Effects of Zinc Supplementation on Serum Lipids

A Systematic Review and Meta-Analysis

Priyanga Ranasinghe; WS Wathurapatha; MH Ishara; R. Jayawardana; P. Galappatthy; P. Katulanda; GR Constantine

Disclosures

Nutr Metab. 2015;12(26) 

In This Article

Discussion

This comprehensive systematic review and meta-analysis summarize the data from 32 studies involving a total of 14,515 participants. The results of the meta-analysis shows Zinc supplementation alone causes a significant reduction in LDL-c concentration (−4.78 mg/dl, p < 0.05) in the absence of a significant heterogeneity among the studies. Although there is considerable heterogeneity amongst the studies, Zinc supplementation alone reported a statistical significant reduction in serum TC level (−10.72 mg/dl, p < 0.05, I2 = 80 %) and TG level (−8.73 mg/dl, p < 0.05, I2 = 64 %). When analyzed by health status, Zinc supplementation reported a significant reduction in TC, LDL-c and TG levels in non-healthy patients and the magnitude of reduction was greater than that in overall analysis. In healthy patients there was a minor but significant reduction in TC level whereas changes in LDL-c and TG were not significant. When consider HDL-c, Zinc supplementation demonstrated a statistically insignificant increase in the ungrouped analysis whereas a statistically significant increase (+6.15 mg/dl) among non-healthy patients. These findings are in contrast to results from a previous meta-analysis of randomized controlled trials, where no beneficial effects of Zinc supplementation were observed on plasma TC, LDL-c or TG concentrations in overall, ungrouped analysis or when interventions were grouped by health status.[25] Zinc supplementation has demonstrated a significant increase in HDL-c levels among patients with diabetes mellitus in previous meta-analyses which also supports our finding.[25,56] A finding probably resulting from favorable results demonstrated in several studies reported since the time of the previous meta-analysis.[17,21,28,33,42,46]

Cardiovascular disease is the leading cause of death in much of the modern world and two major underlying causes are disorders of lipid metabolism and metabolic syndrome.[57] Dyslipidemia is the most important risk factor for atherosclerosis.[58] Atherosclerosis is the main aetiological factor behind coronary artery disease, cerebral vascular disease, and peripheral vascular disease.[59] Within the past decade, clinical trials have demonstrated that LDL-c reduction reduce the clinical cardiac events and the arteriographic investigations have demonstrated that LDL-c reduction can significantly reduce the rate of arteriographically defined disease progression.[60] A recent systematic review and meta-regression analysis concluded that simply increasing the level of circulating HDL-c does not reduce the risk of coronary heart disease events, coronary heart disease deaths, or total death and results supported reduction in low density lipoprotein cholesterol as the primary goal for lipid modifying interventions.[61] Each 40 mg/dl reduction in LDL-c concentration corresponds to 24 % reduction in major cardiovascular events.[62] Therefore, current meta-analysis demonstrates that Zinc supplementation alone can reduce major cardiovascular events by ~2.9 % by lowering LDL-c concentration by 4.78 mg/dl and by 6.8 % in non-healthy individuals by lowering LDL-c by 11.25 mg/dl at an average dose of ~40 mg/day. However, atorvastatin a well established drug for hyperlipidaemia has demonstrated 1.8 mmol/l (69.6 mg/dl) reduction in LDL-c levels at a dose of 10 mg/day in a meta-analysis involving 164 trials.[63]

Previous meta-analyses have reported elevated fasting and non-fasting concentrations of TGs were associated with increased risk of coronary heart disease, even after adjustment for HDL-c concentrations.[64,65] Furthermore three studies between 2007 and 2008 suggested that raised non-fasting TG was strongly associated with increasing risk of myocardial infarction, ischaemic heart disease, ischaemic stroke and all-cause mortality.[66–68] At mild-to-moderately raised triglyceride concentrations (2–10 mmol/l), lipoproteins are small enough to enter into arterial wall and thus have the potential to enter into arterial wall and accumulate causing atherosclerosis.[69,70] High TG concentrations are a marker for raised remnants rich in cholesterol, which can enter into intima and lead to foam cell formation, atherosclerotic plaques and ultimately cardiovascular disease and increased mortality.[71] Understanding from genetic studies and negative results from randomized trials is low HDL-c might not cause cardiovascular disease as originally thought and this understanding has now generated an interest in elevated levels of TGs.[71] Therefore Zinc supplementation could reduce the cardiovascular events and deaths, as it results in significant reduction in TC, TG and LDL-c.

Dyslipidemia is one of the major risk factors for cardiovascular disease in diabetes mellitus. High plasma TG, increased small dense LDL-c particles, low HDL-c are characteristic features of diabetic dyslipidemia and these lipid changes are mainly attributed to increased free fatty acid flux secondary to insulin resistance.[72] The increase in cardiovascular risk in obesity depends to a significant extent on changes in lipid profile, mainly decreased HDL-c and increased TG and insulin resistance is the central cause for these changes.[73] Prominent and known risk factors that contribute to the increased incidence of atherosclerosis in hemodialysis patients are disorders in lipoprotein metabolism and elevated plasma fibrinogen concentrations.[74] Therefore the participants we categorized as non-healthy (patients with - type 2 diabetes, End stage renal failure and on haemodialysis and obesity) are at increased risk of dyslipidemias. Zinc supplementation significantly reduces TC, LDL-c and TG and elevates HDL-c in non-healthy patients. Elevated plasma concentrations of HDL-c are associated with protection from atherosclerotic cardiovascular disease. Cardio protective effect of HDL-c is due to its role in reverse cholesterol transport in which cholesterol from peripheral tissues is returned to the liver for excretion in the bile, its protective effect on endothelial cells and its antioxidant activity.[75] All these evidence support that Zinc supplementation will effectively reduce the cardiovascular risk among non-healthy patients.

Our results demonstrated HDL-c concentration was significantly reduced due to Zinc supplementation among healthy participants. A previous meta-analysis also showed that Zinc supplementation among healthy individuals was associated with a significant reduction in HDL-c concentration supporting our finding.[25] Low HDL-c (=/< 40 mg/dl) is one of the 5 major Coronary Heart Disease (CHD) risk factors, and HDL-c level is also a component of the Framingham scoring system, the method used to estimate 10-year CHD risk and determine the intensity of lipid-lowering therapy.[75] Furthermore Zinc supplementation did not demonstrate a significant reduction in LDL-c or in TG despite a minor reduction in TC. Therefore Zinc supplementation may not have much beneficial effects in healthy people.

Several molecular mechanisms are believed to be involved in reduction in serum lipid levels following Zinc supplementation. In Zinc-deficient rats lowered plasma HDL-c and some apoproteins (A1, A2, C and E) but also elevated total cholesterol concentrations have been observed.[76,77] On the other hand, Zinc supplementation has been shown to inhibit the development of atherosclerosis in rabbits fed a high cholesterol diet.[78] It is well documented that Zinc is an important mediator of insulin storage and secretion from the pancreas.[78] In addition, pancreatic beta-cells utilize a very efficient transporter (ZnT8) to accumulate Zinc inside the cells. Thus, Zinc deficiency or alterations in ZnT8 expression have a potential to depress insulin secretion.[79] Zinc enhances the phosphorylation of insulin-receptor substrates to activate a series of signal transduction, improving insulin sensitivity.[80,81] Insulin resistance at the adipocytes results in increased release of fatty acids into the circulation and then increased free fatty acid flux to the liver stimulates the assembly and secretion of VLDL resulting in hypertriglyceridemia.[82] Zinc supplementation either improving insulin secretion or reducing insulin resistance as described above inhibits the lipolysis in adipose tissues, reduce free fatty acid release into the circulation and its availability to the liver and excessive lipoprotein synthesis. Besides Zinc contribution to insulin secretion and action, Zinc directly affects lipid metabolism. Recently it has been shown that Zinc deficiency down regulates fatty acid utilization in mitochondria and peroxisomes and up regulates lipid synthesis in the rat liver affecting the expression of genes encoding enzymes contributing to liver lipid homeostasis.[83]

The present meta-analysis has notable strengths. These include 1) large number of individuals in the sub group analysis in which the effect of Zinc alone supplementation was studied (n = 1,528), 2) studies were assessed using jaded scale score and the studies with poor methodological quality were excluded from meta-analysis, 3) use of random effect model of meta-analysis which allow heterogeneity among studies and 4) average dose of elemental Zinc used in the interventions included in meta-analysis (39.3 mg/d) does not exceed the tolerable upper intake level (40 mg elemental Zinc per day in adults).[84] A limitation of present meta analysis was presence of considerale heterogeneity when assessing the effect of Zinc supplementation on TC anc TG concentrations which stems from; a) Variations in baseline parameters such as serum Zinc status and lipid levels, b) Differences in Zinc doses, formulae, sample sizes and study durations, and c) Limited availability of data on Zinc intake from other sources such as diet.

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