Combination therapy as a treatment strategy has been adopted in patients with hypertension with good measure for quite some time. When the dose of a single drug (monotherapy) is increased, emergence of adverse effects, coupled with the risk of discontinuation of treatment, is a major concern. Also, high dose does not automatically correlate with superior efficacy. Combining drugs of different classes or different mechanisms of action therefore may be a more pragmatic and effective approach to maximize efficacy, while minimising the side effects at the same time.

A study from South Korea examined the effect of combination therapy in lipid lowering in patients with atherosclerotic cardiovascular disease (ASCVD).¹ Results from the recently published RACING (RAndomized Comparison of efficacy and safety of lipid-lowerING with statin monotherapy versus statin/ezetimibe combination for high-risk cardiovascular diseases) trial show that the combination therapy was better than monotherapy with high-intensity statin in reducing LDL cholesterol and acute cardiovascular events.

The study designed as a randomised, open-label, non-inferiority trial examined 3780 adults, aged 64 years (mean), with ASCVD from 26 clinical centers in South Korea. The study participants were recruited from February 2017 to December 2018 and were followed-up for a median period of 3 years. Men comprised 75% of the study population. At baseline, 40% had a history of previous MI, while 37% had diabetes. The combination of moderate-intensity statin with ezetimibe (rosuvastatin 10 mg + ezetimibe 10 mg) was compared against high-intensity statin monotherapy (rosuvastatin 20 mg).

Results published in The Lancet showed that the primary endpoint, which was a composite of CV death, major CV events or nonfatal stroke (with a non-inferiority margin of 2.0%), occurred in nearly 10% (n = 186) of the patients in the high-intensity statin monotherapy, whereas in the combination therapy group, 172 patients (9.1%) met the primary end point for an absolute difference of –0.78 percentage points.

At one year, 73% patients in the combination therapy group had LDL cholesterol levels below 70 mg/dL. At 2 years, 75% patients had LDL-C less than 70 and at 3 years, 72% had LDL cholesterol levels below 70 mg/dL. The corresponding numbers in the high-intensity statin monotherapy group were 55%, 60% and 58% (absolute differences were 17.5 percentage points at 1 year, 14.9 percentage points at 2 years and 14.8 percentage points at 3 years). There were fewer discontinuations (~5%) and 8% needed dose reduction in the study group due to intolerance.

Statins are very frequently prescribed as lipid-lowering therapy. Statin-induced muscle symptoms are a major reason for treatment discontinuation. This study has demonstrated that a combination of moderate-intensity statin with ezetimibe achieved greater reduction in LDL-cholesterol compared to high-intensity statin monotherapy. At 3 years, a larger number of patients treated with the combination consistently showed LDL-C levels below 70 mg/dL compared to those who received monotherapy. It was also effective in reducing acute cardiovascular events. Hence, combination therapy can be an effective alternative to high-dose statin monotherapy, particularly in statin intolerant patients or those at high risk of statin-associated adverse effects.

Reference

1. Byeong-Keuk Kim, et al; RACING investigators. Long-term efficacy and safety of moderate-intensity statin with ezetimibe combination therapy versus high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease (RACING): a randomised, open-label, non-inferiority trial. Lancet. 2022 Jul 18;S0140-6736(22)00916-3. doi: 10.1016/S0140-6736(22)00916-3.