Which Way Does My Prescription Move the Scale?

Chronic weight management: adults with obesity, or overweight with a 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.

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.

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 dulling, nicknamed 'dopamax'. Metabolic acidosis in 40-71%. Kidney stones in 10.7% of long-term users, per Maalouf 2010. Teratogenic for cleft palate at RR 5.16 above 100 mg, hence the pregnancy REMS.

Chronic weight management: adults with obesity, or overweight with a comorbidity

COR-I at 56 weeks: NB 32/360 reached −6.1% against −1.3% on placebo, and 48% of the treated arm cleared the ≥5% bar where 16% of placebo did

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; Heart failure (HFrEF and HFpEF); CKD progression

In the label's 24-week monotherapy trial, body weight fell 2.8% on 10 mg and 3.2% on 25 mg against 0.4% on placebo (2.5 to 2.8 points more than placebo, from a 78 kg baseline), through glucose lost in the urine. Weight is not the point of it though; the kidney and cardiovascular outcomes are.

Blocks SGLT2 in proximal renal tubule → glucose excretion in urine

ADA 2025 puts the combination first-line where T2D, obesity and cardio-renal risk coincide.

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

Type 2 diabetes

DPP recorded −2.1 kg across 2.8 years, about −2.2% of the 94.3 kg baseline (−2.0 kg after subtracting placebo's −0.1 kg). Seifarth 2013 saw −5.8 kg inside 6 months in non-diabetic obese patients. Among responders, DPPOS (Apolzan 2019) still had −6.2% holding at 15 years

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; CKD progression

In the label's 24-week add-on-to-metformin trial, weight fell 2.9 kg on 10 mg against 0.9 kg on placebo, a 2.0 kg difference (about 2.3% of the 86.3 kg baseline), via urinary glucose excretion. Major indications are heart failure (DAPA-HF, DELIVER) and CKD (DAPA-CKD), not weight.

Blocks SGLT2 in proximal renal tubule

Per ADA 2025 this combination is first-line when T2D, obesity and cardio-renal risk all apply.

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 the Norman 2000 Cochrane review (22 RCTs): mean difference 0.66 kg for estrogen alone and −0.47 kg for estrogen plus progestogen, neither significant. 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 raised breast cancer and cardiovascular signals. NAMS 2022 nonetheless favors HRT for women under 60, or inside 10 years of menopause.

Major depression; Anxiety disorders; OCD; PTSD; PMDD

The reference drug in Petimar 2024 (183,118 patients across 8 US health systems): at 6 months, escitalopram, paroxetine and duloxetine put on 0.34 to 0.41 kg more than sertraline, fluoxetine was similar, and bupropion 0.22 kg less. The study does not give sertraline's own change in its abstract. 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 followed the parent drug, citalopram, not escitalopram, for 2.5 years in OCD: patients gained 2.5% on average across six drugs, with fluoxetine and sertraline lowest.

Selective serotonin reuptake inhibition

No PK interaction.

GI, sexual dysfunction.

Major depression

No significant weight change against placebo in the 6 to 8 week trials or in a 6-month maintenance phase, per the FDA label; weight gain is listed among postmarketing reports.

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.

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.

Major depression; Anxiety disorders; OCD; PTSD; PMDD

About 0.4 kg more than sertraline at 6 months (difference 0.37 kg, CI 0.20 to 0.54; Petimar 2024), with a 10% to 15% higher risk of gaining at least 5% of baseline weight. The figure is relative to sertraline, not an absolute change. Fava 2000 found significantly more patients crossing a 7% gain on paroxetine than on sertraline or fluoxetine. Antihistamine and anticholinergic activity is the likely mechanism.

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.