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The acute effect of beta-guanidinopropionic acid versus creatine or placebo in healthy men (ABC Trial): study
Fares A Karamat1, Deborah L Horjus2, Yentl C Haan3
1Department of Vascular Medicine, Room F4-253, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands. f.a.karamat@amc.nl.
Insights
This study tested the safety of beta-guanidinopropionic acid, a potential new hypertension treatment. The first human trial found it well-tolerated, suggesting promise for creatine kinase inhibition in managing blood pressure.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Biochemistry
Background:
- Up to 30% of patients have uncontrolled hypertension despite treatment.
- High intracellular creatine kinase (CK) activity may increase blood pressure and hypertension risk.
- Plasma CK activity predicts blood pressure and antihypertensive treatment failure.
Purpose of the Study:
- To assess the tolerability of oral beta-guanidinopropionic acid in men.
- To evaluate beta-guanidinopropionic acid as a potential antihypertensive agent.
- To provide first-in-men data on CK inhibition for hypertension.
Main Methods:
- Randomized, triple-blind, placebo-controlled trial in 24 healthy males.
- One week of daily oral administration of beta-guanidinopropionic acid (100 mg), creatine (5 g), or placebo.
- Primary outcome: tolerability of beta-guanidinopropionic acid. Secondary outcomes: biochemical and hemodynamic parameters.
Main Results:
- The study provided the first human safety data for beta-guanidinopropionic acid.
- Tolerability was assessed descriptively.
- Placebo-adjusted differences in biochemical and hemodynamic parameters were analyzed.
Conclusions:
- There is a need for new treatments for resistant hypertension.
- Creatine kinase inhibition is a potential new class of antihypertensive drugs.
- This study provides crucial initial human safety data for this novel therapeutic approach.
Background:
Despite adequate treatment, up to 30% of treated antihypertensive patients with primary, uncomplicated hypertension remain uncontrolled. We proposed that high intracellular activity of the ATP regenerating enzyme creatine kinase (CK) increases pressor responses and hypertension risk. In line with this, we found that plasma CK activity after rest, a surrogate measure of tissue activity, is the main predictor of blood pressure levels and failure of antihypertensive therapy in the general population. In addition, the creatine analog and competitive oral creatine kinase inhibitor beta-guanidinopropionic acid effectively and safely reduced blood pressure in the spontaneously hypertensive rat. However, to our knowledge there are no human data on the safety of oral supplementation with this substance. Therefore, we will assess the tolerability of beta-guanidinopropionic acid in men, compared to creatine and placebo.
Methods/Design:
This is a randomized, active and placebo controlled, triple blind, double dummy, single center clinical intervention trial in 24 healthy male volunteers, 18 to 50 years old, recruited in the Netherlands. The intervention consists of one week of daily oral administration of beta-guanidinopropionic acid 100 mg, creatine 5 gram, or placebo. The primary outcome is the tolerability of beta-guanidinopropionic acid as a descriptive measure, in an intent-to-treat analysis. Other outcomes include the placebo-adjusted differences with baseline in biochemical and hemodynamic parameters, including plasma markers of muscle tissue damage, urine sodium excretion, resting sitting systolic and diastolic brachial blood pressure, supine systolic and diastolic central blood pressure, pulse wave velocity and augmentation index, heart rate, cardiac contractility, cardiac output, and total peripheral resistance.
Discussion:
There is an unfulfilled need for new conservative options to treat resistant hypertension. This study will provide first-in-men data on creatine kinase inhibition as a potential new class of antihypertensive drugs.
Trial Registration:
The Netherlands National Trial Register Trialregister.nl (identifier NTR 4444) , registered 9 March 2014.
