PPAR Agonists and Metabolic Syndrome: An Established Role?

Existing Reviews

Please note, new claims can take a short while to show up.

No claims yet.

Annotation Summary

Term Occurence Count Dictionary
atorvastatin 1 endocrinologydiseasesdrugs
ezetimibe 1 endocrinologydiseasesdrugs
gemfibrozil 1 endocrinologydiseasesdrugs
pioglitazone 18 endocrinologydiseasesdrugs
type 2 diabetes mellitus 1 endocrinologydiseases
bezafibrate 2 endocrinologydiseasesdrugs
rosiglitazone 2 endocrinologydiseasesdrugs
rosuvastatin 1 endocrinologydiseasesdrugs
mixed hyperlipidemia 1 endocrinologydiseases
metabolic syndrome 4 endocrinologydiseases
Insulin 1 endocrinologydiseasesdrugs
diabetes mellitus 2 endocrinologydiseases
fenofibrate 17 endocrinologydiseasesdrugs
glucose intolerance 1 endocrinologydiseases
hyperlipidemia 2 endocrinologydiseases
hypertriglyceridemia 12 endocrinologydiseases
hypoglycemia 2 endocrinologydiseases
obesity 6 endocrinologydiseases

Graph of close proximity drug and disease terms (within 200 characters).

Note: If this graph is empty, then there are no terms that meet the proximity constraint.

Review

Having read the paper, please pick a pair of statements from the paper to indicate that a drug and disease are related.

Select Drug Character Offset Drug Term Instance
Insulin 50883 mm vs. glimepiride2. Progression of maximum CIMT: −0.024 mm vs. glimepiride3. HDL-C: +14%The IRIS ( Insulin Resistance Intervention after Stroke)—NCT00091949Phase 3follow-up: 4.8 yearssubjects: 3876 [[123],[124]]
atorvastatin 25260 423 patients with residual dyslipidemia (TGs ranging from 325 to 333 mg/dL) on statins (most commonly atorvastatin , rosuvastatin and pitavastatin); LDL-C was around 108 mg/dL. Notably, if TGs were ≥ 150 mg/dL after
bezafibrate 7501 eicosanoids [[21]], as well as by small molecules, such as fibrates for PPAR-α, GW501516, GW0742, bezafibrate and Telmisartan for PPAR-β/δ, and glitazones for PPAR-γ. PPAR-α mediates the hypolipidemic function
bezafibrate 19237 clinically relevant [[67]]. These findings have been well characterized from studies with fenofibrate and bezafibrate . This latter, differently from the most selective PPAR-α modulator fenofibrate, acts as a pan PPAR
ezetimibe 36643 persistently hypertriglyceridemic patients already on a maximally tolerated dose of statin or statin + ezetimibe , with TG levels ≥ 200 mg/dL and <500 mg/dL). Compared to olive oil (4 g/day), omega-3-FA 2 g/day or
fenofibrate 9829 stimulated by PPAR-α. This last seems to control liver glucose metabolism as well. Administration of fenofibrate to mice decreases expression levels of glucokinase and flux through this enzyme, suggesting a lower
fenofibrate 17854 recent studies, particularly the ACCORD—Action to Control Cardiovascular Risk in Diabetes—trial with fenofibrate , has clearly indicated that the agent has a heterogeneous response, but may have a valid indication
fenofibrate 19221 thus, not clinically relevant [[67]]. These findings have been well characterized from studies with fenofibrate and bezafibrate. This latter, differently from the most selective PPAR-α modulator fenofibrate, acts
fenofibrate 19317 with fenofibrate and bezafibrate. This latter, differently from the most selective PPAR-α modulator fenofibrate , acts as a pan PPAR activator for all three PPAR isoforms (α, γ and δ) [[68]]. Bezafibrate, similar
fenofibrate 22283 reactions, i.e., serum creatinine and liver enzyme increases.The efficacy of pemafibrate over that of fenofibrate was reported in a 24-week, randomized, double blind, active-controlled, phase 3 trial. Patients with
fenofibrate 22564 ≤55 mg/dL for women were randomly assigned to pemafibrate 0.1 (n = 73) or 0.2 (n = 74) mg bid or to fenofibrate 106.6 mg qd (n = 76). The primary efficacy analysis, i.e., percent change in fasting TG from baseline,
fenofibrate 22763 from baseline, demonstrated that pemafibrate treatments reduced TGs around −46% vs. −39.7% for fenofibrate . These findings can be translated into a further −6.5% and −6.2% difference in TG reduction for
fenofibrate 22922 further −6.5% and −6.2% difference in TG reduction for patients on 0.2 and 0.4 mg/day pemafibrate vs. fenofibrate . TC, non-HDL-C, ApoB, and VLDL-C were significantly decreased, and HDL-C, ApoAI, and ApoAII increased
fenofibrate 23205 groups. Conversely, FGF-21 levels were raised to a greater extent in the 0.4 mg/day pemafibrate group vs. fenofibrate [[76]] (Table 2). Adverse drug reactions, such as rises in liver enzymes and serum creatinine, were
fenofibrate 23333 2). Adverse drug reactions, such as rises in liver enzymes and serum creatinine, were observed in the fenofibrate group, not in the pemafibrate groups.The non-inferiority of pemafibrate over fenofibrate was confirmed
fenofibrate 23422 observed in the fenofibrate group, not in the pemafibrate groups.The non-inferiority of pemafibrate over fenofibrate was confirmed in a 12-week phase 3 trial enrolling 489 patients with TG ≥ 200 mg/dL and HDL-C ≤
fenofibrate 23703 −46.3% (0.1 mg/day), −46.7% (0.2 mg/day) and −51.8% (0.4 mg/day) and non-inferior to those of fenofibrate , −38.3% (100 mg/day) and −51.5% (200 mg/day) (Table 2). Adverse events were less frequent than with
fenofibrate 23819 −38.3% (100 mg/day) and −51.5% (200 mg/day) (Table 2). Adverse events were less frequent than with fenofibrate 200 mg/day [[77]].The long-term efficacy of pemafibrate to treat residual hypertriglyceridaemia during
fenofibrate 27314 patients [[63],[64]]. Long-term re-evaluation of some of the most recent trials has clearly confirmed that fenofibrate in particular may have a valid indication in reducing CVD in patients with diabetes, hypertriglyceridemia
fenofibrate 48374 weekssubjects: 225 [[76]]1. Reduction in TGs: −46.2%2. A further −6.5% TG reduction compared to fenofibrate Phase 3 (JapicCTI-121764; clinicaltrials.jp)follow-up: 12 weekssubjects: 489 [[77]]1. TGs: −46.3% (0.1
fenofibrate 48561 [[77]]1. TGs: −46.3% (0.1 mg/day), −46.7% (0.2 mg/day) and −51.8% (0.4 mg/day) vs. −38.3% ( fenofibrate 100 mg/day) and −51.5% (fenofibrate 200 mg/day)Phase 2follow-up: 12 weekssubjects: 188 [[79]]1. Reduction
fenofibrate 48599 −46.7% (0.2 mg/day) and −51.8% (0.4 mg/day) vs. −38.3% (fenofibrate 100 mg/day) and −51.5% ( fenofibrate 200 mg/day)Phase 2follow-up: 12 weekssubjects: 188 [[79]]1. Reduction in TGs: range from −46.1% to
gemfibrozil 2347 events such as the rise of plasma creatinine, gallstone formation, drug–drug interactions (i.e., gemfibrozil ) and myopathy should also be acknowledged.1. IntroductionThe incidence of metabolic syndrome (MetS),
pioglitazone 16050 resistance in diet-induced obese mice [[56]]. Recently, it has been demonstrated that the PPAR-γ agonist pioglitazone may prevent or delay aortic aneurysm progression in patients [[57]]. Treated patients show decreased
pioglitazone 16453 treatment increased adiponectin expressions in both tissues compared to controls. Neurons are protected by pioglitazone treatment [[58]]; indeed, neuron and axon susceptibility to both nitric-oxide donor-induced and microglia-derived
pioglitazone 39132 the market in Europe. Pioglitazone appears instead to reduce CV events [[117]]. Clinical trials with pioglitazone , e.g., PERISCOPE, PROactive and CHICAGO, have, in fact, demonstrated that in addition to beneficial
pioglitazone 39298 fact, demonstrated that in addition to beneficial effects in reducing TGs and increasing HDL-C levels, pioglitazone can reduce CV risk in T2D patients [[118]].The PERISCOPE trial (pioglitazone effect on regression of
pioglitazone 39375 increasing HDL-C levels, pioglitazone can reduce CV risk in T2D patients [[118]].The PERISCOPE trial ( pioglitazone effect on regression of intravascular sonographic coronary obstruction prospective evaluation) recruited
pioglitazone 39922 levels were decreased by −16.3 mg/dL vs. a rise of +3.3mg/dL. Fasting insulin levels were decreased by pioglitazone and raised by glimepiride. The primary end-point, namely the percent atheroma volume change measured
pioglitazone 40103 atheroma volume change measured by intravascular ultrasound (IVUS), was reduced by −0.16% in the pioglitazone arm vs. a +0.73% rise in the glimepiride group (Table 2); these between group changes were statistically
pioglitazone 40483 (−13.3% vs. −1.9%), TG/HDL-C ratio (−22.5% vs. −9.9%) and HbA1C (−0.6% vs. −0.3%) upon pioglitazone administration, possibly responsible for the atheroma regression [[120]].The CHICAGO (carotid intima-media
pioglitazone 40638 the atheroma regression [[120]].The CHICAGO (carotid intima-media thickness in atherosclerosis using pioglitazone ) trial tested the hypothesis that pioglitazone would have a beneficial effect in reducing carotid intima-media
pioglitazone 40685 (carotid intima-media thickness in atherosclerosis using pioglitazone) trial tested the hypothesis that pioglitazone would have a beneficial effect in reducing carotid intima-media thickness (IMT) progression compared
pioglitazone 40929 reported reduced progression of IMT appeared to be associated with a rise of HDL-C (+14%) following pioglitazone (Table 2) [[122]]. The positive effect of pioglitazone on carotid IMT is thus independent of its glucose
pioglitazone 40984 associated with a rise of HDL-C (+14%) following pioglitazone (Table 2) [[122]]. The positive effect of pioglitazone on carotid IMT is thus independent of its glucose lowering effect. Of note, weight and body mass index
pioglitazone 41119 independent of its glucose lowering effect. Of note, weight and body mass index were higher in the pioglitazone arm.The IRIS (insulin resistance intervention after stroke) trial showed that pioglitazone reduced the
pioglitazone 41210 higher in the pioglitazone arm.The IRIS (insulin resistance intervention after stroke) trial showed that pioglitazone reduced the occurrence of fatal and non-fatal stroke or MI in insulin resistant patients without diabetes,
pioglitazone 41434 halving the occurrence of diabetes (Table 2). Notably, this latter occurred in 3.8% of patients on pioglitazone vs. 7.7% of those assigned to placebo (hazard ratio: 0.48; 95% CI: 0.33–0.69) [[123],[124]]. Evaluation
pioglitazone 41587 (hazard ratio: 0.48; 95% CI: 0.33–0.69) [[123],[124]]. Evaluation of safety outcomes indicated that pioglitazone led to (i) a weight gain of 4.5 kg (52.2% of patients) vs. +13.6 kg (11.4% of patients) for placebo
pioglitazone 42066 of glitazones [[126]].The clinical outcome studies on PPAR-γ agonists have been focused mainly on pioglitazone , particularly in view of the better tolerability. These have concluded that this treatment may be associated
pioglitazone 42331 and a lower incidence of diabetes. Further, the IRIS study provided clear evidence of the efficacy of pioglitazone in preventing CV outcomes in insulin resistant patients [[123],[124]].5. PPAR Dual AgonistsDual PPAR
rosiglitazone 38863 the thiazolidinedione (TZDs) drug class and are currently in use for T2D [[114]]. Pioglitazone and rosiglitazone are the only two drugs available. Following epidemiological data indicative of a raised CV risk after
rosiglitazone 38979 are the only two drugs available. Following epidemiological data indicative of a raised CV risk after rosiglitazone [[115],[116]], the drug was taken off the market in Europe. Pioglitazone appears instead to reduce CV
rosuvastatin 25274 with residual dyslipidemia (TGs ranging from 325 to 333 mg/dL) on statins (most commonly atorvastatin, rosuvastatin and pitavastatin); LDL-C was around 108 mg/dL. Notably, if TGs were ≥ 150 mg/dL after 12 weeks, pemafibrate
Select Disease Character Offset Disease Term Instance
diabetes mellitus 3578 useful definition of MetS in order to identify individuals at high risk of CV disease (CVD) and type 2 diabetes mellitus (T2D) on a worldwide basis [[7]]. In the same year, the American Heart Association (AHA)/National Heart,
diabetes mellitus 33527 recognized at the cellular level, may be followed by biochemical changes in patients with MetS and diabetes mellitus . In these patients, statistically significant TG reductions, compared to placebo, have been observed
glucose intolerance 15793 activation and a strong metabolic phenotype, characterized by diet-induced obesity, insulin resistance, and glucose intolerance [[55]]. In addition, PPAR-γ activation decreases T-lymphocyte-dependent inflammation of adipose tissue
hyperlipidemia 5051 hypertriglyceridemia (i.e., fibrates and omega-3 fatty acids, both PPAR-α agonists), as well as in cases of mixed hyperlipidemia s with raised TGs and low HDL-C; conversely, PPAR-γ activators have become choice drugs in T2D.PPAR
hyperlipidemia 20186 PPAR-γ or -δ (delta) [[72]]. Pemafibrate has been recently approved in Japan for the treatment of hyperlipidemia s, with a recommended dosage of 0.1 mg bid with the possibility of reaching a maximum of 0.2 mg bid [[73]].The
hypertriglyceridemia 4436 elevated low-density lipoprotein cholesterol (LDL-C) among lipid risk factors. It is characterized by hypertriglyceridemia , low high-density lipoprotein (HDL)-cholesterol levels, and the prevalence of small, dense low-density
hypertriglyceridemia 4936 valuable therapeutic target. PPAR activators have provided significant benefit in patients with primary hypertriglyceridemia (i.e., fibrates and omega-3 fatty acids, both PPAR-α agonists), as well as in cases of mixed hyperlipidemias
hypertriglyceridemia 7649 glitazones for PPAR-γ. PPAR-α mediates the hypolipidemic function of fibrates in the treatment of hypertriglyceridemia and hypoalphalipoproteinemia [[22]], being the main regulator of intra- and extracellular lipid metabolism.
hypertriglyceridemia 18045 have a valid indication in reducing CVD in appropriately selected patients, i.e., those with diabetes, hypertriglyceridemia and low HDL-C [[65]]. In these subjects, a definite benefit on the CV outcomes may be predicted.When
hypertriglyceridemia 27411 that fenofibrate in particular may have a valid indication in reducing CVD in patients with diabetes, hypertriglyceridemia and low HDL-C [[65]]. The recently available low-dosage pemafibrate seems to provide a higher activity
hypertriglyceridemia 34044 omega-3 fatty acids (2 g daily) in reducing TGs and other lipid concentrations in patients with severe hypertriglyceridemia (TG > 500 mg/dL and <2500 mg/dL) was evaluated in the EVOLVEII (Epanova® for lowering very high triglycerides
hypertriglyceridemia 35665 lowering very high triglycerides) double-blind, randomized, parallel, 4-arm study. In subjects with severe hypertriglyceridemia (TGs ≥ 500 mg/dL but <2000 mg/dL), administration of omega-3-FA 2 g/die (plus olive oil 2 g/day),
hypertriglyceridemia 36478 to a statin background was evaluated in the ESPRIT (Epanova combined with a statin in patients with hypertriglyceridemia to reduce non-HDL cholesterol) trial, on persistently hypertriglyceridemic patients already on a maximally
hypertriglyceridemia 38138 (study to assess statin residual risk reduction with Epanova in high cardiovascular risk patients with hypertriglyceridemia ) and REDUCE-IT (reduction of cardiovascular events with icosapent ethyl–intervention) trials [[113]]
hypertriglyceridemia 38678 The ongoing studies should shed light on this last issue, particularly as pertains to patients with hypertriglyceridemia associated risk.4. PPAR-γ AgonistsAgonists of PPAR-γ belong to the thiazolidinedione (TZDs) drug class
hypertriglyceridemia 45751 “fraudulent fatty acids”, i.e., fibrates and omega-3 fatty acids, find a growing role in the handling of hypertriglyceridemia and, in the case of fibrates, also positively affecting HDL-cholesterol and the consequently raised
hypertriglyceridemia 46021 the glycemic abnormalities of MetS; they may, however, lead to weight increase. The causal role of hypertriglyceridemia as a CV risk factor, confirmed by Mendelian randomization studies, has brought clinicians back to this
hypoglycemia 8926 upregulated in mouse liver during fasting, whereas PPAR-α knock-out (KO) fasted mice display significant hypoglycemia , hypoketonemia, hypothermia, and increased plasma free fatty acids, thus suggesting an inhibition of
hypoglycemia 10264 pups displayed a primary defect in gluconeogenesis, specifically from glycerol, leading to significant hypoglycemia [[29]].PPAR-α induction also exerts an anti-inflammatory activity in mouse models, even though contrasting
metabolic syndrome 1013 cesare.sirtori@icloud.comPublication date (epub): 4/2018Publication date (collection): 4/2018AbstractTherapeutic approaches to metabolic syndrome (MetS) are numerous and may target lipoproteins, blood pressure or anthropometric indices. Peroxisome
metabolic syndrome 2433 interactions (i.e., gemfibrozil) and myopathy should also be acknowledged.1. IntroductionThe incidence of metabolic syndrome (MetS), representing a global public health issue, has been estimated to vary from 20 to 27% in developing
metabolic syndrome 46938 NFκB, Nuclear Factor-κB.ijms-19-01197-t001_Table 1Table 1Risk factors for the clinical diagnosis of metabolic syndrome .ValueAlternative IndicatorWaist circumference* >94 cm in males, >80 cm in females** >102 cm in males,
metabolic syndrome 47950 Reproduced with permission [[8]].ijms-19-01197-t002_Table 2Table 2Effect of PPARs on the features of metabolic syndrome —evidence from clinical trials.PPAR-α AgonistClinic StudyMajor FindingsPemafibratePhase 3 (JapicCTI-142412;
mixed hyperlipidemia 5045 hypertriglyceridemia (i.e., fibrates and omega-3 fatty acids, both PPAR-α agonists), as well as in cases of mixed hyperlipidemia s with raised TGs and low HDL-C; conversely, PPAR-γ activators have become choice drugs in T2D.PPAR
obesity 13769 thiazolidinediones (TZDs) have a hypoglycemic action in ob/ob mice and improve insulin action in several models of obesity and diabetes [[47],[48]]. A high correlation between the hypoglycemic activity of TZDs and their affinity
obesity 15760 lower alternative macrophage activation and a strong metabolic phenotype, characterized by diet-induced obesity , insulin resistance, and glucose intolerance [[55]]. In addition, PPAR-γ activation decreases T-lymphocyte-dependent
obesity 16818 the Metabolic SyndromeThe characteristic features of MetS, i.e., increased triglyceridemia, abdominal obesity , reduced HDL-C levels and increased glycemia, in addition to raised blood pressure, clearly indicate
obesity 30409 energy expenditure, it being peroxisomal and to some extent also mitochondrial, positive effects on obesity may be observed. Indeed, PPAR-α KO-obese mice show, in fact, a clear worsening of obesity that may
obesity 30500 effects on obesity may be observed. Indeed, PPAR-α KO-obese mice show, in fact, a clear worsening of obesity that may be instead improved by omega-3 administration in different diet-induced conditions [[94]].
obesity 32112 not WAT cells synthesize DHA [[99]].Inflammatory changes in the adipose tissue are characteristic of obesity . They are driven by rises in circulating endotoxins and infiltrate immune cell populations. This will
type 2 diabetes mellitus 3571 clinically useful definition of MetS in order to identify individuals at high risk of CV disease (CVD) and type 2 diabetes mellitus (T2D) on a worldwide basis [[7]]. In the same year, the American Heart Association (AHA)/National Heart,

You must be authorized to submit a review.