Preamble: why we need this consensus
Box 1. Search strategy and selection criteria
Residual vascular risk: a key therapeutic concept
Population | Elevated triglycerides (TG) | Atherogenic dyslipidemia | ||
---|---|---|---|---|
Criterion | Prevalence | Criteria | Prevalence | |
General populations | ||||
Europe [26] | > 2.2 mmol/L | 23.0% (8316/36,160) | TG > 2.2 mmol/L + HDL-C < 1.0 mmol/L (treatment not specified) | 6.0% (2169/36,160) |
On statin [26] | > 2.2 mmol/L | 30.0% (10,848/36,160) | ||
Not on statin | ≥ 2.26 mmol/L | 11.9% (21.5 M/181.0 M)* | TG ≥ 2.26 mmol/L + HDL-C < 1.0 mmol/L (treatment not specified) | 6.6% (13.1 M/199.1 M)* |
On statin | ≥ 2.26 mmol/L | 15.4% (6.0 M/38.9 M)* | ||
High risk populations | ||||
Primary prevention + risk factors [31] | ≥ 2.3 mmol/L | 20.8% (1591/7641) | Elevated TG + HDL-C < 1.0 mmol/L | 9.9% (759/7641) |
With T2DM [31] | ≥ 2.3 mmol/L | 27.5% (562/2046) | Elevated TG + HDL-C < 1.0 mmol/L | 14.9% (305/2046) |
> 1.7 mmol/L | 34.7% (2938/8467) | TG > 2.0 mmol/L + HDL-C < 1.0 mmol/L in men, < 1.2 mmol/L in women | 13–14%** |
Atherogenic dyslipidemia and cardiometabolic risk
Which is the risk factor: triglycerides or triglyceride-rich lipoproteins?
Triglyceride-rich lipoproteins, remnants and ASCVD
Insights from Mendelian randomization and genetic studies
Insights from trials of TG-lowering therapies
PPARα: the nuclear receptor ‘hub’ for TG-rich lipoprotein metabolism
In summary, PPARα is the nuclear receptor ‘hub’ for transcriptional regulation of lipoprotein metabolism and vascular inflammation. Conformational changes induced by binding of a ligand (either endogenous or synthetic) to PPARα facilitate the recruitment of a specific profile of cofactors, which either promote or repress expression of target genes involved in key metabolic pathways. |
Defining the SPPARMα concept
In summary, binding interactions between the ligand and the PPARα receptor modulate the receptor–cofactor binding profile; this rationale underpins the SPPARMα concept. |
Differentiating SPPARMα and PPARα agonists: pharmacology
SPPARMα in pre-clinical studies
In summary, preclinical studies have revealed that enhanced potency, selectivity and cofactor binding profile differentiate this novel SPPARMα agent from traditional non-selective PPARα agonists. Clinically relevant genes regulated by this SPPARMα agonist include those involved in regulation of lipoprotein metabolism, such as VLDLR and ABCA1, inflammation, the innate immune system (MBL2) and energy metabolism (FGF21). In preclinical studies, this SPPARMα activator had lipid modifying and anti-inflammatory effects, as well as regulatory effects in glucose homeostasis and liver dysfunction. |
Differentiating SPPARMα and PPARα agonists: clinical trial evidence
Efficacy
Citation | Patients | Treatment daily dose (mg) and duration | Key findings |
---|---|---|---|
Ishibashi [132] Phase II | N = 224 with high TG + low HDL-Ca | Pemafibrate 0.05, 0.1, 0.2, 0.4 Fenofibrate 100 Placebo 12 weeks | LS mean [SE] percent changes from baseline to 12 weeks (pemafibrate 0.4 vs. fenofibrate) Decrease in TG: 42.7 [6.7]% vs. 29.7 [6.7]% Increase in HDL-C: 21.0 [2.8]% vs. 14.3 [2.8]% LS mean [SD] percent decrease (pemafibrate 0.4 vs. fenofibrate) VLDL-C: 48.4 [27.5]% vs. 25.8 [29.7]%** Remnant-C: 50.1 [31.8]% vs. 31.8 [35.0]% Apo C-III: 33.4 [19.2]% vs. 27.2 [18.9]% Increase in FGF21 (pemafibrate vs. fenofibrate)*** The incidence of adverse events with pemafibrate, fenofibrate or placebo was similar Conclusion: In dyslipidemic patients with high TG and low HDL–C, pemafibrate improved TG, HDL-C, and other lipid parameters without increasing adverse events, compared to placebo and fenofibrate |
Ishibashi [134] Phase III | N = 225 with high TG and low HDL-Cb | Pemafibrate 0.2, 0.4 vs. Fenofibrate 106.6 24 weeks | LS mean [SE] reduction from baseline to 24 weeks in TG: 46.2 [2.0]% with pemafibrate 0.2 and 45.9 [1.9]% with 0.4 vs. 39.7 [1.9]% with fenofibrate* At 24 weeks, significant ↓ALT** and GGT** with pemafibrate compared with fenofibrate Conclusion: Pemafibrate was superior to fenofibrate in terms of serum TG-lowering effect and hepatic and renal safety |
Arai [133] Phase III | N = 526 with high TG and low HDL-Ca | Pemafibrate 0.1, 0.2, 0.4 Fenofibrate 100, 200 vs. placebo 12 weeks | Non-inferior LS mean [SE] decrease in TG vs. fenofibrate 200: 46.7 [1.6]% with pemafibrate 0.2 and 51.8 [2.0]% with 0.4 vs. 51.5 [1.6]% No dose-dependent increase in adverse events with pemafibrate The incidence of adverse events for all pemafibrate doses was similar to that for placebo and fenofibrate 100 and significantly lower than fenofibrate 200 mg* Conclusion: The favorable safety profile of pemafibrate, with fewer adverse effects on kidney/liver-related tests and fewer adverse events over fenofibrate 200 mg/day, may justify the use of this novel and potent treatment option for reducing TG in a broader range of patients |
Arai [135] Phase III | 2 trials, dyslipidemia on statin therapy Trial Ac: N = 188 Trial Bd: N = 423 | Trial A Pemafibrate 0.1, 0.2, 0.4 vs. placebo 12 weeks Trial B Pemafibrate: 0.2, 0.2/0.4g vs. placebo 24 weeks | Trial A LS mean [SE] decrease in TG at 12 weeks: 53.4 [3.8]% with pemafibrate 0.2, 52.0 [3.9]% with 0.4 vs. 6.9 [4.0]% with placebo, p < 0.001 Trial B LS mean [SE] decrease in TG at 24 weeks: 46.8 [2.6]% with pemafibrate 0.2, 50.8 [2.5]% with 0.2/0.4 vs. 0.8 [3.0]% with placebo, p < 0.001 34% of patients were titrated to the higher dose In both trials, pemafibrate ameliorated the atherogenic lipoprotein profiles, i.e. ↓small LDL, ↑ larger LDL and ↓larger HDL, ↑ small HDL Conclusion: These results strongly support the favourable benefit-to-risk ratio of pemafibrate add-on therapy in combination with statin treatment |
Araki [136] Phase III | N = 166, T2DM with high TGe | Pemafibrate 0.2, 0.4 vs. placebo 24 weeks | LS mean reductions with pemafibrate vs. placebo TG: 44.3% with 0.2, 45.1% with 0.4 vs. 10.8%, p < 0.001 Non-HDL-C 6.3% and 12.5%, remnant-C 45.7% and 49.2%, apo B100 9.1% with 0.2 mg, apo B48 43.7% and 50.6%, and apo C-III 32.5% and 34.0%, all p < 0.001 HOMA-insulin resistance score with 0.2 mg, p < 0.05 Both pemafibrate doses significantly ↑ FGF21, p < 0.001 Conclusion: Pemafibrate significantly ameliorated lipid abnormalities and was well tolerated in patients with T2DM with hypertriglyceridemia |
Yamashita [137] | N = 33 with atherogenic dyslipidemiaf | Crossover study, pemafibrate 0.4 or placebo Each period was 4 weeks | Significant (p < 0.001) mean percent LS [SE] changes with pemafibrate vs. placebo Decreases in TG (39.8 [19.4]% vs. increase of 22.5 [36.0]%), non-HDL-C (12.0 [19.9]% vs. increase of 3.5 [12.6]), remnant-C (50.6 [24.5]%), vs. increase of 17.5 [35.6]%, and apo C-III (31.3 [20.1]% vs. increase of 11.6 [28.3]%) Increases in HDL-C (16.1 [15.0]% vs. decrease 1.4 [10.6]%), apo A–I (8.3 [9.1]% vs. 1.3 [9.8]%) and apo A-II (38.2 [17.4]% vs. 5.5 [12.6]%) Pemafibrate significantly increased FGF21 (p < 0.001), and decreased hsCRP and serum amyloid A (p < 0.01) vs. baseline Pemafibrate improved postprandial hyperlipidemia Pemafibrate improved HDL quality (macrophage cholesterol efflux capacity) and increased preβ1 HDL and HDL3 Conclusion: Pemafibrate enhances reverse cholesterol transport and may retard the progression and even promote the regression of atherosclerosis by comprehensively ameliorating the atherogenic lipid profile |
Safety
Clinical trials support the SPPARMα concept, showing robust and sustained reduction of TG-rich lipoproteins in patients with atherogenic dyslipidemia, with or without T2DM. The risk versus benefit profile so far is also encouraging, especially the lack of any effect on serum creatinine during treatment, although longer-term safety data are needed. |