Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes

Michael Lincoff, M.D., Kirstine Brown‐Frandsen, M.D., Helen M. Colhoun, M.D., John Deanfield, M.D., Scott S. Emerson, M.D., Ph.D., Sille Esbjerg, M.Sc., Søren Hardt‐Lindberg, M.D., Ph.D., G. Kees Hovingh, M.D., Ph.D.,
Steven E. Kahn, M.B., Ch.B., Robert F. Kushner, M.D., Ildiko Lingvay, M.D., M.P.H., Tugce K. Oral, M.D., Marie M. Michelsen, M.D., Ph.D., Jorge Plutzky, M.D., Christoffer W. Tornøe, Ph.D., and Donna H. Ryan, M.D.,
for the SELECT Trial Investigators*

ABSTRACT

BACKGROUND

Semaglutide, a glucagon-like peptide-1 receptor agonist, has been shown to reduce the risk of adverse cardiovascular events in patients with diabetes. Whether sema- glutide can reduce cardiovascular risk associated with overweight and obesity in the absence of diabetes is unknown.

METHODS

In a multicenter, double-blind, randomized, placebo-controlled, event-driven supe- riority trial, we enrolled patients 45 years of age or older who had preexisting cardiovascular disease and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 27 or greater but no history of diabetes. Patients were randomly assigned in a 1:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarc- tion, or nonfatal stroke in a time-to-first-event analysis. Safety was also assessed.

RESULTS

A total of 17,604 patients were enrolled; 8803 were assigned to receive semaglutide and 8801 to receive placebo. The mean (±SD) duration of exposure to semaglutide or placebo was 34.2±13.7 months, and the mean duration of follow-up was 39.8±9.4 months. A primary cardiovascular end-point event occurred in 569 of the 8803 patients (6.5%) in the semaglutide group and in 701 of the 8801 patients (8.0%) in the placebo group (hazard ratio, 0.80; 95% confidence interval, 0.72 to 0.90; P<0.001). Adverse events leading to permanent discontinuation of the trial product occurred in 1461 patients (16.6%) in the semaglutide group and 718 pa- tients (8.2%) in the placebo group (P<0.001).

CONCLUSIONS

In patients with preexisting cardiovascular disease and overweight or obesity but without diabetes, weekly subcutaneous semaglutide at a dose of 2.4 mg was superior to placebo in reducing the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke at a mean follow-up of 39.8 months. (Funded by Novo Nordisk; SELECT ClinicalTrials.gov number, NCT03574597.)

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Downloaded from nejm.org at Eli Lilly on November 14, 2023. For personal use only. No other uses without permission. Copyright © 2023 Massachusetts Medical Society. All rights reserved.

The authors’ affiliations are listed in the Appendix. Dr. Lincoff can be contacted at [email protected] or at the Department of Cardiovascular Medicine, Cleveland Clin‐ ic, 9500 Euclid Ave., J2–3, Cleveland, OH 44195.

*A list of the SELECT trial investigators is provided in the Supplementary Ap‐ pendix, available at NEJM.org.

This article was published on November 11, 2023, at NEJM.org.

DOI: 10.1056/NEJMoa2307563

More than half the world popu- lation is projected to have overweight

1
or obesity by the year 2035. High body-

mass index (BMI) is estimated to have accounted for 4 million deaths globally in 2015, more than two thirds of which were caused by cardiovascu- lar diseases.2 Overweight and obesity are inde- pendently associated with an increased risk of cardiovascular events, even after the influence of metabolic cardiovascular risk factors linked to excess weight has been accounted for.3-6 Al- though reducing the risk of cardiovascular dis- ease by treating dyslipidemia,7 hypertension,8 and diabetes9,10 is standard evidence-based prac- tice, the concept of treating obesity to reduce the risk of cardiovascular complications has been hampered by the lack of evidence from trials indicating that lifestyle or pharmacologic inter- ventions for overweight or obesity improve car- diovascular outcomes.11-15

Agonists of the glucagon-like peptide-1 (GLP-1) receptor are used in the management of type 2 diabetes and overweight or obesity and have been shown to reduce the risk of major adverse car- diovascular events in patients with type 2 diabetes who are at high cardiovascular risk.10 Although these agents affect a broad range of metabolic pathways associated with glucose metabolism, energy homeostasis, and inflammation that might be hypothesized to also improve cardiovascular outcomes among people who do not have diabe- tes,16,17 it is unknown whether GLP-1 receptor agonists can reduce the cardiovascular risk asso- ciated with overweight and obesity. Semaglutide, a long-acting analogue of GLP-1, administered at a dose of 2.4 mg subcutaneously once weekly for 104 weeks, was found to reduce body weight by a mean of 15.2% among patients with overweight or obesity who did not have diabetes.18 In the Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) trial, we tested the hypothesis that the addition of semaglutide to standard care would be supe- rior to placebo in reducing the risk of major adverse cardiovascular events among patients with overweight or obesity and preexisting car- diovascular disease who did not have diabetes.

Methods

Trial Design

We conducted this multicenter, double-blind, ran- domized, placebo-controlled, event-driven superi-

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ority trial at 804 clinical sites in 41 countries (details are provided in the Supplementary Ap- pendix, available with the full text of this article at NEJM.org). The trial design has been pub- lished previously.19 The trial protocol (available at NEJM.org) was designed by the sponsor, Novo Nordisk, and the academic steering committee. Details of the organization of the trial are pro- vided in the Supplementary Appendix. National and institutional regulatory and ethical authori- ties approved the protocol, and all the patients provided written informed consent. The first and last authors vouch for the accuracy and com- pleteness of the data and for the fidelity of the trial to the protocol.

Trial Population

Patients were eligible for enrollment if they were 45 years of age or older, had a BMI (the weight in kilograms divided by the square of the height in meters) of 27 or greater, and had established cardiovascular disease. Cardiovascular disease was defined as previous myocardial infarction, previous stroke, or symptomatic peripheral arte- rial disease. Key exclusion criteria were a previous diagnosis of diabetes, a glycated hemoglobin level of 6.5% (48 mmol per mole) or higher mea- sured at screening, treatment with any glucose- lowering medication or GLP-1 receptor agonist within the previous 90 days, New York Heart Association class IV heart failure, or end-stage kidney disease or dialysis. Patients could not be enrolled within 60 days after a cardiovascular or neurologic event or if they planned to undergo coronary, carotid, or peripheral revasculariza- tion. A detailed list of the eligibility criteria is provided in the Supplementary Appendix.

Intervention and Management

Patients were randomly assigned, with the use of a centralized system in a double-blind manner and in a 1:1 ratio without stratification, to re- ceive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. The starting dose of semaglutide was 0.24 mg once weekly, and the dose was increased every 4 weeks (to once- weekly doses of 0.5, 1.0, 1.7, and 2.4 mg) until the target dose of 2.4 mg was reached after 16 weeks. If dose escalation led to unacceptable adverse effects, the dose-escalation intervals could be extended, treatment could be paused, or maintenance doses below the 2.4 mg per week target dose could be used. Semaglutide or pla-

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Semaglutide in Obesity without Diabetes

cebo was to be discontinued if patients became or planned to become pregnant, if pancreatitis developed, or if the patient had a calcitonin level equal to or greater than 100 ng per liter (see the Supplementary Appendix for the calcitonin-mon- itoring protocol). Investigators were encouraged to follow evidence-based recommendations in their choice of medical management of underly- ing cardiovascular disease. If diabetes developed during the trial, the patient continued to take the assigned trial product. The use of glucose- lowering medications was at the discretion of the investigator, although initiation of open- label treatment with a GLP-1 receptor agonist was prohibited.

End Points

The primary cardiovascular efficacy end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or non- fatal stroke, assessed in a time-to-first-event analysis. Confirmatory secondary end points, assessed in time-to-first-event analyses and test- ed in hierarchical order, were death from cardio- vascular causes, a composite heart failure end point (death from cardiovascular causes or hos- pitalization or an urgent medical visit for heart failure), and death from any cause. Supportive secondary end points and adjudicated end-point definitions are provided in the Supplementary Appendix.

Statistical Analysis

This event-driven trial was designed to provide 90% power to detect a relative risk reduction of 17% for a primary end-point event in the sema- glutide group as compared with the placebo group (hazard ratio, 0.83) at an overall one-sided significance level of 0.025. This design required that a minimum of 1225 primary end-point events be accrued. Assuming an event rate for the primary end point of 2.2% per year in the placebo group, a trial duration of 59 months, and a withdrawal or loss-to-follow-up rate of 1% per year in both groups, we estimated that 17,500 patients would need to be enrolled. One interim analysis for superiority with respect to the primary end point was prespecified to occur when two thirds of the total planned number of primary end-point events had accrued (addi- tional details are provided in the Supplementary Appendix).

Efficacy analyses were based on the intention-

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to-treat principle and included all unique patients who underwent randomization irrespective of adherence to semaglutide or placebo or changes to background medications. Data from patients who withdrew from the trial, died from causes not included in the end point, or were lost to follow-up were censored at the time of with- drawal, death, or last contact with the investiga- tor. Cause-specific hazard ratios and 95% confi- dence intervals were generated with the use of a Cox proportional hazards model with random- ization assignment (semaglutide or placebo) as a fixed factor. One-sided P values were obtained from a score test. For the primary end point, the hazard ratio, 95% confidence interval, and P value were adjusted for the group sequential design with the use of likelihood-ratio ordering.20

If primary end-point events occurred in a smaller percentage of patients treated with semaglutide than with placebo, confirmatory secondary end points were to be evaluated in the following hierarchical order: death from cardio- vascular causes, the heart failure composite end point, and death from any cause. A gatekeeping testing strategy was used, with statistical sig- nificance at each step required in order to test the next hypothesis, with the use of a separate alpha-spending function as described by Glimm and colleagues21 to preserve the studywise one- sided type 1 error at 2.5%. Although the statisti- cal analysis plan specified that one-sided P values would be used for hypothesis testing, results are reported here with two-sided P values. Continu- ous supportive secondary end points (changes from baseline to week 104) were assessed by analysis of covariance, with multiple imputation used for missing values under a missing-at-ran- dom assumption; because these supportive end points were not adjusted for multiplicity, confi- dence intervals should not be used in place of a hypothesis test. All statistical analyses were performed with SAS software, version 9.4 TS1M5 (SAS Institute).

Results

Randomization, Patient Characteristics, and Follow-up

From October 2018 through March 2021, a total of 17,604 patients underwent randomization; 8803 were assigned to receive semaglutide and 8801 to receive placebo. The baseline demograph- ic and clinical characteristics of the patients are

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summarized in Table 1 and Table S1 in the Sup- plementary Appendix, and the representative- ness of patients enrolled in the trial is shown in Table S2; detailed characteristics of the pooled patient population (before the randomization assignments were revealed) have been reported previously.23 The mean (±SD) age of the patients was 61.6±8.9 years, and 12,732 patients (72.3%) were male. The mean BMI was 33.3±5.0, and 12,580 patients (71.5%) met the BMI criterion for obesity (≥30). The mean glycated hemoglo- bin level was 5.8±0.3%, and 11,696 patients (66.4%) met the glycated hemoglobin criterion for prediabetes (defined as a mean level of 5.7 to 6.4%). More than three quarters of the patients had had a previous myocardial infarction, and nearly one quarter had chronic heart failure. The use of guideline-based medical therapies for cardiovascular disease appeared to be well bal- anced between the groups. Most of the patients were receiving lipid-lowering medications (90.1%) and platelet-aggregation inhibitors (86.2%), 70.2% of the patients were taking beta-blockers, 45.0% were taking angiotensin-converting– enzyme inhibitors, and 29.5% were taking angiotensin-receptor blockers.

Patient flow through the trial is shown in Figure S1. Patients were followed up for a mean of 39.8±9.4 months. Permanent premature dis- continuation of semaglutide or placebo occurred in 2351 patients (26.7%) in the semaglutide group and 2078 (23.6%) in the placebo group (Fig. S2). The mean duration of exposure to semaglutide or placebo in the overall trial population was 34.2±13.7 months (33.3±14.4 months for sema- glutide and 35.1±13.0 months for placebo); pa- tients received the assigned trial product for 82.5% and 87.7% of the potential treatment time in the semaglutide group and the placebo group, respectively. Administration of semaglutide over time is summarized in Figure S3; by 104 weeks, approximately 77% of the patients receiving sema- glutide were taking the target 2.4-mg weekly dose. Treatment with an open-label GLP-1 recep- tor agonist was initiated during the trial (a viola- tion of the trial protocol) in 36 patients (sema- glutide in 28 patients) in the semaglutide group and in 121 patients (semaglutide in 92 patients) in the placebo group. No patient was taking a sodium–glucose transport protein 2 inhibitor at the time of randomization, but treatment with a medication of that class was initiated in 213

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patients in the semaglutide group and 332 pa- tients in the placebo group. A total of 17,061 patients (96.9%) completed the trial (defined as having died or attended the final trial visit), and vital status was available for 17,495 (99.4%).

Efficacy End Points

A primary cardiovascular end-point event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) occurred in 569 of the 8803 patients (6.5%) in the semaglutide group and 701 of the 8801 patients (8.0%) in the placebo group (hazard ratio, 0.80; 95% confi- dence interval [CI], 0.72 to 0.90; P<0.001 [nomi- nal significance level for superiority after adjust- ment for the interim analysis, 0.046]) (Fig. 1A and Table 2). Death from cardiovascular causes, the first confirmatory secondary end point, oc- curred in 223 patients (2.5%) in the semaglutide group and in 262 patients (3.0%) in the placebo group (hazard ratio, 0.85; 95% CI, 0.71 to 1.01; P=0.07 [nominal significance level for superior- ity, 0.023]) (Fig. 1B). Because the between-group difference with respect to death from cardiovas- cular causes did not meet the required P value for hierarchical testing, superiority testing was not performed for the remaining confirmatory secondary end points (Fig. 1C and 1D). The haz- ard ratio for the heart failure composite end point was 0.82 (95% CI, 0.71 to 0.96), and the hazard ratio for death from any cause was 0.81 (95% CI, 0.71 to 0.93). Directionally consistent effects were observed for all time-to-first-event supportive secondary end points (Fig. S4). The effects of semaglutide on the primary end point appeared to be similar across all prespecified subgroups (Fig. S5).

Body Weight and Other End Points

Table 3 provides a summary of the continuous and binary supportive secondary end points. Changes in body weight and waist circumference over the course of the trial are shown in Figure S6. The mean change in body weight over the 104 weeks after randomization was –9.39% with semaglutide and –0.88% with placebo (estimat- ed treatment difference, –8.51 percentage points; 95% CI, –8.75 to –8.27).

Adverse Events

Adverse events are reported in Table 4 and Table S3. Serious adverse events were reported in 2941

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Semaglutide in Obesity without Diabetes

Table 1. Baseline Characteristics of the Patients.*
Semaglutide Placebo Characteristic (N = 8803) (N = 8801)
Age—yr	61.6±8.9	61.6±8.8

Male sex — no. (%) White

Black

Hispanic or Latino BMI‡

Glycated hemoglobin level — % <5.7%

Median high‐sensitivity CRP level (IQR) — mg/liter Myocardial infarction only
Peripheral arterial disease only
Other§

Median lipid level (IQR) — mg/dl HDL cholesterol
Triglycerides

Diastolic blood pressure — mm Hg EQ‐5D‐5L index score¶

6355 (72.2) 7387 (83.9) 348 (4.0)

914 (10.4) 33.3±5.0 5.78±0.34 2925 (33.2) 1.87 (0.89–4.18) 5962 (67.7) 376 (4.3) 169 (1.9)

44 (37–52) 134 (99–188) 79.4±10.0 0.88±0.15

6377 (72.5) 7404 (84.1) 323 (3.7)

908 (10.3) 33.4±5.0 5.78±0.33 2980 (33.9) 1.80 (0.86–4.06) 5944 (67.5) 401 (4.6) 181 (2.1)

44 (37–52) 135 (100–190) 79.2±9.9 0.88±0.15

Race or ethnic group — no. (%)†

Asian

720 (8.2)

727 (8.3)

Other

253 (2.9)

273 (3.1)

Body weight — kg

96.5±17.5

96.8±17.8

Waist circumference — cm

111.3±13.1

111.4±13.1

Distribution — no. (%)

≥5.7%

5877 (66.8)

5819 (66.1)

Cardiovascular inclusion criteria — no. (%)

Stroke only

1578 (17.9)

1556 (17.7)

Two or more inclusion criteria

718 (8.2)

719 (8.2)

eGFR — ml/min/1.73 m2

82.4±17.5

82.5±17.3

Total cholesterol

153 (131–182)

153 (131–183)

LDL cholesterol

78 (61–102)

Systolic blood pressure — mm Hg

131.0±15.6

130.9±15.3

Pulse — beats/min

68.9±10.6

68.6±10.7

EQ‐5D‐VAS score¶

77.15±15.63

77.15±15.73

* Plus–minus values are means ±SD. To convert the values for high‐density lipoprotein (HDL) cholesterol and low‐ density lipoprotein (LDL) cholesterol to millimoles per liter, multiply by 0.02586. To convert the values for triglycerides to millimoles per liter, multiply by 0.01129. To convert the values for glycated hemoglobin to millimoles per mole, mul‐ tiply by 10.929 and subtract 2.15. CRP denotes C‐reactive protein, eGFR estimated glomerular filtration rate, and IQR interquartile range.

† Race and ethnic group were reported by the patients. Race was not reported for 95 patients (1.1%) in the semaglutide group and 74 patients (0.8%) in the placebo group. The category “Other” includes patients who reported their race as American Indian or Alaska Native, Native Hawaiian or Pacific Islander, or other. Information on whether patients iden‐ tified as Hispanic or Latino was not reported for 95 patients (1.1%) in the semaglutide group and 76 patients (0.9%) in the placebo group.

‡ The body‐mass index (BMI) is the weight in kilograms divided by the square of the height in meters.
§ This category includes patients for whom it was not known whether only one or several criteria were fulfilled and pa‐

tients who underwent randomization in error and did not fulfill any criteria.
¶The EuroQol 5‐Dimension 5‐Level (EQ‐5D‐5L) index score22 ranges from 0 to 1, with higher scores indicating better

patient‐reported health status. The index score is calculated only if responses are available from all five questions. The EuroQol 5‐Dimension Visual Analogue Scale (EQ‐5D‐VAS) score ranges from 0 to 100, with higher scores indicating better patient‐reported health status.

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A Primary Cardiovascular Composite End Point

B
Death from Cardiovascular Causes

100
10
100 4
Hazard ratio, 0.80 (95% CI, 0.72–0.90)
Hazard ratio, 0.85 (95% CI, 0.71–1.01)
90
P<0.001 for superiority
90
P = 0.07
)) 8
Placebo
80
80 3
%( %( Placebo
ee 70
6
70
cncn Semaglutide ee 60
Semaglutide
didi 60 2
4
cncn 50
50
Ie Ie 1
vv ii 40
2
40
taltal uu 30
30 00
mumu 20
0 6 12 18 24 30 36 42 48 20
0 6 12 18 24 30 36 42 48 CC 10
10 00
0 6 12 18 24 30 36 42 48
0 6 12 18 24 30 36 42 48

No. at Risk

Months since Randomization

Placebo
8801 8652 8487 8326 8164 7101 5660 4015 1672 Semaglutide 8803 8695 8561 8427 8254 7229 5777 4126 1734

C Heart Failure Composite End Point

Placebo
8801 8733 8634 8528 8430 7395 5938 4250 1793 Semaglutide 8803 8748 8673 8584 8465 7452 5988 4315 1832

D Death from Any Cause

100
6
100 7
Hazard ratio, 0.82 (95% CI, 0.71–0.96)
Hazard ratio, 0.81 (95% CI, 0.71–0.93)
90
5
90 6
))
((
%%
80
Placebo
80
5
4
Placebo
ecec
70
70 4
nene
3
dd
60
60
Semaglutide
ii
Semaglutide
3
II
cncn
50
2
50
2
evievi
tt
40
1
40
1
alal
uu
30
30 00
mumu
20
0 6 12 18 24 30 36 42 48 20
0 6 12 18 24 30 36 42 48 CC
10
10 00
0 6 12 18 24 30 36 42 48
0 6 12 18 24 30 36 42 48

No. at Risk

Months since Randomization

Placebo
8801 8711 8601 8485 8381 7341 5885 4198 1766 Semaglutide 8803 8740 8654 8557 8425 7409 5944 4277 1816

Placebo
8801 8733 8634 8528 8430 7395 5938 4250 1793 Semaglutide 8803 8748 8673 8584 8465 7452 5988 4315 1832

Figure 1. Time-to-First-Event Analysis for Primary and Confirmatory Secondary Efficacy End Points.
Panel A shows the cumulative incidence of the primary cardiovascular composite end point (death from cardiovascular causes, nonfatal

myocardial infarction, or nonfatal stroke). Panel B shows the cumulative incidence of the first confirmatory secondary end point (death from cardiovascular causes). Panel C shows the cumulative incidence of the second confirmatory secondary end point (heart failure composite end point: death from cardiovascular causes or hospitalization or an urgent medical visit for heart failure). Panel D shows the cumulative incidence of the third confirmatory secondary end point (death from any cause). The definitions of all end points are provid‐ ed in the Supplementary Appendix. Cumulative incidence was estimated with the use of the Aalen–Johansen method with accounting for competing risk,24 and hazard ratios were estimated with the Cox proportional hazards regression model. Because the between‐group difference in death from cardiovascular causes did not meet the required P value for hierarchical testing, results for the two subsequent end points in the testing hierarchy are reported as point estimates and 95% confidence intervals. The widths of these confidence inter‐ vals have not been adjusted for multiplicity and therefore should not be used to infer definitive treatment effects for these secondary end points. The insets show the same data on an enlarged y axis. The x axis is truncated at 48 months because of the limited number

of patients in the trial after 48 months.

patients (33.4%) in the semaglutide group and
group (P<0.001); these events included gastroin- 3204 patients (36.4%) in the placebo group
testinal disorders in 880 patients (10.0%) in the (P<0.001). Adverse events leading to permanent
semaglutide group and 172 patients (2.0%) in discontinuation of semaglutide or placebo oc-
the placebo group (P<0.001) and gallbladder- curred in 1461 patients (16.6%) in the semaglu-
related disorders in 246 patients (2.8%) and 203 tide group and 718 patients (8.2%) in the placebo
patients (2.3%), respectively (P = 0.04).

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Table 2. Primary and Secondary Time-to-First-Event Efficacy End Points.*

End Point

Confirmatory secondary end points‡ Heart failure composite end point§

Supportive secondary end points¶

Nonfatal stroke
Coronary revascularization
Glycated hemoglobin level ≥6.5%††

Semaglutide Placebo (N=8803) (N=8801)

number of patients (percent)

Hazard Ratio (95% CI)

0.82 (0.71 to 0.96)

0.93 (0.74 to 1.15) 0.77 (0.68 to 0.87) 0.27 (0.24 to 0.31)

P Value

NA NA NA

Primary cardiovascular composite end point†

569 (6.5)

701 (8.0)

0.80 (0.72 to 0.90)

<0.001

Death from cardiovascular causes

223 (2.5)

262 (3.0)

0.85 (0.71 to 1.01)

0.07

300 (3.4)

154 (1.7) 473 (5.4) 306 (3.5)

361 (4.1)

165 (1.9)

608 (6.9) 1059 (12.0)

Death from any cause

375 (4.3)

458 (5.2)

0.81 (0.71 to 0.93)

Cardiovascular expanded composite end point‖	873 (9.9)	1074 (12.2)	0.80 (0.73 to 0.87)	NA
Cardiovascular composite end point with death from 710 (8.1) 877 (10.0) 0.80 (0.72 to 0.88) NA any cause**
Nonfatal myocardial infarction	234 (2.7)	322 (3.7)	0.72 (0.61 to 0.85)	NA

Hospitalization or urgent medical visit for heart failure

97 (1.1)

122 (1.4)

0.79 (0.60 to 1.03)

Unstable angina leading to hospitalization

109 (1.2)

124 (1.4)

0.87 (0.67 to 1.13)

Nephropathy composite end point‡‡	155 (1.8)	198 (2.2)	0.78 (0.63 to 0.96)	NA
Glycated hemoglobin level ≥5.7% among patients 623 (21.3) 1501 (50.4) 0.33 (0.30 to 0.36) NA with baseline glycated hemoglobin <5.7%§§

* Data are for the full analysis population during the in‐trial observation period (from randomization to the final follow‐up visit). All end points were analyzed with the use of a Cox proportional hazards model with treatment as a categorical fixed factor. Data from patients without events of interest were censored at the end of their in‐trial period. NA denotes not applicable.

† The primary efficacy end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The hazard ratio, 95% confidence interval, and P value were adjusted for the group sequential design with the use of likelihood‐ratio or‐ dering, and the nominal two‐sided significance level was 0.046.

‡ Confirmatory secondary end points were analyzed under multiplicity control through a stagewise hierarchical testing scheme in which all P values after the first nonsignificant P value are not reported. The P values (unadjusted) for the primary and confirmatory secondary end points were to be compared with the nominal significance level derived from the relevant alpha spending function for the end point; if the P value was below the nominal limit, superiority would be shown. The nominal two‐sided significance level was 0.023 for death from car‐ diovascular causes.

The heart failure composite end point was the first occurrence of death from cardiovascular causes or hospitalization or an urgent medi‐ cal visit for heart failure.

¶ Because supportive secondary end points were not corrected for multiplicity, results are reported as point estimates and 95% confidence intervals. The widths of the confidence intervals have not been adjusted for multiplicity and therefore should not be used to infer definitive treatment effects for supportive secondary end points.

‖ The cardiovascular expanded end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina leading to hospitalization.

** The cardiovascular end point with death from any cause was a composite of death from any cause, nonfatal myocardial infarction, or non‐ fatal stroke.

†† Patients who underwent randomization in error and had a baseline glycated hemoglobin level higher than 6.5% (48 mmol per mole) were excluded from this analysis; 8800 patients in the semaglutide group and 8797 patients in the placebo group were included.

‡‡ The nephropathy end point was a five‐component composite of death from renal causes, initiation of long‐term renal replacement therapy (dialysis or transplantation), onset of a persistent eGFR lower than 15 ml per minute per 1.73 m2, persistent 50% reduction in eGFR rela‐ tive to baseline, or onset of persistent macroalbuminuria (urinary albumin‐to‐creatine ratio, >300 mg per gram).

§ A glycated hemoglobin level of 5.7% or higher was assessed in a time‐to‐first‐event analysis only among patients whose glycated hemoglobin was lower than 5.7% at baseline screening; 2925 patients in the semaglutide group and 2980 patients in the placebo group were included.

Discussion

diabetes. We conducted this trial to determine

whether semaglutide, a potent long-acting medi- GLP-1 receptor agonists are recognized to have cation in this class,25 would diminish excess cardioprotective effects in patients with type 2 cardiovascular risk associated with overweight

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Table 3. Supportive Binary and Continuous Secondary End Points.*
Semaglutide Placebo End Point (N=8803) (N=8801) Difference (95% CI)†
Glycated hemoglobin level of <5.7% among patients with baseline glycated hemoglobin level of ≥5.7% — no./total no. (%)‡

At week 52
Mean change from randomization to week 104

Waist circumference — cm Systolic blood pressure — mm Hg Heart rate — beats/min EQ‐5D‐VAS score§
Total cholesterol level — %
LDL cholesterol level — %

3848/5831 (66.0)

–7.56±0.09 –3.82±0.16 3.79±0.11 2.52±0.16

–4.63 –5.25

1136/5748 (19.8)

–1.03±0.09 –0.51±0.16 0.69±0.11 0.92±0.16 –1.92 –3.14

10.15 (9.18 to 11.23)

–6.53 (–6.79 to –6.27) –3.31 (–3.75 to –2.88) 3.10 (2.80 to 3.39) 1.60 (1.16 to 2.04) –2.77 (–3.37 to –2.16) –2.18 (–3.22 to –1.12)

At week 104

3775/5750 (65.7)

1211/5663 (21.4)

8.74 (7.91 to 9.65)

Body weight — %

–9.39±0.09

–0.88±0.08

–8.51 (–8.75 to –8.27)

Glycated hemoglobin level — percentage points

–0.31±0.00

0.01±0.00

–0.32 (–0.33 to –0.31)

Diastolic blood pressure — mm Hg

–1.02±0.10

–0.47±0.10

–0.55 (–0.83 to –0.27)

EQ‐5D‐5L index score§

0.01±0.00

–0.01±0.00

0.01 (0.01 to 0.02)

High‐sensitivity CRP level — %

–39.12

–2.08

–37.82 (–39.70 to –35.90)

HDL cholesterol level — %

4.86

0.59

4.24 (3.70 to 4.79)

Triglyceride level — %

–18.34

–3.20

–15.64 (–16.68 to –14.58)

* Plus–minus values are means ±SE. Data are from the full analysis population. The binary end points were analyzed by logistic regression with treatment as factor and the baseline glycated hemoglobin level as a covariate. The continuous end points assessing changes from ran‐ domization to week 104 were analyzed with the use of analysis of covariance with treatment as factor and the baseline value as a covariate, with multiple imputation for missing values under a missing‐at‐random assumption. High‐sensitivity CRP, total cholesterol, HDL cholester‐ ol, LDL cholesterol, and triglyceride levels were log‐transformed before analysis, and the results are thus reported as relative changes (i.e., percentage changes). Because supportive secondary end points were not corrected for multiplicity, results are reported as point estimates and 95% confidence intervals. The widths of the confidence intervals have not been adjusted for multiplicity and therefore should not be used to infer definitive treatment effects for supportive secondary end points. To convert values for glycated hemoglobin to millimoles per mole, multiply by 10.929 and subtract 2.15.

† Differences are given as the odds ratio for the binary glycated hemoglobin end points and as the between‐group difference for the changes in continuous end points from baseline to 104 weeks.

‡ This end point was assessed among patients whose glycated hemoglobin level was 5.7% or higher at baseline screening and who had an assessment or imputed data at the time point of interest.

The EQ‐5D‐5L index score ranges from 0 to 1, with higher scores indicating better patient‐reported health status. The index score is calcu‐ lated only if responses are available from all five questions. The EQ‐5D‐VAS score ranges from 0 to 100, with higher scores indicating better patient‐reported health status.

or obesity in patients with no history of diabe- tes. Among 17,604 patients with a BMI of 27 or greater and preexisting cardiovascular disease but without diabetes, treatment with once-week- ly subcutaneous semaglutide at a dose of 2.4 mg for a mean duration of 33 months reduced the risk of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or non- fatal stroke by 20% (hazard ratio, 0.80; 95% CI, 0.72 to 0.90). The effects of semaglutide oc- curred early after the initiation of treatment and were directionally similar across cardiovascular end points and among prespecified patient sub-

8 n engl j med
The New England Journal of Medicine

groups. Semaglutide was associated with de- creases in body weight and waist circumference, findings consistent with the known metabolic effects of this class of medications.

The incidence of serious adverse events was lower among patients assigned to receive sema- glutide than among those assigned to receive placebo. A higher percentage of patients discon- tinued semaglutide than placebo because of ad- verse events, a difference that appeared to be due to the greater incidence of gastrointestinal symptoms with semaglutide. Nausea, vomiting, and diarrhea are not uncommon during treat-

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Table 4. Investigator-Reported Adverse Events.* Event

Cardiac disorders
Nervous system disorders
Neoplasms benign, malignant, and unspecified

Nervous system disorders
General disorders and administration‐site conditions Infections and infestations

Covid‐19–related events Gallbladder‐related disorders Acute pancreatitis¶

Semaglutide Placebo (N=8803) (N=8801)

of patients (%)

P Value†

<0.001 0.08 0.94

0.03 <0.001 0.47

0.46 0.04 0.28

Semaglutide in Obesity without Diabetes

Serious adverse events‡

2941 (33.4)

3204 (36.4)

<0.001

1008 (11.5) 444 (5.0) 405 (4.6)

124 (1.4) 105 (1.2) 75 (0.9)

2108 (23.9) 246 (2.8) 17 (0.2)

1184 (13.5) 496 (5.6) 402 (4.6)

92 (1.0) 47 (0.5) 84 (1.0)

2150 (24.4) 203 (2.3) 24 (0.3)

Infections and infestations

624 (7.1)

738 (8.4)

0.001

Surgical and medical procedures

433 (4.9)

548 (6.2)

<0.001

Gastrointestinal disorders	342 (3.9)	323 (3.7)	0.48
Adverse events leading to permanent discontinuation of trial 1461 (16.6) 718 (8.2) <0.001 product, irrespective of seriousness‡
Gastrointestinal disorders	880 (10.0)	172 (2.0)	<0.001

Metabolism and nutrition disorders

108 (1.2)

27 (0.3)

<0.001

Neoplasms benign, malignant, and unspecified

80 (0.9)

105 (1.2)

0.07

Prespecified adverse events of special interest, irrespective of seriousness§

Malignant neoplasms

422 (4.8)

418 (4.7)

0.92

Acute kidney failure

171 (1.9)

200 (2.3)

0.13

* This trial involved targeted collection of safety data, in which the only adverse events systematically recorded and reported were serious adverse events, adverse events leading to discontinuation of the trial product irrespective of seriousness, and adverse events of prespecified special interest irrespective of seriousness. Details of the adverse‐event reporting are provided in the Supplementary Appendix. Events are classified according to the Medical Dictionary for Regulatory Activities (MedDRA), version 26.0, preferred terms. An expanded list of investigator‐reported adverse events is provided in Table S3.

† P values are two‐sided and were calculated with a Fisher’s exact test for the test of no difference.
‡ Events are listed according to system organ class.
§ The adverse events of special interest were based on prespecified MedDRA queries.
¶Acute pancreatitis events recorded here are those that were confirmed by the events adjudication committee. Investi‐

gators reported pancreatitis (acute or other type) events in 29 patients (0.3%) in the semaglutide group and 30 patients (0.3%) in the placebo group.

ment with GLP-1 receptor agonists, particularly at initiation and dose escalation.26 The incidence of gallbladder-related disorders was higher with semaglutide than with placebo, an association that has also been reported previously.27 Nonethe- less, serious adverse events related to gastroin- testinal disease, acute kidney failure, pancreatitis, cancers, or psychiatric disorders were not more frequent with semaglutide than with placebo.

Mechanisms of cardiovascular risk reduction with semaglutide may include those related to

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physiological benefits from the reduction of ex- cess abnormal body fat and actions of semaglu- tide other than weight loss. Weight loss across a spectrum of elevated BMIs produces not only improvements in glucose levels and the tradi- tional cardiovascular intermediate risk factors28 but also reductions in ectopic adipose tissue depots that may contribute to atherosclerosis and myocardial dysfunction.29 Perivascular and epicardial adipose tissue impose direct adverse effects on the vascular endothelium and myocar-

dium.30 In addition, reductions in excess abnor- mal body fat ameliorate the systemic proinflam- matory and prothrombotic milieu associated with obesity.31

Semaglutide improved cardiovascular out- comes in this trial, whereas lifestyle and pharma- cologic interventions for overweight or obesity tested in previous trials have uniformly failed to do so.11,14 The reductions in body weight achieved with other nonsurgical approaches have been substantially lower than the mean 9.4% decrease observed with semaglutide in this trial, and a post hoc analysis of data from a previous trial has suggested that cardiovascular risk might be decreasedamongpatientswholoseatleast10% of their body weight.32 Similarly, bariatric sur- gery, in which reductions in body weight of more than 20% can be achieved, has been as- sociated with fewer cardiovascular events than usual care.33,34 However, the data are consistent with the between-group difference in the inci- dence of cardiovascular disease emerging early in this trial, which suggests that more rapid treat- ment-induced physiological changes beyond the magnitude of body-weight loss may have medi- ated at least part of the cardiovascular benefit.

Medications in the GLP-1 receptor agonist class have been shown in animals with or with- out diabetes to reduce inflammation, improve endothelial and left ventricular function, promote plaque stability, and decrease platelet aggrega- tion.16 In this trial, semaglutide was associated with changes in multiple biomarkers of cardio- vascular risk, including blood pressure, waist circumference, glycemic control, nephropathy, and levels of lipids and C-reactive protein. For perspective, the observed decrease of 3.3 mm Hg in systolic blood pressure in this trial is greater than the decrease of 2 mm Hg predicted by a meta-analysis to yield a 7% reduction in vascular mortality,35 and the 37.8-percentage-point de- crease in the high-sensitivity C-reactive protein level with semaglutide in this trial is similar to that reported with statins.36 These changes in cardiovascular biomarkers are notable for hav- ing been achieved on a background of high rates of use of statins, antihypertensive agents, and other evidence-based medications for atheroscle- rotic disease. Although our understanding of the mechanisms of cardiovascular protection with semaglutide remains speculative, the consistent effects on cardiometabolic risk factors support

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the hypothesis that clinical benefit is achieved through multiple interrelated pathways.

An important limitation of this trial is that we included only patients with preexisting car- diovascular disease. The effects of semaglutide on primary prevention of cardiovascular events in persons with overweight or obesity but with- out previous atherosclerotic disease were not studied. Moreover, the diversity of the patient group does not duplicate a globally representa- tive population, particularly because only 27.7% and 3.8% of the enrolled patients were women or Black persons, respectively. With regard to the latter group, however, 12.5% of the patients enrolled in the United States identified as Black.

Recommendations for the treatment of type 2 diabetes have long targeted cardiovascular risk reduction,37 and current guidelines recommend the use of GLP-1 receptor agonists in patients with diabetes who need cardiovascular risk reduction, weight management, or both.38,39 Major adverse cardiovascular events were reduced by approxi- mately 14% in a meta-analysis of GLP-1 receptor agonists (hazard ratio, 0.86; 95% CI, 0.80 to 0.93) among patients with type 2 diabetes and preexisting cardiovascular disease or cardiovas- cular risk factors,10 with similar benefits observed in these patient groups in trials of subcutaneous or oral semaglutide (hazard ratios of 0.74 and 0.79, respectively).40,41 The estimated global prev- alence of diabetes is approximately 30% among patients with chronic coronary syndromes, and thus most people with cardiovascular disease do not have diabetes.42 The magnitude of the effect of semaglutide in the current trial was similar to that among patients with diabetes in previous studies (within the constraints of between-trial comparisons), which suggests that treatment with semaglutide could be applied more broadly for secondary prevention of cardiovascular events in the expanding population of patients with overweight and obesity and atherosclerotic vas- cular disease. Moreover, because two thirds of the patients in this trial had dysglycemia (gly- cated hemoglobin levels of 5.7 to 6.4%), our findings support a more attentive therapeutic approach to prediabetes,43 not only because of the association between prediabetes and cardio- vascular risk but also because of the opportunity to improve cardiovascular outcomes through appropriate weight management.

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The new england journal of medicine

In this randomized, placebo-controlled trial involving patients with preexisting cardiovascu- lar disease and overweight or obesity but with- out diabetes, weekly subcutaneous semaglutide at a dose of 2.4 mg was superior to placebo in reducing the incidence of a composite of death from cardiovascular causes, nonfatal myocardial

infarction, or nonfatal stroke at a mean follow- up of 39.8 months.

Supported by Novo Nordisk.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

Semaglutide in Obesity without Diabetes

Appendix

The authors’ affiliations are as follows: the Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland (A.M.L.); Novo Nordisk, Søborg, Denmark (K.B.-F., S.E., S.H.-L., G.K.H., T.K.O., M.M.M., C.W.T.); the Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh (H.M.C.), and the National Institute for Cardiovascular Outcomes Research, University College London, London (J.D.) — both in the United Kingdom; the Department of Biostatistics, University of Washington (S.S.E.), and the Department of Medicine, VA Puget Sound Health Care System and University of Washington (S.E.K.) — both in Seattle; the Department of Vascular Medicine, Academic Medical Center, Amsterdam (G.K.H.); the Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago (R.F.K.); the De- partment of Internal Medicine (Endocrinology Division) and Peter O’Donnell Jr. School of Public Health, University of Texas Southwest- ern Medical Center, Dallas (I.L.); the Department of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston (J.P.); and Pennington Biomedical Research Center, Baton Rouge, LA (D.H.R.).

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