Obesity / insulin resistance
Incretin & energy-partitioning dysfunction; appetite/glycemic control leads.
Decision support, not prescription. You decide.
Candidate agents
8 agents · tap to expand▶TirzepatideLeadStrongTirzepatide is a dual GIP/GLP-1 receptor agonist and one of the most effective pharmacologic tools now available for obesity and insulin resistance; take it very seriously as a first-line agent.expand
Tirzepatide is a dual GIP/GLP-1 receptor agonist and one of the most effective pharmacologic tools now available for obesity and insulin resistance; take it very seriously as a first-line agent.
▸Full clinical story
By co-agonizing both GIP and GLP-1 receptors it amplifies glucose-dependent insulin secretion, slows gastric emptying, and acts centrally on hypothalamic appetite circuits; the added GIP component is thought to enhance insulin sensitivity and energy partitioning beyond GLP-1 alone.
Strong. In the phase 3 SURMOUNT-1 RCT (n=2539, non-diabetic obesity), once-weekly tirzepatide produced mean weight loss of -15.0% at 5 mg up to -20.9% at 15 mg versus -3.1% with placebo at 72 weeks, with improvement across cardiometabolic measures. Grade confirmed as strong.
Anecdotal community signal only: compounded and gray-market tirzepatide is widely used off-label, with users reporting titration schedules slower than label, 'microdosing' at 1-2.5 mg to limit GI effects, and self-reported HbA1c and waist improvements. This is unverified self-report, not evidence.
Context, not a protocol: trial dosing was once-weekly subcutaneous with stepwise titration from 2.5 mg toward 5, 10, or 15 mg maintenance over a 20-week escalation period.
Condition-specific flags include additive hypoglycemia when stacked with insulin or sulfonylureas (dose-reduce those), delayed gastric emptying affecting oral drug absorption, and contraindication with personal/family history of medullary thyroid carcinoma or MEN2. Do not combine with other GLP-1 agents.
Best-in-class efficacy with robust phase 3 support; a legitimate first-line choice for obesity with insulin resistance, with the main real-world caveats being GI tolerability, cost, and weight regain on discontinuation.
▶SLU-PP-332LeadPreclinicalAn exercise-mimetic ERR agonist that made obese mice leaner without dieting — but only in rodents so far.expand
An exercise-mimetic ERR agonist that made obese mice leaner without dieting — but only in rodents so far.
▸Full clinical story
Activates ERRα/β/γ to switch on an exercise-like metabolic program, raising energy expenditure and fatty-acid oxidation without suppressing appetite.
In diet-induced obese and ob/ob mice, twice-daily dosing over ~28 days reduced fat accumulation (~12% body-weight loss) and improved insulin sensitivity while food intake was unchanged.
No verifiable community reports.
No human dose exists; rodent studies used intraperitoneal injection only.
No human safety data; investigational research chemical, not an approved weight-loss drug.
Promising rodent metabolic data, but entirely preclinical — not ready for clinical use.
▶SemaglutideStrongSemaglutide is a GLP-1 receptor agonist with the deepest evidence base for obesity and insulin resistance among incretin drugs; take it seriously as an established first-line therapy.expand
Semaglutide is a GLP-1 receptor agonist with the deepest evidence base for obesity and insulin resistance among incretin drugs; take it seriously as an established first-line therapy.
▸Full clinical story
It activates GLP-1 receptors to enhance glucose-dependent insulin release, suppress glucagon, slow gastric emptying, and reduce appetite via hypothalamic and brainstem signaling, indirectly improving insulin sensitivity through weight loss and reduced glucotoxicity.
Strong. In the phase 3 STEP 1 RCT (n=1961, overweight/obesity without diabetes), once-weekly semaglutide 2.4 mg produced mean weight change of -14.9% versus -2.4% with placebo at 68 weeks, alongside improved cardiometabolic risk factors. Cardiovascular outcome benefit for semaglutide is supported separately (SELECT trial), not by this weight-loss citation. Grade confirmed as strong.
Anecdotal community signal only: extensive off-label and compounded use, with widely shared microdosing and slow-titration schedules to manage nausea, and self-reported improvements in cravings and energy. Popular but unverified; treat as patient-reported context, not proof.
Context, not a protocol: obesity trial dosing was once-weekly subcutaneous escalated over ~16 weeks from 0.25 mg to a 2.4 mg maintenance dose.
Condition-specific flags include additive hypoglycemia with insulin/sulfonylureas, delayed gastric emptying altering absorption of co-administered oral drugs, gallbladder events with rapid weight loss, and the same medullary thyroid carcinoma/MEN2 contraindication. Do not co-prescribe with tirzepatide or other GLP-1 agents.
A well-validated, guideline-supported first-line option; slightly less weight loss than tirzepatide on average but the largest and longest outcome dataset, with regain expected if stopped.
▶SetmelanotideStrongSetmelanotide is an MC4-receptor agonist for specific rare genetic obesity syndromes, not common polygenic obesity; take it seriously but only within its narrow, genetically-defined indication.expand
Setmelanotide is an MC4-receptor agonist for specific rare genetic obesity syndromes, not common polygenic obesity; take it seriously but only within its narrow, genetically-defined indication.
▸Full clinical story
It directly activates the melanocortin-4 receptor to restore downstream signaling in the leptin-melanocortin appetite pathway, addressing the specific defect in patients with impaired upstream signaling (e.g., POMC, LEPR, or BBS-related hyperphagia), rather than acting on incretin or insulin-sensitivity pathways.
Strong within its indication. In a phase 3 RCT (n=38), 32.3% of Bardet-Biedl syndrome patients aged >=12 achieved >=10% weight loss after 52 weeks of setmelanotide (p=0.0006); results were inconclusive in Alstrom syndrome. Evidence is robust for the genetic subgroup studied but does not generalize to typical obesity. Grade confirmed as strong (indication-limited).
Anecdotal community signal only: minimal off-label community use given its rare-disease niche, high cost, and requirement for genetic confirmation; not a general weight-loss peptide in practice.
Context, not a protocol: administered as a once-daily subcutaneous injection (up to 3.0 mg) titrated by response and tolerability within the approved rare-disease programs.
Condition-specific flags include hyperpigmentation and skin/nevus darkening from melanocortin activity, injection-site reactions, and that it is inappropriate and unproven for common obesity or insulin resistance outside the defined genetic syndromes. Requires genetic/diagnostic confirmation before use.
A well-supported precision therapy for a small set of monogenic and syndromic obesities; irrelevant to the incretin/insulin-resistance lever that drives most obesity care, so use it strictly within its genetic indication.
▶CagrilintideEmergingCagrilintide is a long-acting amylin analog studied mainly in combination with semaglutide for obesity; early human data are encouraging but limited, so treat as emerging.expand
Cagrilintide is a long-acting amylin analog studied mainly in combination with semaglutide for obesity; early human data are encouraging but limited, so treat as emerging.
▸Full clinical story
As an amylin receptor agonist it promotes satiety, slows gastric emptying, and reduces food intake through a pathway distinct from and complementary to GLP-1, which is the rationale for pairing it with semaglutide to deepen weight loss.
Emerging. In a phase 1b RCT (n=95 exposed), cagrilintide co-administered with semaglutide 2.4 mg was well tolerated and produced mean bodyweight reductions of roughly 15-17% at 20 weeks (e.g., 17.1% at cagrilintide 2.4 mg vs 9.8% for pooled placebo-plus-semaglutide). This is early-phase, small-sample data; larger CagriSema phase 2/3 trials are the real test. Grade confirmed as emerging.
Anecdotal community signal only: cagrilintide (often as 'CagriSema' stacks) circulates in compounding and peptide communities, with users reporting added appetite suppression on top of a GLP-1. Small, unverified reports; not proof of efficacy or safety.
Context, not a protocol: the phase 1b program co-escalated once-weekly subcutaneous cagrilintide (doses studied ranged up to 4.5 mg) alongside semaglutide 2.4 mg.
Condition-specific flags include additive GI effects and appetite suppression when combined with a GLP-1, additive hypoglycemia risk if background insulin/sulfonylureas are present, and the fact that combination safety is still being characterized in ongoing trials.
A mechanistically complementary add-on to GLP-1 therapy with promising phase 1b signals; not yet approved and not a standalone therapy, so best regarded as an emerging combination approach.
▶RetatrutideEmergingRetatrutide is an investigational triple GIP/GLP-1/glucagon receptor agonist for obesity with striking phase 2 weight loss; promising but not yet approved, so treat as emerging.expand
Retatrutide is an investigational triple GIP/GLP-1/glucagon receptor agonist for obesity with striking phase 2 weight loss; promising but not yet approved, so treat as emerging.
▸Full clinical story
Adding glucagon-receptor agonism to dual incretin action is intended to increase energy expenditure and hepatic fat oxidation on top of the appetite suppression and insulin-sensitizing effects of GIP/GLP-1, potentially driving greater fat loss and improved hepatic insulin resistance.
Emerging. In a phase 2 RCT (n=338, obesity), 48 weeks of retatrutide produced least-squares mean weight loss up to -24.2% at 12 mg versus -2.1% with placebo, with dose-related GI adverse events and transient dose-dependent heart-rate increases. Phase 3 trials are ongoing; no approval or long-term outcome data yet. Grade confirmed as emerging.
Anecdotal community signal only: gray-market and research-chemical retatrutide has appeared ahead of approval, with biohacker self-reports of rapid weight loss and, notably, transient heart-rate increases and glucose fluctuations. Unregulated sourcing makes purity and dosing unreliable; not evidence.
Context, not a protocol: phase 2 used once-weekly subcutaneous dosing titrated to maintenance doses of 4, 8, or 12 mg.
Condition-specific flags include the glucagon component's potential to raise glucose and heart rate, unknown long-term cardiovascular and hepatic safety, and absence of any regulatory-grade product on the market. Off-label/research-chemical use carries meaningful uncertainty.
Possibly the most potent incretin agent in development, but phase 2 only; keep on the radar and await phase 3 before treating it as anything more than investigational.
▶TesofensineEmergingTesofensine is an investigational triple monoamine (noradrenaline/dopamine/serotonin) reuptake inhibitor for obesity; moderate phase 2 efficacy but a cardiovascular-safety shadow keeps it emerging.expand
Tesofensine is an investigational triple monoamine (noradrenaline/dopamine/serotonin) reuptake inhibitor for obesity; moderate phase 2 efficacy but a cardiovascular-safety shadow keeps it emerging.
▸Full clinical story
By blocking reuptake of noradrenaline, dopamine, and serotonin it suppresses appetite centrally and modestly increases energy expenditure; unlike incretins it works through monoaminergic satiety pathways, not glucose-dependent insulin signaling.
Emerging. In a phase 2 RCT (n=203, obesity), tesofensine 0.5 mg with an energy-restricted diet induced 9.2% mean weight loss versus 2.0% with diet plus placebo at 24 weeks, but raised heart rate by about 7.4 bpm. It has not completed phase 3 or gained approval, and the sympathomimetic cardiovascular signal is a key limitation. Grade confirmed as emerging.
Anecdotal community signal only: sold via research-chemical channels and used off-label at low doses for appetite suppression and 'focus,' with users self-reporting stimulant-like effects, elevated heart rate, and insomnia. Unverified and safety-relevant; not proof.
Context, not a protocol: the phase 2 trial used once-daily oral tesofensine, with 0.5 mg emerging as the efficacy/tolerability balance point across the 0.25-1.0 mg range studied.
Condition-specific flags center on sympathomimetic effects: dose-related increases in heart rate and blood pressure, mood/sleep disturbance, and risk of serotonergic and stimulant interactions (MAOIs, other serotonergic agents, sympathomimetics). Caution in cardiovascular disease.
A centrally-acting alternative with real but moderate phase 2 efficacy, overshadowed by cardiovascular and neuropsychiatric safety questions and no phase 3 data; investigational and not a substitute for incretin therapy.
▶MetforminStrongMetformin is a foundational insulin-sensitizing agent for insulin resistance; take it seriously for glycemic and metabolic benefit, but recognize it is only a modest weight-loss drug.expand
Metformin is a foundational insulin-sensitizing agent for insulin resistance; take it seriously for glycemic and metabolic benefit, but recognize it is only a modest weight-loss drug.
▸Full clinical story
It reduces hepatic gluconeogenesis and enhances peripheral glucose uptake largely via AMPK activation and increased GLUT4-mediated transport, directly improving insulin sensitivity rather than driving satiety like incretins.
Strong for insulin resistance/glycemia, based on decades of established clinical use and guideline consensus positioning metformin as the most commonly used insulin-sensitizer. The single cited reference is a mechanistic review (not an RCT) that summarizes the AMPK/GLUT4 pathway underlying this effect; it supports the mechanism, not efficacy magnitude. Metformin's effect on body weight is neutral-to-modest, so it is not a primary obesity agent. Grade confirmed as strong (for insulin resistance).
Anecdotal community signal only: widely used off-label for prediabetes, PCOS, longevity, and as an adjunct to GLP-1 therapy, with patients reporting appetite and 'metabolic' benefits. Common but, for weight loss specifically, claimed larger than the evidence supports.
Context, not a protocol: typically oral 500 mg titrated upward to 1000-2000 mg/day in divided doses or extended-release, limited by GI tolerability.
Condition-specific flags include GI intolerance limiting adherence, B12 depletion with long-term use, rare lactic acidosis risk in renal impairment or hypoxic states, and the need to hold around iodinated contrast. Frequently and reasonably combined with incretins for additive glycemic effect.
A safe, cheap, well-evidenced backbone for insulin resistance and glycemic control and a sensible companion to incretin therapy, but not a meaningful standalone weight-loss drug for obesity.
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