Semaglutide and cardiovascular outcomes in patients with type 2 diabetes

Steven P. Marso, Stephen C. Bain, Agostino Consoli, Freddy G. Eliaschewitz, Esteban Jodar, Lawrence A. Leiter, Ildiko Lingvay, Julio Rosenstock, Jochen Seufert, Mark L. Warren, Vincent Woo, Oluf Hansen, Anders G. Holst, Jonas Pettersson, Tina Vilsboll

Research output: Contribution to journalArticle

1291 Citations (Scopus)

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 a standardcare 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.

Original languageEnglish (US)
Pages (from-to)1834-1844
Number of pages11
JournalNew England Journal of Medicine
Volume375
Issue number19
DOIs
StatePublished - Nov 10 2016

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Type 2 Diabetes Mellitus
Placebos
Confidence Intervals
Stroke
Myocardial Infarction
semaglutide
Vitreous Hemorrhage
Glucagon-Like Peptide 1
Mortality
Light Coagulation
Blindness
Chronic Renal Insufficiency
Half-Life
Cause of Death
Cardiovascular Diseases
Therapeutics
Safety

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Marso, S. P., Bain, S. C., Consoli, A., Eliaschewitz, F. G., Jodar, E., Leiter, L. A., ... Vilsboll, T. (2016). Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. New England Journal of Medicine, 375(19), 1834-1844. https://doi.org/10.1056/NEJMoa1607141

Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. / Marso, Steven P.; Bain, Stephen C.; Consoli, Agostino; Eliaschewitz, Freddy G.; Jodar, Esteban; Leiter, Lawrence A.; Lingvay, Ildiko; Rosenstock, Julio; Seufert, Jochen; Warren, Mark L.; Woo, Vincent; Hansen, Oluf; Holst, Anders G.; Pettersson, Jonas; Vilsboll, Tina.

In: New England Journal of Medicine, Vol. 375, No. 19, 10.11.2016, p. 1834-1844.

Research output: Contribution to journalArticle

Marso, SP, Bain, SC, Consoli, A, Eliaschewitz, FG, Jodar, E, Leiter, LA, Lingvay, I, Rosenstock, J, Seufert, J, Warren, ML, Woo, V, Hansen, O, Holst, AG, Pettersson, J & Vilsboll, T 2016, 'Semaglutide and cardiovascular outcomes in patients with type 2 diabetes', New England Journal of Medicine, vol. 375, no. 19, pp. 1834-1844. https://doi.org/10.1056/NEJMoa1607141
Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. New England Journal of Medicine. 2016 Nov 10;375(19):1834-1844. https://doi.org/10.1056/NEJMoa1607141
Marso, Steven P. ; Bain, Stephen C. ; Consoli, Agostino ; Eliaschewitz, Freddy G. ; Jodar, Esteban ; Leiter, Lawrence A. ; Lingvay, Ildiko ; Rosenstock, Julio ; Seufert, Jochen ; Warren, Mark L. ; Woo, Vincent ; Hansen, Oluf ; Holst, Anders G. ; Pettersson, Jonas ; Vilsboll, Tina. / Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. In: New England Journal of Medicine. 2016 ; Vol. 375, No. 19. pp. 1834-1844.
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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 a standardcare 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.",
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T1 - Semaglutide and cardiovascular outcomes in patients with type 2 diabetes

AU - Marso, Steven P.

AU - Bain, Stephen C.

AU - Consoli, Agostino

AU - Eliaschewitz, Freddy G.

AU - Jodar, Esteban

AU - Leiter, Lawrence A.

AU - Lingvay, Ildiko

AU - Rosenstock, Julio

AU - Seufert, Jochen

AU - Warren, Mark L.

AU - Woo, Vincent

AU - Hansen, Oluf

AU - Holst, Anders G.

AU - Pettersson, Jonas

AU - Vilsboll, Tina

PY - 2016/11/10

Y1 - 2016/11/10

N2 - 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 standardcare 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.

AB - 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 standardcare 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.

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