Cardiovascular Risk Reduction in Type 2 Diabetes
Cardiovascular Risk Reduction in Type 2 Diabetes
Lauren Martens, PharmD., CentraCare St. Cloud
Background: The Center for Disease Control estimates that over 34 million Americans have diabetes, with 90-95% of those patients managing type 2 diabetes. The number one cause of morbidity and mortality in individuals with type 2 diabetes is cardiovascular (CV) disease. As such, it is very important for healthcare providers across disciplines to collaboratively manage diabetes and related comorbidities. The American College of Cardiology (ACC) recently released their 2020 Expert Consensus Decision Pathway (ECDP) on Novel Therapies for Cardiovascular Risk Reduction in Patients with Type 2 Diabetes (T2D) to summarize recent studies showing the benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide receptor agonists (GLP-1RAs) in reducing cardiovascular risk in patients with type 2 diabetes.
Evidence and Discussion: The 2020 American Diabetes Association Standards of Medical Care in Diabetes recommends using SGLT2 inhibitors and GLP-1RAs for patients with either established or a high risk of atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), or chronic kidney disease (CKD). Following the first-line recommendation of metformin and lifestyle management for anyone with type 2 diabetes, it is recommended to consider the use of agents to lower the risk of ASCVD, CKD, or heart failure regardless of the patient’s hemoglobin A1c.
An SGLT2 inhibitor, provided the patient has sufficient kidney function, or GLP-1RA with cardiovascular benefit is preferred for patients with established ASCVD or risk factors for ASCVD, including those at least 55 years old with over 50 percent stenosis of a coronary, carotid, or lower extremity artery, or left ventricular hypertrophy. The GLP-1RA agents with proven CV benefit include dulaglutide, liraglutide, and semaglutide. The SGLT2 inhibitors include canagliflozin, empagliflozin, and dapagliflozin. For patients with heart failure, specifically those with an ejection fraction less than 45 percent, or chronic kidney disease (defined as an estimated glomerular filtration rate (eGFR) of 30-60 mL/min/1.73 m2 or urine albumin-to-creatinine ratio greater than 30 mg/g) an SGLT2 inhibitor is preferred, given sufficient kidney function. A GLP-1RA with CV benefit is recommended if the SGLT2 inhibitor is contraindicated or intolerable.
The 2020 ACC Expert Consensus Decision Pathway provides updates to the 2018 ECDP, highlighting the use of SGLT2 inhibitors and GLP-1RAs in specific comorbidities. The 2018 pathway included patients with type 2 diabetes and clinical ASCVD. This update has expanded to adults with type 2 diabetes and established ASCVD, heart failure, diabetic kidney disease (DKD), and/or a high risk of ASCVD, which includes those with end organ damage or several risk factors. In the 2018 ECDP, it is recommended to follow guideline recommendations for comprehensive CV risk reduction, while simultaneously considering the initiation of an SGLT2 inhibitor or GLP-1RA. While the 2020 ECDP contains a similar recommendation regarding comprehensive risk reduction, the recommendation forSGLT2 inhibitors or GLP-1RAs has been strengthened to recommend an agent from one of these classes with cardiovascular benefit. Since publication of the 2018 ECDP, there are now additional agents to use within each class of medication and the indications for use of these medications have been expanded.
The SGLT2 inhibitors act on the sodium-glucose cotransporter in the kidney, which prevents glucose reabsorption and causes excretion of excess glucose in the urine. They can also assist in weight loss and blood pressure control for patients. Data from multiple large, randomized controlled trials were evaluated and compiled in the ECDP to support the cardiovascular and renal benefits of these agents. Canagliflozin was shown by these trials to reduce the risk of major adverse cardiovascular events (MACE), a composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death, in patients with type 2 diabetes and cardiovascular disease. Dapagliflozin was shown to reduce the risk of HF hospitalization in patients with type 2 diabetes and CV disease or with several risk factors for CV disease. Empagliflozin reduces the risk of cardiovascular death in patients with type 2 diabetes and cardiovascular disease.
GLP-1RAs cause an increase in concentration of GLP-1, a hormone released in response to intake of food. This hormone promotes glucose-dependent insulin secretion, slows gastric emptying, and reduces glucagon secretion. These agents are also beneficial for weight loss, blood pressure, and triglyceride management, and may provide renal benefits. A number of large, randomized controlled trials looking at the cardiovascular effects of these medications were compiled in the ECDP. Only dulaglutide, liraglutide, and subcutaneous semaglutide were shown to reduce MACE in patients with type 2 diabetes and cardiovascular disease, indicating heterogeneity within the pharmacological class. Dulaglutide is also indicated to reduce MACE in those without established ASCVD. Oral semaglutide and exenatide showed positive outcomes for MACE reduction; however, they were not statistically significant.
Clinical Impact: The newly published ACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients with Type 2 Diabetes provides strong support for the use of SGLT2 inhibitors and GLP1 receptor agonists to reduce the risk of cardiovascular morbidity and mortality. Individuals with type 2 diabetes and heart failure, particularly those with an ejection fraction less than or equal to 40 percent, are recommended to initiate an SGLT2 inhibitor. These agents are also recommended for individuals with either established or risk factors for ASCVD, DKD, or heart failure and type 2 diabetes. GLP-1RAs are recommended in patients with a history of ASCVD or a high risk of developing ASCVD. Of course, before the initiation of any medication, potential adverse effects, pertinent medical history, and patient preferences should be taken into consideration.
- National diabetes statistics report 2020. Centers for Disease Control and Prevention. https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf. Published 2020. Accessed November 28, 2020.
- American Diabetes Association. (2020). 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2020. Diabetes Care, 43(Suppl 1), S98.
- 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. J Am Coll Cardiol. 2018;72(24):3200-3223. doi:10.1016/j.jacc.2018.09.020.