PPARγ agonists as a new class of effective treatment for ulcerative colitis

Lewis JD, Lichtenstein GR, Deren JJ, et al. Rosiglitazone for active ulcerative colitis: a randomized placebo-controlled trial. Gastroenterology. 2008;134:688–695. Peroxisome proliferator–activated receptor gamma (PPARγ) is a nuclear receptor, originally described in adipose tissue, that controls the expression of a large number of regulatory genes in lipid metabolism and insulin sensitization. More recently, high PPARγ expression has been reported in the gut, particularly in colonic epithelial cells where microorganisms such as bacteria and yeast are able to increase its expression and/or activation.1 Well known by endocrinologists, thiazolidinediones (TZDs) are PPARγ synthetic agonists currently used as insulin-sensitizing agents in the treatment of type 2 diabetes. TZDs have drawn the attention of gastroenterologists for several years for their prophylactic and therapeutic effects in different experimental models of acute and chronic colitis, reducing intestinal inflammation by 50% to 70%.2 The first data in patients with inflammatory bowel disease (IBD) was reported in 2001 in an open-label pilot trial, evaluating the efficacy of the PPARγ ligand rosiglitazone (4 mg orally, twice daily) in 15 patients with active UC refractory to conventional treatment with either corticosteroids or immunomodulators and 5-ASA.3 After 12 weeks of treatment with rosiglitazone, a substantial decrease in disease activity index score was reported, with clinical and endoscopic remission (27% and 20%, respectively) or partial response (27%) in 8 patients. Encouraging results were also published in January 2008 in a single-center study enrolling 42 patients with active ulcerative colitis, where a more significant decrease in the Mayo score and histological grades were reported in the 21 patients treated with rosiglitazone 4 mg/day + 5-ASA 2 g/day (21 patients) versus 5-ASA 2 g/day alone (21 patients) for 4 weeks.4 In the March issue of Gastroenterology, Lewis et al reported enrolling 105 patients with mild to moderately active UC (4 ≤ Mayo score ≤ 10) between September 2002 and January 2006 in a 15-center randomized, double blind, placebo-controlled clinical trial comparing the efficacy of rosiglitazone 4 mg/day for 12 weeks versus placebo.5 Most patients had previously been treated with oral steroids (>60%), immunomodulators (>25%), or anti–tumor necrosis factor α (TNFα) antibodies (>15%). The median baseline Mayo score was 7–7.5, and 35% of patients had extensive colitis and were concurrently treated with aminosalicylates (80%) or oral corticosteroids not exceeding prednisone 20 mg/day or budesonide 9 mg/day (30%) or azathioprine/6-mercaptopurine (26%). Patients with liver disease, abnormal liver chemistries, or heart failure were excluded. The primary outcome was clinical response defined as a decrease in Mayo score ≥ 2 from baseline at week 12. Secondary clinical outcomes measured clinical remission (week 12 Mayo score ≤ 2) and endoscopic improvement. After 12 weeks, the clinical response rate was significantly higher in patients treated with rosiglitazone than in those who received placebo (44% versus 23%, P = 0.03). Similarly, clinical remission was achieved in 17% of rosiglitazone-treated patients versus in 2% in the placebo group (P = 0.01). Endoscopic remission was uncommon in all patients, but endoscopic improvement was more frequent with rosiglitazone treatment than with the placebo (40% versus 18%, P = 0.03). The therapeutic effects of rosiglitazone were rapid, leading to an improvement in stool frequency, mucosal appearance at endoscopy, and physician rating of disease activity as early as 4 weeks after the beginning of treatment. No specific subgroup of patients having a particular response to rosiglitazone was identified. Adverse events occurred at similar rates in the 2 groups. Edema, weight increase (<2 kg), and myalgia (4 patients) were more common among patients receiving rosiglitazone. No hypoglycemia or cardiac toxicity was observed. The present study is important, confirming that a high dose of the PPARγ agonist rosiglitazone (4 mg/day) results in a rapid response/remission (44% and 17%, respectively) and an improvement in endoscopic lesions in patients with mild to moderately active UC. Data are consistent with the results obtained in the 2 previous uncontrolled clinical trials in which rosiglitazone was shown to be effective in more than 50% of patients with active UC.3,4 The mechanisms sustaining the anti-inflammatory effects of PPARγ are numerous and distinct from the glucocorticoid receptor, indicating that glucorcorticoids and PPARγ ligands could have additive therapeutic effects.6 In the colon, PPARγ activation plays a central role in the regulation of inflammatory signaling pathways by acting on kinases and transcription factors, such as nuclear factor–κB, c-Jun, c-Fos, and nuclear factor of activated T cell and inhibiting mucosal production of inflammatory cytokines (interleukin-1β and TNFα) and chemokines, proliferation of inflammatory cells, and expression of some adhesion molecules.2 Based on the known distribution of PPARγ in tissues,7 we can hypothesize that the therapeutic effects of the highly selective PPARγ ligand rosiglitazone in UC patients may involve, at least in part, systemic (mainly in the liver, adipose tissue, and muscle) and colonic activation of the receptor. In the colon, the use of mice with targeted disruption of the PPARγ gene has demonstrated that activation of PPARγ expressed by both epithelial cells and lamina propria macrophages has a major protective effect against inflammation.8,9 For rosiglitazone, its local anti-inflammatory effect seems to be mediated only through colonic macrophages residing in the colon and expressing PPARγ because rosiglitazone treatment in mice still attenuates colitis regardless of the presence or absence of PPARγ in colonic epithelium.8 Can rosiglitazone be added to our conventional therapeutic guidelines and recommended in patients with active ulcerative colitis? The ability of rosiglitazone to induce a rapid response in more than 40% of UC patients intolerant or refractory to aminosalicylates (≥2 g/day for at least 4 weeks), with a similar efficacy in all subgroups of patients according to varying extent of disease and their ability to respond to steroids or immunomodulators, is attractive.5 Moreover, the ability of PPARγ activation to prevent the colitis associated cancer10 is additional useful evidence for speculating that the PPARγ ligand may be a promising new therapeutic strategy in UC. The choice of a treatment needs to weigh the benefits and risks. The controversial aspect of the use of rosiglitazone in UC concerns safety issues, particularly the greater risk of myocardial infarction estimated with the last updated myocardial event rates as an odds ratio of 1.29 (95% CI, 1.01–1.66, P = 0.05).11,–13 In fact, cardiovascular adverse events occurred more frequently in subgroups of susceptible patients treated with rosiglitazone for at least 24 weeks,14 having type 2 diabetes, long-term nitrate use, and/or concurrent insulin therapy.15 The mechanism for the apparent increase in the rosiglitazone-induced myocardial infarction rate remains unknown but is not regarded as a PPARγ ligand effect because the other thiazolidinedione pioglitazone widely used to treat type 2 diabetes has significant protective effects on coronary and peripheral vascular events.16 In conclusion, all these data support the interest of targeting PPARγ for the treatment of patients with IBD. The description of 5-ASA as a new PPARγ ligand17 opens avenues for the rational development of novel and more powerful molecules with a topical effect in the gut, a better affinity for PPARγ in colonic epithelial cells, and a result of reduced number of adverse events, allowing their use for induction and maintenance therapy in IBD patients.