Px has long been established as a potent prophylactic anti-anginal agent, whether used as monotherapy or in combination with other drugs [38–40]. It has been shown that Px improves symptomatic status and left ventricular systolic function in patients with systolic heart failure [17], as well as cardiac energetics in patients with dilated and hypertrophic cardiomyopathy [16, 18]. Finally, recent preclinical studies have established the potential utility of Px in the treatment of malignancies, both as a sensitizer to chemotherapy or as a tumour-suppressive agent [20–23].
The main residual barrier to the widespread use of Px in the treatment both of cardiovascular disease and of malignancy is therefore the potential for induction of hepato- and neurotoxicity. However, the potential for Px to induce hepatitis and/or peripheral neuropathy during long-term therapy has been dramatically reduced by the availability of therapeutic drug monitoring of plasma concentrations of Px and of its hydroxylated metabolites [12, 41, 42]. This led to the only remaining concern being the risk of hypoglycaemia, which has been reported as a rare but potentially serious adverse effect in some case reports [27, 43, 44], even though the cause of hypoglycaemia remained uncertain. Therefore, the primary objective of the current study was to determine whether induction of hypoglycaemia remains a significant problem when Px is utilized for treatment of heart disease in patients with diabetes.
The results of the study indicate that short-term Px therapy, titrated to achieve therapeutic plasma Px concentrations, does not affect fasting blood glucose concentrations, while significantly increasing plasma insulin concentrations. On this basis, Px technically increased insulin resistance, as measured by HOMA-IR. Furthermore, consistent with previous observations in patients with severe angina pectoris, Px normalises anti-aggregatory responses to the NO donor SNP [10], and thus ameliorates “NO resistance”, a condition known to be an independent negative prognostic marker [5, 6]. This is an important finding, especially in patients with diabetes, as they are at increased risk of adverse outcomes in the presence of acute myocardial ischaemia or heart failure.
To test the hypothesis that the impact of Px on HOMA-IR and platelet responsiveness to NO reflects a common mechanistic pathway, we sought evidence of correlation between these parameters. While there was no significant relationship, the two parameters tended to have an inverse, rather than direct correlation. Thus it seems that these two Px effects reflect different mechanisms: NO sensitization by Px does not result from stimulation of insulin release, despite our previous finding that insulin infusion, administered to patients to correct hyperglycaemia, also reverses NO resistance [7].
As originally proposed by Randle et al [15], fatty acids and glucose compete for selection and oxidation by muscles and adipose tissues. Therefore, inhibition of fatty acid metabolism induces a shift towards glucose utilization, potentially mediating increases in cardiac metabolic efficiency. If glucose utilization were increased simultaneously with glucose uptake into tissues such as muscle, this could potentially induce hypoglycaemia. However, in many circumstances, especially during the fed state, insulin effects on tissue uptake of glucose are primarily associated with increased glycogen synthesis, rather than glucose utilization [45]. Therefore, increased plasma concentrations of insulin in the presence of Px do not always imply increased oxidation of glucose: it may well be that insulin secretion is not in any way a mediator of the “Randle Cycle”. Indeed, previous studies have suggested a dissociation of insulin signalling from substrate utilization [15, 46].
Although the mechanism is unclear, Px can increase plasma insulin concentrations potentially through its CPT-1 inhibition at the pancreatic islet beta-cells. It was previously demonstrated that the sulphonylurea glibenclamide inhibited CPT-1 in islet cells in a KATP-independent manner, as did another CPT-1 inhibitor, etomoxir, thereby stimulating the exocytosis of insulin [47]. Px may well exert a similar effect.
The study has some limitations. First, it is entirely possible, given the results, that risk of hypoglycaemia with Px may be greater in non-diabetic patients, given integrity of glucose uptake mechanisms, but this remains to be explored. We also do not know whether hyperinsulinaemia as a driver of insulin resistance carries adverse prognostic implications in the long-term. A larger sample size with longer duration of investigations would be necessary to evaluate this possibility. Finally, we do not yet understand the extent to which these findings are relevant to the emerging role of Px as an antineoplastic agent, but would emphasise that in this circumstance, the dependency of many cancers on CPT-modulated fatty acid uptake is likely to be a key mechanism of Px action.
In conclusion, in stable patients with T2D, short-term treatment with Px does not induce changes in fasting blood glucose levels, increases plasma insulin concentrations and sensitizes platelets to the anti-aggregatory effects of NO. The two latter effects are mechanistically disparate.