Commentary by Nancy J. Brown, MD and Margaret Eckert-Norton PhD, FNP-BC, CDE
“We need additional strategies to help slow the progression from prediabetes to diabetes,” said Nancy J. Brown, MD, Chair of the Department of Medicine of Vanderbilt University School of Medicine in Nashville, TN. “The gold standard for preventing diabetes is weight loss and exercise. Weight loss and exercise regimens can be difficult to maintain, and some current medications have been limited by concerns about adverse effects. Studies such as this may help us find alternatives for people who have trouble maintaining weight loss and exercise.”
“If changes in insulin action can be delayed or prevented and risk factors for vascular damage reduced, then there is potential for a clinically significant improvement in health outcomes for persons with prediabetes,” commented Margaret Eckert-Norton PhD, FNP-BC, Certified Diabetes Educator, SUNY Downstate, Brooklyn, NY. “These data are preliminary indication of clinical significance.”
The proof-of-concept study involved 51 overweight patients with prediabetes who were randomized to treatment with sildenafil 25 mg 3 times daily or matching placebo for 3 months. Study participants underwent a hyperglycemic clamp at baseline and at the end of treatment to assess glucose-stimulated insulin secretion and estimate insulin sensitivity. Urine samples also were collected for measurement of albumin and creatinine levels.
Among the 42 participants who completed the study (21 patients in each treatment arm), those treated with sildenafil had a significantly greater insulin sensitivity index compared to given placebo (by 1.84 mg/kg/min per mcU/mL*100; P=0.049), after adjusting for baseline insulin sensitivity index and body mass index. In contrast, acute- or late-phase glucose-stimulated insulin secretion was similar between the two groups (P<0.30).
In the sildenafil group, urine albumin-to-creatinine ratio decreased from 12.67±14.67 to 6.84±4.86 mcg/mg Cr and remained at this level at 3 months after treatment. In contrast, the urine albumin-to-creatinine ratio increased from 8.45±14.17 to 13.41±17.71 mcg/mg Cr in the placebo and increased further to 18.35±54.81 mcg/mg Cr after 3-month follow-up.
“The urine albumin-to-creatinine ratio is a marker of early kidney damage and also predicts risk of heart disease,” Dr. Brown noted.
Sildenafil Decreases a Marker of Fibrinolysis
Furthermore, the sildenafil group showed a significant decrease in plasminogen activator inhibitor-1 (PAI-1) concentrations (P=0.01) compared with the placebo group after 3 months of treatment. The groups showed similar levels of tissue-plasminogen activator (t-PA) after 3 months of treatment.
“Higher PAI-1 concentrations are associated with an increased risk of heart attack and diabetes,” Dr. Brown explained.
“It is of interest that even 3 months after treatment with sildenafil was stopped, favorable changes in clotting factors and decreased urinary albumin persisted,” commented Dr. Eckert-Norton, who also is an Endocrine Society Advocacy and Public Outreach Core Committee Member. “If larger studies show similar improvement, it may be that intermittent treatment with sildenafil (or other drugs in this class) might be a clinical strategy to reduce vascular damage. Cost-benefit analyses will need to be conducted before feasibility of sildenafil treatment can be determined.
The mechanisms behind the effects of sildenafil on insulin sensitivity are unknown, and Dr. Brown and colleagues are conducting studies to address this gap in knowledge. “We think it is through better delivery of insulin to the insulin sensitive tissues,” Dr. Brown 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,” Dr. Brown concluded. “Further studies will be needed to determine whether long-term treatment with drugs like sildenafil can prevent the onset of diabetes in high-risk patients.”
Strengths and Limitations of the Study
“The study procedures included in this report are appropriate and rigorous in detail,” Dr. Eckert-Norton said. “Inclusion and exclusion criteria are well described and justified. A standard oral glucose tolerance test (OGTT) was done to confirm prediabetic status. The authors then conducted a hyperglycemic clamp study, which is the gold standard to measure insulin action in clinical research. In addition to insulin action, markers of endothelial function and effects on fibrinolytic factors were assessed prior to initiating the study drug. These tests were repeated at the second hyperglycemic clamp study 3 months later. A final OGTT was conducted at the end of the study period, and at 3 months after sildenafil treatment was completed to assess the long-term impact of sildenafil treatment.”
“The 51 person sample recruited is small, so it is difficult to generalize these findings,” Dr. Eckert-Norton said. “As the authors suggest, although the hyperglycemic clamp is the gold standard for assessing insulin action in clinical research, it is time and resource intensive thus limiting the number of study participants. Additionally, as clamp studies utilize IV administration of glucose, they do not mimic metabolic responses to nutrients we consume in mixed meals. As pointed out by the authors, the mechanism of action by which sildenafil improves insulin sensitivity is not yet known. More research will be needed to address these issues.
December 1, 2015
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 Nov 18:jc20153415. [Epub ahead of print]