62 year-old female presents for follow-up in clinic.
PMH: HTN, type 2 diabetes, ischemic stroke (3 months ago)
Medications:
aspirin 81 mg PO daily
atorvastatin 40 mg PO daily
lisinopril 40 mg PO daily
metformin 1000 mg PO twice daily
Vitals: BP: 143/88 mm Hg, P: 68 beats per minute, BMI 32 kg/m2
Labs: eGFR 65 mL/min/1.73m2, liver function normal, A1C: 8.1%
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 she is willing to take additional medications to lower her risk.
According to recent clinical trial evidence, which ONE of the following medications has been shown to reduce this patient's risk of stroke?
Show Answer
The correct answer is: D. Pioglitazone.
Option D, pioglitazone, is the correct choice. In the PROactive trial (Efficacy of Pioglitazone on Macrovascular Outcomes in Patients With Type 2 Diabetes), pioglitazone was compared to placebo in patients with type 2 diabetes and cardiovascular disease. The primary endpoint (composite of all-cause mortality, nonfatal MI, acute coronary syndrome, coronary or peripheral revascularization, amputation or stoke) was not significantly reduced (10% relative risk reduction, HR 0.90, 0.80-1.02, p = 0.095). The primary endpoint included peripheral revascularizations and amputations, which occurred more often in the pioglitazone group. The second primary outcome (composite all-cause mortality, non-fatal MI or stroke) was reduced (16% RRR, HR 0.84, 0.72-0.98, p = 0.027). Pioglitazone reduced the risk of fatal or non-fatal stroke in patients who previously had a stroke (HR 0.53, 95% CI 0.34-0.85; p = 0.0085). In IRIS (Insulin Resistance Intervention After Stroke Trial), patients with a recent transient ischemic attack or stroke (<6 months) and insulin resistance were randomized to either pioglitazone or placebo. Although patients with a diagnosis of diabetes were excluded, some of the patients in the IRIS trial had A1C baseline ≥6%. Follow-up was 4.8 years. Pioglitazone lowered the primary endpoint, risk of ischemic stroke or MI (HR 0.76, 95% CI 0.62-0.93; p = 0.007); however, pioglitazone did not lower the secondary endpoint of stroke (HR 0.82, 0.61-1.10, p = 0.19). The potential benefits of pioglitazone should be weighed against the potential adverse effects in each individual patient. The incidence of heart failure was higher in patients who received pioglitazone compared to placebo in the PROactive trial, but not in the IRIS trial. In the IRIS trial, pioglitazone was associated with a higher risk of weight gain exceeding 4.5 kg (52.2% vs. 33.7%, p < 0.001), edema (35.6% vs. 24.9%, p < 0.001), and bone fracture requiring surgery or hospitalization (5.1% versus 3.2%, p = 0.003).
Options A, B, and C are not correct. Stroke was not the primary endpoint in the CANVAS (CANagliflozin cardioVascular Assessment Study), EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), and LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trials. Canagliflozin, empagliflozin and liraglutide did not reduce the risk for stroke when compared to placebo in the subgroup analysis in the CANVAS, EMPA-REG and LEADER trials respectively.
References
Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279-89.
Wilcox R, Bousser MG, Betteridge DJ, et al. Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04). Stroke 2007;38:865-73.
Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 2016;374:1321-31.
Young LH, Viscoli CM, Curtis JP, et al. Cardiac outcomes after ischemic stroke or transient ischemic attack: effects of pioglitazone in patients with insulin resistance without diabetes mellitus. Circulation 2017;135:1882-93.
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.
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.
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