5 research outputs found
3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial
Background:
Liraglutide 3·0 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes.
Methods:
In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m2, or at least 27 kg/m2 with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3·0 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT01272219.
Findings:
The study ran between June 1, 2011, and March 2, 2015. We randomly assigned 2254 patients to receive liraglutide (n=1505) or placebo (n=749). 1128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2·7 times longer with liraglutide than with placebo (95% CI 1·9 to 3·9, p<0·0001), corresponding with a hazard ratio of 0·21 (95% CI 0·13–0·34). Liraglutide induced greater weight loss than placebo at week 160 (–6·1 [SD 7·3] vs −1·9% [6·3]; estimated treatment difference −4·3%, 95% CI −4·9 to −3·7, p<0·0001). Serious adverse events were reported by 227 (15%) of 1501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group.
Interpretation:
In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3·0 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes.
Funding:
Novo Nordisk, Denmark
Proteolytic dynamics of human 20S thymoproteasome
An efficient immunosurveillance of CD8+ T cells in the periphery depends on positive/negative selection of thymocytes and thus on the dynamics of antigen degradation and epitope production by thymoproteasome and immunoproteasome in the thymus. Although studies in mouse systems have shown how thymoproteasome activity differs from that of immunoproteasome and strongly impacts on the T cell repertoire, the proteolytic dynamics and the regulation of human thymoproteasome are unknown. By combining biochemical and computational modeling approaches, we show here that human 20S thymoproteasome and immunoproteasome differ not only in the proteolytic activity of the catalytic sites but also in the peptide transport. These differences impinge upon the quantity of peptide products rather than where the substrates are cleaved. The comparison of the two human 20S proteasome isoforms depicts different processing of antigens that are associated to tumors and autoimmune diseases
Effects of the lercanidipine - Enalapril combination vs. The corresponding monotherapies on home blood pressure in hypertension: Evidence from a large database
103siObjective: To compare a combination of a dihydropyridine
calcium-channel blocker with an angiotensin converting
enzyme inhibitor vs. monotherapy with one or the other
drug and placebo for their effects on home blood pressure
(HBP).
Methods: After a 2-week placebo wash-out, patients with
an elevated office blood pressure (BP) (diastolic 100–109
and systolic <180 mmHg) and HBP (diastolic 85 mmHg)
were randomized double-blind to a 10-week treatment
with placebo, lercanidipine, 10 or 20mg daily, enalapril,
10 or 20mg daily, or the four possible combinations. In
addition to office BP, HBP was self-measured via a
validated semiautomatic device twice in the morning and
twice in the evening during the 7 days before
randomization and at the end of treatment. Baseline and
treatment HBP values were separately averaged for each
day, morning, evening or the whole monitoring period,
excluding the first day. Day-by-day HBP variability was
defined as the SD or the variation coefficient of the daily
BP averages.
Results: Eight hundred and fifty-four patients with valid
HBP recordings at baseline and at the end of treatment
were analyzed (intention-to-treat population). From the
baseline value (147.011.6 mmHg) systolic/diastolic HBP
showed a small reduction (average baseline-adjusted
change: –1.8/–1.6 mmHg) with placebo, a more marked
significant fall with monotherapies (8.8/5.9 mmHg,
P<0.001/<0.001 vs. placebo) and even more with
combination treatment (11.6/7.6 mmHg, P<0.001/
<0.001 vs. placebo and P<0.01/<0.05 vs.
monotherapy). A similar pattern was observed for each of
the days of the BP self-monitoring period as well as for
either morning or evening values, although the difference
between mono and combination treatment appeared to be
consistently significant for the morning values only. Dayby-
day systolic BP-SD was unaffected by placebo and
slightly reduced by drug treatments, with no, however,
significant changes in SBP-variation coefficient. Baseline
and end of treatment HBP values showed a limited
correlation with office BP values, this being particularly the
case for treatment-induced changes (correlation
coefficients: 0.37 for systolic and 0.45 for diastolic BP).
Conclusion: This large HBP database shows that the
lercanidipine–enalapril combination lowers HBP more
effectively than the corresponding monotherapies and
placebo, and that this greater effect is consistent between
days.reservedmixedMancia, Giuseppe; Omboni, Stefano; Chazova, Irina; Coca, Antonio; Girerd, Xavier; Haller, Hermann; Parati, Gianfranco; Pauletto, Paolo; Pupek-Musialik, Danuta; Svyshchenko, Yevgeniya; Boye, Alain; Charrier, Bruno; Couffin, Yvon; Marmor, Philippe; Marty, Jacques; Navarre, Jean Louis; Ansari, Anwar; Büttner, Claudia; Kropp, Maximilian; Mehling, Heidrun; Paschen, Christine; Schenkenberger, Isabelle; Schneider, Helmut; Sperling, Karsten; Stübler, Petra; Von Behren, Volker; Lembo, Giuseppe; Scanferla, Flavio; Sechi, Leonardo Alberto; Gębala, Andrzej; Hoffmann, Andrzej; Janik, Krzysztof; Klimza-Masłowska, Anna; Kaczmarek, Barbara; Koźminski, Piotr; Makowiecka-Cies̈la, Magdalena; Mordaka, Robert; Nowakowski, Tomasz; Pasternak, Dariusz; Skibińska, Elzbieta; Sulik, Piotr; Szpajer, Michał; Walczewska, Jolanta; Zaczek, Marcin; Zienciuk-Krajka, Agnieszka; Alexeeva, Nadezhda; Bokarev, Igor; Chazova, Iina; Conrady, Alexandra; Emelyanov, Alexander; Galustyan, Anna; Idrisova, Elena; Khasanov, Niyaz; Khokhlov, Alexander; Libov, Igor; Reshetko, Olga; Sokurenko, German; Stryuk, Raisa; Tereshchenko, Sergey; Trofimov, Vasily; Zrazhevsky, Konstantin; Carlos Calvo, S.; De Teresa, Luis; Ferre, Raimon; García, Juan; Gil, Apolonia; Gil, Blas; Montenegro, Jesús; Oliván, Josefina; Ortiz, Jacinto; Pascual, José María; Rivera, Antonio; De Quevedo, José Antonio Sainz; Zúñiga, Manuel; Martinez, Valentin; Pujol, Montserrat; Bazylevych, Andriy; Gyrina, Olga; Ignatenko, Grygoriy; Kazymyrko, Vitaly; Khomazyuk, Tetyana; Kononenko, Lyudmyla; Korzh, Oleksii; Kovalenko, Volodymyr; Kuryata, Oleksander; Kushnir, Mykola; Lishnevska, Viktoriia; Lymar, Iurii; Ostrovska, Lidiia; Popik, Galyna; Rudyk, Yuriy; Shershnyova, Oxana; Sierkova, Valentyna; Storozhuk, Borys; Tseluyko, Vira; Vatutin, Mykola; Vayda, Myroslava; Vizir, Vadym; Volkov, Volodymyr; Voloshyna, Olena; Yagensky, Andriy; Zhurba, Svitlana; Zorin, ValeriiMancia, Giuseppe; Omboni, Stefano; Chazova, Irina; Coca, Antonio; Girerd, Xavier; Haller, Hermann; Parati, Gianfranco; Pauletto, Paolo; Pupek Musialik, Danuta; Svyshchenko, Yevgeniya; Boye, Alain; Charrier, Bruno; Couffin, Yvon; Marmor, Philippe; Marty, Jacques; Navarre, Jean Louis; Ansari, Anwar; Büttner, Claudia; Kropp, Maximilian; Mehling, Heidrun; Paschen, Christine; Schenkenberger, Isabelle; Schneider, Helmut; Sperling, Karsten; Stübler, Petra; Von Behren, Volker; Lembo, Giuseppe; Scanferla, Flavio; Sechi, Leonardo Alberto; Gębala, Andrzej; Hoffmann, Andrzej; Janik, Krzysztof; Klimza Masłowska, Anna; Kaczmarek, Barbara; Koźminski, Piotr; Makowiecka Cies̈la, Magdalena; Mordaka, Robert; Nowakowski, Tomasz; Pasternak, Dariusz; Skibińska, Elzbieta; Sulik, Piotr; Szpajer, Michał; Walczewska, Jolanta; Zaczek, Marcin; Zienciuk Krajka, Agnieszka; Alexeeva, Nadezhda; Bokarev, Igor; Chazova, Iina; Conrady, Alexandra; Emelyanov, Alexander; Galustyan, Anna; Idrisova, Elena; Khasanov, Niyaz; Khokhlov, Alexander; Libov, Igor; Reshetko, Olga; Sokurenko, German; Stryuk, Raisa; Tereshchenko, Sergey; Trofimov, Vasily; Zrazhevsky, Konstantin; Carlos Calvo, S.; De Teresa, Luis; Ferre, Raimon; García, Juan; Gil, Apolonia; Gil, Blas; Montenegro, Jesús; Oliván, Josefina; Ortiz, Jacinto; Pascual, José María; Rivera, Antonio; De Quevedo, José Antonio Sainz; Zúñiga, Manuel; Martinez, Valentin; Pujol, Montserrat; Bazylevych, Andriy; Gyrina, Olga; Ignatenko, Grygoriy; Kazymyrko, Vitaly; Khomazyuk, Tetyana; Kononenko, Lyudmyla; Korzh, Oleksii; Kovalenko, Volodymyr; Kuryata, Oleksander; Kushnir, Mykola; Lishnevska, Viktoriia; Lymar, Iurii; Ostrovska, Lidiia; Popik, Galyna; Rudyk, Yuriy; Shershnyova, Oxana; Sierkova, Valentyna; Storozhuk, Borys; Tseluyko, Vira; Vatutin, Mykola; Vayda, Myroslava; Vizir, Vadym; Volkov, Volodymyr; Voloshyna, Olena; Yagensky, Andriy; Zhurba, Svitlana; Zorin, Valeri