Steven P Marso1, Stephen C Bain1, Agostino Consoli1, Freddy G Eliaschewitz1, Esteban Jódar1, Lawrence A Leiter1, Ildiko Lingvay1, Julio Rosenstock1, Jochen Seufert1, Mark L Warren1, Vincent Woo1, Oluf Hansen1, Anders G Holst1, Jonas Pettersson1, Tina Vilsbøll1. 1. From the Research Medical Center, Kansas City, MO (S.P.M.); School of Medicine, Swansea University, Swansea, United Kingdom (S.C.B.); Department of Medicine and Aging Science and Center of Excellence on Aging and Translational Medicine, G. d'Annunzio University, Chieti-Pescara, Italy (A.C.); CPClin Research Center/Hospital Israelita Albert Einstein, São Paulo (F.G.E.); Hospital Universitario Quirón Salud Madrid, Facultad de Ciencias de la Salud, Universidad Europea de Madrid, Madrid (E.J.); Li Ka Shing Knowledge Institute and Keenan Research Centre for Biomedical Science, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.), and the University of Manitoba, Winnipeg (V.W.) - both in Canada; University of Texas Southwestern Medical Center (I.L.) and Dallas Diabetes Research Center at Medical City (J.R.) - both in Dallas; University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany (J.S.); Physicians East, Greenville, NC (M.L.W.); and Novo Nordisk, Søborg (O.H., A.G.H., J.P.), and the Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup (T.V.) - both in Denmark.
Abstract
BACKGROUND: Regulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The cardiovascular effects of semaglutide, a glucagon-like peptide 1 analogue with an extended half-life of approximately 1 week, in type 2 diabetes are unknown. METHODS: We randomly assigned 3297 patients with type 2 diabetes who were on astandard-care regimen to receive once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. The primary composite outcome was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. We hypothesized that semaglutide would be noninferior to placebo for the primary outcome. The noninferiority margin was 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio. RESULTS: At baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both. The primary outcome occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001 for noninferiority). Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P=0.12); nonfatal stroke occurred in 1.6% and 2.7%, respectively (hazard ratio, 0.61; 95% CI, 0.38 to 0.99; P=0.04). Rates of death from cardiovascular causes were similar in the two groups. Rates of new or worsening nephropathy were lower in the semaglutide group, but rates of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation) were significantly higher (hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P=0.02). Fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal. CONCLUSIONS: In patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the noninferiority of semaglutide. (Funded by Novo Nordisk; SUSTAIN-6 ClinicalTrials.gov number, NCT01720446 .).
RCT Entities:
BACKGROUND: Regulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The cardiovascular effects of semaglutide, a glucagon-like peptide 1 analogue with an extended half-life of approximately 1 week, in type 2 diabetes are unknown. METHODS: We randomly assigned 3297 patients with type 2 diabetes who were on a standard-care regimen to receive once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. The primary composite outcome was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. We hypothesized that semaglutide would be noninferior to placebo for the primary outcome. The noninferiority margin was 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio. RESULTS: At baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both. The primary outcome occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001 for noninferiority). Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P=0.12); nonfatal stroke occurred in 1.6% and 2.7%, respectively (hazard ratio, 0.61; 95% CI, 0.38 to 0.99; P=0.04). Rates of death from cardiovascular causes were similar in the two groups. Rates of new or worsening nephropathy were lower in the semaglutide group, but rates of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation) were significantly higher (hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P=0.02). Fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal. CONCLUSIONS: In patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the noninferiority of semaglutide. (Funded by Novo Nordisk; SUSTAIN-6 ClinicalTrials.gov number, NCT01720446 .).
Authors: Matthew J O'Brien; Susan L Karam; Amisha Wallia; Raymond H Kang; Andrew J Cooper; Nicola Lancki; Margaret R Moran; David T Liss; Theodore A Prospect; Ronald T Ackermann Journal: JAMA Netw Open Date: 2018-12-07
Authors: Anna Norhammar; Johan Bodegard; Thomas Nyström; Marcus Thuresson; Klas Rikner; David Nathanson; Jan W Eriksson Journal: Diabetes Obes Metab Date: 2019-08-26 Impact factor: 6.577