Benefits and Harms of Sodium-Glucose Co-Transporter 2 Inhibitors in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis

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Term Occurence Count Dictionary
glipizide 2 endocrinologydiseasesdrugs
obesity 1 endocrinologydiseases
Glimepiride 3 endocrinologydiseasesdrugs
dapagliflozin 12 endocrinologydiseasesdrugs
metformin 18 endocrinologydiseasesdrugs
pioglitazone 4 endocrinologydiseasesdrugs
rosiglitazone 1 endocrinologydiseasesdrugs
sitagliptin 5 endocrinologydiseasesdrugs
Insulin 4 endocrinologydiseasesdrugs

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Select Drug Character Offset Drug Term Instance
Glimepiride 16910 2012[[76]]Dapagliflozin 10 mgPlaceboPioglitazone42048**53.853.5--8.48.3Strojek 2011[[77], [78]]Dapagliflozin 10 mgPlacebo Glimepiride 59748*58.960.3--8.18.2Wilding 2009[[79]]Dapagliflozin 10 mgPlaceboMetformin, insulin, pioglitazone, rosiglitazone711255.758.435.534.88.48.4Wilding
Glimepiride 18063 mgPlaceboMetformin9831658.157.932.1327.77.7RCTs with OAD controlCefalu 2013 [[89], [90]]Canagliflozin 300 mg Glimepiride 8 mgMetformin1,452104*55.856.331.230.97.87.8Gonzalez 2013[[50]]Canagliflozin 300 mgSitagliptin 100 mgMetformin1,2842655.355.531.4327.97.9Rosenstock
Glimepiride 18957 25 mgLinagliptin5 mgNone68652*5653.831.231.98.08.1Ridderstråle 2014[[99], [100]]Empagliflozin 25 mg Glimepiride 1 to 4 mgMetformin1,549104*56.255.73030.37.97.9Roden 2013[[52]]Empagliflozin 25 mgSitagliptin 100 mgNone6772453.855.128.228.27.97.9BMI,
Insulin 15941 [72]]Dapagliflozin 10 mgPlaceboMetformin466102*60.660.832.131.77.27.2Cefalu 2015[[65]]Dapagliflozin 10 mgPlacebo Insulin , metformin92252*62.86332.632.98.28.1Ferrannini 2010[[12]]Dapagliflozin 10 mgPlaceboNone4852450.652.733.632.38.07.8Jabbour
Insulin 17110 pioglitazone, rosiglitazone711255.758.435.534.88.48.4Wilding 2012[[18], [19]]Dapagliflozin 10 mgPlacebo Insulin 10848*59.358.833.433.18.68.5Ferrannini 2013[[80], [81]]Empagliflozin 25 mgPlaceboNone40812575828.328.87.87.8Häring
Insulin 17777 2013[[85]]Empagliflozin 25 mgPlaceboMetformin49512596031.531.38.18.0Rosenstock 2014[[86]]Empagliflozin 25 mgPlacebo Insulin +/- metformin563525855.33534.78.38.3Rosenstock 2015[[87]]Empagliflozin 25 mgPlaceboInsulin +/- metformin
Insulin 17868 mgPlaceboInsulin +/- metformin563525855.33534.78.38.3Rosenstock 2015[[87]]Empagliflozin 25 mgPlacebo Insulin +/- metformin and SU4947859.958.132.731.88.18.3Ross 2015[[88]]Empagliflozin 25 mgPlaceboMetformin9831658.157.932.1327.77.7RCTs
dapagliflozin 1656 evaluating SGLT2-i administered in the highest approved therapeutic doses (canagliflozin 300 mg/day, dapagliflozin 10 mg/day, and empagliflozin 25 mg/day) for ≥12 weeks. Comparison groups could receive placebo or
dapagliflozin 3811 [3]]. Between 2012 and 2014, three sodium-glucose co-transporter 2 inhibitors (SGLT2-i), canagliflozin, dapagliflozin and empagliflozin, were approved by the US Food and Drug Administration (FDA) [[4]–[6]] and the European
dapagliflozin 5235 effect for SGLT2-i will be assessed in on-going RCTs assessing the effect of canagliflozin [[22]]. and dapagliflozin [[23]] on CVD in patients with type 2 diabetes. However, the efficacy and safety of SGLT2-i in patients
dapagliflozin 6397 review with meta-analyses of RCTs evaluating the safety and efficacy of the SGLT2-i canagliflozin, dapagliflozin , and empagliflozin administered in highest clinically relevant doses for at least 12 weeks compared
dapagliflozin 7248 2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol (All Fields) OR dapagliflozin (All Fields)) OR (canagliflozin (Supplementary Concept) OR canagliflozin (All Fields)) OR (empagliflozin
dapagliflozin 7994 interventions assessed were the recommended daily target doses of the SGLT2-i canagliflozin 300 mg; dapagliflozin 10 mg; empagliflozin 25 mg [[4]–[6], [8]]. Controls could receive placebo or OAD including metformin,
dapagliflozin 12494 than 0.10 as small.[[46]] We conducted subgroup analyses on the basis of SGLT2-i type (canagliflozin, dapagliflozin , empagliflozin), and on the basis of the type of OAD (metformin, SU, or DPP-4-i). Differences between
dapagliflozin 14014 SGLT2-i versus placebo. Seven RCTs evaluated canagliflozin 300 mg,[[17], [50], [53]–[59]] 17 evaluated dapagliflozin 10 mg,[[12], [18], [19], [51], [60]–[79]] and 10 evaluated empagliflozin 25 mg[[13]–[16], [52],
dapagliflozin 14334 compared canagliflozin versus glimepiride [[89], [90]] or sitagliptin[[17], [50], [91]] and four compared dapagliflozin versus metformin [[51], [92]], glipizide [[93]–[95]] or saxagliptin [[96]]. The remaining four studies
dapagliflozin 23619 (1.04, 0.6 to 1.83; 19 RCTs). Only one case of bladder cancer was reported, in the placebo arm of a dapagliflozin study [[71]]. Six of 2,767 patients were diagnosed with breast cancer in the SGLT2-i arms compared with
dapagliflozin 34234 confidence intervals) and heterogeneity, respectively.DiscussionThe highest approved doses of canagliflozin, dapagliflozin and empagliflozin compared with placebo, were effective in reducing HbA1c in patients with type 2 diabetes.
dapagliflozin 38985 contrast to our meta-analysis, they included trials with several different doses of canagliflozin, dapagliflozin and empagliflozin and they reported fewer secondary outcomes than us (we also include e.g. ALT, Creatinine
glipizide 14379 [90]] or sitagliptin[[17], [50], [91]] and four compared dapagliflozin versus metformin [[51], [92]], glipizide [[93]–[95]] or saxagliptin [[96]]. The remaining four studies compared empagliflozin versus linagliptin
glipizide 14697 2000 mg [[92]] or 1500 mg [[51]]. The doses of the other OADs was 1 to 8 mg for glimepiride, 20 mg for glipizide , 100 mg for sitagliptin, 5 mg for saxagliptin and 5 mg for linagliptin.10.1371/journal.pone.0166125.t001Table
metformin 1810 for ≥12 weeks. Comparison groups could receive placebo or oral antidiabetic drugs (OAD) including metformin , sulphonylureas (SU), or dipeptidyl peptidase 4 inhibitors (DPP-4-i). Trials were identified through
metformin 4284 [[11]]. SGLT2-i have been assessed as monotherapy or combined with other antidiabetic agents including metformin , sulphonylureas (SU), dipeptidyl peptidase 4 inhibitors (DPP-4-i), thiazolidinediones (pioglitazone)
metformin 8101 dapagliflozin 10 mg; empagliflozin 25 mg [[4]–[6], [8]]. Controls could receive placebo or OAD including metformin , SU or DPP-4-i. We only included RCTs with a treatment duration of at least 12 weeks. Co-interventions
metformin 12562 of SGLT2-i type (canagliflozin, dapagliflozin, empagliflozin), and on the basis of the type of OAD ( metformin , SU, or DPP-4-i). Differences between subgroups were reported using tests for subgroup differences expressed
metformin 14355 versus glimepiride [[89], [90]] or sitagliptin[[17], [50], [91]] and four compared dapagliflozin versus metformin [[51], [92]], glipizide [[93]–[95]] or saxagliptin [[96]]. The remaining four studies compared empagliflozin
metformin 14579 versus linagliptin [[97], [98]], glimepiride [[99], [100]] or sitagliptin [[52]]. The maximum doses of metformin were 2000 mg [[92]] or 1500 mg [[51]]. The doses of the other OADs was 1 to 8 mg for glimepiride, 20
metformin 15950 mgPlaceboMetformin466102*60.660.832.131.77.27.2Cefalu 2015[[65]]Dapagliflozin 10 mgPlaceboInsulin, metformin 92252*62.86332.632.98.28.1Ferrannini 2010[[12]]Dapagliflozin 10 mgPlaceboNone4852450.652.733.632.38.07.8Jabbour
metformin 16655 2009[[51]]Dapagliflozin 10 mgPlaceboNone38912545331328.07.9Mathieu 2015[[73]]Dapagliflozin 10 mgPlaceboSaxagliptin + metformin 3202455.25531.24.78.28.2Matthaei 2015[[74], [75]]Dapagliflozin 10 mgPlaceboMetformin, SU21852*61.160.931.9328.18.2Rosenstock
metformin 17789 mgPlaceboMetformin49512596031.531.38.18.0Rosenstock 2014[[86]]Empagliflozin 25 mgPlaceboInsulin +/- metformin 563525855.33534.78.38.3Rosenstock 2015[[87]]Empagliflozin 25 mgPlaceboInsulin +/- metformin and SU4947859.958.132.731.88.18.3Ross
metformin 17880 mgPlaceboInsulin +/- metformin563525855.33534.78.38.3Rosenstock 2015[[87]]Empagliflozin 25 mgPlaceboInsulin +/- metformin and SU4947859.958.132.731.88.18.3Ross 2015[[88]]Empagliflozin 25 mgPlaceboMetformin9831658.157.932.1327.77.7RCTs
metformin 22398 trials stratified by the OAD (P = 0.11). We found no difference in HbA1c-reduction between SGLT2-i and metformin (-0.05%, 0.21 to 0.12%, Fig 3), but a larger HbA1c reducing effect of SGLT2-i compared with SU (-0.15%,
metformin 27323 a test for subgroup differences (reported using P-values)We found no difference between SGLT2-i and metformin [[51], [92]] or SU [[57], [90], [93]–[95], [99], [100]] but a beneficial effect compared with DPP-4-i
metformin 27810 blind, randomised controlled trials comparing SGLT2-i versus oral antidiabetic drugs.SGLT2-i versus metformin Total nMD (CI)I2(Q)%Fasting plasma glucose (mmol/L)526-0.3 (-0.5; 0.0)54.7Body weight (kg)530-1.3 (-1.8;
metformin 31418 seen for canagliflozin. Analysis of SGLT2-i versus other OAD showed no difference between SGLT2-i and metformin or DPP-4-i (Table 3).Non-serious adverse eventsCompared with placebo, SGLT2-i were associated with an
metformin 31674 GTI (4.34, 3.35 to 5.63). SGLT2-i were also associated with an increased risk of UTI compared with metformin (2.01, 1.01, 3.98), but not SU (1.05, 0.84 to 1.31) or DPP-4-i (0.89, 0.67 to 1.19). SGLT2-i were associated
metformin 31837 or DPP-4-i (0.89, 0.67 to 1.19). SGLT2-i were associated with an increased risk of GTI compared with metformin (4.48, 1.76 to 11.42), SU (5.41, 3.64 to 8.03) and DPP-4-i (3.69, 2.42 to 5.63; P < 0.00001).An analysis
metformin 32517 decreased risk of non-severe hypoglycaemia compared with SU (0.16, 0.11, 0.22), but not compared with metformin (0.5, 0.18 to 1.43) or DPP-4-i (1.00, 0.49 to 2.02). In the SGLT2-i group, more participants experienced
metformin 39573 of SGLT2-i [[36]]. The investigators only included trials on SGLT2-i in monotherapy or as add on to metformin in patients with type 2 diabetes. Only a total of 10 trials were included and no data on adverse events
pioglitazone 4381 including metformin, sulphonylureas (SU), dipeptidyl peptidase 4 inhibitors (DPP-4-i), thiazolidinediones ( pioglitazone ) or insulin [[12]–[19]].In 2015 the American Diabetes Association (ADA) and the European Association
pioglitazone 15269 mgPlaceboPre-existing treatment714104*63.463.231.531.87.77.8Forst 2014[[55]]Canagliflozin 300 mgPlaceboMetformin, pioglitazone 344265758.332.832.57.98.0Gonzalez 2013[[50]]Canagliflozin 300 mgPlaceboMetformin1,2842655.355.331.431.17.98.0Inagaki
pioglitazone 17007 mgPlaceboGlimepiride59748*58.960.3--8.18.2Wilding 2009[[79]]Dapagliflozin 10 mgPlaceboMetformin, insulin, pioglitazone , rosiglitazone711255.758.435.534.88.48.4Wilding 2012[[18], [19]]Dapagliflozin 10 mgPlaceboInsulin10848*59.358.833.433.18.68.5Ferrannini
pioglitazone 17538 mgPlaceboNone5471257.358.725.125.67.97.9Kovacs 2014[[15], [16]]Empagliflozin 25 mgPlaceboMetformin, pioglitazone 49976*54.254.629.129.38.18.2Roden 2013[[52]]Empagliflozin 25 mgPlaceboNone8992453.854.928.228.77.97.9Rosenstock
rosiglitazone 17021 mgPlaceboGlimepiride59748*58.960.3--8.18.2Wilding 2009[[79]]Dapagliflozin 10 mgPlaceboMetformin, insulin, pioglitazone, rosiglitazone 711255.758.435.534.88.48.4Wilding 2012[[18], [19]]Dapagliflozin 10 mgPlaceboInsulin10848*59.358.833.433.18.68.5Ferrannini
sitagliptin 14286 versus OAD (Table 1). Of these 12 trials, four compared canagliflozin versus glimepiride [[89], [90]] or sitagliptin [[17], [50], [91]] and four compared dapagliflozin versus metformin [[51], [92]], glipizide [[93]–[95]]
sitagliptin 14538 remaining four studies compared empagliflozin versus linagliptin [[97], [98]], glimepiride [[99], [100]] or sitagliptin [[52]]. The maximum doses of metformin were 2000 mg [[92]] or 1500 mg [[51]]. The doses of the other
sitagliptin 14719 [[51]]. The doses of the other OADs was 1 to 8 mg for glimepiride, 20 mg for glipizide, 100 mg for sitagliptin , 5 mg for saxagliptin and 5 mg for linagliptin.10.1371/journal.pone.0166125.t001Table 1Characteristics
sitagliptin 16118 2010[[12]]Dapagliflozin 10 mgPlaceboNone4852450.652.733.632.38.07.8Jabbour 2014[[66]]Dapagliflozin 10 mgPlaceboMetformin, sitagliptin 4512454.855--7.98.0Ji 2014[[67]]Dapagliflozin 10 mgPlaceboNone3932451.249.9--8.38.4Kaku 2013[[68]]Dapagliflozin
sitagliptin 23929 comparing SGLT2-i with other OAD, seven patients allocated to canagliflozin and three allocated to sitagliptin were diagnosed with other types of cancer than bladder or breast cancer (2.41, 0.69 to 8.37; 2 RCTs).
Select Disease Character Offset Disease Term Instance
obesity 40792 increased as a result of SGLT2-i, but reporting was inconsistent. Several CVD risk factors such as obesity , blood pressure and HDL cholesterol may be improved by SGLT2-i therapy, whereas the incidences of UTI

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