Sildenafil Improves Risk Markers in Prediabetes, Small Study Shows

The erectile dysfunction drug sildenafil improves insulin sensitivity and markers of endothelial function in people with prediabetes, a new study finds.

The results were published online November 18 in the Journal of Clinical Endocrinology and Metabolism by Claudia E Ramirez, MD, and colleagues, of Vanderbilt University, Nashville, Tennessee.

"Prediabetes is certainly associated with increased risks of heart disease and kidney disease. One of the things that was attractive to us about our findings was that we [also] seemed to improve some other risk factors related to heart and kidney disease," coauthor Nancy J Brown, MD, professor and chair of the department of medicine at Vanderbilt, told Medscape Medical News.

The mechanism is likely due to increased blood flow via phosphodiesterase 5 (PDE5) inhibition and thus is probably a class effect of drugs in that category, she and her colleagues say.

Dr Brown said her group is now planning a larger and longer-term randomized, placebo-controlled trial investigating whether PDE5 inhibition can improve clinical markers of diabetes in subjects with prediabetes.

Sildenafil Did Not Affect Weight or Blood Pressure

The researchers used the approved dose of sildenafil for treating pulmonary hypertension, 25 mg three times a day (Revatio, Pfizer, until it went off patent and then a generic version from Greenstone), in this study of 51 overweight volunteers with prediabetes.

This is higher than the dose of sildenafil used for erectile dysfunction, and it's not likely that the same effect would be seen with the as-needed dosing used for erectile dysfunction, Dr Brown noted.

The subjects — 35 women and 16 men — were randomized to either placebo or sildenafil for 3 months and underwent hyperglycemic clamp studies at baseline and at the end of treatment. A total of 21 subjects each in the sildenafil and placebo groups completed the study.

After 3 months, the insulin-sensitivity index was significantly greater in the sildenafil group compared with placebo (P = .049) after researchers adjusted for baseline factors. The disposition index (a composite measure of insulin sensitivity and secretion) also trended higher in the sildenafil group (P = .070).

However, there were no significant differences in first-phase or late-phase glucose-stimulated insulin secretion, insulin concentrations after L-arginine infusion, or C-peptide concentrations (all P > .30).

Sildenafil did not significantly affect weight, resting energy expenditure, or free fat mass.

Microalbuminuria was present at randomization in two placebo and four sildenafil group subjects. Sildenafil reduced the urine albumin/creatinine ratio from 12.67 to 6.84 µg/mg, and the effect persisted 3 months after discontinuation of the drug.

In contrast, in the placebo group, the urine albumin/creatinine ratio increased from 8.45 to 13.41 µg/mg at the end of the study and was 18.35 µg/mg 3 months following discontinuation.

Thus, four placebo subjects had microalbuminuria at 3 months after treatment vs none of the sildenafil subjects (P = 0.036), Dr Ramirez and colleagues point out.

Sildenafil treatment also significantly reduced plasma plasminogen activator inhibitor-1 concentrations (P = .01) without affecting tissue-plasminogen activator, while placebo had no effect on either. Neither treatment affected circulating cyclic guanosine monophosphate, cytokine concentrations, aldosterone, or urine F2-isoprostanes.

Sildenafil did not affect systolic or diastolic blood pressure, either.

There were no significant differences between sildenafil and placebo in the rate of discontinuation due to side effects or in the frequency of specific side effects.

Other Drug Classes May Have Similar Effects

As well as the larger, longer-term trial being planned with PDE5 inhibition by her team, Dr Brown noted that other related classes of drugs under development also appear promising, particularly stimulators of soluble guanylate cyclase.

Riciguat (Adempas, Bayer) was the first of these to be approved in the United States, in 2013, for the treatment of pulmonary hypertension. "This is another group of drugs that could potentially have these same beneficial effects," Dr Brown said.

She emphasized, "Obviously, the best treatment is diet and exercise in terms of prevention, but patients have trouble sustaining that."

This study was funded by the National Institutes of Health. Dr Brown is a consultant (on unrelated work) for Novartis and receives grant funding from Shire and New Haven Pharmaceuticals. She is also on the advisory board for Alnylam Pharmaceuticals. The coauthors have no relevant financial relationships.

via : http://www.medscape.com/viewarticle/854769