Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor alpha modulator for management of atherogenic dyslipidaemia.

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Term Occurence Count Dictionary
gemfibrozil 1 endocrinologydiseasesdrugs
pioglitazone 1 endocrinologydiseasesdrugs
simvastatin 1 endocrinologydiseasesdrugs
type 2 diabetes mellitus 8 endocrinologydiseases
diabetes mellitus 8 endocrinologydiseases
diabetic retinopathy 3 endocrinologydiseases
ezetimibe 1 endocrinologydiseasesdrugs
fenofibrate 22 endocrinologydiseasesdrugs
obesity 7 endocrinologydiseases

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Select Drug Character Offset Drug Term Instance
ezetimibe 3148 With Acute Coronary Syndrome: Vytorin Ezetimibe/Simvastatin) vs Simvastatin (IMPROVE-IT) trial with ezetimibe [[9]], and the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated
fenofibrate 13153 PPARα. Indeed, there was early evidence for this as regulation of human apoA-I by gemfibrozil and fenofibrate was mediated by selective modulation of PPARα [[40]]. From the clinical perspective, the development
fenofibrate 14216 pemafibrate was shown to be > 2500-fold more potent than fenofibric acid, the active metabolite of fenofibrate , for human PPARα with > 5000-fold greater activity for PPARα than either PPARγ or δ [[42]].Fig. 2Structure
fenofibrate 15341 Anti-inflammatory effects were observed in human umbilical vein endothelial cells with pemafibrate 0.1 μM whereas fenofibrate at concentrations up to 10 μM had no effect [[44], [45]].Other important differences were evident.
fenofibrate 16910 pharmacological profile of pemafibrate, showing enhanced TG lowering and elevation in HDL-C levels compared with fenofibrate . In a rat model of hypertriglyceridaemia, the effect of pemafibrate 3 mg/kg on TG lowering was significantly
fenofibrate 17072 effect of pemafibrate 3 mg/kg on TG lowering was significantly greater (by about 2-fold) compared with fenofibrate (300 mg/kg), and was also accompanied by a greater increase in plasma levels of FGF21 (Data presented
fenofibrate 17977 pemafibrate to transgenic apoE2 mice led to more pronounced HDL-C elevation at a 100-fold lower dose than fenofibrate (1 mg/kg versus 100 mg/kg) [Data presented at the 80th European Atherosclerosis Society Congress.
fenofibrate 18438 lesion burden in Western diet-fed apoE2KI mice compared with control; in contrast, the effect with fenofibrate was not statistically significant (Fig. 3) [[55]]. There was also evidence that the potent anti-inflammatory
fenofibrate 18909 transgenic mice. ApoE2KI mice were fed a Western diet and treated with pemafibrate (0.1 or 1 mg/kg), fenofibrate (250 mg/kg) or control (carboxy methyl cellulose) daily and were sacrificed after 10 weeks. The left
fenofibrate 21234 placebo but although numerically larger, did not differ significantly from those observed with micronized fenofibrate capsules 100 mg/day (Table 1, Fig. 4). Lipoprotein analysis showed that the increase in HDL-C levels
fenofibrate 21937 highest doses (0.2 and 0.4 mg/day), reduction in VLDL-cholesterol was significantly greater than with fenofibrate 100 mg/day (44 and 48%, versus 26%, respectively) (Table 2) [[56]]. While there was a slight increase
fenofibrate 22408 and apoAII (by 9% and 30%, respectively with pemafibrate 0.2 mg twice daily versus 6 and 20% with fenofibrate 100 mg/day) [[56]].Table 1Summary efficacy data from published Phase II trials with pemafibrateCitation
fenofibrate 24792 (HDL-C) (bottom panel) after 12 weeks treatment with pemafibrate (0.05, 0.1, 0.2 or 0.4 mg/day), fenofibrate (100 mg/day) or placebo in patients with elevated TG (≥ 200 mg/dL or 2.3 mmol/L) and low HDL-C(Adapted
fenofibrate 26849 p < 0.05, †† p < 0.01, ††† p < 0.001Figures in italics: significantly different from fenofibrate p < 0.01aMeasured by ultracentrifugationThe TG-lowering effects of pemafibrate were confirmed in combined
fenofibrate 27175 doses of pemafibrate (0.1, 0.2 or 0.4 mg) resulted in significantly greater reduction in TGs than fenofibrate 100 mg/day (by 45–52% versus 38%, p < 0.01), although the response was similar to fenofibrate 200 mg
fenofibrate 27274 fenofibrate 100 mg/day (by 45–52% versus 38%, p < 0.01), although the response was similar to fenofibrate 200 mg daily (decrease by 51%) [[57]]. Taken together, these findings suggest that pemafibrate has
fenofibrate 28726 pemafibrate 0.1–0.4 mg/day for 12 weeks compared with placebo, whereas no effect was observed with fenofibrate 100 mg/day [[56], [58]]. Taken together, these findings suggest that pemafibrate may have important
fenofibrate 31270 was well tolerated, with adverse event rates similar to or lower than those reported for placebo or fenofibrate . Notably, pemafibrate was associated with a lower rate of abnormal liver function tests compared with
fenofibrate 31384 Notably, pemafibrate was associated with a lower rate of abnormal liver function tests compared with fenofibrate ; only one patient discontinued due to this event compared with 3 and 11 patients allocated fenofibrate
fenofibrate 31487 fenofibrate; only one patient discontinued due to this event compared with 3 and 11 patients allocated fenofibrate 100 mg and 200 mg, respectively.Importantly, the available safety data show that treatment with pemafibrate
fenofibrate 31847 estimated glomerular filtration rate (eGFR), whereas a significant decline in eGFR was observed with fenofibrate treatment over 12 weeks (p < 0.001) [[57]], consistent with previous findings from both the Fenofibrate
fenofibrate 33637 mellitus. Both the FIELD and ACCORD Lipid trials have failed to provide definitive answers with the use of fenofibrate , largely due to methodological reasons. The FIELD trial was initiated before statin use was considered
fenofibrate 36444 microvascular complications of type 2 diabetes, notably diabetic retinopathy, previously reported for fenofibrate [[72], [73]], merit investigation. While the pathogenesis of diabetic retinopathy is still incompletely
gemfibrozil 13137 been recognized for PPARα. Indeed, there was early evidence for this as regulation of human apoA-I by gemfibrozil and fenofibrate was mediated by selective modulation of PPARα [[40]]. From the clinical perspective,
pioglitazone 12930 MK0533, have been shown in preclinical studies to exhibit at least comparable antidiabetic effects to pioglitazone but with an improved adverse event profile [[23], [38], [39]]. The SPPARM concept has also been recognized
simvastatin 34195 low HDL-C and elevated triglycerides) [[66]]. While in ACCORD Lipid all patients received concomitant simvastatin treatment, and the study population was at higher cardiovascular risk than in FIELD (37% had previous
Select Disease Character Offset Disease Term Instance
diabetes mellitus 721 contributor to lipid-related residual risk, especially in insulin resistant conditions such as type 2 diabetes mellitus . Current therapeutic options include peroxisome proliferator-activated receptor alpha (PPARα) agonists,
diabetes mellitus 3788 in small dense LDL particle numbers, typically seen in insulin resistant conditions such as type 2 diabetes mellitus , as a contributor to lipid-related residual cardiovascular risk, as well as the risk of silent coronary
diabetes mellitus 20243 date, over 2300 patients, the majority with dyslipidaemia and over one-quarter with concomitant type 2 diabetes mellitus , have been studied [Data on file, Kowa Company, Ltd.]. Key published trials are summarised in Table 2.
diabetes mellitus 24151 high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, TG triglycerides, T2DM type 2 diabetes mellitus ** p < 0.01, *** p < 0.001 versus controlaTG ≥ 2.3 mmol/L (200 mg/dL) and low HDL-CbTG 1.9–5.7 mmol/L
diabetes mellitus 30193 36%, and plasma HDL-C concentration was increased by 13%. Post hoc analysis in patients with type 2 diabetes mellitus at baseline showed improved lipid-modifying efficacy with pemafibrate, with reduction in TGs by up to
diabetes mellitus 32282 were considered clinically negligible or not associated with treatment, even in patients with type 2 diabetes mellitus at baseline. A small increase in serum homocysteine levels (by 2.4 μmol/L) was noted at a dose of
diabetes mellitus 33521 in statin-treated patients with atherogenic dyslipidaemia, especially those with concomitant type 2 diabetes mellitus . Both the FIELD and ACCORD Lipid trials have failed to provide definitive answers with the use of fenofibrate,
diabetes mellitus 34696 triglycerides IN diabetic patiENTs) has been initiated. This study aims to recruit 10,000 patients with type 2 diabetes mellitus and elevated TGs (≥ 200 mg/dL or 2.3 mmol/L and < 500 mg/dL (5.7 mmol/L) and low HDL-C (≤ 40 mg/dL
diabetic retinopathy 36398 [[71]].Finally, potential benefits of pemafibrate on microvascular complications of type 2 diabetes, notably diabetic retinopathy , previously reported for fenofibrate [[72], [73]], merit investigation. While the pathogenesis of diabetic
diabetic retinopathy 36517 retinopathy, previously reported for fenofibrate [[72], [73]], merit investigation. While the pathogenesis of diabetic retinopathy is still incompletely understood, evidence suggests a role for diabetes-induced down-regulation of PPARα
diabetic retinopathy 38477 possible role for pemafibrate in the management of microvascular complications of diabetes, notably diabetic retinopathy , as well as in NAFLD, may be merited. A novel approach to addressing residual cardiovascular risk may
obesity 2246 middle-income countries have a growing burden of CVD mortality and disability, driven by increasing rates of obesity , diabetes and dyslipidaemia [[1]–[3]]. Indeed, with the exception of the USA, the top 10 countries
obesity 5449 remnant cholesterol has been implicated as a contributor to the increased CVD risk associated with obesity [[20]]. These findings have prompted a rethink of the role of lipid targets beyond LDL-C, with for example,
obesity 7107 more so in individuals with baseline hypertriglyceridaemia [[28]].With escalating rates of diabetes, obesity and CVD, especially in developing regions, management of atherogenic dyslipidaemia, as well as metabolic
obesity 10911 inflammatory genes of monocytes and macrophages [[23], [32], [33]]. PPARα is therefore at the cross-roads of obesity , diabetes and CVD, and thus a logical target for therapeutic intervention. In contrast, PPARγ targets
obesity 11048 logical target for therapeutic intervention. In contrast, PPARγ targets include genes involved in obesity and insulin resistance, and thus regulates adipogenesis and glucose homeostasis.PPARs possess a large
obesity 16253 fatty liver disease (NAFLD), given that FGF21 decreases TGs, improves insulin sensitivity and counters obesity by suppressing weight gain, the major risk factor for NAFLD [[49], [51]]. These findings implicate a
obesity 37336 complication.ConclusionsAtherogenic dyslipidaemia, prevalent among patients with type 2 diabetes and obesity , is a contributor to lipid-related residual cardiovascular risk. Accumulating evidence has led to renewed
type 2 diabetes mellitus 714 important contributor to lipid-related residual risk, especially in insulin resistant conditions such as type 2 diabetes mellitus . Current therapeutic options include peroxisome proliferator-activated receptor alpha (PPARα) agonists,
type 2 diabetes mellitus 3781 increase in small dense LDL particle numbers, typically seen in insulin resistant conditions such as type 2 diabetes mellitus , as a contributor to lipid-related residual cardiovascular risk, as well as the risk of silent coronary
type 2 diabetes mellitus 20236 To date, over 2300 patients, the majority with dyslipidaemia and over one-quarter with concomitant type 2 diabetes mellitus , have been studied [Data on file, Kowa Company, Ltd.]. Key published trials are summarised in Table 2.
type 2 diabetes mellitus 24144 high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, TG triglycerides, T2DM type 2 diabetes mellitus ** p < 0.01, *** p < 0.001 versus controlaTG ≥ 2.3 mmol/L (200 mg/dL) and low HDL-CbTG 1.9–5.7 mmol/L
type 2 diabetes mellitus 30186 apoCIII by 36%, and plasma HDL-C concentration was increased by 13%. Post hoc analysis in patients with type 2 diabetes mellitus at baseline showed improved lipid-modifying efficacy with pemafibrate, with reduction in TGs by up to
type 2 diabetes mellitus 32275 pemafibrate were considered clinically negligible or not associated with treatment, even in patients with type 2 diabetes mellitus at baseline. A small increase in serum homocysteine levels (by 2.4 μmol/L) was noted at a dose of
type 2 diabetes mellitus 33514 persists in statin-treated patients with atherogenic dyslipidaemia, especially those with concomitant type 2 diabetes mellitus . Both the FIELD and ACCORD Lipid trials have failed to provide definitive answers with the use of fenofibrate,
type 2 diabetes mellitus 34689 triglycerides IN diabetic patiENTs) has been initiated. This study aims to recruit 10,000 patients with type 2 diabetes mellitus and elevated TGs (≥ 200 mg/dL or 2.3 mmol/L and < 500 mg/dL (5.7 mmol/L) and low HDL-C (≤ 40 mg/dL

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