SPPARM alpha: the Lazarus effect

Abstract

Purpose of review Atherogenic dyslipidaemia, characterized by high plasma triglycerides (a surrogate for triglyceride-rich remnant lipoproteins) and low high-density lipoprotein cholesterol (HDL-C), is prevalent in patients with type 2 diabetes mellitus (T2DM) and contributes to a high modifiable residual cardiovascular risk. Fibrates are effective in managing hypertriglyceridaemia but lack consistent cardiovascular benefit in clinical trials and exhibit pharmacokinetic interaction with statins (gemfibrozil) and renal and hepatic safety issues (fenofibrate). The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm offers potential for improving potency, selectivity and the benefit-risk profile. Recent findings The present review discusses evidence for the novel SPPARMα agonist, pemafibrate. Clinical trials showed robust lowering of triglyceride-rich lipoproteins, elevation in HDL-C and nonlipid beneficial effects including anti-inflammatory activity. There was a favourable safety profile, with no increase in serum creatinine, evident with fenofibrate, and improved renal and hepatic safety. The cardiovascular outcomes study PROMINENT is critical to confirming the SPPARMα concept by validating reduction in residual cardiovascular risk in patients with T2DM and long-term safety. Summary SPPARMα offers a new paradigm for reducing residual cardiovascular risk in T2DM. PROMINENT will be critical to differentiating the first SPPARMα, pemafibrate, as a novel therapeutic class distinct from current fibrates.

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“…In 2014 Fruchart et al introduced the R3I that had to find out how to treat atherogenic dyslipidemia ( 10 ). This R3I group introduced therapy of atherogenic dyslipidemia with selective PPAR-α modulators (SPPARα), such as pemafibrate ( 55 ). In 2015, the PPARα/γ agonist, saroglitazar, was reported to be of substantial benefit for patients with atherogenic dyslipidemia and/or diabetes ( 56 ), and in 2017 therapy with statin plus K-877 (pemafibrate) was advocated as therapy with a favorable benefit-to-risk ratio ( 57 ).…”

“…In 2015, the PPARα/γ agonist, saroglitazar, was reported to be of substantial benefit for patients with atherogenic dyslipidemia and/or diabetes ( 56 ), and in 2017 therapy with statin plus K-877 (pemafibrate) was advocated as therapy with a favorable benefit-to-risk ratio ( 57 ). The PROMINENT study was performed with pemafibrate in patients with HTG and T2DM and close to/on target LDL-c levels, but was stopped in April 2022 for reasons of futility ( 55 ). While pemafibrate successfully decreased TGRLs and their remnants, it led to an opposing outcome of elevated LDL-C and ApoB levels.…”

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“… [132] A CVD outcome study of a selective peroxisome proliferator-activated receptor alpha modulator (pemafibrate) is ongoing, with an entry criteria being patients with diabetes mellitus having hypertriglyceridemia and low HDL-C levels. [133 , 134] Sentinel Guidelines and References 2020 Handelsman Y. Consensus Statement By The American Association Of Clinical Endocrinologists And American College Of Endocrinology On The Management Of Dyslipidemia And Prevention Of Cardiovascular Disease [116] 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines [6] 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.…”

“… [132] A CVD outcome study of a selective peroxisome proliferator-activated receptor alpha modulator (pemafibrate) is ongoing, with an entry criteria being patients with diabetes mellitus having hypertriglyceridemia and low HDL-C levels. [133 , 134] …”