Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

In the citing paper

“Major cardiovascular trials in patients with T2DM, including the LEADER, SUSTAIN-6, HARMONY Outcomes and REWIND trials, 22 -25 have collectively demonstrated a significant reduction in cardiovascular death with GLP-1RA therapy, ranging from 12% to 26%.”

In the citing paper

“Serious adverse events varied from 7% to 25.2%”

In the citing paper

“In the SUSTAIN program, 83 patients (1.4%) treated with semaglutide developed a gallbladder event, compared with 39 patients (1.9%) in the placebo group”

In the citing paper

“Specifically, compared with placebo, empagliflozin reduced the risk of incident or worsening nephropathy (a composite of progression to UACR >300 mg/g creatinine, doubling of serum creatinine, ESKD, or death from ESKD) by 39%”

In the citing paper

“and the risk of reduction in eGFR, ESKD, or death from ESKD by 40%”

In the citing paper

“liraglutide reduced the risk of new or worsening nephropathy (a composite of persistent macroalbuminuria, doubling of serum creatinine, ESKD, or death from ESKD) by 22%”

In the citing paper

“and the risk of doubling of serum creatinine accompanied by eGFR #45 mL/min/1.73m 2 by 44%”

In the citing paper

“canagliflozin reduced the risk of progression of albuminuria by 27% and the risk of reduction in eGFR, kidney failure, or death from kidney failure by 40%”

In the citing paper

“empagliflozin reduced the risk of incident or worsening nephropathy (a composite of progression to UACR >300 mg/g creatinine, doubling of serum creatinine, kidney failure, or death from kidney failure) by 39% and the risk of doubling of serum creatinine accompanied by eGFR ≤45 mL/ min/1.73m 2 by 44%”

In the citing paper

“liraglutide reduced the risk of new or worsening nephropathy (a composite of persistent macroalbuminuria, doubling of serum creatinine, kidney failure, or death from kidney failure) by 22%”

In the citing paper

“dulaglutide reduced the composite kidney outcome (risk of ≥40% sustained decline in eGFR, kidney failure, or kidney-related death) by 25%”

In the citing paper

“The selection of medications to lower BP in persons with T2D should be guided by individual-specific considerations and may include nontraditional BP-lowering agents such as SGLT2is and GLP-1 RAs, though these drugs alone may be inadequate to control BP.”

In the citing paper

“Therapies shown to positively affect albuminuria and declining eGFR include ACE inhibitors, ARBs, SGLT2is, GLP-1 RAs, and the nonsteroidal mineralocorticoid antagonist finerenone.197,209,239,242,393,423–435”

In the citing paper

“Multiple studies have shown renal and CV benefits of SGLT2is239,424–426,444,1052–1054”

In the citing paper

“Empagliflozin and canagliflozin demonstrated reduction in MACE in CVOTs; empagliflozin also demonstrated decreased CV death and all-cause mortality.”

In the citing paper

“GLP‐1 receptor agonists (GLP‐1RAs) improve glycemic control, promote weight loss and reduce major adverse cardiovascular events in high‐risk patients with T2DM [1, 2, 3]”

In the citing paper

“A once-weekly injection of 2.4 mg of semaglutide resulted in a remarkable reduction in body weight by − 14.9% in adults with obesity, along with substantial improvements in glucose homeostasis and reduced risk of cardiovascular events [66, 67].”

In the citing paper

“Cardiovascular outcome trials show that treatment with long-acting GLP-1 medicines such as liraglutide, dulaglutide, and semaglutide reduces cardiovascular events in people living with T2D and with semaglutide also in people living with obesity (60–62).”

In the citing paper

“Glucagon-like peptide-1 receptor agonist (GLP-1 RA) medications improve health outcomes in patients with type 2 diabetes mellitus (T2DM).”

In the citing paper

“Prior to this pooled analysis, it was known that treatment with semaglutide in patients with diabetes, obesity, or both conditions improves cardiometabolic risk factors and reduces major adverse CV events. 25-27”

In the citing paper

“including nausea (2.05% to 19.95%)”

In the citing paper

“GLP-1RAs, approved by the US Food and Drug Administration (FDA) for type 2 diabetes (T2D) treatment in 2017, offer well-documented benefits in reducing cardiovascular and kidney complications.”

In the citing paper

“Semaglutide predictably resulted in greater reductions in both plasma glucose and HbA1c concentrations than standard-of-care treatment.”

In the citing paper

“Based on the MACE reduction observed in SUSTAIN 6 [30], it should be preferred in patients with established ASCVD (secondary prevention).”

In the citing paper

“Despite promising data showing 20%-26% reductions in cardiovascular and some diabetes-related microvascular outcomes in high-risk populations with T2D or established cardiovascular disease treated with semaglutide for 1.3-3.3.years, 12,99”

In the citing paper

“None of these were medullary carcinoma.”

In the citing paper

“The events mainly included cholelithiasis.”

In the citing paper

“In the SUSTAIN program, acute kidney failure was only reported in SUSTAIN 6, where its occurrence was similar between semaglutide and placebo”

In the citing paper

“The SUSTAIN6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) trial reported that only 22.6% of patients prematurely discontinued semaglutide during the 24-month trial period.”

In the citing paper

“By contrast, we observed no meaningful differences in persistence or dosing patterns by CVD history, despite robust evidence for cardioprotective benefits of GLP‐1RAs in patients with established CVD. 7 , 8 , 9 , 10”

In the citing paper

“Across these trials, semaglutide demonstrated significant body weight reductions from baseline to end of treatment versus all comparators.”

In the citing paper

“and semaglutide reduced the risk of new or worsening nephropathy (a composite of persistent UACR >300 mg/g creatinine, doubling of serum creatinine, or ESKD) by 36% (each P < 0.01).”

In the citing paper

“Large clinical trials have shown benefits of newer glucose-lowering medications on cardiovascular and kidney outcomes in patients with CKD with type 2 diabetes.5, 6, 7, 8, 9, 10, 11, 12, 13, 14”

In the citing paper

“Five large randomized clinical trials (the EMPA-REG OUTCOME, the Canagliflozin Cardiovascular Assessment Study [CANVAS], the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 [DECLARE–TIMI 58], CREDENCE, and DAPA-CKD) demonstrated cardiovascular benefits, and kidney protective benefits of SGLT2i.5, 6, 7, 8,11,12,34”

In the citing paper

“However, significant benefits of SGLT2i were shown among the subgroup patients (aged greater than or equal to 65 years) in the study of EMPAREG, CANVAS, DECLARE, and DAPA-CKD.6, 7, 8,11,12,34”

In the citing paper

“The clinical trials that may have impacted our results were the CANVAS (canagliflozin, published 2017), EMPA-REG OUTCOME (empagliflozin, 2015), the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) trial (semaglutide, 2016), and the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEAD”

In the citing paper

“This stepwise approach anchored in trial evidence strengthens confidence in the validity and applicability of the current results, reinforcing the role of GLP-1-based therapies beyond previously established benefits in the evolving management of cardiometabolic HFpEF.54,56-62”

In the citing paper

“Large cardiovascular outcome trials have shown that GLP‐1RAs reduce major adverse cardiovascular events and slow progression of kidney disease in high‐risk patients [1, 2, 3].”

In the citing paper

“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”

In the citing paper

“Initially approved for T2D management, GLP-1 RAs have also demonstrated cardiovascular and renal benefits [5–7].”

In the citing paper

“It was then found that patients with diabetes and high cardiovascular risk that were treated with liraglutide and semaglutide, but not exenatide, had a lower risk of non-fatal myocardial infarction and stroke [66, 70, 71] and another GLP-1R agonist, dulaglutide, reduced major adverse cardiovascular events [72].”

In the citing paper

“In SUSTAIN 6, semaglutide significantly reduced the risk of major adverse cardiovascular events compared with placebo, and was non-inferior to placebo in PIONEER 6, in people of varying cardiovascular risk, with type 2 diabetes.30,31”

In the citing paper

“The CV outcomes trials, SUSTAIN 6 and PIONEER 6, which were part of these programs, demonstrated CV benefits with s.c. semaglutide and CV non-inferiority with oral semaglutide vs placebo, respectively [14, 15].”

In the citing paper

“The SUSTAIN‐6 trial of semaglutide for T2D suggested a potential link of this GLP‐1RA with worsening diabetic retinopathy, 114 which was not observed in, for example, the liraglutide or dulaglutide trials. 115”

In the citing paper

“Patients receiving semaglutide (0.5 or 1.0 mg) for 104 weeks demonstrated a significantly higher risk of diabetic retinopathy complications, including vitreous hemorrhage, blindness, or required procedural treatment compared to those receiving placebo (HR, 1.76; 95% CI, 1.11 to 2.78).”

In the citing paper

“Subcutaneous semaglutide treatment led to an increased number of retinopathy complications in the SUSTAIN-6 cardiovascular outcomes trial (81).”

In the citing paper

“In SUSTAIN-6, severe or plasma glucose-confirmed (<56 mg/dl [3.1 mol/L]) hypoglycemia occurred in similar rates between patients with semaglutide (23.1% in the 0.5 mg group and 21.7% in the 1 mg group) and placebo (21.2%) (28).”

In the citing paper

“In SUSTAIN 6, acute pancreatitis occurred in 9 semaglutide-treated patients, and in 12 placebo-treated patients.”

In the citing paper

“Pancreatic cancer occurred in one and four patients, respectively (28).”

In the citing paper

“Despite evidence from clinical trials demonstrating benefits in glycaemic control, weight loss, and cardiorenal outcomes, 7 , 8 , 9 , 10 real‐world adherence to GLP‐1RA therapy remains suboptimal in patients with type 2 diabetes. 11 , 12 , 13”

In the citing paper

“Glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) have also been shown to improve kidney outcomes (95-100).”

In the citing paper

“The SUSTAIN-6 trial is another example in which semaglutide was compared to placebo and was demonstrated to result in reduced cardiovascular risk.8”

In the citing paper

“Similarly, previously mentioned clinical trials have demonstrated superiority of certain GLP-1 receptor agonists to placebo in reducing the risk of MACE.[7][8][9]”

In the citing paper

“As previously discussed, several medications in the SGLT-2 inhibitor and GLP-1 receptor agonist drug classes have been demonstrated to have cardiovascular and renal benefits for patients.[7][8][9][37][38][39]”

In the citing paper

“No increased risk of heart failure hospitalization has been identified in the cardiovascular outcomes trials of the GLP-1 RAs lixisenatide, liraglutide, semaglutide, exenatide once weekly, albiglutide, or dulaglutide compared with placebo (261,264,265,296,297).”

In the citing paper

“Results of trials with the GLP-1 RAs liraglutide (once daily) and semaglutide, albiglutide, efpeglenatide, and dulaglutide (once weekly) have all shown evidence of a reduction in major atherosclerotic cardiovascular outcomes (MI, stroke, or cardiovascular death) (251–256).”

In the citing paper

“In cardiovascular outcomes trials, GLP-1 receptor agonists reduced risk of major adverse cardiovascular events (MACE) in patients with T2D (67–70).”

In the citing paper

“The GLP-1 receptor agonists with favorable CKD outcomes include lixisenatide, exenatide (once weekly), liraglutide, semaglutide, albiglutide, dulaglutide, and efpeglenatide (67,68,70,72–76).”

In the citing paper

“s.c. semaglutide has demonstrated cardiovascular benefits in the SUSTAIN-6 trial, which was designed to assess the non-inferiority of s.c. semaglutide as compared with placebo in terms of cardiovascular safety in people with type 2 diabetes at increased cardiovascular risk [31]”

In the citing paper

“The intervention duration ranged from 24 to 28 weeks in five trials and from 30 to 56 weeks in 21 trials. The remaining two trials, a trial with tirzepatide in people with obesity and type 2 diabetes (SURMOUNT-2) [50] and a cardiovascular outcomes trial with semaglutide (SUSTAIN 6) [31], had a duration of 72 and 104 weeks, respectively.”

In the citing paper

“Multiple large CVOTs and kidney outcome trials of SGLT2is have demonstrated robust and consistent reductions in the risk of hospitalization for HF in persons with T2D.239,423,425,426,648”

In the citing paper

“Empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin have shown a decrease in hospitalization for HF in their CVOTs.”

In the citing paper

“More recently, empagliflozin was demonstrated to reduce the combined risk of CV death or hospitalization for HF in persons with HFpEF, regardless of the presence or absence of DM.239,425,426,443”

In the citing paper

“However, the exogenous administration of GLP-1RAs can mitigate sympathetic excitability by suppressing the peripheral chemoreflex originating from the carotid body.467”

In the citing paper

“In this study, baseline retinopathy status had, perhaps surprisingly, not been assessed, and there were not any systematic follow-up examinations during the trial.”

In the citing paper

“longterm results with GLP1-RAs are still not comparable to surgical outcomes.”

In the citing paper

“Serum calcitonin was measured during these trials, and no notable difference in mean levels was seen between the treatment arms.”

In the citing paper

“In the SUSTAIN program, three adjudicated events of malignant thyroid neoplasm were identified, two in semaglutide-treated patients (combined n = 5,933), and one in the comparator group (n = 4,736)”

In the citing paper

“More than 62% of adults with T1D in the United States are either OW (34%) or OB (28%), similar to the 64% of adults without diabetes who are OW (36%) or OB (28%) although lower than the 86% of adults with type 2 diabetes (T2D) who are OW (34%) or OB (52%).19”

In the citing paper

“canagliflozin reduced the risk of progression of albuminuria by 27%”

In the citing paper

“However, the composite kidney outcomes in these trials were evaluated as secondary outcomes, and the reported effects were largely driven by a lower risk of new-onset macroalbuminuria. 23-25”

In the citing paper

“In line with this, subcutaneous semaglutide 0.5 and 1.0 mg once weekly, like other GLP‐1RAs [15], has been shown to reduce major adverse CV events (MACE) in patients with type 2 diabetes and high CV risk [16].”

In the citing paper

“Following these regulatory requirements, several cardiovascular outcomes trials (CVOT) have been completed, which demonstrate that certain anti-diabetic treatments are associated with a lower risk of CVD [17–20].”

In the citing paper

“Newer antidiabetic drugs have been shown to lower the risk of CVD in T2DM patients [17–20]; however, these drugs are often intended to be used as second- to third-line treatments and many years may pass before patients can benefit.”

In the citing paper

“Emerging data support the efficacy of GLP-1RAs, in reducing the incidence of major adverse cardiovascular events (MACEs), preventing the onset of macroalbuminuria and slowing the progression of renal damage toward ESRD [5, 6]”

In the citing paper

“Emerging data support the efficacy of GLP-1RAs, in reducing the incidence of major adverse cardiovascular events (MACEs), preventing the onset of macroalbuminuria and slowing the progression of renal damage toward ESRD [5, 6]”

In the citing paper

“Emerging data support the efficacy of GLP-1RAs, in reducing the incidence of major adverse cardiovascular events (MACEs), preventing the onset of macroalbuminuria and slowing the progression of renal damage toward ESRD [5, 6]”

In the citing paper

“Semaglutide reduces the incidence of de novo macroalbuminuria. Nevertheless, no difference was found regarding the incidence of ESRD and death for renal causes.”

In the citing paper

“Semaglutide reduces the incidence of de novo macroalbuminuria. Nevertheless, no difference was found regarding the incidence of ESRD and death for renal causes.”

In the citing paper

“MACE was reduced by 26% (HR, 0.74 [95% CI, 0.58-0.95];P<0.001 for noninferiority; P=0.02 for superiority, not prespecified) with semaglutide”

In the citing paper

“Both doses of semaglutide yielded similar risk reductions for MACE and nonfatal stroke.”

In the citing paper

“and the nonfatal stroke component of MACE was reduced by 39% (HR, 0.61 [95% CI, 0.38-0.99];P=0.04; Figure 1B).”

In the citing paper

“There was no significant decrease in the outcomes of fatal/nonfatal stroke or fatal stroke alone, and only 5 study participants experienced a fatal stroke.29,40,41”

In the citing paper

“GLP1-RA have been shown to reduce MACE in patients with T2D with A1c elevation >6.5%, who were at high cardiovascular risk or had established CVD (Table 1) [37], [38], [39], [40], [41].”

In the citing paper

“Given the additional beneficial effects of GLP-1 RAs and SGLT2 inhibitors on CV outcomes in T2DM (Section 5.3), these agents should be the preferred glucose-lowering medication in overweight and obese patients with CVD and T2DM, as obesity medications have, to date, not shown to reduce CV events.[70][71][72]”

In the citing paper

“A sustained decrease in BP was observed with semaglutide therapy (SBP dose dependent: -1.3 to -2.6 mmHg) with a slight increase in heart rate (+2 to 2.5 beats per minute [b.p.m.]).72”

In the citing paper

“Trials testing GLP-1 RAs have shown a BP decrease with these drugs, partly due to weight loss.”

In the citing paper

“Most GLP-1 RAs had a neutral effect on risk of HF hospitalization in the placebo-controlled RCTs assessing CV safety of glucose-lowering medications in patients with T2DM with or at high risk of ASCVD, despite increasing heart rate by 3-5 b.p.m. 70,72,158- 163,544”

In the citing paper

“cardiovascular event rates remain high, even among the patients with well-managed T2DM enrolled in contemporary outcomes trials,8–10”

In the citing paper

“several cardiovascular outcomes trials (CVOTs) demonstrated that drugs that lowered HbA1c to similar levels had different effects on cardiovascular outcomes”

In the citing paper

“semaglutide produced a 26% RRR in MACEs (6.6% versus 8.9%) but no reduction in cardiovascular mortality”

In the citing paper

“A limitation of our study is that it was started before GLP-1 receptor agonists 24 and SGLT2 inhibitors 25 were shown to reduce major cardiovascular events and mortality in patients with stable cardiovascular disease and type 2 diabetes.”

In the citing paper

“More patients discontinued treatment in the semaglutide group because of adverse events, mainly gastrointestinal.”

In the citing paper

“The primary outcome (the fi rst occurrence of cardiovascular death, nonfatal MI, or nonfatal stroke) occurred in 108 patients (6.6%) in the semaglutide group vs. 146 patients (8.9%) in the placebo group (HR 0.74 [95% CI 0.58 -0.95]; P &lt; 0.001).”

In the citing paper

“and four FDA-approved GLP-1 receptor agonists (liraglutide, albiglutide [although that agent was removed from the market for business reasons], semaglutide [lower risk of cardiovascular events in a moderate-sized clinical trial but one not powered as a cardiovascular outcomes trial], and dulaglutide).”

In the citing paper

“No increased risk of heart failure hospitalization has been identi fi ed in the cardiovascular outcomes trials of the GLP-1 receptor agonists lixisenatide, liraglutide, semaglutide, exenatide once-weekly, albiglutide, or dulaglutide compared with placebo ( Table 10.3 B ) (203,204,207 -209).”

In the citing paper

“Additionally, GLP-1 analogues also appear to decrease the risk of cardiovascular pathology in patients, according to some studies, and preliminary data suggest they do so to a greater degree than other oral glucose-lowering drugs.262,275–277”

In the citing paper

“However, these benefits were driven by a lower risk of persistent macroalbuminuria [6,10,13].”

In the citing paper

“In older patients with T2DM, weight loss not only improves glycemic control but also reduces the risk of cardiovascular disease,11 which is especially important in this population.”

In the citing paper

“The primary composite outcome -- death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke -- occurred in significantly fewer participants treated by semaglutide (6.6%) than by placebo (8.9%) (HR, 0.74; 95% CI, 0.58 to 0.95; p<0.001 for noninferiority; p=0.02 for superiority).”

In the citing paper

“The small mean increase in pulse rate does not appear to adversely affect cardiovascular outcomes, as revealed by results of the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6).(39)”

In the citing paper

“Glucagon-like peptide-1 receptor agonists (GLP1-RAs) are the currently most efficacious weight lowering drugs.”

In the citing paper

“The efficacy and safety profile of the GLP1-RAs liraglutide and semaglutide are well-documented, with an average body weight loss of up to 15%, usually transient mild to moderate gastrointestinal side effects, and cardiorenal benefits [6–8].”

In the citing paper

“In SUSTAIN-6, treatment with semaglutide 1 mg led to the development of retinopathy-related complications in more people (3%) compared to placebo (1.8%)”

In the citing paper

“the risk was higher for people with a history of proliferative or non-proliferative diabetic retinopathy at baseline, with higher baseline HbA1c and longer diabetes duration”

In the citing paper

“the SUSTAIN-6 clinical trial that showed a statistically significant reduction in the risk of cardiovascular events in the semaglutide group compared with placebo group (6.6 vs. 8.9%, hazard ratio, 0.74; 95% confidence interval [CI], 0.58–0.95; p < 0.001) (4, 5).”

In the citing paper

“Subsequently, in January 2020, the FDA expanded the indication of semaglutide to include T2DM adults with cardiovascular disease based primarily on the SUSTAIN-6 clinical trial that showed a statistically significant reduction in the risk of cardiovascular events in the semaglutide group compared with placebo group (6.6 vs. 8.9%, hazard ratio, 0.74; 95% confidence interval [CI], 0.58–0.95; p < 0.”

In the citing paper

“The SUSTAIN 6 clinical trial found that older patients with comorbid conditions were treated with semaglutide for 104 weeks, the incidence of gastrointestinal disorders was somewhat higher (4).”

In the citing paper

“Gastrointestinal side effects are typically classed as mild or moderate, and reported to subside in most patients following titration up to maintenance doses (77, 79, 104), although they still lead to permanent discontinuation of treatment in 4% to 10% of participants (77, 79, 95).”

In the citing paper

“However, recent investigations reported that the suppression of composite cardiovascular events and cardiovascular death by SGT2 inhibitors799), and that the suppressive effects of glucagonlike peptide-1 (GLP-1) receptor agonists on ASCVD incidence800, 801).”

In the citing paper

“Clinical trials found that GLP-1 receptor agonists as a class reduced major adverse cardiovascular events [12–15].”

In the citing paper

“In addition to providing control of diabetes mellitus, GLP-1 receptor agonists have shown to provide weight loss and cardiovascular protective effects [12–15].”

In the citing paper

“To date, randomized clinical trials of albiglutide, dulaglutide, liraglutide, and injectable semaglutide have reported favorable cardiovascular outcomes.”

In the citing paper

“In addition, GLP-1RAs have a favorable safety profile and have been associated with substantial weight loss.4,6,7,9”

In the citing paper

“Complications of diabetic retinopathy were rare but more commonly seen in patients who received injectable semaglutide vs placebo (3.0% vs 1.8%) in SUSTAIN-6.7”

In the citing paper

“Recent randomized clinical trials have demonstrated that glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce cardiovascular events in at-risk individuals with type 2 diabetes.”

In the citing paper

“GLP-1RA therapy has a favorable safety profile.”

In the citing paper

“This findins has been attributed to the rapid reduction in blood glucose in a patient population at higher risk for retinopathy complications, which has been observed with insulin therapy when poorly controlled hyperglycemia is rapidly rectified.”

In the citing paper

“In these trials, GLP-1 receptor agonists had a neutral effect on the risk for HF hospitalization.”

In the citing paper

“Semaglutide (0.5 or 1 mg/week) reduced the primary composite endpoint of first occurrence of death from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke in patients with T2DM and a HbA1c 7% or more compared to placebo (HR 0.74, 95% CI 0.58 to 0.94, P<0.001).210”

In the citing paper

“Body weight decreased 3.6 kg and 4.9 kg in the 0.5 and 1.0 mg groups.”

In the citing paper

“Importantly, long-acting GLP-1 agonists reduce mortality in patients with T2DM.”

In the citing paper

“In clinical trials, semaglutide reduced peripheral inflammation [41] and decreased the risk of major adverse cardiovascular (CV) events (MACE) compared with placebo [38–40, 42–45].”

In the citing paper

“In previous clinical trials, semaglutide has demonstrated significant reductions in MACE, including CV-related death, non-fatal myocardial infarction, and non-fatal stroke [38–40, 42–45].”