We bring to you a summary of the ACC 2020 decision pathway which provides a practical guide to CV specialists for the initiation and monitoring of SGLT2 inhibitors and GLP-1RAs with the goal of reducing CV risk.

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Cardiovascular (CV) disease remains the leading cause of morbidity and mortality in patients with type 2 diabetes (T2D). Development of therapeutic approaches to improve CV outcomes in this group of patients is a major priority. In order to optimise patient care in patients with T2D, the CV specialist should address the following three key areas:

• Screen for T2D in patients with or at high risk of CV disease
• Aggressively treat CV risk factors
• Incorporate newer glucose-lowering agents with evidence for improving CV outcomes into routine practice.

Recent evidence suggests that sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) can directly improve CV outcomes. Herewith, we summarise the key recommendation from the decision pathway which support the use of specific SGLT2 inhibitors and GLP-1RAs to reduce risk in patients with T2D and established CV disease.

SGLT2 Inhibitors and GLP-1RAs - Considerations for optimal therapy initiation and treatment individualisation

In patients with T2D, clinicians might consider initiating SGLT2 Inhibitors and GLP-1RAs in one of the following situations:

• In a patient with T2D and atherosclerotic cardiovascular disease (ASCVD) - SGLT2 inhibitor or GLP-1RA
• At the time of diagnosis of clinical ASCVD (SGLT2 inhibitor or GLP-1RA), diabetic kidney disease (DKD), and/or heart failure (HF) (SGLT2 inhibitor) in a patient with T2D on a drug regimen that does not include an SGLT2 inhibitor or GLP-1RA with CV benefit
• At the time of diagnosis of T2D in a patient with clinical ASCVD (SGLT2 inhibitor or GLP-1RA), DKD, and/or HF (SGLT2 inhibitor)
• At hospital discharge (with close outpatient follow-up) after admission for an ASCVD (SGLT2 inhibitor or GLP-1RA) or HF (SGLT2 inhibitor) event
• In a patient with T2D and diabetic kidney disease (SGLT2 inhibitor, alternatively GLP-1RA for eGFR <30 ml/min/1.73 m²)
• In patients determined to be at high risk of ASCVD‖ (SGLT2 inhibitor or GLP-1RA) or HF (SGLT2 inhibitor)

SGLT2 inhibitor vs GLP-1RA – Which one to pick?

SGLT2 inhibitor and GLP-1RA, both have non-glycaemic benefits in systolic blood pressure and weight. Both possess a low risk of hypoglycaemia even when used with metformin and other oral glucose-lowering medications (except for insulin secretagogues). However, certain factors, especially safety factors, can favour one agent from the other and help clinicians make the right choice. Following are the key aspects to consider:

1. The use of SGLT2 inhibitors is associated with an increased risk of genital mycotic infections, polyuria, and potential volume depletion in the context of hyperglycaemia. It is recommended to use clinical judgement when initiating an SGLT2 inhibitor in a patient who will be starting or up-titrating an angiotensin-converting enzyme (ACE) inhibitor or angiotensin reception blocker (ARB) if the patient’s renal function is impaired.
2. GLP-1RAs are associated with transient nausea and vomiting, especially when initiating therapy or up-titrating doses.
3. Differences in the route of administration may also influence the choice of treatment. SGLT2 inhibitors are given orally, while GLP-1RA’s are given via subcutaneous or oral route. Injectable GLP-1RAs are also given with a small needle and pen device to ease administration and patient acceptance.
4. Due to the risk of amputation, caution should be exercised when initiating a SGLT2 inhibitor in patients with a history of peripheral artery disease, severe peripheral neuropathy, lower extremity diabetic ulcers, or soft tissue infections.
5. For patients with active proliferative retinopathy (especially if HbA1c is high and significant rapid reduction is expected), consider a GLP-1RA alternative to semaglutide SQ.
6. Caution is suggested when using GLP-1RAs in patients with active gallbladder disease or a history of pancreatitis.

Drug initiation and monitoring in patients starting an SGLT2 Inhibitor or GLP-1RA with demonstrated CV benefit

The following points should be considered for drug initiation and monitoring in patients starting a SGLT2 inhibitor with demonstrated CV benefit:

1. If HbA1c is well-controlled at baseline, or known history of frequent hypoglycaemic events, wean or stop sulfonylurea and consider reducing total daily insulin dose by ∼20% when starting therapy.
2. Patients should be educated regarding potential genital mycotic infections and importance of genital hygiene.
3. Hypovolemia should be avoided. Diuretic dose should be reduced in patients with symptoms of dehydration. Patients should be educated regarding symptoms of dehydration (lightheadedness, orthostasis, weakness) and to hold medication if low oral intake.
4. Patients should be instructed to closely monitor glucose at home for the first 4 weeks of therapy (especially if on insulin, sulfonylurea, and/or glinides). Discontinue any sulfonylurea or glinide. For patients taking insulin, modestly reduce total daily insulin dose (by up to 20%).
5. Patients should be educated regarding symptoms of diabetic ketoacidosis (nausea, vomiting, abdominal pain, weakness). Patients should be aware that diabetic ketoacidosis can occur even if blood glucose readings are in the 150–250 mg/dL range. If patient experiences diabetic ketoacidosis-like symptoms, he/she should be instructed to seek urgent medical attention.
6. Patients should be educated regarding foot care, especially when suffering from diabetic neuropathy. Patients should be instructed to report any foot wounds immediately.

The following points should be considered for drug initiation and monitoring in patients starting a GLP-1RA with demonstrated CV benefit:

1. If HbA1c is well-controlled at baseline or known history of frequent hypoglycaemic events, wean or stop sulfonylurea and consider reducing total daily insulin dose by ∼20% when starting therapy.
2. Patients should be instructed to closely monitor glucose at home for the first 4 weeks of therapy. Discontinue any sulfonylurea or glinide. In patients taking insulin, it is suggested to modestly reduce total daily insulin dose (by up to 20%).
3. Discontinue DPP-4 inhibitor before starting.
4. 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.
5. Advise patients to undergo appropriate, guideline-recommended eye examinations before starting therapy if not done within the last 12 months. The risk of diabetic retinopathy complications (for dulaglutide or injectable semaglutide) should be discussed with the patients.
6. GLP-1RA should be avoided in patients with diabetic gastroparesis or active gallbladder disease.

Metformin before initiating an SGLT2 Inhibitor or a GLP-1RA

There is no evidence to suggest that the cardioprotective effects differ with regards to whether patients were taking metformin at baseline. The panel recommends that most patients with T2D and CV disease should be continued to be treated with metformin along with an SGLT2 inhibitor and/or GLP-1RA with proven CV benefit.

SGLT2 Inhibitor and/or a GLP-1RA for CV protection in patients with well-controlled HbA1c

The panel suggests that decisions regarding initiation of an SGLT2 inhibitor (for CV or kidney risk reduction) or a GLP-1RA (for CV risk reduction) should not depend on HbA1c levels. However, if an SGLT2 or GLP-1RA is added to the regimen of a patient with well-controlled T2D, dose adjustment of background medications may be required to avoid hypoglycaemia in the context of insulin, sulfonylurea, or glinide therapy, particularly in patients at or near glycaemic goals.

Approach for optimising the use of SGLT2 Inhibitor and GLP-1RA

The panel recommends “consultative” approach and “team” approach to optimise the use of SGLT2 Inhibitor and GLP-1RA in patients with T2D and CV disease. With both approaches, the key elements are patient-centered care, shared decision making, and integration across disciplines and patient care roles.

This article was originally published on October 19, 2020.