R3i Editorial

Reducing residual vascular risk in statin-treated patients who have achieved evidence-based lipid goals remains an ongoing mission of the Residual Risk Initiative (R3i). Much attention has focused on reducing residual macrovascular risk with the addition of novel lipid-modifying agents to statins. Beyond a role for additional lowering of low-density lipoprotein cholesterol (LDL-C) with ezetimibe in IMPROVE-IT ¹, and encouraging preliminary findings from exploratory analyses of trials with the PCSK9 monoclonal antibody therapy ^2,3, results from other trials have been somewhat disappointing.

The gut microbiome: a contributor to residual vascular risk?
This month’s Focus article suggests a novel approach to this issue: targeting the gut microbiome. Emerging evidence implicates the gut microbiome in the development of cardiovascular disease, with mechanistic studies showing that the host-microbe interaction plays a role in the regulation of immune and metabolic pathways ⁴. It has been suggested that imbalance of the gut microbiota may influence cellular processes that directly affect the body’s susceptibility to atherogenesis. For example, increased levels of certain bacterial products may induce a low-grade chronic inflammation, predisposing to atherogenesis, as well as influencing insulin sensitivity and lipid pathways ^5,6. Therefore, the gut microbiome may be a novel contributor to lipid and lipoproteins levels, a proposal borne out by this study.

Fu and colleagues ⁷ performed a systematic analysis of host genome, gut microbiome, body mass index (BMI) and blood lipids in 893 subjects from the Dutch LifeLines-DEEP general population cohort. Using a two-part model for association analysis to take into account the complicated features of the microbial data, they showed that the gut microbiota composition can explain up to 6% of the variation in triglycerides and 4% in high-density lipoproteins (HDL), independent of age, gender and host genetics. Moreover, this result was not due to confounding, as even when BMI was included in the risk model, the gut microbiome was still a significant contributor to plasma levels of triglycerides and HDL.

These findings pose a question: could targeting the gut microbiome offer a novel approach to addressing residual vascular risk, beyond effects of pharmacotherapy? One approach may be dietary intervention, known to influence the gut microbiome. Whether the use of antimicrobial therapy or probiotics may offer potential also merits investigation. Mechanistic studies into the gut microbiome in humans are also needed.

Don’t forget diet and lifestyle
Lifestyle, notably dietary intervention, may also be a player in counteracting residual microvascular risk, based on the results of two studies discussed this month. The Diabetes Prevention Program (DPP) Outcomes Study, involving 15-year follow-up of 2,776 subjects at high risk of developing diabetes, demonstrated the importance of preventing diabetes, with lifestyle playing a key role ⁸. Importantly, the prevalence of microvascular complications was 28% lower in individuals who did not develop diabetes than in those who did. Given that management of microvascular complications is associated with substantial cost, which increases as the severity of disease progresses, these findings clearly underline the importance of lifestyle intervention as a key component in preventing cardiometabolic disease and associated vascular complications.

Moreover, there are novel insights from the PREDIMED study that the Mediterranean diet not only has a beneficial effect in reducing macrovascular events in high-risk patients, but when supplemented with extra virgin olive oil, may have benefit in reducing incident retinopathy in elderly individuals with type 2 diabetes ^9,10. Over a median 6 year follow-up, a Mediterranean diet plus extra virgin olive oil reduced the risk of diabetic retinopathy by 43% in this PREDIMED cohort compared with a control, low-fat diet. In addition, there was also a 38% reduction in the risk of diabetic retinopathy with a Mediterranean diet supplemented with mixed nuts, although this effect was not statistically significant. However, neither intervention had any effect on diabetic nephropathy. While there are the typical limitations inherent with a post hoc analysis, the findings from this study make a case for consideration of the dietary profile as an additional intervention for reducing residual microvascular risk in diabetic patients.

In conclusion, this month’s featured articles make a case for consideration of interventions beyond pharmacotherapy for reducing residual vascular risk. The gut microbiome is a potential target, given evidence that this is a contributor to variation in plasma levels of triglycerides and HDL cholesterol, independent of body mass index. Moreover, lifestyle, notably a Mediterranean diet, has potential value for reducing diabetes-related microvascular outcomes, in particular diabetic retinopathy. Taken together, these findings have important public health implications for addressing the ongoing challenge of residual cardiovascular and microvascular risk.

References

1. Cannon CP, Blazing MA, Giugliano RP et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-97.
2. Sabatine MS, Giugliano RP, Wiviott SD et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500-9.
3. Robinson JG, Farnier M, Krempf M et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489-99.
4. Tremaroli V, Bäckhed F. Functional interactions between the gut microbiota and host metabolism.
Nature. 2012;489:242–9..
5. Karlsson FH, Tremaroli V, Nookaew I et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 2013;498:99–103.
6. Kau AL, Ahern PP, Griffin NW et al. Human nutrition, the gut microbiome, and immune system: envisioning the future. Nature. 2012;474:327–36.
7. Fu J, Bonder MJ, Cenit MC et al. The gut microbiome contributes to a substantial proportion of the variation in blood lipids. Circ Res 2015; DOI: 10.1161/CIRCRESAHA.115.306807.
8. Diabetes Prevention Program Research Group. Long term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol 2015; Published Online September 14, 2015.
9. Estruch R, Ros E, Salas-Salvado J et al. PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368:1279–90.
10. Diaz-Lopez A, Babio N, Mart?nez-Gonzalez MA et al. Mediterranean diet, retinopathy, nephropathy, and microvascular diabetes complications: A post hoc analysis of a randomized trial. Diabetes Care 2015; Epub ahead of print.