. Off-label use for weight loss is not evidence-based.

Catecholamine release; appetite suppression

Off-label and not evidence-based for weight loss.

DEA Schedule II. Same CV and psychiatric warnings as Vyvanse. Currently in shortage as of April 2026.

Hypertension; Heart failure; Hyperaldosteronism

No meaningful weight effect in general populations. Used off-label for PCOS hyperandrogenism (acne, hirsutism), not weight loss. Patients sometimes notice short-term water weight changes from diuresis.

Aldosterone antagonist; potassium-sparing diuresis; anti-androgen

No PK interaction. Sometimes co-prescribed in PCOS patients on a GLP-1.

Hyperkalemia risk; gynecomastia in men; teratogenic.

Vasomotor symptoms; Osteoporosis prevention; Genitourinary symptoms

No significant effect on body weight per Norman 2000 Cochrane review (28 RCTs, n=28,559). HRT does NOT prevent menopausal weight gain.

Estrogen receptor activation

Prefer transdermal HRT over oral when patient is on a GLP-1 (especially Foundayo or tirzepatide) due to gastric emptying interaction with oral hormonal contraceptives.

WHI cardiovascular and breast cancer signals; NAMS 2022 favors HRT for women under 60 / within 10 years of menopause.

Major depression; Anxiety disorders; OCD; PTSD; PMDD

Small long-term weight gain in cohort data (Gafoor 2018 BMJ: 21% higher rate of ≥5% gain across all antidepressants combined). Sertraline is among the more weight-neutral SSRIs.

Serotonin reuptake inhibition

No PK interaction. Watch for additive nausea early in GLP-1 titration; staggered initiation is the workaround.

GI side effects, sexual dysfunction.

Major depression; Generalized anxiety disorder

Modest long-term weight gain (Maina 2004 in OCD: greater gain than sertraline / fluoxetine). Among the more weight-positive SSRIs.

Selective serotonin reuptake inhibition

No PK interaction.

GI, sexual dysfunction.

Major depression

Weight-neutral per FDA label and Mahableshwarkar 2015 Phase 3 trial. Cognitive benefits in addition to mood effects.

Multimodal serotonergic activity

No PK interaction.

GI side effects, sexual dysfunction (less than other SSRIs).

Type 2 diabetes

+4.8 kg vs +1.6 kg glyburide vs −2.8 kg metformin at 4 years (ADOPT trial Kahn 2006). Worst T2D oral drug for weight.

PPAR-γ activation drives adipogenesis and fluid retention

Avoid combining; metabolic profile cancels GLP-1 weight benefit.

Heart failure boxed warning; bone fracture risk in women. Use is now uncommon.

Major depression

1.4-3.6 kg gain in first 6-8 weeks across multiple trials, plateauing around 6-8 months. Mechanism: appetite stimulation via histamine H1 antagonism. Most weight-positive antidepressant in common use.

H1 antihistamine activity drives appetite stimulation; serotonergic + adrenergic effects

No PK interaction. Avoid as first-line in patients trying to lose weight; bupropion or vortioxetine are better choices.

Sedation; weight gain; rare agranulocytosis.

Major depression; Anxiety disorders; OCD; PTSD; PMDD

The most weight-positive SSRI. Significantly more ≥7% weight gain than fluoxetine or sertraline (Fava 2000). Mechanism likely anticholinergic + antihistamine activity.

Serotonin reuptake inhibition + anticholinergic + antihistamine

No PK interaction. Consider switching to a weight-neutral SSRI (sertraline) or weight-loss antidepressant (bupropion) if weight is a major concern.

GI, sexual dysfunction, withdrawal syndrome on cessation.

Type 2 diabetes

+1.6 kg at 4 years (ADOPT trial). Sulfonylureas as a class cause modest weight gain via insulin release.

Stimulates pancreatic insulin release

Increases hypoglycemia risk when combined; dose reduction often needed.

Hypoglycemia risk (more than other oral drugs). Largely supplanted by newer classes.