Three-month treatment with sildenafil (Viagra) improved insulin sensitivity in overweight patients with prediabetes, according to a small trial reported in the Journal of Clinical Endocrinology & Metabolism.
The treatment also lowered urinary albumin excretion and improved fibrinolytic balance, said senior investigator Nancy Brown, MD, of the Vanderbilt University School of Medicine in Nashville, Tenn., and colleagues.
"We need additional strategies to help slow the progression from prediabetes to diabetes," Brown said in a statement. "Weight loss and exercise regimens can be difficult to maintain, and some current medications have been limited by concerns about adverse effects. Sildenafil and related drugs could offer a potential avenue for addressing the rising number of diabetes diagnoses."
In addition, she said, "because existing drug therapies to prevent type 2 diabetes can have negative effects on the heart or be of limited use in patients with kidney disease, strategies to prevent diabetes without adversely affecting the risk of kidney and heart disease could have a large impact on public health."
Previous studies have reported that treatment with a phosphodiesterase-5 (PDE5) inhibitor improved measures of insulin sensitivity in insulin-resistant and severely obese patients, Brown and colleagues noted.
The current study enrolled 51 overweight patients with prediabetes, about two-thirds of whom were women. The investigators collected blood samples and measured insulin resistance via hyperglycemic clamp at baseline.
The volunteers were then randomized to receive either sildenafil 25 mg three times per day or a matching placebo. Volunteers underwent a second hyperglycemic clamp and blood tests after 3 months.
The study's primary endpoints were measures of insulin resistance including the insulin sensitivity index, glucose-stimulated insulin secretion, and the disposition index, a composite measure of insulin sensitivity and secretion.
Secondary endpoints included blood pressure, levels of tissue-plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1), urine albumin and creatinine, body weight, resting energy expenditure, and the incidence of side effects.
Key results included the following:
The insulin sensitivity index was significantly greater in the treatment group compared to the placebo group by 1.84 mg/kg/min per µU/mL*100 (95% CI 0.01-3.67; P=0.049).
There was a weak trend toward a higher disposition index in the treatment group by 83.5 mg/kg/min (95% CI -7.01-174.02 mg/kg/min; P=0.70.)
The investigators found no significant effect of treatment on first-phase or late phase glucose-stimulated insulin secretion. Sildenafil treatment also had no significant effect on body weight, resting energy expenditure, or blood pressure, Brown and colleagues reported.
The urine albumin-to-creatinine ratio decreased in the treatment group from 12.67 ± 14.67 µg/mg to 6.84 ± 4.86 µg/mg.
In contrast, the ratio increased from 8.45 ± 14.17 µg/mg to 13.41 ± 17.71 µg/mg in the placebo group (P=0.036 for the treatment effect).
Sildenafil also significantly reduced PAI-1 concentrations (P=0.01) without affecting t-PA.
These findings suggest PDE5 inhibition may improve glucose homeostasis while avoiding detrimental effects on fibrinolysis, Brown and colleagues wrote.
Four patients in the treatment group and three in the placebo group discontinued because of side effects, a nonsignificant difference, the investigators said.
"In conclusion, our study suggests that chronic PDE5 inhibition improves insulin sensitivity, fibrinolytic balance, and albuminuria in subjects with prediabetes," Brown and colleagues wrote. "Larger randomized trials using clinical endpoints are needed to assess whether PDE5 inhibition can prevent the onset of diabetes in high-risk patients."
"The present study does not address the mechanism through which PDE5 inhibition improves tissue insulin sensitivity," Brown and colleagues noted, adding that, "In rodent models, sildenafil improves muscle glucose uptake through recruitment of vasculature and has no effect on insulin signaling in the muscle."
"Future studies of the effect of PDE5 inhibition on insulin signaling in muscle biopsies after hyperinsulinemia are needed to address this mechanism," they said.
An important limitation of the study was the exclusion of patients with renal dysfunction.
"Studies are needed to assess the effect of long-term PDE5 inhibition on albuminuria in patients who are heterogeneous with respect to renal function," Brown and colleagues said.
Why did PDE5 inhibition improve insulin sensitivity but not glucose-stimulated insulin secretion? "Insulin sensitivity and insulin secretion are controlled by different factors," Brown told MedPage Today via email. "If insulin sensitivity improves, the body does not need to make as much insulin to maintain normal glucose."
"We plan a longer and larger study to look at effects [of PDE5 inhibition] on glucose, hemoglobin A1C, and urine albumin," Brown said.