# A systematic review and meta-analysis of randomized controlled trials exploring the role of inter-individual variability on the effect of flavanols on insulin and HOMA-IR

N. Alshammari, S. A. Palma-Duran, G. Jiang, A. Gonzalez-Sarrias, P. Pinto, M. Garcia-Aloy, E. Gibney, M. Garcia-Conesa, P. Kroon, A. K. Ristic, et al.

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N. Alshammari, S. A. Palma-Duran, G. Jiang, A. Gonzalez-Sarrias, P. Pinto, et al. A systematic review and meta-analysis of randomized controlled trials exploring the role of inter-individual variability on the effect of flavanols on insulin and HOMA-IR. 2018 Spring Conference on Nutrient-Nutrient Interaction, Mar 2018, NA, France. 10.1017/s0029665118000344. hal-02062457

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# A systematic review and meta-analysis of randomized controlled trials exploring the role of inter-individual variability on the effect of flavanols on insulin and HOMA-IR

N. Alshammari<fnref n="1" />, S.A. Palma-Duran<fnref n="1" />, G. Jiang<fnref n="1" />, A. González-Sarriás<fnref n="2" />, P. Pinto³, M. Garcia-Aloy⁴, E. Gibney⁵, MT. García-Conesa<fnref n="2" />, P. Kroon⁶, A. Konić Ristić⁷, A. Katsaltou⁸, C. Morand⁹, A. Rodriguez-Mateos¹⁰ and E. Combet<fnref n="1" />

¹University of Glasgow, UK, ²Centro de Edafologia y Biologia Aplicada del Segura-Consejo Superior de Investigaciones Científicas, Spain, ³Polytechnic Institute of Santarem, Portugal, ⁴University of Barcelona, Spain, ⁵University College, Dublin, Ireland, ⁶Quadram Institute, Norwich, UK, ⁷University of Belgrade, Serbia, ⁸University of Thessaly, Greece, ⁹Institut National de la Recherche Agronomique, France and ¹⁰King's College London, UK.

Meta-analyses of randomised controlled trials (RCTs) report that polyphenol-rich diets can modulate a range of cardiometabolic bio-markers, with increasing evidence that inter-individual factors (e.g. age, BMI, or ethnicity) contribute toward the variability in the response to the bioactive<fnref n="1" />,<fnref n="2" />. This systematic review and meta-analysis assessed the effect of flavanols from cocoa, apple and tea on fasting insulin and HOMA-IR and explored the role of inter-individual variability.

PubMed and Web of Science databases were searched from inception to October 2017 (PROSPERO reg. CRD42016033878). The effect of flavanols supplementation on insulin and HOMA-IR was estimated using a random effects meta-analysis model and reported as standardised mean difference (SMD) and 95%CI. Subgroup analyses (Q tests; multivariate meta-regression) focused on baseline BMI, gender, age, and geographical location to explore the role of inter-individual variability.

Out of 1409 studies identified, 31 RCTs were included for insulin (n = 1792) and 21 RCTs for HOMA-IR (n = 1152). Low heterogeneity was found between studies (insulin I<fnref n="2" /> = 0%, p = 0.98; HOMA-IR I<fnref n="2" /> = 5.9%, p = 0.38) with evidence of low publication bias. Flavanol-rich interventions (2–26 weeks; 88 to 1344 mg flavanols/day) decreased both insulin (SMD –0.25, 95% CI –0.33; –0.16) and HOMA-IR (SMD –0.26; 95% CI –0.36, –0.16). Results were consistent across subgroups (Q tests) with lack of effect in subgroups with BMI<25 or male subjects only; multivariate meta-regression showed that baseline BMI (overweight versus lean, coef. –1.07; 95% CI –2.03, –0.08; p = 0.03) and study location (Asia versus other sites, coef. 0.94; 95% CI 0.03, 1.84; p = 0.04) impacted on the effect on HOMA-IR significantly. There was no impact of age, gender, baseline BMI or geographical location on the effect on insulin.

<table><thead><tr><th>Factor</th><th>Subgroup</th><th>Insulin (95% CI)</th><th>Q value</th><th>(n, N)</th><th>HOMA-IR (95% CI)</th><th>Q value</th><th>(n, N)</th></tr></thead><tbody><tr><td rowspan="3">Age</td><td>&lt;50 years</td><td>-0.21 (-0.36, -0.05)</td><td>Q bet 0.276<br>p = 0.6</td><td>(15, 662)</td><td>-0.34 (-0.54, -0.14)</td><td>Q bet 0.62<br>p = 0.43</td><td>(13, 522)<br>(14, 630)</td></tr><tr><td>&gt;50 years</td><td>-0.26 (-0.36, -0.15)</td><td></td><td>(24, 1373)</td><td>-0.22 (-0.35, -0.10)</td><td></td><td></td></tr><tr><td>All</td><td>-0.24 (-0.33, -0.15)</td><td></td><td></td><td>-0.25 (-0.36, -0.15)</td><td></td><td></td></tr><tr><td rowspan="3">Gender</td><td>Male</td><td>-0.12 (-0.40, 0.15)</td><td>Q bet 1.46,<br>p = 0.48</td><td>(3, 14)</td><td>N/A</td><td></td><td></td></tr><tr><td>Female</td><td>-0.21 (-0.37, -0.04)</td><td></td><td>(9, 475)</td><td>-0.09 (-0.28, 0.09)</td><td>N/A</td><td>(7, 372)</td></tr><tr><td>All</td><td>-0.25 (-0.33, -0.16)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td rowspan="3">Baseline BMI (kg/M<fnref n="2" />)</td><td>&lt;25</td><td>-0.2 (-0.44, 0.03)</td><td>Q bet 1.67<br>p = 0.4</td><td>(4, 156)</td><td>-0.10 (-0.42, 0.22)</td><td>Q bet 2.4<br>p = 0.29</td><td>(2, 98)<br>(12, 653)<br>(12, 401)</td></tr><tr><td>25–30</td><td>-0.31 (-0.34, -0.16)</td><td></td><td>(13, 898)</td><td>-0.32 (-0.46, -0.19)</td><td></td><td></td></tr><tr><td>&gt;30</td><td>-0.19 (-0.33, -0.05)</td><td></td><td>(12, 696)</td><td>-0.23 (-0.43, -0.04)</td><td></td><td></td></tr><tr><td rowspan="3">Geographical location</td><td>All</td><td>-0.25 (-0.33, -0.16)</td><td></td><td></td><td>-0.27 (-0.38, -0.17)</td><td></td><td></td></tr><tr><td>Asia</td><td>-0.19 (-0.33, -0.04)</td><td>Q bet 1.01<br>p = 0.79</td><td>(13, 748)</td><td>-0.20 (-0.34, -0.05)</td><td>Q bet 2.27<br>p = 0.51</td><td>(8, 496)<br>(6, 106)</td></tr><tr><td>USA</td><td>-0.27 (-0.52, -0.02)</td><td></td><td>(5, 213)</td><td>-0.29 (-0.63, 0.06)</td><td></td><td></td></tr><tr><td></td><td>Europe</td><td>-0.29 (-0.42, -0.16)</td><td></td><td>(21, 731)</td><td>-0.36 (-0.53, -0.19)</td><td></td><td></td></tr><tr><td></td><td>Other</td><td>-0.33 (-0.69, 0.05)</td><td></td><td>(3, 100)</td><td>-0.29 (-0.74, 0.17)</td><td></td><td></td></tr><tr><td></td><td>All</td><td>-0.25 (-0.33, -0.16)</td><td></td><td></td><td>-0.27 (-0.37, -0.17)</td><td></td><td></td></tr></tbody></table>

Values are showed in SMD (95%CI). n, number of trials; N, number of participants.

Flavanols from tea, apple and cocoa were effective in modulating insulin and HOMA-IR. Inter-individual variability in the response was limited in contrast to previous studies<fnref n="1" />,<fnref n="2" />. This could be partly explained by the small number of trials reporting data for specific subgroups, and the broad range of doses and duration tested among the studies.

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<footnote n="1">1. Pinto P & Santos C. *Eur J Nutr.* 2017;56(4):1393–1408.</footnote>

<footnote n="2">2. González-Sarriás A, Combet E, Pinto P *et al. Nutrients*. 2017;9(7):746.</footnote>