in vivo actions of peroxisome proliferator activated receptors · in vivo actions of peroxisome...

In Vivo Actions of PeroxisomeProliferator–Activated ReceptorsGlycemic control, insulin sensitivity, and insulin secretion

ROY ELDOR, MD, PHD

RALPH A. DEFRONZO, MD

MUHAMMAD ABDUL-GHANI, MD

Peroxisome proliferator–activated re-ceptors (PPARs) form a family of nu-clear hormone receptors involved in

energy hemostasis and lipid metabolism(1,2) and include three isotypes encodedby different genes: PPARa (chromo-some22q12–13.1), PPARb/d (chromosome6p21.2–21.1), and PPARg (chromosome3p25). PPARa was the first discoveredand causes cellular peroxisome prolifera-tion in rodent livers (3), giving this recep-tor family its name. Upon activation,PPARs interact with retinoid X receptorto create heterodimers, which bind to aspecific DNA sequence motif termed per-oxisome proliferator response element(4). Peroxisome proliferator response ele-ment usually appears in promoter regionsand is constructed from repeats of nucle-otide sequence AGGTCA separated by asingle nucleotide.

PPARa is widely expressed in tissueswith high fatty acid catabolic activity:brown fat, heart, liver, kidney, and intes-tine (5). Upon activation by endogenousfatty acids and their derivatives, PPARamediates fatty acid catabolism, gluconeo-genesis, and ketone body synthesis,mainly in liver (6–9). In rodents, PPARaactivation also influences immune modu-lation (10,11) and amino acidmetabolism(12), reduces plasma triglyceride, reducesmuscle and liver steatosis, and amelio-rates insulin resistance (IR) (13,14). Phar-macologic PPARa activation is achieved

by fibrates (7) and results in reduced(30–50%) triglyceride and VLDL levelsby increasing lipid uptake, lipoproteinlipase–mediated lipolysis, and b-oxidation(15). This is accompanied by a modestincrease in HDL cholesterol (5–20%),secondary to transcriptional induction ofapolipoprotein A-I/A-II synthesis in liver(15). In man, the primary effect of PPARais to reduce plasma triglyceride concentra-tion; effects on plasma free fatty acid (FFA)concentration/FFA oxidation, muscle/liverfat content, andmuscle/hepatic insulin sen-sitivity have not been demonstrated withcurrent PPARa agonists such as fenofibrate(16,17). Fibrates are used to treat severehypertriglyceridemia and combined hyper-lipidemia (18–20). Clinical trials toestablish a role for PPARa agonists (feno-fibrate, gemfibrozil) in primary or sec-ondary cardiovascular prevention inpatients with hypertriglyceridemia or di-abetes have been disappointing (21,22).Clinically significant effects of fibrates onglucose homeostasis, IR, and insulin secre-tion in man have not been demonstrated(16,17,23).

PPARb/d is expressed ubiquitously,correlating with the level of cellular pro-liferation exhibited in different tissues(24). In rodents, PPARb/d activation ex-erts metabolic effects in skin, gut, skeletalmuscle, adipose tissue, and brain (25,26).Several PPARb/d agonists are in clinicaltrials because of their beneficial effects

on dyslipidemia (27,28) and other com-ponents of metabolic syndrome (29,30).

PPARg has two splice variants,PPARg1 and PPARg2, differing by 30amino acids in the N9 terminal end.WhilePPARg1 is widely expressed in tissues(skeletal muscle heart, liver) at low levels,both are highly expressed in adipose tis-sue (31,32). PPARg is considered the“master” regulator of adipogenesis (33).PPARg overexpression in cultured fibro-blasts transforms them into adipocytes(34), while selective adipose deletion ofPPARg results in lipodystrophy and IR(35–37). Dominant negative PPARg mu-tations are associated with lipodystrophy(in the limbs and gluteal region), dyslipi-demia, hypertension, and severe IR (38–40). PPARg polymorphisms (specifically,Pro12Ala) are associated with increasedrisk of developing type 2 diabetes(T2DM) (41–43). PPARg agonists, thiazo-lidinediones (2,44,45), are potent insulinsensitizers, enhance insulin secretion, im-prove glucose tolerance, and are the focusof this review.

THIAZOLIDINEDIONES: PASTTO PRESENTdTroglitazone was thefirst thiazolidinedione approved by theU.S. Food and Drug Administration(FDA) and shown to improve insulinsensitivity and b-cell function in T2DM,impaired glucose tolerance (IGT), andnondiabetic individuals (46–50). Trogli-tazone also was shown to improve endo-thelial dysfunction in obesity and T2DM(49,51), induce ovulation in PCOS (52),and effectively treat lipodystrophy (53).Troglitazone also caused fat redistribu-tion from visceral to subcutaneous adiposetissue (54,55) and reduced circulatinglevels of inflammatory adipocytokinesand FFAs, while increasing plasma adipo-nectin levels (2). Thus, troglitazone sharesmany beneficial effects with pioglitazoneand rosiglitazone. However, because ofhepatotoxicity troglitazone was removedfrom the U.S. market by the FDA in 1997(56). However, the idiosyncratic liver tox-icity observed with troglitazone does notappear to be a class effect. In a review ofthe literature, alanine aminotransferase

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From the Diabetes Division, Department of Medicine, University of Texas Health Science Center, San Antonio,Texas.

Corresponding author: Ralph A. DeFronzo, [email protected] publication is based on the presentations from the 4thWorld Congress on Controversies to Consensus in

Diabetes, Obesity and Hypertension (CODHy). The Congress and the publication of this supplement weremade possible in part by unrestricted educational grants from Abbott, AstraZeneca, Boehringer Ingelheim,Bristol-Myers Squibb, Eli Lilly, Ethicon Endo-Surgery, Janssen, Medtronic, Novo Nordisk, Sanofi, andTakeda.

DOI: 10.2337/dcS13-2003© 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly

cited, the use is educational and not for profit, and thework is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

S162 DIABETES CARE, VOLUME 36, SUPPLEMENT 2, AUGUST 2013 care.diabetesjournals.org

D I A B E T E S T H E R A P Y

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levels .10 times the upper limit of nor-mal were observed in 0.68% of diabeticpatients treated with troglitazone versusno individuals treated with pioglitazoneor rosiglitazone (57). (See subsequentdiscussion on nonalcoholic steatohepatitis[NASH].)

Rosiglitazone shares similar beneficialeffects with pioglitazone and troglitazoneon insulin sensitivity, b-cell function, gly-cemic control, endothelial function, andadipocyte metabolism (see subsequentdiscussion). However, because of con-cerns about cardiovascular safety rosigli-tazone has been severely restricted in theU.S. and has been removed from the mar-ket in Europe and many other countries.In 2007, a meta-analysis by Nissen andWolski (58) suggested an increased inci-dence of cardiovascular events in diabeticpatients treated with rosiglitazone. In2010, a patient-level analysis by FDA statis-ticians of data supplied byGlaxoSmithKlinegave hazard ratio (HR) 1.4 for compositeMACE end point (cardiovascular death,myocardial infarction [MI], stroke) and1.80 for MI (59), leading to removal of ro-siglitazone from the U.S. market for allpractical purposes. In a recent literature re-view, Schernthaner and Chilton found thatrosiglitazone consistently was associatedwith HR .1.0 for cardiovascular events,while pioglitazone was associated withHR,1.0 (60).

In subsequent sections, we will focuson the pleotrophic effect of thiazolidine-diones, with emphasis on pioglitazoneand rosiglitazone.

Pleotrophic effects of PPARg agonistsPPARg agonists exert pleotrophic effectson glucose and lipid metabolism in mul-tiple tissues and have become an impor-tant therapeutic agent for treating T2DM(45,61,62).Glycemic control. Thiazolidinedionesare potent insulin sensitizers in liver/mus-cle/adipocytes (14,61–67), augment/pre-serve b-cell function (68), and producedurable HbA1c reduction in T2DM. Ineight of eight long-term (.1.5 years),double-blind, or active comparator stud-ies (Fig. 1), thiazolidinediones caused du-rable HbA1c reduction (rev. in 61) lastingup to 5–6 years (69). Their durable effecton glycemic control results from com-bined action to both augment b-cell func-tion and enhance insulin sensitivity. InT2DM patients with starting HbA1c 8.0–8.5%, one can expect a 1.0–1.5% decreasein HbA1c (70–76). Thiazolidinediones areapproved for monotherapy and add-on

therapy to all oral hypoglycemic agents,glucagon-like peptide-1 analogs, and in-sulin (76).Insulin sensitivity in liver and muscle.In liver, thiazolidinediones augmentinsulin sensitivity and inhibit gluconeo-genesis, leading to reduction in fastingplasma glucose concentration (63,64). Inmuscle, thiazolidinediones are the onlytrue insulin sensitizers, producing a de-cline in postprandial glucose levels(61,66,67). Metformin is a weak insulinsensitizer in muscle, and it has been diffi-cult to demonstrate a muscle insulin-sensitizing effect in absence of weightloss (77,78). Thiazolidinedione-mediatedimprovement in insulin sensitivity inT2DM is mediated via multiple mecha-nisms: PPARg activation, enhanced insu-lin signaling, increased glucose transport,enhanced glycogen synthesis, improvedmitochondrial function, and fat mobiliza-tion out of muscle/liver, i.e., reversal oflipotoxicity (45,62,79–82). Recent stud-ies suggest that metabolic effects ofthiazolidinediones are mediated by mito-chondrial target of thiazolidinediones,mtot1 and mtot2, which represent thepyruvate transporter (83,84).

For insulin to exert its metaboliceffects, it must first bind to and activateinsulin receptor by phosphorylating threekey tyrosine molecules on b chain (Fig.2). This causes insulin receptor substrate(IRS)-1 translocation to plasmamembrane,where it undergoes tyrosine phosphoryla-tion, leading to phosphatidylinositol 3-kinase (PI3 kinase) and Akt activation.This causes glucose transport into cell, ac-tivation of nitric oxide synthase with arte-rial vasodilation (85–87), and stimulationof multiple intracellular metabolic pro-cesses (45).

In humans, we demonstrated thatinsulin-stimulated tyrosine phosphoryla-tion of IRS-1 in muscle is severely im-paired in lean T2DM (81,88,89), in obesenormal glucose tolerant (NGT) individu-als (89), and in insulin-resistant NGT off-spring of two T2DM parents (90,91) (Fig.2); similar results have been reported byothers (92–95). This insulin-signaling de-fect leads to reduced glucose transport,impaired nitric oxide release (explainingendothelial dysfunction), and multipledefects in intramyocellular glucose me-tabolism.

In contrast to the defect in IRS-1activation, the mitogen-activated protein(MAP) kinase pathway, which can beactivated by Shc, is normally responsiveto insulin (61,62,88,89) (Fig. 2). Stimu-lation of MAP kinase activates multipleintracellular pathways involved in inflam-mation, cellular proliferation, and athero-genesis (62,96–98).

The defect in IRS-1 tyrosine phos-phorylation impairs glucose transport,and resultant hyperglycemia stimulatesfasting/postprandial insulin secretion. Be-causeMAPkinase retains normal sensitivityto insulin (62,88,89,94), hyperinsulinemiacauses excessive stimulation of this path-way and activation of multiple intracellularpathways involved in inflammation andatherogenesis. This provides a pathogeniclink that, in part, can explain the strongassociation between IR and atheroscleroticcardiovascular disease in nondiabetic andT2DM individuals (99–102).

Thiazolidinediones are the only anti-diabetes drugs that simultaneously aug-ment insulin signaling through IRS-1 andinhibit MAP kinase pathway (61,77,81),providing a molecular mechanism toexplain results from CHICAGO (104)and Pioglitazone Effect on Regression ofIntravascular Sonographic CoronaryObstruction Prospective Evaluation(PERISCOPE) (105) studies, in whichpioglitazone reduced progression ofcarotid intima-media thickness (IMT)and coronary atherosclerosis in T2DM.Consistent with these anatomical studies,pioglitazone in PROactive (106) de-creased (P = 0.027) MACE end point(death, MI, stroke) by 16%.Adipocyte insulin sensitivity. In adi-pose tissue, thiazolidinediones are potentinsulin sensitizers, inhibiting lipolysisand release of inflammatory cytokines,while increasing adiponectin secretion(67,79,80,107–109). In T2DM and obeseNGT individuals, adipocytes are resistantto insulin’s antilipolytic effect, resulting in

Figure 1dThiazolidinediones produce a sus-tained long-term reduction in HbA1c in eightof eight double-blind or placebo- or active-comparator controlled studies. (See text fora more detailed discussion.) Reprinted withpermission from DeFronzo (61).

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Eldor, DeFronzo, and Abdul-Ghani

accelerated triglyceride breakdown withrelease of FFA. Elevated plasma FFAs en-hance FFA flux into cells, leading to accu-mulation of toxic lipid metabolites (fattyacyl CoAs, diacylglycerol, ceramides),which inhibit insulin action in muscle/liver (62,110–112) and impair b-cellfunction (113). Thus, these lipotoxicmolecules antagonize the core defectsthat characterize T2DM. By improving in-sulin sensitivity in adipocytes and inhib-iting lipolysis, thiazolidinediones reduceplasma FFA, leading to enhanced insulinsensitivity in muscle/liver and improvedb-cell function in T2DM.

In T2DM, adipocytes are in a state ofchronic inflammation, as evidenced bymonocyte infiltration (114). Inflamedadipocytes release adipocytokines (tumornecrosis factor-a, resistin, angiotensino-gen, plasminogen activator inhibitor 1,interleukin-6, and others), which causeIR, impair b-cell function, promote in-flammation in distant tissues, augmentthrombosis, and accelerate atherogenesis(79,80). Adipocytes from T2DM patientshave reduced ability to secrete adiponectin(81,82), a potent vasodilator and antia-therogenic molecule. Thiazolidinedionessuppress inflammation in adipose tissue,inhibit release of inflammatory and pro-thrombotic adipokines, and augment adi-ponectin secretion.

Thiazolidinediones reverselipotoxicityThe current diabetes epidemic is beingdriven by the obesity epidemic. Bothobesity and T2DM are characterized bytissue fat overload (Fig. 3). Accumulationof intracellular toxic lipid metabolitescauses IR in muscle/liver by inhibiting in-sulin signaling, glycogen synthesis, andglucose oxidation (rev. in 61,62). Fat ac-cumulation in liver causes nonalcoholic

fatty liver disease (NAFLD) and NASH(115), which has become the leadingcause of cirrhosis in Westernized coun-tries. Fat accumulation in b-cells impairsinsulin secretion and promotes apoptosis(113). Fat deposition in arteries promotesatherogenesis (62), while fat accumula-tion in visceral depots is associated withcoronary arterial disease (116).

Thiazolidinediones reverse lipotoxic-ity by mobilizing fat out of muscle/liver/b-cells/arteries and relocating fat to sub-cutaneous adipose depots where it is met-abolically “benign” (62,79,80) (Fig. 3).After binding to PPARg, thiazolidine-diones stimulate subcutaneous adipo-cytes to divide and induce multiplegenes involved in lipogenesis (117).Newly formed subcutaneous adipocytestake up FFA, leading to marked reductionin plasma FFA and decreased FFA fluxinto liver/muscle/b-cells/arteries. Thiazo-lidinediones also increase expression of

PPARg coactivator (PGC-1), the masterregulator of mitochondrial biogenesis(118,119). Increased PGC-1 upregulatesmultiple mitochondrial oxidative phos-phorylation genes, increasing fat oxida-tion and decreasing levels of intracellulartoxic lipid metabolites.

Thiazolidinediones and b-cellfunctionThiazolidinediones exert potent effects toimprove/preserve b-cell function (68)and demonstrate durability of glycemiccontrol for up to 5–6 years in eight ofeight studies (rev. in 61). This is in con-trast to sulfonylureas and metformin,which, after initial HbA1c decline, are as-sociated with progressive HbA1c rise, re-sulting from progressive b-cell failure(120–122).

In addition to studies performed inT2DM, six studies demonstrate that thia-zolidinediones prevent IGT progression

Figure 2dInsulin signal transduction in healthy nondiabetic (left panel) and T2DM (right panel) subjects. Thiazolidinediones improve insulinsignaling through the PI-3 kinase pathway, while inhibiting insulin signaling through the MAP kinase pathway. Reprinted with permission fromDeFronzo (61).

Figure 3dBody fat distribution in T2DM patients and its redistribution with thiazolidinediones(TZD). (See text for a detailed discussion.) TG, triglyceride. Reprinted with permission fromDeFronzo and colleagues (79).


In vivo action of PPARs

to T2DM (123–128). In Diabetes Reduc-tion Assessment with Ramipril and Rosi-glitazone Medication (DREAM), T2DMwas reduced by 62% with rosiglitazone(124), while in Actos Now for the preven-tion of diabetes (ACT NOW) (127) pio-glitazone decreased IGT conversion toT2DM by 72%. All six studies demon-strated that, in addition to their insulin-sensitizing effect, thiazolidinedionespreserved b-cell function. b-Cells re-spond to increased plasma glucose levelswith an increase in insulin secretion, andΔI/ΔG is modulated by severity of IR(128). The insulin secretion/IR index

(ΔI/ΔG 4 IR) represents the gold stan-dard for b-cell function and should notbe equated with plasma insulin response.In ACT NOW, improvement in insulinsecretion/IR index was the strongest pre-dictor of diabetes prevention in IGT sub-jects and reversion to NGT. Similarresults have been demonstrated in TRo-glitazone In the Prevention Of Diabetes(TRIPOD) and Pioglitazone In PreventionOf Diabetes (PIPOD) (123,126), in whichdevelopment of diabetes in Hispanicwomen with GDM was decreased by 52and 62%. In Canadian NormoglycemiaOutcomes Evaluation (CANOE) (128),

low-dose rosiglitazone (4 mg/day), com-bined with low-dose metformin (1,000mg/day), reduced IGT conversion toT2DM by 70%. In vivo and in vitro stud-ies with human/rodent islets demonstratethat thiazolidinediones exert protectiveeffects on b-cell function (129–131).Studies from our group using insulinsecretion/IR index have shown that thia-zolidinediones markedly augment b-cellfunction in T2DM patients (68) (Fig. 4).

Improved b-cell function with thia-zolidinediones results from 1) stimulatoryeffect of PPARg to increase GLUT2, glu-cokinase (132), and Pdx (133) in b-cells;2) reduced intracellular levels of toxiclipid metabolites (129,132,134,135); 3)muscle/liver insulin-sensitizing effect ofthiazolidinediones, which reduce insulinand, therefore, amylin secretion (amylindegradation products are toxic to b-cells[136,137]; the ability of thiazolidine-diones to protect human islets fromamylin toxicity is mediated via PI3 kinase–dependent pathway [138]); and 4) studiesin b-cell insulin receptor knockout(BIRKO) mice suggest that defective insu-lin signaling through IRS-1/PI3 kinase im-pairs insulin secretion (139) and thatthiazolidinediones correct this insulin sig-naling defect (129), resulting in enhancedinsulin secretion.

SummaryThiazolidinediones improve multiple de-fects (IR in liver/muscle/adipocytes andb-cell dysfunction) that comprise theOminous Octet (61) (Fig. 5), cause dura-ble HbA1c reduction, and can be used asmonotherapy or in combination with anyother antidiabetes agent. Pioglitazone androsiglitazone similarly reduce HbA1c, im-prove insulin sensitivity in muscle/liver/adipocytes, and enhance b-cell function.

THIAZOLIDINEDIONES ANDIR SYNDROMEdIR (metabolic) syn-drome represents a cluster of metabolicand cardiovascular disorders, each ofwhich represents a major cardiovascularrisk factor (62). A common thread linkingall IR syndrome components is the basicmolecular etiology of IR (61,62,81,88,89),which not only promotes inflammationand atherogenesis but also aggravates othercomponents of the syndrome. Pioglitazoneand rosiglitazone ameliorate the moleculardefect in insulin signaling, enhancemuscle/hepatic/adipocyte insulin sensitivity, cor-rect hyperinsulinemia, improve glucosetolerance and endothelial dysfunction, re-duce blood pressure, decrease plasma FFA

Figure 4dThiazolidinediones enhance b-cell function (insulin secretion/IR index) in new-onset, drug-naïve T2DM patients and in long-standing, sulfonylurea-treated T2DM individuals(69). *P , 0.01.

Figure 5dPioglitazone corrects four of the eight pathophysiologic components of the OminousOctet. Modified with permission from DeFronzo (61). TZD, thiazolidinediones.



levels, increase HDL cholesterol, transformsmall dense LDL particles into larger lessatherogenic ones, shift body fat from vis-ceral to subcutaneous depots, mobilize fatout of muscle/liver, reduce plasminogenactivator inhibitor 1/tumor necrosis fac-tor-a levels, and increase plasma adiponec-tin (rev. in 62). Rosiglitazone producesmetabolic effects similar to those of piogli-tazone with two notable exceptions: rosi-glitazone increases both plasma LDLcholesterol and triglycerides (140). Con-cerns about cardiovascular safety (58)have led to removal of rosiglitazone fromU.S. (56) and European markets.

Pioglitazone reduces cardiovasculareventsPioglitazone is the only antidiabetes med-ication shown, in a large prospectiveplacebo-controlled outcome study, toreduce cardiovascular events. In PROac-tive, 5,238 T2DM patients with priorcardiovascular event or multiple CVD riskfactors were randomized to pioglitazoneor placebo plus standard of care for all

cardiovascular risk factors (106). Com-pared with placebo, pioglitazone reducedthe second principal MACE end point(cardiovascular mortality, MI, stroke) by16% (P, 0.02) (Fig. 6A). Cardiovascularbenefit most likely resulted from com-bined improvements in dyslipidemia (in-creased HDL cholesterol), endothelialdysfunction, blood pressure, HbA1c, otherinflammatory markers that were not mea-sured, and direct effect on arterial wall toinhibit atherogenesis (141). In a subgroupof 2,445 patients with previous MI, piogli-tazone reduced (HR 0.72, P = 0.04) likeli-hood of subsequentMI by 16% (142) (Fig.6C). In 984 patients with previous stroke,pioglitazone caused 47% reduction (HR0.53, P = 0.008) in recurrent stroke(3,143) (Fig. 6D).

The composite primary end point(mortality, nonfatal MI, silent MI, stroke,acute coronary syndrome, coronaryartery bypass grafting/percutaneouscoronary intervention, leg amputation,leg revascularization) did not reach sig-nificance (HR 0.90, P = 0.09) because of

increased number of leg revascularizationprocedures in the pioglitazone group. Legrevascularization is not aMACE end pointand typically is excluded from cardiovas-cular intervention trials, i.e., with statins,because the major risk factors for periph-eral vascular disease are gravity (i.e., sub-ject’s height) and smoking, which arenot influenced by antidiabetes therapy.Subsequent PROactive analyses con-firmed that pioglitazone has no beneficialeffect on peripheral vascular disease(144). Consistent with PROactive, ameta-analysis of all pioglitazone studiespublished (excluding PROactive) and re-ported to the FDA demonstrated a 25% de-crease in cardiovascular events (145) (Fig.6B), and a recent review recommendedthat pioglitazone should be considered indiabetic patients with cardiovascular dis-ease (146).

Two additional studies demonstratedthat pioglitazone slows anatomicalprogression of atherosclerotic cardiovas-cular disease. In PERISCOPE (105),T2DM patients with established coronary

Figure 6dA: Kaplan-Meier plot of time to MACE end point (mortality, MI, stroke) in T2DM patients treated with pioglitazone (PIO) or placebo(Plc) in PROactive. Redrawn with permission from Dormandy et al. (106). B: Pioglitazone reduces recurrent MI in diabetic patients with a previousMI in PROactive. Redrawn with permission from Erdmann et al. (142). C: Pioglitazone reduces recurrent stroke in diabetic patients with a previousstroke or PROactive. Redrawn with permission from Wilcox et al. (143). D: Meta-analysis of all published studies (excluding PROactive) in whichthe effect of pioglitazone versus placebo or active comparator on cardiovascular events is examined. Redrawn with permission from Lincoff et al.(145).



artery disease were randomized to piogli-tazone or glimepiride for 1.5 years. In theglimeperide-treated group, percent ath-eroma volume progressed, while per-cent atheroma volume regressed in thepioglitazone-treated group. In CHICAGO,pioglitazone halted progression of carotidIMT, whereas carotid IMT progressed inthe glimepiride-treated group (P = 0.008)(104). Results of these two anatomical trials(104,105), when viewed in concert withcardiovascular outcome trials (106,145),strongly suggest that pioglitazone providescardiovascular protection, especially in in-dividuals with established cardiovasculardisease.

The different effects of pioglitazoneand rosiglitazone on cardiovascular out-comes remains unexplained. One obvi-ous explanation is rise in plasma LDLcholesterol and triglyceride observedwithrosiglitazone (140). Another explanationinvolves differential regulation of gene ex-pression by rosiglitazone and pioglita-zone. In muscle (147) and adipocytes(148), multiple genes are differentiallystimulated or inhibited by the two thiazo-lidinediones, and the function of thesegenes is largely unknown.

Thiazolidinediones prevent T2DM inhigh-risk individualsSix large prospective, randomized, double-blind, placebo-controlled studies (TRIPOD[126], PIPOD [123], DPP [125], DREAM[124], CANOE [128], and ACT NOW[127]) have provided conclusive evidencethat thiazolidinediones dramatically re-duce by 52–72% conversion of predia-betes (IGT and/or IFG) to T2DM. In ACTNOW, IGT conversion to T2DM was re-duced by72%and carotid IMTprogressionwas diminished by .50% versus placebo(127). Increased b-cell function (insulinsecretion/IR index) was the strongest pre-dictor of diabetes prevention. In ACTNOW and other prevention trials reduc-tions in HbA1c, blood pressure, triglycer-ides, inflammatory cytokines, and rise inHDL cholesterol also have been observed(127).

THIAZOLIDINEDIONES ANDNASHdIn T2DM hepatic fat accumu-lation, NAFLD is common and representsa precursor for NASH. NASH is associ-ated with hepatic/muscle IR (115) andaccelerated atheogenesis (148). Severallarge, placebo-controlled studies havedemonstrated that pioglitazone mobili-zes fat from liver, reduces hepatic injury,and causes histologic improvement in

inflammation/fibrosis in NASH (149–151). Pioglitazone also reduces liver fatand improves IR in lipodystrophic pa-tients (152). Studies examining effect ofrosiglitazone in NASH have shown an ini-tial beneficial effect on liver histologic pa-rameters with no benefit from prolongedcontinuous treatment (153).

THIAZOLIDINEDIONES ANDKIDNEYdDiabetic rodents developrenal insufficiency and histologic lesionsanalogous to those in man, and thiazoli-dinediones reduce mesangial matrix(hallmark lesion of diabetic nephropa-thy) volume, decrease urinary proteinexcretion, and prevent renal failure(154,155). PPARg is expressed diffuselythroughout kidney, and PPARg agonistsinhibit mesangial cell proliferation andreduce mRNA expression of matrix pro-teins (collagen, fibronectin) and trans-forming growth factor-b, which hasbeen implicated in glomerular injury(156). In diabetic humans, pioglitazone(157) and rosiglitazone (158) reducealbuminuria, although long-term studiesexamining effect of thiazolidinediones onGFR have not been performed. Beneficialeffect of thiazolidinediones to reduce al-buminuria cannot be explained by im-proved glycemic control and is closelycorrelated with improved insulin sensi-tivity (159).

Diabetic individuals with renal insuf-ficiency are at increased risk for cardio-vascular disease/mortality (159). InPROactive, pioglitazone significantly re-duced MACE end point in patients withand without reduced GFR (160). Thiazo-lidinediones also reduced all-cause mor-tality in hemodialysis-treated patients(161).

SAFETYdBenefits of pioglitazone onglycemic control and prevention of car-diovascular disease are well established.However, physicians must be cognizantof potential side effects to maximize ben-efit and minimize risk. The majority ofpioglitazone’s beneficial effects on glu-cose metabolism, insulin sensitivity, insu-lin secretion, and cardiovascular riskfactors are observed with a dose of 30mg/day (70,162). At this dose, side effectsare mild and manageable. Increasing doseto 45 mg/day provides little more efficacyand substantially increases risk of side ef-fects (70). Therefore, we recommend astarting dose of 7.5–15 mg/day, tritiatedto 30 mg/day (163–165). Combined pio-glitazone/metformin therapy (166,167) is

particularly effective in reducing HbA1c,does not cause hypoglycemia, and mini-mizes side effects. Moreover, both piogli-tazone (106,145) and metformin (121)reduce cardiovascular events, althoughthe number (n = 344) of subjects in themetformin arm of the UK Prospective Di-abetes Study (UKPDS) was small andwould not satisfy current standards for acardiovascular intervention study.

Fat weight gainOn average, pioglitazone-treated subjectsgain ;2–3 kg of fat weight after 1 year(70,76,106,168), which results fromPPARg stimulation of hunger centers inhypothalamus (169). Simultaneously,PPARg activation redistributes fat from vis-ceral to subcutaneous depots (55,79,170),mobilizes fat out of muscle/liver/b-cells(79,80,149,150,171), inhibits lipolysis/reduces plasma FFA (79,80,109), andstimulates PGC-1/other mitochondrialgenes involved in lipid oxidation (118).The net result is a metabolically more fa-vorable fat distribution from visceral tosubcutaneous depots where it is metabol-ically benign (79,80) and depletion oftoxic lipid metabolites in muscle/liver/b-cells (62). Of note, the greater theweight gain, the greater the improve-ments in b-cell function and insulin sen-sitivity and the greater the reduction inHbA1c (68,170,172). On a short-termbasis, i.e., up to 3 years (106), no adverseeffects of thiazolidinedione-associatedweight gain have been observed. Long-term effects, if any, of thiazolidinedione-associated weight gain remain unknown.Weight gain, if excessive, should be man-aged with reinforcement of dietary adviceand exercise, reduction in pioglitazonedose, or use of pharmacologic agents ap-proved for weight loss.

Bone fracturesT2DM patients treated with thiazolidine-diones have increased risk of fracture(173–176), which primarily occurs in dis-tal long bones of upper (forearm, hand,wrist) and lower (foot, ankle, fibula, tibia)limbs and is related to trauma. Excessfracture risk is 0.8 fractures per 100patient-years (1.9 in pioglitazone treatedvs. 1.1 in comparator treated) (173–176).This represents a small but significantrisk. Since increased fracture risk pri-marily occurs in postmenopausal fe-males and not in premenopausal womenor men, pioglitazone should be used withcaution in postmenopausal women or notat all.



Fluid retention and congestive heartfailureThiazolidinediones may cause fluid re-tention, which can exacerbate heart fail-ure in diabetic patients who do notuncommonly have underlying diastolicdysfunction (106). When used as mono-therapy, edema occurs in 3–5% of indi-viduals and is dose related (177). Edemamost commonly occurs when thiazolidi-nediones are used with sulfonylureas andespecially with insulin (177–180). Fluidretention occurs secondary to peripheralvasodilation (181) and stimulation ofENac (epithelial sodium) channel in col-lecting duct (182). Sodium retention re-sponds well to distally acting diuretics,spironolactone or triamterene (183).Pedal edema identifies individuals atrisk to develop congestive heart failure(CHF) and who should be treatedwith a diuretic or reduction in pioglita-zone dose. In PROactive, incidence ofCHF was 6%. However, cases were notadjudicated, and mortality and cardio-vascular events tended to be decreasedin pioglitazone-treated individuals whodeveloped CHF (106,184). These resultssuggest that after excess fluid has beendiuresed, the cardioprotective effect ofpioglitazone becomes evident. Lastly,pioglitazone has no negative impact oncardiac function (185) and improves en-dothelial dysfunction (186).

THIAZOLIDINEDIONES ANDCANCERdIn PROactive (106), inci-dence of malignancy was similar in pio-glitazone (3.7%) and placebo (3.8%)groups. However, two imbalances werenoted. There were more cases of bladdercancer in pioglitazone (n = 16) versus pla-cebo (n = 6) groups (P = 0.069). Prior tounblinding, external experts adjudicatedthat 11 cases could not plausibly be re-lated to treatment. Of the remainingnine case subjects, six were treated withpioglitazone and three with placebo (P =0.309). The other imbalance was relatedto breast cancer; there were fewer breastcancers in the pioglitazone versus placebogroup (3 vs. 11, P = 0.034). Thus, thenonsignificant increase in bladder cancerwas numerically offset by the statisticallysignificant decrease in breast cancer.

In 2003, the FDA requested that asafety study be conducted to assesswhether pioglitazone increased bladdercancer risk. After 4 years of a 10-yearlongitudinal cohort study of 193,099patients (187), ever use of pioglitazonewas not associated with increased bladder

cancer risk (HR 1.2 [95% CI 0.9–1.5]).However, in patients receiving pioglita-zone for $24 months, there was slightincreased bladder cancer risk (1.4[1.03–2.0]); 95% of cancers were detectedat an early in situ stage, and authorsacknowledged that this could have beenattributed to the fact that pioglitazone-treated patients underwent greater sur-veillance for bladder cancer. Bladdercancer risk increased from 7/10,000patient-treatment years (no pioglitazone)to 10/10,000 (with pioglitazone)danincrease of 3 cases per 10,000 patient-treatment years. Overall, there was noincrease in total cancers in pioglitazone-treated patients (187,188), and risk ofsome cancers (colon, kidney/renal pelvis,breast) was decreased (188). In a recent8-year analysis of the same study popula-tion, HR for bladder cancer was 0.98(95% CI 0.81–1.18) (189). If pioglita-zone actually increased bladder cancerrisk, one would have expected HR toincreasednot decreasedafter 8 years.These results argue against a putativerole for pioglitazone in development ofbladder cancer. Further, overall inci-dence of malignancy has been reportednot to increase (106) or decrease in cer-tain cancer types (breast and liver) inpioglitazone-treated patients (188,190–192). Lastly, any increased bladdercancer risk must be viewed in the contextof protection against all-cause death, MI,and stroke, i.e., MACE end point in

PROactive. It has been estimated that treat-ment of 10,000 patients with pioglitazonewould avoid 210 MIs, stroke, or deathsover 3 years (193) compared with a poten-tial increase of three cases of bladder cancerper 10,000 patients over the same period.Moreover, even this increase of 3/10,000disappeared after 8 years (189).

Based upon the body of evidencereviewed above (not including 8-yearfollow-up data reported by Lewis), theFDA recommended that pioglitazone notbe used in patients with active bladdercancer or prior bladder cancer history.We recommend that any hematuria beevaluated to exclude bladder cancer be-fore starting pioglitazone.

BENEFIT-RISK ANALYSISdAsreviewed in preceding sections, thebenefit-to-risk ratio for pioglitazone isvery favorable. Importantly, if physiciansare aware of potential risks associatedwith thiazolidinediones and if the piogli-tazone dose does not exceed 30 mg/day,side effects can be reduced even further(Table 1).

AcknowledgmentsdR.A.D. is a member ofthe Advisory Board of Takeda, Bristol-MyersSquibb, Janssen, Boehringer Ingelheim, NovoNordisk, Lexicon, and Amylin. R.A.D. is a mem-ber of the Speakers Bureau of Novo Nordisk,Amylin, Bristol-Myers Squibb, and Janssen. Noother potential conflicts of interest relevant tothis article were reported.

Table 1dBenefits and risks associated with thiazolidinedione therapy

Benefit Risk

c Potent, durable HbA1c reduction c Fat weight gainc Low risk of hypoglycemia c Fluid retention/heart failurec Reduces IR c Bone fractures (distal long bones; trauma-related)c Improves b-cell functionc Improves cardiovascular riskfactors (↑ HDL, ↓ triglyceride,↓ blood pressure, ↓ inflammation,↓ microalbuminuria)

c Bladder cancer (potentially)

c Decreases cardiovascular events inhigh-risk diabetic patients(PROactive; meta-analysis)

c Reduces cardiovascular events indiabetic patients with chronickidney disease

c Improves endothelial dysfunctionc Improves liver damage in NASHc Prevents IGT progression toT2DM (ACT NOW, TRIPOD,PIPOD, DREAM)



R.E., R.A.D., and M.A.-G. contributed towriting, revising, and reviewing the manu-script. R.A.D. is the guarantor of this workand, as such, had full access to all the data inthe study and takes responsibility for the in-tegrity of the data and the accuracy of the dataanalysis.

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