Perhexiline Therapy in Patients with Type 2 Diabetes: Dissociation Between Potentiation of Nitric Oxide Signalling and Changes in Insulin Resistance

Purpose: Perhexiline (Px) has previously been utilized primarily in the treatment of otherwise refractory angina pectoris and/or systolic heart failure. In recent years, Px has also shown increasing promise as a potential chemotherapeutic agent. Px inhibits carnitine palmitoyltransferases 1 and 2 (CPT1, CPT2), which control uptake of long-chain fatty acids into mitochondria and thus represent the rate-limiting steps in their metabolism. However, occasional cases of hypoglycaemia have been reported in Px-treated patients, raising the possibility that Px may also increase sensitivity to insulin. Furthermore, Px increases anti-aggregatory responses to nitric oxide (NO), an effect which may parallel insulin sensitization. No previous studies have examined either the effect of Px on insulin sensitivity, or the relationship of such putative changes with effects on NO signalling. We therefore sought to examine these relationships in patients with stable T2D and cardiovascular disease.Methods: In 30 patients with concomitant T2D and cardiovascular disease, Px was initiated, and dosage was titrated to reach therapeutic range and to prevent toxicity. Investigations were performed before and after 2 weeks, to examine changes in insulin sensitivity, platelet responsiveness to the anti-aggregatory effects of the NO donor sodium nitroprusside (SNP), as well as other markers of inflammation and modulators of NO signaling.Results: Px substantially potentiated inhibition of ADP-induced platelet aggregation by SNP (from 16.7±3.0 to 27.3±3.7%; p=0.005). Px did not change fasting blood glucose concentrations and reduced insulin sensitivity (HOMA-IR score increased from median of 4.47 to 6.08; p=0.028), via increasing fasting plasma insulin concentrations (median 16.5 to 19.0 mU/L: p=0.014). Increases in SNP responses tended (r=-0.30; p=0.11) to be reciprocally related to increases in HOMA-IR. No patient developed symptomatic hypoglycaemia, nor was there any other short-term toxicity of Px.Conclusions: In patients with stable T2D and cardiovascular disease, Px is not an insulin sensitizer, and does not normally induce hypoglycaemia. These results effectively dissociate the NO-sensitizing effect of Px from variability in insulin signaling.