The acute effect of beta‐guanidinopropionic acid versus creatine or placebo in healthy men (ABC‐Trial): A randomized controlled first‐in‐human trial

Abstract

AimsIncreasing evidence indicates that the ATP‐generating enzyme creatine kinase (CK) is involved in hypertension. CK rapidly regenerates ATP from creatine phosphate and ADP. Recently, it has been shown that beta‐guanidinopropionic acid (GPA), a kidney‐synthesized creatine analogue and competitive CK inhibitor, reduced blood pressure in spontaneously hypertensive rats. To further develop the substance as a potential blood pressure‐lowering agent, we assessed the tolerability of a sub‐therapeutic GPA dose in healthy men.MethodsIn this active and placebo‐controlled, triple‐blind, single‐centre trial, we recruited 24 healthy men (18–50 years old, BMI 18.5–29.9 kg m−2) in the Netherlands. Participants were randomized (1:1:1) to one week daily oral administration of GPA 100 mg, creatine 5 g, or matching placebo. The primary outcome was the tolerability of GPA, in an intent‐to‐treat analysis.ResultsTwenty‐four randomized participants received the allocated intervention and 23 completed the study. One participant in the placebo arm dropped out for personal reasons. GPA was well tolerated, without serious or severe adverse events. No abnormalities were reported with GPA use in clinical safety parameters, including physical examination, laboratory studies, or 12‐Lead ECG. At day 8, mean plasma GPA was 213.88 (SE 0.07) in the GPA arm vs. 32.75 (0.00) nmol l−1 in the placebo arm, a mean difference of 181.13 (95% CI 26.53–335.72).ConclusionIn this first‐in‐human trial, low‐dose GPA was safe and well‐tolerated when used during 1 week in healthy men. Subsequent studies should focus on human pharmacokinetic and pharmacodynamic assessments with different doses.

Creatine kinase, sodium retention, and blood pressure: Is there a link?

“…In addition, it would be interesting to see the effects of diuretic use on the CK activity of subjects exposed to a high sodium diet. Last, the best way to define a causal relationship between CK activity and urinary sodium excretion would be to repeat this experiment assessing BP and urinary sodium excretion after a high sodium diet before and after administering beta‐guanidinopropionic acid, a CK inhibitor that is now available for human use . We are looking forward to more studies offering a better understanding on this new and exciting area of clinical HTN.…”

“…Last, the best way to define a causal relationship between CK activity and urinary sodium excretion would be to repeat this experiment assessing BP and urinary sodium excretion after a high sodium diet before and after administering beta-guanidinopropionic acid, a CK inhibitor that is now available for human use. 18 We are looking forward to more studies offering a better understanding on this new and exciting area of clinical HTN. As it was pointed out in an editorial by Dr. Pickering almost a decade ago in this journal, "genetically determined variations in muscle fiber composition could well be of considerable importance in furthering our understanding of the deadly combination of HTN, obesity, and type 2 diabetes", 19 our understanding continues to evolve on this subject.…”

Creatine kinase and renal sodium excretion in African and European men on a high sodium diet

“…Future studies could assess renal CK activity in relation to sodium handling as a more direct measure. In addition, the recently reported specific oral CK inhibitor for human use, beta‐guanidinopropionic acid might provide a new tool to further assess the potential role of CK in sodium handling of the human kidney in relation to blood pressure.…”

Targeting AMPK Signaling as a Neuroprotective Strategy in Parkinson’s Disease

“…Unlike metformin and resveratrol, GPA activates AMPK without inhibiting the electron transport chain. Rather, it increases the ratio of AMP to ATP by decreasing the function of creatine kinase [55]. …”

“…And indeed, a number of AMPK activating compounds do have similar neuroprotective effects [160]. Of the available pharmacological activators, resveratrol, GPA, and metformin have particular clinical relevance because they have each been tested or are used clinically (although not currently for PD) and are well tolerated in humans [55,161,162]. However, these agents also have AMPK-independent effects, so it is not always clear whether their effects are related to AMPK activation [49].…”