Triangulating evidence for the causal impact of single-intervention zinc supplement on glycaemic control for type 2 diabetes: systematic review and meta-analysis of randomised controlled trial and two-sample Mendelian randomisation.

Although previous studies suggested the protective effect of Zn for type 2 diabetes (T2D), the unitary causal effect remains inconclusive. We investigated the causal effect of Zn as a single intervention on glycaemic control for T2D, using a systematic review of randomised controlled trials and two-sample Mendelian randomisation (MR). Four primary outcomes were identified: fasting blood glucose/fasting glucose, HbA1c, homeostatic model assessment for insulin resistance (HOMA-IR) and serum insulin/fasting insulin level. In the systematic review, four databases were searched until June 2021. Studies, in which participants had T2D and intervention did not comprise another co-supplement, were included. Results were synthesised through the random-effects meta-analysis. In the two-sample MR, we used single-nucleotide polymorphisms (SNP) from MR-base, strongly related to Zn supplements, to infer the relationship causally, but not specified T2D. In the systematic review and meta-analysis, fourteen trials were included with overall 897 participants initially. The Zn supplement led to a significant reduction in the post-trial mean of fasting blood glucose (mean difference (MD): -26·52 mg/dl, 95 % CI (-35·13, -17·91)), HbA1c (MD: -0·52 %, 95 % CI: (-0·90, -0·13)) and HOMA-IR (MD: -1·65, 95 % CI (-2·62, -0·68)), compared to the control group. In the two-sample MR, Zn supplement with two SNP reduced the fasting glucose (inverse-variance weighted coefficient: -2·04 mmol/l, 95 % CI (-3·26, -0·83)). From the two methods, Zn supplementation alone may causally improve glycaemic control among T2D patients. The findings are limited by power from the small number of studies and SNP included in the systematic review and two-sample MR analysis, respectively.