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Cardiovascular outcome trials in type 2 diabetes: A nurse practitioner perspective

Kruger, Davida F. MSN, APN-BC, BC-ADM; (Certified Nurse Practitioner)

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Journal of the American Association of Nurse Practitioners: October 2018 - Volume 30 - Issue - p S43-S52
doi: 10.1097/JXX.0000000000000126
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Type 2 diabetes and cardiovascular risk

Although the overall rates of cardiovascular disease (CVD) have declined in recent years, CVD remains the leading cause of hospitalization, morbidity, and mortality in patients with type 2 diabetes (T2D) (Rawshani et al., 2017). Indeed, patients with diabetes are at approximately 2-fold greater risk of death from vascular disease compared with those without diabetes (Rao Kondapally Seshasai et al., 2011), and approximately 10% of vascular deaths in developed countries are attributable to diabetes (Emerging Risk Factors Collaboration, 2010). Cardiovascular (CV) complications associated with T2D include coronary heart disease, heart failure (HF), peripheral vascular disease, and cerebrovascular disease. In the United States, rates of myocardial infarction (MI), stroke, unstable angina, and HF admission among patients with T2D were recently estimated to be 3.3, 2.4, 3.2, and 4.0 times higher, respectively, than in patients without T2D (Fitch, Engel, Sander, Kuti, & Blumen, 2017).

Given the association of T2D with CVD, improved glycemic control would be expected to reduce the risk of CV events. Early trials of the impact of intensive over less stringent glucose control on long-term outcomes showed improvements in microvascular complications, but failed to demonstrate a reduction in CV mortality (Action to Control Cardiovascular Risk in Diabetes Study Group, 2008; Advance Collaborative Group et al., 2008; UKPDS Group, 1998). Benefits of intensive glycemic control on macrovascular disease and mortality only emerged after long-term follow-up (Holman, Paul, Bethel, Matthews, & Neil, 2008) and meta-analysis (Ray et al., 2009). However, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial terminated its intensive therapy regimen (targeting HbA1c <6.0%) early due to the finding of increased all-cause mortality and increased CV mortality (Action to Control Cardiovascular Risk in Diabetes Study Group, 2008), and the Veterans Affairs Diabetes Trial (VADT) reported more sudden deaths with intensive therapy (Duckworth et al., 2009). Post hoc analyses of ACCORD suggested that excess mortality in the intensive therapy group was most apparent in the subgroup of subjects whose high HbA1c levels persisted during the first 12 months of follow-up despite use of intensive therapeutic strategies (Miller et al., 2014; Riddle et al., 2010). Although the increased risk of mortality decreased when the extended follow-up of the ACCORD study participants were analyzed (Accord Study Group, 2016; Hayward et al., 2015), the early findings brought long-term outcomes of intensive glycemic control in patients with T2D under scrutiny.

Cardiovascular outcomes trials in type 2 diabetes

Prior to 2008, new drugs for T2D were approved based on their ability to reduce HbA1c, and few studies looked directly into the relationship between a glucose-lowering drug and CV risk. After an initial meta-analysis raised significant concerns over the CV safety of rosiglitazone, the US Food and Drug Administration (FDA) issued guidance to sponsors mandating demonstration that any new glucose-lowering therapy does not result in an unacceptable increase in CV risk (US Food and Drug Administration, 2008). Since 2008, a number of preapproval and postapproval cardiovascular outcome trials (CVOTs) have been performed or are ongoing across a range of drug classes, involving more than 160,000 patients with T2D.

In CVOT design, a glucose-lowering drug (trial drug) is added to glycemic and CV standard of care therapies, and investigators are encouraged to add or adjust other clinically appropriate glucose-lowering drugs to achieve glycemic targets, and CV drugs for the duration of the study. By aiming for similar glycemic levels between arms throughout the trial, the assessment of whether an antidiabetic drug can achieve CV safety/benefit is independent of its glucose-lowering action. Although trial design is not uniform across the CVOTs, due to stage of drug development, study aim, inclusion criteria, and study duration, the majority of CVOTs use a 3-point major adverse cardiac event (MACE) composite endpoint, comprising: CV death; nonfatal MI; and nonfatal stroke, as the primary outcome, and a few use a 4-point MACE, which also includes hospitalization for unstable angina. As noted previously, CVOTs are designed to rule out an unacceptable increased risk of CV events, which is demonstrated by noninferiority of the trial drug against a control group treated with standard of care therapies alone. The estimated risk of CV events in a CVOT is typically expressed as a hazard ratio (HR) including 95% confidence intervals (CIs), and regulators require a “reassuring” point estimate for the HR and the upper estimate (upper limit of the 95% CI) to be <1.8 (preapproval) or <1.3 (postapproval). Some, mostly postapproval, CVOTs have been designed as superiority trials, requiring the upper estimate to be <1.0 to show a lowered risk of MACE or a CV benefit.

In this article, we review the primary results reported from CVOTs with dipeptidyl peptidase 4 inhibitors (DPP-4is), sodium-glucose cotransporter-2 inhibitors (SGLT-2is), and glucagon-like peptide-1 receptor agonists (GLP-1RA) (Table 1).

Table 1.:
Overview of all cardiovascular outcome trials started after 2008
Table 1-A.:
Overview of all cardiovascular outcome trials started after 2008

Cardiovascular outcome trials of dipeptidyl peptidase 4 inhibitors and sodium-glucose cotransporter-2 inhibitors

After the FDA guidance, some of the first completed CVOTs were those of the DPP-4is, saxagliptin (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus Thrombolysis in Myocardial Infarction trial; SAVOR-TIMI 53; AstraZeneca and Bristol-Myers Squibb), alogliptin (Examination of Cardiovascular Outcomes with Alogliptin vs. Standard of Care trial; EXAMINE; Takeda), and sitagliptin (Trial Evaluating Cardiovascular Outcomes with Sitagliptin; TECOS) (Green et al., 2015; Scirica et al., 2013; White et al., 2013). All three trials demonstrated no increased risk of 3-point MACE (SAVOR-TIMI 53 and EXAMINE) or 4-point MACE (TECOS; Duke Clinical Research Institute [DCRI] and the University of Oxford Diabetes Trials Unit [DTU] in academic collaboration with Merck Sharp & Dohme) compared with placebo (Table 1) (Green et al., 2015; Scirica et al., 2013; White et al., 2013). Post hoc analyses of SAVOR-TIMI 53 data showed a statistically significant increase in hospitalization for HF, a predefined component of the secondary endpoint, with saxagliptin compared with placebo (HR = 1.27 [95% CI, 1.07–1.51]) (Scirica et al., 2014). A similar, but not statistically significant, increased risk of hospitalization for HF was observed with alogliptin treatment compared with placebo in the EXAMINE study (HR = 1.19 [95% CI, 0.90–1.58]) (Zannad et al., 2015). However, no increase in risk of hospitalization for HF was found with sitagliptin in post hoc analysis of TECOS (HR 1.00 [95% CI, 0.83–1.19]), suggesting that this may not be a class effect (McGuire et al., 2016). Cardiovascular outcome trials of the DPP-4is, linagliptin (Cardiovascular and Renal Microvascular Outcome Study with Linagliptin in Patients with Type 2 Diabetes Mellitus trial; CARMELINA; Boehringer Ingelheim), and glimepiride (Design and Baseline Characteristics of the CARdiovascular Outcome Trial of LINAgliptin vs. Glimepiride in Type 2 Diabetes Trial; CAROLINA; Boehringer Ingelheim) are currently in progress (, 2017a,, 2017c).

In 2015, the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA REG OUTCOME; Boehringer Ingelheim) study published results showing that the SGLT-2i empagliflozin not only demonstrated noninferiority but also showed superiority by reducing the risk of MACE by 14% compared with placebo in patients with T2D and established CVD (Table 1). The reduction in risk with empagliflozin versus placebo was driven by a significant reduction in CV death (HR = 0.62 [95% CI, 0.49–0.77]), with no significant difference in the occurrence of nonfatal MI (HR = 0.87 [95% CI, 0.70–1.09]) and a nonsignificant increase in the point estimate for nonfatal stroke (HR = 1.24 [95% CI, 0.92–1.67]) (Zinman et al., 2015). Jansen's Canagliflozin Cardiovascular Assessment Study (CANVAS) Program, which integrated data from 2 trials with similar design and inclusion criteria (CANVAS and CANVAS-Renal), also reported a 14% reduction in the risk of CV events with the SGLT-2i canagliflozin compared with placebo in patients with T2D and established CVD or multiple CV risk factors, although unlike EMPA REG OUTCOME, none of the individual components reached significance (CV death, HR = 0.87 [95% CI, 0.72–1.06]; nonfatal stroke, HR = 0.90 [95% CI, 0.71–1.15], nonfatal MI, HR = 0.85 [95% CI, 0.69–1.05]) (Neal et al., 2017). The consistent composite endpoint results across EMPA REG OUTCOME and the CANVAS Program indicate that a CV benefit could be a class effect for SGLT2is, and the results from ongoing CVOTs with dapagliflozin (Dapagliflozin Effect on CardiovascuLAR Events Thrombolysis in Myocardial Infarction trial; DECLARE-TIMI 58; AstraZeneca and Bristol-Myers Squibb) and ertugliflozin (Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease trial; VERTIS CV; Merck, Sharp & Dohme) are awaited with interest (, 2017b,, 2017e).

Cardiovascular outcome trials of glucagon-like peptide-1 receptor agonists

The first GLP-1RA CVOT to report results was the preapproval Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With Lixisenatide (ELIXA; Sanofi) study, which showed that once-daily lixisenatide was noninferior to placebo with respect to the risk of CV events (4-point MACE) (Table 1) (Pfeffer et al., 2015). The safety of lixisenatide on CV events was reflected in the components of the primary composite endpoint, CV death (HR = 0.98 [95% CI, 0.78–1.22]), nonfatal MI (HR = 1.03 [95% CI, 0.87–1.22]), nonfatal stroke (HR = 1.12 [95% CI, 0.79–1.58]), and hospitalization for unstable angina (HR = 1.11 [95% CI, 0.47–2.62]). This was followed by the postapproval Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER; Novo Nordisk) trial results in 2016, which demonstrated that liraglutide reduced the risk of CV outcomes (13% risk reduction for MACE vs. placebo) (Marso et al., 2016b). This lower risk was driven by a statistically significant 22% reduction in CV death (HR = 0.78 [95% CI, 0.66–0.93]), with nonsignificant reductions in the other two MACE components (nonfatal MI, HR = 0.88 [95% CI, 0.75–1.03]; nonfatal stroke, HR = 0.89 [95% CI, 0.72–1.11]).

The once-weekly GLP-RA, semaglutide, was the second GLP-1RA to show positive CV results. The primary endpoint of the preapproval Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6; Novo Nordisk) trial assessed the CV safety of semaglutide versus placebo and standard of care in ∼3,000 patients with T2D and established CVD (Table 2) (Marso et al., 2016a). The trial confirmed noninferiority with respect to the risk of CV events (Marso et al., 2016a) and, while not designed to assess superiority, post hoc analysis showed that semaglutide reduced the risk of CV events compared with standard of care. The reduction in risk was driven by a statistically significant reduction in the rate of nonfatal stroke (HR = 0.61 [95% CI, 0.38–0.99]) and a nonsignificant decrease in nonfatal MI (HR = 0.74 [95% CI, 0.51–1.08]), with a similar rate of CV death between treatment arms (HR = 0.98 [95% CI, 0.65–1.48]). Although investigators in SUSTAIN-6 were encouraged to treat all patients to glycemic targets, semaglutide was associated with significant and sustained reductions in HbA1c compared with standard of care, and this may have contributed to the observed reduction in CV risk with semaglutide. Semaglutide has recently been approved by the FDA.

Table 2.:
Study design and patient populations of completed cardiovascular outcome trials
Table 2-A.:
Study design and patient populations of completed cardiovascular outcome trials

The EXenatide Study of Cardiovascular Event Lowering (EXSCEL) trial (AstraZeneca) of the once-weekly extended release (ER) formulation of exenatide reported noninferiority for CV outcomes in patients with T2D with or without previous CVD but with no reduction in CV risk compared with placebo (Table 1) (Holman et al., 2017). The rates of the components of the primary outcome did not differ significantly between the two groups (CV death, HR = 0.88 [95% CI, 0.76–1.02]; nonfatal MI, HR = 0.95 [95% CI, 0.84–1.09]; nonfatal stroke, HR = 0.86 [95% CI, 0.70–1.07]). The CV safety data reported from EXSCEL are consistent with the initial announcement from the preapproval FREEDOM trials of ITCA 650 (Intarcia), a continuous delivery of exenatide via a subdermal miniature osmotic pump, which reported noninferiority for MACE compared with placebo (Intercia Therapeutics Inc., 2016). Postapproval CVOTs are ongoing for other once-weekly GLP-1RAs, albiglutide (Effect of Albiglutide, When Added to Standard Blood Glucose Lowering Therapies, on Major Cardiovascular Events in Patients With Type 2 Diabetes Mellitus [HARMONY Outcomes; HARMONY Outcomes; GlaxoSmithKline]) and dulaglutide (Researching Cardiovascular Events With a Weekly Incretin in Diabetes [REWIND; Eli Lilly & Co]) (, 2017e). However, albiglutide has been removed from the market (July 2018) (GlaxoSmithKline, 2017).


Of the completed CVOTs, the majority have been conducted with agents that act through the incretin pathway (3 with DPP-4is and 5 with GLP-1RAs), and 2 have been conducted with drugs that inhibit SGLT-2 activity. Of the GLP-1RA CVOTs to have reported data, three exendin-based GLP-1RAs demonstrated CV safety (lixisenatide, exenatide ER, and ITCA 650) while two (based on human GLP-1) demonstrated a reduction in CV risk (liraglutide and semaglutide [post hoc analysis of SUSTAIN-6]) (Marso et al., 2016a; Pfeffer et al., 2015). However, the results of a meta-analysis examining the effect of GLP-1RAs indicate that the GLP-1RA class of drugs reduces all-cause mortality, CV mortality, and the incidence of MI (Monami et al., 2017). Although the exact mechanisms underpinning the reduction in CV risk with GLP-1RAs are not fully understood, improvements to risk factors, such as glycemia, weight, bloodsssure, and lipid profiles, as well as direct effects of GLP-1RAs on inflammation, platelets, vasculature, and immune cells have been proposed (Drucker, 2016). The article by Ridge in this supplement has further details (Ridge, 2018).

Implications for nurse practitioners

As the number of available primary care physicians and endocrinologists diminishes (Vigersky et al., 2014), the role of the nurse practitioner in the area of diabetes will continue to grow. The nurse practitioner is in a prime position to work one-to-one with patients on all aspects of diabetes care, including patient education and therapy choices. Indeed, patients who are knowledgeable about their treatment regime are more likely to follow recommendations for care than similar patients who do not participate in diabetes education (Duncan et al., 2009). Additionally, evidence suggests that inclusion of nurse practitioners in primary care practice improves adherence and clinical outcomes in T2D (Jackson, Lee, Edelman, Weinberger, & Yano, 2011; Richardson, Derouin, Vorderstrasse, Hipkens, & Thompson, 2014). As both the understanding of the underlying pathophysiologic defects and the number of available therapies increases, it is a key that nurse practitioners have a solid understanding of all T2D treatment options, including GLP-1RAs. As GLP-1RAs target the majority of the known defects associated with T2D, they are considered to have many clinical benefits beyond glycemic efficacy and weight loss (DeFronzo, 2009). Given that half the mortality and a significant amount of morbidity in patients with T2D is related to CVD, the benefits of SGLT-2is and GLP-1RAs highlighted in recent CVOTs ought to be understood and considered by nurse practitioners as they educate, counsel, and adapt treatment regimens for their patients.

It should be recognized that patients enrolled in CVOTs already have established CVD or multiple CV risk factors (a requirement of CVOT design) and the benefits in lower CV risk patients remain to be established. Although a reduction in CV risk with any of these drugs would not necessarily be generalizable to patients with a lower CV risk, the absence of harm is likely applicable to most patients (Schnell et al., 2016). As CVOTs are typically designed to record a defined number of events, any future trial assessing CV benefits in lower CV risk patients will be constrained by the timescales and participant number required to capture meaningful estimates of risk.

The particular patient groups included in CVOTs may also limit extrapolation of the findings to general populations in real-world practice. Of particular note is the variation in the history of CVD or CVD risk factors and the duration of diabetes at baseline between trials. For example, only patients with a recent acute coronary event were eligible for inclusion in the EXAMINE and ELIXA trials, and the duration of diabetes ranges from 9 years in ELIXA and EXAMINE, to 14 years in SUSTAIN-6 (Table 2). Furthermore, in all CVOTs, patients were followed for a relatively short period (median follow-up ranged from 1.5 to 3.8 years), and further studies will be necessary to interrogate the long-term use of GLP-1RAs and SGLT-2is as strategies to reduce CV events. The Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD REAL; AstraZeneca) study, a large multinational retrospective study of patients with T2D, both with and without established CVD, demonstrated that SGLT-2is versus other diabetes treatments were associated with a lower risk of hospitalization for HF and death (Kosiborod et al., 2017). The Evidence for cArdiovascular outcomes with Sodium glucose co-transporter 2 inhibitors in the rEal worLd (EASEL) study, a population-based cohort study among patients with T2D and established CV disease, also concluded that, compared with initiation of non-SGLT2is, initiation of SGLT2i was associated with a lower risk of death, 3-point MACE (all-cause mortality, nonfatal MI, and nonfatal stroke), and hospitalization for HF (Udell et al., 2017). These studies of real-world practice indicate that the outcomes of the SGLT-2i CVOTs translate into real-world practice.

Another barrier to translation of findings from CVOTs to routine clinical practice is that adherence to medication is likely be better in clinical trials. However, this issue may be reduced with once-weekly GLP-1RAs, which have the potential for greater acceptance and adherence by patients in clinical practice, compared with once-daily treatments (Amblee, 2016; Qiao, Ouwens, Grandy, Johnsson, & Kostev, 2016), as discussed in more details earlier in the supplement (Hinnen, 2018).

Based on CVOT data reported to date, the focus of diabetes management is shifting from solely glycemic control and HbA1c, to include glycemic control, weight reduction plus the prevention of CVD and death from CV events. Indeed, CVOTs have prompted an update in the 2018 American Diabetes Association Standards of Care, which now recommend the use of glucose-lowering drugs with known CV benefit in patients with suboptimally controlled T2D and established CVD (American Diabetes Association, 2018). Both empagliflozin and liraglutide have recently had a CV indication added to their FDA drug label, and canagliflozin has filed for an indication. Also as a result of CVOT outcomes suggesting that saxagliptin and alogliptin may increase the risk of HF, the FDA has added warnings to these drug labels. Prescribers are cautioned not to initiate these DPP-4 inhibitors in patients at risk of HF and to discontinue treatment if HF develops. Nurse practitioners who manage high-risk patients with CVD should strongly consider prescribing medications that offer glycemic control while reducing the risk of stroke, CV death, and nonfatal MIs.


Since the FDA issued guidance for the assessment of CV outcomes, CVOTs have shed new light on the understanding of and expectations for a number of glucose-lowering drugs (US Food and Drug Administration, 2008). While all new therapies are required to meet inferiority for MACE, recent trials suggest that some—including the SGLT-2is and the once-weekly GLP-1RA semaglutide—may exceed these standards and reduce the risk of CV morbidity and mortality. The nurse practitioner is in a prime position to share this information with patients and chose therapies that have the potential for CV benefit. This is a new era for the management of diabetes care, and nurse practitioners will be instrumental in ensuring that patients are provided with the best possible care.

Acknowledgments:The author is grateful to Helen Parker, PhD, of Watermeadow Medical, an Ashfield company, for writing assistance in the development of this manuscript. This assistance was funded by Novo Nordisk, who also had a role in the review of the manuscript for scientific accuracy.


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            Cardiovascular disease; glucagon-like peptide-1; glucose-lowering therapy; semaglutide; type 2 diabetes

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