Selenium supplementation for the primary prevention of cardiovascular disease: a Cochrane review Clinical

2 Clinical questions Do selenium supplements help prevent cardiovascular disease? Do selenium supplements have beneficial effect on cardiovascular disease risk factors, such as blood lipids and blood pressure? Does selenium supplementation increase the risk of type 2 diabetes? Source: Rees K, Hartley L, Day C, Flowers N, Clarke A, Stranges S. Selenium supplementation for the primary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 2013, Issue 1. Art. No.: CD DOI: / CD pub2.Selenium supplementation for the primary prevention of cardiovascular disease.

3 Context Selenium is an essential trace mineral. There is large variation in selenium status across countries. There is conflicting observational and trial evidence on the effect of selenium status and supplementation on cardiovascular. It has been suggested that long-term selenium supplementation increases the risk of type 2 diabetes.

4 Methods Several electronic databases were searched from their inception to October These included MEDLINE, EMBASE, CINAHL, the Web of Science (SCI-EXPANDED, SSCI, CPCI-S), PsycINFO, the Cochrane Central Register of Controlled Trials, and the DARE, HTA, NHS EED databases in The Cochrane Library. Trial registers were searched and relevant experts were asked for advice. Screening of titles and abstracts for possible inclusion, eligibility assessment, data extraction and assessment of trial quality was done independently by two reviewers. Study authors were contacted for additional information.

5 PICO(S) to assess eligible studies Participants: Adults of all ages from the general population and those at high risk of cardiovascular disease. Intervention: Selenium only supplementation as a single ingredient. Comparison: Placebo or no interventions. Outcomes: Deaths from all causes or from cardiovascular disease, major cardiovascular disease events (fatal and non- fatal), changes in levels of blood pressure and blood lipids, and type-2 diabetes. Studies: Randomised trials.

6 Description of eligible studies Nine randomised trials (19,655 participants), reported in 11 papers. Six of the trials were restricted to men (17,843 randomised). Four trials (18,954 participants) were done in the USA, including the two largest trials the Selenium and Vitamin E Cancer Prevention Trial (SELECT) and the Nutritional Prevention of Cancer trial (NPC). The other studies were conducted in Australia, China, Denmark, Finland and UK. The intervention and follow-up periods varied across the trials, from 1-2 weeks to long-term follow-up of several years for SELECT and NCP. The dose of selenium supplementation varied from 100 to 800 μg/day. Baseline selenium status varied by country. It was lowest in China and highest in the USA.

7 Results Deaths and cardiovascular disease Only two trials reporting clinical events could be included in the meta-analyses. These were the SELECT and NPC trials, and the analysis was dominated by the SELECT trial, which carried over 80% of the weight. There were no statistically significant effects of selenium supplementation on all-cause mortality (relative risk (RR): 0.97, 95% CI: 0.88 to 1.08), deaths from cardiovascular disease (RR: 0.97, 95% CI: 0.79 to 1.20), non-fatal cardiovascular events (RR: 0.96, 95% CI: 0.89 to 1.04) or all cardiovascular events (fatal and non-fatal, RR: 1.03, 95% CI: 0.95 to 1.11)

8 Results Changes in cardiovascular risk factors Six of the nine trials measured lipid levels, but only three could be used in the meta-analysis. This analysis found that selenium supplementation reduced total cholesterol but this was not statistically significant (mean difference (MD): mmol/L, 95% CI: -0.3 to 0.07). No effect was found of selenium supplementation on HDL levels (MD: 0.01 mmol/L, 95% CI: to 0.08). Non-HDL cholesterol was measured in only one trial of varying doses of a six-month selenium supplementation, which showed a statistically significant reduction in non-HDL cholesterol (WMD: -0.2 mmol/L, 95% CI to 0.00). None of the included trials examined the effects of selenium supplementation on blood pressure levels.

9 Results Type 2 diabetes The SELECT trial dominated the findings of the three trials reporting the incidence of type 2 diabetes, contributing 17,448 of the 18,790 randomised participants in this analysis. In the meta-analysis, selenium supplementation did not significantly increase the risk of type 2 diabetes (RR: 1.06, 95% CI: 0.97 to 1.15).

10 Results Type 2 diabetes

11 Conclusions for practice Current trial evidence does not support the use of selenium supplements for the primary prevention of cardiovascular disease. Results did not show a statistically significant increased risk of type 2 diabetes with single selenium supplements. Most of the available evidence comes from post-hoc analyses of cancer prevention trials conducted in the USA, a selenium-replete population. There is a lack of evidence from selenium supplementation trials specifically designed to prevent cardiovascular disease, and across a wide range of selenium concentrations. At present, the widespread use of selenium supplements for people with adequate-to-high selenium status is not justified and should not be encouraged.

12 Useful links Cochrane Journal Club discussion points Selenium supplementation for the primary prevention of cardiovascular disease Selenium supplementation for the primary prevention of cardiovascular disease