SynthesisBMC cardiovascular disorders2014
The risk of heart failure associated with the use of noninsulin blood glucose-lowering drugs: systematic review and meta-analysis of published observational studies.
Synthesis in BMC cardiovascular disorders, 2014. The graph read 7 numbers from its abstract, feeding 7 cells of the map: it favours the comparator in 3. Cited by 25 papers, 3 of them syntheses that pooled it.
What it found
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For example, because at Maccabi Healthcare Services rosiglitazone could be prescribed only if there was an inadequate control of blood glucose with sulfonylurea, metformin, or both, the heart failure effect estimate for rosiglitazone versus metformin monotherapy in the study by Loebstein et al. [40] (relative risk, 2.23; 95% CI, 1.41-3.53) might be overestimated.
Read, but not usablea number the graph found but could not read as for or against
Only 2 studies were restricted to new users, yielding a summary relative risk of 1.22 (95% CI, 1.02-1.46) (Table 3 and Additional file 1: Figure S3e) [38, 41].Table 3 Risk of heart failure in sulfonylurea users compared with metformin users, overall and subgroup analyses Relative risk (95% confidence interval)Subgroup analysesStudy Author, YearOverallCohort studiesMonotherapy a Incident heart failureNew usersNew 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, RR1.19 (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, RR1.17 (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 statisticsτ2 = 0.00τ2 = 0.00τ2 = 0.00
Monotherapy sulfonylurea users exposed to high doses (defined as higher than the median daily dose for each individual medication) were more likely to develop heart failure than those using lower doses (hazard ratio, 1.38; 95% CI, 1.20-1.60) [41].
The only study evaluating the risk of heart failure in rosiglitazone users compared with sulfonylureas users reported a relative risk of 1.22 (95% CI, 0.86-1.74) [36].
Two of these studies evaluated the risk of heart failure in pioglitazone users compared with metformin users, yielding a summary relative risk of 1.14 (95% CI, 0.86-1.50); we included these studies in the overall forest plot for completeness [36, 42].
Based on 3 studies, the summary relative risk for rosiglitazone, as monotherapy or in combination with other blood glucose-lowering agents, versus metformin was 1.36 (95% CI, 1.17-1.59) [36, 40, 42] (Figure 2).
In that study, stratified results suggested that, among patients without a prior history of heart failure, new users of rosiglitazone had a greater risk of heart failure hospitalization than new users of pioglitazone (relative risk, 1.21; 95% CI, 1.03-1.42), and patients with prior heart failure did not experience increased risk (relative risk, 1.04; 95% CI, 0.89-1.22).Table 2 Risk of heart failure in Rosiglitazone users compared with Pioglitazone users, overall and subgroup analyses Relative risk (95% Confidence interval)Subgroup analysesStudy (Author, Year)All usersNew usersNew 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, RR1.20 (1.15-1.27)1.22 (1.16-1.28)1.23 (1.17-1.30)Random effects, RR1.16 (1.05-1.28)1.21 (1.14-1.30)1.23 (1.14-1.32)Heterogeneity statisticsτ2 = 0.01τ2 = 0.00τ2 = 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%Df = degrees of freedom; RR =
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Metformin×cardiovascular events
ContradictsOpen on the map →What to test next →5 readable studies in this cell: 4 favour the treatment, 1 find no difference, 0 favour the comparator.
This paper's own estimate is on a different scale from the rest of the cell, so it is not drawn here.
Sulfonylureas & glinides×cardiovascular events
ContradictsOpen on the map →What to test next →3 readable studies in this cell: 2 favour the treatment, 1 find no difference, 0 favour the comparator.
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Thiazolidinediones×cardiovascular events
ContradictsOpen on the map →What to test next →2 readable studies in this cell: 0 favour the treatment, 2 find no difference, 0 favour the comparator.
This paper's own estimate is on a different scale from the rest of the cell, so it is not drawn here.
Metformin×glycemic control
No readable resultOpen on the map →What to test next →40 readable studies in this cell: 41 favour the treatment, 13 find no difference, 7 favour the comparator.
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Other glucose-lowering×glycemic control
No readable resultOpen on the map →What to test next →8 readable studies in this cell: 5 favour the treatment, 0 find no difference, 3 favour the comparator.
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Thiazolidinediones×glycemic control
No readable resultOpen on the map →What to test next →16 readable studies in this cell: 9 favour the treatment, 4 find no difference, 3 favour the comparator.
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Thiazolidinediones×adverse events & safety
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Who cites it
25 citing papers in PubMed, 3 syntheses or guidelines pooled it, 68 citations in OpenAlex.
- Response to pioglitazone in non-alcoholic fatty liver disease patients withFrontiers in endocrinology · 2023Pooled it
- Pioglitazone and the secondary prevention of cardiovascular disease. A meta-analysis of randomized-controlled trials.Cardiovascular diabetology · 2017Pooled it
- Cardiovascular risk associated with the use of glitazones, metformin and sufonylureas: meta-analysis of published observational studies.BMC cardiovascular disorders · 2016 · on this mapPooled it
- Effect of sitagliptin on the echocardiographic parameters of left ventricular diastolic function in patients with type 2 diabetes: a subgroup analysis of the PROLOGUE study.Cardiovascular diabetology · 2017Trial
- Rationale and design of a randomized trial to test the safety and non-inferiority of canagliflozin in patients with diabetes with chronic heart failure: the CANDLE trial.Cardiovascular diabetology · 2016Trial
- Diabetes and NAFLD: A Synergistic Threat to Metabolic Health.Advanced pharmaceutical bulletin · 2025Review
- Comparative effectiveness and cost-effectiveness of cardioprotective glucose-lowering therapies for type 2 diabetes in Brazil: a Bayesian network model.Health economics review · 2023Article
- Comparative safety of sulfonylureas among U.S. nursing home residents.Journal of the American Geriatrics Society · 2023Article
- Observational
- Evaluation of pancreatic regeneration activity ofJournal of traditional and complementary medicine · 2021Article
- Evaluation of Antidiabetic Activity of the Leaf Latex ofEvidence-based complementary and alternative medicine : eCAM · 2020Article
- Sodium glucose cotransporter (SGLT)-2 inhibitors: Do we need them for glucose-lowering, for cardiorenal protection or both?Diabetes, obesity & metabolism · 2019Review
- Evaluation of in vivo antidiabetic, antidyslipidemic, and in vitro antioxidant activities of hydromethanolic root extract ofJournal of experimental pharmacology · 2019Article
- Pioglitazone Induces Cardiomyocyte Apoptosis and Inhibits Cardiomyocyte Hypertrophy Via VEGFR-2 Signaling Pathway.Arquivos brasileiros de cardiologia · 2018Article
- Clinical impact of oral antidiabetic medications in heart failure patients.Heart failure reviews · 2018Review
- Comparative Safety of Sulfonylurea and Metformin Monotherapy on the Risk of Heart Failure: A Cohort Study.Journal of the American Heart Association · 2017Article
- Cardiovascular effects of anti-diabetes drugs.Expert opinion on drug safety · 2016Review
- Review
- A Safety Evaluation of Empagliflozin for the Treatment of Type 2 Diabetes.Expert opinion on drug safety · 2016Review
- Noninsulin Antidiabetic Drugs for Patients with Type 2 Diabetes Mellitus: Are We Respecting Their Contraindications?Journal of diabetes research · 2016Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The marked sentences are the ones the graph read a number from.
backgroundPatients with type 2 diabetes mellitus (T2DM) are at high risk of heart failure. A summary of the effects of blood glucose-lowering drugs other than glitazones on the risk of heart failure in routine clinical practice is lacking. The objective of this study was to conduct a systematic review and meta-analysis of observational studies on the risk of heart failure when using blood glucose-lowering drugs.
methodsWe systematically identified and reviewed cohort and case-control studies in which the main exposure of interest was noninsulin blood glucose-lowering medications in patients with T2DM. We searched Medline, Embase, and the Cochrane Library to identify publications meeting prespecified eligibility criteria. The quality of included studies was assessed with the Newcastle-Ottawa Scale and the RTI item bank. Results were combined using fixed and random-effects models when at least 3 independent data points were available for a drug-drug comparison.
resultsThe summary relative risk of heart failure in rosiglitazone users versus pioglitazone users (95% CI) was 1.16 (1.05-1.28) (5 cohort studies). Heterogeneity was present (I2 = 66%). For new users (n = 4) the summary relative risk was 1.21 (1.14-1.30) and the heterogeneity was reduced (I2 = 31%);. The summary relative risk for rosiglitazone versus metformin was 1.36 (95% CI, 1.17-1.59) (n = 3). The summary relative risk (95% CI) of heart failure in sulfonylureas users versus metformin users was 1.17 (95% CI, 1.06-1.29) (5 cohort studies; I2 = 24%) and 1.22 (1.02-1.46) when restricted to new users (2 studies).Information on other comparisons was very scarce. Information on dose and duration of treatment effects was lacking for most comparisons. Few studies accounted for disease severity; therefore, confounding by indication might be present in the majority of the within-study comparisons of this meta-analysis.
conclusionsUse of glitazones and sulfonylureas was associated with an increased risk of heart failure compared with metformin use. However, indication bias cannot be ruled out. Ongoing large multidatabase studies will help to evaluate the risk of heart failure in treated patients with diabetes, including those using newer blood glucose-lowering therapies.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.