Effect of the Combination of Creatine Monohydrate Plus HMB Supplementation on Sports Performance, Body Composition, Markers of Muscle Damage and Hormone Status: A Systematic Review

This systematic review was carried out in accordance with PRISMA^® (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement guidelines and the PICOS model for the definition of the inclusion criteria: P (Population): “athletes”, I (Intervention): “impact of the combination of HMB and CrM in sport”, C (Comparators): “same conditions with control, placebo, only HMB or only CrM”, O (Outcome): “sport performance, body composition, markers of muscle damage and hormone status”, and S (study design): “clinical trial” [41]. A systematic search of the current scientific literature was undertaken for studies that investigated the mixed supplementation of CrM plus HMB in sports performance and recovery. Studies were found by searching PubMed/MEDLINE, Web of Science (WOS), and Scopus from inception to July 3rd 2019, using the following Boolean search equation: (“creatine monohydrate supplementation”[All Fields] OR “creatine supplementation”[All Fields]) AND (”HMB supplementation”[All Fields] OR ”beta hydroxy beta methylbutyrate supplementation”[All Fields] OR (beta-Hydroxy[All Fields] AND methylbutyrate[All Fields] AND supplementation[All Fields])) AND (”muscle damage” [All Fields] OR “hormone status”[All Fields] OR (”athletes”[MeSH Terms] OR ”athletes”[All Fields]) OR (”exercise”[MeSH Terms] OR ”exercise”[All Fields]) OR ”sport performance”[All Fields] OR ”body composition”[All Fields]). Through this equation, relevant articles in this field were obtained by applying the snowball strategy. All titles and abstracts from the search were cross-referenced to identify duplicates and any potential missing studies. The titles and abstracts were screened for a subsequent full-text review. The search for published studies was independently performed by two authors (J.F.L. and J.M.A.), and disagreements about all outcomes were resolved through discussion.

For the articles obtained in this search, the following inclusion criteria were applied to select studies: (1) a well-designed experiment that included ingestion of the combination of CrM plus HMB; (2) with an identical experimental situation related to the ingestion of a placebo, CrM only, and/or HMB only; (3) testing the effects of mixed supplementation on sports performance, body composition, markers of muscle damage, and/or hormone status; (4) clinical trial; (5) with clear information regarding the administration of ergogenic aids (dosage and timing); and (6) published in any language. The following exclusion criteria were applied to the experimental protocols of the investigation: (1) supplementation was mixed with other supplements or was a multi-ingredient compound; (2) carried out in participants with a previous condition, injury, or health problems. There were no filters applied to the athletes’ level, gender, ethnicity, or age to increase the analytic power of the analysis.

Once the inclusion/exclusion criteria were applied to each study, data on study source (including authors and year of publication), study design, supplement administration (dose and timing), sample size, characteristics of the participants (level, race and gender), and final outcomes of the interventions were extracted independently by two authors (J.F.L. and J.M.A.) using a spreadsheet (Microsoft Inc, Seattle, WA, USA). Subsequently, disagreements were resolved through discussion until a consensus was reached, or by third-party adjudication (J.C.G.).

One reviewer (J.F.L.) searched the databases and selected the studies. A second reviewer (J.M.A.) was available to help with study eligibility. No disagreements about the appropriateness of an article were encountered.

The literature was examined regarding the effects of the combination of CrM plus HMB in sports performance using several outcome variables, such as athletic performance [35,36,37,39,40], body composition [36,37,40], markers of muscle damage [35,36,37,38,39], and hormone status [38].

Methodological quality and risk of bias were assessed by two authors independently (J.F.L. and J.M.A.), and disagreements were resolved by third-party evaluation (J.C.G.), in accordance with the Cochrane Collaboration Guidelines [42]. The items on the list were divided into six domains: selection bias (random sequence generation, allocation concealment); performance bias (blinding of participants and researchers); detection bias (blinding of outcome assessment); attrition bias (incomplete outcome data); reporting bias (selective reporting); and other types of bias. For each research paper, domains were judged by consensus (J.F.L., J.M.A.), or third-party adjudication (J.C.G.). They were characterized as ‘low’ if criteria for a low risk of bias were met (plausible bias unlikely to seriously alter the results) or ‘high’ if criteria for a high risk of bias were met (plausible bias that seriously weakens confidence in the results), or it was considered ‘unclear’ (plausible bias that raises some doubt about the results), if the risk of bias was unknown. Full details are given in Figure 1 and Figure 2.

A search of electronic databases revealed seventeen relevant studies, with an additional three studies found by searches in reference lists (Figure 3). After removing duplicate studies (n = 14) and screening titles and abstracts (n = 6), eight studies were retained [35,36,37,38,39,40,43,44]. Following full-text screening, only two studies were excluded [43,44] (one was combined with a non-usual training [43] and the other one was performed with only one of the supplements [44]). Thereby, six studies were included for this systematic review [35,36,37,38,39,40].

The design of the six studies included one randomized, double-blind, placebo-controlled study [36], two randomized, placebo-controlled studies [35,37], and three controlled studies [38,39,40]. Five out of six studies were conducted in intermittent team sports: three in rugby [38,39,40], one in basketball [37], and one in soccer [35]. The last study was carried out on healthy males [36]. The sum of all study participants included in this review were 201 males, with 161 being participants in high-level sports leagues (five studies) [35,37,38,39,40] and the remaining 40 being moderately trained participants [36].

Some studies divided the participants into four different supplementation groups: placebo group (PLAG) or control group (CON), creatine group (CrMG), HMB group (HMBG), and CrM plus HMB group (CrM/HMBG) [36,37]. Other studies assigned participants to three groups: PLAG or CON, HMBG, and CrM/HMBG [35,38,39,40].

The duration of the interventions in the studies was between six days and six weeks (42 days). In four of the studies included in this systematic review the supplementation protocol consisted of 3 g/day of CrM and 3 g/day of HMB [35,38,39,40]. The exceptions were the studies by Jowko et al. [36] and Zajac et al. [37], in which the CrM supplementation consisted of 20 g/day for the first 7 days followed by 10 g/day the next 14 days, and 15 g/day the first 5 days followed by 5 g/day the next 25 days, respectively. Moreover, the training program frequency performed by the athletes was 3 or 4 days per week [36,37,38,39,40] or 6 days per week [35] in a resistance training program.

Table 1 presents the different tests carried out to determine the performance measured outcomes by running an anaerobic speed test (RAST) [35], one repetition maximum (1-RM) test of different strength exercises [36], multistage aerobic capacity test, cycling maximally for 60 seconds [39], muscular strength, muscular endurance, leg power tests [40], and a triple Wingate test [37].

The combination of CrM plus HMB showed improvements in strength performance in one study [36], but the other study that measured this parameter did not find performance changes among groups [40]. On the other hand, anaerobic capacity was enhanced in two investigations [36,37] when the athletes ingested CrM plus HMB, although the study by O’Connor et al. [39] did not find any improvement. The last performance variable was aerobic capacity, measured by a multistage aerobic capacity test, and it was unchanged in all groups [39].

Table 2 shows the body composition measures. Zajac et al. [37] found reductions in FM (regarding CON/PLG and CrMG) in basketball players when they were supplemented with CrM plus HMB, although Jowko et al. [36] did not. On the other hand, Zajac et al. found an increase in BM and FFM (regarding CON/PLG and HMBG), contrasting to studies by Jowko et al. [36] and O’Connor et al. [40], who did not find changes in this parameter among groups when CrM plus HMB was ingested.

Table 3 displays muscular blood isoenzymes, such as creatine kinase (CK) [35,36,38], lactate dehydrogenase (LDH) [35], and blood lactate concentration (LA) [37,39], which were unchanged after supplementation with CrM plus HMB. Moreover, anabolic/catabolic blood hormones (testosterone and cortisol) did not show changes when the athletes were supplemented with CrM plus HMB [36].

To obtain maximum performance, athletes need to have an optimal body composition for the concrete sport practice, with a low-fat mass percentage and optimal skeletal muscle mass [51]. HMB could increase muscle mass [52] by augmenting protein synthesis after an intense training session [27], by activation of mTOR [53]. Equally, it can reduce protein breakdown through reducing the ubiquitin-proteasome system [54] and by increasing the GH-IGF-I axis [55]. In addition, HMB could augment fat oxidation, improving mitochondrial biogenesis by activation of PGC-1α, and thereby, lowering the fat mass percentage [30]. On the other hand, CrM supplementation has been proposed to increase muscle mass by increasing osmotic pressure in muscle, which increases the water content of the muscle [56,57,58], which in turn promotes glycogen synthesis [14,15].

The mixture of CrM plus HMB could augment FFM or LBM more than taking them in an isolated way, as the study by Zajac et al. [37] demonstrated. However, in the study by Jowko et al. [36], no changes were found. FM had also can be reduced [37] or unchanged [36]. In this sense, Zajac et al. [37] obtained an interesting result, given that mixed supplementation combined with three full-body resistance training sessions per week appeared to help to increase BM and decrease FM. HMBG decreased BF in comparison to CRG and CONG, and CRG increased BM (without increasing FM) in contrast to HMBG and CONG, showing an accumulative effect in terms of enhancing body composition when they were ingested together. Moreover, in the investigation by O’Connor et al. [40], body composition parameters measured (BM, sum of six skinfolds, arm girth (relaxed), arm girth (fixed), chest girth, waist girth, hip girth, and thigh girth) were not changed when combined with three full body resistance training sessions and one speed/power session per week. These results might be explained by the high training level of the participants. Therefore, the combination of CrM plus HMB could have an additive effect due to the performance of different energetic pathways.

In this systematic review, we analyzed six studies [35,36,37,38,39,40] considering different sport modalities (rugby, basketball, and soccer), outcomes, and supplementation duration. Moreover, the tests used to measure strength, anaerobic performance, and aerobic performance were completely different. These differences resulted in difficulties in comparing the different outcomes of the studies. Furthermore, not all the studies analyzed the effect of the supplementation mixture on different groups. Therefore, the results of this systematic review should be treated with caution due to the small number of research works available to include that are relevant to this area. Accordingly, more studies with similar measurement methodologies are needed in order to determine the efficacy of mixing CrM plus HMB for improving sports performance, and in order to understand the potential additive effect of this combination.