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MyDeficiencies

Metreleptin

Leptin analog (endocrine, adipokine replacement therapy)

Also sold as Myalept.

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Findings for this medication

Research about this medication, graded for how strongly each finding can be attributed to it. Nothing here describes your own levels.

Metreleptin has no classical small-molecule depletion mechanism. It is a 147-amino-acid recombinant human leptin analog given once daily by subcutaneous injection, with no oral or gastrointestinal absorption route at all, so the chelation, gastric-pH, bile-acid-sequestration, and transporter-competition mechanisms that drive nutrient depletion for orally dosed drugs do not apply. It is not a cytochrome P450 substrate itself; elimination is renal, by proteolytic catabolism in the renal tubules, not hepatic metabolism, with a labeled elimination half-life of 3.8 to 4.7 hours (the FDA's Clinical Pharmacology Review separately reports 3.3 to 3.4 hours in healthy, antibody-negative subjects across a 0.3 to 3.0 mg/kg/day dose range; both figures are drawn from documents opened for this review and are disclosed together rather than reconciled). Leptin itself may alter the formation of CYP450 enzymes, a labeled drug-drug interaction consideration for narrow-therapeutic-index co-medications such as warfarin, cyclosporine, and theophylline, not a drug-nutrient one. No renal or hepatic impairment pharmacokinetic studies have been conducted, and no food, mineral, or antacid interaction is documented anywhere in the label or the FDA review documents opened for this dossier.

Leptin analog (endocrine, adipokine replacement therapy) · ATC A16AA07 · also sold as Myalept · reviewed 2026-09-28. This describes research about the medication. It does not say anything about your own levels or health.

How to read the evidence grades

These colours describe how strongly a finding can be attributed to the medication in the research. They are not a severity score and they say nothing about your own health.

Grades describe how strongly a finding can be attributed to Metreleptin in the research — not how common it is, how serious it would be, and not anything about you personally.

Red — Severe
Two or more independent Tier A sources, this drug in the cohort, the nutrient directly measured, consistent direction, clinically meaningful magnitude, a named mechanism, no substantial contradicting Tier A evidence.
Orange — Moderate
At least one Tier A source with this drug in the cohort showing a real but bounded deficit: an exposure window, a subgroup, low frequency, or a functional rather than circulating deficit.
Yellow — Low
Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction.
Not graded — disclosed evidence gap
Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result.Source definition: Not gradeable under the rules above because nothing has been measured. Published as a documented gap, never as reassurance that there is no effect.

What the research found

Hypoglycemia risk from glucose and triglyceride lowering, intended replacement-therapy effect

Orange — Moderate

See study details

Metreleptin's intended mechanism, replacing a hormone that is absent in leptin-deficient generalized lipodystrophy, produces large, real reductions in HbA1c, fasting glucose, and fasting triglycerides, and a correspondingly real, labeled hypoglycemia risk requiring insulin or secretagogue dose reduction; this is the drug doing what it is designed to do, not a vitamin or mineral deficiency, and is included because it is the single most consequential metabolic signal tied to this drug's mechanism.

Full detail and limits

What the grade means here: At least one Tier A source with this drug in the cohort showing a real but bounded deficit: an exposure window, a subgroup, low frequency, or a functional rather than circulating deficit. orange

Limits on what this shows

  • Key negative/null findings: No trial arm reviewed showed glucose or triglycerides failing to improve or worsening. The FHA101 cohort's higher hypoglycemia rate (25% versus 11% in the NIH studies) is a real, disclosed population-dependent difference that the FDA Summary Review attributes in part to that cohort's different (predominantly partial-lipodystrophy, higher baseline antidiabetic-medication) composition rather than to a larger drug effect; this was not independently re-verified beyond what the Summary Review states.
  • At-risk subgroups: Patients on concomitant insulin or insulin secretagogues, a labeled requirement for dose reduction and close monitoring; the FHA101 population specifically. No placebo-controlled trial exists for generalized lipodystrophy specifically (the NIH studies were single-arm, open-label), which bounds how these effect sizes should be read.

Regulatory status

MYALEPT label, Section 14.1, Table 4 (pooled pivotal population, month 12): HbA1c mean baseline 8.5%, mean reduction 2 percentage points; fasting glucose mean baseline 174 mg/dL, mean reduction 49 mg/dL; fasting triglycerides median baseline 348 mg/dL, median reduction 184 mg/dL. Section 5.4, Hypoglycemia: "dosage adjustments, including possible large reductions" of insulin or insulin secretagogue "may be necessary"; closely monitor blood glucose with concomitant antidiabetic therapy.

Population evidence

FDA Summary Review, BLA 125390 (Tier A, opened and read in full): NIH studies 991265/20010796, n=72, open-label single-arm, initially 4 months extended to 8 and 12 months, entry criteria "males and females greater than 14 years of age, clinically-significant lipodystrophy" with low leptin and metabolic abnormalities. At 12 months: HbA1c baseline mean(SD) 8.2(2.2)%, change -1.4(0.2), 95% CI -1.8 to -0.9; fasting glucose baseline mean(SD) 170(89) mg/dL, change -42(12) mg/dL, 95% CI -65 to -18; fasting triglycerides baseline mean(SD) 1016(1780) mg/dL, change -673(223), a -32% change from baseline. A second, smaller open-label treatment-IND population, study FHA101 (n=28, majority partial rather than generalized lipodystrophy), showed a substantially higher hypoglycemia rate (25%) than the NIH studies (11%).

Mechanism

Named: this is metreleptin's direct, intended pharmacologic action. Metreleptin binds and activates the human leptin receptor (ObR), signaling through the JAK/STAT pathway to restore central and peripheral leptin effects on glucose and lipid metabolism that are absent in leptin-deficient lipodystrophy; as insulin sensitivity improves, patients on unchanged insulin or secretagogue doses become vulnerable to hypoglycemia.

Counter-evidence held on record

The baseline values themselves (HbA1c 8.2%, fasting triglycerides above 1,000 mg/dL before any drug exposure) are direct, quantified evidence that the underlying disease, not metreleptin, produces the severe metabolic derangement; metreleptin's measured effect runs toward correcting it. This is the drug's own intended replacement-therapy effect correcting a disease-driven derangement, not a nutrient or mineral deficiency, and no vitamin, mineral, or antioxidant supplementation addresses it. Glucose monitoring and any insulin/secretagogue dose adjustment are prescriber decisions.

Reduced appetite and weight loss, labeled anorexigenic mechanism

Orange — Moderate

See study details

Leptin's central, appetite-suppressing action is metreleptin's core pharmacology, not a side effect of some other mechanism; "decreased weight" is a common (10% or greater incidence), labeled adverse reaction, and this is a real, drug-specific reason to monitor overall dietary and nutritional intake in an already metabolically fragile population, though no study located ties it to a specific vitamin or mineral deficit.

Full detail and limits

What the grade means here: At least one Tier A source with this drug in the cohort showing a real but bounded deficit: an exposure window, a subgroup, low frequency, or a functional rather than circulating deficit. orange

Limits on what this shows

  • Key negative/null findings: None located specifically quantifying the degree of intake reduction or any resulting vitamin or mineral deficit. This is the entry's central limitation: it is included as a mechanism-grounded monitoring flag precisely because no metreleptin-specific nutrient-deficit study exists to confirm or rule out a downstream effect, not because such a study found no effect.
  • At-risk subgroups: None specifically identified in the sources opened for this review. General caution applies to a population that characteristically already has near-absent adipose tissue and, in acquired generalized lipodystrophy, a history of autoimmune or pancreatitis-related nutritional stress documented elsewhere in the same regulatory record.

Regulatory status

MYALEPT label, Section 6.1: most common adverse reactions (≥10%) are headache (13%), hypoglycemia (13%), decreased weight (13%), and abdominal pain (10%). Section 1.1: metreleptin is indicated "as an adjunct to diet," implying dietary intake management is expected to accompany therapy.

Population evidence

FDA Summary Review and Medical Review, BLA 125390 (same NIH n=72 and FHA101 n=28 populations as the preceding entry, both opened and read in full for this review): "decreased weight" is reported as a common adverse reaction by frequency category; neither document opened for this review reports a specific quantified mean weight-loss figure or a corresponding nutrient-intake or micronutrient panel.

Mechanism

Named: leptin acts on hypothalamic ObR to suppress appetite and increase energy expenditure. This is metreleptin's direct, intended pharmacologic action, since the drug is a leptin analog, not an off-target nutrient effect of an unrelated molecule.

Counter-evidence held on record

No source opened for this review quantifies a resulting micronutrient deficit; the finding is the appetite/weight signal itself, not a downstream nutrient claim. This is the drug's own intended appetite-suppressing mechanism, not evidence of any specific vitamin or mineral deficiency, and does not support targeted supplementation. General nutritional status monitoring, in line with the label's own framing of metreleptin as an adjunct to diet, is the appropriate response, not an assumption that any particular nutrient runs low.

The five body-system areas

Each finding is counted once, in a single area. Where a study is mentioned in a second area it is context only.

Mitochondrial Burden

Each finding below is counted once, in this area only.

Mitochondrial burden

Yellow — Low

See study details

Leptin administration significantly increased skeletal-muscle PGC-1alpha protein expression, the master regulator of mitochondrial biogenesis, in leptin-deficient mice; mitochondrial biogenesis, mitochondrial DNA content, and respiratory function were not themselves directly measured in this study, so this entry is deliberately limited to the upstream regulator that was measured.

Full detail, limits and 1 references

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. yellow

Limits on what this shows

  • Key negative/null findings: Minokoshi et al. 2002 (Nature 415:339-343) reported a mechanistically adjacent leptin/AMPK/fatty-acid-oxidation finding but remains excluded from evidentiary use here because of Nature's 2024 Editorial Expression of Concern about that specific article; it is not used to support this entry. No metreleptin-specific mitochondrial study exists in the FDA reviews or in Brown et al. 2018 / Oral et al. 2019.
  • At-risk subgroups: None established for metreleptin.

Regulatory status

None. Re-confirmed: no mitochondrial content anywhere in the label or the FDA reviews.

Population evidence

Sainz N, Rodriguez A, Catalan V, Becerril S, Ramirez B, Gomez-Ambrosi J, Fruhbeck G. "Leptin Administration Favors Muscle Mass Accretion by Decreasing FoxO3a and Increasing PGC-1alpha in ob/ob Mice." PLoS ONE. 2009;4(9):e6808. DOI 10.1371/journal.pone.0006808. Opened and read in full (PLoS ONE, fully open access). Leptin 1 mg/kg/day, intraperitoneal, twice daily, for 28 days in ob/ob mice versus untreated ob/ob and wild-type controls. PGC-1alpha protein expression significantly increased (P=0.005) with leptin treatment; the study's stated primary finding is increased gastrocnemius/EDL/soleus muscle mass and fiber size (P<0.001) via FoxO3a inactivation and reduced MAFbx/MuRF1 (atrophy-pathway) expression, not a mitochondrial-biogenesis study per se.

Mechanism

Named: PGC-1alpha is a validated upstream transcriptional regulator of mitochondrial biogenesis; its increase is used here cautiously as a biogenesis-pathway signal, explicitly not equated with a directly measured increase in mitochondrial mass, membrane integrity, or electron transport capacity, which this study did not assess.

Counter-evidence held on record

This finding does not extend to the ATP production entry, which remains ungraded: this study measured PGC-1alpha expression only, not ATP synthesis or cellular energy output, and Hard Rule 7 keeps Mitochondrial burden and ATP production as independent entries even where a shared upstream mechanism could plausibly link them. Class-level, animal, upstream-marker evidence only. No mitochondrial-support supplement (CoQ10, L-carnitine, riboflavin, or similar) is supported by this entry.

  • Sainz N, Rodriguez A, Catalan V, Becerril S, Ramirez B, Gomez-Ambrosi J, Fruhbeck G. — In vivo study, ob/ob (leptin-deficient) mice, leptin (not metreleptin) 1 mg/kg/day intraperitoneal, twice daily, 28 days. Opened and read in full (PLoS ONE, fully open access). PGC-1alpha protein significantly increased (P=0.005); primary finding is muscle-mass accretion via FoxO3a/MAFbx/MuRF1 atrophy-pathway inhibition, not a direct mitochondrial-function study. Tier C for metreleptin. Basis for the Mitochondrial burden yellow entry.

Oxidative Stress

Each finding below is counted once, in this area only.

Oxidative stress

Yellow — Low

See study details

A 1999 in vitro study reported that leptin increases reactive oxygen species in human endothelial cells; this dossier cites only the documented title-level finding, because the full abstract and text could not be independently accessed despite multiple attempts this session.

Full detail, limits and 1 references

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. yellow

Limits on what this shows

  • Key negative/null findings: None located. No metreleptin-specific oxidative-stress marker study exists in the FDA reviews or in Brown et al. 2018 / Oral et al. 2019.
  • At-risk subgroups: None established for metreleptin.

Regulatory status

None. Re-confirmed: no oxidative-stress, antioxidant, or free-radical content anywhere in the label or the FDA reviews for BLA 125390.

Population evidence

Bouloumie A, Marumo T, Lafontan M, Busse R. "Leptin induces oxidative stress in human endothelial cells." FASEB J. 1999;13(10):1231-1238. PMID 10385613. Confirmed as a real, indexed primary research article via the Crossref API and the Semantic Scholar API (title, authors, journal, year, PMID all independently verified across both). The full abstract and text could not be opened: a direct DOI/Wiley fetch returned HTTP 403; Unpaywall confirms the article is closed access with no repository copy; Semantic Scholar's own abstract field is elided by the publisher; PubMed's abstract page returned only an unrenderable script shell.

Mechanism

Named at title level only (leptin inducing ROS accumulation in endothelial cells); the specific concentrations, time course, and downstream signaling reported in the paper could not be independently verified and are therefore deliberately not claimed here.

Counter-evidence held on record

Because the full text could not be accessed, this entry deliberately claims only what the title itself asserts (leptin, direction: increases oxidative stress, in one endothelial cell type) and nothing about magnitude, concentration, or downstream consequence. Leptin, not metreleptin; in vitro endothelial cells, not metreleptin-treated patients. No antioxidant supplementation is supported by this entry.

  • Bouloumie A, Marumo T, Lafontan M, Busse R. — In vitro study, human umbilical vein endothelial cells, leptin (not metreleptin). Confirmed as a real, indexed article (title, authors, journal, year, PMID 10385613) via the Crossref API and the Semantic Scholar API. Full abstract and text NOT accessible: direct DOI/Wiley fetch returned HTTP 403; Unpaywall confirms closed access, no repository copy; Semantic Scholar's abstract field is elided by the publisher; PubMed's abstract page returned an unrenderable script shell. Cited at title level only. Tier C for metreleptin. Basis for the Oxidative stress yellow entry.Bibliographic metadata verified across two independent sources; full text could not be opened despite four distinct attempts. Cited narrowly for this reason.

Copper and Iron Balance

Copper and iron are assessed separately. Nothing here is counted twice.

Iron

Yellow — Low

See study details

Leptin (not metreleptin specifically) upregulates hepcidin, the master iron-restricting hormone, through the same JAK2/STAT3 pathway metreleptin itself is labeled to use, in a human liver-cell line in vitro; this is mechanistically plausible but unconfirmed for metreleptin, and no metreleptin-specific iron study exists to test it.

Full detail and limits

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. yellow

Limits on what this shows

  • Key negative/null findings: No metreleptin-specific hepcidin, ferritin, transferrin saturation, or serum iron measurement was located in the FDA reviews or in the two independent long-term metreleptin studies opened for this revision (Brown et al. 2018, n=66, 36 months, generalized lipodystrophy; Oral et al. 2019, partial lipodystrophy). Chung et al. 2007's own stated conclusion is about overweight/obese individuals with elevated endogenous leptin, the opposite direction of exposure from lipodystrophy patients receiving exogenous replacement of a hormone they lack; this population difference is a genuine limitation on transferring the finding to metreleptin, disclosed here rather than smoothed over.
  • At-risk subgroups: None established for metreleptin. Speculatively, this mechanism could be one explanation for the labeled anemia adverse reaction (see Oxygen delivery/utilization and the Overlap map), but that link is not established in any source opened for this review.

Regulatory status

None. Re-confirmed for this revision: the MYALEPT label and the FDA Summary, Medical, and Clinical Pharmacology Reviews for BLA 125390 contain no iron, ferritin, transferrin, or hepcidin data anywhere in the metreleptin program.

Population evidence

Chung B, Matak P, McKie AT, Sharp P. "Leptin Increases the Expression of the Iron Regulatory Hormone Hepcidin in HuH7 Human Hepatoma Cells." J Nutr. 2007;137(11):2366-2370. In vitro, human hepatoma (HuH7) cells exposed to leptin 7.5 to 125 nmol/L; hepcidin mRNA and peptide levels significantly increased at concentrations above 50 nmol/L, in a time- and dose-dependent manner, with maximal induction within approximately 1 hour. Opened and read in full via the publisher's freely available (Bronze open access, confirmed via Unpaywall) version.

Mechanism

Named: a JAK2 inhibitor significantly blocked the hepcidin response, and mutating the STAT3 binding site in the hepcidin promoter reduced promoter activity, establishing JAK2/STAT3 signaling as the mechanism. This is the same pathway this dossier's own Pharmacokinetic Basis section states metreleptin signals through, which is why this is graded yellow (mechanistically plausible) rather than white, despite using leptin rather than metreleptin and an in vitro cell line rather than metreleptin-treated patients.

Counter-evidence held on record

This is an in vitro, class-level finding using leptin, not metreleptin, and not conducted in metreleptin-treated patients or in lipodystrophy. No metreleptin-specific iron marker has ever been measured and published. The direction implied, if it applies to metreleptin at all, runs toward reduced iron availability, not deficiency requiring supplementation, and is not established for this drug. No iron dosing recommendation is made from this entry; any iron supplementation decision requires an actual iron panel and a prescriber, not this mechanistic flag.

Copper

Not graded — disclosed evidence gap

See study details

A dedicated re-research pass for this revision, using a wider range of query phrasings and channels than the original review, still located no metreleptin- or leptin-specific copper or ceruloplasmin study of any kind, and no circulating consumer claim about metreleptin and copper exists to rebut.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. ungraded

Limits on what this shows

  • Why no grade: Both conditions for ungraded are met, now confirmed by a second, independent search pass. (1) No Tier A/B/C evidence: re-opened and re-confirmed for this revision, the FDA Summary, Medical, and Clinical Pharmacology Reviews for BLA 125390 contain no copper or ceruloplasmin data anywhere in the metreleptin program; the two newly located independent long-term metreleptin studies (Brown et al. 2018, n=66, 36 months; Oral et al. 2019, partial lipodystrophy), both opened for this revision, likewise report no copper data. No leptin-level (class, non-drug-specific) copper or ceruloplasmin study was found either, despite four distinct query phrasings run this session. (2) No circulating claim: Wikipedia's metreleptin article and Drugs.com's Myalept monograph, both re-checked this session, contain no copper- or trace-mineral-related claim about metreleptin.

Tooling disclosure

This revision ran four distinct Crossref API bibliographic queries for this category: "metreleptin copper" (no metreleptin-specific hit), "leptin copper ceruloplasmin trace element" (returned only an unrelated leptin/adipokine/angiogenesis book-chapter reference list, no copper content), "serum copper ceruloplasmin obesity adipokine correlation" (HTTP 429, rate-limited), and "serum copper ceruloplasmin leptin correlation human" (returned only Wilson-disease, assay-biological-variation, and oncology ceruloplasmin papers with no leptin or leptin-analog connection), plus a general "trace element / micronutrient status lipodystrophy patients" query (no lipodystrophy-specific hit at all). The OpenAlex API, the Semantic Scholar API's search endpoint, and the Europe PMC REST API were each retried this session and each failed again (HTTP 429, or blocked at the network-policy layer for europepmc/ebi.ac.uk, disclosed in full in the Sources access note). This session's own WebSearch budget was found already exhausted (0 of 200 remaining) before this revision's research began. This is recorded as a genuine, twice-confirmed literature gap for metreleptin and for leptin as a class, not a single-attempt or tooling-only absence.

Gut Microbiome Risk

Each finding below is counted once, in this area only.

Gut microbiome risk

Yellow — Low

See study details

In a pair-feeding-controlled study, leptin deficiency itself, not just the resulting obesity or higher food intake, explained a real share of gut microbial compositional variance in leptin-deficient mice; this makes it mechanistically plausible that restoring leptin signaling (metreleptin's own mechanism) could affect gut microbiota in leptin-deficient humans, though direction and magnitude are unconfirmed and the animal model is obesity, the physiological opposite of lipodystrophy's severe leanness.

Full detail, limits and 1 references

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. yellow

Limits on what this shows

  • Key negative/null findings: Pair-feeding did significantly alter several individual taxa and did not fully replicate the ad libitum ob/ob microbiome, so caloric intake is not irrelevant, only insufficient on its own to explain the full compositional shift. No human lipodystrophy or metreleptin-specific microbiome study exists in the FDA reviews or in Brown et al. 2018 / Oral et al. 2019.
  • At-risk subgroups: None established for metreleptin or for human lipodystrophy.

Regulatory status

None. Re-confirmed: no microbiome or intestinal-flora content anywhere in the label or the FDA reviews.

Population evidence

Kashani A, et al. "Impaired glucose metabolism and altered gut microbiome despite calorie restriction of ob/ob mice." Animal Microbiome. 2019;1:11. DOI 10.1186/s42523-019-0007-1. Opened and read in full (Springer/BMC open access). 10-week study: ob/ob mice fed ad libitum (n=12) vs. wild-type controls (n=12) vs. pair-fed ob/ob mice restricted to control-level food intake (n=11). Leptin deficiency explained 18.3% of gut microbial compositional variance; pair-feeding altered individual taxa but did not significantly change overall community composition by study end, meaning the leptin-deficiency signal persisted after controlling for the caloric-intake/obesity confound. 24 microbial taxa were associated with leptin deficiency specifically, including enrichment of Lactobacillus and depletion of Akkermansia muciniphila.

Mechanism

Named as a hypothesis by the study's authors: leptin's known role in immune response and inflammation (part of the cytokine cascade) as a plausible route by which its absence, independent of diet, reshapes gut microbial ecology. Not a metreleptin mechanism directly tested.

Counter-evidence held on record

ob/ob mice are obese because they lack leptin; lipodystrophy patients are severely lean despite low leptin, for a different reason (absent adipose tissue, not receptor or ligand mutation in an otherwise normal-fat animal). Whether metreleptin's leptin-replacement mechanism moves a lipodystrophy patient's gut microbiome in the same, the opposite, or no direction at all relative to this mouse model is not established by this source and is not claimed here. This is disease-model, class-level evidence only. No probiotic, prebiotic, or other microbiome-targeted intervention is supported by this entry.

  • Kashani A, Rondeau I, D'Aquino M, Berube-Simard FA, Kramer JS, et al. — In vivo study, ob/ob (leptin-deficient) mice, ad libitum (n=12) vs. wild-type (n=12) vs. pair-fed ob/ob (n=11), 10 weeks. Opened and read in full (Springer/BMC, fully open access). Leptin deficiency explained 18.3% of gut microbial compositional variance, persisting after pair-feeding controlled for caloric intake/obesity; enriched Lactobacillus, depleted Akkermansia muciniphila. Tier C for metreleptin: disease model (genetic obesity), not metreleptin or lipodystrophy. Basis for the Gut microbiome risk yellow entry.

Oxygen and ATP Output

Oxygen delivery and ATP production are assessed separately. Nothing here is counted twice.

Oxygen delivery / utilization

Orange — Moderate

See study details

Anemia is listed as an adverse reaction in 3 of 48 patients (6%) in MYALEPT's generalized-lipodystrophy safety population; this is a real, Tier A, drug-labeled signal, but it is bounded by low frequency, by the complete absence of any accompanying hemoglobin value, severity grade, or causality assessment in the sources opened for this review, and by the fact that no iron, hepcidin, or hemolysis workup was ever reported to explain it.

Full detail and limits

What the grade means here: At least one Tier A source with this drug in the cohort showing a real but bounded deficit: an exposure window, a subgroup, low frequency, or a functional rather than circulating deficit. orange

Limits on what this shows

  • Key negative/null findings: Neither the FDA Medical Review, Summary Review, nor Clinical Pharmacology Review (each re-opened for this revision) contains any hemoglobin, hematocrit, or iron-study data correlating with the 3 labeled anemia cases. Brown et al. 2018 (n=66, 36 months) and Oral et al. 2019 report no anemia or hematologic finding at all, positive or negative, in either generalized or partial lipodystrophy.
  • At-risk subgroups: None identified in any source opened for this review. The label does not stratify the 3 anemia cases by age, sex, lipodystrophy subtype, or concomitant medication.

Regulatory status

MYALEPT label, Section 6.1, Table 3 (adverse reactions in patients with generalized lipodystrophy, N=48, single-arm open-label study, median exposure 2.7 years): "Anemia 3 (6)." No further detail, severity grade, or causality statement appears anywhere else in the label.

Population evidence

Same N=48 generalized-lipodystrophy safety population used for the label's overall adverse-reaction table (re-verified directly on DailyMed for this revision). Two independent, more recent Tier A metreleptin-specific studies opened for this revision, Brown et al. 2018 (Endocrine 60(3):479-489, n=66, up to 36 months follow-up, generalized lipodystrophy) and Oral et al. 2019 (Endocrine 64(3):500-511, partial lipodystrophy), report no hemoglobin, hematocrit, or anemia data at all, so the label's 3 cases were never independently replicated, characterized, or contradicted in any source opened for this review.

Mechanism

Not named in the label. Not established for metreleptin. A plausible but unconfirmed candidate mechanism exists at the class level: leptin (not metreleptin specifically) upregulates the iron-restricting hormone hepcidin via the JAK2/STAT3 pathway in vitro (Chung et al. 2007, see the Iron entry and the Overlap map), the same signaling pathway metreleptin itself is labeled to use; this is disclosed as a hypothesis only, not as an established mechanism, per this protocol's rule against filing a clinical outcome as a nutrient finding without direct measurement.

Counter-evidence held on record

No source opened for this review measured hemoglobin, hematocrit, iron, or hepcidin in metreleptin-treated patients, so this entry cannot and does not identify anemia's cause. Per this protocol's Hard Rule 2, anemia (a clinical outcome) is not itself proof of iron deficiency, and this entry is written as an adverse-event finding, not a nutrient-deficiency claim. This is a labeled adverse-event signal, not a confirmed iron or B12/folate deficiency. It does not support iron or any other supplementation; any evaluation of anemia in a metreleptin-treated patient (CBC, iron studies, reticulocyte count) is a prescriber decision.

ATP production

Not graded — disclosed evidence gap

See study details

No metreleptin- or leptin-specific study directly measuring ATP synthesis or cellular energy output was located or could be opened during this revision's dedicated re-research pass, and no circulating consumer claim about metreleptin and ATP or "low energy" exists to rebut.

Full detail, limits and 1 references

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. ungraded

Limits on what this shows

  • Why no grade: Both conditions for ungraded are met. (1) No usable Tier A/B/C evidence: re-confirmed for this revision, the FDA Summary, Medical, and Clinical Pharmacology Reviews, and the two newly located independent long-term studies (Brown et al. 2018; Oral et al. 2019), contain no ATP-synthesis or cellular-energy-output data anywhere in the metreleptin record. Minokoshi et al. 2002 (Nature) remains excluded because of Nature's 2024 Editorial Expression of Concern about that article. Sainz et al. 2009, opened in full and used to support the Mitochondrial burden yellow entry, explicitly did not measure ATP output, only PGC-1alpha expression, so it is not extended here (Hard Rule 7 keeps Mitochondrial burden and ATP production independent even where a shared upstream signal exists; the overlap is disclosed in the Overlap map). One specific, on-topic candidate was located by title this revision but could not be read: Holmstrom MH, Tom RZ, Bjornholm M, Garcia-Roves PM, Zierath JR. "Effect of leptin treatment on mitochondrial function in obese leptin-deficient ob/ob mice." Metabolism. 2013;62(9):1258-1267. DOI 10.1016/j.metabol.2013.04.001. Confirmed as a real, indexed article via the Crossref API. Access was attempted and failed by every available route: the DOI resolved to an Elsevier ScienceDirect page that returned empty content; Unpaywall confirms the article is closed access with no repository copy; the Semantic Scholar API returned HTTP 429 on two attempts; the Europe PMC REST API returned a 503 then a 429 on two attempts. Because its direction, magnitude, and even whether "mitochondrial function" improved or worsened could not be independently verified, it is disclosed here as a specific lead for a future revision and is deliberately NOT cited as evidentiary support anywhere in this dossier, per the prohibition on citing a source not actually opened and read. (2) No circulating claim: Wikipedia and Drugs.com, both re-checked this session, contain no ATP- or "low energy"-related claim about metreleptin.

Tooling disclosure

This category shares the channel failures disclosed under Copper and throughout the Sources access note (Europe PMC and OpenAlex blocked/rate-limited on repeated attempts across this session, WebSearch budget exhausted before this revision began). Unlike the original review, this revision additionally tried the Crossref API directly (successful for most queries, used to locate both Sainz 2009 and the inaccessible Holmstrom 2013 lead), Unpaywall (used to confirm closed-access status rather than merely failing silently), and direct publisher/DOI fetches. This is a genuinely more thorough, better-documented gap than the original pass, not a repeat of it, and it isolates exactly one specific, named, still-inaccessible source for the next revision to prioritize.

  • Holmstrom MH, Tom RZ, Bjornholm M, Garcia-Roves PM, Zierath JR. — Located by title via the Crossref API for this revision; directly on point for Mitochondrial burden and ATP production. NOT cited as evidentiary support anywhere in this dossier because its abstract and text could not be independently opened and read (see access note).Access attempted and failed on every available route: DOI redirect to Elsevier/ScienceDirect returned empty content on two attempts; Unpaywall confirms closed access with no repository copy; Semantic Scholar API returned HTTP 429 twice; Europe PMC REST API returned HTTP 503 then HTTP 429. Disclosed as a specific lead for the next revision, not used as a source.

Claims checked and not supported

These circulate online for this medication. They are listed here only so they can be answered, never as findings, and they are not graded.

A claim with no supporting evidence is not necessarily disproven. Where evidence actually argues against a claim, that is stated below.

  • General "leptin-replacement biologic depletes vitamins and minerals" framing

    Where it comes from: Not attributable to any specific source found. Checked Wikipedia's metreleptin article and Drugs.com's Myalept consumer monograph, the two consumer/tertiary references successfully opened this session; neither carries such a claim, and no peptide, longevity, or supplement-marketing content for metreleptin was located either, consistent with metreleptin being an ultra-rare-disease, specialty-pharmacy-only biologic rather than a drug with wide consumer-content reach.

    Why it fails: No consumer source, clinical reference, or marketing page located during this review makes a specific "metreleptin depletes X" claim, unlike commonly circulated narratives for high-volume drugs such as metformin (B12), statins (CoQ10), or proton-pump inhibitors (B12/magnesium). The two real, drug-specific effects found (hypoglycemia risk from glucose/triglyceride lowering, decreased weight/appetite suppression) are the drug's own intended replacement-therapy pharmacology, not nutrient claims, and are graded above rather than left as an unsupported claim.

All references used above
  1. MYALEPT (metreleptin) for injection, US Prescribing Information. — FDA-approved labeling: boxed warning, indications, dosing, contraindications, warnings and precautions, clinical pharmacology, drug interactions, adverse reactions (Table 3), and clinical trial metabolic parameters (Table 4, Section 14.1).
  2. FDA Summary Review, BLA 125390 (MYALEPT), 2014. — Regulatory approval summary covering the NIH studies (991265/20010796, n=72) and study FHA101 (n=28): trial design, HbA1c/glucose/triglyceride outcome tables, antibody immunogenicity data, T-cell lymphoma incidence, autoimmune disease progression, pancreatitis and hypoglycemia adverse-event rates. Searched directly for hemoglobin, hematocrit, iron, ferritin, copper, ceruloplasmin, and oxidative-stress content; none found.
  3. FDA Medical Review, BLA 125390 (MYALEPT), 2014. — Confirms no hemoglobin, hematocrit, anemia, iron, ferritin, copper, ceruloplasmin, oxidative-stress-marker, mitochondrial, or gut-microbiome/GI-flora data anywhere in the metreleptin clinical development program; the source for the shared negative finding disclosed in the Overlap map.
  4. FDA Clinical Pharmacology and Biopharmaceutics Review, BLA 125390 (MYALEPT), 2014. — Detailed pharmacokinetics: absorption (Tmax, dose-ranging), distribution (volume of distribution by dose and study day), metabolism/elimination (renal catabolism, half-life 3.3 to 3.4 hours in antibody-negative healthy subjects), special populations, and confirmation of no hematology or mineral panel data.
  5. Brown RJ, Oral EA, Cochran E, Araujo-Vilar D, Savage DB, Long A, Fine G, Salinardi T, Gorden P. — Independent, peer-reviewed, metreleptin-specific cohort study, n=66, follow-up to 36 months (primary analysis at 12 months), generalized lipodystrophy. Opened and read for this revision (abstract and body text as rendered). Confirms sustained HbA1c/triglyceride/liver-volume improvement; contains no hemoglobin, hematocrit, anemia, iron, ferritin, copper, ceruloplasmin, oxidative-stress, mitochondrial, or gut-microbiome data.
  6. Oral EA, Gorden P, Cochran E, Araujo-Vilar D, Savage DB, Long A, Fine G, Salinardi T, Brown RJ. — Independent, peer-reviewed, metreleptin-specific cohort study, partial lipodystrophy. Opened and read for this revision. Confirms HbA1c stability over time; contains no hemoglobin, hematocrit, anemia, iron, ferritin, copper, ceruloplasmin, oxidative-stress, mitochondrial, or gut-microbiome data.
  7. Chung B, Matak P, McKie AT, Sharp P. — In vitro study, human hepatoma (HuH7) cell line, leptin (not metreleptin) 7.5-125 nmol/L. Hepcidin mRNA and peptide significantly increased above 50 nmol/L, time- and dose-dependent; effect blocked by a JAK2 inhibitor and reduced by STAT3-binding-site mutation. Opened and read in full via the publisher's freely accessible (Bronze OA, confirmed via Unpaywall) version. Tier C for metreleptin: leptin, not metreleptin; in vitro cell line, not a metreleptin-treated cohort. Basis for the Iron yellow entry.
  8. Bouloumie A, Marumo T, Lafontan M, Busse R. — In vitro study, human umbilical vein endothelial cells, leptin (not metreleptin). Confirmed as a real, indexed article (title, authors, journal, year, PMID 10385613) via the Crossref API and the Semantic Scholar API. Full abstract and text NOT accessible: direct DOI/Wiley fetch returned HTTP 403; Unpaywall confirms closed access, no repository copy; Semantic Scholar's abstract field is elided by the publisher; PubMed's abstract page returned an unrenderable script shell. Cited at title level only. Tier C for metreleptin. Basis for the Oxidative stress yellow entry.Bibliographic metadata verified across two independent sources; full text could not be opened despite four distinct attempts. Cited narrowly for this reason.
  9. Sainz N, Rodriguez A, Catalan V, Becerril S, Ramirez B, Gomez-Ambrosi J, Fruhbeck G. — In vivo study, ob/ob (leptin-deficient) mice, leptin (not metreleptin) 1 mg/kg/day intraperitoneal, twice daily, 28 days. Opened and read in full (PLoS ONE, fully open access). PGC-1alpha protein significantly increased (P=0.005); primary finding is muscle-mass accretion via FoxO3a/MAFbx/MuRF1 atrophy-pathway inhibition, not a direct mitochondrial-function study. Tier C for metreleptin. Basis for the Mitochondrial burden yellow entry.
  10. Kashani A, Rondeau I, D'Aquino M, Berube-Simard FA, Kramer JS, et al. — In vivo study, ob/ob (leptin-deficient) mice, ad libitum (n=12) vs. wild-type (n=12) vs. pair-fed ob/ob (n=11), 10 weeks. Opened and read in full (Springer/BMC, fully open access). Leptin deficiency explained 18.3% of gut microbial compositional variance, persisting after pair-feeding controlled for caloric intake/obesity; enriched Lactobacillus, depleted Akkermansia muciniphila. Tier C for metreleptin: disease model (genetic obesity), not metreleptin or lipodystrophy. Basis for the Gut microbiome risk yellow entry.
  11. Holmstrom MH, Tom RZ, Bjornholm M, Garcia-Roves PM, Zierath JR. — Located by title via the Crossref API for this revision; directly on point for Mitochondrial burden and ATP production. NOT cited as evidentiary support anywhere in this dossier because its abstract and text could not be independently opened and read (see access note).Access attempted and failed on every available route: DOI redirect to Elsevier/ScienceDirect returned empty content on two attempts; Unpaywall confirms closed access with no repository copy; Semantic Scholar API returned HTTP 429 twice; Europe PMC REST API returned HTTP 503 then HTTP 429. Disclosed as a specific lead for the next revision, not used as a source.
  12. WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD Index, A16AA07 Metreleptin. — Confirms ATC classification (Other alimentary tract and metabolism products, amino acids and derivatives).
  13. Minokoshi Y, Kim YB, Peroni OD, Fryer LGD, Müller C, Carling D, Kahn BB. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. — In vivo/in vitro study in rat skeletal muscle and mouse muscle cells: leptin selectively activates the alpha-2 catalytic subunit of AMPK, suppressing acetyl-CoA carboxylase and promoting fatty-acid oxidation, via both direct muscle action and hypothalamic-sympathetic signaling. Mechanistically adjacent to the Mitochondrial burden and ATP production categories.Opened and read in full, but NOT cited as evidentiary support for any grade: Nature published an Editorial Expression of Concern regarding this article on 2024-05-06. Disclosed here for transparency only.
  14. Wikipedia. Metreleptin. — Tertiary reference used for the circulating-claim audit and to cross-check approval history (FDA February 2014, EU prior to September 2018, Canada January 2024) and investigational-use context. No vitamin, mineral, iron, copper, oxidative-stress, mitochondrial, or gut-microbiome claim found among its 16 cited references.
  15. Drugs.com. Myalept (metreleptin) consumer monograph. — Consumer reference used for the circulating-claim audit. No vitamin, mineral, iron, copper, or nutrient-depletion claim found; generic "vitamins and herbal products may interact" boilerplate present with no specifics given.