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01-13-2017 | Cardiovascular outcomes | Editorial | Article

Clinical implications of cardiovascular outcomes trials in type 2 diabetes

Carol Wysham MD

Cardiovascular disease (CVD) remains the most common cause of death in patients with type 2 diabetes. On average, diabetes doubles the risk for myocardial infarction (MI), stroke, coronary death, and congestive heart failure. Moreover, a history of MI or stroke confers higher mortality risk in those with diabetes. To prevent cardiovascular (CV) events, a multifactorial approach is recommended, with control of weight, glucose, blood pressure and hyperlipidemia, and judicious use of antiplatelet therapy.

Reducing CV risk with lipid-lowering and antihypertensive therapies

The American Diabetes Association (ADA) and American Association of Clinical Endocrinology (AACE) recommend specific goals for control of CV risk factors in our patients with diabetes (Table 1).

Table 1. ADA/AACE recommendations for control of CV risk factors in patients with diabetes

HbA1c (%)
Blood pressure (mmHg)
LDL-C (mg/dL)
Moderate to high dose statin for all >40 (or LDL-C <100)

Multiple studies confirm that treatment with statins is associated with an approximate 25% reduction in CV events among patients with diabetes, both as primary and secondary prevention. The ADA has adopted the American Heart Association/American College of Cardiology recommendation for routine moderate- or high-intensity statins in all patients with diabetes aged 40 years and older.

Similarly, control of blood pressure to less than 140/90 mmHg in patients with diabetes reduces the risk for CV events, with ACE inhibitors or angiotensin II receptor blockers as preferred first line therapies.

Can effective glycemic control reduce CV risk?

Intensive glucose control failed to alter the risk for CV events in the short-term ACCORD, ADVANCE and VADT trials. However, a meta-analysis of these studies suggested a benefit of a 15% reduction in coronary heart disease events with tight glycemic control [1]. Moreover, the extension study of the VADT did demonstrate a significant reduction in CV events in the intensively treated subjects when analyzed after 5 years of observational follow-up, despite similar glycemic control in the extension part of the study [2]. Similar results were reported in the UKPDS and its 10-year follow-up study. These results suggest that the CV benefits of tight glycemic control likely take more than 5 years to manifest.

CV safety trials of all new antihyperglycemic therapies have been mandated by the US Food and Drug Administration (FDA) since 2008. However, at least three CV outcome studies predated that mandate. The UGDP trial [3] suggested that treatment with the short-acting sulfonylurea tolbutamide was associated with an increase in CV death. However, concern about methodology limited the impact of this study. Although not designed to test the CV safety of metformin, a secondary analysis of overweight patients in the UKPDS substudy showed that treatment with metformin was associated with a 39% reduction in MI, compared with diet and exercise [4]. The PRO-ACTIVE study failed to show benefit of pioglitazone in the primary endpoint (a composite of death, MI, stroke, acute coronary syndrome, leg revascularization or amputation, percutaneous coronary intervention, or coronary artery bypass graft) [5], but did show a significant 16% reduction in the 3-point major adverse CV event (MACE) endpoint (CV death, nonfatal MI and nonfatal stroke), which has been a more typical endpoint for CV trials [6]. The ORIGIN study was designed to test the hypothesis that treatment with glargine insulin might reduce secondary CVD events in patients with CVD and prediabetes or recent onset diabetes. The results showed no difference between glargine and placebo in the occurrence of the 3-point MACE endpoint [7].

CV safety studies of new antihyperglycemic agents

CV safety studies have been completed for three dipeptidyl peptidase-4 (DPP-4) inhibitors, three glucagon-like peptide 1 (GLP-1) receptor agonists and one sodium/glucose cotransporter 2 (SGLT-2) inhibitor. All three of the DPP-4 inhibitors demonstrated CV safety, but did not show any CV benefit over placebo [8, 9, 10]. On secondary analysis, there was a significant increase in hospitalizations for congestive heart failure (CHF) compared with placebo in the saxagliptin CV trial [8].

The first of the GLP-1 CV safety studies to report was ELIXA, which demonstrated that in comparison to placebo, treatment with lixisenatide (a recently approved short-acting GLP-1 receptor agonist) was associated with no increase, but no decrease in CV events [11].

The first of the modern CV trials to show treatment benefit was the EMPA-REG study, in which empagliflozin met the primary endpoint of CV safety, but also showed benefit in the key secondary endpoint of 3-point MACE. A 38% reduction in CV death was the primary driver of the outcome. There was no significant benefit for either MI or stroke. Empagliflozin was also associated with a 35% reduction in hospitalization for CHF, another key secondary endpoint of this study [12]. Recently, despite the fact that the mechanism for the improvement in CV outcomes is unknown, the FDA approved the indication of empagliflozin for reduction of CV death in patients with type 2 diabetes and CVD [13].

The last two trials to report their findings both involved longer-acting GLP-1 receptor agonists. In the LEADER trial, liraglutide met the primary endpoint of CV safety, but also met the key secondary endpoint of reduction in the incidence of 3-point MACE compared with placebo. This was also primarily driven by a reduction in CV death, though there were nonsignificant trends towards reduction in nonfatal MI and stroke. There was no reduction in hospitalizations for CHF with liraglutide versus placebo [14]. Again, the mechanism leading to improved CV outcomes with liraglutide is uncertain.

SUSTAIN-6 is the CV safety trial for semaglutide, an investigational, once-weekly GLP-1 receptor agonist. As in the previous studies, it met both the primary endpoint of CV safety as well as the reduction in incidence of 3-point MACE compared with placebo. Unlike in the previous studies, a reduction in nonfatal stroke was the key driver for the overall benefit. Also of note, there was a significant increase in the risk for retinopathy seen in the subjects treated with semaglutide [15].

Reducing CV risk in our patients with diabetes

In early 2017, we now have at least two medications with proven CV benefit in patients with type 2 diabetes and established CVD. Additionally, metformin is widely regarded as having benefit for reducing MI in patients with new-onset diabetes. Pioglitazone has also demonstrated benefit for secondary prevention of MI and stroke. Most guidelines agree that metformin should be used as initial antihyperglycemic therapy for patients with type 2 diabetes, without regard to the presence of CVD. With the new data showing CV benefit of diabetes drugs in patients with established CVD, should we be using these agents preferentially in patients with known CVD? The Canadian Diabetes Association updated their Clinical Practice Guidelines for Pharmacologic Management of Type 2 Diabetes in November 2016. In this update, they recommend prioritizing medications with known CV benefit for those patients with established CVD [16]. Similarly, the Israel National Diabetes Council updated their guidelines to include SGLT-2 inhibitors as second-line therapy in patients with established CVD [17]. Most recently, the ADA 2017 Standards of Medical Care in Diabetes now includes the recommendations to consider empagliflozin or liraglutide in patients with known CVD to reduce their risk of mortality [18], but to date no other organization has updated their guidelines to include these new data.

As for the practicing clinician, the recommendations for individualization of therapy remain the cornerstone for selection of therapy for hyperglycemia in type 2 diabetes. In patients with type 2 diabetes and CVD and in the absence of contraindications, the addition of empagliflozin or liraglutide should be considered as add-on therapy to metformin to reduce risk of death from CVD. In the absence of clinical trial data to compare the outcomes of these two therapies, the optimal choice is unknown. As in every patient encounter, healthcare providers should engage in shared decision-making with their patients.


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