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Aic3.1

AICAR (Acadesine) Research

Mostly mechanism / observationalLimited safety

6 peer-reviewed studies

What the evidence says

Mostly mechanism / observational

Most AICAR (Acadesine) studies are mechanism or observational rather than RCTs that measure a clinical effect — keep findings provisional.

Most evidence is from medium-quality meta-analyses and randomised trials published 1997–2019 with a typical study size of 4,043 participants.

Based on 6 studies · 1 meta-analysis · 1 RCT · 7,123 total participants

Confidence

Moderate

By outcome

Metabolic & AMPK
Mostly mechanism / observational4 studies
Endurance & exercise (preclinical)
Mostly mechanism / observational3 studies
Cardiac surgery & ischemia (human)
Too few graded studies2 studies
Safety profile
Too few graded studies2 studies

Older research base

Newest study from 2019 · Latest meta-analysis: 1997

199720082019

1RCTn=3,080 · very large study2012

In this population of intermediate- to high-risk patients undergoing CABG surgery, acadesine did not reduce the composite of all-cause mortality, nonfatal stroke, or SLVD.

Newman MF, Ferguson TB, White JA, Ambrosio G, Koglin J, Nussmeier NA, et al. · JAMA (2012)

The definitive human trial of AICAR (as acadesine) — and the best counter-evidence: a large, double-blind, placebo-controlled RCT (~3080 patients, 300 sites, 7 countries)
Tested acadesine infusion to protect the heart during on-pump CABG surgery — a different indication from exercise or longevity
NEGATIVE: the primary composite (all-cause mortality, nonfatal stroke, severe LV dysfunction) occurred in 5.1% of acadesine vs 5.0% of placebo (OR 1.01)

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2Meta-Analysisn=4,043 · very large study1997

Treatment with acadesine before and during surgery can reduce early cardiac death, MI, and combined adverse cardiovascular outcomes.

Mangano DT (McSPI Research Group) · JAMA (1997)

Individual-patient meta-analysis of 5 randomized, placebo-controlled CABG trials (4043 patients) — the early positive human signal
Acadesine reduced perioperative myocardial infarction by 27% and the combined MI/stroke/cardiac-death outcome by 26%
Reduced early cardiac death; safety similar to placebo apart from a transient rise in serum uric acid

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3Animal2008

Even in sedentary mice, 4 weeks of AICAR treatment alone induced metabolic genes and enhanced running endurance by 44%.

Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, et al. · Cell (2008)

The foundational 'exercise mimetic' study — but entirely in mice: a treadmill running test, not a human trial
The orally active AMPK agonist AICAR, given for 4 weeks to SEDENTARY mice, increased running endurance by 44% with no exercise
AICAR and a PPARβ/δ agonist induced oxidative myofibers and metabolic genes via the AMPK–PGC-1α pathway

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4Review2018

The most efficacious compounds that induce muscle hypertrophy or endurance are hampered by severe side effects and are classified as doping.

Weihrauch M, Handschin C · Biochemical Pharmacology (2018)

Review of 'exercise mimetics' including AICAR, weighing the AMPK–PGC-1α rationale against translational reality
Notes that the most potent muscle/endurance compounds carry severe side effects and are classified as doping (AICAR is WADA-banned)
Frames the feasibility of pharmacological exercise mimicry as highly debated, not established

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5Review2016

Such so-called exercise or caloric restriction 'mimetics' have so far mostly been described in pre-clinical, experimental settings with limited translation into humans.

Handschin C · Pharmacological Research (2016)

Review explicitly addressing whether exercise/caloric-restriction mimetics (including AICAR-class AMPK activators) are ready for human use
Concludes they remain largely preclinical with limited human translation — a direct caution against the 'exercise in a pill' framing
Most candidates converge on PGC-1α in skeletal muscle, the same pathway AICAR engages

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6In Vitro2019

Stimuli-inducible GLUT4 release relies on Tbc1d1-evoking proximal stimuli, such as AICAR and intracellular Ca2+.

Hatakeyama H, Morino T, Ishii T, Kanzaki M · The Journal of Biological Chemistry (2019)

Mechanistic cell-based reconstitution study grounding the GLUT4/glucose-uptake arm of AICAR's action
AICAR acts as an exercise-mimetic stimulus that triggers GLUT4 release via the RabGAP Tbc1d1 (the contraction/AMPK pathway, distinct from insulin's AS160 route)
Clarifies how AMPK-type stimuli mobilize glucose transporters in muscle cells

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View in Research Library

AICAR (Acadesine) Research

Mostly mechanism / observational

Effect of adenosine-regulating agent acadesine on morbidity and mortality associated with coronary artery bypass grafting: the RED-CABG randomized controlled trial.

Effects of acadesine on myocardial infarction, stroke, and death following surgery. A meta-analysis of the 5 international randomized trials.

AMPK and PPARdelta agonists are exercise mimetics.

Pharmacological targeting of exercise adaptations in skeletal muscle: Benefits and pitfalls.

Caloric restriction and exercise "mimetics": Ready for prime time?

Cooperative actions of Tbc1d1 and AS160/Tbc1d4 in GLUT4-trafficking activities.