Roflumilast

selective PDE4 inhibitor

Also sold as Daliresp.

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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.

Roflumilast has almost no classical depletion machinery. It is metabolized by CYP1A2 and CYP3A4 to an active N-oxide, about 70% of a dose is recovered in urine as metabolites, and the label does not mention any vitamin, mineral, iron, copper, anemia or microbiome effect [1]. The one mechanism class that is clearly present is changed intake (category H): decreased appetite, nausea, diarrhea and weight loss are among the most frequent adverse reactions. In the US label pool (4,438 on roflumilast 500 mcg, 4,192 on placebo), weight decrease was reported in 7.5% versus 2.1%, decreased appetite 2.1% versus 0.4%, nausea 4.7% versus 1.4%, and diarrhea 9.5% versus 2.7% [1]. In the two 52-week pivotal trials M2-124 and M2-125 (1,537 on roflumilast, 1,554 on placebo) the pooled between-group weight difference was -2.17 kg [4], consistent with an independent review figure of 2.2 kg [10] and the EU assessment report's "approximately -2 kg" [3]. Under Hard Rule 2 this is a drug adverse effect and a clinical outcome, not a nutrient deficiency, and it is filed as an outcome entry. No study retrieved measured dietary intake, body composition, or any vitamin or mineral level in roflumilast users.

selective PDE4 inhibitor · ATC R03DX07 (via Wikipedia [27]; WHO index not opened) · also sold as Daliresp and Daxas; topical forms (Zoryve) are not the subject · reviewed 2026-10-08. 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 Roflumilast 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

Dietary intake and body weight: appetite loss, nausea, diarrhea (outcome entry, direction: reduced intake and weight)

Yellow — Low

See study details

Roflumilast reliably lowers appetite and body weight (about 2 kg over 52 weeks, with a tail of 5 to 10% and over 10% losses), but this is an adverse-effect outcome. No nutrient, dietary intake or body composition was measured, so it is not a nutrient deficiency.

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

Null findings: No nutrient, serum protein, dietary recall or body-composition measurement was reported in any roflumilast source opened. PSORRO reported no laboratory changes [9] (parameters not itemized in the abstract). A search for vitamin, mineral, hemoglobin and anemia data in roflumilast users returned no measured values (see Ungraded and Sources).
At-risk subgroups: Patients who are already underweight or have COPD-related cachexia, older adults, and people who develop persistent diarrhea. Confounding by indication applies: COPD itself causes weight loss, and the placebo arm also lost weight (2.1% reported weight decrease) [1].

Regulatory status

US label sec 5.3 and 6.1 (read via summarizer) [1]: weight decreased 331/4,438 (7.5%) versus 89/4,192 (2.1%); decreased appetite 91 (2.1%) versus 15 (0.4%); nausea 209 (4.7%) versus 60 (1.4%); diarrhea 420 (9.5%) versus 113 (2.7%). Moderate weight loss (5 to 10% of body weight) in 20% of roflumilast patients (placebo figure not captured in the extract); severe loss (over 10%) in 7% versus 2% on placebo. The label gives percentages only, no kg. It directs regular weight monitoring and discontinuation if unexplained or clinically significant loss occurs. EU SmPC [2] lists diarrhoea 5.9%, weight decreased 3.4%, nausea 2.9% as the most common reactions and advises stopping for unexplained, clinically concerning weight decrease.

Population evidence

M2-124 and M2-125, two identical 52-week double-blind placebo-controlled trials, 1,537 on roflumilast 500 mcg and 1,554 on placebo [4] (cohort confirmed as roflumilast 500 mcg, pooled N 3,091 in a later post hoc analysis [28]): pooled between-group weight difference -2.17 kg; adverse events 67% versus 62%; discontinuation for adverse events 14% versus 12% (95% CI for the weight difference not retrieved). REACT (roflumilast added to ICS/LABA, 973 versus 972 for 1 year): adverse events 67% versus 59%, withdrawals due to adverse events 11% versus 5% [6]; the weight effect size was NOT retrieved (abstract has no weight figure; full text 403; trial record [30] did not render adverse-event counts). M2-127/M2-128 (1,676 randomized, roflumilast on top of long-acting bronchodilators): weight loss, nausea, diarrhea and headache more frequent with roflumilast, no numbers in the abstract [5]. EPAR: first-year weight loss "seems small in magnitude (approximately -2 kg)", text truncated before the progression conclusion [3]. Review: weight loss averaged 2.2 kg [10]. Cochrane 2017, 20 roflumilast trials with 17,627 participants: weight loss associated with roflumilast; diarrhoea NNTH 15 (95% CI 13 to 17) [7]. PSORRO (psoriasis, n=46, baseline 103.6 kg, 12 weeks then open label): median weight change -2.6% at week 12 and -4% at week 24 versus 0.0% and 1.3% in placebo-first patients, with reduced appetite more frequent on drug; no blood pressure or laboratory changes [9]. Real-world chart review, n=83: appetite loss 10.8%, weight loss 10.8%, nausea 8.4% [11]. Case report: a woman lost over 25% of body weight with intractable diarrhea and three admissions [12]. Meta-analyses of roflumilast trials list appetite loss, nausea and weight loss as higher than placebo without numbers in the abstracts [26]. In a pooled analysis of 10 asthma studies (5,169 patients, 2,851 on roflumilast) weight loss was described as small, no numbers in the abstract [24].

Mechanism

Class H (changed intake) present. The label ties effects to raised cAMP [1] but no retrieved source demonstrates the appetite pathway in humans. In high-fat-diet mice roflumilast reduced weight gain through higher energy expenditure, with improved glucose tolerance [19]. A 4-week 250 mcg up-titration regimen in 1,321 patients lowered combined adverse-event rates (OR 0.63) versus 500 mcg from the start [25], suggesting a dose-onset component to tolerability.

Counter-evidence held on record

Counter-evidence and confounding Weight loss and appetite loss are outcomes of a drug adverse effect and of the underlying disease, not measured nutrient deficits (Hard Rule 2). Insomnia, anxiety and depression (label: 5.9% versus 3.3% psychiatric reactions; a 2025 FAERS analysis of 3,140 reports called depression and suicidal ideation notable signals, no ratios given [23]) and nausea can reduce eating independent of any appetite pathway [1]. Framing caution This is a monitoring prompt for weight and intake, not a nutrient-depletion claim for roflumilast. Do not recommend any supplement from this entry.

Glucose handling: pharmacologic effect, reverse direction (not a nutrient finding)

Yellow — Low

See study details

Roflumilast lowers HbA1c and insulin resistance in people with type 2 diabetes; this is a drug effect with a measured outcome, not a nutrient depletion or excess.

Full detail and limits

Limits on what this shows

Null findings: HbA1c unchanged between groups in a hospitalized COPD pilot (n=64) [29].

Regulatory status

No glucose-lowering statement was found in the US label sections retrieved [1].

Population evidence

Tier A, roflumilast in cohort: 12-week randomized placebo-controlled trial in 205 adults with newly diagnosed type 2 diabetes, HbA1c least-squares mean difference -0.45% versus placebo (P<0.0001) [13]. Randomized trial of 58 patients with type 2 diabetes and neuropathy, roflumilast 500 mcg/day versus alpha-lipoic acid 600 mg/day: HbA1c fell 0.7% versus 0.3% (P<0.001), fasting glucose, insulin and HOMA-IR fell more with roflumilast [14]. A COPD pilot (n=64) found HbA1c not different between groups [29]. Mouse data: improved glucose tolerance and steatosis [19].

Mechanism

cAMP-mediated effects on energy expenditure and insulin sensitivity per mouse data [19].

Counter-evidence held on record

Counter-evidence Weight loss can itself lower HbA1c and insulin resistance, so the glucose effect and the weight effect are partly entangled (see Overlap map). Framing caution A glucose change is a pharmacologic effect, not a nutrient status finding. It matters to patients on glucose-lowering drugs and belongs with their prescriber. No supplement is implied.

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: reverse direction, preclinical protection

Yellow — Low

See study details

In cell and animal models roflumilast preserved or improved mitochondrial morphology and membrane potential; no human in vivo mitochondrial measurement exists, and there is no signal of mitochondrial toxicity.

Full detail and limits

Limits on what this shows

Null findings: No study showing mitochondrial inhibition or toxicity by roflumilast was found in the 10 of 17 PubMed records displayed. 7 records were not displayed.

Regulatory status

No mitochondrial warning or statement in the label [1].

Population evidence

None in humans. Tier B, roflumilast-specific: human primary cortical neurons exposed to quinolinic acid, roflumilast raised mitochondrial membrane potential and NAD+ and lowered ROS and caspase 3/7 [15]; HT-22 cells and rats after ischemia/reperfusion, roflumilast ameliorated mitochondrial morphology and membrane potential [16]; mice with isoproterenol cardiac injury, roflumilast reduced mitochondrial injury while PDE4D overexpression reduced PINK1/Parkin mitophagy [17]; rat and H9C2 myocardial ischemia/reperfusion, reduced mitochondrial damage (JC-1, ATP and mPTP assays run, values not shown in the abstract) [18]; high-fat-diet mice, increased hepatic PGC-1 alpha-dependent mitochondrial biogenesis and hepatocyte respiratory capacity [19]. Numbers were not reported in the abstracts read.

Mechanism

cAMP/PKA/CREB signaling and Nrf2 activation are the proposed routes in the models. Direction is protective, not burdening.

Counter-evidence held on record

Counter-evidence Disease-model protection in rodents or cell lines does not establish an effect in human COPD patients at 500 mcg daily. Doses and tissue concentrations differ. Framing caution Not a mitochondrial benefit claim and not a deficiency claim. Do not recommend mitochondrial cofactors (CoQ10, carnitine, B vitamins) from this entry.

Oxidative Stress

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

Oxidative stress: reverse direction, lower lipid peroxidation in animal models

Yellow — Low

See study details

Across multiple animal and cell studies roflumilast lowered oxidative stress markers and raised glutathione; no human study measured oxidative stress in roflumilast users.

Full detail and limits

Limits on what this shows

Null findings: The ensifentrine comparison showed limited roflumilast effect in human COPD patient cells in vitro [15]. No pro-oxidant effect was reported in the records displayed.

Regulatory status

No oxidative-stress statement in the label [1].

Population evidence

PubMed query "roflumilast oxidative stress" returned 64 records; 10 displayed, none a human study of roflumilast-treated patients [15]. Tier B examples: rats with cadmium injury, roflumilast lowered MDA and restored GSH, SOD and nitric oxide in liver and testes, and lowered cardiac MDA while restoring GSH, SOD and catalase; rabbit acute lung injury, reduced 3-nitrotyrosine and TBARS in lung tissue and plasma; HT-22 cells and rats after ischemia, increased GSH, decreased lipid peroxidation, Nrf2 nuclear translocation [15][16]; human primary cortical neurons, lower ROS [15]. A cell study with COPD patient PBMCs found roflumilast had limited effects on H2O2-induced apoptosis while ensifentrine reversed it (cells only, no dosing) [15].

Mechanism

Present in models: Nrf2 pathway activation and cAMP-linked anti-inflammatory action. Not shown in humans.

Counter-evidence held on record

Counter-evidence All models are injury models in which the drug opposes an insult. They do not describe redox status in an uninjured, treated person. Framing caution This is not an antioxidant benefit claim and not an antioxidant-depletion claim. Do not recommend antioxidant supplements from this entry.

Copper and Iron Balance

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

Iron: reverse direction, lower tissue iron accumulation in animal models

Yellow — Low

See study details

In bleomycin, ischemia and spinal injury models roflumilast reduced tissue iron accumulation and ferroptosis markers; no human iron status measurement exists for roflumilast users.

Full detail and limits

Limits on what this shows

Null findings: Hematologic records from the anemia/hemoglobin query contained no iron-deficiency or anemia reports for roflumilast (see Oxygen delivery entry).

Regulatory status

Iron is not mentioned in the label [1].

Population evidence

PubMed "roflumilast AND (iron OR ferroptosis)": 10 records, none measuring iron status in people taking roflumilast. Tier B: bleomycin pulmonary fibrosis in mice, reduced iron accumulation and ferroptosis, raised Slc40a1, Fth1, GPX4 and FSP1 and lowered Tfrc [20]; rat and HT-22 ischemia/reperfusion, lower Fe2+ and NCOA4, higher ferroportin and FTH1 [16]; rat spinal cord injury, lower intracellular iron in vitro and higher FTH1 [20]; 3-NP rat model, improved GPx4, GSH and MDA [20]. No numeric iron values were in the abstracts.

Mechanism

Modulation of iron handling genes through cAMP/CREB and Nrf2 in injury models; not tested in healthy tissue.

Counter-evidence held on record

Counter-evidence Local tissue iron in an injury model is not systemic iron status, and there is no basis for either an iron deficiency or an iron overload claim. Framing caution Not an iron-deficiency claim, and not a reason to supplement or to withhold iron. Iron is a separate entry from copper (Hard Rule 7).

Copper

Not graded — disclosed evidence gap

See study details

No study or claim linking roflumilast to copper status, chelation or ceruloplasmin was found.

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 of Step 7 are met on the evidence reachable: no Tier B or C source supports even a yellow, and no circulating copper claim for roflumilast was found (the consumer-claim search itself was tooling-limited). This is a genuine literature gap with a tooling caveat on the claim sweep. It is not a finding of safety.

Regulatory status

Copper is not mentioned in the label [1].

Channels tried

PubMed "roflumilast AND copper": 1 result, an emphysema review that lists copper and roflumilast as separate "promising candidates" and reports no copper-roflumilast interaction [29]. PubMed "roflumilast copper" with ceruloplasmin as an OR term returned 9,993 unrelated ceruloplasmin records (invalid query, discarded). DailyMed label text search for copper: not mentioned. WebSearch for consumer copper claims: failed (budget exhausted).

Gut Microbiome Risk

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

Gut microbiome risk: diarrhea signal, no human microbiome data

Yellow — Low

See study details

Roflumilast causes diarrhea in roughly 1 in 10 trial patients, but no human study of gut microbiome composition on oral roflumilast was found, and the one microbiome observation is a mouse study of a drug-loaded vesicle.

Full detail and limits

Limits on what this shows

Null findings: No human microbiome data exist in the retrieved literature, so there is no null result to quote either. The PubMed query on roflumilast with microbiota, microbiome, dysbiosis, fecal or colitis returned 18 records; the 10 displayed contained no human microbiome study (page 2 not displayed). Two narrower PubMed queries ("roflumilast gut microbiota" and "roflumilast AND (gut microbiota OR 16S OR intestinal flora OR short-chain fatty)") returned HTTP 404, which PubMed gives for zero hits; that reading is inferred, not confirmed.
At-risk subgroups: Not defined for microbiome. For diarrhea itself: patients on CYP3A4/1A2 inhibitors with raised exposure may have more adverse reactions [1].

Regulatory status

No microbiome statement in the label [1]. Diarrhea 9.5% versus 2.7%; serious reactions more frequent on roflumilast include diarrhea [1].

Population evidence

Human diarrhea data only: Cochrane NNTH 15 (95% CI 13 to 17) [7]; Cochrane 2020 update (42 RCTs, 28 roflumilast trials) reports diarrhoea OR 3.20, abstract relayed via a PubMed listing summary [8]; EPAR: 585 diarrhea cases in 5,766 roflumilast 500 mcg patients, 10 serious [3]. No stool sequencing, diversity, SCFA, or C. difficile study of roflumilast users was located. Tier B animal data: in a mouse colitis study, MnO2 and roflumilast co-loaded probiotic membrane vesicles reduced colitis and shifted gut taxa (less Escherichia-Shigella, more Akkermansia), with roflumilast acting on macrophage cAMP [21]; this is a combination formulation, so the effect of roflumilast alone on the microbiome is not isolated. Rat TNBS colitis: oral and rectal roflumilast partly reduced colitis, no microbiota outcome [22].

Mechanism

Present as a hypothesis: drug-induced diarrhea and cAMP-mediated GI effects can change luminal transit and composition. Not demonstrated for oral roflumilast. PDE4 inhibitors reduced experimental colitis in animals, but human IBD studies had not shown clear superiority [22].

Counter-evidence held on record

Counter-evidence Diarrhea is not dysbiosis, and a mouse vesicle formulation is not oral dosing. The grade is yellow only because a roflumilast-containing Tier B animal observation exists and a quantified human GI effect is present. Framing caution This is not a claim that roflumilast disrupts the human gut microbiome. Do not recommend probiotics from this entry.

Oxygen and ATP Output

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

ATP production: reverse direction, higher respiratory capacity in mouse hepatocytes

Yellow — Low

See study details

The only roflumilast data touching cellular energy output show more mitochondrial respiratory capacity and energy expenditure in mice; no ATP value was available in any abstract and no human data exist.

Full detail and limits

Limits on what this shows

Null findings: No study reporting lower ATP, impaired oxidative phosphorylation or mitochondrial membrane potential loss from roflumilast was found.

Regulatory status

No energy-metabolism statement in the label [1].

Population evidence

None in humans. Tier B: high-fat-diet mice, roflumilast reduced weight gain via higher energy expenditure, with PKA-dependent increase in hepatocyte respiratory capacity [19]. Myocardial ischemia/reperfusion in rats and H9C2 cells included ATP assays, but values are not given in the abstract [18]. Human neurons: higher mitochondrial membrane potential and NAD+ [15].

Mechanism

PGC-1 alpha-dependent mitochondrial biogenesis, per the mouse study [19]. Not shown in humans.

Counter-evidence held on record

Counter-evidence The mouse energy-expenditure finding is conceptually adjacent to weight loss in people, but a human mechanism was not shown, and fatigue or "low energy" claims are not supported or refuted by these data. Framing caution Not an energy-boost claim and not a depletion claim. Do not recommend energy-support supplements from this entry.

Oxygen delivery/utilization: small SpO2 gain (intended effect), no red-cell data

Yellow — Low

See study details

The only oxygenation measure in roflumilast users is a small rise in exercise oxygen saturation in COPD, an intended pulmonary effect; hemoglobin, hematocrit and methemoglobin were never reported, so no oxygen-carrying deficiency is claimed.

Full detail and limits

Limits on what this shows

Null findings: Animal records in the same query (rat air-embolism lung injury, hypoxia-induced pulmonary hypertension, LPS capillary leak) reported no arterial oxygen values or only qualitative statements [31]. No hemolysis, methemoglobinemia or anemia report for roflumilast was found.

Regulatory status

No anemia, hemoglobin or hematologic statement in the label sections retrieved [1].

Population evidence

Tier A, roflumilast in cohort: randomized double-blind placebo-controlled trial, 250 randomized COPD patients, physiological effects at rest and during exercise [31] (abstract via a summarized PubMed listing). Versus placebo at a standardized exercise time, SpO2 was 0.7% higher (P=0.020), inspiratory capacity 0.12 L higher (P=0.008), and peak ventilation 1.9 L/min higher (P=0.014); the authors described small but consistent SpO2 improvements. Confidence intervals were not retrieved. PubMed "roflumilast AND (anemia OR hemoglobin OR erythropoiesis OR hemolysis OR methemoglobin)" returned 5 records with no red-cell data; the only hemoglobin mentions were HbA1c [13][14][29].

Mechanism

Hard Rule 2 applies: improved lung mechanics and oxygen saturation are the drug's intended pharmacologic effect in COPD, not an oxygen-delivery finding in the nutrient sense. No mechanism for lowered oxygen-carrying capacity is reported.

Counter-evidence held on record

Counter-evidence A 0.7% SpO2 difference is small and was measured during exercise in a lung-disease population. It says nothing about hemoglobin or tissue oxygen extraction. Framing caution This is a mechanism clarification, not a benefit claim and not a deficiency claim. Do not recommend iron, B12 or other hematinic supplements from this entry. ATP production is a separate entry.

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.

None located
Where it comes from: A consumer and retailer depletion-claim sweep could not be run (WebSearch budget exhausted; direct consumer-site search not attempted through third-party readers). No roflumilast-specific depletion claim appeared in any PubMed record, the label, or the EU documents opened.
Why it fails: Nothing to rebut from sources actually opened. This row is a disclosure, not a finding that no claim exists. A later revision should repeat the consumer sweep.
Weight loss read as "malnutrition" or a vitamin/protein deficiency
Where it comes from: Implied reading of the label's weight-decrease warning, not a traced published claim.
Why it fails: Listed only to prevent misreading: the label and trials report weight and appetite outcomes, not nutrient levels (Hard Rule 2). Handled as the yellow outcome entry, not as a white claim.

How the body handles this medication

Metabolism and enzymes: Biotransformation to roflumilast N-oxide is mediated by CYP1A2 and CYP3A4, plus conjugation. The N-oxide is the only major plasma metabolite; its AUC is about 10-fold that of the parent and it is about 3-fold less potent in vitro. Roflumilast did not inhibit P-gp in vitro. No CYP induction by roflumilast is described in the sections retrieved.[1] DailyMed Daliresp label, sec 12.3; [2] EU SmPC sec 5.2
Interactions that change drug exposure: Strong inducers lower exposure (rifampicin: roflumilast Cmax -68%, AUC -79%) and are not recommended; named examples include phenobarbital, carbamazepine and phenytoin. CYP3A4 or dual CYP3A4/1A2 inhibitors raise exposure: erythromycin AUC +70%, ketoconazole +99%, fluvoxamine +156%, enoxacin +56%, cimetidine +85%, gestodene/ethinyl estradiol +51%. No significant interaction with antacids (Maalox) was seen. The direction is other drug to roflumilast, not roflumilast to nutrient (Hard Rule 4).[1] sec 7, 12.3 (read via summarizer)
Elimination: About 70% of radioactivity was recovered in urine, as metabolites. Plasma clearance after IV dosing is about 9.6 L/h. Median effective half-lives are about 17 hours (roflumilast) and 30 hours (N-oxide); steady state takes about 4 and 6 days.[1] sec 12.3
Absorption and distribution: Absolute oral bioavailability about 80%. Food does not change total absorption but delays Tmax and lowers roflumilast Cmax by about 40%. Plasma protein binding is about 99% (parent) and 97% (N-oxide); volume of distribution about 2.9 L/kg. No named absorption transporter appears in the label text retrieved; OATP is not mentioned.[1] sec 12.3
Hepatic impairment: Contraindicated in moderate to severe liver impairment (Child-Pugh B or C). In Child-Pugh A roflumilast AUC rises 51% (N-oxide 24%); in Child-Pugh B 92% (N-oxide 41%).[1] sec 4, 8.6
Mechanism screen (classes A to I): H present (appetite, nausea, weight) with Tier A incidence data. A (diarrhea-linked absorption interference) is plausible but not tested for any nutrient. B, C, D, E, F, G and I: no mechanism reported in the label or retrieved literature. PDE4 inhibition raises intracellular cAMP [1], which is the proposed route for both the efficacy and the GI and appetite effects.[1] sec 12.1, 5.3, 6.1

What the research says is worth watching

General information from the medication label and the studies above. It is not personal medical advice, and any change belongs with your prescriber.

Label-directed
Body weight and appetite
The label directs regular weight monitoring and re-evaluation of therapy for unexplained or clinically significant loss [1][2]. Baseline and periodic weights are the practical measure.
At-risk groups
Underweight and cachectic patients
Average loss is about 2 kg but a tail of 5 to 10% and over 10% exists [1][4]. A clinician may add albumin, a dietary review or a micronutrient panel in patients who lose weight; that is general practice, not a roflumilast-specific finding.
Diarrhea
Persistent diarrhea
Diarrhea is the most frequent reaction (9.5% versus 2.7%) and can be serious [1]. Prolonged diarrhea with weight loss warrants a prescriber conversation about hydration and the drug. No nutrient-specific lab is evidence-based here.
Safety outcome
Mood and sleep
Psychiatric reactions 5.9% versus 3.3%, including suicidal ideation and behavior in trials and postmarketing [1]. Not a nutrient entry; reduced eating from low mood or insomnia can add to weight loss.
Drug interactions
CYP3A4/1A2 modulators
Strong inducers (rifampicin, phenobarbital, carbamazepine, phenytoin) lower exposure; inhibitors (erythromycin, ketoconazole, fluvoxamine, enoxacin, cimetidine) raise it [1]. The label names no mineral or vitamin separation interval, and antacids showed no significant interaction. Herbal or supplement inducers were not named in the label text retrieved; ask the pharmacist.
Diabetes
Glucose-lowering therapy
HbA1c fell by 0.45 percentage points versus placebo in newly diagnosed type 2 diabetes [13]. Patients on glucose-lowering drugs should tell their prescriber about the start of roflumilast. No supplement is implied.

Overlap map, to prevent double counting

Entries that rest on the same source or mechanism.

Mitochondrial burden
Shares evidence with: Oxidative stress, ATP production, Iron
Note: The same preclinical injury-model papers (ischemia/reperfusion [16][18], cardiac mitophagy [17], neuronal OGD/R [16]) appear across these four entries. They are one body of rodent and cell evidence, not independent confirmations.
ATP production
Shares evidence with: Mitochondrial burden, Glucose handling, Dietary intake
Note: The mouse study [19] supports the respiratory-capacity finding, the glucose finding and the energy-expenditure explanation for weight loss; count it once.
Glucose handling
Shares evidence with: Dietary intake and body weight
Note: Weight loss itself lowers HbA1c; the glucose trials [13][14] and the weight data are partly one signal.
Gut microbiome risk
Shares evidence with: Dietary intake and body weight
Note: Both draw on the same diarrhea counts [1][3][7]. The microbiome entry adds only the mouse vesicle study [21].
Oxygen delivery/utilization
Shares evidence with: None (adjacent to ATP production and Mitochondrial burden by concept only)
Note: The SpO2 finding [31] is a pulmonary-function effect of the drug action that treats COPD. It shares no source with ATP production and is kept as a separate entry (Hard Rule 7). Hemoglobin was unmeasured in all sources.
Oxidative stress
Shares evidence with: Iron
Note: Ferroptosis papers [16][20] report both lipid peroxidation/GSH and iron handling in the same experiments.

All references used above

Roflumilast

Findings for this medication

What the research found

Dietary intake and body weight: appetite loss, nausea, diarrhea (outcome entry, direction: reduced intake and weight)

Glucose handling: pharmacologic effect, reverse direction (not a nutrient finding)

The five body-system areas

⚡Mitochondrial Burden

Mitochondrial burden: reverse direction, preclinical protection

💥Oxidative Stress

Oxidative stress: reverse direction, lower lipid peroxidation in animal models

⚖️Copper and Iron Balance

Iron: reverse direction, lower tissue iron accumulation in animal models

Copper

🌿Gut Microbiome Risk

Gut microbiome risk: diarrhea signal, no human microbiome data

💨Oxygen and ATP Output

ATP production: reverse direction, higher respiratory capacity in mouse hepatocytes

Oxygen delivery/utilization: small SpO2 gain (intended effect), no red-cell data

Claims checked and not supported

None located

Weight loss read as "malnutrition" or a vitamin/protein deficiency

How the body handles this medication

What the research says is worth watching

Overlap map, to prevent double counting

Mitochondrial Burden

Oxidative Stress

Copper and Iron Balance

Gut Microbiome Risk

Oxygen and ATP Output