The Renin-Atherosclerosis Link in Diabetes

Activation of the renin-angiotensin-aldosterone-system (RAAS) is linked to atherosclerotic burden, especially in T2DM, according to a study published online in BMC Cardiovascular Disorders.

“Our findings provide clinical evidence for an association between RAAS activation and atherosclerotic burden both in subjects with and without T2D. Plasma renin and atherosclerosis are concomitantly increased in subjects with T2D as compared to age and sex-matched subjects without T2D suggesting that these associations may be of particular importance in vascular complication of diabetes,” wrote first author Isabel Gonçalves, MD, PhD, of Lund University (Malmö, Sweden), and colleagues.

“Importantly, the association between renin and atherosclerotic burden was independent of blood pressure and other major cardiovascular risk factors suggesting involvement of a direct effect of RAAS activation on the vascular wall,” they added.

The main activator of the RAAS system is renin, whose production may be increased by levels of angiotensinogen in abdominal fat, as well as by hyperinsulinemia related to sympathetic nervous activation. Renin sets off a series of actions that ultimately results in the production of angiotensin II, a powerful vascoconstrictor that has been linked to smooth muscle proliferation, oxidative stress, pro-inflammatory cytokines, and pro-fibrotic factors-- all of which may play a role in the macrovascular complications of diabetes.

In the study, researchers measured renin and IL-6 in 985 individuals with diabetes, and 515 without T2DM, matched for age, gender, and CVD prevalence. Participants were part of the SUMMIT (SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools) trial, which took place at hospitals in four European academic medical centers (Malmo, Sweden; Pisa, Italy; and Dundee and Exeter, UK) between December 2010 and April 2013. Researchers evaluated the ankle-brachial pressure index (ABPI) to assess peripheral artery disease, carotid intima-media thickness (IMT) to assess carotid disease, carotid plaque area, pulse wave velocity (PWV) to measure arterial stiffness, and the reactivity hyperemia index (RHI) to assess endothelial function.

They also analyzed renin and markers of inflammation (cytokines and growth factors) and fibrous components (elastin and collagen) from plaques obtained from 205 patients who had undergone carotid endarterectomy.

Key Results:

• Renin:

♦ Increased in T2DM, as well as with increasing age, BMI, HbA1c, and triglycerides

♦ Increased odds of CVD with higher renin levels for both T2DM (OR 1.55) and non-T2DM (OR 1.45)

♦ The association between CVD and renin levels was independent of other risk factors in individuals with and without T2DM

♦ Significantly associated with increased IL-6 in individuals with T2DM (P<1.0 x 10-¹⁶) and without T2DM (P=4.9 x 10 ^-11)

• Renin was independently linked to peripheral artery disease, bulb carotid intima media thickness, and carotid plaque area in both T2DM and non-T2DM

♦ The association was independent of treatment with RAAS inhibitors

• Results from 205 endarterectomy patients showed only weak associations between renin and cytokines, growth factors, elastin, and collagen in plaques

The authors noted that these results agree with the hypothesis that RAAS activation may play a role in CV complications of T2DM. Patients with CVD but without T2DM also had elevated renin levels that were significantly linked to markers of atherosclerosis. However, these individuals had lower renin levels and less severe vascular changes than those with both T2DM and CVD. That points to a role for insulin resistance in stimulating renin expression, which may contribute to more severe atherosclerosis in T2DM, according to the authors.

In addition, the results from the carotid endarterectomy patients suggests that systemic RAAS activation may not play a large role in plaque composition and vulnerability, though the authors did not rule out a role for local RAAS activation.

They also highlighted the rather counterintuitive results suggesting that RAAS inhibitors are not associated with decreased atherosclerosis, and proposed several explanations. First, renin may be associated with some other atherogenic factor and may not have a direct effect on the development of atherosclerosis. Second, vascular changes that develop over many years and are associated with RAAS activation may not be easily reversed with RAAS inhibition. Finally, the effect of RAAS inhibitors may not be as obvious when they are given with other anti-atherogenic drugs, like statins. They mentioned that these results should be interpreted with caution given the observational nature of the study, and lack of data on length of treatment with RAAS inhibitors.

Take-home Points

• The main activator of the RAAS system is renin, which sets off a series of actions that ultimately results in the production of angiotensin II, a powerful vascoconstrictor that may play a role in the macrovascular complications of diabetes.

• A European study found that higher renin levels were associated with increased odds of CVD in individuals with and without T2DM.

• The association between CVD and renin levels was independent of blood pressure and other cardiovascular risk factors in individuals with and without T2DM.

• Patients with CVD but without T2DM had elevated renin levels that were significantly linked to markers of atherosclerosis, but these individuals had lower renin levels and less severe vascular changes than those with both T2DM and CVD.

• RAAS inhibitors were not associated with decreased atherosclerosis, but these results may need to be interpreted with caution given the limitations of the trial.

Reference: Gonçalves I, et al. for the SUMMIT consortium. Association between renin and atherosclerotic burden in subjects with and without type 2 diabetes. BMC Cardiovasc Disord. 2016 Sep 5;16(1):171.