Cardiovascular Risk Reduction in Patients with Type 2 Diabetes

Case Continued

The patient is started on a statin because of his elevated LDL-C level in the context of being over the age of 40 years with T2DM. He is also started on an ACE inhibitor to address the hypertension. In addition, a dipeptidyl peptidase-4 inhibitor is added to his metformin to address the elevated A1c. He continues to follow up every 3 to 6 months.

Six years later, he experiences an episode of retrosternal chest discomfort while exercising. He is brought to hospital and is found to have a non-ST elevation myocardial infarction. He is admitted to hospital, undergoes percutaneous revascularization of a single lesion, and is discharged to a rehabilitation center. He is discharged on aspirin, clopidogrel, an ACE inhibitor, a beta blocker, and a high-intensity statin. His blood pressure is well managed, and he has lost further weight since he was last seen. When he returns to clinic, he wonders if there is anything more he can do to prevent further events.

• What secondary prevention of cardiovascular disease is recommended for patients with T2DM?

Optimal secondary prevention following a major vascular event includes a combination of pharmacologic and nonpharmacologic interventions. In the population without diabetes, evidence supports smoking cessation, exercise, cardiac-specific rehabilitation, antiplatelets, RAAS antag-onists, beta-blockade, and statins. Most of the trials that led to this standard suite of interventions had large diabetes subgroups. Therefore, there is no difference in the secondary prevention of cardiovascular disease in the population with diabetes with regard to these interventions.

• Have any antihyperglycemic agents been shown to reduce cardiovascular events?

Metformin

A summary of the vascular effects observed during trials of antihyperglycemic agents is shown in Table 3.

Empagliflozin

Many large randomized, controlled cardiovascular outcome trials have been completed or are ongoing looking at the cardiovascular safety of newer antihyperglycemic agents. The majority of the completed trials have shown a neutral effect, suggesting that the agents are safe. However, in September 2015, the first cardiovascular outcome trial of an antihyperglycemic agent with a positive result was published. The Empagliflozin Cardiovascular Outcome Event Trial (EMPA-REG OUTCOME) randomized 7020 patients with T2DM and cardiovascular disease (defined as nonacute myocardial infarction, multivessel coronary artery disease, unstable angina, nonacute stroke, or occlusive peripheral arterial disease) to placebo or 1 of 2 doses of empagliflozin. The primary outcome of cardiovascular mortality, nonfatal myocardial infarction, or stroke was reduced by 14% in the empagliflozin-treated group. Key secondary outcomes of all-cause mortality (HR 0.68) and heart failure hospitalization (HR 0.65) were also statistically different in favor of the empagliflozin arm [63].

On the basis of this trial’s results, empagliflozin should be considered for treatment of all patients with type 2 diabetes and known cardiovascular disease. It is as yet unknown whether this effect will translate to the other members of the sodium-glucose co-transporter 2 (SGLT-2) inhibitor class, although results of studies involving other SGLT-2 inhibitors are expected in the next 2 to 3 years.

Liraglutide

In 2016, the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial reported results of its cardiovascular safety trial. In this trial, 9340 patients with either established vascular disease or risk factors for vascular disease were randomized to daily liraglutide or placebo injections. The primary composite outcome of cardiovascular death, nonfatal myocardial infarction, or stroke was reduced by 13%. A key secondary outcome of all-cause mortality also showed a significant reduction (HR 0.85). There was no reduction in hospitalization for heart failure [64].

Semaglutide

Most recently, the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) was completed, assessing cardiovascular safety of a once-weekly injectable glucagon-like peptide-1 (GLP-1) analogue. This noninferiority trial studied 3297 patients with type 2 diabetes over the age of 50 years with established macrovascular disease, chronic heart failure, or chronic kidney disease (stage III or higher), or over the age of 60 years with at least 1 other cardiovascular risk factor. The patients were randomized to 1 of 2 doses of once-weekly semaglutide or placebo injection. A composite cardiovascular outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was decreased by 26% in the pooled semaglutide group. This was driven primarily by a reduction in nonfatal stroke, with no statistically significant reduction in nonfatal myocardial infarction or cardiovascular mortality. Significant secondary outcomes showed a reduction in new or worsening nephropathy (HR 0.64), and an unexpected increase in retinopathy (HR 1.76) [65].

All of these trials utilized their respective agents as add-on to existing antihyperglycemic therapy. Therefore, first-line antihyperglycemic therapy in a patient with T2DM remains metformin. For the patient with established vascular disease or who is at high risk for developing vascular disease, add-on therapy using an antihyperglycemic agent with proven cardiovascular benefits, such as empagliflozin or liraglutide, is suggested [9,11]. Semaglutide is not yet available for clinical use. The choice between these agents should be based on patient preference, cost, side effect profile, and absence of contraindications.

Currently, there are more studies underway with similar designs with different agents. As these studies are reported in the upcoming years, it is hoped that the options for reduction of cardiovascular risk will increase, and that we will have multiple antihyperglycemic agents that will provide not only glycemic benefit but also cardiovascular risk reduction.

Case Conclusion

The patient continues to abstain from smoking. He follows up with a dietitian and is enrolled in an exercise program. He remains on his cardiac medications. For glycemic control, he continues on his previous antihyperglycemic therapy and an antihyperglycemic agent with proven cardiovascular benefit is added. With these interventions, he understands that his risk is mitigated, but given his history and previous event, he remains at high risk for future vascular disease.

Conclusion

The care of a patient with diabetes requires a multifactorial approach. All patients are at risk for developing the vascular complications of diabetes, and it is these complications that ultimately result in the nearly doubled risk of mortality in patients with diabetes. Various trials have shown that targeted interventions can and do reduce the risk for cardiovascular disease in a measurable way. Above and beyond targeted interventions, we now know that strict multifactorial interventions can result in a clinically significant reduction in both mortality and cardiovascular disease. This multifactorial approach is supported by guidelines around the world [12,44,45]. A standardized approach to the assessment of risk and the application of interventions is critical. More recent data show that specific antihyperglycemic therapies can also reduce cardiovascular events above and beyond their glycemic effects. The rates of cardiovascular events in patients with diabetes have declined over time, and hopefully this trend will continue as further research supports additional interventions.

Corresponding author: Bikrampal S. Sidhu, MD, Toronto General Hospital, 200 Elizabeth St., 12 EN 242, Toronto, ON, M5G 2C4, bikrampal.sidhu@mail.utoronto.ca.

Financial disclosures: Dr. Cheng has received fees for speaking and/or consulting from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Merck, Novo Nordisk, Sanofi, Servier, and Takeda.