Fixed dose combination of Rosuvastatin plus ezetimibe for lipid management in clinical practice – The road less travelled!

INTRODUCTION Atherosclerotic cardiovascular (ASCVD) diseases are the leading causes of death worldwide. Meta-analyses of statin trials have convincingly shown that low-density lipoprotein cholesterol (LDL-C) lowering unequivocally reduces cardiovascular (CV) events (21% per mmol of LDL-C reduction) irrespective of age, sex, and presence of prior vascular disease.[1,2] More intensive statin therapy leads to further 0.5 mmol LDL-C reduction and 15% additional CV event reduction vis-à-vis less intensive regimens.[3] Consequently, both national and international guidelines recommend statin therapy as the first-line lipid-lowering agent.[4–6] However, real-world studies have shown poor uptake of LDL-C lowering in clinical practice and consequent failure to achieve LDL-C goals as prescribed by guidelines in the management of patients with ASCVD [Figure 1]. The DA VINCI study was a large observational cross-sectional study across 18 European countries and revealed that only 56% achieved their LDL-C goal (<70 mg/dl) as per 2016 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines, while only 33% did so as per 2019 ESC/EAS guidelines.[7] More recently, the SANTORINI study across 14 European countries also revealed that 22% patients were not taking any lipid-lowering drugs and only 20% patients achieved LDL-C goals as per the 2019 ESC/EAS guidelines.[8] These data mirror values from previous studies like EUROASPIRE IV, DYSIS, DYSIS II, and CEPHEUS [Figure 2].[9] These data are from the best of the European centers where management processes are streamlined and health insurance is universal.Figure 1: Contemporary low-density lipoprotein cholesterol (LDL-C) goals in secondary prevention of atherosclerotic cardiovascular (ASCVD) as prescribed by Global guidelines. *The European Society of Cardiology/European Atherosclerosis Society and Cardiological Society of India guidelines recommend LDL-C goal is <40 mg/dl for recurrent acute coronary syndrome. In 2020, the LAI guidelines introduced Extreme Risk Category and advocated an LDL-C goal of <30 mg/dl for selected ASCVD patients with additional features such a polyvascular disease, recurrent ACS, Homozygous Familial Hypercholesterolemia and Diabetes with target organ damage (Extreme risk category B). ACC/AHA: American College of Cardiology/American Heart Association, ESC/EAS: European Society of Cardiology/European Atherosclerosis Society, LAI: Lipid Association of India, CSI: Cardiological Society of IndiaFigure 2: Rates of low-density lipoprotein cholesterol (LDL-C) target attainment in atherosclerotic cardiovascular patients in large observational studies across the globe. In most of these studies, the LDL-C target utilized was <70 mg/dl except for SANTORINI and DA VINCI ESC/EAS 2019, where the target was <55 mg/dl. ACS: Acute coronary syndrome, CHD: Stable coronary heart disease, ESC/EAS: European Society of Cardiology/European Atherosclerosis SocietyOn the contrary, global guidelines have gradually become more aggressive in recommending stricter LDL-C goals over the decades. This has necessitated the use of a combination of lipid-lowering therapy in practice for achieving these targets. Data accumulated from large RCTs over the past 4 decades have revealed that LDL-C lowering is more or less predictable with the commonly used agents either as monotherapy or combination therapy [Figure 3].[4]Figure 3: Low-density lipoprotein cholesterol (LDL-C)-lowering efficacy of the contemporary lipid-lowering therapy (LLT) armamentarium. Based on the baseline LDL-C values and the expected reduction needed to reach the target, one can plan the initial LLT in primary prevention. In secondary prevention, it is usually advised to start with high-intensity statins at least. PCSK-9i: Proprotein Convertase Subtilisin/Kexin type 9 inhibitor, LLT: Lipid-lowering therapyEzetimibe - the drug Ezetimibe is an oral Niemann Pick C-1-like-1 protein which inhibits cholesterol absorption from the gastrointestinal tract. When used as monotherapy, it lowers LDL-C by around 20% while in combination with Statin therapy, it offers an additional 15% LDL-C reduction.[10,11] In the IMPROVE-IT study, the addition of ezetimibe to statin therapy in patients with a recent acute coronary syndrome (ACS) led to 7% reduction in major adverse cardiovascular events (MACE) at 7 years.[12] It is worthwhile to note here that doubling the statin dose offers only 6%–7% extra LDL-C lowering.[13] Because of the lack of muscle side effects, neutral effect on glycemic parameters, and good overall safety profile, it has emerged as an ideal combination agent to statin monotherapy. Consensus is emerging on the use of the upfront use of high-intensity statin and ezetimibe combination universally in ACS patients.[14] HILL study - exploring the combination lipid lowering therapy In this issue of the Journal, Nagarajan et al. present data from the HILL-India study on rosuvastatin and ezetimibe fixed-dose combination.[15] In this retrospective, observational, and pan-India registry, the authors recruited >1400 patients with uncontrolled dyslipidemia despite statin therapy. Their primary endpoint was LDL-C reduction. The criteria for uncontrolled dyslipidemia used a high/very high-risk category patient in the study (>70 mg/dl) are quite liberal, going beyond the ESC/EAS (<55 mg/dl) and Lipid Association of India (LAI) guidelines (<50 mg/dl).[4–6] The study population was a mixed bag of primary and secondary prevention, with the former dominating (around 90%). But even in the primary prevention subset, the prevalence of diabetes or hypertension was high (roughly 50%). But despite such a high-risk population, the LDL-C levels were around 181 mg/dl at baseline on statin therapy, indicating both physician inertia and poor adherence. A fixed dose combination (FDC) of Rosuvastatin plus ezetimibe in the study reduced LDL-C by 55% with a good compliance rate of 72%. These effects were complemented by additional lowering of triglyceride (31%), total cholesterol (30%), and elevation of high-density lipoprotein cholesterol (HDL-C) (48%). The benefits were spread equally across all statin dose subgroups at baseline. More than 95% patients were able to achieve the LDL-C targets. The large sample size, multicenter design, and enrollment of high-risk patients are positive aspects of the study. Observational design, retrospective nature, and the shorter duration of follow-up represent the flip side. The addition of CV outcome data and lifestyle data would have enhanced the quality of the manuscript. The adverse outcome data could have been characterized better rather than simply stating a muscular disorder. The good adherence rates with the FDC and HDL-C elevation are reassuring, as was the lowering of liver enzymes with the drug. CONCLUSION In summary, the study strongly supports the use of rosuvastatin + ezetimibe FDC as an effective, practical, and tolerable therapy for Indian patients with uncontrolled dyslipidemia, but long-term randomized trials are still needed to confirm CV outcome benefits. In this light, the recently published data from the SWEDEHEART registry are notable.[16] In the study, early use of ezetimibe in addition to statin therapy (<12 weeks from discharge) in >35,000 patients with a diagnosis of myocardial infarction led to a significant reduction of MACE compared to no ezetimibe or late initiation of ezetimibe. The LAI and Cardiological Society of India guidelines already recommend upfront high-intensity Statin plus ezetimibe combination in all ACS patients.[4,17] The availability of an FDC of rosuvastatin and ezetimibe in all strengths (10/10, 20/10, and 40/10) in our country has boosted the physician’s armamentarium. While the 10 mg/10 mg and 20 mg/10 mg FDCs are ideally suited for stable ASCVD subjects, the 40/10 FDC is ideal in ACS patients for early attainment of stringent LDL-C targets laid down by the guidelines. Ethical approval Not needed as it is an invited editorial. Authors’ contributions Akshyaya Pradhan and Abhishek Singh conceived the manuscript. Akshyaya Pradhan did the literature search. Abhishek Singh and Alok Kumar Singh prepared the draft and AP critically reviewed it.