PDE-5 Inhibitors May Improve Insulin Sensitivity in Patients at High Risk for Diabetes

Treatment with a phosphodiesterase 5 (PDE-5) inhibitor may improve insulin sensitivity and improve markers of endothelial function, according to recently published data. However, clinicians are hesitant to prescribe the medications for this use because of unknown risk factors and cost.¹

In a randomized, double-blind, placebo-controlled study, overweight individuals with prediabetes who were randomly assigned to receive sildenafil (Viagra) for 3 months were significantly more sensitive to insulin than those assigned to placebo.  

“We and another group have found improvement in a less direct measurement of insulin secretion and sensitivity called the disposition index with tadalafil (Cialis), so we think this is a class effect,” said study investigator Nancy Brown, MD, professor of medicine and pharmacology and chair of the Department of Medicine at Vanderbilt University School of Medicine in Nashville, Tennessee.

Although further studies are needed to determine whether long-term treatment can prevent the onset of diabetes in high-risk patients, PDE-5 inhibitors may offer a potential avenue for addressing the increasing number of diabetes diagnoses, according to Dr Brown.  She added that weight loss and exercise regimens are difficult for many patients, and some current medications aimed at preventing diabetes are limited by concerns about adverse effects.

Sildenafil causes the relaxation of smooth muscle, vasodilation, and increases blood flow. Currently, it is approved by the US Food and Drug Administration to treat erectile dysfunction and pulmonary arterial hypertension. The current study suggests that sildenafil and other agents in this class prevent PDE-5 from breaking down cyclic guanosine monophosphate (GMP), which relaxes blood vessels and increases insulin sensitivity. However, unlike other methods of raising cyclic GMP, sildenafil did not affect fibrinolytic balance.

“This was a short-term study and we measured insulin secretion and sensitivity. We hope to do a larger, long-term clinical study next,” Dr Brown told Endocrinology Advisor.

Brown and colleagues randomly assigned patients to treatment with 25 mg of sildenafil 3 times a day or to a matching placebo for 3 months. Patients in the treatment arm were aged a mean of 51 years. Twenty-one patients in each group completed the study. 

After adjustment for baseline insulin sensitivity index and body mass index (BMI), the insulin sensitivity index was significantly greater in the sildenafil group compared with the placebo group, with a difference of 1.84 mg/kg/min per U/mL×100. The researchers also found that sildenafil decreased the urine albumin-to-creatinine ratio and decreased the plasminogen activator inhibitor-1 without altering the tissue-plasminogen activator. These findings confirm previous animal studies that demonstrated sildenafil can improve insulin sensitivity.  However, sildenafil had no effect on acute- or late-phase glucose-stimulated insulin secretion.

“The observation confirming mouse studies is likely correct,” John Buse, MD, chief of the Division of Endocrinology at the University of North Carolina School of Medicine, Chapel Hill, told Endocrinology Advisor. “What remains to be worked out is how clinically significant the findings are for people with erectile dysfunction and for the hundreds of millions of people with diabetes and prediabetes worldwide. Certainly this is potentially good news for many people.”

While this study looked at sildenafil, previous studies have demonstrated beneficial effects of tadalafil in combating diabetes. One study showed that PDE-5 inhibition may represent a novel strategy for improving beta-cell function in metabolic syndrome.²

In a randomized, double-blind, placebo-controlled study published last year, Ho et al found there may be significant benefits with daily use of tadalafil in specific patient populations.³

The researchers randomly assigned patients to 20 mg of tadalafil daily (N=25) or placebo (N=28) for 3 months. Measures of insulin resistance were not significantly different between patients in the tadalafil arm and those in the placebo arm at 3 months. However, in individuals with severe obesity (BMI ≥ 36.2 kg/m²), tadalafil use was associated with improved insulin resistance (homeostatic model assessment for insulin resistance) compared with placebo. The investigators also found that one measure of beta-cell compensation for insulin resistance (oral disposition index) improved with tadalafil in the overall sample and in the subgroup with severe obesity.

Sandeep Dhindsa, MD, associate professor of medicine and chief of the Division of Endocrinology and Metabolism at Texas Tech University Health Sciences Center in Odessa, Texas, said the tadalafil studies and the current sildenafil study are intriguing but much more research is required before these agents can be adopted as a means of preventing diabetes. He added that the sildenafil study included a small number of patients and has significant limitations.

“The study is interesting, but I would hesitate to draw any clinically relevant conclusions from it,” Dr Dhindsa told Endocrinology Advisor. “Measurement of insulin sensitivity was not the primary end point. The primary end point was insulin secretion during hyperglycemic clamp at a blood sugar of 200 mg/dL, which did not change. Insulin sensitivity is ideally measured by euglycemic (usually at 100 mg/dL) clamp. Hence, the results of the study need to be confirmed by a study designed to investigate insulin sensitivity.”

Dr Dhindsa said at this time, he would not prescribe a PDE-5 inhibitor to prevent diabetes or reduce HbA1c. ”Giving sildenafil 3 times a day to improve insulin sensitivity does not sound very appealing when we already have drugs such as pioglitazone or metformin,” he said.

Jessica Castle, MD, assistant professor of medicine in the Division of Endocrinology, Diabetes, and Clinical Nutrition at the Oregon Health & Science University School of Medicine in Portland, Oregon, agreed with Dr Dhindsa. She said these medications come with risks, including hypotension, which have not been thoroughly investigated in women.

“I would not recommend patients go on Cialis to prevent diabetes or lower HbA1c levels,” Dr Castle told Endocrinology Advisor. “This approach is unproven for either preventing or treating diabetes. Lifestyle changes and/or metformin are still the cornerstone treatments for preventing the development of prediabetes into type 2 diabetes  Cialis and Viagra are expensive medications, and therefore, they are not cost-effective as compared to metformin.”

Currently, sildenafil is under consideration as a treatment for heart failure. However, there are concerns it may work differently in men than in women. Some clinicians note that these agents are expensive and question whether their modest potential benefits for cardiovascular disease and diabetes may be worth their costs. John Morley, MD, director of endocrinology at Saint Louis University in Missouri, said it has always been known there may be cardiovascular benefits from daily use of these agents, but the benefits have not been quantified for men or women.

“Clearly, there is a potential, but these are among the most expensive drugs there are,” Dr Morley told Endocrinology Advisor. “Viagra started out for heart disease. So that was the starting effect and it was always a drug that was going to be good for people with vascular disease. The PDE-5 inhibitors increase blood flow in the muscle and you increase the insulin receptors. So you might be making the insulin work better just like when you exercise. Both open up more blood vessels in the muscles and so there are more receptors available.”

However, Dr Morley added that those benefits need to be thoroughly evaluated in large, multicenter trials before clinicians will know when these agents can be optimally prescribed and for whom. Due to skyrocketing diabetes rates worldwide, even modest benefits from PDE-5 inhibitors may be worth further exploration.

References

1. Ramirez CE, Hui N, Yu C, et al. Treatment with sildenafil improves insulin sensitivity in prediabetes: A randomized, controlled trial. J Clin Endocrinol Metab. 2015;100(12):4533-4540.
2. Hill KD, Eckhauser AW, Marney A, Brown NJ. Phosphodiesterase 5 inhibition improves  ß-cell function in metabolic syndrome. Diabetes Care. 2009;32:857–859.
3. Ho JE, Arora P, Walford GA, et al. Effect of phosphodiesterase inhibition on insulin resistance in obese individuals. J Am Heart Assoc. 2014;3(5):e001001.