Guidance is provided for cardiovascular (CV) specialists for the initiation and management of glucose-lowering therapies in patients with type 2 diabetes, in a 2020 Expert Consensus Decision Pathway (ECDP) published in the Journal of the American College of Cardiology.1

Several sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1RAs), which were developed for glucose lowering, have been associated with improved CV outcomes, noted the American College of Cardiology’s (ACC) Solution Set Oversight Committee, which prepared the report.

“The paradigm of how the CV specialist should approach the care of patients with type 2 diabetes is changing, and that change is reflected in this ECDP,” noted committee members. “Previously, CV specialists focused on risk factor optimization in patients with diabetes. Medications used for glycemic control were not adjusted by CV specialists, in part because they were not expected to demonstrate direct CV benefit.”


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The ECDP serves as an update to the 2018 ACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease (ASCVD) and is also endorsed by the American Diabetes Association.2

The main focus of the report is to provide guidance for the management of patients with type 2 diabetes and CV disease or those who are at high risk for CV disease.

SGLT2 Inhibitors and GLP-1RAs

Large, randomized controlled trials in patients with type 2 diabetes and established ASCVD and/or diabetic kidney disease (DKD) indicate an effectiveness of a number of SGLT2 inhibitors — including canagliflozin, dapagliflozin, and empagliflozin — in reducing major adverse cardiovascular events (MACE) and the risk for heart failure hospitalizations.3, 4

GLP-1RAs also have demonstrated benefits for preventing CV events in patients with type 2 diabetes, particularly in those with established ASCVD. “The potential for clinically relevant heterogeneity within the class exists, leaving dulaglutide, liraglutide, and injectable semaglutide the currently preferred agents,” noted the report authors.

“[A]n SGLT2 inhibitor with demonstrated cardiovascular benefit is recommended for patients with type 2 diabetes and heart failure, especially heart failure with reduced ejection fraction, or who are at high risk [for] developing heart failure, DKD, clinically evident ASCVD, or any combination of these conditions,” they added.

“A GLP-1RA with demonstrated CV benefit is recommended for patients with established or at very high risk for ASCVD,” advised the committee. “Alternatively, or in conjunction with a patient-clinician discussion, consider discussing these medications with the clinician caring for the patient’s blood glucose control.”

The ECDP recommends that a GLP-1RA with demonstrated CV benefit should be initiated at the lowest dose and up-titrated stepwise to the doses used in the trials or the maximally tolerated dose.

SGLT2 inhibitors may increase the risk of genital mycotic infections, polyuria, potential volume depletion in the context of hyperglycemia, and other rare events. “Clinical judgment should be used when initiating an SGLT2 inhibitor in a patient who will be starting or uptitrating an angiotensin-converting enzyme inhibitor or angiotensin reception blocker if the patient’s renal function is impaired,” noted the committee.

GLP-1RAs are associated with transient nausea and vomiting, especially when initiating therapy or up-titrating doses, and with possible additional risks [for] rare events.

Both classes of drugs have nonglycemic benefits on systolic blood pressure and weight, and have a low risk for hypoglycemia on their own or when used with metformin and other oral glucose-lowering medications, except for insulin secretagogues.

Prior to initiating type 2 diabetes therapies for CV disease risk reduction, a thorough patient-clinician discussion is advised. Patient preferences and medical history may help determine which specific agent is most appropriate. The route of administration (oral for SGLT2 inhibitors, subcutaneous or oral for GLP-1RAs) also may influence patient and clinician decision-making, and cost should be considered as well.

Drug Initiation and Monitoring

The ECDP listed the following considerations for drug initiation and monitoring in patients beginning SGLT2 inhibitor therapy with demonstrated CV benefit:

  • If hemoglobin A1c (HbA1c) is well-controlled at baseline, or if patients have a history of frequent hypoglycemic events, sulfonylurea should be tapered or discontinued and a reduction in total daily insulin dose by ~20% should be considered when starting therapy.
  • Patients need to be educated regarding the potential for genital mycotic infections and the importance of genital hygiene.
  • Hypovolemia should be avoided. The diuretic dose may need to be reduced in patients with symptoms of dehydration. Patients should be educated regarding symptoms of dehydration (lightheadedness, orthostasis, weakness) and medication should be held in cases of low oral intake.
  • Patients should be instructed to more closely monitor glucose at home for the first 4 weeks of therapy (especially if on insulin, sulfonylurea, and/or glinides). Consider discontinuing any sulfonylurea or glinide. For patients taking insulin, consider modestly reducing total daily insulin dose (by up to 20%).
  • Educate patients regarding symptoms of diabetic ketoacidosis (nausea, vomiting, abdominal pain, weakness) and that diabetic ketoacidosis can occur even if blood glucose readings are in the 150-250 mg/dL range. If a patient experiences diabetic ketoacidosis-like symptoms, he or she should be instructed to seek urgent medical attention.
  • Educate patients regarding foot care, especially in those with diabetic neuropathy. Ask patients to report any foot wounds immediately.

The ECDP noted the following considerations for drug initiation and monitoring in patients starting a GLP-1RA with demonstrated CV benefit:

  • If HbA1c is well-controlled at baseline or known history of frequent hypoglycemic events, wean or stop sulfonylurea and consider reducing total daily insulin dose by ~20% when starting therapy.
  • Instruct patients to more closely monitor glucose at home for the first 4 weeks of therapy. Consider discontinuing any sulfonylurea or glinide. For patients taking insulin, consider modestly reducing total daily insulin dose (by up to 20%).
  • Discontinue DPP-4 inhibitor before starting.
  • To mitigate nausea, recommend small portion sizes for meals, start at the lowest dose, and up-titrate as tolerated toward the goal doses used in CV outcome trials.
  • Advise patients to undergo appropriate, guideline-recommended eye examinations before starting therapy if not done within the last 12 months.
  • Discuss potential risk of diabetic retinopathy complications (for dulaglutide or injectable semaglutide).
  • Avoid in patients with diabetic gastroparesis or active gallbladder disease.

Clinical Implications

The ECDP provides a practical guide for CV specialists in initiating and monitoring the use of SGLT2 inhibitors and GLP-1RAs with the goal of reducing CV risk, according to the committee.

“This ECDP and associated treatment algorithms should be used in concert with established risk factor modification guidelines for the prevention of MACE in patients with type 2 diabetes, including guidelines on lipids, blood pressure, and antiplatelet therapy,” the group stated. “This ECDP should also be applied in the context of guideline-directed diabetes care.”

The main goals of care for high-risk patients are improving survival and quality of life, noted the committee.

“Achieving these important goals requires a team-based approach to achieve optimal outcomes,” the committee stated. “If used appropriately, the SGLT2 inhibitors and GLP-1RAs discussed in this ECDP should significantly reduce CV morbidity and mortality in these patients.”

Disclosures: Three writing committee members reported relationships with the pharmaceutical industry. Please see the original reference for a full list of disclosures.

References

  1. Das SR, Everett BM, Birtcher KK, et al. 2020 Expert Consensus Decision Pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes. A report of the American College of Cardiology Solution Set Oversight Committee [e-pub ahead of print]. J Am Coll Cardiol.
  2. Das SR, Everett BM, Birtcher KK, Brown JM, Cefalu CT, Januzzi JL, 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 Dec, 72 (24) 3200-3223.
  3. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.
  4. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–57