Reducing Risk of Major Adverse Cardiovascular Events: Role of SGLT2 Inhibitors, GLP-1 Agonists

The burden of type 2 diabetes mellitus (T2DM) has grown significantly over the last several decades, and the problem is anticipated to worsen. In a 2018 study, investigators from the Centers for Disease Control and Prevention projected that the prevalence of adults with diagnosed diabetes would increase from 22.3 million (9.1% of the US population) in 2014, to 39.7 million (13.9% of the US population) in 2030, and then to 60.6 million (17.9% of the US population) by 2060. The number of people 65 years or older with diabetes would increase from 9.2 million in 2014 to 21.0 million in 2030 and 35.2 million in 2060.1 More than 34.2 million Americans are living with diabetes, and 90% to 95% of this population has T2D.2 Due to high-risk factors associated with their disease, there is a high prevalence of atherosclerotic cardiovascular disease (ASCVD) among individuals with T2DM; the risk of death among those who have experienced a prior CVD-related event is 2-fold that of people with T2DM who have not had a previous CVD event.3-5

The associated adverse events of CVD are closely linked to increased mortality risk among individuals with T2DM, and CVD is 1 of the major reasons for hospitalizations (Figure 1).1 Approximately 65% of CVD-related deaths are associated with ischemic heart disease, congestive heart failure (HF), or stroke.3 The high prevalence, early onset, increased severity, and overall health impact of CVD on individuals with T2DM underscore the need for effective management strategies to reduce the risk of CV events in this population.

Reducing Major Adverse Cardiovascular Events Among Patients With Comorbid T2DM and Heart Disease

If not monitored and treated promptly and aggressively, T2DM can trigger dysfunction and damage multiple organs. Microvascular and macrovascular damage can lead to nephropathy, neuropathy, retinopathy, and ultimately CV complications and reduced quality of life.6 Management of T2DM involves a combination of lifestyle modifications and medications to effectively control hyperglycemia, blood pressure, and lipid levels. People with T2DM may experience HF, another major cause of morbidity and mortality from CVD; owing to the high prevalence of major CVD events with poor outcomes in patients with T2DM, treatment of T2DM should focus on medications with CV benefits. Reducing the risk of major adverse cardiovascular events (MACE) — a composite endpoint frequently used in cardiovascular research, includes cardiovascular and all-cause death, myocardial infarction (MI), stroke, and hospitalization from HF (HHF)7 — is included in the American Diabetes Association targets for T2DM management.5

Sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists are antihyperglycemic agents that have emerged as the standard of care for T2DM due to their CV benefits.8 A systematic review and meta-analysis from several clinical trials have provided unequivocal evidence that SGLT2 inhibitors and GLP-1 receptor agonists reduce the risk of CV and all-cause mortality in patients with T2DM who are at high risk for MACE.8-11 Based on the compelling evidence of benefit, the American Diabetes Association recommended the use of SGLT2 inhibitors and GLP-1 receptor agonists in patients with T2DM for CVD risk reduction.5

SGLT2 Inhibitors

SGLT2 inhibitors act on SGLT receptors in the kidney proximal tubules to increase urinary excretion of glucose, thereby lowering blood sugar levels. They also cause weight loss and reduce blood pressure.12,13 Several large-scale randomized trials with SGLT2 inhibitors found CV benefits associated with this class of agents. Trials that specifically evaluated the CV benefits of SGLT2 inhibitors in patients with T2DM and are at risk for CVD are summarized in Table 1.12,13-18

A meta-analysis of 10 trials involving 71,553 patients with T2DM who were at high risk for CVD was performed; a total of 39,053 patients received SGLT2 inhibitors and 32,500 received placebo. At a mean follow-up of 2.3 years, the primary outcome of CV death or HHF was significantly lower among patients treated with SGLT2 inhibitors compared with placebo (8.10% vs 11.56%; P <.001). The incidence of MACE was also significantly lower among patients receiving SGLT2 inhibitors compared with placebo (9.82% vs 10.22%; P  =.03).9

The trials outlined in Table 1 included patients with a risk factor for CVD or with established CVD. Overall, these trials found significant reductions in CV death and HHF in patients receiving SGLT2 inhibitors compared with placebo.The degree of treatment benefit as it relates to CV death or HHF varied between the different SGLT2 inhibitors investigated.9,12

Results from 2 of these trials, CANVAS ( Identifier: NCT01032629) and EMPA-REG OUTCOME ( Identifier: NCT01131676), illustrate the significant CV benefits of SGLT2 inhibitors. In the CANVAS trial, 10,142 patients with T2DM and a high risk of CVD were randomly assigned to receive canagliflozin or placebo and were followed for a mean duration of 188.2 weeks. Patients who received canagliflozin had a lower risk of CV events (CVD-related deaths, nonfatal MI, and nonfatal stroke) compared with patients who received placebo (CV events, 26.9 vs 31.5 participants per 1000 patient-years, respectively; P <.001 for noninferiority; P =.02 for superiority).12

Empagliflozin has shown similar CV benefits. In the EMPA-REG OUTCOME trial, 7020 patients with T2DM and CVD were randomly assigned to receive empagliflozin or placebo and were observed for a median duration of 3.1 years. The composite primary outcome — death from CV causes, nonfatal MI, or nonfatal stroke — occurred in a significantly lower percentage of patients in the empagliflozin group (10.5%) compared with the placebo group (12.1%; P =.04 for superiority).13 In the EMPEROR-Reduced trial ( Identifier: NCT03057977), among patients with chronic HF New York Heart Association (NYHA) II to IV,  the percentage of CVD-related death or HHF was lower in the group randomly assigned to receive empagliflozin (19.4%) compared with those assigned to receive placebo (24.7%; P <.001). The superior response with empagliflozin was seen across prespecified subgroups, including patients with T2DM.14

GLP-1 Receptor Agonists

Although several GLP-1 receptor agonists are now available, their CV risk reduction benefits vary among patients with T2DM. For example, lixisenatide is noninferior to placebo but not superior with respect to CV outcome.11 In contrast, albiglutide, dulaglutide, liraglutide, and semaglutide have demonstrated CV protective effects in patients with T2DM.11,19 Several clinical trials have evaluated the CV benefits of GLP-1 receptor agonists (Table 2).19-25

Overall, results from the HARMONY (albiglutide; Identifier: NCT02465515), REWIND (dulaglutide; Identifier: NCT01394952),and LEADER (liraglutide; Identifier: NCT01179048) trials demonstrated that these agents were superior to placebo in reducing the risk of MACE in patients with T2DM and prior CVD. This reduction in the risk of MACE was driven by fewer strokes, MIs, and CVD-related deaths for patients treated with dulaglutide, albiglutide, and liraglutide, respectively.19-21

The CV benefit of semaglutide was evaluated in the SUSTAIN-6 (subcutaneous formulation; Identifier: NCT01720446)22 and PIONEER-6 (oral formulation; Identifier: NCT02692716)23 clinical trials. In SUSTAIN-6, among patients with T2DM and high CV risk factors, the primary composite MACE outcome of CV death, nonfatal MI, or nonfatal stroke was significantly lower in patients receiving semaglutide (6.6%) compared with placebo (8.9%; P <.001 for noninferiority; P =.02 for superiority). However, nonfatal MI (2.9% vs 3.9%; P =.12) and risk of CV death (2.7% vs 2.8%; P =.92) were not significantly different between patients who received semaglutide vs placebo.22

In the PIONEER-6 trial evaluating oral semaglutide, among patients with T2DM, the CV risk profile was not inferior to that of patients in the placebo group but it did not show superiority of this agent to placebo.23 The SUSTAIN-6 and PIONEER-6 trials used different criteria for established CVD than those used in the REWIND trial. A subsequent reanalysis assessed the effect of semaglutide on MACE in a pooled population of patients who participated in the SUSTAIN-6 and PIONEER-6 trials and recategorized them into CV risk subgroups using the REWIND CVD criteria. The pooled analysis included 6480 patients; after recategorization using the REWIND CVD criteria, the risk of MACE was significantly lower in patients with established CVD receiving semaglutide compared with placebo, suggesting CV benefits of semaglutide in patients with T2DM who have CVD risk factors.26

Semaglutide adverse effects
Adverse effects most commonly reported with semaglutide include nausea, vomiting, diarrhea, abdominal pain, and constipation.

Tirzepatide, approved by the US Food and Drug Administration (FDA) in 2022 for adults with T2DM,27 is being evaluated against dulaglutide for CV benefits in participants with T2DM who have increased cardiovascular risk (SURPASS-CVOT; Identifier: NCT04255433).

Candidates for Treatment With SGLT2 Inhibitors or GLP-1 Receptor Agonists 

In general, SGLT2 inhibitors are recommended for patients with established ASCVD or HF who do not reach appropriate glycemic goals through treatment with metformin and lifestyle modifications. This class of agents can be used as a third agent in patients without established cardiac disease who fail to meet glycemic goals with use of 2 oral agents if insulin is contraindicated.28

GLP-1 receptor agonists can be considered in patients with the existing ASCVD when weight loss and/or avoidance of hypoglycemia are part of the treatment goal. However, GLP-1 receptor agonists should not be used in combination with dipeptidyl peptidase-4 inhibitors (due to a relatively minimal additional benefit) or in combination with prandial insulin (due to lack of supporting data for their use).28

Both SGLT2 inhibitors and GLP-1 receptor agonists are contraindicated in patients with T1DM. Although the cutoff estimated glomerular filtration rate (eGFR) is different for each agent, in general, all SGLT2 inhibitors and GLP-1 receptor agonists are contraindicated below an eGFR of 30 mL/minute/1.73 m2.28

Other Approaches to CVD Risk Reduction

Risk reduction for CVD among patients with T2DM is achieved by targeting modifiable risk factors such as high blood pressure, high cholesterol, hyperglycemia, smoking, obesity, chronic kidney disease, and albuminuria (Figure 2).2,3,5

Lifestyle Modifications

Lifestyle modifications are critical to reducing the risk of MACE and other T2DM complications. Modifications often include increased physical activity, moderate alcohol intake, smoking cessation, weight loss for patients who are overweight or obese, and dietary changes (Table 3).2,5


If it can be safely achieved, the recommended target blood pressure (BP) for patients with T2DM and ASCVD is less than 130/80 mm Hg.2,5 In the Hypertension Optimal Treatment trial of a 5-step intensive BP-lowering regimen, there was a 51% reduction in MACE among the T2DM subpopulation assigned to a diastolic BP target of less than 80 mm Hg.29 In contrast, the ACCORD trial ( Identifier: NCT00000620), which compared intensive BP control to less than 120 mm Hg vs standard BP control to less than 140 mm Hg, did not reduce total MACE but demonstrated a reduced risk of stroke.30

Angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) are recommended as first-line antihypertensive agents for patients with T2DM and coronary artery disease or albuminuria.2


The American Diabetes Association recommends high-intensity statin therapy in combination with lifestyle modifications for all patients with T2DM and ASCVD.5 The Treating to New Targets study compared treatment with atorvastatin 10 mg vs atorvastatin 80 mg in 1501 patients with T2DM, coronary heart disease, and low-density lipoprotein cholesterol (LDLC) levels greater than 130 mg/dL. The investigators reported a 25% reduction in the risk of MACE (coronary heart disease, death, nonfatal MI, resuscitated cardiac arrest, or stroke) in the high-intensity statin group.31

Patients with LDLC levels greater than 70 mg/dL despite a maximally tolerated statin dose should receive ezetimibe or a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor.5 Ezetimibe reduces intestinal cholesterol absorption. One study involving participants hospitalized for acute coronary syndrome evaluated the effect of ezetimibe added to simvastatin; ezetimibe further lowered LDLC and reduced CV events compared with simvastatin alone. This benefit was even more pronounced in the patient subpopulation with T2DM.32

Evolocumab is a monoclonal antibody that inhibits PCSK9 and lowers LDL. In a randomized controlled study that included 27,654 patients with atherosclerotic disease, the addition of evolocumab to statin therapy lowered LDL levels by 59% (median, 30 mg/dL) from baseline compared with placebo and it conferred a 15% relative risk reduction in the primary outcome of CVD death, MI, or stroke. A similar benefit was seen in the subgroup of patients with T2DM.33 Alirocumab, another PCSK9 inhibitor, showed similar superior benefits for LDL levels and CVD-related death when it was added to intensive statin therapy in the ODYSSEY trial ( Identifier: NCT01663402).34

Platelet Dysfunction

Platelet dysfunction plays a critical role in the high prevalence of ASCVD in patients with T2DM. Factors contributing to increased thrombosis include hyperreactive platelets with intensified adhesion, activation, and aggregation.35 Other important factors include increased fibrinogen, decreased antithrombin III activity, and impaired fibrinolysis.2 The role of antiplatelet therapy in the secondary prevention of CVD is well documented in patients with and without T2DM. Aspirin (at a dosage of 75-162 mg/day) is recommended for all patients with T2DM and a history of ASCVD.5

Dual antiplatelet therapy should be considered in selected clinical situations, such as after acute coronary syndrome or a coronary intervention, to lower the risk of MACE.5 Use of clopidogrel, prasugrel, or ticagrelor with aspirin has been demonstrated to reduce rates of CV events but is associated with an increased risk of bleeding.36 Rivaroxaban added to aspirin should be considered in patients with stable coronary artery disease. The benefit of a rivaroxaban plus aspirin was demonstrated in the COMPASS trial ( Identifier: NCT01776424). Rivaroxaban 2.5 mg added to low-dose aspirin reduced CV events with a more clinically meaningful absolute risk reduction for patients with T2DM.37


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Updated July 2021