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. 2022 Dec;21(4):665-681.
doi: 10.1007/s42000-022-00396-5. Epub 2022 Sep 21.

Fragility of cardiovascular outcome trials (CVOTs) examining nutrition interventions among patients with diabetes mellitus: a systematic review of randomized controlled trials

Niki Taouktsi  1 , Stefanos T Papageorgiou  1 , Georgios Tousinas  2 , Stavroula Papanikolopoulou  1 , Maria G Grammatikopoulou  2   3 , George Giannakoulas  4 , Dimitrios G Goulis  5
Affiliations

Fragility of cardiovascular outcome trials (CVOTs) examining nutrition interventions among patients with diabetes mellitus: a systematic review of randomized controlled trials

Niki Taouktsi et al. Hormones (Athens). 2022 Dec.

Abstract

Purpose: There is controversy regarding the optimal statistical method to interpret how robust is a statistically significant result. The fragility index (FI) and the reverse fragility index (RFI) are quantitative measures that can facilitate the appraisal of a clinical trial's robustness. This study was performed to evaluate the FI and RFI of randomized controlled trials (RCTs) examining nutritional interventions in patients with diabetes mellitus, focusing on cardiovascular outcomes.

Methods: A systematic search was conducted and relevant RCTs were identified in three databases. RCTs examining nutritional interventions (supplements or dietary patterns) in patients with DM with dichotomous primary endpoints involving cardiovascular outcomes were eligible. Data were extracted to compose 2 × 2 event tables and the FI and RFI were calculated for each comparison, using Fisher's exact test. Risk of bias (RoB) of the included RCTs was assessed with the Cochrane RoB 2.0 tool.

Results: A total of 14,315 records were screened and 10 RCTs were included in the analyses. The median FI of the paired comparisons was 3 (IQR: 2-4) and the median RFI was 8 (IQR: 4.5-17). RoB and heterogeneity were low.

Conclusions: RCTs examining nutritional interventions and cardiovascular outcomes among patients with diabetes mellitus appear to be statistically fragile. Τhe FI and the RFI can be reported and interpreted as an additional perspective of a trial's robustness.

Highlights: • In the evidence-healthcare era, assessing how robust statistically significant results are remains a matter of controversy. • Recently, the fragility index (FI) and reverse fragility index (RFI) were proposed to assess the robustness of randomized controlled trials (RCTs) with 2 × 2 comparisons. • When applying the FI and RFI, RCTs examining nutritional interventions and cardiovascular outcomes among patients with diabetes mellitus (DM) appear to be statistically fragile. • Τhe FI and the RFI can be reported and interpreted as an additional perspective of a trial's robustness. • RCTs implementing nutrition interventions among patients with DM can improve their methodology.

Keywords: Cardiovascular disease; Dietary supplements; Fragility quotient; Meta-epidemiology; RCT; Research methodology; Statistical robustness.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Search string used for the PubMed database
Fig. 2
Fig. 2
PRISMA flowchart of the studies selection process
Fig. 3
Fig. 3
Risk of Bias of the included RCTs. ASCEND, A Study of Cardiovascular Events in Diabetes; ATBC, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study; PREDIMED, Prevención con Dieta Mediterránea; RCT, randomized controlled trial; REDUCE-IT, Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial; RoB, Risk of bias [24]; TIDE, thiazolidinedione intervention with vitamin D evaluation; WAFACS, the Women’s Antioxidant and Folic Acid Cardiovascular Study
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