R3i Publications

Purpose of Review
Chronic kidney disease (CKD) poses a major global challenge, which is exacerbated by aging populations and the pandemic of type 2 diabetes mellitus. Much of the escalating burden of CKD is due to cardiovascular complications. Current treatment guidelines for dyslipidemia in CKD prioritize low-density lipoprotein cholesterol management, but still leave a high residual cardiovascular risk. Targeting elevated triglycerides and low plasma high-density lipoprotein cholesterol, a com- mon feature of CKD, could offer additional benefit. There are, however, safety issues with current fibrates (peroxisome proliferator–activated receptor alpha [PPARα] agonists), notably the propensity for elevation in serum creatinine, indicating the need for new approaches.
 
Recent Findings
Interactions between the ligand and PPARα receptor influence the specificity and potency of receptor binding, and downstream gene and physiological effects. The peroxisome proliferator–activated receptor alpha modulator (SPPARMα) concept aims to modulate the ligand structure so as to enhance binding at the PPARα receptor, thereby improving the ligand’s selectivity, potency, and safety profile. This concept has led to the development of pemafibrate, a novel SPPARMα agent. This review discusses evidence that differentiates pemafibrate from current fibrates, especially the lack of evidence for elevation in serum creatinine or worsening of renal function in high-risk patients, including those with CKD.
 
Summary
Differentiation of pemafibrate from current fibrates aims to address unmet clinical needs in CKD. The ongoing PROMINENT study will provide critical information regarding the long-term efficacy and safety of pemafibrate in patients with type 2 diabetes mellitus, including those with CKD, and whether the favorable lipid-modifying profile translates to reduction in residual cardiovascular risk.
 

Clinicians need to consider other targets to reduce residual cardiovascular risk in diabetes. The SPPARMα concept is a leading contender, offering the opportunity to act at multiple targets relevant to vascular risk.
 
Even with best guideline-recommended treatment, patients with diabetes continue to experience cardiovascular events. This high residual cardiovascular risk is an urgent unmet clinical need. We need to intervene against other targets, especially high triglycerides that are common in these patients.
 
A key contender to overcoming this enigma is PPARα, which controls key metabolic and inflammatory pathways. But current fibrates are not the answer; these did not definitively reduce cardiovascular events against a background of statin treatment, and may have safety issues.
 
One approach to tackling this high residual cardiovascular risk in diabetes patients is the SPPARMα concept. This concept has been a catalyst for the development of a novel SPPARMα agent, pemafibrate, which acts at multiple targets relevant to vascular risk. Will pemafibrate be the key to reducing residual cardiovascular risk? The answer lies in PROMINENT.
 

Over 50 internationally renowned clinical and scientific experts came together to discuss the SPPARMα concept and its therapeutic potential for addressing residual vascular risk. This landmark paper provides the essentials for clinicians.
 
Atherogenic dyslipidemia remains the enigma for clinicians in this era of precision medicine. It is clear that we need new treatments to target this dyslipidemia, characterised by elevated plasma triglycerides with or without low levels of high-density lipoprotein cholesterol, that is common in high risk patients, especially those with type 2 diabetes mellitus. The development of selective peroxisome proliferator- activated receptor α modulators (SPPARMα) offers an approach to address this treatment gap.
 
This Joint Consensus of the R3i and the International Atherosclerosis Society, comprising over 50 world- leading experts, reviewed the evidence for the first SPPARMα agonist, pemafibrate. This expert consensus concluded that pemafibrate represents a novel therapeutic class, distinct from fibrates, based on pharmacological activity, and, importantly, a safe hepatic and renal profile. The ultimate answer lies with the PROMINENT cardiovascular outcomes trial with pemafibrate in 10,000 very high-risk patients with type 2 diabetes mellitus and atherogenic dyslipidemia.
 

SPPARMaα – a revival of the fibrates or a new drug class?
 
Atherogenic dyslipidemia, elevated triglycerides with or without low HDL cholesterol, has been previously overlooked as a contributor to residual cardiovascular risk. In part, this was because clinical studies with the fibrates, PPARα agonists, did not conclusively show that targeting this dyslipidemia, against a background of statin treatment, reduces cardiovascular events. Some also had safety issues.
 
This review discusses the evidence for the SPPARMα concept and its therapeutic application, with pemafibrate. Clinical trials to date have indicated a favourable benefit vs. risk profile, especially with the lack of elevation in serum creatinine, evident with fenofibrate, and improved renal and hepatic safety. The cardiovascular outcomes study PROMINENT will be critical to validating the SPPARMαconcept as an approach to reducing residual cardiovascular risk.
 

Microvascular complications associated with type 2 diabetes, including diabetic retinopathy, nephropathy and neuropathy, account for much of the societal burden of diabetes. Even with effective multifactorial intervention, targeting glycemia, blood pressure and lowdensity lipoprotein cholesterol, in addition to lifestyle intervention, a high residual microvascular risk persists. The Residual Risk Reduction Initiative (R3i) highlights two key priorities for reducing this residual risk. First, there should be optimal management of cardiometabolic risk factors, including atherogenic dyslipidemia, elevated triglycerides and low plasma high-density lipoprotein cholesterol, to improve lipid goal attainment. Second, consistent evidence from two major trials may merit consideration of adjunctive fenofibrate therapy to slow progression of diabetic retinopathy in type 2 diabetes patients with pre-existing disease. These data provide a strong rationale for testing in a prospective study. The R3i strongly believes that addressing both priorities is critical to reducing the substantial residual risk of microvascular complications in type 2 diabetes.
 

The International Steering Committee of the Residual Risk Reduction Initiative (R3i), comprising 40 leading specialists from North and South America, Europe, the Middle East, Asia and Japan, has today highlighted priorities for action against atherogenic dyslipidaemia, an important contributor to lipid-related residual cardiovascular risk. The R3i defines atherogenic dyslipidaemia as the imbalance between triglyceride-rich apolipoprotein B-containing-lipoproteins, for which triglycerides are a marker, and apolipoprotein A-I-lipoproteins (as in high-density lipoprotein, HDL).   The R3i has identified three key priorities: • To improve recognition of atherogenic dyslipidaemia in high risk patients, including those with diabetes • To target atherogenic dyslipidaemia, using non-HDL cholesterol (total cholesterol – HDL cholesterol) for treatment decisions • To improve management of atherogenic dyslipidaemia, and adherence to guideline-recommended therapies. The addition of a fibrate, niacin (North and South America), omega-3 fatty acids or ezetimibe to statin therapy are all approaches to reduce non-HDL cholesterol.   The R3i recognises that there is a need for new treatment options that can more effectively target atherogenic dyslipidaemia, and reviews future possibilities in this paper. This paper will have important implications for the routine management of patients who remain at high residual cardiovascular risk despite well controlled low-density lipoprotein (LDL) cholesterol levels
 

 

This ancillary study evaluated postprandial lipaemia after an oral fat test in a subgroup of patients in the ACCORD Lipid study. Fenofibrate treatment reduced postprandial exposure to atherogenic apolipoprotein B48 only in patients with elevated fasting triglycerides at baseline. This suggests that fenofibrate improves clearance of atherogenic triglyceride-rich remnant lipoproteins and reduces residual macrovascular risk in type 2 diabetes patients, only if fasting levels are sufficiently increased at baseline.
 

The author reminds the physiology and roles of PCSK9, notably in the regulation of LDL-C levels through its ability to target the LDL-C receptor. Then, he describes the way statins and fibrates, notably fenofibrate, act on PCSK9. Finally, he concludes that the existing data (1) provide a functional rationale for the combination of fenofibrate with a statin for optimizing LDL-C lowering efficacy, (2) suggest that PSCK9 may be a potential target in patients with type 2 diabetes or metabolic syndrome, opening new approaches that could impact the substantial residual cardiovascular risk that exists in statin-treated patients.
 

This review, based on 25 studies including 54,117 patients highlights the association between micro- and macrovascular disease in type 2 diabetes, underlining the importance of early detection of microangiopathy for vascular risk assessment in type 2 diabetes.
 

Discussing the ACCORD Lipid study results, this commentary concludes that they suggest that dyslipidemia management in type 2 diabetes requires a targeted approach based on the lipid profile of individual patients. In particular, in statin-treated patients with atherogenic dyslipidemia, adding fenofibrate can provide additional reduction in cardiovascular risk.
 

To assess the non-LDL-C-related dyslipidaemia risk of MI, 823 men aged 23 to 65 with a first MI were compared with 823 MI-free PROCAM controls matched for sex, age, smoking, DM, BP and LDL-C. This case-control study has two main findings: first, dyslipidemia is associated with the greatest increase in relative risk of MI in persons with low levels of LDL-C; second, low HDL-C makes a greater contribution to MI risk than do high TG once other conventional MI risk factors are accounted for.
 

Based on a meta-analysis of 5 trials (FIELD, BIP, HHS, VA-HIT and ACCORD), the authors conclude that fibrate treatment reduces coronary heart disease events among patients with dyslipidemia.
 

In this review, the authors highlight an urgent need to address the residual microvascular risk that remains high in patients with type 2 diabetes mellitus even if they receive optimal management according to current standards of care. They also conclude that correction of atherogenic dyslipidemia might provide additional benefit.
 

The Residual Risk Reduction Initiative: A call to action to reduce residual vascular risk in dyslipidemic patients