Mr. Young is a 63-year-old African American man who has been recently diagnosed with lower extremity peripheral artery disease (PAD). He states, "My legs hurt when I walk, and I can hardly make it out to my mailbox."
PMH: Hypertension, diabetes mellitus type 2
Family History: mother and brother with history of diabetes, father died at age 72 of myocardial infarction
Social History: non-smoker, 4 ounces of alcohol per week
aspirin 81 mg PO daily
amlodipine besylate 5 mg PO daily
atorvastatin 40 mg PO daily
cilostazol 100 mg PO two times daily
lisinopril/hydrochlorothiazide 20 mg -- 12.5 mg PO daily
metformin 1000 mg PO twice daily
Vitals: BP: 148/96 mm Hg, P: 74 beats per minute, RR: 14 breaths per minute, Height: 5'6" Weight: 185 lbs
The patient states adherence with appropriate dietary habits.
During the clinician-patient discussion at today's visit, you express concern about the patient's high atherosclerotic cardiovascular disease risk. The patient states he is willing to take non-injectable medications to lower his cardiovascular risk and improve symptoms.
Which one of the following medications would be the best choice to lower this patient's cardiovascular risk?
The correct answer is: B. Empagliflozin 10 mg once daily.
Canagliflozin and empagliflozin, which are SGLT2 inhibitors, are available in oral formulations. In addition to lower blood glucose, patients who take these medications lower their blood pressure and lose weight. This patient may benefit from SGLT2 inhibitor therapy, since he is overweight, his blood pressure is not well-controlled on three blood pressure medications, and his A1C is elevated.
Option B is the best choice for this patient. In the EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial, empagliflozin, an SGLT2 inhibitor, demonstrated superiority when compared to placebo in reducing the composite endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke in patients with diabetes treated with standard care and existing cardiovascular disease (10.5% vs. 12.1%; HR 0.86, 95% CI 0.74-.99; p < 0.001 for noninferiority; p = 0.04 for superiority). This was primarily driven by a reduction in cardiovascular death (3.7% vs. 5.9%; HR 0.62 95% 0.49-0.77; p < 0.001). The mean age of patients enrolled was 63 years, and the mean A1C was 8.1% at baseline. There were more genital infections in patients receiving empagliflozin, but the incidence of other adverse events was similar between the study arms. In December 2016, the FDA approved empagliflozin to reduce the risk of cardiovascular death in adult patients with type 2 diabetes and established cardiovascular disease.
Option A is not the best choice for this patient. In the CANVAS Program (CANagliflozin cardioVascular Assessment Study), canagliflozin, an SGLT2 inhibitor, demonstrated superiority when compared to placebo in reducing the composite endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke in patients with diabetes and high cardiovascular risk (26.9 vs. 31.5 participants per 1000 patient-years; HR 0.86, 95% CI 0.75-0.97; p < 0.001 for noninferiority; p = 0.02 for superiority). There was no difference in the rate of cardiovascular death (HR 0.87, 0.72-1.06). The mean age of patients enrolled was 63 years, and the mean A1C was 8.2% at baseline. The CANVAS Program also showed a significantly increased risk for lower limb amputation (6.3 vs. 3.4 participants per 1000 patient-years; HR 1.97, 95% CI 1.41-2.75), which prompted the FDA to issue a black box warning for lower limb amputation in May 2017. At this time, canagliflozin does not have an FDA-approved indication for reducing cardiovascular events in patients with diabetes. Using canagliflozin for a patient like Mr. Young, who has comorbid PAD and diabetes, could be a safety issue.
Answer C is not the best choice for this patient. Although the combination of moderate-intensity statin and ezetimibe reduced cardiovascular events in patients post-acute coronary syndrome in IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial), the combination was not studied in patients with PAD not associated with ACS.
Answer D is not the best choice for this patient. Liraglutide, a GLP-1 receptor agonist, demonstrated superiority when compared to placebo in reducing the composite endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke in patients with high cardiovascular risk in the LEADER (Liraglutide Effect and Actions in Diabetes: Evaluation of Cardiovascular Outcome Results) trial (13% vs. 14.9%; HR 0.87, 95% CI 0.78-0.97; p < 0.001 for noninferiority; p = 0.001 for superiority). The mean age of patients enrolled was 60 years, and the mean A1C was 7.7% at baseline. Liraglutide may promote weight loss and lowered blood glucose. Liraglutide now has an FDA-approved indication for reducing the risk of cardiovascular events in patients with type 2 diabetes and established cardiovascular disease. Liraglutide is only available as an injection, and Mr. Young stated that he does not want to take injectable medications.
Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-97.
US Food and Drug Administration. FDA Drug Safety Communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). Accessed Sept 11 2017. https://www.fda.gov/Drugs/DrugSafety/ucm557507.htm.
Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311-22.
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.
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.
Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017;69:1465-1508.