In August 2020, the U.S. Food and Drug Administration (FDA) removed the boxed warning regarding lower limb amputations from the prescribing information for canagliflozin. Although the risk of amputation is increased with canagliflozin, the risk is lower than previously reported, particularly with appropriate monitoring. In the updated prescribing information, the FDA recommends that the clinician consider patient factors that may predispose the patient to the need for amputations (e.g., history of prior amputation, peripheral vascular disease, neuropathy, foot ulcers). Patients should be taught to report signs and symptoms of infections, new pain or tenderness, or sores or ulcers on the lower limbs; canagliflozin should be discontinued if these occur.
CC is a 67-year-old Caucasian male with a past medical history of peripheral artery disease (PAD), hypertension, diabetes, and chronic kidney disease (CKD) (CrCl 39 mL/min) who presents to the clinic for his annual wellness check. He is asymptomatic and adherent to a heart healthy diet and exercise.
Height: 69 inches; Weight: 223 pounds; Blood pressure 128/78; Pulse: 60; BMI: 32 kg/m2
Past medical history: hypertension (15 years), type 2 diabetes (12 years), lower extremity PAD (2 years ago: atherectomy and angioplasty of right posterior tibial and peroneal arteries, 1 year ago – angioplasty of left distal anterior artery, unsuccessful attempt at crossing severe stenosis at tortuous segment of distal posterior tibial artery at ankle; 1 year ago: angioplasty of left anterior tibial artery and mid-posterior tibial artery; last month, ankle-brachial index: right 0.95; left: 1.44; nonhealing wound on bottom of left foot x 2.5 years)
Family history: mother – diabetes; dad – diabetes
Social history: past smoker (quit 5 years ago)
Medications: lisinopril/HCTZ 20/12.5 mg PO daily, atorvastatin 20 mg PO daily, metformin 1000 mg PO bid, aspirin 81 mg PO daily, amlodipine 10 mg PO daily
Today's lipid panel: total cholesterol 175 mg/dL, HDL-C 60 mg/dL, triglycerides 140 mg/dL, LDL-C 87 mg/dL
A1c: 7.1%, UACR 45 mg/g
The correct answer is: C. Initiate liraglutide
This patient has ASCVD and CKD. According to the 2020 Standards of Medical Care in Diabetes ADA guidelines, this patient should receive either a SGLT-2 inhibitor or GLP-1RA without regard to baseline A1c or the patient's A1c target.1 If CKD predominates, a SGLT-2 inhibitor, with evidence of decreasing CKD progression, is preferred if estimated glomerular filtration rate (eGFR) is adequate.1 If a SGLT-2 inhibitor is contraindicated, not tolerated, or eGFR is not adequate based on product labeling, then a GLP-1 RA with proven ASCVD risk reduction is recommended.1 This patient has established ASCVD (PAD), type 2 diabetes, and his eGFR is 39 mL/min/1.73 m2. Canagliflozin is the only SGLT-2 inhibitor with an approved indication for use in patients with eGFR <45 mL/min/1.73m2 (specifically eGFR 30 to <45 mL/min/1.73 m2 with albuminuria >300 mg/day; urine albumin-to-creatinine ratio (UACR) in mg/g is approximately equal to albuminuria in mg/day). However, canagliflozin has a black box warning about the increased risk of amputations in patients with PAD.2 As proven by the LEADER trial, liraglutide has shown benefit regardless of blood sugar levels to reduce the risk of ASCVD events in patients with CKD and type 2 diabetes.3 It is safe to use GLP-1RAs in patients with an eGFR as low as 30 mL/min/1.73m2.4 Of the answer choices given, liraglutide is the preferred treatment for this patient.
Option A is incorrect. Even though this patient is taking metformin and his A1c is 7.1%, this patient requires additional therapy. According to the 2020 Standards of Medical Care in Diabetes ADA guidelines, this patient should receive either a SGLT-2 inhibitor or GLP-1RA without regard to baseline A1c or the patient's A1c target.1 If CKD predominates (specifically eGFR 30-60 mL/min/1.73 m2 or UACR >30 mg/g), a SGLT-2 inhibitor, with evidence of decreasing CKD progression, is preferred if eGFR is adequate.1 If a SGLT-2 inhibitor is contraindicated, not tolerated, or eGFR is not adequate based on product labeling, then a GLP-1 RA with proven ASCVD risk reduction is recommended.1
Option B is not the best option for this patient. Canagliflozin is the only SGLT-2 inhibitor with an approved indication for use in patients with eGFR <45 mL/min/1.73m2; however, canagliflozin has a black box warning about lower limb amputation risk.2 There was an increased risk of lower limb amputations associated with canagliflozin use when compared to placebo in the CANVAS trial (5.9 versus 2.8 events per 1000 patient-years) and CANVAS-R (7.5 versus 4.2 events per 1000 patient-years).5 Amputations of the toe and midfoot were most frequent; however, amputations of the leg were also observed.5 Before initiating canagliflozin, the clinician should consider factors (eg, history of prior amputation, peripheral vascular disease, neuropathy, diabetic foot ulcers), which may increase the risk of amputations.2 In addition, patients taking canagliflozin should be monitored for infections, new pain or tenderness, sores or ulcers of the lower limbs; and canagliflozin should be discontinued if these occur.2 This patient is not a good candidate for canagliflozin therapy, since he has confirmed PAD, with a non-healing wound.
Option D is not correct. According the ELIXA trial, lixisenatide has no proven ASCVD benefit.6
- American Diabetes Association. 10. Cardiovascular disease and risk management: standards of medical care in diabetes—2020. Diabetes Care 2020;43:S111-S134.
- Prescribing information for canagliflozin
(FDA website). 2020. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/204042s036lbl.pdf. Accessed 02/12/2020.
- Marso S, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311-22.
- Prescribing information for liraglutide
(FDA website). 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022341s031lbl.pdf. Accessed 02/12/2020.
- 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.
- Pfeffer MA, Clagget B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;373:2247-57.