The association between cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) is well accepted, but somehow, still poorly understood. This comes at a time that diabetes affects 29.1 million people in the United States (most them type 2 diabetics), and 92.1 million people have some form of cardiovascular disease.1,2 Patients with T2DM have several comorbidities that are highly associated with cardiovascular risk, such as hypertension, being overweight or obese, and high lipid levels. It is not surprising that death from CVD is 70% higher in adults with diabetes, and many of these patients have decreased life expectancy mostly due to premature cardiovascular death.1 Additionally, the question of cardiovascular safety of anti-diabetic drugs has contributed to the complexity that clinicians face in managing T2DM. Following the Food and Drug Administration’s (FDA) mandate that all new anti-diabetic drugs introduced since 2008 have to be evaluated for their long-term cardiovascular safety in T2DM patients, many cardiovascular outcome trials (CVOTs) of these drugs have been completed or are ongoing. In addition to safety, these trials have explored the possibility of long-term cardiovascular protection, however many questions still remain unanswered for clinicians in developing appropriate treatments for T2DM patients with CVD. This article will review and summarize the results from the major CVOT trials in anti-diabetic drugs and their potential implications in optimizing clinical care in this patient population.
Why the need for CVOTs in T2DM?
It all started when Rosiglitazone, the insulin-sensitizer drug, was shown to be linked to increased rates of myocardial infarction (MI) in patients with T2DM in a large-scale meta-analysis.3 That evidence prompted FDA to add prescribing restrictions on the drug, a restriction which has since been lifted.4 Given that many type 2 diabetics were taking rosiglitazone to improve insulin resistance and glucose homeostasis, the concern was immediate: are we treating T2DM but also at the same time increasing the risk of cardiovascular complications? What about the cardiovascular safety of other anti-diabetic medications? This huge knowledge gap led to the FDA’s decision in 2008 to require the assessment of CV safety before approval of glucose-lowering medications. Since the Rosiglitazone controversy, many CVOTs in high-risk T2DM patients have been completed or are currently ongoing. Initially, the diabetes medical community was hoping for the best, but expecting the worst. Understandably, when results from early CVOTs showed that some anti-diabetic drugs were safe in high-risk T2DM patients, it was a great sign of relief. Results from the three CVOTs evaluating Dipeptidyl Peptidase-4 (DDP-4) inhibitors, SAVOR-TIMI (saxaglipitin), EXAMINE (aloglipitin), and TECOS (saxaglipitin, aloglipitin, and sitaglipitin), reported that they did not affect the rate of a major adverse cardiac event (MACE), measured by the composite score of cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal ischemic stroke.5,6,7 Furthermore, most of the T2DM patients in these trials were at high-risk for cardiovascular complications and had preexisting heart disease.5,6,7 The ELIXA trial, demonstrated the cardiovascular safety of glucagon-like peptide 1 (GLP-1) receptor agonist (RA) Lixisenatide in T2DM patients with a recent acute coronary event, as no effect on a 4-point MACE (composite of CV death, non-fatal MI, non-fatal stroke, and hospitalization for unstable angina) was reported.8 These results were a major step forward in the care for patients with T2DM and with CVD, and paved the way for additional studies that would reveal some very exciting outcomes.
The next wave: glucose-lowering and improved cardiovascular safety
Among the sodium-glucose cotransporter 2 (SGLT-2) inhibitors, the Empagliflozin Reducing Excess Glucose (EMPA-REG) OUTCOME trial demonstrated superiority in reducing MACE.9 Patients receiving the drug had a 14% reduction in the primary composite outcome of death from CV causes, non-fatal MI, or non-fatal stroke than those receiving placebo, which was driven by the significant reduction in death from CV causes. There was no significant difference in the key secondary outcome, the risk of hospitalization for unstable angina. However, researchers did see a 38% reduction in CV mortality, a 32% reduction in all-cause mortality, and a 35% reduction in hospitalizations for heart failure compared to placebo.9 These benefits were unprecedented and had not been observed with any antidiabetic drugs to date. The positive results of the CVOT for empagliflozin led the FDA to approve empagliflozin for the new indication to reduce the risk of CV death in adult patients with T2DM and CV disease in December 2016. Furthermore, the CANVAS and CANVAS-R trials showed that another SGLT-2 inhibitor, canagliflozin, lowered the risk of cardiovascular events as evaluated by a 3P-MACE in T2DM patients, but did not show significant decreases in CV death, nonfatal MI, or nonfatal stroke when evaluated separately.10Because of these promising results, CVOTs with two other SGLT-2 inhibitors, dapagliflozin (DECLARE-TIMI) and ertugliflozin (VERTIS-CV) are currently ongoing, with results expected in 201911.
In addition to Lixisenatide, CVOTs with other GLP-1 RAs have were recently concluded and showed very different results. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial found a 13% reduction in the primary 3P-MACE composite outcome in T2DM patients treated with liraglutide compared to those receiving placebo, as well as a 22% reduction in CV death and a 15% reduction in all-cause death.12 The SUSTAIN-6 trial with semaglutide showed a robust reduction in 3P-MACE, but no reduction in CV death, all-cause death, and hospitalizations due to heart failure.13 However, the EXCEL trial, which evaluated the cardiovascular safety of GLP-1 RA exenatide, did not report improved cardiovascular outcomes as measured by the composite 3P-MACE, or cardiovascular and all-cause mortality, but confirmed the non-inferiority of this agent compared to placebo.14 Furthermore, two more GLP-1 RAs, dulaglutide (REWIND) and albiglutide (HARMONY) are currently being evaluated in clinical trials, with results anticipated later this year.
The results from the concluded CVOTs have provided evidence about the non-inferiority of cardiovascular safety of most anti-diabetic drugs, suggesting that at least there is no increased risk of adverse cardiovascular events in high-risk T2DM patients. Results with some agents, particularly empagliflozin, canagliflozin, liraglutide, and semaglutide show that they decrease the likelihood of adverse cardiovascular events in T2DM patients with established CVD, however, it is unclear whether they can be used for primary prevention of CVD in type 2 diabetics. Results from ongoing CVOTs will provide additional information on the utility of these agents for primary CVD prevention, and to discern whether beneficial effects on cardiovascular health represent a class effect, since different outcomes have been reported even in drugs within the same class.
A look ahead
Based on the evidence from the LEADER, EMPA-REG, and CANVAS trials, the American Diabetes Association, in their newly released 2018 Standards of Medical Care in Diabetes, has incorporated the use of empagliflozin, canagliflozin, and liraglutide in T2DM patients with established cardiovascular disease.15 Since semaglutide was only approved by the FDA in December of 2017, it did not make it to this list, but may be added in future recommendations due to the positive results of the SUSTAIN-6 trial. Results from the CVOT trials have provided strong evidence about the CV benefits and the lack of CV risk for many antidiabetic drugs. The hope is that these drugs will revolutionize patient care and lead to overall improved quality of life by making CVD prevention a near-reality in T2DM. As we all know, T2DM is a complex and chronic disease, and patients have many diverse comorbidities, including hypertension, obesity, dyslipidemia, chronic kidney disease (CKD), which all impact the selection of antihyperglycemic therapies. Thus, a “one-size-fits-all” approach to treatment is insufficient, and there is an ever-growing need for individualized therapies that are specific to each patient. A multi-faceted approach to T2DM treatment should incorporate lifestyle modifications and the appropriate pharmacological therapies to meet glycemic targets. With the plethora of pharmacological agents now available, it is easy to get confused about which treatment plan is better for every individual patient. In addition, clinicians must consider psychosocial issues in all aspects of care, taking into account the patient’s emotional well-being and needs15. Although there is no shortcut to the complex clinical decisions that need to be made in T2DM care, some of the strategies can include:
- Staying current with new and emerging advancements in the field
- Reviewing updated standards of care, clinical practice guidelines and recommendations
- Improving patient communication
- Individualizing therapy that is specific to each patient
The success of recent CVOTs has given clinicians more tools at their disposal, however, awareness about the efficacy and safety of these new agents is crucial in optimizing management plans for T2DM patients at high-risk for cardiovascular events. Strategies that can improve the current poor cardiovascular outcomes in T2DM patients are around the corner and combination of existing and newer therapies that lower the risk of cardiovascular complications while maintaining glycemic control provide an exciting opportunity. However, more research is needed to understand the mechanisms responsible for these protective cardiovascular outcomes in order to determine whether these benefits are class-or even drug-specific, and if they can be used in T2DM patients without established CVD.16