This study shows that AP is effective and safe in reducing insulin resistance in a group of patients with MetS. We observed a significant reduction in the HOMA-IR index after 18 wk of treatment; this finding was accompanied by an improvement of postprandial glucose handling, as well as by beneficial effects on multiple clinical and biochemical parameters of MetS.
The HOMA index is a well validated surrogate measure of insulin resistance, and a strong predictor of CV risk in several classes of patients[10
]. Mounting evidence from the last years supports the importance of the HOMA-IR index as a prognosticator even at values very close to the normal range, i.e., in patients not fitting a diagnosis of T2D. Recent studies demonstrated its independent value in the prediction of CV events in the general adult non-diabetic population[12
]. In light of these epidemiological findings, our results appear strengthened in their clinical significance, strongly advocating further research in the field. The effect of AP on insulin resistance may be chiefly explained by the action of BRB on glucose metabolism. BRB has been used for more than 2000 years in traditional Asian medicine for the treatment of many unrelated disorders including diabetes mellitus. Two randomized controlled trials have investigated, to date, the metabolic effects of BRB on glucose metabolism in T2D patients: in both studies BRB was effective in improving glucose control and indices of insulin resistance, to an extent similar to commonly employed hypoglycemic agents, which were used as control[6
]. Our results concerning insulin resistance substantially confirm that found in these reports in a different, “less advanced” population of patients with MetS. Of note, the dose of BRB employed in the aforementioned clinical experiences is much higher than the one used in our study (approximately twice as high).
Several experimental studies recently provided insights into the pharmacodynamic basis of such therapeutic effects of BRB, in which it differs substantially from all the most prescribed molecules in the field. In fact, BRB activates AMP-activated protein kinase leading to metabolic gene regulation, with beneficial effects on adipose tissue and muscle[7
]; moreover, the AMP-mediated activation reduces insulin secretion by pancreatic β-cells[15
]. Another recognized mechanism is the upregulation of insulin-receptor expression through protein kinase C activation[16
]. On the other hand, evidence from both in vivo
and in vitro
studies suggest that part of the antihyperglycemic activity of BRB is due to a decrease in the availability of glucose after a meal. In particular, BRB suppresses intestinal disaccharidases, reducing the intestinal absorption of glucose[17
]. This latter effect is very interesting and may explain the slight but significant reduction in postprandial glycemia observed in the treated group.
AP treatment led to a significant reduction in total and LDL cholesterol, confirming previous reports[5
]. Interestingly, the therapeutic effect seemed evident also in those patients who were already under treatment with statins. These results are extremely meaningful in light of the recommendation to reduce LDL-cholesterol below 100 mg/dL to reduce the risk of CV events in patients with MetS. Both BRB and RYR monotherapy have been proven to reduce blood lipid levels at higher doses, even being advocated by many as a first-line therapy for statin-intolerant subjects; once again, the doses used in the present trial were much lower than the ones commonly used in the past monotherapy studies[19
The positive effects on both glucose and lipid metabolism were accompanied by a marked improvement in endothelial function. In fact, this study shows a significant increase in FMD values in the AP group compared with the placebo group. Such a finding may arise not only from the improvement of metabolic alterations, but also from the demonstrated antiproliferative and vasodilatatory effects of BRB[21
]. Moreover, BRB has shown beneficial effects on endothelial function also by inducing upregulation of the endothelial progenitor cells related to nitric oxide production. The importance of this improvement of vascular reactivity seems also reinforced by the unexpected reduction of blood pressure values in the treated arm.
In both groups, a slight reduction in body weight was observed and the magnitude of this reduction was comparable. This effect may be related to the diet. Nevertheless this slight weight loss in the placebo arm was not associated with an improvement in metabolic parameters, suggesting a beneficial effect of AP independent of weight loss. In addition, patients in the active arm also showed a trend to reduced waist circumference, which was not observed in the placebo arm. We can postulate that this reflects a better disposal of fat, with a relative reduction of visceral fat in the AP arm. The effect on waist circumference confirms previous results in animal models, in which treatment with BRB led to a significant reduction in abdominal fat[23
]. However, we also acknowledge that study design and duration did not aim at demonstrating effects on anthropometric parameters.
In conclusion, we demonstrated that a combination of BRB, RYR and policosanol exerts beneficial effects on all components of MetS, despite the short duration of the study and the low doses of the individual components; the clinical benefit seems pleiotropic, involving both markers of insulin-resistance, dyslipidemia, and endothelial function. The treatment was well tolerated with negligible side effects.
Management of MetS is nowadays based on lifestyle intervention and treatment of its individual components. Effective prevention is based on strategizing health policies and mass intervention programs; anyway, given its high prevalence and significance, an effective therapy to contrast the cluster of components of MetS and reduce risk at the patient level is increasingly felt as an urgent need; if our results are confirmed by larger studies with harder outcome measures, we believe that nutraceuticals may play an important role in such a scenario, given their strong rationale, pleiotropic action, efficacy, and tolerability. Upcoming research shall also focus on dose ranging, patient selection and association studies with other “pharmaceutical” molecules, i.e., statins, polyunsaturated fatty acids, and metformin, possibly in the context of large multicenter trials.
The results of this study should be interpreted in light of some limitations. This was a short-term study, while metabolic interventions may require longer periods to assess stable beneficial effects. On one hand, this could have led to an underestimation of the actual effects of chronic treatment; on the other hand, some long-term safety and tolerability questions, as well as efficacy on hard clinical endpoints, remain unanswered and need further investigation.
The improvement in the HOMA-IR index could have been influenced, at least in part, by the dietary intervention; however, patients in the placebo arm, who followed the same diet, experienced a slight worsening of the index. Another point is that, although this was a randomized study, fasting glucose levels were not well balanced between the 2 groups; since the groups appeared comparable regarding all other measures of insulin resistance, including the predefined primary endpoint, this inequality seems to be acceptable and justified by the wide phenotypic variability of MetS.
The present study shows that the administration of AP in a group of MetS patients is safe and effective in reducing more than one feature of MetS. Further studies are needed to investigate whether long-term treatment with this kind of nutraceutical combination may prevent CV and T2D complications.