Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P = 0.98). There were no significant between-group differences in rates of acute pancreatitis (P = 0.07) or pancreatic cancer (P = 0.32). CONCLUSIONS: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events

Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, 120.29 percentage points; 95% confidence interval [CI], 120.32 to 120.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P=0.98). There were no significant between-group differences in rates of acute pancreatitis (P=0.07) or pancreatic cancer (P=0.32). CONCLUSIONS Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events. (Funded by Merck Sharp & Dohme; TECOS ClinicalTrials.gov number, NCT00790205.

Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study

reserved328Background No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor 1,5 modulator, on disability progression in patients with SPMS.Methods This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18-60 years) with SPMS and an Expanded Disability Status Scale score of 3.0-6.5 were randomly assigned (2: 1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials. gov, number NCT01665144.Findings 1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16.8 years (SD 8.3), and the mean time since conversion to SPMS was 3.8 years (SD 3.5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0.79, 95% CI 0.65-0.95; relative risk reduction 21%; p=0.013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups.Interpretation Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS.mixedKappos L.; Bar-Or A.; Cree B.A.C.; Fox R.J.; Giovannoni G.; Gold R.; Vermersch P.; Arnold D.L.; Arnould S.; Scherz T.; Wolf C.; Wallstrom E.; Dahlke F.; Achiron A.; Achtnichts L.; Agan K.; Akman-Demir G.; Allen A.B.; Antel J.P.; Antiguedad A.R.; Apperson M.; Applebee A.M.; Ayuso G.I.; Baba M.; Bajenaru O.; Balasa R.; Balci B.P.; Barnett M.; Bass A.; Becker V.U.; Bejinariu M.; Bergh F.T.; Bergmann A.; Bernitsas E.; Berthele A.; Bhan V.; Bischof F.; Bjork R.J.; Blevins G.; Boehringer M.; Boerner T.; Bonek R.; Bowen J.D.; Bowling A.; Boyko A.N.; Boz C.; Bracknies V.; Braune S.; Brescia Morra V.; Brochet B.; Brola W.; Brownstone P.K.; Brozman M.; Brunet D.; Buraga I.; Burnett M.; Buttmann M.; Butzkueven H.; Cahill J.; Calkwood J.C.; Camu W.; Cascione M.; Castelnovo G.; Centonze D.; Cerqueira J.; Chan A.; Cimprichova A.; Cohan S.; Comi G.; Conway J.; Cooper J.A.; Corboy J.; Correale J.; Costell B.; Cottrell D.A.; Coyle P.K.; Craner M.; Cui L.; Cunha L.; Czlonkowska A.; da Silva A.M.; de Sa J.; de Seze J.; Debouverie M.; Debruyne J.; Decoo D.; Defer G.; Derfuss T.; Deri N.H.; Dihenia B.; Dioszeghy P.; Donath V.; Dubois B.; Duddy M.; Duquette P.; Edan G.; Efendi H.; Elias S.; Emrich P.J.; Estruch B.C.; Evdoshenko E.P.; Faiss J.; Fedyanin A.S.; Feneberg W.; Fermont J.; Fernandez O.F.; Ferrer F.C.; Fink K.; Ford H.; Ford C.; Francia A.; Freedman M.; Frishberg B.; Galgani S.; Garmany G.P.; Gehring K.; Gitt J.; Gobbi C.; Goldstick L.P.; Gonzalez R.A.; Grandmaison F.; Grigoriadis N.; Grigorova O.; Grimaldi L.M.E.; Gross J.; Gross-Paju K.; Gudesblatt M.; Guillaume D.; Haas J.; Hancinova V.; Hancu A.; Hardiman O.; Harmjanz A.; Heidenreich F.R.; Hengstman G.J.D.; Herbert J.; Herring M.; Hodgkinson S.; Hoffmann O.M.; Hofmann W.E.; Honeycutt W.D.; Hua L.H.; Huang D.; Huang Y.; Huang D.; Hupperts R.; Imre P.; Jacobs A.K.; Jakab G.; Jasinska E.; Kaida K.; Kalnina J.; Kaprelyan A.; Karelis G.; Karussis D.; Katz A.; Khabirov F.A.; Khatri B.; Kimura T.; Kister I.; Kizlaitiene R.; Klimova E.; Koehler J.; Komatineni A.; Kornhuber A.; Kovacs K.; Koves A.; Kozubski W.; Krastev G.; Krupp L.B.; Kurca E.; Lassek C.; Laureys G.; Lee L.; Lensch E.; Leutmezer F.; Li H.; Linker R.A.; Linnebank M.; Liskova P.; Llanera C.; Lu J.; Lutterotti A.; Lycke J.; Macdonell R.; Maciejowski M.; Maeurer M.; Magzhanov R.V.; Maida E.-M.; Malciene L.; Mao-Draayer Y.; Marfia G.A.; Markowitz C.; Mastorodimos V.; Matyas K.; Meca-Lallana J.; Merino J.A.G.; Mihetiu I.G.; Milanov I.; Miller A.E.; Millers A.; Mirabella M.; Mizuno M.; Montalban X.; Montoya L.; Mori M.; Mueller S.; Nakahara J.; Nakatsuji Y.; Newsome S.; Nicholas R.; Nielsen A.S.; Nikfekr E.; Nocentini U.; Nohara C.; Nomura K.; Odinak M.M.; Olsson T.; van Oosten B.W.; Oreja-Guevara C.; Oschmann P.; Overell J.; Pachner A.; Panczel G.; Pandolfo M.; Papeix C.; Patrucco L.; Pelletier J.; Piedrabuena R.; Pless M.; Polzer U.; Pozsegovits K.; Rastenyte D.; Rauer S.; Reifschneider G.; Rey R.; Rizvi S.A.; Robertson D.; Rodriguez J.M.; Rog D.; Roshanisefat H.; Rowe V.; Rozsa C.; Rubin S.; Rusek S.; Sacca F.; Saida T.; Salgado A.V.; Sanchez V.E.F.; Sanders K.; Satori M.; Sazonov D.V.; Scarpini E.A.; Schlegel E.; Schluep M.; Schmidt S.; Scholz E.; Schrijver H.M.; Schwab M.; Schwartz R.; Scott J.; Selmaj K.; Shafer S.; Sharrack B.; Shchukin I.A.; Shimizu Y.; Shotekov P.; Siever A.; Sigel K.-O.; Silliman S.; Simo M.; Simu M.; Sinay V.; Siquier A.E.; Siva A.; Skoda O.; Solomon A.; Stangel M.; Stefoski D.; Steingo B.; Stolyarov I.D.; Stourac P.; Strassburger-Krogias K.; Strauss E.; Stuve O.; Tarnev I.; Tavernarakis A.; Tello C.R.; Terzi M.; Ticha V.; Ticmeanu M.; Tiel-Wilck K.; Toomsoo T.; Tubridy N.; Tullman M.J.; Tumani H.; Turcani P.; Turner B.; Uccelli A.; Urtaza F.J.O.; Vachova M.; Valikovics A.; Walter S.; Van Wijmeersch B.; Vanopdenbosch L.; Weber J.R.; Weiss S.; Weissert R.; Vermersch P.; West T.; Wiendl H.; Wiertlewski S.; Wildemann B.; Willekens B.; Visser L.H.; Vorobeychik G.; Xu X.; Yamamura T.; Yang Y.N.; Yelamos S.M.; Yeung M.; Zacharias A.; Zelkowitz M.; Zettl U.; Zhang M.; Zhou H.; Zieman U.; Ziemssen T.Kappos, L.; Bar-Or, A.; Cree, B. A. C.; Fox, R. J.; Giovannoni, G.; Gold, R.; Vermersch, P.; Arnold, D. L.; Arnould, S.; Scherz, T.; Wolf, C.; Wallstrom, E.; Dahlke, F.; Achiron, A.; Achtnichts, L.; Agan, K.; Akman-Demir, G.; Allen, A. B.; Antel, J. P.; Antiguedad, A. R.; Apperson, M.; Applebee, A. M.; Ayuso, G. I.; Baba, M.; Bajenaru, O.; Balasa, R.; Balci, B. P.; Barnett, M.; Bass, A.; Becker, V. U.; Bejinariu, M.; Bergh, F. T.; Bergmann, A.; Bernitsas, E.; Berthele, A.; Bhan, V.; Bischof, F.; Bjork, R. J.; Blevins, G.; Boehringer, M.; Boerner, T.; Bonek, R.; Bowen, J. D.; Bowling, A.; Boyko, A. N.; Boz, C.; Bracknies, V.; Braune, S.; Brescia Morra, V.; Brochet, B.; Brola, W.; Brownstone, P. K.; Brozman, M.; Brunet, D.; Buraga, I.; Burnett, M.; Buttmann, M.; Butzkueven, H.; Cahill, J.; Calkwood, J. C.; Camu, W.; Cascione, M.; Castelnovo, G.; Centonze, D.; Cerqueira, J.; Chan, A.; Cimprichova, A.; Cohan, S.; Comi, G.; Conway, J.; Cooper, J. A.; Corboy, J.; Correale, J.; Costell, B.; Cottrell, D. A.; Coyle, P. K.; Craner, M.; Cui, L.; Cunha, L.; Czlonkowska, A.; da Silva, A. M.; de Sa, J.; de Seze, J.; Debouverie, M.; Debruyne, J.; Decoo, D.; Defer, G.; Derfuss, T.; Deri, N. H.; Dihenia, B.; Dioszeghy, P.; Donath, V.; Dubois, B.; Duddy, M.; Duquette, P.; Edan, G.; Efendi, H.; Elias, S.; Emrich, P. J.; Estruch, B. C.; Evdoshenko, E. P.; Faiss, J.; Fedyanin, A. S.; Feneberg, W.; Fermont, J.; Fernandez, O. F.; Ferrer, F. C.; Fink, K.; Ford, H.; Ford, C.; Francia, A.; Freedman, M.; Frishberg, B.; Galgani, S.; Garmany, G. P.; Gehring, K.; Gitt, J.; Gobbi, C.; Goldstick, L. P.; Gonzalez, R. A.; Grandmaison, F.; Grigoriadis, N.; Grigorova, O.; Grimaldi, L. M. E.; Gross, J.; Gross-Paju, K.; Gudesblatt, M.; Guillaume, D.; Haas, J.; Hancinova, V.; Hancu, A.; Hardiman, O.; Harmjanz, A.; Heidenreich, F. R.; Hengstman, G. J. D.; Herbert, J.; Herring, M.; Hodgkinson, S.; Hoffmann, O. M.; Hofmann, W. E.; Honeycutt, W. D.; Hua, L. H.; Huang, D.; Huang, Y.; Huang, D.; Hupperts, R.; Imre, P.; Jacobs, A. K.; Jakab, G.; Jasinska, E.; Kaida, K.; Kalnina, J.; Kaprelyan, A.; Karelis, G.; Karussis, D.; Katz, A.; Khabirov, F. A.; Khatri, B.; Kimura, T.; Kister, I.; Kizlaitiene, R.; Klimova, E.; Koehler, J.; Komatineni, A.; Kornhuber, A.; Kovacs, K.; Koves, A.; Kozubski, W.; Krastev, G.; Krupp, L. B.; Kurca, E.; Lassek, C.; Laureys, G.; Lee, L.; Lensch, E.; Leutmezer, F.; Li, H.; Linker, R. A.; Linnebank, M.; Liskova, P.; Llanera, C.; Lu, J.; Lutterotti, A.; Lycke, J.; Macdonell, R.; Maciejowski, M.; Maeurer, M.; Magzhanov, R. V.; Maida, E. -M.; Malciene, L.; Mao-Draayer, Y.; Marfia, G. A.; Markowitz, C.; Mastorodimos, V.; Matyas, K.; Meca-Lallana, J.; Merino, J. A. G.; Mihetiu, I. G.; Milanov, I.; Miller, A. E.; Millers, A.; Mirabella, M.; Mizuno, M.; Montalban, X.; Montoya, L.; Mori, M.; Mueller, S.; Nakahara, J.; Nakatsuji, Y.; Newsome, S.; Nicholas, R.; Nielsen, A. S.; Nikfekr, E.; Nocentini, U.; Nohara, C.; Nomura, K.; Odinak, M. M.; Olsson, T.; van Oosten, B. W.; Oreja-Guevara, C.; Oschmann, P.; Overell, J.; Pachner, A.; Panczel, G.; Pandolfo, M.; Papeix, C.; Patrucco, L.; Pelletier, J.; Piedrabuena, R.; Pless, M.; Polzer, U.; Pozsegovits, K.; Rastenyte, D.; Rauer, S.; Reifschneider, G.; Rey, R.; Rizvi, S. A.; Robertson, D.; Rodriguez, J. M.; Rog, D.; Roshanisefat, H.; Rowe, V.; Rozsa, C.; Rubin, S.; Rusek, S.; Sacca, F.; Saida, T.; Salgado, A. V.; Sanchez, V. E. F.; Sanders, K.; Satori, M.; Sazonov, D. V.; Scarpini, E. A.; Schlegel, E.; Schluep, M.; Schmidt, S.; Scholz, E.; Schrijver, H. M.; Schwab, M.; Schwartz, R.; Scott, J.; Selmaj, K.; Shafer, S.; Sharrack, B.; Shchukin, I. A.; Shimizu, Y.; Shotekov, P.; Siever, A.; Sigel, K. -O.; Silliman, S.; Simo, M.; Simu, M.; Sinay, V.; Siquier, A. E.; Siva, A.; Skoda, O.; Solomon, A.; Stangel, M.; Stefoski, D.; Steingo, B.; Stolyarov, I. D.; Stourac, P.; Strassburger-Krogias, K.; Strauss, E.; Stuve, O.; Tarnev, I.; Tavernarakis, A.; Tello, C. R.; Terzi, M.; Ticha, V.; Ticmeanu, M.; Tiel-Wilck, K.; Toomsoo, T.; Tubridy, N.; Tullman, M. J.; Tumani, H.; Turcani, P.; Turner, B.; Uccelli, A.; Urtaza, F. J. O.; Vachova, M.; Valikovics, A.; Walter, S.; Van Wijmeersch, B.; Vanopdenbosch, L.; Weber, J. R.; Weiss, S.; Weissert, R.; Vermersch, P.; West, T.; Wiendl, H.; Wiertlewski, S.; Wildemann, B.; Willekens, B.; Visser, L. H.; Vorobeychik, G.; Xu, X.; Yamamura, T.; Yang, Y. N.; Yelamos, S. M.; Yeung, M.; Zacharias, A.; Zelkowitz, M.; Zettl, U.; Zhang, M.; Zhou, H.; Zieman, U.; Ziemssen, T