SPPARM alpha: the Lazarus effect

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 (SPPARM alpha) paradigm offers potential for improving potency, selectivity and the benefit-risk profile. Recent findings The present review discusses evidence for the novel SPPARM alpha 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 SPPARMa concept by validating reduction in residual cardiovascular risk in patients with T2DM and long-term safety. Summary SPPARM alpha offers a new paradigm for reducing residual cardiovascular risk in T2DM. PROMINENT will be critical to differentiating the first SPPARMa, pemafibrate, as a novel therapeutic class distinct from current fibrates.