Repatha vs Losartan: Combining the Two (Rationale + Risk)

Two drugs, two jobs

The versus framing suggests a choice. It is not one. High LDL cholesterol and high blood pressure are separate risk factors, and neither drug stands in for the other.

What Repatha does

Evolocumab is a monoclonal antibody that inhibits PCSK9, the protein that otherwise pushes LDL receptors on liver cells toward degradation; blocking it leaves more receptors free to clear LDL cholesterol from the blood [1]. It is injected under the skin at 140 mg every 2 weeks or 420 mg once monthly [1].

The label covers reducing major cardiovascular events in adults at increased risk and lowering LDL-C alongside diet and exercise in hypercholesterolemia and in familial hypercholesterolemia from age 10 [1].

FOURIER randomized 27,564 people with atherosclerotic cardiovascular disease and LDL-C of 70 mg/dL or higher who were already on a statin [4]. At 48 weeks LDL-C fell 59% versus placebo, from a median 92 to 30 mg/dL. The primary composite of cardiovascular death, myocardial infarction, stroke, unstable angina hospitalization or coronary revascularization occurred in 1,344 patients (9.8%) versus 1,563 (11.3%), hazard ratio 0.85 (95% CI 0.79-0.92), over a median 2.2 years [4].

Repatha has no boxed warning [1]. Its only Warning and Precaution is hypersensitivity, including angioedema; the label says to stop treatment and treat if serious symptoms occur [1].

What losartan does

Losartan is an angiotensin II receptor blocker, a class that lowers blood pressure by blocking the angiotensin II type-1 receptor. Its label carries a boxed warning for fetal toxicity and says to discontinue it as soon as pregnancy is detected.

LIFE compared losartan-based with atenolol-based treatment in 9,193 people aged 55 to 80 with high blood pressure and electrocardiographic left ventricular hypertrophy [3]. Blood pressure fell 30.2/16.6 mmHg on losartan and 29.1/16.8 mmHg on atenolol. The primary composite of death, myocardial infarction or stroke occurred at 23.8 versus 27.9 per 1,000 patient-years (relative risk 0.87, 95% CI 0.77-0.98) [3].

RENAAL gave 1,513 people with type 2 diabetes and nephropathy losartan 50 to 100 mg daily or placebo on top of other antihypertensives for a mean 3.4 years. The composite of doubling serum creatinine, end-stage renal disease or death fell 16% (P=0.02), and proteinuria fell 35% [5].

Is there a drug interaction?

The Repatha label has no drug-interactions section [1]. Evolocumab is eliminated by target binding and proteolysis [1].

Losartan is converted to its active metabolite E-3174 by cytochrome P450 enzymes; both CYP2C9 and CYP3A4 are involved in vitro, and clinical data point to CYP2C9 as the main route [2]. The one study in the evidence tested losartan with fluconazole and itraconazole, not with Repatha [2]. In that randomized, double-blind crossover study, 11 healthy volunteers took fluconazole, itraconazole or placebo for four days before a single 50 mg dose of losartan [2]. Fluconazole cut the peak concentration of E-3174 to 30% and its AUC to 47% of control and raised its half-life to 167%. Itraconazole had no significant effect, and blood pressure and heart rate did not change significantly [2].

Do you need both?

That depends on which problems are present. Repatha's cardiovascular indication covers adults at increased risk of major cardiovascular events [1]. Losartan is a blood pressure drug, and in LIFE it reduced a cardiovascular composite compared with atenolol in people with hypertension and left ventricular hypertrophy [3]. Repatha lowers LDL cholesterol and losartan lowers blood pressure, so one does not replace the other.