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Norris SL, Carson S, Thakurta S, et al. Drug Class Review: Thiazolidinediones: Final Report Update 1 [Internet]. Portland (OR): Oregon Health & Science University; 2008 Aug.

Appendix ESystematic reviews identified for the update review

Author Year

AimsDatabases searched; Literature search dates; Other data sourcesEligibility criteriaNumber of trials/Number of patientsCharacteristics of identified articles: Study designsCharacteristics of identified articles: populationsCharacteristics of identified articles: InterventionsEfficacy and effectiveness resultsSubgroupsAdverse eventsComments
Berlie 2007To obtain a precise estimate of the odds for developing TZD-induced edema and to compare rates between pio and rosi and with various combinations of oral agentsMedline (1966-5/2006), CINHAL (1982-5/2006), Cochrane Control Trials Register (to 1st quarter 2006), EMBASE (1996–2005)
“manual search for review articles and original manuscript” (no details)
Abstracts; ADA, AHA, ACC (2003-present)
Takeda and GlaxoSmithKline were contacted for studies in their new Drug Applications
Prospective, RCTS, active- or placebo-controlled; monotherapy or combined therapy; data on edema26 RCTs
15,332 subjects with DM2
7/26 were open label trialsAll subjects with DM2
Average age range across studies: 53.7 to 61.9y
Average duration diabetes across studies: 5.6m to 13.6y
Mean baseline A1c across studies 7.5 to 10.2% with pio and 7.9 to 9.1% with rosi
Total daily dosage (mg)
Monotherapy-placebo trials: pio 7.5–45, rosi 4–8
Combination trials: pio 15–30; rosi 4–8
A1c mean reduction; 0.56 – 2.3%NoneWeight gain (kg): pio −0.59 3.86; rosi 1.2 to 5.0
Pooled OR:
All included studies (pio and rosi, all comparators): 2.26(95% CI, 2.02 – 2.53), P <0.000001
Placebo-controlled pio compared with rosi, indirect comparisons: 3.03(95% CI, 2.15 – 3.91)
TZD monotherapy placebo-controlled studies: 2.35 (95% CI, 1.40 – 3.91)
TZD combination therapy placebo- or no-treatment control: 2.14 (95% CI, 1.88 – 2.43)
Bolen 2007
(and AHRQ 2007 Review)
To summarize the literature on the benefits and harms of oral agents in the treatment of adults with type 2 diabetesMedline, EMBASE, Cochrane Central Register of Controlled Trials (inception to 1/2006); industry data and FDA web-site; hand search 15 journals, reviewed reference listsEnglish-language, assessed benefits and/or harms of oral diabetes drugs (excluding 1st generation SU) compared to other oral agents (not insulin)RCTs: 216
Systematic reviews: 2
Intermediate outcomes: 135 RCTs and 1 systematic review
Final health outcomes:
Adverse events: 167 studies, 1/3 of which were RCTs; 2 systematic reviews
Adults with type 2 diabetesVarious dosages and combinationsA1c: decreased 1% which was similar to SU and metformin
HDL: pio increased more than rosi (1–2 mg/dL); pio increased compared with metformin or SU (3–5 mg/dL)
LDL: rosi increased LDL more than pio (10–15 mg/dL)
Triglycerides: pio decreased (15–52 mg/dL) compared with rosi (increase 6–13 mg/dL); pio decreased more than metformin
Age, sex, comorbiditiesMortality: insufficient data
CV D mortality: insufficient data
CHF: risk is increased with TZDs compared with other oral agents
Microvascular outcomes: insufficient data

Weight: TZDs increased weight similar to SU (3kg) as monotherapy or in combination with other oral agents; TZDs increased weight compared with metformin, acarbose, and repaglinide

Hypoglycemia: less frequent with TZDs than SU (risk difference 4–9%)
Edema: TZDs higher risk than SU (absolute risk difference 2 to 21%)
CHF: TZDs higher risk than with metformin or SU, absolute risks 0.8 to 3.6%; absolute risk difference 0.7 to 2.2%)
Mild anemia: TZDs higher risk than other drugs (absolute risk difference 1 to 5%)
Elevated ALT: low rates (<1%) with TZDs

Hospitalizations for acute cholecystitis: pio 12 patients compared with placebo 1 patient (pooled, unpublished analysis of 1526 patients)
Eurich 2007To review literature on the association between antidiabetic agents and morbidity and mortality in people with heart failure and diabetesMedline, Health-STAR, EMBASE, CINAHL, international Pharmaceutical Abstracts, Allied and Complementary Medicine, cochran Controlled Trials
Register date of inception to 7/07
Manual search reference lists; contacted experts
Contemporaneous comparison group; examined association between antidiabetic agents and hospital admission or mortality4 TZD trials
22,476 patients
Unclear from review; reviewing primary studies, 1 RCT and 3 cohort with comparisonPatients with diabetes and heart failureTZD compared with a variety of comparators and placeboNRNRPooled OR for TZDs compared with other treatments for all cause mortality: 0.83 (95% CI, 0.71 – 0.97)
Pooled OR for TZDs compared with other treatments on hospital admissions for heart failure 1.13 (95% CI, 0.1.04 – 1.22)
Pooled estimates included observational studies and RCTs AEs
Lagu 2007To examine the risk of heart failure and of cardiac death in patients given TZDsMedline, Database of Abstracts of Reviews of Effects, Cochrane Library; up to 3/2007; start date NR; databases of European Society of Cardiology, AHA, ACC, ADA by hand; reference listsRCTs, double-blind studies with risk estimates or frequency data for congestive heart failure and cardiovascular death7 trials
20191 patients
RCTs onlyDiabetes and prediabetesTZD compared with a variety of comparators and placeboNRNRRisk of CHF compared to controls (placebo- and active-controlled trials): RR 1.72 (95% CI, 1.21 – 2.42), P =0.002; placebo-controlled trials only: RR 1.97 (95% CI, 0.94 – 4.13); pio only: RR 1.32 (95% CI, 1.04 – 1.68); rosi only: RR 2.18 (95% CI, 1.44 – 3.32), P =0.0003
Risk of cardiovascular death compared to controls: RR 0.93 (95% CI, 0.67 – 1.29), P =0.68; placebo-controlled trials only: RR 1.08 (95% CI, 0.66 – 1.76): pio only: RR 1.01 (95% CI, 0.51 – 2.09); rosi only: RR 0.91 (95% CI, 0.63 – 1.3)

Overall event rate for CHF: TZD 2.3%; comparator group 1.4%

NNH for CHF 107 over 29.7m F/U; range 35 to 491
Phatak, 2006To examine factors affecting the size of A1c response to TZDsPubMed, EBSCO, Sci-lit; dates
GlaxoSmithKline public web-site
RCTs, English-language, placebo- and active-controlled42
8322 subjects
RCTs onlyDiabetes; mean age 57.5y; 42.3% female subjects; baseline A1c 8.9% (SD 0.8)TZDs compared with a variety of comparators and placebo; 50% of studies were monotherapy; mean baseline A1c 9.1%(SD 1.0)Weighted between-group change in A1c (all comparators)
TZDs: −0.82% (SD 0.13)
Pio: −1.04% (SD 0.07)
Rosi: −0.67% (SD 0.10)

Weighted between-roup change in A1c for placebo-controlled trials:
Pio: −1.03 (SD 0.19)
Rosi: −0.98 (SD 0.18)

Change in A1c greater with higher baseline A1c (>9.0%) (no statistics)
Duration of study treatment correlated with decrease in A1c (P =0.003)
Study duration, age, sex duration therapy examined with meta-regressionNR
Riche, 2007To evaluate the impact of TZDs on repeat TVR after PCIMedline, EMBASE, CINAHL, Cochrane database; through 7/2006 (start date NR); English only; abstracts from AHA, ACC, ADA searched 2001 – 2006RCTS evaluating TZDs compared with standards of care; ≥ 6m follow-up; data provided on repeat TVR with number of patients receiving repeat TVR reported7
608 subjects
RCTs only; all placebo-controlled with comparator standard drug therapy1/7 studies non-diabetic;
1/7 metabolic syndrome;
5/7 type 2 diabetes
Pio or rosi given at various dosages either 1-day pre-operatively or 1–2 weeks post-operativelyRepeat TVR RR
Overall: range 0.13 to 0.67; pooled estimate 0.35 (95% CI, 0.22 – 0.57)
Pio: 0.24 (95% CI, 0.11 –0.51)
Rosi: 0.45 (95% CI, 0.25 – 0.83)
Diabetes: 0.34 (95% CI, 0.19 – 0.63)
No diabetes: 0.37 (95% CI, 0.18 – 0.77)
Pio, rosi, diabetes, no diabetesNR
Richter, 2007 (Rosi cochran)To assess the effects of rosi in the treatment of type 2 diabetesMedline, EMBASE, Cochrane database; last search 8/2006; reference lists searchedRCTs in adults with type 2 diabetes; study duration ≥ 24w18
RCTs only; various comparatorsType 2 diabetes, largely Caucasian populations; mostly persons on other oral hypoglycemic agents; mean age patients 47 – 61y; diabetes duration 4 – 9y; baseline A1c 6.8 – 9.5%, mean 8.8%Rosi mono- or combined therapy at various dosagesMortality: only reported by 1 study (ADOPT): 2.3% with rosi, 2.1% metformin, 2.2% glyburide

A1c: similar reductions with rosi as metformin, glibenclamide, or glimepiride
NREdema: OR rosi compared with comparators, random effects model: 4.62 (95% CI, 2.28 – 9.38)

Severe hypoglycemic episodes: somewhat lower with rosi than active monotherapy, particularly SU; no pooled data and no statistics

From ADOPT trial only:
CVD events: % serious/% total events: rosi 3.4/4.3; metformin 3.2/4.0; glyburide 1.8/2.8 CHF, total events (%): rosi 1.5, metformin 1.3, glyburide 0.6
Fracture rates: higher with rosi than; no statistics reported
Richter, 2006 (Pio cochran)To assess the effects of pio in the treatment of type 2 diabetesMedline, EMBASE, Cochrane database; last search 8/2006; reference lists searchedRCTs in adults with type 2 diabetes; study duration ≥ 24w22
RCTs only; various comparatorsType 2 diabetes, largely Caucasian populations; mostly persons on other oral hypoglycemic agents; mean age patients 53 – 63y; diabetes duration 3 – 14y; baseline A1c 7.4 – 10.3%Pio mono- or combined therapy at various dosagesMortality: only reported by 1 study (Proactive) as part of a composite endpoint (mortality, stroke, nonfatal MI, surgical vascular intervention: placebo-controlled, HR 0.90 (95% CI, 0.80 – 1.02)

A1c: reductions similar to other oral agents
NR7/22 trials reported AEs
Overall and serious AEs comparable between intervention groups
Hb: decrease noted in 6 studies examining this outcome: range 0.5 – 0.75 g/dL
Weight: increased in 15 studies examining this outcome: up to 3.9kg

Edema: RR 2.86 (95% CI, 1.14 – 3.18)

Hypoglycemia episodes: Pio rates < SU rates; pio + insulin increased rates
No pooled data and no statistics
Rosmarakis, 2007To review RCT evidence on the effect of TZDs on in- stent restenosis after PCIPubMed, last search 6/2006; reference lists reviewedRCTs examining TZDs compared with various comparators and effect on in-stent restenosis after coronary stent implantation; in English5
235 (text states 259)
RCTs only; various comparators4/5 studies diabetes; 1/5 non diabetesPio or rosi; dosages and use of other oral agents NR; first dose of TZD given between 1d prior to procedure up to 2w after; 3/5 studies compared pio to standard treatment; 2/5 studies compared pio to rosi; all studies 6 month durationRestenosis rate measured with quantitative coronary angiography at 6m: pio or rosi compared with standard therapy: OR 0.29 (95% CI, 0.15 – 0.56)NRMortality: 2/259: 1 in control arm; 1 with TZD
“No drug-related side effects”
Singh 2007 (Diabetes Care)To evaluate the risk of CHF with TZDs in type 2 diabetes and to classify this AE under the dose-time-susceptibility systemRCTS: existing reviews; PubMed (1/2003 to 9/2006); manufacturer’s web-site Controlled observational studies and case reports: PubMed (to 9/2006, start date NR); Web of Knowledge Cited References and PubMed related articles Case reports also: EMBASE, Google Scholar (to 9/2006, start date NR)Controlled observational studies with data to calculate OR of new onset CHF in patients receiving TZDs compared with other oral agents Case reports with CHF and TZDRCTs: 3

Observational studies: 4

Case reports: 162
case subjects
RCTs, observational studies, case reportsPrediabetes or diabetesTZD compared with placebo at various dosagesNRNRNew onset CHF:
RCTs: (3): OR 2.1 (95% CI, 1.08 – 4.08)
Observational studies: (4): OR 1.55 (95% CI, 1.33 – 1.80)
Case reports: 162 case subjects with 99 analyzable cases; median duration of onset of CHF 24w; CHF occurred in subjects <60y (26% of cases) and with low and high dosage
Singh 2007 (JAMA)To review the long-term cardiovascular risks of rosiMedline, GlaxoSmithKline clinical trials register, FDA website; product information sheets; last search 5/2007RCTs in DM2 or IGT and trial duration ≥ 12m; provided numerical data on all AEs and monitored CVD AEs4
Also 3 systematic reviews
RCTs, systematic reviews, meta- analyses; rosi compared with placebo or active oral agentPrediabetes or type 2 diabetesRosi compared with active drug or placeboNRNRRelative risk (95% CI) rosi compared with comparator:
MI: 1.42 (1.06 – 1.91)
Heart failure: 2.09 (1.52 – 2.88)
CV mortality: 0.90 (0.63 – 1.26)

Number needed to harm:
MI: 822 per year with rosi if baseline risk 0.29% (low risk, ADOPT)
CHF; 383 per year with rosi if baseline risk 0.24 (low risk, ADOPT)

Abbreviations: ACC, American College of Cardiology; AEs, adverse events; ADA, American Diabetes Association; AHA, American Heart Association; CHF, congestive heart failure; CVD, cardiovascular disease; DM2, type 2 diabetes mellitus; m, month(s); MI, myocardial infarction; NR, not reported; NSD, no significant difference; OR, odds ratio; PCI, percutaneous coronary intervention; pio, pioglitazone; RCTs, randomized controlled trials; rosi, rosiglitazone; RR, relative risk; SU, sulfonylurea; TVR, target vessel revascularization; TZD, thiazolidinedione; w, week(s); y, year(s).

Copyright © 2008, Oregon Health & Science University, Portland, Oregon.
Cover of Drug Class Review: Thiazolidinediones
Drug Class Review: Thiazolidinediones: Final Report Update 1 [Internet].
Norris SL, Carson S, Thakurta S, et al.
Portland (OR): Oregon Health & Science University; 2008 Aug.

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