Table 2.

Clinical Trials

Reference, Study Group, and Treatment	Study Goal, Design, and Years	Disease State and Cohort Size	Inclusion and Major Exclusion Criteria	Primary Outcome and Results	Secondary Outcomes and Results	General and Cardiac Toxicity
Kernan et al., 2016 (7) IRIS Pioglitazone vs. placebo • Initial 15 mg daily • If asymptomatic, increase dose to 30 mg daily at 4 wk and then 45 mg daily at 8 wk	Pioglitazone ↓ rates of stroke and MI in insulin-resistant patients without DM International double-blind, placebo-controlled clinical trial 1:1 ratio pioglitazone/placebo	Insulin-resistant patients with stroke or TIA 3,895 enrolled 3,876 analyzed 1,939 pioglitazone 1,937 placebo	Inclusion • Age >40 yr • Ischemic stroke or TIA 6 mo before randomization • HOMA-IR index >3.0 Major exclusion • DM • NYHA 3–4 • Class 2 HF with ↓ LVEF	Primary outcome Fatal or nonfatal stroke or MI Results • HR for pioglitazone 0.76; 95% CI, 0.62–0.93 (P = 0.007) • Pioglitazone 175/1,939 (9.0%) vs. placebo 228/1,937 (11.8%)	Secondary outcomes • Stroke, MI, or HF resulting in hospitalization or death • Death of any cause • Cognitive decline • DM Results • ↓ Progression to DM in pioglitazone group with HR 0.48; 95% CI, 0.33–0.69 (P < 0.001) • Effect on cognition (ns) Additional metabolic effects • After 1 yr, HOMA-IR index and CRP lower in pioglitazone group; ↓ insulin resistance • Years 1–4 ↓ fasting glucose, triglycerides, and systemic blood pressure; ↑ LDL and HDL in pioglitazone group	General • Pioglitazone ↑ weight gain, edema, shortness of breath, and bone fractures vs. placebo Cardiac toxicity • No ↑ HF in 74 pioglitazone vs. 71 placebo patients (P = 0.80) • No ↑ in HF hospitalizations in 51 pioglitazone vs. 42 placebo patients (P = 0.35) Drug discontinuation • 40% pioglitazone, 33% placebo • Edema, weight gain 172 pioglitazone vs. 51 placebo patients (ns) • HF, repeat fractures, or bladder cancer 146 pioglitazone vs. 117 placebo patients (ns)
Young et al., 2017 (8) IRIS Pioglitazone vs. placebo • Initial 15 mg daily • If asymptomatic, increase dose to 30 mg daily at 4 wk and then 45 mg daily at 8 wk	Pioglitazone ↓ rates of stroke and MI in patients without DM with insulin resistance Secondary analysis of the IRIS trial	Insulin-resistant patients with stroke or TIA 3,895 enrolled 3,876 analyzed 1,939 pioglitazone 1,937 placebo	Inclusion • Age >40 yr • Ischemic stroke or TIA 6 mo before randomization • HOMA-IR index >3.0 Major exclusion • DM • NYHA 3–4 • Class 2 HF with ↓ LVEF	Adjudicated events either UA or MI • Pioglitazone 99 ACS events (61 MI and 38 UA) in 83 patients • Placebo 126 events (80 MI and 46 UA) in 116 patients • HR, 0.71; 95% CI, 0.54–0.94 (P = 0.02)	Secondary outcomes • ACS (UA, fatal or nonfatal MI) Results • Pioglitazone ↓ risk for ST-segment elevation MI with troponin increase >100× ULN or death compared with placebo (18 vs. 36 patients; HR, 0.50; 95% CI, 0.28–0.88; P = 0.02)	General • Pioglitazone ↑ weight gain, edema, shortness of breath, and bone fractures vs. placebo Cardiac toxicity • Pioglitazone ↓ risk of MI vs. placebo; HR, 0.69; 95% CI, 0.48–0.99 (P = 0.04) • Patients with MI with more frequent subsequent HF episodes vs. patients without MI in both treatment groups (16/51 [31.4%] vs. 51/1,872 [2.7%] in pioglitazone group; 17/74 [25.7%] vs. 45/1,854 [2.4%] in placebo group; P < 0.0001 for both)
Young et al., 2018 (51) IRIS Pioglitazone vs. placebo • Initial 15 mg daily • If asymptomatic, increase dose to 30 mg daily at 4 wk and then 45 mg daily at 8 wk	Post hoc secondary analysis to identify which pioglitazone-exposed patients had associated HF among patients without DM with insulin resistance Secondary analysis of the IRIS trial	Insulin-resistant patients with stroke or TIA 3,895 enrolled 3,851 analyzed 1,923 pioglitazone 1,928 placebo	Inclusion • Age >40 yr • Ischemic stroke or TIA 6 mo before randomization • HOMA-IR index >3.0 Major exclusion • DM • NYHA 3–4 • Class 2 HF with ↓ LVEF	Adjudicated episodes of HF • Pioglitazone 187 HF events in 151 patients. Among 67 patients with HF, 15 died (1 of HF) • Placebo 180 HF events in 144 patients. Among 66 patients with HF, 17 died (2 of HF) • For any HF episodes, HR, 1.04; 95% CI, 0.73–1.44 (P = 0.89)	Secondary outcomes • ACS (UA, fatal or nonfatal MI) Results • Pioglitazone ↓ risk for ST-segment elevation MI with troponin increase >100× ULN or death compared with placebo (18 vs. 36 patients; HR, 0.50; 95% CI, 0.28–0.88; P = 0.02)	General • Pioglitazone ↑ weight gain, edema, shortness of breath, and bone fractures vs. placebo Cardiac toxicity • Pioglitazone ↓ risk of MI vs. placebo; HR, 0.69; 95% CI, 0.48–0.99 (P = 0.04) • Patients with MI with more frequent subsequent HF episodes vs. patients without MI in both treatment groups (16/51 [31.4%] vs. 51/1,872 [2.7%] in pioglitazone group; 17/74 [25.7%] vs. 45/1,854 [2.4%] in placebo group; P < 0.0001 for both)
Viscoli et al., 2017 (64) IRIS Pioglitazone vs. placebo • Initial 15 mg daily • If asymptomatic, increase dose to 30 mg daily at 4 wk and then 45 mg daily at 8 wk	Characterize fractures associated with pioglitazone by location, mechanism, severity, timing, and sex Secondary analysis of the IRIS trial	Insulin-resistant patients with stroke or TIA; 3,895 enrolled 3,876 analyzed 1,939 pioglitazone 1,937 placebo	Inclusion • Age >40 yr • Ischemic stroke or TIA 6 mo before randomization • HOMA-IR index >3.0 Major exclusion • DM • NYHA 3–4 • Class 2 HF with ↓ LVEF	Primary outcome • Fracture associated with pioglitazone use Results • Pioglitazone increased the absolute fracture risk by 1.6–4.9% and the relative risk by 47–60%, depending on the fracture classification		General • Pioglitazone ↑ weight gain, edema, shortness of breath, and bone fractures vs. placebo Cardiac toxicity • Not assessed
Tanaka et al., 2018 (65) PRIDE Study Investigators Pioglitazone vs. placebo • Initial 15 mg daily • If asymptomatic, increase dose to 30 mg daily	Determine if pioglitazone affects cardiometabolic profiles and cardiovascular safety in patients with T2DM who underwent elective PCI Prospective, multicenter, open-label, randomized study in Japan 1:1 ratio of pioglitazone/placebo	T2DM 94 enrolled (48 pioglitazone, 46 control), 71 completed study (39 pioglitazone, 32 control)	Inclusion • T2DM with elective PCI Major exclusion • Symptomatic HF • Serious liver or renal dysfunction at time of elective PCI	Primary outcome • Effects of pioglitazone on change in cardiometabolic profiles at 48 h post-PCI and at follow-up coronary angiography at 5–8 mo Results • BNP and NT-proBNP elevated vs. baseline at 48 h post-PCI (ns) • BNP and NT-proBNP at follow-up CAG were ↓ than baseline in pioglitazone group	Secondary outcomes • Change from baseline in systemic blood pressure • Body weight, glycemic control (HbA1c and fasting plasma glucose) • Lipid profiles • Renal function • Echocardiographic cardiac function Results • Nonsignificant ↑ BNP and NT-proBNP vs. baseline at 48 h post-PCI • BNP and NT-proBNP at follow-up CAG were significantly ↓ compared with baseline in pioglitazone group	General • Hypoglycemia • Peripheral edema Cardiac toxicity • Pioglitazone 1 patient subacute stent thrombosis 3 d after elective PCI • 5 patients (12.8%) in pioglitazone group and 5 patients (15.6%) in control group needed coronary revascularization at follow-up CAG • No HF in pioglitazone group Drug discontinuation in pioglitazone group • Lower extremity edema (n = 1) • Hypoglycemia (n = 1)
Breunig et al., 2014 (66) Rosiglitazone vs. pioglitazone vs. metformin	Determine the relative risk of HF development in high-risk, underrepresented patients starting treatment with rosiglitazone or pioglitazone and metformin in real-world practice Retrospective cohort analysis of Maryland state Medicaid and managed care or fee-for-service programs	T2DM 6,271 enrolled 5,548 (88%) started on metformin 413 (7%) started on pioglitazone 310 (5%) started on rosiglitazone	Inclusion • T2DM newly initiated on metformin monotherapy or pioglitazone or rosiglitazone within 6 mo Major exclusion • N/A	Primary outcome • Patients receiving rosiglitazone had ↑ risk of HF compared with patients receiving metformin • No difference in HF rates between pioglitazone and metformin • HF incidence was 7.7% for the sample: 7.0% (n = 389) among patients started on metformin, 8.0% (n = 33) for pioglitazone, and 19% (n = 59) for rosiglitazone at mean follow-up of 1.6 yr	Secondary outcomes • Compare risk of HF associated with rosiglitazone vs. pioglitazone in a subsample of patients started on TZDs Results • Subsample of rosiglitazone patients matched to pioglitazone patients had 72% ↑ risk for HF (HR, 1.72; 95% CI, 1.08–2.74; P = 0.023)	General • None reported Cardiac toxicity • HF Drug discontinuation • Proportion started on pioglitazone stayed at 5–6% • Proportion started on rosiglitazone ↓ from 6.5% to 1.6% after 2006
van der Meer et al., 2009 (43) PIRAMID Pioglitazone vs. metformin • 15 mg once daily • Titrated to 30 mg once daily after 2 wk	Evaluate pioglitazone vs. metformin effects on myocardial function, dimensions, and perfusion in association with cardiac glucose, fatty acid metabolism, triglycerides, and high-energy phosphate metabolism 24-wk prospective, randomized, double-blind, double-dummy with active comparator, two-center parallel-group intervention	78 enrolled 34 pioglitazone 37 metformin	Inclusion • Men aged 45–65 yr with uncomplicated T2DM without ischemic heart disease • Glycohemoglobin concentration 6.5–8.5% at screening, BMI of 25–32 kg/m2, and blood pressure not >150/85 mm Hg (with or without antihypertensives) Major exclusion • Cardiovascular disease • Liver disease • DM-related complications	Primary outcome • Change baseline to follow-up at 24 wk in diastolic function Results • Pioglitazone ↑ in indices of diastolic function, ↑ LVEDP, and improved LV compliance • Pioglitazone ↑ stroke volume • Metformin did not impact diastolic parameters	Secondary outcomes • Difference in cardiac dimensions, systolic function, blood pressure, myocardial metabolism, perfusion variables, hepatic and myocardial triglycerides, plasma lipids, BMI, glycohemoglobin, and whole-body insulin sensitivity Results • Pioglitazone ↑ HDL and weight gain and ↓ hepatic triglycerides • No difference between groups on ↑ insulin sensitivity, systolic BP • No change in myocardial fatty acid uptake, but metformin ↓ myocardial fatty acid oxidation • Additional metabolic effects: ↓ plasma lactate in pioglitazone compared with metformin	General • None reported Cardiac toxicity • No fluid retention or HF Drug discontinuation • Patient decision (n = 1) • Loss of glycemic control (n = 2) • Hypertriglyceridemia requiring therapy (n = 1) • Incidentaloma (n = 1)

Definition of abbreviations: ACS = acute coronary syndrome; BMI = body mass index; BP = blood pressure; BNP = brain natriuretic peptide; CAG = coronary angiography; CI = confidence interval; CRP = C-reactive protein; DM = diabetes mellitus; HbA1c = glycated hemoglobin; HDL = high-density lipoprotein; HF = heart failure; HOMA-IR = homeostatic model assessment of insulin resistance; HR = hazard ratio; IRIS = Insulin Resistance Intervention after Stroke trial; LDL = low-density lipoprotein; LV = left ventricle; LVEDP = left ventricular end-diastolic pressure; LVEF = left ventricular ejection fraction; N/A = not applicable; ns = nonsignificant; NYHA = New York Heart Association; PCI = percutaneous coronary intervention; PIRAMID = Pioglitazone Influence on Triglyceride Accumulation in the Myocardium in Diabetes; PRIDE = Pioglitazone Reduce Inflammation and Restenosis with and without Drug Eluting Stent; T2DM = diabetes mellitus type 2; TIA = transient ischemic attack; TZD = thiazolidinediones; UA = unstable angina; ULN = upper limit of normal.

See data supplement for more detailed table (Table E1).