Should Sodium-Gluarate Transporter (SGLT) inhibitors be discontinued in a diabetic patient with Peripheral Artery Disease (PAD)?

From the Guidelines

SGLT-2 inhibitors should not be stopped in diabetic patients with peripheral vascular disease (PVD) unless there are specific contraindications, as they may offer cardiovascular benefits that could be advantageous for patients with vascular disease, as recommended by the 2024 ESC guidelines for the management of peripheral arterial and aortic diseases 1.

Key Considerations

• The 2024 ESC guidelines recommend the use of SGLT2 inhibitors with proven CV benefit in patients with T2DM and PAAD to reduce CV events, independent of baseline or target HbA1c and concomitant glucose-lowering medication 1.
• Caution is warranted in patients with severe PVD, especially those with critical limb ischemia or active foot ulcers, as there is a small increased risk of lower limb amputations reported with some SGLT-2 inhibitors, particularly canagliflozin 1.
• Regular foot examinations are essential, and patients should be educated about proper foot care and to report any new pain, sores, or infections immediately.
• If a patient develops a diabetic foot ulcer or critical limb ischemia, temporarily discontinuing the SGLT-2 inhibitor may be appropriate until the condition resolves.

Management Recommendations

• Individualize HbA1c targets according to comorbidities, diabetes duration, and life expectancy, as recommended by the 2024 ESC guidelines 1.
• Prioritize the use of glucose-lowering agents with proven CV benefits, followed by agents with proven CV safety over agents without proven CV benefit or safety 1.
• Consider metformin if additional glucose control is needed in patients with T2DM and PAAD, as recommended by the 2024 ESC guidelines 1.

From the FDA Drug Label

5.2 Lower Limb Amputation An increased risk of lower limb amputations associated with INVOKANA use versus placebo was observed in CANVAS (5.9 vs 2.8 events per 1,000 patient-years) and CANVAS-R (7.5 vs 4. 2 events per 1,000 patient-years), two randomized, placebo-controlled trials evaluating adult patients with type 2 diabetes mellitus who had either established cardiovascular disease or were at risk for cardiovascular disease. The risk of lower limb amputations was observed at both the 100 mg and 300 mg once daily dosage regimens The amputation data for CANVAS and CANVAS-R are shown in Tables 3 and 4, respectively [see Adverse Reactions (6. 1)]. Amputations of the toe and midfoot (99 out of 140 patients with amputations receiving INVOKANA in the two trials) were the most frequent; however, amputations involving the leg, below and above the knee, were also observed (41 out of 140 patients with amputations receiving INVOKANA in the two trials). Some patients had multiple amputations, some involving both lower limbs Lower limb infections, gangrene, and diabetic foot ulcers were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy. Counsel patients about the importance of routine preventative foot care Monitor patients receiving INVOKANA for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue INVOKANA if these complications occur.

The SGLT inhibitor should be used with caution in diabetic patients with peripheral vascular disease, as the risk of lower limb amputations is increased in these patients 2.

• The risk of amputation is highest in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy.
• Patients with peripheral vascular disease should be closely monitored for signs and symptoms of infection, new pain or tenderness, sores or ulcers involving the lower limbs.
• Discontinuation of the SGLT inhibitor should be considered if these complications occur.

From the Research

SGLT Inhibitor Use in Diabetic Patients with Peripheral Vascular Disease

• The use of SGLT inhibitors in diabetic patients with peripheral vascular disease is a topic of interest due to the potential increased risk of amputation associated with these medications 3.
• Studies have shown that SGLT2 inhibitors can reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes and cardiovascular risk, but the effect on peripheral vascular disease is less clear 4.
• A review of the current literature suggests that SGLT2 inhibitors may increase the risk of amputation in patients with peripheral artery disease, although the evidence is not conclusive 3.

Risk of Amputation with SGLT Inhibitor Use

• The CANVAS and CANVAS-R trials found that leg and mid-foot amputations occurred about twice as often in patients treated with canagliflozin compared to placebo, leading to a black box warning from the FDA 3.
• However, other studies have suggested that the risk of amputation may be related to the individual drug rather than a class effect of SGLT2 inhibitors 3.
• The association between SGLT2 inhibitors and peripheral vascular disease events, including amputation, requires further study to fully understand the risks and benefits of these medications in patients with diabetes and peripheral vascular disease 4, 3.

Management of Diabetic Patients with Peripheral Vascular Disease

• Intensive therapy targeting glycemia and other modifiable cardiovascular risk factors can help prevent micro- and macrovascular complications, including peripheral vascular disease, in patients with diabetes 5.
• Peripheral vascular intervention (PVI) can improve health status in patients with diabetes and peripheral arterial disease, although the response to PVI may be similar in patients with and without diabetes 6.
• Counseling regarding screening and prevention for peripheral vascular disease may be useful in individuals with diabetes and multiple risk factors 7.

Considerations for SGLT Inhibitor Use

• The decision to stop SGLT inhibitor therapy in a diabetic patient with peripheral vascular disease should be made on a case-by-case basis, taking into account the individual patient's risk factors and medical history 4, 3.
• Healthcare providers should carefully weigh the potential benefits of SGLT2 inhibitors against the potential risks, including the risk of amputation, when making treatment decisions for patients with diabetes and peripheral vascular disease 3.