Background
Methods
Literature search
Study selection and data abstraction
Quality assessment
Data synthesis and analysis
Results
Study selection and characteristics of included studies
Author, year | Source population, study period | Study design, population, age | Diabetes Type 2 population definition | Study endpoint ascertainment (Number of cases) | Case validation | Exposure assessment | Exposure recency | Exposure Group(s) (n) vs. reference group (n) |
---|---|---|---|---|---|---|---|---|
A: Comparison(s) Contributing to Meta-analysis | ||||||||
B: Other Reported Comparison(s) | ||||||||
Studies included in the meta-analysis (n = 12) | ||||||||
Chou [33] | Taiwan Longitudinal Health Insurance Database 1998-2006 | Cohort N = 7725 < 110 years | ICD-9 code 250.xx in the study period with prescriptions for glitazones | Incident outpatient and emergency department diagnoses of nonfatal HF (ICD-9: 428 and diuretic use) (N = 356) | None | Prevalent and new users Dispensed prescriptions | Current, continuous use of more than 120 days in last 180 days after index date of cohort inclusion | A: Rosiglitazone (n = 6048) vs. pioglitazone (n = 1677); as add-on treatment to other medications |
Graham [34] | Medicare, USA 2006-2009 | Cohort N = 227571 ≥ 65 years | First prescriptions for glitazones | Hospitalization for HF (ICD-9: 402.x1; 404.x3; 428) (N = 3307) | External; PPV: range, 85%-96% | New users Dispensed prescriptions | Current, continuous use including 7 days gap | A: Rosiglitazone (n = 67593) vs. pioglitazone (n = 159978) |
Horsdal [35] | Danish National Registries, Denmark 1996-2004 | Cohort N = 8494 Patients hospitalized for AMI receiving monotherapy with OHA | Subjects were classified as with T1DM and excluded if they were younger than 30 years at the time of their first related prescription or diagnosis and had never received a prescription for an oral glucose-lowering drug. Subjects with T2DM were those with codes for diabetes mellitus who had not received pharmacotherapy, or had received prescriptions for oral glucose-lowering drugs, or were older than 30 years when they had their first diagnostic code or prescription. | Hospital admission for HF (ICD-10: I11.0, I13.0, I13.2, I25.5, I42.0, I42.7, I42.8, I42.9, I50.0, I50.1, I50.9) within 1 year of AMI (N = NR) | None | Prevalent and new users Dispensed prescriptions | At least one prescription of study drug within 90 days before hospitalization | A: Metformin monotherapy (n = 396) vs. SU monotherapy (n = 2382) |
Hsiao [36] | Taiwan Longitudinal Health Insurance Database 2001-2005 | Cohort N = 473483 Age, NR | Subjects with their first ambulatory visit with ICD-9-CM code 250.xx who were prescribed oral blood glucose lowering agents at least three times. Subjects were excluded if they had T1DM (ICD-9-CM codes 250.x1) or if they had been prescribed insulin only during the study period. | Hospitalization for HF (ICD-9: 428, 402.01, 402.11, 402.91; 404) (N = 2530) | None | New users Dispensed prescriptions | Current, continuous use during study period | A: Pioglitazone monotherapy (n = 495) or rosiglitazone monotherapy (n = 2093) vs. metformin-based therapy (n = 46444) and vs. SU-based therapy (n = 97651) B: Pioglitazone + SU + metformin (n = 9510) vs. Rosiglitazone + SU + metformin (n = 39962) Pioglitazone + metformin (n = 774) vs. Rosiglitazone + metformin (n = 2408) Pioglitazone + SU (n = 1231) vs. Rosiglitazone + SU (n = 5141) |
Juurlink [37] | Ontario diabetes database, Canada 2002-2008 | Cohort N = 39736 ≥ 66 years | First prescription for a glitazone. | Hospitalization for HF (ICD-10: I50) (N = 1330) | External; PPV ≈ 90% | New users Dispensed prescriptions | Current use, if refill occurred < 1.5 times the days’ supply of the preceding glitazone claim | A: Pioglitazone (n = 16951) vs. rosiglitazone (n = 22785) |
Karter, [38] | Kaiser Permanente, diabetes registry, USA 1999-2001 | Cohort N = 23440 Age, mean (SD): 58.9 (12.3) years | Diagnosis of T2DM in the Kaiser Permanente Northern California Diabetes Registry, initiation of diabetes treatment, and at least one refill of the initial drug. | Incident; excluded within 5 years prior to baseline outpatient, emergency or hospital discharge diagnoses of CHF Hospitalization for CHF (ICD-9: 428; 401.91, 402.01, 402.11, 402.91; 404.01, 404.03, 404.11, 404.13, 404.93, 425.1, 425.4, 425.5, 425.7) (N = 320) | External, PPV = 97% | New users Dispensed prescriptions | Current, continuous use during study period | A: Pioglitazone (n = 3556) or metformin (n = 11937) vs. SU (n = 5921) as single index therapy but with other maintenance therapy |
Koro [39] | GPRD, United Kingdom 1987-2001 | Nested case–control N = 9089 ≥ 30 years | The cohort follow-up started with the earliest diagnosis of T2DM in the electronic medical record. | First ever diagnosis of CHF according to GPs recorded OXMIS/Read codes (N = 1301) | External | Prevalent and new users Prescriptions issued | Current use in last 3 months before index date (case date or matched date for controls) | A: Metformin (152 cases; 915 controls) or metformin + SU (177 cases, 817 controls) vs. SU (591 cases, 3547 controls) |
Loebstein [40] | Maccabi Healthcare Services, Israel 2000-2007 | Cohort N = 15436 Age, mean (SD): 59.1 (11.4) years | Subjects in the Maccabi diabetes registry with prescriptions for rosiglitazone or metformin for at least 6 months. | Hospitalization for HF (wrong code reported as ICD-9 150) (N = NR) | None | Prevalent and new users Dispensed prescriptions | Current, continuous use within study period with gaps not longer than 3 months | A: Rosiglitazone monotherapy (n = 745) or in combination with metformin (n = 2753) vs. metformin monotherapy (n = 11938) (Formulary restriction for rosiglitazone only if not adequate control after SU, metformin, or both) |
McAlister [41] | Saskatchewan Health beneficiaries, Canada 1991-1996 | Cohort N = 5631 ≥ 30 years | New prescription for an oral blood glucose-lowering drug. The authors describe the study population as subjects with recent onset of diabetes. | Incident during prior 3 years Hospitalization for CHF or physician visit with HF diagnosis (ICD-9: 428) (N = 981) | External | New users Dispensed prescriptions | At least one prescription for an OHA | A: SU (glyburide, chlorpropamide or tolbutamide) monotherapy (n = 4162) vs. metformin monotherapy (n = 1469) |
Tzoulaki, [42] | GPRD, United Kingdom 1990-2005 | Cohort N = 91521 35-90 years | One episode of care associated with a clinical or referral event for diabetes and prescriptions for oral blood glucose-lowering treatment. | First ever diagnosis of CHF according to Read codes (N = 6900) | External; confirmed 83% of the CHF diagnoses | Prevalent and new users Prescriptions issued | Current, continuous intervals of use within the study period | A: First-generation SU monotherapy (n = 6053) or second-generation SU monotherapy (n = 58095) or rosiglitazone monotherapy (n = 8442) and combination therapy (n = 9640) or pioglitazone including monotherapy and combination therapy (n = 3816) vs. metformin (n = 68181) B: Glibenclamide or gliclazide or glimepiride or glipizide or gliquidone vs. metformin (n = 68181) |
Wertz [43] | HealthCore Integrated Research Database, USA 2001-2005 | Cohort N = 36628 ≥ 18 years | First prescription for glitazones. | Hospitalizations for AHF (ED visits included) (ICD-9: 402.01, 402.11, 402.91; 404.01, 404.03, 404.11, 404.13, 404.91, 404.93) (N = 508) | None | New users Dispensed prescriptions | Current use, if refill occurred < 1.5 times the days’ supply of the preceding claim for TZD | A: Rosiglitazone (n = 14469) vs. pioglitazone (n = 14469) |
Winkelmayer [44] | Medicare, New Jersey, USA 1999-2005 | Cohort N = 28361 > 65 years | First prescription for a glitazone, regardless of previous treatment with other diabetes drug. | Hospitalization for CHF (ICD-9: 428) (N = 1259) | External PPV = 94% | New users Dispensed prescriptions | Current, continuous use until 60 days after the supply date of their most recently filled prescription duration or until switching to other TZD | A: Rosiglitazone (n = 14101) vs. pioglitazone (n = 14260) |
Studies reviewed but not included in the meta-analysis (n = 8)
| ||||||||
Delea [45] | Pharmetrics integrated outcomes database USA 1997-2001 | Cohort N = 33544 ≥ 18 years | Subjects with one or more claims with ICD-9 codes 250.x0 or 250.x2 and one or more prescriptions for oral blood glucose-lowering drugs (first prescription in the case of glitazones). | First ever inpatient or outpatient claim for CHF (ICD-9-CM: 402.11, 402.91, 428, 428.0, 428.1, 428.9) (N = 423) | None | New users Dispensed prescriptions | Current, continuous use with permitted gaps of 90 days after the last refill | A: NA B: Troglitazone or rosiglitazone or pioglitazone (n = 5441) vs. other OHA or vs. non-TZD noninsulin OHA or vs. no use of TZD (n = 28103) |
Habib [46] | Henry Ford, USA 2000-2006 | Cohort N = 19171 > 18 years | Subjects with one or more claims with ICD-9 code 250.xx and one or more prescriptions for oral blood glucose-lowering drugs. | Hospitalization for CHF (codes not reported) (N = 2725) All-cause mortality | None | Prevalent and new users Dispensed prescriptions | Days’ supply of medication dispensed in a 6-month period divided by the number of days | A: NA B: Rosiglitazone, pioglitazone, or rosiglitazone + pioglitazone(n = 4580) vs. other OHA or vs. nonuse of TZD (n = 14591) |
Hartung, [47] | Medicaid USA 1999-2001 | Case–control N = 1940 ≥ 18 years | Subjects were eligible as cases or controls if they had one or more records with ICD-9 code 250.xx as primary diagnosis and one or more prescriptions for oral blood glucose-lowering drugs. | Hospitalization for HF (DRG 127.xx) (N = 288) (Controls: hospitalizations for other conditions) | None | Prevalent and new users Dispensed prescriptions | Current, at least use of one prescription within 60 days before index hospitalization for cases and controls | A: NA B: TZD (n = 275) vs. nonuse of TZD (n = 1665) B: TZD (n = 275) vs. nonuse of TZD (n = 1665) |
Horsdal [48] | Danish National Registries, Denmark 1996-2004 | Cohort N = 3930 Patients aged ≥ 30 years hospitalized for AMI | At least one prescription for a sulfonylurea in the 90 days before hospitalization for myocardial infarction. | Hospital admission for HF within 1 year of AMI (ICD 10: I11.0, I13.0, I13.2, I25.5, I42.0, I42.6-I42.9, I50.0, I50.1, I50.9) (N = 329) | External | Prevalent and new users Dispensed prescriptions | Use of at least one prescription of study drug within 90 days before the index hospitalization for AMI | A: NA B: Gliclazide (n = 216) or glimepiride (n = 906) or glipizide (n = 616) or glibenclamide (n = 1238) vs. tolbutamide (n = 472) |
Hsiao [49] | Taiwan Longitudinal Health Insurance 2001-2005 | Cohort N = 8139 Patients hospitalized for CHF and prescribed either TZD or SU monotherapy | At least one code for T2DM (ICD-9 code 250.xx [sic]). Subjects were excluded if they had T1DM (mechanism for identification not explained) or if they only had prescriptions for insulin during the study period (description not clear). | Hospital readmission for HF (ICD-9: 428, 402.01, 402.11, 402.91, 404.01, 404.03, 404.11, 404.13, 404.91, 404.92) (N = 2536) | None | Prevalent and new users Dispensed prescriptions | Cumulative use (DDD) since index hospitalization | A: NA B: TZD (n = 7023) vs. SU (n = 204) |
Lipscombe [50] | Ontario Health Care Database, Canada 2002-2006 | Nested case–control N = 159026 ≥ 66 years | Subjects registered in the Ontario Diabetes Database were followed since their last prescription for an oral hypoglycemic agent. | Hospitalization for CHF or emergency visit (ICD 10: I50) (N = 12491) | External | Prevalent and new users Dispensed prescriptions | Current, use in last 14 days before index date (admission date and corresponding date for matched controls) | A: NA B: Rosiglitazone or pioglitazone monotherapy or combination (n = 1692) vs. other OHA monotherapy or combination (n = 87253) |
Rajagopalan [51] | Pharmetrics integrated outcomes database USA 1999-2002 | Cohort N = 3336 ≥ 18 years | Subjects with one or more claims with ICD-9 code 250.x0 or 250.x2 and/or “evidence of use of antidiabetic medications who began receiving pioglitazone or insulin” during the study period. | First ever, ≥ 1 provider or facility claim with diagnosis of CHF or ≥ 1 inpatient claim with CHF diagnosis (n = NR) | None | New users Dispensed prescriptions | Continuous use for ≥ 90 days of the index therapy | A: NA B: Pioglitazone (n = 1668) vs. insulin as monotherapy or with metformin or SU (n = 1668) |
Toprani [52] | USA Veterans Administration 1999-2004 | Cohort N = 3956 (only males) | Subjects with one more records with ICD-9 code 250.xx and one or more prescriptions for thiazolidinediones. | First ever, at least one inpatient or outpatient visit with a recorded diagnosis of CHF (ICD-9: 428) (N = 1157) | None | Prevalent and new users Dispensed prescriptions | Users of at least 2 OHAs | A: NA B: TZD vs. non-TZD OHAs (n = not provided) |
Meta-analysis results with quality assessment
Risk of heart failure in rosiglitazone users compared with pioglitazone users
Relative risk (95% Confidence interval) | |||
---|---|---|---|
Subgroup analyses | |||
Study (Author, Year) | All users | New users | New users, Aged ≥ 65 years |
Individual Studies
| |||
Chou [33] | 0.82 (0.62-1.09) | — | — |
Graham [34] | 1.25 (1.16-1.34) | 1.25 (1.16-1.34) | 1.25 (1.16-1.34) |
Juurlink [37] | 1.30 (1.16-1.46) | 1.30 (1.16-1.46) | 1.30 (1.16-1.46) |
Wertz [43] | 1.12 (0.94-1.33) | 1.12 (0.94-1.33) | — |
Winkelmayer [44] | 1.13 (1.01-1.26) | 1.13 (1.01-1.26) | 1.13 (1.01-1.26) |
Meta-Analysis
| |||
Fixed effects, RR | 1.20 (1.15-1.27) | 1.22 (1.16-1.28) | 1.23 (1.17-1.30) |
Random effects, RR | 1.16 (1.05-1.28) | 1.21 (1.14-1.30) | 1.23 (1.14-1.32) |
Heterogeneity statistics | τ
2
= 0.01 | τ
2
= 0.00 | τ
2
= 0.00 |
χ
2
= 11.81 (df = 4) |
χ
2
= 4.35 (df = 3) |
χ
2
= 3.33 (df = 2) | |
I
2
= 66% |
I
2
= 31% |
I
2
= 40% |
Risk of heart failure in glitazone users compared with metformin users
Risk of heart failure in glitazones users compared with sulfonylurea users
Risk of heart failure in sulfonylurea users compared with metformin users
Relative risk (95% confidence interval) | ||||||
---|---|---|---|---|---|---|
Subgroup analyses | ||||||
Study Author, Year | Overall | Cohort studies | Monotherapya
| Incident heart failure | New users | New or prevalent users |
Individual Studies
| ||||||
Koro [39] | 0.96 (0.78, 1.19) | — | 0.96 (0.78, 1.19) | 0.96 (0.78, 1.19) | — | 0.96 (0.78, 1.19) |
McAlister [41] | 1.16 (0.96, 1.41) | 1.16 (0.96, 1.41) | 1.16 (0.96, 1.41) | 1.16 (0.96, 1.41) | 1.16 (0.96, 1.41) | — |
Horsdal [35] | 1.23 (0.78, 1.96) | 1.23 (0.78, 1.96) | 1.23 (0.78, 1.96) | — | — | 1.23 (0.78, 1.96) |
Tzoulaki [42] | 1.21 (1.13, 1.30) | 1.21 (1.13, 1.30) | 1.21 (1.13, 1.30) | 1.21 (1.13, 1.30) | — | 1.21 (1.13, 1.30) |
Karter [38] | 1.43 (1.01, 2.04) | 1.43 (1.01, 2.04) | — | 1.43 (1.01, 2.04) | 1.43 (1.01, 2.04) | — |
Meta-Analysis
| ||||||
Fixed-effects, RR | 1.19 (1.12, 1.26) | 1.21 (1.14, 1.29) | 1.18 (1.11, 1.26) | 1.19 (1.12, 1.26) | 1.22 (1.03, 1.44) | 1.18 (1.11, 1.27) |
Random effects, RR | 1.17 (1.06, 1.29) | 1.21 (1.14, 1.29) | 1.15 (1.04, 1.28) | 1.16 (1.03, 1.31) | 1.22 (1.02, 1.46) | 1.13 (0.95, 1.33) |
Heterogeneity statistics | τ2 = 0.00 | τ2 = 0.00 | τ2 = 0.00 | τ2 = 0.01 | τ2 = 0.00 | τ2 = 0.01 |
χ
2 = 5.25 |
χ
2 = 1.06 |
χ
2 = 4.15 |
χ
2 = 5.22 |
χ
2 = 1.04 |
χ
2 = 4.11 | |
(df = 4) | (df = 3) | (df = 3) | (df = 3) | (df = 1) | (df = 2) | |
I2 = 24% | I2 = 0% | I2 = 28% | I2 = 43% | I2 = 4% | I2 = 51% |