Table 1.

Selected key clinical studies of TZDs and related drugs.

Trial/Publication	Type	Design	Details	Outcome	Result	Comment
ADOPT: A Diabetes Outcome Progression Trial (Kahn et al, 2006)	RCT	Patients with newly diagnosed T2DM randomized to rosiglitazone, metformin, or glyburide	4,360 patients, median 4 years	Time to monotherapy failure	Only 15% failure at 5 years for rosiglitazone, lower than 21% for metformin and 34% for glyburide	Supports notion that reducing insulin resistance is beneficial in diabetes pathophysiology
ACT NOW: Actos Now for the prevention of diabetes (DeFronzo et al, 2011)	RCT	Patients with prediabetes randomized to pioglitazone or placebo	602 patients, median 2.4 years	Conversion to diabetes	Pioglitazone decreased conversion to diabetes by 72%	Similar studies previously showed diabetes prevention by troglitazone and rosiglitazone
PIVENS: PIoglitazone or Vitamin E for Nonalcoholic Steatohepatitis (NASH) (Sanyal et al, 2010)	RCT	Patients with NASH and without diabetes randomized to pioglitazone, vitamin E, or placebo	247 patients, 96 weeks treatment	Improvement in histologic features of NASH	Vitamin E, but not pioglitazone, significantly improved primary histological composite endpoint	Pioglitazone improved all secondary endpoints: liver fat, inflammation, and serum aminotransferase levels
Nissen and Wolski, 2007	meta-analysis	Data combined by fixed effects model	42 studies met inclusion criteria	MI or cardiovascular death	Rosiglitazone's odds ratio for MI 1.43 (1.03 to 1.98; P=0.03), for death 1.64 (0.98 to 2.74; P=0.06)	Despite many subsequent studies, the association between rosiglitazone and MI remains controversial (see text for details)
RECORD: Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes (Home et al, 2007)	RCT	Patients with T2DM on metformin or sulfonylurea monotherapy randomized to addition of rosiglitazone	4,447 patients, mean 5.5 years	Cardiovascular hospitalization or death	No significant increase in cardiovascular mortality with rosiglitazone	Re-adjudicated results (Mahaffey et al, 2013) support original conclusions, though study was likely underpowered
BARI 2D: Bypass Angioplasty Revascularization Investigation in type 2 Diabetes (Bach et al, 2013)	post-hoc analysis	In original RCT, patients with T2DM and stable coronary disease were randomized to several interventions	992 on rosiglitazone, mean 4.5 years	Mortality, MI, stroke	No increase in MI on rosiglitazone, with significant decrease in composite endpoint	Agrees with RECORD, though trial not originally designed to study effects of rosiglitazone
TIDE: Thiazolidinedione Intervention with vitamin D Evaluation (Punthakee et al, 2012)	RCT	Patients with T2DM randomized to rosiglitazone, pioglitazone, vitamin D, or placebo	2,553 patients, mean 162 days	MI, stroke, or cardiovascular death	Study initially required by FDA but terminated in 2013 when deemed no longer feasible or necessary	Would have been the only trial comparing rosiglitazone and pioglitazone head-to-head
CHICAGO: Carotid Intima-Media Thickness (CIMT) in Atherosclerosis Using Pioglitazone (Mazzone et al, 2006)	RCT	Patients with T2DM randomized to pioglitazone or glimepiride	462 patients, mean 7.7 years	Change from baseline in CIMT	Pioglitazone slowed progression of CIMT compared to glimepiride	Evidence that pioglitazone is beneficial in atherosclerosis, slowing plaque progression
PERISCOPE: Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation (Nissen et al, 2008)	RCT	Patients with coronary disease and T2DM randomized to pioglitazone or glimeperide	543 patients, duration 18 months	Change from baseline in atheroma	Coronary atheroma volume decreased on pioglitazone, but progressively increased on glimeperide	Evidence that pioglitazone is beneficial in atherosclerosis, even causing plaque regression
PROactive: PROspective pioglitAzone Clinical Trial In macroVascular Events (Dormandy et al, 2005)	RCT	Patients with T2DM and evidence of macrovascular disease randomized to pioglitazone or placebo	5,238 patients, mean 2.9 years	Composite of mortality, MI, stroke, and leg artery revascularization or amputation	Pioglitazone did not affect primary composite endpoint (−10%, P=0.09), but reduced predefined secondary endpoint (mortality, MI, and stroke; −16%, P=0.03)	Pioglitazone is effective in secondary prevention of cardiovascular disease; follow-up analyses showed even more impressive effects in subgroups with prior MI or stroke
Colhoun et al, 2012	database cohort	Scottish national database of prescriptions, hospitalizations, and deaths	37,479 patients exposed to TZD	Hospitalization for hip fracture	Pioglitazone and rosiglitazone increased risk of hip fracture by 15–20% in men and women	Prior studies had shown mainly an association of TZDs with distal extremity fractures in women
Neumann et al, 2012	database cohort	French national databases	155,535 patients exposed to pioglitazone	Incident cases of bladder cancer	Pioglitazone significantly increased bladder cancer by 22%, with dose- and duration-dependent effects	Other studies support a small but significant increase in bladder cancer on pioglitazone, but not rosiglitazone
Colmers et al, 2012b	meta-analysis	4 RCTs, 7 cohort studies, and 9 nested case control studies were pooled	data on 2.5 million patients	Incidence of cancers at various sites	TZDs confer a small (5–10%) but significant decreased risk of lung, colorectal, and breast cancers	Compared to bladder cancer, cancers that TZDs may prevent are more common and have greater morbidity and mortality
AleCardio: a study with Aleglitazar in patients with a recent acute Coronary syndrome and type 2 diabetes mellitus (Lincoff et al, 2014)	RCT	Patients with T2DM and hospitalized with acute coronary syndrome were randomized to aleglitazar versus placebo	7,226 patients, stopped early after median 2 years	Recurrent heart attack, stroke, or cardiovascular death	Aleglitazar did not affect the primary endopoint despite having the expected effects on lipids and glucose	This trial was stopped early due to futility, as this dual PPAR agonist showed no benefit and the suggestion of serious adverse events

Fourteen key clinical studies are summarized, in the order they are presented in the text. RCT: randomized controlled trial.