Daily use of tadalafil is likely to be a new therapeutic option for heart, kidney and immune complications of diabetes, but with different benefits, in men and women. The drug, a type 5 phosphodiesterase enzyme (PDE5i) inhibitor, initially indicated for erectile dysfunction, optimizes the dynamics of cardiac contraction in men but not in postmenopausal women. In any case, improves the immune and renal function of men and women, revealing a hitherto unknown sexual and tissue specificity. These are the main results of the Italian clinical study published in ‘Science Translational Medicine’.
“It is a very interesting example of drug repurposing, that is pharmacological repositioninga topic that is also discussed a lot in the NRP because the use, with a new indication, of a drug already on the market is a quick way to translate scientific research into benefits for the patient, saving time, resources and minimal environmental impact ”, he explains Andrea Isidori, Full Professor of Endocrinology at the Department of Experimental Medicine of the University of Rome Sapienza and president of the Italian Society of Andrology and Sexual Medicine and coordinator of the newly published study.
The burden of diabetes-related cardiovascular disease is increasing and diabetic nephropathy is the number one cause of dialysis. Chronic low-grade inflammation leads to heart damage (diabetic cardiomyopathy) and kidney damage, against which there are currently no effective treatments.
The work, entitled ‘Sex-specific effects of daily tadalafil on diabetic heart kinetics in Recogito, a randomized, double-blind, placebo-controlled trial‘is the result of an independent research of the Sapienza University of Rome, conceived and conducted at the Policlinico Umberto I of the Capital which involved a team of researchers at national level. “Once the patent has expired – explains Isidori – it is possible to carry out independent research on drugs. The PDE5i drug class to which tadalafil belongs – he continues – was initially developed for cardiac angina. The pro-erectile side effect has distracted studies from what it was originally investigated for”.
The independent group continued to explore the potential of PDE5i. “First of all – specifies Isidori – we published their anti-vascular remodeling effects (on ‘Circulation’), then theefficacy in heart failure (‘Bmc-Medicine’) and in diabetic nephropathy (‘Scientific-Report’). In ‘Science Translational Medicine’, we completed the hardest part, documenting the specificity of sex and tissues. By identifying a complex cross-talk between renal and cardiac changes due to diabetes. By investigating possible molecular markers, we identified klotho and monocyte subpopulations as new players in this context. We have therefore shown that tadalafil reverses the changes induced by diabetes. But not everyone gets better in the same way because there is a difference in sex ”.
The Italian study enrolled 122 subjects, both men and women, with diabetes (age 45-80 years) and diabetic cardiomyopathy. Half were given tadalafil once daily and the other were given placebo. “We chose this PDE5i because it has a longer half-life – observes Isidori – and remains in circulation for more than 24 hours, after a single intake”. After 5 months “we observed what was happening in the heart – continues the expert – how the cardiac contraction that is typical of the heart of the diabetic patient changed, with complex rotational movements visible on magnetic resonance imaging”. The researchers saw that in men taking tadalafil it improved the mode of contractionthe movement that had been altered due to diabetes was reversed, almost returning to normalization.
“In women, this phenomenon on the heart did not occur – Isidori underlines -. We found out why: they were all menopausal women. This element assumes that there is a role for female hormones on cardiac responsiveness. In both sexes, however, there was an improvement in the kidney and in the parameters related to the chronic inflammation characteristic of the diabetic patient. “The work in fact demonstrates a tissue and sex-specific action of the drug and brings precision medicine, adapted to the individual patient, closer,” he summarizes.
“Ideal candidates for further studies, which are needed to authorize the new primary prevention indication, are men with diabetes who are starting to develop erectile dysfunction and cardiac hypertrophy. In women– adds the andrologist – it can have beneficial effects on the heart before menopause or in perimenopause or if they have kidney problems such as diabetic nephropathy. Compared to other drugs, the cost-effectiveness of PDE5i is advantageous because, with the expiration of the patent, they have become extremely cheap. Tadalafil – concludes Isidori – becomes a convenient alternative also because the effects occur independently of the glycaemia, so it can be combined with the hypoglycemic treatments available “.