In Part 1 of our weight loss series, we focused on medications that are specifically standalone options for weight loss (some off label).
Part 2 is about something often just as impactful: optimizing the medications you already need by replacing weight-promoting (or neutral) options with valid alternatives that are more neutral or weight-negative on average.1
This is educational information, not personal medical advice. Do not start, stop, or change prescribed medications without clinician supervision. Some medicines must be tapered (for example: antidepressants, beta blockers, and chronic steroids). Some switches are inappropriate depending on your medical history, pregnancy plans, kidney function, blood pressure, and drug interactions. Weight effects are averages. Your individual response may be vary.
Quick Guide
Caption: These are examples to discuss with your clinician. They are not a substitution guide and should not be used for self-directed medication changes.
Type 2 diabetes: sulfonylureas (e.g., glipizide), higher-dose insulin, or thiazolidinediones (e.g., pioglitazone) → consider (when appropriate) medications that are more weight-neutral or weight-negative such as SGLT2 inhibitors (e.g., dapagliflozin/Farxiga) and/or GLP-1 receptor agonists (e.g., semaglutide), often alongside metformin when tolerated.1
Depression/anxiety: if multiple options are clinically reasonable, consider weight trajectory as one factor. For example, bupropion tends to be associated with less weight gain (it can actually help with weight loss) than several other common first-line antidepressants in comparative data.2
“Sleep” via antidepressant sedation: mirtazapine (Remeron) can be effective for depression but is commonly associated with increased appetite and weight gain, so using it primarily as a sleep aid can create metabolic headwinds.3 Quetiapine (Seroquel), an antipsychotic sometimes used for sleep is in a similar bucket
Migraine prevention: if a beta blocker is being used mainly for migraine prevention and weight gain is a major concern, a clinician may consider switching to a weight-negative preventive option such as topiramate, when appropriate and tolerated.4,5,6
Long-term systemic steroids: chronic prednisone (or similar) → explore “steroid-sparing” strategies and the lowest effective dose/duration when clinically feasible.1
Blood pressure/cardiac meds: older beta blockers (especially if not clearly indicated) → consider guideline-supported BP options (ACE inhibitors/ARBs/CCBs/thiazides) or, if a beta blocker is necessary, consider newer agents that may be less associated with weight gain.1,6
Overactive bladder: antimuscarinics with higher anticholinergic burden (e.g., oxybutynin) → consider beta-3 agonists such as mirabegron or vibegron when appropriate, based on shared decision-making and clinical context.7,8
Contraception: if weight gain is a major concern and options are otherwise clinically acceptable, discuss whether depot medroxyprogesterone acetate (DMPA/Depo-Provera) should be continued versus alternatives (e.g., copper IUD or LNG IUD), recognizing differences are reported as group averages, not guarantees for any one person.9
Don’t make weight loss harder than it has to be
A lot of people are told to “eat less and move more” while taking medications that increase appetite, worsen fatigue/sedation, or push metabolism in an unhelpful direction. When there are multiple medically appropriate options, choosing the more weight-friendly one can remove avoidable barriers so lifestyle changes have a fair chance to work.1
Type 2 diabetes
Treating glucose while supporting weight loss
If you have type 2 diabetes, medication selection can have a meaningful effect on weight. Some glucose-lowering medications are associated with weight gain, while others are weight-neutral or weight-negative on average.1
Why this matters
Endotext summarizes a consistent pattern seen in clinical practice and studies: insulin, sulfonylureas, and thiazolidinediones are commonly associated with weight gain; metformin and DPP-4 inhibitors are generally weight-neutral (or slightly negative); and GLP-1 receptor agonists and SGLT2 inhibitors are associated with weight loss on average.1
Examples to discuss with your clinician
Sulfonylurea (e.g., glipizide) → SGLT2 inhibitor (e.g., dapagliflozin/Farxiga): When clinically appropriate, this can reduce hypoglycemia risk and support modest weight loss while improving glucose control.1
Weight-promoting diabetes regimen → adding a GLP-1 receptor agonist: In eligible patients, GLP-1 receptor agonists can support significant weight loss and glycemic improvement, and in some cases allow down-titration of other weight-promoting therapies under supervision.1
Safety note: Diabetes medication changes should be monitored to avoid hypoglycemia or hyperglycemia. Kidney function and other comorbidities can change what is appropriate.
Depression & Anxiety
Choosing options with less weight impact (when clinically reasonable)
Mental health comes first. But when multiple antidepressants are reasonable choices for a given person, weight trajectory can be one factor in shared decision-making.
What comparative data shows
In a large comparative study emulating a target trial among adults starting common antidepressants, bupropion was associated with less weight gain and a lower risk of gaining at least 5% of baseline weight compared with several other commonly prescribed antidepressants.2 In part one we discuss how it can be used to help with weight loss.
Mirtazapine can be an effective antidepressant, but it is widely associated with increased appetite and weight gain, which is worth considering if weight is a major concern.3
Examples to discuss with your clinician
Mirtazapine used mainly for “sleep” or mild depression and anxiety → alternative plan: If mirtazapine is being used primarily as a sedative or if anxiety and depression symptoms are mild, a more weight friendly approach may help with weight management.3,10
Considering bupropion when appropriate: For some patients, bupropion may be a good fit, including for those who want to minimize weight gain risk, but it is not suitable for everyone (for example, it may be avoided in people with certain seizure risks or other contraindications).2
Safety note: Antidepressants should generally be tapered, not abruptly stopped. Any change should be coordinated with the prescribing clinician.
Migraine prevention:
Migraine prevention often has multiple legitimate options. If weight gain has been an issue, it can be worth reviewing whether the current preventive medication is contributing.
Beta blockers: effective for migraine, but can be weight-unfriendly for some
Beta blockers such as propranolol are established migraine preventive options.4 Some beta blockers are associated with modest weight gain over time, especially certain older agents (though individual responses vary).6
Topiramate: migraine prevention that is often weight-negative
Topiramate is an evidence-based migraine preventive option.4 In migraine trials, appetite suppression and weight loss are listed among common adverse effects in the prescribing information, which is why it is often considered when migraine and weight goals overlap.5
Safety note: Topiramate can cause side effects (for example, tingling, taste changes, cognitive slowing, mood changes, and kidney stones) and has important pregnancy-related risks. It should be used only with careful counseling and monitoring, and it is not appropriate for everyone.5
Also important: Do not stop beta blockers abruptly, especially if they are prescribed for a cardiac reason.
Long-term systemic steroids:
When “steroid-sparing” is weight-friendly care
Systemic glucocorticoids (like prednisone) are strongly associated with weight gain and changes in fat distribution, especially with longer-term use.1
If steroids are medically necessary, weight loss is not the priority over disease control. But it is often reasonable to discuss steroid-sparing strategies, the lowest effective dose, the shortest effective duration, and alternative routes or therapies where clinically appropriate.1
Safety note: Chronic steroids should not be stopped abruptly due to risk of adrenal suppression.
Blood pressure and cardiac meds:
Choose wisely, don’t swap recklessly
We do not treat weight loss by casually changing cardiac medications that are needed for safety (for example, after a heart attack or for certain arrhythmias). But when several medically appropriate options exist, it can be reasonable to choose options that are more metabolically neutral.
Beta blockers are listed among medication classes associated with weight gain in metabolic medicine references, and some patient-facing clinical resources describe modest weight gain on average with certain beta blockers, especially older agents.1,6
Example decision points to discuss with your clinician: If a beta blocker is being used primarily for blood pressure (without a compelling indication), it may be reasonable to ask whether another guideline-supported BP option would meet your goals with fewer metabolic headwinds. If a beta blocker is necessary, a clinician may consider agent selection as one factor among many.6
Safety note: Do not stop beta blockers suddenly.
Overactive bladder:
Reducing anticholinergic burden when appropriate
Overactive bladder (OAB) medications are not typically “weight loss drugs,” but switching away from medications with high anticholinergic burden can still matter for overall health and tolerability (for example, constipation, weight gain, dry mouth, and cognitive effects in some people). Anticholinergics like Oxybutynin may be slightly weight positive while Beta-3 agonists like mirabegron may be slightly weight negative
The AUA/SUFU guideline includes both antimuscarinics and beta-3 agonists as pharmacologic options for idiopathic OAB, emphasizing shared decision-making and individualized care.7
Named example: If someone is taking oxybutynin and side effects or anticholinergic burden are a concern, a clinician may consider switching to a beta-3 agonist such as mirabegron or vibegron when appropriate.7,8
Safety note: Beta-3 agonists may affect blood pressure in some patients, so monitoring and individualized selection matters.
Contraception:
Contraception choice is personal. The “best” method is the one that fits your health profile, preferences, and pregnancy-prevention goals. Weight impact can be a valid consideration, especially when multiple effective options are acceptable.
In a large randomized trial analysis comparing DMPA-IM, an LNG implant, and a copper IUD, average weight increased in all groups over 12 to 18 months, but the magnitude differed: DMPA-IM showed the largest average increase, followed by the LNG implant, with the copper IUD showing the smallest average increase.9
This does not mean “everyone gains weight on Depo.” It means that if weight gain has been a major issue, it is reasonable to discuss whether another method could better match your priorities.9
Insomnia:
Stop using “metabolic grenades” as sleep aids
Chronic insomnia is common and miserable. Treating it matters. But treating insomnia by borrowing sedating medications with meaningful metabolic risks can backfire.
Example pitfall: Quetiapine is sometimes prescribed off-label for insomnia at low doses, despite limited evidence for insomnia and known risks, including weight gain and metabolic effects even at low doses.11
Example pitfall: Using mirtazapine primarily for sedation may worsen appetite and weight trajectory for some people, even when it helps sleep.3
Practical takeaway: Treat insomnia as insomnia: with habits first and careful medication selection when needed, personalized to your risks (for example, weight gain, next-day sedation, falls risk, sleep apnea risk, drug interactions).10
Mitigation strategies:
When we can’t switch a weight-positive medication:
Sometimes the “weight-positive” medication is essential. In those cases, the plan shifts from “swap” to “mitigate.” This typically includes early monitoring, lifestyle support, and evidence-based medication add-ons when needed.
For example, antipsychotic-associated weight gain is a well-recognized issue. Meta-analytic data support several pharmacologic approaches for weight mitigation, with metformin among the most consistently supported options in many analyses.12
More recently, a guideline development and consensus validation paper supports co-commencing metformin in some patients when starting antipsychotics, with the goal of reducing the magnitude of weight gain.13
GLP-1 receptor agonists have also been studied in specific high-risk settings. In a randomized clinical trial of patients treated with clozapine or olanzapine, liraglutide improved glucose tolerance and produced clinically meaningful weight loss compared with placebo.14
Safety note: These mitigation strategies require individualized risk-benefit assessment and monitoring. They are not appropriate for everyone, and they should be coordinated with the treating clinicians (including psychiatry when relevant).
Bottom line
Weight loss treatment isn’t only about adding new interventions. Sometimes the highest-value move is removing or replacing what’s quietly working against you.
We approach medication optimization like this: treat the primary condition first, avoid meds that cause weight gain as a side effect when reasonable alternatives exist, make changes safely, and focus outcomes with patient goals in mind.1
References
1. Verhaegen AA, Van Gaal LF. Drugs that affect body weight, body fat distribution, and metabolism. In: Feingold KR, Anawalt B, Blackman MR, et al, eds. Endotext [Internet]. MDText.com, Inc; updated February 11, 2019. Accessed January 5, 2026. https://www.ncbi.nlm.nih.gov/books/NBK537590/
2. Petimar J, Young JG, Yu H, et al. Medication-induced weight change across common antidepressant treatments: a target trial emulation study. Ann Intern Med. 2024;177(8):993-1003. doi:10.7326/M23-2742. Accessed January 5, 2026. https://doi.org/10.7326/M23-2742
3. Cochrane. Mirtazapine versus other antidepressants for depression. Accessed January 5, 2026. https://www.cochrane.org/CD006528/DEPRESSN_mirtazapine-versus-other-antidepressants-depression
4. Tzankova V, Becker WJ, Chan TLH. Pharmacologic prevention of migraine. CMAJ. 2023;195(5):E187-E192. doi:10.1503/cmaj.221607. Accessed January 5, 2026. https://doi.org/10.1503/cmaj.221607
5. TOPAMAX (topiramate) [prescribing information]. Janssen Pharmaceuticals, Inc. Revised 2017. Accessed January 5, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020505s057_020844s048lbl.pdf
6. Mayo Clinic. Beta blockers: Do they cause weight gain? Updated April 30, 2024. Accessed January 5, 2026. https://www.mayoclinic.org/diseases-conditions/high-blood-pressure/expert-answers/beta-blockers/faq-20058385
7. Cameron AP, et al. The AUA/SUFU guideline on the diagnosis and treatment of idiopathic overactive bladder. J Urol. 2024. Accessed January 5, 2026. https://pubmed.ncbi.nlm.nih.gov/38651651/
8. Kennelly MJ, Rhodes T, Girman CJ, Thomas E, Shortino D, Mudd PN Jr.
Efficacy of Vibegron and Mirabegron for Overactive Bladder: A Systematic Literature Review and Indirect Treatment Comparison. Adv Ther. 2021;38(11):5452–5464. doi:10.1007/s12325-021-01902-8
https://pmc.ncbi.nlm.nih.gov/articles/PMC8520873/
9. Beksinska ME, Issema R, Beesham I, et al. Weight change among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception. eClinicalMedicine. 2021;34:100800. doi:10.1016/j.eclinm.2021.100800. Accessed January 5, 2026. https://doi.org/10.1016/j.eclinm.2021.100800
10. Qaseem A, Kansagara D, Forciea MA, Cooke M, Denberg TD. Management of chronic insomnia disorder in adults: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2016;165(2):125-133. doi:10.7326/M15-2175. Accessed January 5, 2026. https://doi.org/10.7326/M15-2175
11. Brett J. Concerns about quetiapine. Aust Prescr. 2015;38(3):95-97. Accessed January 5, 2026. https://pmc.ncbi.nlm.nih.gov/articles/PMC4653966/
12. Pharmacologic interventions for antipsychotic-induced weight gain in schizophrenia: a network meta-analysis. Accessed January 5, 2026. https://pubmed.ncbi.nlm.nih.gov/38878592/
13. Metformin for the Prevention of Antipsychotic-Induced Weight Gain: Guideline Development and Consensus Validation. Schizophrenia Bulletin. 2025;51(5):1193–1205. Published online Dec 9, 2024.
https://academic.oup.com/schizophreniabulletin/article/51/5/1193/7919241
14. Larsen JR, et al. Effect of liraglutide treatment on prediabetes and overweight or obesity in clozapine- or olanzapine-treated patients with schizophrenia spectrum disorder: a randomized clinical trial. JAMA Psychiatry. 2017. Accessed January 5, 2026. https://pmc.ncbi.nlm.nih.gov/articles/PMC5710254/
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