A Pilot, Randomised, Double-blind, Cross-over Study to Assess the Renal and Systemic Effects of NCX4016 in Patients With Type 2 Diabetes and Early Nephropathy

Nitric oxide-releasing, non-steroidal anti-inflammatory drugs (NO-NSAIDs) are new chemical entities obtained by adding a nitric oxide-releasing moiety to the parent NSAID via a short-chain ester linkage. NCX4016 (Nitro-aspirin), a acetoxy-benzoate 2-(2-nitroxymethyl)-phenyl ester of acetylsalicylic acid, is one of these novel compounds developed with the dual aim to expand the pharmacological properties of the parent drug and to spare some of its side effects, in particular on the gastrointestinal mucosa. Decreased NO synthesis may contribute to some of the abnormalities associated with diabetes such as decreased insulin activity, impaired endothelium-dependent/insulin-induced vasodilatation, increased sympathetic vasoconstrictor outflow and increased platelet activation, that may result in increased vascular resistance and arterial hypertension and, in the long term, to an increased risk of micro- and macrovascular complications.

Low-dose aspirin represents the antiplatelet drug of choice for prevention of vascular complications in diabetes. Preclinical data on NCX4016 support the possibility that Nitro-aspirin may shear with aspirin the antithrombotic activity and may offer the additional benefits related to increased NO bioavailability. Actually NCX4016 inhibits cyclooxygenase (COX) activity in platelets both in vitro and ex vivo and, similar to aspirin, prevents the release of thromboxane (TX) A2 and arachidonic acid-induced platelet aggregation. Moreover Nitro-aspirin inhibits aspirin-insensitive platelet aggregation and adhesion, possibly by inhibiting the expression of platelet adhesion molecules by a specific COX-independent mechanism, probably NO-mediated, that is not show by the parent compound. Therefore Nitro-aspirin can exceed the cardioprotective action of the parent compound, by adding the aspirin-like moiety and the NO-releasing moiety, which both contribute to its benefits effects, such as multiple anti-thrombotic and, possibly, anti-atherosclerotic activities, restoration of insulin-related metabolic and vascular effect and finally blood pressure reduction. Moreover, experimental and clinical data suggest that Nitro-aspirin will offer significant safety advantages by its NO moiety that may limit aspirin gastrotoxicity by preventing the vasocontriction of the mucosal microvasculature.

In the present randomised, double-blind, cross-over study, we evaluated the efficacy and safety profile of Nitro-aspirin (800 mg bid), and of an equiactive dose of aspirin (325 mg od), as compared to placebo, in thirteen patients with type 2 diabetes and micro or macro-albuminuria (overnight albumin excretion rate > 20 µg/min for at least 6 months), without overt renal insufficiency (serum creatinine concentration < 2 mg/dl) and no specific controindication to aspirin therapy. Eligible patients who provided written informed consent, withdrew any previous treatment with NSAIDs or aspirin and, after a 4-week placebo run-in period, entered two consecutive 4-week treatment periods with Nitro-aspirin plus aspirin placebo or Nitro-aspirin placebo plus aspirin in a random order. Primary efficacy variables were changes in urinary albumin excretion (UAE) and in insulin activity at the end of Nitro-aspirin treatment as compared to baseline. UAE (mean of three overnight urine collection), insulin sensitivity (glucose disposal rate as measured by an hyperinsulinemic euglycemic clamp), cardiac haemodynamics (evaluated by echocardiography), NO bioavailability and oxidative stress (measured as nitrite/nitrate plasma levels) and other clinical and laboratory variables, were measured at baseline and at the end of each treatment periods.