Patients

From February 2013 through December 2013, a total of 4346 patients were screened, and 3297 underwent randomization; of these patients, 3232 (98.0%) attended the last follow-up visit at an investigator site, were contacted by telephone, or died during the trial. The date of the last patient visit was March 15, 2016. Vital status was known for 99.6% of the patients by the end of the trial (Figs. S1A and S1B in the Supplementary Appendix).

The median observation time was 2.1 years. Rates of premature treatment discontinuation were similar across groups (20% overall) (Table S5 in the Supplementary Appendix). The mean percentage of time during which patients received semaglutide was 86.5% (87.7% among those receiving 0.5 mg and 85.3% among those receiving 1.0 mg), and the mean percentage during which patients received placebo was 89.5% (89.4% among those receiving 0.5 mg and 89.6% among those receiving 1.0 mg).

Table 1. Table 1. Characteristics of the Patients at Baseline.

Demographic and clinical characteristics of the patients at baseline were similar across treatment groups (Table 1, and Table S6 in the Supplementary Appendix). Of the 3297 patients, 2735 (83.0%) had established cardiovascular disease (including chronic kidney disease of stage 3 or higher), 1940 patients (58.8%) had established cardiovascular disease without chronic kidney disease, 353 (10.7%) had chronic kidney disease only, and 442 (13.4%) had both cardiovascular disease and kidney disease; 17% of the patients had cardiovascular risk factors and were 60 years of age or older. The overall mean duration of type 2 diabetes was 13.9 years, and the mean glycated hemoglobin level was 8.7%. The use of antihyperglycemic and cardiovascular medications was well balanced between the groups (Tables S7A and S8A in the Supplementary Appendix). Most patients (93.5%) were taking antihypertensive medication, including angiotensin-converting–enzyme inhibitors (49.8%) and angiotensin-receptor blockers (33.7%); 76.5% were receiving lipid-lowering medications; and 76.3% were receiving antithrombotic medications, including acetylsalicylic acid (63.9%) and adenosine diphosphate receptor inhibitors (21.1%) (Table S8A in the Supplementary Appendix).

Cardiovascular Outcomes

Figure 1. Figure 1. Cardiovascular Outcomes. Shown are Kaplan–Meier plots of the primary outcome (a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) (Panel A), nonfatal myocardial infarction (Panel B), nonfatal stroke (Panel C), and death from cardiovascular causes (Panel D). The trial included a planned observation period of 109 weeks for all patients (a 104-week treatment period with a 5-week follow-up period). In Panel C, there were no events in the semaglutide group after week 104. Insets show the same data on an expanded y axis.

The composite primary outcome occurred in 108 of 1648 patients (6.6%) in the semaglutide group and 146 of 1649 (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001 for noninferiority; P=0.02 for superiority) (Figure 1A). Sensitivity analyses supported the findings from the primary analysis (Fig. S2 in the Supplementary Appendix). Nonfatal myocardial infarction occurred in 47 patients (2.9%) in the semaglutide group and 64 (3.9%) in the placebo group, a difference that was not significant (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P=0.12) (Figure 1B). Nonfatal stroke occurred in 27 patients (1.6%) in the semaglutide group and 44 (2.7%) in the placebo group (hazard ratio, 0.61; 95% CI, 0.38 to 0.99; P=0.04) (Figure 1C). The risk of cardiovascular death was similar in the two groups, with deaths reported in 44 patients (2.7%) in the semaglutide group and 46 (2.8%) in the placebo group (hazard ratio, 0.98; 95% CI, 0.65 to 1.48; P=0.92) (Figure 1D).

Table 2. Table 2. Primary and Secondary Cardiovascular and Microvascular Outcomes.

No significant treatment interactions were identified for any subgroups (Fig. S3 in the Supplementary Appendix). Similar risk reductions for the primary outcome and its components were observed for both doses of semaglutide (Fig. S4 in the Supplementary Appendix). Cardiovascular outcomes are provided in Table 2, and in Table S9 in the Supplementary Appendix. Throughout the trial, a greater proportion of patients in the placebo group than in the semaglutide group received additional cardiovascular medications, including antihypertensive agents, diuretics, and lipid-lowering medications (Table S8B in the Supplementary Appendix).

Glycemic Control

Figure 2. Figure 2. Glycated Hemoglobin and Body Weight. Shown are the mean values for glycated hemoglobin (Panel A) and body weight (Panel B) during the trial period. The I bars represent standard errors. Data were estimated on the basis of scheduled visits in the full analysis set with the use of a mixed model for repeated measures with treatment group (semaglutide doses of 0.5 mg and 1.0 mg and corresponding placebo doses) and all possible combinations of stratification factors used for randomization as fixed factors.

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) (Figure 2A, and Table S10 in the Supplementary Appendix). 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 (Table S7B in the Supplementary Appendix).

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. Thus, the 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) (Figure 2B, and Table S10 in the Supplementary Appendix).

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) (Table 2, and Table S9 and Fig. S5 in the Supplementary Appendix). The treatment difference between groups was first seen very early in the trial. The 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 diabetes-related blindness were 5 (0.3%) versus 1 (0.1%) (Table S9 in the Supplementary Appendix). 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) (Table 2, and Table S9 and Fig. S5 in the Supplementary Appendix).

Other Outcomes

At week 104, among patients receiving semaglutide, the mean systolic blood pressure decreased from 135.6 mm Hg at baseline to 132.2 mm Hg among those receiving 0.5 mg and to 130.3 mm Hg among those receiving 1.0 mg, for reductions of 3.4 mm Hg and 5.4 mm Hg, respectively; in the placebo group, the mean systolic blood pressure decreased to 133.5 mm Hg and 132.8 mm Hg, for reductions of 2.2 mm Hg and 2.8 mm Hg, respectively. Thus, the mean systolic blood pressure in the semaglutide group, as compared with the placebo group, was 1.3 mm Hg lower in the group receiving 0.5 mg (P=0.10) and 2.6 mm Hg lower in the group receiving 1.0 mg (P<0.001) (Table S10 and Fig. S6 in the Supplementary Appendix).

At week 104, among patients in the semaglutide group, the mean pulse rate increased from a baseline value of 72.0 bpm by 2.1 bpm among those receiving 0.5 mg and by 2.4 bpm among those receiving 1.0 mg; in the placebo group, the corresponding changes were an increase of 0.1 bpm and a decrease of 0.1 bpm. Thus, the mean pulse rate in the semaglutide group, as compared with the placebo group, was 2.0 bpm higher in the group receiving 0.5 mg and 2.5 bpm higher in the group receiving 1.0 mg (P<0.001 for both comparisons). Changes in diastolic blood pressure were similar in the treatment groups. Lipid measurements are provided in Table S10 in the Supplementary Appendix.

Safety

Table 3. Table 3. Selected Adverse Events.

Gastrointestinal disorders were more frequent in the semaglutide group than in the placebo group (Table 3, and Table S11 in the Supplementary Appendix). The majority of gastrointestinal events were mild or moderate in severity and occurred during the first 30 weeks. Treatment discontinuation because of adverse events (mainly gastrointestinal) was more frequent in the semaglutide group than in the placebo group. The frequency and rate of serious adverse events, including serious cardiac disorders, were lower in the semaglutide group than in the placebo group (Table S11 in the Supplementary Appendix).

Acute pancreatitis occurred in 9 patients in the semaglutide group and in 12 in the placebo group; all events were mild, according to the revised Atlanta criteria.7 Lipase and amylase levels were significantly higher in the semaglutide group than in the placebo group (Fig. S7 in the Supplementary Appendix). Gallbladder disorders occurred in 58 patients in the semaglutide group and 61 in the placebo group. The rates of malignant neoplasms, which were similar in the two groups, were higher in the semaglutide group receiving 1.0 mg and lower in the group receiving 0.5 mg than in the placebo groups (Table 3, and Fig. S8 in the Supplementary Appendix). Pancreatic cancer occurred in 1 patient receiving 1.0 mg of semaglutide and in 4 patients receiving placebo. No medullary thyroid carcinomas were confirmed by the event-adjudication committee in either treatment group. Antibodies against semaglutide were detected in 30 patients treated with semaglutide, with the greatest number of patients (14) testing positive at week 44. In the majority of patients, antibody formation was transient — only 4 patients tested positive during follow-up — and antibody titers were generally low.

Similar numbers and occurrence rates of severe hypoglycemic episodes or hypoglycemia as confirmed on plasma glucose testing were seen with semaglutide doses of 0.5 mg and 1.0 mg (191 [23.1%] and 178 [21.7%], respectively), as compared with placebo doses of 0.5 and 1.0 mg (177 [21.5%] and 173 [21.0%]).