Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes

Obesity is a global epidemic affecting 2.5 billion people and is recognized as the fourth leading cause of global mortality. Obesity is characterized by excessive accumulation of body fat and is associated with a range of health consequences, including an elevated risk of cardiovascular disease (CVD). Glucagon-like peptide-1 (GLP-1) receptor agonists have been proven to reduce cardiovascular outcomes in patients with diabetes. Study and results: The SELECT trial was a multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial, conducted at 804 clinical sites in 41 countries. 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 efficacy endpoint was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, assessed in a time-to-first-event analysis. A total of 17,604 patients were recruited, with a mean age of 61.6 years and 72.3% males. The mean duration of exposure to semaglutide or placebo in the overall trial population was 34.2±13.7 months. The primary CVD endpoint occurred in 6.5% (n=569) of the semaglutide group and 8% (n=701) in the placebo group (hazard ratio, 0.80; 95% CI, 0.72 to 0.90; P<0.001). There was also a significant reduction of 9.39% in body weight among the patients taking semaglutide over 104 weeks after randomization versus 0.88% among the placebo group. Semaglutide reduces the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in obese and overweight non-diabetic patients with preexisting cardiovascular disease.

The triglyceride-glucose (TyG) index, a surrogate marker for insulin resistance, has been shown to be closely associated with cardiovascular risk. However, it remains unclear whether diabetes status affects the association between the TyG index and the risk of major adverse cardiovascular events (MACEs) in patients with coronary heart disease (CHD). The aim of this study is to systematically evaluate the relationship between the TyG index and MACEs among CHD patients with different diabetes statuses. We systematically searched PubMed, the Cochrane Library, Web of Science, and Embase from inception to March 13, 2025, for cohort studies examining the association between TyG and MACEs in patients with CHD with different diabetes statuses. The outcomes included all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, and revascularization. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were extracted for the TyG index as both categorical and continuous variables. Study quality was assessed using the Newcastle-Ottawa Scale (NOS). All the statistical analyses were performed using Stata (version 17.0) and R (version 4.4.1). Depending on heterogeneity, either a fixed-effect or random-effects model was used to pool the data. Subgroup analysis and meta-regression are used to explore the sources of heterogeneity. This study was registered in PROSPERO (CRD: 420251018545). A total of 36 longitudinal cohort studies comprising 173,851 participants (119,232 with diabetes and 54,619 without diabetes) were included, with 9159 MACEs reported during the follow-up period. In diabetic patients, a higher TyG index significantly increased the risk of MACEs (categorical HR = 1.98, 95% CI 1.61-2.43; continuous HR = 1.57, 95% CI 1.38-1.78), all-cause mortality (HR = 1.74, 95% CI 1.45-2.08), nonfatal myocardial infarction (HR = 2.05, 95% CI 1.52-2.77), nonfatal stroke (HR = 1.73, 95% CI 1.12-2.66), and revascularization (HR = 2.52, 95% CI 1.26-5.04). In nondiabetic patients, a higher TyG index also significantly increased the risk of MACEs (categorical HR = 1.65, 95% CI 1.33-2.05; continuous HR = 1.74, 95% CI 1.46-2.06), all-cause mortality (HR = 1.50, 95% CI 1.18-1.90), nonfatal myocardial infarction (HR = 2.46, 95% CI 1.11-5.47), and revascularization (HR = 2.09, 95% CI 1.57-2.76). However, no association was observed between the TyG index and nonfatal stroke (HR = 1.66, 95% CI 0.88-3.12) in nondiabetic patients. Higher TyG index values appear to be associated with an increased risk of adverse cardiovascular events, all-cause mortality, nonfatal myocardial infarction, and revascularization in both diabetic and nondiabetic patients with CHD. However, no significant association was found between the TyG index and the risk of nonfatal stroke in nondiabetic patients. These findings suggest that the TyG index may offer potential prognostic value in CHD, but further high-quality prospective studies are warranted to confirm these associations and clarify their clinical implications.

Current guideline statements for primary and secondary prevention of cardiovascular disease (CVD) rely on estimates of absolute risk of coronary events. For example, the American Heart Association guidelines on primary prevention state that persons with ≥10% risk over 10 years of myocardial infarction (MI) or coronary death should be considered for antiplatelet therapy with aspirin.1 Similarly, the National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines2 state that target low-density lipoprotein level should be based on projected absolute risk of future coronary events rather than on presence or absence of specific risk factors. These guidelines state that patients at high risk of MI and coronary death, defined as an absolute 10-year risk of ≥20%, should have a target low-density lipoprotein level <100 mg/dL and should receive statin therapy if needed to achieve this goal. Stroke, however, is not included as one of the outcomes contributing to these absolute risk levels. Included in the group of patients with elevated risk, moreover, are those who already have ischemic heart disease, as well as patients deemed to be “coronary heart disease (CHD) risk equivalents,” indicating those at the same elevated risk as patients with ischemic heart disease. CHD risk equivalents include patients with diabetes mellitus, those with multiple risk factors that put them at elevated risk based on calculation of their Framingham Score, and patients with “other forms of symptomatic atherosclerotic disease.” The latter group is further defined to include those with peripheral arterial disease (PAD), abdominal aortic aneurysm (AAA), and carotid artery disease. The category of “risk equivalents” in the ATP III guidelines, however, does not include the vast majority (≈80%3) of ischemic stroke patients without carotid artery disease as cause of their stroke. Ischemic stroke is therefore notably excluded from the list of outcomes contributing to …

INTRODUCTION: Noninvasive assessment of carotid atherosclerotic plaque (CAP) morphology represents a promising direction, allowing to optimize not only cardiovascular event risk assessment, but also the selection of patients for carotid revascularization. Determination of CAP echogenicity by means of GSM-analysis can be used as part of multiparametric assessment of CAP instability and prediction of adverse cardiovascular events.OBJECTIVE: To assess the predictive value of echogenicity of carotid atherosclerotic plaques in relation to the development of adverse cardiovascular events in patients 40–64 years old.MATERIALS AND METHODS: The study included 191 patients with carotid atherosclerosis aged 40–64 years. All patients underwent duplex scanning of the arteries of the carotid basin with determination of the echogenicity of carotid ASBs. The combined end point (CEP) consisted of the following possible events: nonfatal myocardial infarction or unstable angina, nonfatal stroke, coronary revascularization or peripheral artery revascularization, and death from cardiovascular causes. Data on the onset of CVD were collected during follow-up visits and using medical information systems. Statistics: Data were analyzed using MedCalc software (version 20.216). Frequencies and percentages were used to describe nominal data, and medians and quartiles were used for quantitative data. The Kaplan-Meier survival analysis method was used to estimate the probability of events constituting the combined endpoint. Cox regression analysis was used to estimate the risk of the event and the influence of independent variables on the risk.RESULTS: By correlation analysis, carotid AP echogenicity (GSM) was inversely correlated with BMI (r=-0,355; p&lt;0,0001), waist circumference (r=-0.37; p&lt;0.0001), triglyceride levels (r=-0.163; p=0.027), uric acid (r=-0.188; p=0.028). The duration of the follow-up period was 15.1 (12.2; 22.9) months. Events constituting CEP occurred in 15 (7.85%) patients: nonfatal myocardial infarction in 2 (1.05%) patients, nonfatal stroke in 2 (1.05%) patients, myocardial revascularization in 6 (3.14%) patients, unstable angina in 5 (2.61%) patients. The presence of carotid AP with echogenicity ≤39 conventional units allowed predicting the development of events constituting CEP with sensitivity of 53.3% and specificity of 80.7%. Kaplan-Meier survivalanalysis revealed that cumulative survival of patients with carotid AP with echogenicity ≤39 conventional units was statistically significantly lower compared to patients with carotid ASB with echogenicity &gt;39 conventional units.DISCUSSION: It should be noted that in the presented study, decreased echogenicity of carotid AP was associated with the risk of adverse cardiovascular events only in the simple and sex- and age-adjusted models, but not in the full-adjusted model. It is likely that this may be due to the fact that the echogenicity of CAP is closely related to the cumulative burden of cardiovascular risk factors, which has been shown in earlier studies including. Probably, combined assessment of carotid atherosclerosis burden and morphological features of CAP may be the most promising approach to obtain additional prognostic information in patients with carotid atherosclerosis.CONCLUSION: Among patients with carotid atherosclerosis 40–64 years old, the presence of ACS with echogenicity ≤39 conventional units was associated with a 3.44 (95% CI 1.19–9.91) fold increase in the relative risk of events constituting the combined endpoint after adjusting for sex and age.

Effects of once-weekly semaglutide on major adverse cardiovascular events in patients with type 2 diabetes and polyvascular disease: a post hoc analysis of the SUSTAIN 6 trial

Background Recently published, SELECT trial has shown that semaglutide, a glucagon-like peptide-1 (GLP1) receptor agonist, reduces the risk of adverse cardiovascular events in patients 45 years of age or older who had preexisting cardiovascular disease and a body-mass index of 27 or greater but no history of diabetes (1). Purpose Our purpose is to calculate the percentage of patients attending a cardiac rehabilitation (CR) program who would have indication of a GLP1 receptor agonist based on the SELECT trial eligibility criteria. And to describe their main features and their weight and body mass index change during a CR program without specific pharmacological management for obesity. Methods Retrospective observational study. We reviewed data of all the patients who attended our CR unit since April 2014 to September 2023. Obesity management in our CR unit includes dietary counselling and structured centre-based exercise program. GLP1 agonist receptors are not financed by our country's public health system for the indication of body weight loss. Body mass index (BMI) was calculated as weight in kilograms divided by the square of the height in meters. To compare related means, we used the paired samples t-test. Results Since 2014, 692 patients have been treated in the CR program. 92% of them had preexisting coronary disease (638). 90% of patients with coronary disease were 45 years old or older (575). Their mean BMI was 29.0. Only 17,2% of them had a normal BMI. 45,4% were overweight and 37,4 were obese. 64% of patients with coronary disease and 45 years of age or older had a BMI of 27 or more (361). 66% of patients with coronary disease who were 45 years of age or older and had a BMI of 27 or more were non diabetic (238). Sumarizing, 34,3% (238 of 692) of patients who attended the CR program would have had indication of a GLP1 receptor agonist based on the SELECT trial eligibility criteria. Their mean age was 58,6 (SD=8,0) years, 84% men, their mean initial BMI was 31,5 (SD=4,6), mean initial weight 90,7 (SD=13) kg. They had acceptable levels of adherence to the Mediterranean diet measured in Medas-14 Predimed test (9,2 SD=2,2). There was a statistically significant improvement in MI and weight loss during the CR program in these patients (31,5 -SD=3,8- vs 31,1 -SD=3,9- kg/m2 ,p 0,002 and 90,7 -SD=13,1- vs 89,7 -SD=13,6- kg, p:0,002). But both average improvement in BMI and weight loss were of small amount (0,3kg/m2 -SD=1,5- and 0,9 kg -SD=4,4-). Average percentage of body weight loss was 1,0% (SD=4,7). Only 11% of patients achieved a 5% or more of weight loss. Conclusions 34,3% of patients attending a CR program would have indication of a GLP1 receptor agonist based on the SELECT trial eligibility criteria. The mean percentage of body weight loss was of small amount (1%) in a CR program based on behavioural counselling and structured exercise. GLP1 receptor agonists could help to improve these results.

Introduction: Meta-analyses on glucagon-like peptide-1 (GLP-1) receptor agonists have shown beneficial effects in reducing major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus. However, it is unclear if they have similar beneficial effects in patients with type 2 diabetes mellitus and chronic heart failure. Methods: A search was performed on online databases - MEDLINE (via PubMed) and ClinicalTrials.gov, using the search words GLP-1 receptor agonist and cardiovascular outcomes. The references from the search results were also reviewed for potential studies that can be included. We identified four cardiovascular outcome studies with GLP-1 receptor agonists on patients with type 2 diabetes mellitus with data on patients with chronic heart failure, and included them in our meta-analysis. Results: 6189 patients were evaluated in this meta-analysis, with 3053 in the GLP-1 receptor agonist group and 3136 in the placebo group. Among them, 475 (15.56%) major adverse cardiovascular events (i.e., cardiovascular death, stroke, or myocardial infarction) occurred in the GLP-1 receptor agonist group and 536 events (17.09%) in the placebo group with a hazard ratio (HR) of 0.90, 95% confidence interval (CI) of 0.79 to 1.01 and a p-value of 0.08, indicating a favorable effect with GLP1 agonists though statistically not significant. Conclusion: In patients with type 2 diabetes mellitus and chronic heart failure, GLP-1 receptor agonists may have a favorable effect in reducing major adverse cardiovascular events, though statistically not significant.

BackgroundThe cardiovascular effects of glucagon-like peptide-1 (GLP-1) receptor agonists are still controversial in the treatment of type 2 diabetes mellitus (T2DM) patients. The purpose of this study was to evaluate the risk of cardiovascular events of GLP-1 (albiglutide, exenatide, liraglutide, semaglutide, lixisenatide and dulaglutide) receptor agonists in T2DM patients.MethodsPubMed and Embase were searched to find relevant randomized controlled trials (RCTs) from inception to June 2019 that evaluated the effect of GLP-1 receptor agonists on cardiovascular events in patients with T2DM. The T2DM patients of all the eligible trials received either GLP-1 therapy or placebo, and the cardiovascular outcomes included death from cardiovascular causes, fatal or non-fatal myocardial infarction and fatal or non-fatal stroke.ResultsWe included 6 multinational double-blind randomized placebo-control trials that included a total of 52821 T2DM patients. The results indicated that GLP-1 receptor agonists reduced the risk of death from cardiovascular causes (RR: 0.90; 95% CI: 0.83–0.97; P = 0.004) and fatal or non-fatal stroke (RR: 0.85; 95% CI: 0.77–0.94; P = 0.001) compared with the placebo controls. But GLP-1 receptor agonists did not significantly alter the fatal or non-fatal myocardial infarction compared with the placebo (RR: 0.91; 95% CI: 0.82 – 1.01; P = 0.06).ConclusionWe concluded that GLP-1 receptor agonist therapy could reduce the risk of death from cardiovascular causes and fatal or non-fatal stroke compared with the placebo in the treatment of T2DM patients in trials with cardiovascular outcomes.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown encouraging results regarding cardiovascular outcomes mainly in patients with diabetes. In the present study, we compared the efficacy of GLP-1 RAs in cardiovascular events between patients with and without diabetes. After finding eligible studies assessing the impact of GLP-1 RAs on cardiovascular events in patients with and without diabetes using a systematic search, we performed a meta-analysis on randomized-controlled trials (RCTs) comparing cardiovascular outcomes between patients taking GLP-1 RAs and placebo stratified by the presence or absence of diabetes. Relative risk (RR) and its 95% confidence interval (CI) were set as the reporting effect size using the random-effects model. A total of 24 RCTs (50 033 with GLP-1 RAs and 44 514 with placebo) were included. Patients on GLP-1 RAs had lower risk of major adverse cardiovascular events (MACE) (RR 0.87, 95% CI0.82-0.93), cardiovascular death (RR 0.88, 95% CI0.82-0.94), myocardial infarction (MI) (RR 0.87, 95% CI0.77-0.97), stroke (RR 0.86, 95% CI0.80-0.92), and hospitalization for heart failure (RR 0.90, 95% CI0.83-0.98). Both subgroups were shown to be effective in terms of MACE and mortality. Nondiabetic patients had decreased risk of hospitalization for heart failure and MI, whereas the diabetic subgroup had marginally nonsignificant efficacy. The findings of this meta-analysis indicated that patients who are overweight/obese but do not have diabetes have a comparable reduction in the risk of adverse cardiovascular events as those with diabetes. These results need to be confirmed further by large-scale randomized trials in the future.

Background The triglyceride-glucose index (TyG) has gained attention as an alternative indicator for assessing insulin resistance (IR). The purpose of this study was to comprehensively summarize the correlation between the TyG index and cardiovascular events in patients with coronary revascularization. Methods PubMed, Web of Science, Embase, and The Cochrane Library databases were searched to find relevant literature on the prognostic assessment of TyG index in patients undergoing coronary artery revascularization. Utilize the risk ratio (RR) and its 95% confidence interval (CI) as the standard for assessing the correlation between TyG and major adverse cardiovascular events (MACEs) in patients undergoing coronary artery revascularization. Conduct sensitivity analysis and subgroup analysis to detect the sources of heterogeneity and assess the stability of the results. Results A total of 12 studies involving 9,973 participants were included. The results of the study indicate that a high TyG index was related to the major adverse cardiovascular event in patients undergoing coronary artery revascularization (RR:2.0,95%CI: 1.71–2.35, I2 =76.2%, p < 0.0001). Subgroup analysis reveals that the probability of MACEs occurring in patients with high TyG index is higher than in those with low TyG index after two different coronary artery revascularization procedures: CABG group (RR:2.10, 95%CI:1.80–2.45, I2 = 20.9%, p = 0.0001). PCI group: (RR:1.94, 95%CI:1.54–2.46, I2 = 84.2%, p < 0.00001). Additionally, we also demonstrated the prognostic value of the TyG index in all-cause mortality(p = 0.003), non-fatal myocardial infarction(p = 0.003), non-fatal stroke(p < 0.0001) and repeat revascularization(p < 0.0001). Conclusions Higher TyG index may be independently associated with higher incidence of MACEs in patients with coronary revascularization.

Tiotropium and risk for fatal and nonfatal cardiovascular events in patients with chronic obstructive pulmonary disease: Systematic review with meta-analysis

Objective: To determine the impact of low T3 syndrome on adverse cardiovascular events in adult patients with acute viral myocarditis. Methods: The study population consisted of 134 consecutive patients admitted between January 2002 and March 2018 with diagnoses of acute viral myocarditis (onset of symptoms<1 month,patients were divided into low serum free triiodothyronine (FT3, n=20) group and normal FT3 (n=114) group. General information, clinical presentation,electrocardiography at admission,laboratory tests,echocardiography features were analyzed. Low T3 syndrome was defined as a state with decreased FT3 and total triiodothyronine (TT3), normal or decreased free thyroxine (FT4) and total thyroxine (TT4) as well as normal thyroid stimulating hormone (TSH). Composite adverse cardiovascular events included death, persistent ventricular tachycardia (VT) or ventricular fibrillation (VF) and cardiac arrest. Risk factors related with composite adverse cardiovascular events in adult patients with acute viral myocarditis were analyzed by logistic regression analysis. Results: Systolic blood pressure was significantly lower (P<0.01),while heart rate (P=0.004) and the prevalence of VT/VF were significantly higher (P=0.017) in low T3 group than in the normal T3 group. Level of white blood cell,C response protein,fasting glucose (all P<0.01) as well as creatinine (P=0.035) were significantly higher, while level of FT3 and left ventricular ejection fraction (LVEF) were significantly lower (both P<0.01) in low T3 group than in normal T3 group. Multivariate logistic regression analysis revealed that LVEF at admission less than 40% (OR=6.615,95%CI 1.186-36.907, P=0.031) and FT3 level less than 1.79 ng/L (OR=9.131, 95%CI 1.577-52.857, P=0.014) were independent risk factors of increased composite adverse cardiovascular events in patients with acute viral myocarditis. Conclusion: Low FT3 increases the risk of adverse cardiovascular events in adult patients with acute viral myocarditis.

Monoclonal gammopathy of undetermined significance (MGUS) is associated with an increased risk of cardiovascular disease. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have demonstrated cardiorenal benefits in patients with type 2 diabetes, but their effectiveness in patients with MGUS remains unexplored. To assess the effectiveness of GLP-1 RAs for primary prevention of major adverse cardiovascular and cerebrovascular events (MACCE) in patients with MGUS and diabetes. This retrospective cohort study used a propensity score-matched analysis of data from the TriNetX Global Database, encompassing patients diagnosed with diabetes and MGUS between January 1, 2018, and January 13, 2023. Patients with prior heart failure (HF), ischemic heart disease, coronary revascularization, or stroke or transient ischemic attack before MGUS diagnosis were excluded. The cohort was divided into 2 groups: GLP-1 RA users and nonusers at baseline. After 1:1 propensity score matching, GLP-1 RA users and nonusers were compared up to 5 years from the MGUS diagnosis date. Data analyses were completed January 19, 2025. GLP-1 RA use within 1 year before MGUS diagnosis. The primary end point was MACCE, defined as a composite of all-cause mortality, new-onset HF, acute coronary syndrome, and stroke or transient ischemic attack. Secondary end points included individual MACCE components, decompensated HF, and acute kidney injury or end-stage kidney disease. A total of 4871 patients with MGUS (mean [SD] age, 68.9 [10.1] years; 2366 [48.5%] male) were included (473 GLP-1 RA users and 4398 non-users). A total of 460 users were matched to 460 nonusers, with balanced characteristics (mean [SD] age, 65.0 [10.6] vs 65.1 [11.0] years; 229 [49.7%] male vs 234 [50.8%] male), including 14 patients (3.0%) vs 13 patients (2.8%) identifying as Asian, 8 (21.3%) vs 92 (20.0%) as Black or African American, 25 patients (5.4%) vs 20 patients (4.3%) as Hispanic or Latino, and 243 patients (52.8%) vs 250 patients (54.3%) as White. GLP-1 RA use was associated with a significantly lower risk of MACCE (hazard ratio [HR], 0.75; 95% CI, 0.60-0.93). Significant reductions were also observed in all-cause mortality (HR, 0.57; 95% CI, 0.37-0.87), new-onset HF (HR, 0.69; 95% CI, 0.54-0.90), decompensated HF (HR, 0.60; 95% CI, 0.43-0.84), and acute kidney injury or end-stage kidney disease (HR, 0.73; 95% CI, 0.57-0.92). The findings of this cohort study of GLP-1 RA use vs no use in patients with MGUS and diabetes suggest the potential of GLP-1 RA for primary prevention of MACCE. These findings warrant further investigation in prospective randomized trials.

To explore the association between the use of β-blockers and the risks of all-cause mortality and major adverse cardiovascular events (MACEs) in patients with stable coronary artery disease (SCAD) after percutaneous coronary intervention (PCI). We performed secondary analyses of the data of 55 SCAD patients receiving post-PCI β-blocker treatment and 149 patients without post-PCI β‑blockers (control group) from the Dryad database. The clinical and coronary artery disease characteristics of the patients were analyzed, and propensity score matching was used to compare all-cause mortality and MACEs (including cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) between the two groups. The overall patients (69.6% were male) had a mean age of 72.6±10.3 years with a median follow-up time of 783 days. A total of 18 patients (8.8%) died, and MACEs occurred in 19 patients (9.3%), including cardiovascular death in 6 cases (2.9%), non-fatal myocardial infarction in 3 cases (1.5%) and non-fatal stroke in 11 cases (5.4%). In the β‑blocker group, deaths occurred in 5 cases (9.1%), and MACEs in 4 cases (7.3%), including 2 cases with cardiovascular death (3.6%) and 2 cases with non-fatal stroke (3.6%). Kaplan-Meier survival curve analysis showed that the use of β-blockers after PCI was not associated with a reduced all-cause mortality (8.7% vs 9.1%, log-rank P=0.870) or incidence of MACEs (10.1% vs 7.3%, log-rank P=0.510) either before or after adjusting for age, sex, aspartate aminotransferase, estimated glomerular filtration rate, left ventricular ejection fraction, and history of atrial fibrillation (HR=0.81, 95% CI: 0.24-2.72; HR=0.62, 95% CI: 0.22-1.69). No significant differences were found in all-cause death or MACEs between the two groups after propensity score adjustment, matching, or IPTW inverse probability weighting (all P>0.05). Routine use of β-blockers after PCI does not reduce the incidence of all-cause death or MACEs in patients with SCAD.

BackgroundThe cardiovascular safety of testosterone-replacement therapy in middle-aged and older men with hypogonadism has not been determined.MethodsIn a multicenter, randomized, double-blind, placebo-controlled, noninferiority trial, we enrolled 5246 men 45 to 80 years of age who had preexisting or a high risk of cardiovascular disease and who reported symptoms of hypogonadism and had two fasting testosterone levels of less than 300 ng per deciliter. Patients were randomly assigned to receive daily transdermal 1.62% testosterone gel (dose adjusted to maintain testosterone levels between 350 and 750 ng per deciliter) or placebo gel. The primary cardiovascular safety end point was the first occurrence of any component of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, assessed in a time-to-event analysis. A secondary cardiovascular end point was the first occurrence of any component of the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization, assessed in a time-to-event analysis. Noninferiority required an upper limit of less than 1.5 for the 95% confidence interval of the hazard ratio among patients receiving at least one dose of testosterone or placebo.ResultsThe mean (±SD) duration of treatment was 21.7±14.1 months, and the mean follow-up was 33.0±12.1 months. A primary cardiovascular end-point event occurred in 182 patients (7.0%) in the testosterone group and in 190 patients (7.3%) in the placebo group (hazard ratio, 0.96; 95% confidence interval, 0.78 to 1.17; P<0.001 for noninferiority). Similar findings were observed in sensitivity analyses in which data on events were censored at various times after discontinuation of testosterone or placebo. The incidence of secondary end-point events or of each of the events of the composite primary cardiovascular end point appeared to be similar in the two groups. A higher incidence of atrial fibrillation, of acute kidney injury, and of pulmonary embolism was observed in the testosterone group.ConclusionsIn men with hypogonadism and preexisting or a high risk of cardiovascular disease, testosterone-replacement therapy was noninferior to placebo with respect to the incidence of major adverse cardiac events. (Funded by AbbVie and others; TRAVERSE ClinicalTrials.gov number, NCT03518034.)