What are the 2018 ACC decision pathway and 2020 ACC recommendations on novel therapies for atherosclerotic CV risk reduction in patients with type 2 diabetes?

Updated: Apr 09, 2021
  • Author: Sandy N Shah, DO, MBA, FACC, FACP, FACOI; Chief Editor: Yasmine S Ali, MD, MSCI, FACC, FACP  more...
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2018 ACC pathway and recommendations

The expert consensus decision pathways on the use of two major new classes of diabetes drugs—sodium-glucose cotransporter type 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1RAs)—for cardiovascular (CV) risk reduction in patients with type 2 diabetes (TD2) and atherosclerotic CV disease (ASCVD) were released in November 2018 by the American College of Cardiology (ACC). [105, 106] The main focus of management is in the outpatient ambulatory setting.

The SGLT2 inhibitors appear to reduce major adverse CV events (MACE) and the risk of heart failure (HF) but increase the risk for genital mycotic infections, whereas GLP-1RAs offer reductions in MACE but are associated with transient nausea and vomiting. Both classes of agents have benefits in reducing blood pressure and weight, and they have a low risk for hypoglycemia.

For CV risk reduction, initiate agents with demonstrated CV benefit from either drug class at the lowest doses; no uptitration is necessary for SGLT2 inhibitors, whereas the GLP-1RAs should be slowly uptitrated (to avoid nausea) to the maximal tolerated dose.

At the initiation of an SGLT2 inhibitor or a GLP-1RA agent, clinicians should avoid hypoglycemia in patients by monitoring those with A1C levels near or below target, particularly when patients’ existing diabetes therapies include sulfonylureas, glinides, or insulin.

In addition to reducing MACE and CV death, SGLT2 inhibitors are also suitable for preventing hospitalization for HF.

Empagliflozin is the preferred SGLT2 inhibitor based on the available evidence and overall benefit-risk balance.

Liraglutide should be the preferred agent among the GLP-1RAs for CV event risk reduction.

Two SGLT2 inhibitors (ie, canagliflozin, ertugliflozin) appear to be associated with an increased risk of amputation. It is unclear whether or not this is a class effect; therefore, clinicians should closely monitor patients on these agents who have a history of amputation, peripheral arterial disease, neuropathy, or diabetic foot ulcers.

Patients with T2D and clinical ASCVD on metformin therapy (or in whom metformin is contraindicated or not tolerated) should have an SGLT2 inhibitor or GLP-1 RA with proven CV benefit added to their treatment regimen. For patients not on background metformin therapy, practitioners may use their clinical judgment to prescribe an SGLT2 inhibitor or GLP-1RA for CV risk reduction.

It appears reasonable to concomitantly use an SGLT2 inhibitor and a GLP-1RA with demonstrated CV benefit if clinically indicated, although such combination therapy has not been studied for CVD risk reduction.

2020 ACC recommendations

In July 2020, the ACC published their updated clinical recommendations regarding CVD risk reduction using SGLT2 inhibitors and GLP-1RAs in patients with T2D. [103, 104]  These are outlined below.

It is recommended that for patients with T2D who have or are at very high risk for clinical ASCVD, HF, and/or diabetic kidney disease, a patient-clinician discussion be initiated, at a clinical follow-up visit, regarding the use of an SGLT2 inhibitor and/or a GLP-1RA, with demonstrated CV benefit.

Recommendations regarding the choice of an SGLT2 inhibitor or a GLP-1RA

Many SGLT2 inhibitors and GLP-1RAs have shown CV benefit in patients with T2D, so patient-clinician discussions regarding their use must involve consideration of which agent is most appropriate.

In patients with impaired renal function, clinical judgement must be employed when initiating an SGLT2 inhibitor if the patient will be starting or up-titrating an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB).

It is suggested that in patients with a history of peripheral artery disease, severe peripheral neuropathy, lower extremity diabetic ulcers, or soft tissue infections, caution be exercised when starting an SGLT2 inhibitor, even though questions remain regarding the association of these agents with an increased amputation risk.

A GLP-1RA alternative to semaglutide SQ should be considered in patients with active proliferative retinopathy (especially those with high HbA1c and in whom significant rapid reduction is expected).

Owing to a lack of research on the use of GLP-1RAs in individuals with active gallbladder disease or a history of pancreatitis, it is suggested that these agents be employed cautiously in such patients.

Diabetes control and the initiation of SGLT2 inhibitors and GLP-1RAs

Because evidence indicates that the CV effects of SGLT2 inhibitors and GLP-1RAs are not influenced by HbA1c or background antidiabetic agent use, the decision to initiate an SGLT2 inhibitor (for CV or kidney risk reduction) or a GLP-1RA (for CV risk reduction) should not depend on HbA1c levels.

Even so, the addition of an SGLT2 or a GLP-1RA to the regimen of a patient with well-controlled T2D may require dose adjustment of background medications to avoid hypoglycemia in the context of insulin, sulfonylurea, or glinide therapy, particularly in patients in whom glycemic goals have or nearly have been reached.

Continue full efforts to achieve glycemic and blood pressure targets and to adhere to lipid, antiplatelet, antithrombotic, and smoking cessation guidelines after the addition of an SGLT2 inhibitor or a GLP-1RA to therapy.

Concomitant use of SGLT2 inhibitors and GLP-1RAs

It appears reasonable that an SGLT2 inhibitor and a GLP-1RA, with demonstrated CV benefit, be used together, if clinically indicated, despite a lack of research regarding the employment of such combination therapy for CV risk reduction.

Patient monitoring in SGLT2 inhibitor therapy

Inform patients starting an SGLT2 inhibitor about the higher risk of genital mycotic infections, as well as the ability to lower such risk through careful attention to personal hygiene of the perineum.

Patients should understand the potential risk of developing hyperglycemic or euglycemic diabetic ketoacidosis and learn prevention strategies. In addition, they should be told to seek immediate care if symptoms potentially associated with diabetic ketoacidosis arise (eg, nausea, vomiting, abdominal pain, generalized weakness).

It may be reasonable to use home monitoring with urine ketone test strips in some higher-risk patients.

Precipitation of diabetic ketoacidosis should be avoided by steering clear of initial reductions in total daily insulin dose of over 20%.

Initiation of an SGLT2 inhibitor should be made in collaboration with the clinician managing the patient’s diabetes, for those individuals on a complex insulin regimen or with a history of labile blood glucose.

Inform patients taking insulin or an insulin secretagogue (ie, a sulfonylurea or glinide) of the risk of hypoglycemic events when an SGLT2 inhibitor is added for CV benefit, particularly in cases where HbA1c is already well-controlled at baseline. The hypoglycemia risk in these patients could be reduced by discontinuing or weaning the sulfonylurea or glinide or reducing total daily insulin dose by up to 20%. However, dose adjustments should hinge on clinical judgment and be customized to each patient’s needs and requirements.

Coordinate management of complex insulin regimens or “brittle” diabetes with the patient’s diabetes care provider. Following the initiation of SGLT2 inhibitors, patients should self-monitor blood glucose levels closely during the first 3-4 weeks.

Advise patients that SGLT2 inhibitors may lead to a diuretic effect and that administration of SGLT2 inhibitors with loop diuretics has potentially additive natriuretic effects.

Patients should monitor themselves for signs of volume depletion such as orthostatic lightheadedness and, if these arise, should contact their clinician. If these symptoms occur in patients on concomitant loop diuretics who are starting an SGLT2 inhibitor, a reduction in the diuretic dose may be warranted.

In the first few weeks of treatment, it is reasonable to monitor renal function, especially in patients with impaired baseline renal function.

When patients with a history of amputations, severe peripheral neuropathy, severe peripheral artery disease, or active lower-extremity soft tissue ulcers or infections are being prescribed an SGLT2 inhibitor, consider alternatives to canagliflozin.

All patients should undergo regular foot exams in accordance with the American Diabetes Association’s Standards of Medical Care in Diabetes.

Patient monitoring in GLP-1RA therapy

The same strategy used to reduce hypoglycemic events with SGLT2 inhibitors is employed with GLP-1RAs.

Inform patients initiating a GLP-1RA that transient nausea is a relatively common side effect.

Minimization of nausea and vomiting can be achieved by starting with the lowest dose, up-titrating gradually according to the label recommendations, and ceasing up-titration when the nausea becomes uncomfortable, as well as by having the patient consume smaller food portions. A low-fat diet can also be useful.

In patients who have suffered problems with clinically significant gastroparesis, use GLP-1RAs with caution. In cases of treatment suspension, therapy should be reinitiated at the lowest dose, with recurrent nausea and vomiting avoided via gradual up-titration.

Since GLP-1RAs and dipeptidyl peptidase-4 (DPP-4) inhibitors each work through GLP-1 signaling and have not been studied for combined use, do not coadminister these two agents.

Semaglutide has been associated with an increased risk of diabetic retinopathy complications, primarily in patients with a history of proliferative retinopathy. Therefore, regular eye examinations should be administered to these patients.

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