SUPPLEMENTAL MATERIAL

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14

Author/trialClinicalTrials.govIdentifier

Year Treatment Control Treatment

(n)Control

(n)Total

(n)

Follow-up

(weeks)

Age(yrs)

Women(%)

Years

DMBMI

DPP4-Is

Ahren B (HARMONY 3)1* NCT00838903 2014 Sita Pla/Met/Glime/Albi

302 710 1012 156 55 53 NA NA

Al Sifri (RAMADAN study)2* NCT01131182 2011 Sita Su 507 514 1021 4 55 49 5.5 31Arechavaleta R3* NCT00701090 2011 Sita Glime 516 519 1035 30 56 46 6.7 30Aschner P (EASIE)4* NCT00751114 2012 Sita Insuline

Glargine265 250 515 26 54 45 4.4 31

Aschner P5* NCT00449930 2010 Sita Met 528 522 1050 24 56 46 2.4 31Bajaj M6* NCT00996658 2014 Lina Pla 183 89 272 25 54 51 NA 28Barnett AH7* NCT00740051 2012 Lina Pla/

Glime151 76 227 52 57 61 NA 29

Barnett AH8* NCT01084005 2013 Lina Pla 162 79 241 24 75 32 NA 30Barnett AH9* NCT00757588 2012 Saxa Pla 304 151 455 52 57 59 11.9 32Bergenstal RM (DURATION-2)10*

NCT00637273 2010 Sita Pio 166 165 331 26 52 50 5.5 32

Bergenstal RM11* NCT00754988 2012 Sita Taspo 177 369 546 156 57 44 6 33Blonde L (GALIANT Trial)12* NCT00396627 2009 Vilda TZD 1776 888 2664 12 56 48 5.1 32Bolli G13* NCT00237237 2009 Vilda Pio 295 281 576 52 57 37 6.4 32Bosi E14* NCT00099892 2007 Vilda Pla 362 182 544 24 54 33 6.3 33Bosi E15* NCT00382096/

NCT004680392009 Vilda Met 300 294 594 24 53 41 2 31

Bosi E15* NCT00382096/NCT00468039

2009 Vilda Pla 585 294 879 24 53 43 2 31

Chacra AR16* NCT00313313 2011 Sax Pla 501 267 768 76 55 55 6.9 29Del Prato S (ENDURE)17* NCT00856284 2014 Alo Glipi 1765 874 2639 104 55 50 5.5 31Dobs AS18* NCT00350779 2013 Sita Pla 181 97 278 54 55 40 9.3 30Duran-Garcia S19* NCT00954447 2015 Lina Pla 631 630 1261 110 60 48 NA NA

15

Ferrannini E20* NCT00106340 2009 Vilda Glime 1396 1393 2789 52 57 47 5.7 32Filozof C21* NA 2010 Vilda Glicla 513 494 1007 52 59 48 6.6 31Fonseca V22* NCT00960076 2012 Saxa Pla 138 144 282 18 55 54 6.2 31Fonseca V23* NCT00099931 2007 Vilda Pla 144 152 296 24 59 49 14.7 33Fonseca V24* NCT00885352 2013 Sita Pla 157 156 313 26 56 38 9.8 30Frederich R.25* NCT00316082 2012 Saxa Pla 291 74 365 76 55 54 1.7 31Gallwitz B26* NCT00622284 2012 Lina Glime 776 775 1551 105 60 40 NA 30Garber AJ27* NCT00099853 2007 Vilda Pla 305 158 463 24 54 43 4.7 32Göke B28* NCT00138567 2008 Vilda Met 304 158 462 104 54 NA 2.4 NAGreen JB (TECOS)9 NCT00790205 2015 Sita Pla 7332 7339 14671 209 66 29 11.6 NAHaak T29* NCT00798161 2012 Lina Pla 428 363 791 24 55 66 NA 29Hermans MP (PROMPT)30* NCT01006590 2012 Saxa Pla 147 139 286 24 59 43 6.4 32Hollander PL31* NCT00295633 2011 Saxa Pla 381 184 565 76 54 50 5.2 30Kawamori R32* NCT00654381 2012 Lina Vogli 319 162 481 26 60 30 NA 25Kikuchi M33* NA 2009 Vilda Pla 219 72 291 12 59 40 5.3 24Kothny W34* NA 2012 Vilda Pla 216 153 369 52 66 44 24.1 30Kothny W35* NA 2013 Vilda Pla 228 221 449 24 59 50 63.8 29Leiter LA36* NCT01098539 2014 Sita Albi 246 249 495 26 NA 46 11.2 39Lewin AJ37* NCT00819091 2012 Lina Pla 161 84 245 19 57 47 NA 28Lukashevich V38* NA 2014 Vilda Pla 158 160 318 24 55 52 7.3 28Lukashevich V39* NA 2011 Vilda Pla 289 226 515 24 66 43 16.6 30Mathieu C40* NCT01462266 2015 Sita Pla 329 329 658 24 59 52 13.5 32Matthews DR41* NA 2010 Vilda Glime 1562 1556 3118 104 58 47 5.7 32McMurray J (VIVIDD study)10 NCT00894868 2013 Vilda Pla 128 126 254 52 NA NA NA NAMita T (SPEAD-A)42* NA 2016 Alo Conventi

onal Treatment

172 169 341 104 65 42 8.6 NA

Mohan V43* NCT00289848 2009 Sita Pla 352 178 530 18 51 42 2.0 25NaucK M44* NCT00286442 2009 Alo Pla 423 104 527 28 55 50 6.0 32Nauck M45* NCT00734474 2014 Sita Dula 315 606 921 54 54 53 7.0 31

16

NCT0008651546* NCT00086515 2015 Sita Pla/Glipi 464 237 701 104 55 43 NA NANCT0009475746* NCT00094757 2010 Sita Pla/Pio 411 110 521 54 55 46 NA NANCT0010670446* NCT00106704 2013 Sita Pla/Pio 222 219 441 54 56 47 NA NANCT0012719246* NCT00127192 2010 Sita Pla 290 73 363 12 60 38 NA NANCT0028642946* NCT00286429 2012 Alo Pla 260 130 390 26 NA 59 NA NANCT0028646846* NCT00286468 2012 Alo Pla 401 99 500 26 NA 48 NA NANCT0030960846* NCT00309608 2013 Lina Pla 197 71 268 16 60 43 NA 32NCT0032862746* NCT00328627 2013 Alo Pla 1037 517 1554 26 54 59 6.2 31NCT0039534346* NCT00395343 2010 Sita Pla 322 319 641 24 58 49 NA NANCT0039551246* NCT00395512 2013 Alo Pla/Pio 492 163 655 26 52 51 3.2 31NCT0039763146* NCT00397631 2015 Sita Pla 261 259 520 24 51 46 NA NANCT0050926246* NCT00509262 2014 Sita Gli 211 212 423 54 64 40 NA NANCT0057558846* NCT00575588 2012 Saxa Gli 428 430 858 104 58 48 NA NANCT0060125046* NCT00601250 2013 Lina Pla 523 177 700 24 57 46 NA 30NCT0060247246* NCT00602472 2013 Lina Pla 792 263 1055 24 58 53 NA 28NCT0064104346* NCT00641043 2014 Lina Pla 259 130 389 24 57 39 NA 29NCT0066136246* NCT00661362 2012 Saxa Pla 283 287 570 24 54 52 NA NANCT0072237146* NCT00722371 2015 Sita Pla 922 693 1615 54  NA 43 NA NANCT0081399546* NCT00813995 2011 Sita Pla 197 198 395 24 55 49 NA NANCT0091577246* NCT00915772 2013 Lina Pla 396 170 566 54 56 45 NA 29NCT0102358146* NCT01023581 2013 Alo Pla 225 109 334 26 53 50 3.9 31NCT0107607546* NCT01076075 2015 Sita Pla/Pio 213 214 427 54 55 54 NA NANCT0107608846* NCT01076088 2015 Sita Pla 120 127 247 24 53 35 NA NANCT0108750246* NCT01087502 2013 Lina Pla/

Glime113 122 235 52 67 37 NA 32

NCT0117738446* NCT01177384 2015 Sita Pla 191 190 381 24 57 49 NA NANCT0118301346* NCT01183013 2014 Lina Pla/Pio 501 392 893 54 57 46 NA NANCT0118989046* NCT01189890 2013 Sita Glime 241 239 480 30 71 58 NA NANCT0120429446* NCT01204294 2014 Lina Met 143 63 206 54 62 28 NA NANCT0121423946* NCT01214239 2013 Lina Pla 200 99 299 24 54 41 NA 25

17

NCT0121509746* NCT01215097 2013 Lina Pla 205 100 305 24 56 50 NA 26NCT0126348346* NCT01263483 2012 Alo Pla/Vogli 155 75 230 12  NA 38 NA NANCT0126349646* NCT01263496 2012 Alo Vogli 391 83 474 40 NA 28 NA NANCT0131807046* NCT01318070 2012 Alo Pla 224 115 339 12 NA NA NA NANCT0159079746* NCT01590797 2015 Sita Pla 234 233 467 26 58 47 NA NANCT0170890246* NCT01708902 2015 Lina Met 147 289 436 24 51 41 NA NANCT0188290746* NCT01882907 2015 Vilda Pio 117 111 228 16 55 57 NA 25NCT0200868246* NCT02008682 2015 Sita Lira 184 184 368 26 52 40 5.3 27Olansky L47* NCT00482729 2011 Sita Pla 625 621 1246 44 50 43 3.4 33Pan C48* NA 2012 Vilda Pla 294 144 438 24 54 53 5.0 26Pan CY49* NCT00698932 2012 Saxa Pla 284 284 568 24 51 45 1.0 26Pfützner A50* NCT00327015 2011 Saxa Pla/Met 978 328 1306 76 52 37 1.6 30Philis-Tsimikas51* NCT01046110 2013 Sita Insuline

Degludec222 225 447 26 56 36 7.8 30

Pratley RE52* NCT00286494 2009 Alo Pla 396 97 493 28 55 42 7.6 33Pratley RE53* NCT00700817 2010 Sita Lira 219 439 658 26 55 48 6.2 33Ristic S54* NA 2005 Vilda Pla 221 58 279 12 57 46 2.9 31Roden M55* NCT01289990 2015 Sita Pla 155 136 291 76 55 64 NA NARosenstock J56* NCT00121641 2009 Saxa Pla 306 95 401 209 53 49 NA 32Rosenstock J57* NCT00707993 2013 Alo Glipi 222 219 441 54 70 55 6.1 30Rosenstock J58* NCT00138619 2009 Vilda Rosi 396 202 598 80 54 43 2.2 38Rosenstock J59* NCT0009918 2007 Vilda Rosi 459 238 697 24 54 42 2.4 33Rosenstock J60* NCT00121667 2013 Saxa Pla 564 179 743 209 55 49 6.5 31Ross SA61* NCT01012037 2012 Lina Pla 447 44 491 12 59 43 NA 29Russel-Jones D (DURATION-4)62*

NCT00676338 2012 Sita Met/Pio 163 246 409 36 53 39 2.6 31

Scherbaum WA63* NCT00101712 2008 Vilda Pla 156 150 306 56 63 41 2.6 30Schernthaner G64* NCT01006603 2015 Saxa Glime 360 360 720 52 73 38 NA NASchweizer A65* NCT00246619 2009 Vilda Met 169 166 335 24 71 51 2.9 30Schweizer A66* NCT00099866 2007 Vilda Met 526 254 780 52 53 46 1.0 32Scirica BM (SAVOR-TIMI-53)7 NCT01107886 2013 Saxa Pla 8280 8212 16492 110 65 33 10.3 31

18

Seck T67* NCT00094770 2010 Sita Glipi 588 584 1172 104 57 41 5.8 31Seino Y68* NCT01318083 2012 Alo Pla 209 103 312 24 NA 35 NA 25Seino Y69* NCT01263470 2011 Alo Pla 322 75 397 52 59 27 6.6 25Strain WD (INTERVAL)70* NCT01257451 2013 Vilda Pla 139 139 278 24 75 55 11.4 30White WB (EXAMINE)8 NCT00968708 2013 Alo Pla 2701 2679 5380 174 61 32 7.2 30Williams-Herman D71* NCT00103857 2010 Sita Pla/Met 551 540 1091 54 NA NA NA 32Yang W72* NCT01357252 2015 Vilda Pla 143 136 279 24 58 43 6.9 25Yoon KH73* NCT01028391 2012 Sita Pla 164 153 317 30 52 44 2.1 30

SGLT2-IsAmin NB74* NCT01059825 2015 Ertug Pla 219 54 273 12 55 37 6.3 30Bailey CJ75* NCT00528879 2013 Dapa Pla 409 137 546 102 54 46 6.1 NABarnett AH (EMPA-REG RENAL)76*

NCT01164501 2014 Empa Pla 419 319 738 52 64 42 NA 32

Bode B77* NCT01106651 2015 Cana Pla 477 237 714 104 NA 44 11.7 32CANTATA-D46* NCT01106677 2013 Cana Pla 735 183 918 26 55 53 NA NACANTATA-MP46* NCT01106690 2013 Cana Pla 227 115 342 26 57 37 NA NACANTATAT-MSU46* NCT01106625 2013 Cana Pla 313 156 469 52 57 49 NA NACefalu WT78* NCT01031680 2015 Dapa Pla 455 459 914 52 63 32 12.4 32Del Prato S79* NCT00660907 2015 Dapa Glipi 406 408 814 209 59 45 6.5 31

Ferrannini E80* NCT00789035 2013 Empa Pla 244 82 326 12 58 50 NA 29Fulcher G (CANVAS-INCRETIN)81*

NCT01032629 2016 Cana Pla 214 102 316 18 62 34 13.4 32

Haering HU (EMPA-REG EXTENDED)82*

NCT01289990 2015 Empa Pla 441 225 666 76 57 49 NA NA

Henry RR83* NCT00859898 2012 Dapa Pla 430 208 638 24 NA NA NA NAHenry RR83* NCT00643851 2012 Dapa Pla 397 201 598 24 NA NA NA NAJabbour SA84* NCT00984867 2014 Dapa Pla 223 224 447 24 55 45 5.7 NAKaku K85* NCT00972244 2013 Dapa Pla 225 54 279 16 57 23 NA NAKohan DE86* NA 2014 Dapa Pla 168 84 252 104 67 35 16.9 NAKovacs CS (EMPA-REG EXTEND PIO)87*

NCT01210001 2015 Empa Pla 212 93 305 76 55 52 NA 29

Leiter LA88* NCT01042977 2014 Dapa Pla 480 482 962 52 64 33 13.2 33Leiter LA (CANTATA-SU)89* NCT00968812 2015 Cana Glime 968 482 1450 104 56 48 6.6 31

19

Mathieu C90* NCT01646320 2015 Dapa Pla 160 160 320 24 55 54 7.6 32Merker L (EMPA-REG EXTENDED MET)91*

NCT01289990 2015 Empa Pla 325 138 463 76 58 43 NA 29

NCT0052837246* NCT00528372 2015 Dapa Pla 483 75 558 102 NA 50 NA NANCT0064227846* NCT00642278 2013 Cana Pla 321 65 386 12 53 49 NA NANCT0074919046* NCT00749190 2014 Empa Pla 353 71 424 12 58 33 NA NANCT0088153046* NCT00881530 2014 Empa Met 215 56 271 78 58 50 NA NANCT0113747446* NCT01137474 2014 Dapa Pla 633 311 944 12 NA 44 NA NANCT0121789246* NCT01217892 2014 Dapa Pla 299 101 400 16 58 55 NA NANCT0136808146* NCT01368081 2014 Empa Met 273 63 336 52 61 28 NA NANCT0138190046* NCT01381900 2014 Cana Pla 450 226 676 18 56 46 NA NANCT0164929746* NCT01649297 2015 Empa Pla 876 107 983 17 58 45 NA NANeal B (CANVAS-INSULIN)92* NCT01032629 2015 Cana Pla 1382 690 2072 52 62 34 13.4 33Ridderstrale M (EMPA-REG H2H-SU)93*

NCT01167881 2014 Empa Glime 765 780 1545 104 56 45 NA 30

Roden M (EMPA-REG EXTENDED MONO)54*

NCT01289990 2015 Empa Pla 324 136 460 76 55 39 NA 29

Rosenstock J94* NCT00683878 2012 Dapa Pla 281 139 420 48 54 50 5.5 NARosenstock J (EMPA-REG BASAL)95*

NCT01011868 2015 Empa Pla 324 170 494 78 59 44 NA 32

Rosenstock J (EMPA-REG MDI)21

NCT01306214 2014 Empa Pla 375 188 563 52 57 55 NA 35

Stenlof K (CANTATA-M)96* NCT01081834 2014 Cana Pla 392 192 584 26 55 56 4.3 32Strojek K97* NCT00680745 2014 Dapa Pla 447 145 592 48 60 52 7.4 30Tikkanen I (EMPA-REG BP)98* NCT01370005 2015 Empa Pla 552 271 823 12 60 40 NA 33Wilding JP99* NCT00673231 2014 Dapa Pla 607 193 800 104 59 52 13.6 33Yale JF100* NCT01064414 2014 Cana Pla 179 90 269 52 69 39 17.3 33Zinman B (EMPA-REG OUTCOME)12

NCT01131676 2015 Empa Pla 4687 2333 7020 162 63 29 NA 31

Supplemental Table S1. Baseline characteristics of trials included in the analysis.

Albi: Albiglutide Alo: Alogliptin; Cana: Canagliflozin; Dapa: Dapagliflozin Dula: Dulaglutide; Empa: Empagliflozin; Ertu: Ertugliflozin; Glicla: Gliclazide; Glime: Glimepiride; Glipi: Glipizide; Glybu: Glyburide; Lina: Linagliptin; Lira: Liraglutide; Met: Metformin; NA: Not Available; Pio:

20

Pioglitazone; Pla: PlaCebo; Rosi: Rosigitazone; Saxa: Saxagliptin; Sita: Sitagliptin; Su: Sulfonylurea; Taspo: Taspoglutide; TZD: Thiazolidinediones; Vilda: Vildagliptin; Vogli: Voglibose; DM: Diabetes Mellitus; BMI: Body Mass Index. *denotes references reported in the Supplementary Data.

21

Supplemental Figure S1. Risk Ratios (RRs) of all-cause death in DPP4-Is. Solid squares represent RRs in trials and have a size proportional to the number of events. The 95% confidence intervals (CI) for individual trials are denoted by lines and those for the pooled RRs by empty diamonds.

22

Supplemental Figure S2. Risk Ratios (RRs) of cardiovascular death in DPP4-Is. Solid squares represent RRs in trials and have a size proportional to the number of events. The 95% confidence intervals (CI) for individual trials are denoted by lines and those for the pooled RRs by empty diamonds.

23

Supplemental Figure S3. Risk Ratios (RRs) of myocardial infarction in DPP4-Is. Solid squares represent RRs in trials and have a size proportional to the number of events. The 95% confidence intervals (CI) for individual trials are denoted by lines and those for the pooled RRs by empty diamonds.

24

Supplemental Figure S4. Risk Ratios (RRs) of stroke in DPP4-Is. Solid squares represent RRs in trials and have a size proportional to the number of events. The 95% confidence intervals (CI) for individual trials are denoted by lines and those for the pooled RRs by empty diamonds.

25

Supplemental Figure S5. Risk Ratios (RRs) of heart failure in DPP4-Is. Solid squares represent RRs in trials and have a size proportional to the number of events. The 95% confidence intervals (CI) for individual trials are denoted by lines and those for the pooled RRs by empty diamonds.

26

Supplemental Figure S6. Risk Ratios (RRs) of all-cause death in SGLT2-Is. Solid squares represent RRs in trials and have a size proportional to the number of events. The 95% confidence intervals (CI) for individual trials are denoted by lines and those for the pooled RRs by empty diamonds.

27

Supplemental Figure S7. Risk Ratios (RRs) of cardiovascular death in SGLT2-Is. Solid squares represent RRs in trials and have a size proportional to the number of events. The 95% confidence intervals (CI) for individual trials are denoted by lines and those for the pooled RRs by empty diamonds.

28

Supplemental Figure S8. Risk Ratios (RRs) of myocardial infarction in SGLT2-Is. Solid squares represent RRs in trials and have a size proportional to the number of events. The 95% confidence intervals (CI) for individual trials are denoted by lines and those for the pooled RRs by empty diamonds.

29

Supplemental Figure S9. Risk Ratios (RRs) of stroke in SGLT2-Is. Solid squares represent RRs in trials and have a size proportional to the number of events. The 95% confidence intervals (CI) for individual trials are denoted by lines and those for the pooled RRs by empty diamonds.

30

Supplemental Figure S10. Risk Ratios (RRs) of heart failure in SGLT2-Is. Solid squares represent RRs in trials and have a size proportional to the number of events. The 95% confidence intervals (CI) for individual trials are denoted by lines and those for the pooled RRs by empty diamonds.

31