Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes
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 were investigated in this non-inferiority trial:
- 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
- study authors 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
- 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
- glycaemic control:
- at week 104, among patients receiving semaglutide, the mean glycated hemoglobin level decreased from 8.7% at baseline to 7.6% in the group receiving 0.5 mg and to 7.3% in the group receiving 1.0 mg, for changes of -1.1% and -1.4%, respectively; in the placebo group, the mean level decreased to 8.3% in the two dose groups, for a reduction of 0.4% in each group
- thus, the mean glycated hemoglobin level in the semaglutide group, as compared with the placebo group, was 0.7 percentage points lower in the group receiving 0.5 mg and 1.0 percentage point lower in the group receiving 1.0 mg (estimated treatment difference) (P<0.001 for both comparisons)
- during the trial, significantly more patients in the placebo group than in the semaglutide group received additional antihyperglycemic agents, including insulin, which was initiated more than twice as frequently in the placebo group
- body weight
- at week 104, among patients receiving semaglutide, the mean body weight decreased from 92.1 kg at baseline to 88.5 kg in the group receiving 0.5 mg and to 87.2 kg in the group receiving 1.0 mg, for changes of -3.6 kg and -4.9 kg, respectively; in the placebo group, the mean body weight decreased to 91.4 kg and 91.6 kg, for changes of -0.7 kg and -0.5 kg, respectively
- mean body weight in the semaglutide group, as compared with the placebo group, was 2.9 kg lower in the group receiving 0.5 mg and 4.3 kg lower in the group receiving 1.0 mg (P<0.001 for both comparisons)
- microvascular outcomes
- diabetic retinopathy complications occurred in 50 patients (3.0%) in the semaglutide group and 29 (1.8%) in the placebo group (hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P = 0.02)
- treatment difference between groups was first seen very early in the trial
- numbers of patients who required retinal photocoagulation were 38 (2.3%) in the semaglutide group versus 20 (1.2%) in the placebo group, the numbers of those who required the use of an intravitreal agent were 16 (1.0%) versus 13 (0.8%), the numbers of those who had a vitreous hemorrhage were 16 (1.0%) versus 7 (0.4%), and the numbers of those who had an onset of diabetesrelated blindness were 5 (0.3%) versus 1 (0.1%)
- of the 79 patients with retinopathy complications, 66 (83.5%) had preexisting retinopathy at baseline (42 of 50 [84.0%] in the semaglutide group and 24 of 29 [82.8%] in the placebo group)
- new or worsening nephropathy occurred in 62 patients (3.8%) in the semaglutide group and 100 (6.1%) in the placebo group (hazard ratio, 0.64; 95% CI, 0.46 to 0.88; P = 0.005)
The study authors' concluded that:
- 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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