The American College of Cardiology (ACC) published a new expert consensus statement in the Journal of the American College of Cardiology regarding decision considerations for novel cardiovascular risk reduction therapies in patients with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD).1 In their statement for clinicians who jointly manage patients with T2D and ASCVD, the ACC provides mechanism of action summaries, benefit and safety concern information, decision-making recommendations, and monitoring advice for sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists.
Examples of SGLT2 inhibitor drugs include empagliflozin and canagliflozin, both of which may reduce major adverse cardiac events (MACE) as well as heart failure hospitalization. The EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in T2D Patients-Remove Excess Glucose) trial and CANVAS (Canagliflozin Cardiovascular Assessment Study) Program demonstrated greater reductions in MACE compared with placebo for these 2 therapies.2,3
In the consensus statement, the ACC writing committee suggests the benefit associated with SGLT2 inhibitors may be derived from their natriuretic and diuretic effects, positive effect on blood pressure, and associated weight loss. Although these drugs have demonstrated cardiovascular benefit, safety concerns include an increased risk for genital mycotic infections, which tend to resolve after the introduction of antifungal agents. Diabetic ketoacidosis in the absence of significant hyperglycemia may also be associated with SGLT2 inhibitors.
GLP-1 Receptor Agonists
GLP-1 receptor agonists affect uptake of the peptide hormone GLP-1 and reduce glucose by increasing glucose-dependent insulin secretion and decreasing glucagon secretin. As of 2018, liraglutide is the only GLP-1 receptor agonist approved by the US Food and Drug Administration that has demonstrated a clear effect for reducing cardiovascular events. Other GLP-1 receptor agonists that may be effective in patients with T2D and ASCVD include semaglutide, exenatide, and lixisenatide.
The LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial demonstrated that liraglutide reduced cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke (3-point MACE) to a greater degree than placebo in patients with T2D.1,4 The SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes) and EXSCEL (Exenatide Study of Cardiovascular Event Lowering) trials also found that semaglutide and exenatide, respectively, were more effective than or noninferior to placebo or usual care for reducing 3-point MACE.1,5,6
The main safety concerns stated in the decision pathway relating to GLP-1 receptor agonists are negative gastrointestinal symptoms, which can be mitigated by gradual escalation of treatment dose.
Recommendations for Optimal Therapy Initiation
According to the ACC writing committee, T2D and clinical ASCVD should be addressed concurrently. Clinicians should consider recommending guideline-directed medical therapy, including lifestyle modification, antiplatelet therapies, blood pressure lowering, and metformin for glucose control. SGLT2 inhibitors or GLP-1 receptor agonists should also be considered and initiated after a clinician-patient discussion. The ACC also recommends that clinicians discuss these medications with the caregiver of the patient with diabetes (eg, a family member) in conjunction with the patient-physician discussion. Management of glucose levels via concomitant use of SGLT2 inhibitor and a GLP-1 receptor agonist is in accord with current T2D guidelines; however, a reduction in cardiovascular disease risk with dual use of these drug classes has not been conclusively established.
SGLT2 Inhibitor: Monitoring Considerations
The risk for genital mycotic infections with SGLT2 inhibitors should be communicated to the patient who is beginning this therapy. To mitigate the risk, physicians are recommended to advise meticulous attention to personal hygiene and possibly antifungal medication at the start of treatment. The risk for hypoglycemic events should also be communicated to patients who are receiving insulin or an insulin secretagogue (eg, a sulfonylurea). Insulin or sulfonylurea dose adjustments are recommended to reduce further risk after initiation of a SGLT2 inhibitor.
GLP-1RA: Monitoring Considerations
Patients receiving a GLP-1 receptor agonist should be monitored for transient nausea and vomiting, which are relatively common adverse effects of this drug class. In patients who receive semaglutide, there may be an increased risk for diabetic retinopathy. The ACC recommends that patients undergo an eye examination before starting semaglutide.
“We anticipate that the algorithms proposed here will change as new evidence emerges,” the ACC writing committee concluded, “but that the overarching goal of improving [cardiovascular] outcomes in patients with T2D and clinical ASCVD will remain consistent.”
- Das SR, Everett BM, Birtcher KK, et al. 2018 ACC expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes and atherosclerotic cardiovascular disease: a report of the American College of Cardiology Task Force on expert consensus decision pathways [published online November 26, 2018]. J Am Coll Cardiol. doi:10.1016/j.jacc.2018.09.020
- Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128.
- Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644-657.
- Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311-322.
- Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834-1844.
- Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377:1228-1239.