Effect of Mineralocorticoid Receptor Blockade in T2D
Effect of Mineralocorticoid Receptor Blockade in T2D
Addition of spironolactone to standard therapy, including ACEI, improved CFR in patients with well-controlled T2DM without clinical ischemic heart disease, suggesting that excess MR activation contributes to coronary microvascular dysfunction in T2DM. Our observation that MR blockade improves CFR is consistent with the current understanding of MR biology. MR is expressed in endothelium, vascular smooth muscle cells, cardiomyocytes, and circulating leukocytes. MR activation causes vascular inflammation with increased ROS production and increased expression of PAI-1 and ICAM, vascular damage, vascular dysfunction, and perivascular fibrosis. In rodents, excess MR activity is associated with a proinflammatory phenotype involving the intramural coronary circulation and myocardium.
The improvement in CFR with MR blockade in the current study is consistent with the results of our pilot study assessing effects of eplerenone in a crossover design on cardiac MRI determinations of CFR in 12 individuals with type 1 diabetes mellitus or T2DM and microalbuminuria. Additionally, we report herein that both statin use and weight loss were significant predictors of an improvement in CFR with treatment in our multivariable model; we believe the weight loss association is novel. The CFR benefits contrast with studies in diabetes showing no improvement (and in one study a detriment) with MR blockade in forearm vascular endothelial function, perhaps related to intrinsic differences in the regulation of the coronary versus peripheral vasculature.
The strengths of this physiological study include the well-controlled cardiometabolic phenotype, addition of MR blockade to standard medical therapy, comparison of MR blockade to another antihypertensive medication and to placebo, and the assessment of coronary microvascular function under highly controlled conditions that controlled for possible confounders such as dietary sodium, low or high glucose levels, lipid levels, and BP. We hypothesize that since this study excluded patients with ischemic heart disease, the improvements we saw in CFR with MR blockade reflect improvement in microvascular function. Furthermore, since 87% of our 69 participants had interpretable pre- and posttreatment CFR data, our results are likely applicable to patients with clinical characteristics similar to our study population.
Limitations include the lack of assessment of cardiovascular events, sample size, and duration of this physiological study. Further, although spironolactone improved CFR as compared with HCTZ and as compared with combined HCTZ and placebo treatments, we cannot rule out the possibility that HCTZ may have impaired CFR. We did not see an effect of MR blockade on diastolic function, possibly related to the lack of diastolic dysfunction at baseline, or on myocardial extracellular volume, possibly because cardiac remodeling takes longer than 6 months. Due to spironolactone's effects on potassium homeostasis, we restricted this study to individuals with good renal function. Novel MR antagonists, which preserve the cardiovascular benefits of spironolactone but lack the adverse potassium effects, are currently in development and could prove to be useful in patients with diabetes. Also, selective MR antagonists, like eplerenone, may prove to be beneficial in patients who cannot tolerate the antiandrogen or antiprogesterone effects of spironolactone. Finally, CFR is an intermediate marker for cardiovascular outcomes. It remains to be determined if there is a cause and effect relationship between CFR and cardiovascular health, and whether increasing CFR through administration of an MR antagonist will lead to reductions in cardiovascular events.
This proof-of-concept study demonstrating improvement in CFR with MR blockade may have important clinical implications. Impaired CFR is associated with increased mortality in patients with no evidence for CAD. Thus, it is possible that MR antagonists over and above ACEI/angiotensin receptor blocker therapy may lead to significant cardiovascular benefits in patients with diabetes. Future studies are needed to address this possibility.
Discussion
Addition of spironolactone to standard therapy, including ACEI, improved CFR in patients with well-controlled T2DM without clinical ischemic heart disease, suggesting that excess MR activation contributes to coronary microvascular dysfunction in T2DM. Our observation that MR blockade improves CFR is consistent with the current understanding of MR biology. MR is expressed in endothelium, vascular smooth muscle cells, cardiomyocytes, and circulating leukocytes. MR activation causes vascular inflammation with increased ROS production and increased expression of PAI-1 and ICAM, vascular damage, vascular dysfunction, and perivascular fibrosis. In rodents, excess MR activity is associated with a proinflammatory phenotype involving the intramural coronary circulation and myocardium.
The improvement in CFR with MR blockade in the current study is consistent with the results of our pilot study assessing effects of eplerenone in a crossover design on cardiac MRI determinations of CFR in 12 individuals with type 1 diabetes mellitus or T2DM and microalbuminuria. Additionally, we report herein that both statin use and weight loss were significant predictors of an improvement in CFR with treatment in our multivariable model; we believe the weight loss association is novel. The CFR benefits contrast with studies in diabetes showing no improvement (and in one study a detriment) with MR blockade in forearm vascular endothelial function, perhaps related to intrinsic differences in the regulation of the coronary versus peripheral vasculature.
The strengths of this physiological study include the well-controlled cardiometabolic phenotype, addition of MR blockade to standard medical therapy, comparison of MR blockade to another antihypertensive medication and to placebo, and the assessment of coronary microvascular function under highly controlled conditions that controlled for possible confounders such as dietary sodium, low or high glucose levels, lipid levels, and BP. We hypothesize that since this study excluded patients with ischemic heart disease, the improvements we saw in CFR with MR blockade reflect improvement in microvascular function. Furthermore, since 87% of our 69 participants had interpretable pre- and posttreatment CFR data, our results are likely applicable to patients with clinical characteristics similar to our study population.
Limitations include the lack of assessment of cardiovascular events, sample size, and duration of this physiological study. Further, although spironolactone improved CFR as compared with HCTZ and as compared with combined HCTZ and placebo treatments, we cannot rule out the possibility that HCTZ may have impaired CFR. We did not see an effect of MR blockade on diastolic function, possibly related to the lack of diastolic dysfunction at baseline, or on myocardial extracellular volume, possibly because cardiac remodeling takes longer than 6 months. Due to spironolactone's effects on potassium homeostasis, we restricted this study to individuals with good renal function. Novel MR antagonists, which preserve the cardiovascular benefits of spironolactone but lack the adverse potassium effects, are currently in development and could prove to be useful in patients with diabetes. Also, selective MR antagonists, like eplerenone, may prove to be beneficial in patients who cannot tolerate the antiandrogen or antiprogesterone effects of spironolactone. Finally, CFR is an intermediate marker for cardiovascular outcomes. It remains to be determined if there is a cause and effect relationship between CFR and cardiovascular health, and whether increasing CFR through administration of an MR antagonist will lead to reductions in cardiovascular events.
This proof-of-concept study demonstrating improvement in CFR with MR blockade may have important clinical implications. Impaired CFR is associated with increased mortality in patients with no evidence for CAD. Thus, it is possible that MR antagonists over and above ACEI/angiotensin receptor blocker therapy may lead to significant cardiovascular benefits in patients with diabetes. Future studies are needed to address this possibility.