Medications:
aspirin 81 mg PO daily
cilostazol 100 mg PO twice daily
lisinopril/hydrochlorothiazide 20 mg/12.5 mg 2 tablets PO daily
metformin 1000 mg PO twice daily
rosuvastatin 20 mg PO daily
Vitals: BP: 142/96 mm Hg, P: 68 beats per minute, BMI 28.7 kg/m2
Labs: Kidney/liver function normal, A1C: 8.3%
Lipids (mg/dL): Total Cholesterol: 148, Triglycerides: 180, HDL-C: 42, LDL-C: 70
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 additional oral medications to lower his risk.
Which ONE of the following medications will be the best addition to the patient's current regimen to lower his patient's cardiovascular risk and blood glucose?
Show Answer
The correct answer is: B. Empagliflozin.
The SGLT2 inhibitors canagliflozin and empagliflozin are both available in oral formulations. SGLT2 inhibitors lower blood glucose and may lower blood pressure and promote weight loss. An SGLT2 inhibitor may be beneficial for this patient, since he is overweight, his blood pressure is not well-controlled and his A1C is elevated. Clinical trial results may help discern which SGLT2 inhibitor is best suited for this patient.
Option B is the best choice for this patient. In the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), empagliflozin 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 0.74-0.99; 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). Empagliflozin has an FDA approved indication to reduce the risk of cardiovascular death in adult patients with type 2 diabetes and established cardiovascular disease. In a recent subgroup analysis comparing patients with and without PAD at baseline in the EMPA-REG OUTCOME trial, empagliflozin reduced mortality, heart failure hospitalizations and progression of renal disease with no increase in lower limb amputation risk in patients with PAD. The number needed to treat calculation showed that 29 patients with type 2 diabetes and PAD over 3.1 years to prevent one cardiovascular death. In a recent post-hoc analysis of the EMPA-REG OUTCOME trial, empagliflozin was not associated with an increased risk of lower leg amputations compared with placebo.
Option A is not the best choice for this patient. In the CANVAS (CANagliflozin cardioVascular Assessment Study) Program, canagliflozin 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 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. This patient has PAD, so using canagliflozin may not be the best SGLT2 inhibitor for him. If canagliflozin is prescribed, the patient should be monitored for infections or ulcers of the lower limbs, and canagliflozin should be discontinued if these occur. At the time this case was written, canagliflozin does not have an FDA-approved indication for reducing cardiovascular events in patients with diabetes.
Option C is not the best choice for this patient. Although clinical trial evidence supports using liraglutide in this patient, this patient prefers to only take oral medication, and liraglutide is only available as a daily injection. 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 Action 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 non-inferiority; p = 0.001 for superiority). Liraglutide now has a FDA-approved indication for reducing the risk of cardiovascular events in patients with type 2 diabetes and established cardiovascular disease.
Answer D is not the best choice for this patient. SAVOR-TIMI 53 (Does Saxagliptin Reduce the Risk of Cardiovascular Events When Used Alone or Added to Other Diabetes Medications) demonstrated non-inferiority for the primary outcome of CVD death, MI or stroke with saxagliptin compared placebo (HR 1.00, 95% CI 0.89-1.12; p = 0.99). In addition, more patients in the saxagliptin arm than in the placebo arm were hospitalized for heart failure (HR 1.27, 95% CI 1.07-1.51; p = 0.007).
References
U.S. Food & Drug Administration. FDA Drug Safety Communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). Retrieved September 11, 2017. https://www.fda.gov/Drugs/DrugSafety/ucm557507.htm.
Inzucchi SE, Iliev H, Pfarr E, Zinman B. Empagliflozin and assessment of lower-limb amputations in the EMPA-REG OUTCOME trial. Diabets Care 2018;41:e4-5.
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, Parkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644-57.
Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317-26.
Verma S, Mazer CD, Al-Omran M, et al. Cardiovascular outcomes and safety of empagliflozin in patients with type 2 diabetes mellitus and peripheral artery disease: a subanalysis of EMPA-REG OUTCOME. Circulation 2018;137:405-7.
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: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol 2017;69:e71-126.
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