European Journal of Cardiovascular Medicine

Dyslipidemia is becoming more common in India. According to recent estimates from the Indian Council of Medical Research–India Diabetes (ICMR-INDIAB), the reported prevalence was 81.2% (95% confidence interval [CI]:77.9–84.5; 14,895 of 18,492) [1]. In India, dyslipidemia predominantly manifests as borderline elevated low-density lipoprotein cholesterol (LDL-C) and triglycerides, accompanied by diminished high-density lipoprotein cholesterol (HDL-C) values [2]. Dyslipidemia is associated with several comorbidities and serves as a substantial independent risk factor for coronary artery disease (CAD). It plays a crucial role in the progression of atherosclerosis and related cardiovascular events. Dyslipidemia is strongly linked to the pathophysiology of cardiovascular diseases (CVDs) [3]. It is also one of the main risk factors for acute coronary syndrome (ACS) [4]. Lipoprotein abnormalities, which include increased triglyceride levels and small dense LDL particles, decreased HDL-C levels, are characteristics of diabetic dyslipidemia [5]. Non-HDL-C is a co-primary target for lipid-lowering therapy that is equally significant as LDL-C (a position endorsed by LAI since 2016) as per the Lipid Association of India [6]. Nonetheless, it is crucial to note that despite substantial data endorsing the predictive significance of non-HDL-C (and its practical applicability for testing in non-fasting states), it has not achieved widespread acceptance in clinical practice [7]. To reduce the possibility of CVDs, lowering the LDL-C level to <50 mg/dL is safe. Lower LDL-C levels are linked to improved outcomes in those with a high risk of ASCVD [8]. In Indian settings, the target LDL-C levels for high-risk and very high-risk patients are <70 mg/dL and <50 mg/dL, respectively. These levels are in line with the European standards' conservative cut-offs of <70 mg/dL and <55 mg/dL [3]. Studies have indicated that Asians are more likely to develop lipid abnormalities than people from other regions due to differences in the dyslipidemia pattern [3]. Many developed countries have established their own sets of guidelines for dyslipidemia management and provide clinical advice for appropriate healthcare, particularly for addressing the major health effects of dyslipidemia. Currently, the American Heart Association/ American College of Cardiology (AHA/ACC), and the European Society of Cardiology/European Atherosclerosis Society guidelines are the most commonly used. These recommendations, however, are suited to Western populations and do not take into account the geographic distribution, ethnicity, genetic makeup, and environment of other population groups. Therefore, there is a requirement for guidelines tailored specifically for managing dyslipidemia in India [3]. The usual course of treatment is to take statins to lower LDL-C levels; they also lower the morbidity and mortality associated with CVDs. Statins are generally safe, yet there have been reports of intolerance [5]. In India, statin intolerance (SI) is reported in the range of 0%–20% in clinical practice. Treatment options in patients with SI include lowering the statin dose, stopping statin and restarting at a lower dose, using an alternative statin, using non-statin drugs and lifestyle modifications [9]. Bempedoic acid is a once-daily, oral, first-in-class small molecule that competitively inhibits an important enzyme, adenosine triphosphate (ATP) –citrate lyase in the cholesterol production pathway upstream of 3-hydroxy-3-methylglutaryl coenzyme A reductase, thereby lowering LDL-C levels [10]. It effectively reduces high-sensitivity C-reactive protein (hs-CRP) and LDL-C and prevents the development of diabetes or worsening of glycemia. [11]. Based on the guidelines from the European Medicines Agency (April 2020), bempedoic acid is recommended for adults with primary hypercholesterolemia (both heterozygous familial and heterozygous non-familial) or mixed dyslipidemia, along with dietary restrictions. This medication is also advised for use in conjunction with a statin in patients who cannot meet the target LDL-C levels, in patients with SI or who are not able to tolerate statins, and in patients who are being treated with a combination of ezetimibe and bempedoic acid as separate medications, with or without statins [12]. As a practical standard of treatment, the first step of such a regimen for patients with a greater risk of CVD is to begin with ezetimibe combined with statin to achieve a significant decrease of >50% in LDL-C levels. Patients should receive a third lipid-lowering medication, such as bempedoic acid or PCSK9-targeted therapeutics (either monoclonal antibodies against PCSK9 or PCSK9 siRNA), if they fail to reach the LDL-C goal of >50% reduction and levels <1.4 mmol/L [13]. This article aims to summarize experts’ insights into the current approach toward dyslipidemia management, the role and place of different non-statin lipid-lowering therapies, early high-intensity lipid-lowering therapy vs. high intensity statins (HIS) therapy as the new standard of treatment to meet the LDL-C targets, and the use of different combinations of lipid-lowering therapies.

A total of six advisory board meetings were conducted in Bangalore, Delhi, Kolkata, Mumbai, Ahmedabad, and Bhubaneshwar (India) on dyslipidemia management in a span of 4 months (May 2023–August 2023) to understand the management of dyslipidemia with a focus on the role of bempedoic acid and other lipid-lowering therapies. Each panel constituted 7 cardiology experts of national and international stature. The proceedings of the meeting included a presentation on dyslipidemia management followed by a group discussion in the presence of a moderator at each meeting. A literature search using MEDLINE (via PubMed), EMBASE, and Cochrane-indexed databases was carried out to identify the relevant topics for discussion during the meetings. The research was conducted using search terms such as “dyslipidemia”, “management”, “statin intolerance”, “partial”, “total”, “bempedoic acid”, “monotherapy”, “combination therapy”, “PCSK9i”, “challenges”, “diabetic dyslipidemia”, “saroglitazar”, “key barriers”, “icosapent ethyl”, “high-risk”, “CVD”, “colchicine”, and “atheroprotective”. 2.1 Definitions Partial statin intolerance is defined as the inability to tolerate high-intensity statin therapy but tolerance to lower doses or alternative statins. Total statin intolerance is defined as the inability to tolerate at least two different statins, including one at the lowest approved dose. [14]

3.1 Burden of High-Risk CVD in India     

In India, CVD accounted for 13.6% (12.5%–14.6%) of disability-adjusted life years (DALYs) and 26.6% (25.3%–27.4%) of all fatalities in 2017. This is in contrast to 6.9% (6.3–7.4) DALYs and 15.2% (13.7–16.2) of all fatalities in 1990. Additionally, the prevalence of CVDs increased by more than two-fold between 1990 and 2016. For instance, the number of CVD cases in 1990 was 25.7 million (95% confidence interval [CI]: 25.1–26.0), which increased to 54.5 million (53.7–55.3) by 2016 [15].

3.1.1 Experts’ Opinion

All the experts shared that 20%–30% of CVD patients in India fall into thehigh-risk or very high-risk categories, including those with established ASCVD, diabetes with organ damage, or multiple risk factors. One of the experts mentioned that a significantly high prevalence of high-risk CVD among the total patients with CVD is seen in India (approximately 70%).

3.1.2 Key Takeaways

1) High-risk ASCVD burden is substantial in India. 2) Early LDL-C reduction is critical to improve outcomes

3.2 Statin intolerance: Incidence and Management

 Although statins are the widely approved mainstay treatment for dyslipidemia, non-adherence and treatment discontinuation are global problems associated with them. According to the National Lipid Association in the United States, SI is “defined as the inability to tolerate two or more statins, one at the lowest starting daily dose and the other at any daily dose, because of unpleasant symptoms or abnormal laboratory results that are temporary and reversible when the statin treatment is stopped” [16]. As per observational research, 10%–15% of patients experience SI. The occurrence of SI in randomized controlled trials (RCTs) is estimated to range from 1.5% to 5%. However, this figure may be underestimated since many studies exclude participants with a history of SI prior to randomization or during the run-in phase. Accurately diagnosing SI requires a systematic method that includes a dechallenge and rechallenge process to determine causation, conducting multiple challenges with statins to confirm the diagnosis, and ruling out any other potential underlying causes for the reported adverse effects [17].

3.2.1 Experts’ opinion

According to experts, around 5%–20% of the patients exhibit partial SI (roughly 1–6 cases/month) and around 1%–10% of the patients exhibit total SI (roughly 1–3 cases/month) in their clinical practice.

3.2.2 Management of patients with SI to meet LDL-C targets

In patients with partial SI, transitioning to another statin, reducing the dosage of statin, or using a different dosage schedule can be useful. In certain patients who cannot tolerate the maximum tolerated dose or any dose of statin, it is imperative to add a non-statin lipid-lowering therapy [18]. In these patients’ addition of ezetimibe (10 mg once daily) to a lower dose of statin is the first choice of therapy. Ezetimibe monotherapy can also be used, resulting in a 20% reduction in LDL-C levels and is generally well tolerated. If the patient cannot achieve target LDL-C levels by adding ezetimibe, including fibrates or resins to a low dose of statins may be considered. Fibrates reduce LDL-C levels by around 15%. However, the addition of gemfibrozil with statins must be avoided due to the risk of myopathy. PCSK9i evolocumab and alirocumab lower LDL-C by more than 50% [19]. Bempedoic acid (180 mg once daily) is another non-statin lipid-lowering therapy. In a pooled analysis of four trials of bempedoic acid, the average LDL-C decrease in patients with ASCVD, heterozygous familial hypercholesterolemia, or both, as well as those with SI, appeared substantially different with bempedoic acid in contrast to the placebo (difference between the groups: –17.8% and –24.5%). In the Indian scenario, both bempedoic acid and ezetimibe are appropriate choices as add-on therapies to statins. According to a recent Lipid Association of India consensus, individuals with ASCVD should start bempedoic acid following ezetimibe [11].

3.2.3 Experts’ opinion

Experts suggested reducing the dose of statins if the patients cannot tolerate HIS but can tolerate low or moderate doses. In patients with partial SI, it is preferable to switch to non-statin drugs such as ezetimibe, bempedoic acid, and PCSK9i to achieve LDL-C targets. In patients with complete SI, the bempedoic acid and ezetimibe combination, followed by PCSK9i can be used.

3.2.4 Key Takeaways

1) SI is common and under-recognized. 2) Non-statin therapies are essential to achieve LDL-C goals.

3.3 Role of bempedoic acid in the management of dyslipidemia

Bempedoic acid inhibits ATP-citrate lyase, reducing hepatic cholesterol synthesis upstream of HMG-CoA reductase. It is activated only in the liver, minimizing muscle-related adverse effects. The Cholesterol Lowering by Bempedoic Acid, an ACL-inhibiting Regimen (CLEAR) trials, constituting four phase 3 trials, have investigated the effectiveness and safety of bempedoic acid for long-term use. A percentage decrease in the levels of LDL-C in comparison with the placebo was shown in all 4 trials [20-23]. The effects of bempedoic acid in CLEAR trials are described in Table 1 [20–23]. The mean LDL-C levels between the bempedoic acid and placebo groups were compared in the CLEAR outcomes trial (n=13,970), with bempedoic acid group (n=6992) and placebo group (n=6978). The study had a median follow-up time of 40.6 months. A four-component composite of significant adverse CV events defined as “death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization” was the main endpoint of the CLEAR outcomes trial. In both groups, the baseline mean LDL-C level was 139.0 mg/dL (3.6 mmol/L). After 6 months, bempedoic acid lowered LDL-C levels by 29.2 mg/dL (0.76 mmol/L) (21.1%). Bempedoic acid, in contrast to placebo, notably lowered the occurrence of CV events (11.7% in 819 patients vs. 13.3% in 927 patients; hazard ratio of 0.87; 95% CI: 0.79–0.96; p=0.004). Additionally the rate of the combined outcomes of nonfatal stroke, nonfatal myocardial infarction, and death from CV causes (8.2% in 575 patients vs. 9.5% in 663 patients; hazard ratio of 0.85; 95% CI: 0.76–0.96; p=0.006), fatal or nonfatal myocardial infarction (3.7% in 261 patients vs. 4.8% in 334 patients; hazard ratio of 0.77; 95% CI: 0.66–0.91; p=0.002), and coronary revascularization (6.2% in 435 patients vs. 7.6% in 529 patients; hazard ratio of 0.81; 95% CI: 0.72–0.92; p=0.001) was decreased [24,25]. A meta-analysis of 10 RCTs (n=3788) has emphasized the impact of bempedoic acid on several risk factors for CVD. A significant decrease in newly diagnosed or worsening diabetes was shown with bempedoic acid therapy (odds ratio [OR], 0.59; 95% CI: 0.39–0.90; p=0.01) [24,26].

3.3.1 Experts’ opinion:

 Profiles of patients for whom bempedoic acid is currently considered are given below: (1) Patients with SI or for whom statins are contraindicated; (2) patients who need more LDL-C reduction; (3) adults with primary hypercholesterolemia, mixed dyslipidemias, or established atherosclerotic cardiovascular disease (ASCVD); and (4) patients with diabetic dyslipidemia.

3.3.2 Key Takeaways

1) Bempedoic acid offers liver-selective LDL-C reduction. 2) Mechanistic complementarity supports combination therapy.

3.4 Bempedoic acid in combination with statin and ezetimibe

The effectiveness of reducing the levels of LDL-C with a combination of atorvastatin, ezetimibe, and bempedoic acid was evaluated in a phase II, placebo-controlled, double-blind, randomized trial. Patients were randomized at a ratio of 2:1 to either placebo (n=20) or triple treatment (bempedoic acid 180 mg, ezetimibe 10 mg, and atorvastatin 20 mg; n=43) once daily for 6 weeks following the washout of lipid-lowering therapies. Compared to placebo, triple therapy demonstrated a markedly larger average decrease in LDL-C values (– 63.6%), with a difference of –60.5% (95% CI: – 68.0% to – 53.0%; p<0.001). Using triple therapy, 90% of patients achieved LDL-C levels <70 mg/dL, and 95% showed a reduction of ≥ 50% in LDL-C from the baseline by week 6. The combination of ezetimibe, bempedoic acid, and atorvastatin resulted in a substantial decrease in LDL-C, enabling over 90% of participants in the study to achieve the guideline-recommended LDL-C levels [27]. Bempedoic acid has been used in combination with statin and ezetimibe and has shown promising results. Zhao et al. performed a meta-analysis of RCTs to evaluate the effectiveness and safety of bempedoic acid either alone or in combination with other treatments (bempedoic acid + ezetimibe, bempedoic acid + statin) for patients with hypercholesterolemia. This analysis included 13 trials with 4,858 participants. The results indicated that combination therapies were more effective in lowering LDL-C levels compared to monotherapy. Specifically, bempedoic acid combined with statins showed a least square means (LSM) difference of -18.37% compared to statins alone (95% CI: -20.16 to -16.57, I2=0), while bempedoic acid combined with ezetimibe showed an LSM difference of -18.89% compared to ezetimibe alone (95% CI: -29.66 to -8.13, I2=87%) [28]. The LDL-C reduction results for bempedoic acid combination therapies are presented in Table 2 [21,29–34]. According to experts from the present consensus meeting, a majority of the patients encountered in clinical practice were on HIS. Around 30%−40% of the patients were on low- or moderate-intensity statins, and two-drug combinations (statin + ezetimibe) were used in 5% of the patients.        

3.4.1 Experts’ opinion

Triple drug therapy can be used in patients with partial SI who cannot achieve their LDL-C target. In patients with partial SI, bempedoic acid can be used with low- or moderate-intensity statins. If the LDL-C levels are within the desired range, the statin dose can be reduced, and bempedoic acid can be added. For patients who cannot meet LDL-C targets with HIS, bempedoic acid can be added. In patients with SI or mild side effects, low-dose statins with bempedoic acid can be used. Triple drug combination can be used if the LDL-C levels are very high; otherwise, ezetimibe followed by bempedoic acid can be used. In individuals without additional risk factors, dietary therapy may be attempted. If LDL-C levels remain elevated, a combination of statins and nutraceuticals can be considered.

3.4.2 Key Takeaways

1) Combination therapy accelerates LDL-C target achievement. 2) Bempedoic acid is effective in statin-intolerant patients.

3.5 Role of PCSK9i in the management of dyslipidemia

PCSK9i was first developed in 2015 with a substantial lipid-lowering impact and good safety and tolerability, and it is increasingly being used in clinical practice. Presently, alirocumab, evolocumab, and inclisiran are the primary PCSK9i used in clinical settings [35].

3.5.1 Experts’ opinion

The LDL-C target is not met in more than 20% of the patients even when treated with HIS + ezetimibe. In such cases, the use of PCSK9i should be considered as the next line of therapy. 3.5.2 Key Takeaways

• Combination therapy accelerates LDL-C target achievement. 2) Bempedoic acid is effective in statin-intolerant patients.

3.6 PCSK9i therapy with triple combination therapy

PCSK9i is a key player in reducing LDL-C in blood circulation because it targets the breakdown of LDL receptor [35]. A meta-analysis assessing a large patient population (n=28,319) discovered a statistically significant positive correlation between circulating PCSK9 levels and the risk of major adverse CV events. This suggests that the inhibition of PCSK9 expression lowers serum LDL levels and lowers the risk of CVD [34]. Robinson et al. investigated   the effects of including ezetimibe or evolocumab into moderate- or HIS therapy on reducing LDL-C levels in patients with hypercholesterolemia. Initially, a daily statin that was either high-intensity (atorvastatin [80 mg], rosuvastatin [40 mg]) or moderate-intensity (atorvastatin [10 mg], simvastatin [40 mg], or rosuvastatin [5 mg]) was randomly given to each patient. Patients (n=1899) were randomly assigned to receive either ezetimibe (10 mg or placebo daily; atorvastatin patients alone) or evolocumab (140 mg every two weeks or 420 mg monthly) as an adjunct to statin therapies after a 4-week interval for lipid stabilization. When evolocumab was added to moderate- or HIS medication, individuals with primary hypercholesterolemia and mixed dyslipidemia experienced further LDL-C reduction over the 12-week trial [36]. Elosco et al. examined the use of PCSK9i and their outcomes in conjunction with other lipid-lowering treatments among veterans. Subgroup analysis included PCSK9i alone, PCSK9i + statin, PCSK9i + ezetimibe, and PCSK9i + statin + ezetimibe. The analysis cohort (n=2428) included veterans on PCSK9i monotherapy in 36.2% of cases; PCSK9i + statin in 24% of cases; PCSK9i + ezetimibe in 27.4% of cases; and triple therapy (PCSK9i + statin + ezetimibe) in 12.4% of cases. In comparison to the concomitant statin (66.5 mg/dL), ezetimibe (65.7 mg/dL), and triple therapy subgroups (68.1 mg/dL), the PCSK9i monotherapy subgroup was associated with higher mean LDL levels (85.6 mg/dL) [37].            

3.6.1 Experts’ opinion

In case of failure of a triple combination therapy in patients with dyslipidemia, PCSK9i can be considered.

3.6.2 Key takeaways:

1) PCSK9i enable further LDL-C reduction. 2) PCSK9i represent an effective next-line therapy for high-risk patients.

3.7 Dyslipidemia in patients with diabetes: Preferred treatment approach for patients with diabetic dyslipidemia

 Dyslipidemia is a frequent condition in type 2 diabetes mellitus that affects 72%–85% of patients [4].

3.7.1 Statin therapy

LDL-C is the most consistent indicator of cardiovascular risk. According to the American Diabetes Association's recommendations, lowering LDL-C levels is the primary goal in the treatment of diabetes [38]. Statins are highly effective at reducing LDL-C levels, making them the recommended first-line treatment for managing dyslipidemia in patients with diabetes. Landmark trials on statins have shown that statins are beneficial for both primary and secondary prevention of CAD. According to a subgroup analysis of statin studies, rapidly lowering LDL-C to ≤100 mg/dL can lower the occurrence of CV events in individuals with diabetes. In the majority of patients with diabetic dyslipidemia, statins are effective. However, many patients would benefit from a more effective treatment regimen, such as combination therapies [37]. Barakat et al. evaluated the efficacy and safety of rosuvastatin, atorvastatin, and pravastatin in treating dyslipidemia in diabetic individuals, concluding that rosuvastatin 10 mg was the most effective statin for lowering LDL-C levels [39]. A comparative, randomized, double-blind study concluded that, in diabetes patients with dyslipidemia, rosuvastatin may be preferable to atorvastatin because it has fewer pleiotropic effects, less microsomal interactions, causes less variance in blood sugar parameters, and exhibits efficient lipid profile control [40]. Using a randomised, open-label, parallel-group, comparative, prospective design, Adsule et al. evaluated the effectiveness and safety of rosuvastatin, simvastatin, and atorvastatin for 12 weeks in 60 patients with dyslipidemia and type 2 diabetes mellitus. Their findings indicated that 10 mg of rosuvastatin was superior to 10 mg of simvastatin in reducing LDL-C levels. Nevertheless, the effectiveness of 10 mg of rosuvastatin was comparable to that of 10 mg of oral atorvastatin [41]. In patients aged 40–75 years with diabetes mellitus and LDL-C levels ≥70 mg/dL (≥1.8 mmol/L), the AHA/ACC 2018 lipid management guidelines recommend initiating moderate-intensity statin medication without considering the 10-year risk of ASCVD. Administration of a HIS is a rational approach to reduce the LDL-C level by a minimum of 50% in patients with diabetes mellitus who are at an elevated risk, especially those with several risk factors or falling within the age range of 50-75 [42].

3.7.2 Non-statin therapy

The first comprehensive study to demonstrate enhanced CV outcomes with a statin plus a non-statin add-on was the Improved Reduction of Outcomes: Vytorin Efficacy International Trial. This trial randomly allocated 18,144 patients with ACS to receive either simvastatin 40 mg + ezetimibe 10 mg daily or simvastatin alone. The combination of ezetimibe and simvastatin reduced major CV events, stroke, and myocardial infarction as well as the primary outcome of CV mortality by 34.7% vs. 32.7% (p=0.016). These results, which were most likely brought on by lowering LDL-C levels, led to the guidelines being altered to incorporate ezetimibe as an adjuvant to statin treatment. Moreover, a subgroup analysis of 27% of trial participants with baseline diabetes revealed that ezetimibe was most helpful to those with diabetes [43]. A meta-analysis compared the effect of PCSK9i vs. controls in individuals with diabetes. It included 12 RCTs involving 14,702 patients with primary efficacy endpoints of percentage changes in the lipid profile. PCSK9i was found to reduce non-HDL-C levels by 45.23% (95% CI: 39.43%–51.02%), total cholesterol by 30.39% (95% CI: 24.61%–36.17%), triglycerides by 11.96% (95% CI: 6.73%–17.19%), lipoprotein(a) by 27.87% (95% CI: 22.50%–33.17%), apolipoprotein B by 42.43% (95% CI: 36.81%–48.06%), and increase in HDL-C levels by 5.97% (95% CI: 4.59%–7.35%) [44]. Leiter et al. showed that regardless of baseline glycemic conditions (diabetes, prediabetes, or normoglycemia), the administration of bempedoic acid consistently and significantly reduced LDL-C levels in comparison to a placebo [45]. In patients with diabetic dyslipidemia, target LDL-C and non-HDL-C levels can be achieved by using bempedoic acid as an addition or alternative to statins, especially in patients with SI [46].

3.7.3 Experts’ opinion

For patients with diabetes and dyslipidemia, statins are preferred over non-statin therapy. Bempedoic acid is a suitable option for individuals with diabetes. Nevertheless, there is an absence of definitive evidence concerning its use for managing dyslipidemia in individuals with diabetes.

3.7.4 Key takeaways

1) Statins remain first-line in diabetes. 2) Combination therapy aids LDL-C targets.                                                         

3.8 Role of saroglitazar in the management of dyslipidemia

Saroglitazar, a new antidiabetic agent, has been approved for the treating dyslipidemia. The safety and anti-hyperlipidemic impact of saroglitazar in interventional studies with or without a control group(s) was evaluated in a systematic review and meta-analysis. The meta-analysis comprised six trials including a total of 581 participants. In comparison to saroglitazar 2 mg therapy (standardised mean difference [SMD]: −0.23 mg/dL, 95% CI: −0.47 to 0.00; p=0.05; 2 studies) and control (SMD: −0.36 mg/dL, 95% CI: −0.59 to −0.12; p=0.0026; 3 studies), saroglitazar 4 mg therapy showed a substantial reduction in LDL-C levels. Furthermore, the administration of saroglitazar 4 mg resulted in a notable reduction in total cholesterol levels compared to saroglitazar 2 mg (SMD: −0.28 mg/dL, 95% CI: −0.52 to −0.04; p<0.01; 2 trials) and the control (SMD: −0.49 mg/dL, 95% CI: −0.72 to −0.26; p<0.0001; 3 studies) [47].

 3.8.1 Experts’ opinion:

Saroglitazar has shown good efficacy for the management of dyslipidemia in people with diabetes, especially those with concomitant hypertension.

3.8.2 Key takeaways

1) Saroglitazar improves dyslipidemia in diabetes 2) Beneficial in diabetic hypertensive patients.

Table 1. LDL-C reduction with bempedoic acid in CLEAR trials [20-23]

 ASCVD: Atherosclerotic cardiovascular disease; CI: Confidence interval; CLEAR: Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen; LDL-C: Low-density lipoprotein cholesterol; SI: Statin intolerance.

3.10 Key barriers to the use of the following drugs in dyslipidemia in Indian patients

The key barriers to the use of PCSK9i: Evolocumab and alirocumab, icosapent ethyl, and bempedoic acid are described in Table 3 [6,11,49–51].

3.10.1 Expert’s opinion: Availability and cost are the key barriers for using PCSK9i: evolocumab, alirocumab, and icosapent ethyl. The practice of adding PCSK9i has been reported to change with the launch of bempedoic acid and ezetimibe, although some experts stated that it has not been affected by these treatments. It is not necessary to reduce the dose of statin upon adding PCSK9i. The dose of statin should only be reduced in case the addition of PCSK9i reduces LDL-C to 10 mg/dL or 5 mg/dL.

3.10.2 Key Takeaways

1) Cost and access limit PCSK9i use. 2) Oral alternatives improve treatment adoption.

4. Safety, Limitations, and Indian Context

Bempedoic acid is a new-age molecule that has shown promising results in lowering LDL-C and hs-CRP levels and preventing the development of diabetes or worsening of glycemia. However, additional data on the use of bempedoic acid for managing diabetic dyslipidemia is needed. It is generally well tolerated; however, safety concerns include hyperuricemia, gout, and rare tendon rupture. Cost and accessibility remain important considerations in India.

4.1 Limitations

1) Limited long-term Indian real-world data, 2) Absence of formal Delphi consensus methodology.

Table 2. LDL-C reduction with bempedoic acid combination therapies [22,29–34]

 CI: Confidence interval; LDL-C: Low-density lipoprotein cholesterol; LSM: Least square mean; SE: Standard error.

3.9 Potential treatment option for ASCVD—colchicine

There is growing fundamental and clinical evidence that colchicine, an affordable immunomodulatory medication usually used to treat gout and familial Mediterranean fever, might be used therapeutically to treat ASCVD. Its influence on tubulin polymerization is believed to be the main factor behind its atheroprotective properties, enabling a diverse array of effects on different cell types within atherosclerotic plaques and various cellular processes, including cell division, migration, and the secretion of pro-inflammatory cytokines and chemokines. These characteristics suggest that they may have a positive impact on the development of atherosclerotic plaque at all stages, including formation, progression, destabilization, and rupture [48].

3.9.1 Experts’ opinion: As per the experts, the use of the first anti-inflammatory drug, colchicine, for atheroprotective CV treatment has shown good results in a patient. Colchicine may be prescribed for patients with hsCRP, younger patients, and those with heart failure who have not responded to other treatments.

3.9.2 Key takeaways

1) Colchicine reduces inflammation in ASCVD. 2) Adjunct option for residual inflammatory risk              .

Table 3. Barriers to the use of PCSK9i: Evolocumab and alirocumab, icosapent ethyl, and bempedoic acid in dyslipidemia in Indian patients [6,11,49–51]

 CV: Cardiovascular; REDUCE-IT: Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial.

In order to effectively manage dyslipidemia in individuals with ASCVD, statin intolerance must be addressed. Bempedoic acid, whether used alone or in combination with ezetimibe, provides a viable alternative for patients unable to tolerate statins. Early initiation of combination therapy may enhance LDL-C goal attainment, particularly in high-risk populations. Further research, including real-world evidence and long-term outcome studies in Indian patients, is essential to optimize dyslipidemia management strategies and improve cardiovascular outcomes.

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