R3i Editorial

The Residual Risk Reduction Initiative (R3i) has led the field in highlighting the importance of residual vascular risk ^1,2. This risk encompasses both macrovascular and microvascular residual risk, the latter highly relevant to the management of diabetic microvascular complications such as retinopathy, nephropathy and amputation due to lower extremity complications which confer substantial burden of disease. With residual vascular risk now established in the lexicon of the clinical community ³, it is an opportune time to take a step back and review what we know – and need to know – about contributors to this risk.

Much of the focus is on residual cardiovascular risk, specifically identifying the contributors to this risk, beyond low-density lipoprotein cholesterol (LDL-C). Atherogenic dyslipidemia, characterised by elevated plasma triglycerides (TG), low plasma concentration of high-density lipoprotein cholesterol (HDL-C) and a preponderance of small, dense LDL particles, is present among 10-15% of high-risk individuals, especially those with type 2 diabetes mellitus ^4-6 While early attention focused on HDL-C, given that low plasma HDL-C concentration is a marker of cardiovascular risk and included in SCORE risk assessment ⁷, the failure of outcomes studies of novel HDL-targeted therapies, and lack of association demonstrated in genetic studies ², turned the tide in favour of TG. It is, however, important to note that TG are a surrogate for the likely culprits – TG-rich lipoproteins and their remnants, often measured using remnant cholesterol ⁸.

Establishing causality for TG (or TG-rich lipoproteins and their remnants) is challenging given that TG-related metabolism is more complex than that of LDL. There have also been difficulties with cardiovascular outcomes studies, specifically in recruiting patients with sufficiently elevated TG, against a background of well-controlled LDL-C levels, as exemplified by ACCORD Lipid ⁶. Despite these obstacles, there is accumulating evidence that TG-rich lipoproteins play a role in the causal pathway of atherosclerotic cardiovascular disease ⁹. Genetic studies evaluating variants affecting the expression of different proteins involved in the regulation of TG levels have provided critical support (10), as well as driving the development of novel therapeutic strategies for managing hypertriglyceridemia.

Key questions remain, notably in defining the level at which elevated TG become clinically relevant. On this point, recent insights from the PESA (Progression of Early Subclinical Atherosclerosis) Study are informative, showing increased incident subclinical atherosclerosis from a TG level of 150 mg/dL (1.7 mmol/L), as discussed in this month’s Focus ¹¹. Guidelines have, however, not defined a goal for TG due to insufficient evidence from cardiovascular outcomes studies that lowering elevated TG, against a background of well-controlled LDL-C levels, reduces cardiovascular events ⁷. PROMINENT (Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patients With diabetes) will be pivotal to resolving this uncertainty ¹².

Beyond TG, there are other contributors to residual cardiovascular risk. There is clearly a role for targeting residual inflammatory risk, which affects up to 25% of high-risk individuals, as demonstrated by the proof-of-concept CANTOS (Canakinumab Antiinflammatory Thrombosis Outcome Study) ^13,14. Residual thrombotic risk is another consideration, supported by the COMPASS trial (Cardiovascular Outcomes for People using Anticoagulation Strategies), in which low dose rivaroxaban plus aspirin significantly reduced cardiovascular events and major adverse limb events in patients with stable atherosclerotic cardiovascular disease ¹⁵. Other lipoproteins and lipids may be implicated; lipoprotein(a) is one potential contributor, currently being evaluated in the HORIZON trial.

Finally, further study of contributors to residual microvascular risk is urgently needed, against the escalating pandemic of obesity and type 2 diabetes mellitus. Plasma TG may be relevant to diabetic kidney disease, and possibly retinopathy ¹⁶. Understanding the underlying molecular mechanisms is essential. For example, emerging evidence implicates a role for dysregulation of long non-coding RNAs in modulating the expression of key inflammatory genes and fibrotic genes associated with diabetic vascular complications, which may offer direction for future therapeutic innovation ¹⁷.

We face ongoing challenges to reduce the high residual vascular risk that persists despite best evidence-based treatment. The burden of cardiovascular disease and microvascular diabetic complications continues to escalate globally, especially among lower- and middle-income countries. The R3i will continue its mission to educate and advocate to reduce residual vascular risk.

References

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