Comparative cardiovascular outcomes in the era of novel anti-diabetic agents: a comprehensive network meta-analysis of 166,371 participants from 170 randomized controlled trials.

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Term Occurence Count Dictionary
rosiglitazone 1 endocrinologydiseasesdrugs
sitagliptin 2 endocrinologydiseasesdrugs
dapagliflozin 2 endocrinologydiseasesdrugs
dulaglutide 2 endocrinologydiseasesdrugs
hypoglycemia 18 endocrinologydiseases
metformin 2 endocrinologydiseasesdrugs

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Select Drug Character Offset Drug Term Instance
dapagliflozin 10349 sitagliptin, vildagliptin, albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, canagliflozin, dapagliflozin , empagliflozin, MET, SU, TZD, INS and PLA. Most trials (159 [93.5%] of 170) were two-armed studies.
dapagliflozin 12684 empagliflozin, LIX lixisenatide, ALO alogliptin, EXE exenatide, LIR liraglutide, CAN canagliflozin, DAP dapagliflozin , DUL dulaglutide, SIT sitagliptin, LIN linagliptin, ALB albiglutide, SAX saxagliptinIn the network meta-analyses,
dulaglutide 10283 groups were analyzed: alogliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin, albiglutide, dulaglutide , exenatide, liraglutide, lixisenatide, canagliflozin, dapagliflozin, empagliflozin, MET, SU, TZD, INS
dulaglutide 12703 lixisenatide, ALO alogliptin, EXE exenatide, LIR liraglutide, CAN canagliflozin, DAP dapagliflozin, DUL dulaglutide , SIT sitagliptin, LIN linagliptin, ALB albiglutide, SAX saxagliptinIn the network meta-analyses, MACE
metformin 3506 co-transporter 2 inhibitors (SGLT2i), and the more traditional classes of drugs, including insulin (INS), metformin (MET), sulfonylureas (SU) and thiazolidinedione (TZD). In doing so, we aimed at providing evidence-based
metformin 12504 peptide-1 receptor agonist(s), DPP4i dipeptidyl peptidase 4 inhibitor(s), TZD thiazolidinedione, MET metformin , SU sulfonylurea, INS insulin, PLA placebo, VIL vildagliptin, EMP empagliflozin, LIX lixisenatide, ALO
rosiglitazone 23307 hypoglycemia. Such a result could be explained by the previous observation that the use of TZD (especially rosiglitazone ) is associated with potential increase of CV risks independent of hypoglycemia [[42]].Our study is limited
sitagliptin 10243 For individual comparison, 18 treatment groups were analyzed: alogliptin, linagliptin, saxagliptin, sitagliptin , vildagliptin, albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, canagliflozin, dapagliflozin,
sitagliptin 12720 alogliptin, EXE exenatide, LIR liraglutide, CAN canagliflozin, DAP dapagliflozin, DUL dulaglutide, SIT sitagliptin , LIN linagliptin, ALB albiglutide, SAX saxagliptinIn the network meta-analyses, MACE were reported in
Select Disease Character Offset Disease Term Instance
hypoglycemia 1111 obtain estimates for the outcomes of interests. In addition, post hoc correlation analysis of severe hypoglycemia and primary outcome as per ranking order was conducted. Outcomes were major adverse cardiovascular events
hypoglycemia 1790 ranking orders of MACE and all-cause mortality were both positively correlated with that of severe hypoglycemia risk (by individual: R2 = 0.3178, P = 0.018; by class: R2 = 0.2574, P = 0.038).ConclusionsNovel
hypoglycemia 2154 in CV risk was again shown to be partly attributable to a concomitant increase in the risk of severe hypoglycemia , for which SU performed the worst.Electronic supplementary materialThe online version of this article
hypoglycemia 6358 unstable angina or hospitalization for unstable angina, and all-cause mortality. We included severe hypoglycemia as an outcome during the data extraction phase for post hoc analysis. Severe hypoglycemia was defined
hypoglycemia 6448 included severe hypoglycemia as an outcome during the data extraction phase for post hoc analysis. Severe hypoglycemia was defined as hypoglycemia episode requiring the assistance of another person or medical assistance,
hypoglycemia 6476 outcome during the data extraction phase for post hoc analysis. Severe hypoglycemia was defined as hypoglycemia episode requiring the assistance of another person or medical assistance, regardless of documentation
hypoglycemia 9507 impairment; and sample size less than 100 in one arm.Finally, to explore the potential impact of severe hypoglycemia on the association between anti-diabetic drugs and CV outcomes, additional correlation analysis of severe
hypoglycemia 9626 association between anti-diabetic drugs and CV outcomes, additional correlation analysis of severe hypoglycemia and outcome of interest according to the ranking order was conducted.ResultsThe PRISMA flowchart showing
hypoglycemia 16558 ranking order of MACE or all-cause mortality was positively correlated with the ranking order of severe hypoglycemia (R2 = 0.3178, P = 0.018; R2 = 0.2574, P = 0.038, respectively), whereas for drug classes,
hypoglycemia 16872 correlation between the ranking order of MACE and all-cause mortality risk and the ranking order of severe hypoglycemia risk. Color of circle represents different drugs shown above. Area of a circle reflects sample size.
hypoglycemia 17062 circle reflects sample size. a, b, c, d The panels indicates the correlation relationship between severe hypoglycemia and outcome of interest according to the ranking orderDiscussionTo the best of our knowledge, our network
hypoglycemia 17800 all-cause mortality. Finally, the ranking of CV risk was linearly correlated with the ranking of severe hypoglycemia risk by individual comparisons, with SU displaying the highest risks in both endpoints.Our study found
hypoglycemia 20711 only to MET. However, the undesirable effect of weight gain [[27]], the greatest risk of iatrogenic hypoglycemia [[28]–[31]], a potential increase in CV morbidity and mortality [[32]–[36]], and adding to that,
hypoglycemia 22631 analysis, the ranking of MACE and mortality risk were both linearly correlated with the ranking of severe hypoglycemia risk by individual comparisons, with SU at the top of risks, corroborating the already well-founded
hypoglycemia 22814 corroborating the already well-founded connection, if not causality, between the elevated risk of iatrogenic hypoglycemia with the use of SU and the inferior CV safety of this class of traditional anti-diabetic agents, although
hypoglycemia 23200 are shown to be an outlier in both correlations, with higher ranking of CV risk but lower ranking of hypoglycemia . Such a result could be explained by the previous observation that the use of TZD (especially rosiglitazone)
hypoglycemia 23387 of TZD (especially rosiglitazone) is associated with potential increase of CV risks independent of hypoglycemia [[42]].Our study is limited in several ways. First, although comprehensive systematic search strategies
hypoglycemia 25236 all-cause mortality, which could potentially explained by its concomitant increase in the risk of severe hypoglycemia . Such correlation should probably call for a reassessment of the role of SU as first-line additive to

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