This randomized clinical trial examined the effects of phlebotomy and controlled reduction of body iron in patients with METS. Reduction in iron stores resulted in substantial reduction in BP and improvement in glycemic control, LDL/HDL ratio, and resting HR at 6 weeks. No significant effect on insulin sensitivity was seen. Changes in BP and of insulin sensitivity correlated with decreases in serum ferritin concentration.

To our knowledge, there have been no randomized trials to date evaluating the effects of phlebotomy and iron reduction in METS or hypertension. However, an anti-hypertensive effect of repeated phlebotomy was described in an early uncontrolled study on 15 patients with hypertension resistant to triple antihypertensive medication [25]. In that study, phlebotomy lowered mean BP from 140.1 ± 12.2 mmHg to 123.8 ± 14.9 mmHg after 14 days. In another uncontrolled study, 12 patients with renal transplant and erythrocytosis received three phlebotomies of 500 ml over 6 weeks, which induced BP reductions from 153/95 mmHg to 139/85 mmHg [32].

Arterial hypertension, which affects about one-third of the adult population in the USA and Europe, causes enormous morbidity and mortality. Antihypertensive drug therapy is efficient and reduces morbidity and mortality, but is costly and causes undesirable AEs. In our study, we found a mean reduction in SBP of > 15 mmHg, indicating a clinically relevant effect. It has been estimated that that a 22% reduction in coronary events and a 41% reduction in stroke can be expected for a reduction in SBP of 10 mm Hg [33]. Furthermore, the observed reduction in resting HR of about 5 beats/min may translate to further cardiovascular risk reduction.

The effect of iron reduction on glucose metabolism was not consistent in our study. Whereas blood glucose and HbA1c were significantly reduced after iron-reduction therapy, there were no changes in insulin sensitivity or adiponectin secretion. In muscle, iron interferes with glucose uptake [34], and increased iron stores predict the development of diabetes in epidemiological studies [8–11]. A previous study found beneficial effects of phlebotomy in patients with type 2 diabetes with increased ferritin concentration [21]. In that study, patients 500 ml of blood removed three times at 2-weekly intervals, which resulted in a mean ferritin reduction from 500 to 230 ng/ml and significant reductions in HbA1c and HOMA index after 4 months. In a small safety study on blood donation, phlebotomy resulted ina significant decrease in serum glucose and blood lipids in patients with diabetes [22]. Iron reduction by phlebotomy also enhanced insulin sensitivity in patients with iron-induced insulin resistance and in carriers of the hemochromatosis gene [20]. Notably, in these studies, the amount of removed blood was larger than in our study and the study period was longer. Furthermore, we did not specify any predefined target ferritin level, and only a moderate ferritin reduction was achieved. Thus, it may be that the shorter duration of our study and the moderate reduction in body iron stores were not sufficient to improve insulin sensitivity. Moreover, the putative anti-diabetic effect of blood removal is likely to be more pronounced in patients with higher iron stores. The magnitude of effect might be smaller in an unselected population of patients with metabolic syndrome. In addition, measurement of insulin sensitivity by the HOMA method we used differs from intravenous methods. Given the assumption that the intravenous insulin tolerance test is more sensitive than the HOMA index, our trial might have been underpowered. Therefore, our results should be interpreted with caution regarding insulin sensitivity, and the clinical effect of iron reduction on insulin sensitivity in METS will need to be verified in larger trials.

We also found a modest effect of iron-reduction therapy on blood lipids, with an improved LDL/HDL ratio. In an earlier study, repeated phlebotomies decreased concentrations of triglycerides and total cholesterol [22]. In light of our findings, further evaluation of the effects of phlebotomy on blood lipids and metabolism seems warranted. Results from a controlled trial in patients with peripheral arterial disease found improved outcomes after iron reduction in younger and middle-aged subjects [35]. Our findings support a putative beneficial effect of iron reduction by phlebotomy on factors that can promote atherosclerosis.

The mechanisms responsible for the beneficial effects of venesection and blood letting in METS also need to be addressed. Based on our results, reductions in BP and HOMA index correlate significantly with ferritin reduction. Iron-catalyzed oxidative stress may have a negative effect on METS and BP through several mechanisms. In human monocytes of patients with hyperferritinemia associated with METS, manipulation of iron status induced cytokine release, and the degree of induction was correlated with carotid atherosclerosis [28]. Endothelium-dependent vasodilation is affected by oxidative stress, and thus iron-mediated oxidative stress may modulate vascular tone [26]. Generation of excess free oxygen radicals and loss of redox homeostasis have been related to insulin signaling, vascular tone, and associated cardiovascular functional abnormalities, with a putative dominant role of labile iron in the imbalance in redox homeostasis [4] However, some cardiovascular effects may also be related to the hemodynamic and hematologic consequences of phlebotomies. The reduction in blood volume caused by phlebotomy may lead to decreased extracellular fluid volume, peripheral resistance, and reductions in blood viscosity [36]. It was estimated that a 10% increase in hematocrit produces a 20% increase in blood viscosity, and that vasodilation or an increase of BP are required to compensate physiologically for the increased viscosity [37]. Thus, particularly in vessels with low vasodilatory capacity, phlebotomy might induce an additional antihypertensive effect by causing a reduction in viscosity.

The results of the present study should be interpreted in light of certain limitations inherent to the study design. Firstly, the study intervention was not blinded, and therefore we cannot exclude the possibility that non-specific effects contributed to the effectiveness of the intervention. We attempted to reduce the effects of disappointment in the control group by offering iron reduction therapy at the end of the study period, and we found that overall satisfaction with study participation was not different between groups. Secondly, we could not control for the lifestyle habits of our patients during the study. Patient self-reports and interviews and the unchanged BMI and waist circumference measurements did not indicate that relevant lifestyle changes had occurred in our study patients; however, modifications in diet and physical exercise over a short 6-week period could result in biochemical effects and reductions in BP without producing significant variations in weight and BMI. Thirdly, the definition of METS is not very specific, and our sample of patients was small; thus, our results may not be applicable to patients with METS in general. Finally, the study follow-up was limited to 6 weeks in this proof-of-concept study and, therefore, the results of the present trial should be regarded as preliminary. Further trials with longer observation periods should evaluate the long-term effects and potential rebound effects of phlebotomy therapy.