Cardiovascular disease (CVD) remains the leading cause of mortality in developed nations and is a significant contributor to death and disability in developing countries.1 In India, the incidence of atherosclerotic cardiovascular disease (ASCVD) has been rising at an alarming rate.2,3 According to the Global Burden of Disease study, CVDs contribute to approximately one-fifth of total deaths in India, making it the leading cause of death in the country.4 While multiple factors contribute to CVD, dyslipidaemia remains one of the most critical factors.1 Data from the INTERHEART study suggest that dyslipidaemia is the strongest contributor to acute MI in South Asians, with an elevated apolipoprotein B100/apolipoprotein A-I (ApoB100/ApoA-I) ratio observed in 61.5% of patients.5 Furthermore, the study demonstrated that among South Asians, an elevated ApoB100/ApoA-I ratio had the highest population-attributable risk (PAR) of 46.8%, underscoring the significant role of dyslipidaemia in driving cardiovascular (CV) events in this population. Among various lipid parameters, LDL cholesterol (LDL-C) has been firmly established as a key contributor to ASCVD, supported by extensive evidence from large-scale epidemiological studies, interventional trials, and genetic research.6 The recent ICMR-INDIAB-17 national cross-sectional study revealed an alarmingly high prevalence of dyslipidaemia in India, affecting 85.1% of the population with 213 million people having hypercholesterolaemia and 185 million individuals with high LDL-C levels.7 Thus, managing this risk factor needs to be prioritised in clinical practice.
With advances in lipid-lowering therapy (LLT), LDL-C targets have progressively evolved, reinforcing the concept that ‘lower is better’ for reducing CV risk. Current guidelines, including those from the European Society of Cardiology (ESC)/European Atherosclerosis Society (ESC/EAS), American College of Cardiology/American Heart Association (ACC/AHA), Cardiological Society of India (CSI) and Lipid Association of India (LAI), emphasise a risk-based approach to lipid management with different LDL targets based on the CV risks.8–11 While the Indian guidelines suggest aggressive LDL-C targets, taking into consideration the ethnicity, the target of <55 mg/dl (<1.4 mmol/l) recommended by ESC/EAS and CSI is most commonly followed in clinical practice in India. While these targets theoretically align with the clinical practice of cardiologists, many patients fail to achieve their target LDL-C goals. In India, 80% of post-acute coronary syndrome (ACS) patients fail to achieve LDL-C target goals despite high-intensity LLT, mirroring the global findings from the DA VINCI study in which only 22% of the very-high-risk patients on high-intensity statins achieved their risk-based LDL-C goals.12,13
Despite the availability of effective LLT, as well as increased awareness and counselling on the importance of LDL-C reduction, many patients still fail to achieve LDL-C targets. While multiple factors contribute to this gap, this expert opinion document focuses on two key challenges that are particularly relevant in real-world clinical practice: treatment adherence and delayed escalation of therapy. Treatment adherence refers specifically to the extent to which patients follow their prescribed LLTs, both in terms of correct dosage and timing over a period. An Indian study reported that only 66% of patients adhered to LLT for secondary prevention.14 This poor adherence directly impacts not only the attainment of LDL-C targets but also adds to the LDL-C variability, which itself leads to additional risks of CV events.15 A post hoc analysis of the TNT trial found that increased visit-to-visit LDL-C variability increased the risk of CV events by 11%, coronary events by 16%, MI by 10%, stroke by 17%, and death by 23%, irrespective of achieved LDL-C levels.16 This challenge is further compounded by a delayed escalation of LLT.
While various guidelines advocate for a stepwise approach to intensify therapy, including the addition of non-statin therapies when LDL-C remains above target, these recommendations are often not implemented in routine clinical practice. Delaying the escalation of LLT in very-high-risk patients is another significant reason why many patients fail to achieve guideline-recommended LDL-C targets, exposing these patients to prolonged periods of elevated LDL-C. This sustained exposure to LDL-C levels higher than the recommended target contributes to an increased risk of recurrent CV events, thereby negating the potential benefits of intensive lipid management. The longer a patient remains above their LDL-C goal, the greater their cumulative CV risk, reinforcing the urgency of timely escalation strategies.
Thus, despite the availability of India-specific guidelines, such as those from the CSI and LAI, which advocate aggressive LDL targets and CV risk-based treatment approach with sequential LLT strategies to reduce risk-based LDL-C targets, significant challenges remain in real-world implementation.10,11 This expert opinion aims to provide a pragmatic, real-world-driven framework for optimising LDL-C management, which would simplify decision-making in very-high-risk Indian patients.
Methodology
The program involved two virtual meetings endorsed by the ESC, including an ESC lipid expert and a panel of Indian experts. The meetings aimed to develop an expert opinion document on targeted lipid control for very-high-risk Indian patients for bridging the gap in real-world practice to address the crucial aspects not currently covered in the existing guidelines, particularly emphasising treatment adherence and implementing individualised treatment approaches.
A group of senior cardiologists were identified based on their expertise, clinical experience, and contributions to cardiovascular research and practice. The panel consisted of an international expert, a national coordinator, and nine Indian experts. Two focus group virtual meetings were conducted to ensure a productive discussion on targeted LDL-C in Indian patients at very high CV risk.
In the first meeting, the international expert presented key evidence on the global and Indian burden of high LDL-C, risk factors for high CV risk, impact of adherence to therapy, and pharmacological management of dyslipidaemia in patients at high CV risk. This was followed by a collaborative discussion moderated by a national coordinator to identify the gaps in current guidelines and areas that need refinement. In the second meeting, the panel emphasised the need for a simplified treatment approach for managing LDL-C in clinical practice. Live polling questions were used in both meetings to capture expert opinions. Insights from both the meetings were compiled into this expert opinion document.
Recommendations by the Expert Panel
Cardiovascular Risk Stratification
For stratifying CV risk, risk calculators are essential tools and guiding treatment decisions; however, their implementation in routine clinical practice remains a significant challenge. Given the challenges in applying risk calculators consistently in clinical settings, a simplified approach to risk stratification is necessary. Hence, the panellists agreed upon the following key factors as a guide in routine clinical practice for CV risk stratification: diabetes, coronary artery disease, heterozygous familial hypercholesterolaemia, chronic kidney disease (CKD), peripheral vascular disease, hypertension, cerebrovascular disease and a history of recurrent CV events. Individuals with one or more of these risk factors fall into the very-high-risk category.8–11 In addition, the panellists also emphasised the significance of lipoprotein (a) (Lp[a]) as a key risk enhancer. Unlike the ESC/EAS and CSI recommended Lp(a) threshold of >50 mg/dl (>108 nmol/l), the panellists emphasised that an Lp(a) level >30 mg/dl (>65 nmol/l) is associated with an increased risk of CV events and should be considered in CV risk assessment. As per ESC/EAS guidelines, patients with evidence of ASCVD (clinical/imaging), high-risk conditions like familial hypercholesterolaemia with ASCVD or another major risk, severe CKD (estimated glomerular filtration rate [eGFR] <30 ml/min), diabetes with end-organ damage, Systematic Coronary Risk Estimation (SCORE) ≥10% or SCORE2 ≥7.5% for people aged <55 years, and ≥10% for people aged >55 years are categorised as very high CV risk profiles.8,17 The panellists agreed that, though rarely used, the ESC/EAS and SCORE2 risk stratification criteria may be used for Indian patients. Furthermore, the panel highlighted that young patients with CVD and recurrent events should also be included in the very-high-risk category due to their significant prevalence in the Indian population.
The panel also discussed the recently developed SMART model, which shows promise for routine use for CV risk prediction (residual risk for recurrent MI, stroke or vascular death over the next 10 years) in routine healthcare settings, assisting both population-level and individual-level decision-making for the secondary prevention.18,19 However, in the Indian context, the use of such models for risk assessment is not consistent.
Recommendations on Treatment Goals for LDL Cholesterol for Secondary Prevention
ESC/EAS 2019 guidelines recommend LDL-C reduction of ≥50% from baseline and an LDL-C goal of <55 mg/dl (<1.4 mmol/l) for secondary prevention in very-high-risk patients.8 Similarly, CSI 2024 guidelines also recommended LDL-C target of <55 mg/dl (<1.4 mmol/l).11 Robust evidence from multiple randomised controlled trials, meta-analyses and imaging studies consistently supports lowering LDL-C levels <55 mg/dl (<1.4 mmol/l) for optimal CV risk reduction.8,11 Hence, recognising this compelling evidence, the expert panel unequivocally supports an LDL-C target of <55 mg/dl (<1.4 mmol/l) in very-high-risk patients for secondary prevention in Indian patients, aligning with international best practices to achieve maximal ASCVD risk reduction. Moreover, panellists were more inclined to a target of <55 mg/dl (<1.4 mmol/l) as recommended by ESC/EAS and CSI guidelines rather than ≥50% reduction from baseline as majority of Indian patients present with significantly high baseline LDL-C levels. Hence, targeting ≥50% reduction from baseline may not be sufficient to achieve optimal lipid lowering. A fixed LDL-C target of <55 mg/dl (<1.4 mmol/l) is more relevant in Indian patients, because it ensures that patients with very high baseline LDL-C levels receive more intensive LLTs to reach an absolute goal that effectively reduces CV risk.
Adherence-based Treatment Algorithm for LDL Cholesterol Management in Indian Patients
Non-adherence to LLT remains a significant challenge in real-world clinical practice. Data suggest that patients adhering to high-intensity statins showed highest reduction in LDL-C and had a 40% lower risk of CV events than those untreated for at least 1 year, while non-adherent patients on low-intensity statins experienced highest CV risk.20 A study evaluating correlation of adherence and treatment intensity with LDL-C reduction and CV outcomes in patients with CVD, diabetes or CKD found that each 10% increase in combined measure of adherence and treatment intensity correlated with a 10% reduction in CV events.20 The panel emphasised that adherence to LLT is a critical determinant of CV outcomes across all risk categories; patients at high risk of ASCVD with poor adherence to treatment face the greatest risk of CV events. Conversely, high-risk patients who consistently adhere to their prescribed therapy can substantially lower their risk. Recognising the heavy burden of non-adherence in Indian patients, impacting attainment of target LDL-C goals, LDL-C variability, residual CV risk and adverse CV outcomes, an expert panel developed a simplified and pragmatic 2 x 2 treatment algorithm tailored for Indian patients, ensuring early and sustained LDL-C control for effective secondary prevention of ASCVD. This algorithm categorises patients based on their risk level (low versus high) and treatment adherence (low versus high). The matrix consists of four quadrants, each representing a unique patient category with specific treatment recommendations by the panellist (Figure 1 ). This treatment matrix emphasises that the choice of LLT should be guided not only by CV risk and baseline LDL-C levels but also by patient adherence, as highlighted by the panellists. Tailoring therapy based on adherence patterns is crucial to optimising long-term CV outcomes.
As depicted in Figure 1, for patients with low CV risk and high adherence, monotherapy with statin is a reasonable option. In cases of statin intolerance, alternative agents may be considered. Patients categorised as low risk with low adherence can be treated with statins or statin-based fixed-dose combination. For patients with high risk and low adherence, the panel suggested the addition of inclisiran to statin for simplifying the treatment regimen, enhancing adherence and providing sustained LDL-C reduction. Also, the panel members agreed that a triple-drug combination is potent and should be implemented in patients with high risk and high adherence and if the target LDL-C of <55 mg/dl (<1.4 mmol/l) is not achieved, the addition of bempedoic acid (BA) or PCSK9-targeted therapies, such as PCSK9 monoclonal antibodies (mAbs) or inclisiran, can be considered.
Simplifying Combination Treatment Approach
Who Needs Aggressive Treatment?
The expert panel agreed with the ESC/EAS 2019 risk stratification for Indian patients at very high CV risk as detailed above, including young patients with CVD and recurrent events. These very-high-risk groups require aggressive lipid-lowering treatment to achieve an LDL-C target of <55 mg/dl (<1.4 mmol/l) to improve long-term CV outcomes.
Why Is It Important to Treat Aggressively?
All panel members emphasised that LDL-C should be lowered efficiently, pragmatically and without delay in very-high-risk individuals as early and persistent LDL-C reduction significantly lowers major adverse cardiovascular event (MACE) risk. The SWEDEHEART study demonstrated that intensive, early and sustained lipid-lowering post-MI provides greater CV benefits than a gradual, stepwise approach.21 The findings demonstrated that the lowest risk of MACE was observed in patients who achieved their non-HDL-C target early (8 weeks) and maintained it at 1 year (HR 0.80; 95% CI [0.74–0.86]). In contrast, those who either achieved the target only early and not maintained at 1 year (HR 0.86; 95% CI [0.80–0.93]) or only late (HR 0.86; 95% CI [0.79–0.93]) had a higher risk of MACE.21 Patients achieving the non-HDL-C target early and sustaining it for 1 year had 10% lower risk of MI compared to patients who achieved the target early but were not able to sustain it for 1 year.
How to Treat Aggressively?
Combination therapy is crucial for achieving LDL-C targets, especially in patients at very high risk. The DA VINCI study showed that most patients at high CV risk are unlikely to achieve LDL-C goals by statin optimisation and ezetimibe and will require a PCSK9 inhibitor, leading to a greater reduction in CV risk.22 CSI 2024 guidelines also recommended the addition of inclisiran if a target LDL-C goal of <55 mg/dl (<1.4 mmol/l) is not achieved.11 In patients without ASCVD at very high risk, 88.1% achieved their LDL-C goals with the addition of a PCSK9 inhibitor. Data from the LAI-REACT study showed that triple combination oral therapy may help achieve the goal when targets are low.23 However, despite being on triple-drug combination therapy, nearly 25% of patients did not reach the LDL-C target goal of <55 mg/dl (<1.4 mmol/l). These patients may be better suited for injectables, such as PCSK9 mAbs or inclisiran. Combination treatment strategy is further supported by the recently published 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline, which states that in ACS patients on maximally tolerated statins, adding a non-statin LLT is recommended if LDL-C is ≥70 mg/dl (≥1.8 mmol/l) and reasonable if LDL-C is 55–69 mg/dl (1.4–1.8 mmol/l) to further reduce MACE risk.24
Based on evidence in favour of combination therapy, the panel recommended simplifying the ESC/EAS 2019 guidelines for high-risk patients by streamlining the treatment approach from three steps to two steps:
- Initiate high-intensity statin therapy with ezetimibe as the first-line approach.
- Consider the addition of a PCSK9 inhibitor (PCSK9 mAbs or inclisiran) in patients who do not achieve LDL-C goals within 4–8 weeks.
To further simplify decision-making, the panel emphasised that clinicians should be familiar with the ESC 2019 guidelines, which outline absolute LDL-C reductions achievable with different therapeutic approaches, helping physicians tailor combination treatments based on patient-specific baseline LDL-C levels (Table 1 ). The table clearly demonstrates that in patients with very high baseline LDL-C levels, monotherapy or a less intensive approach is often inadequate to achieve the guideline-recommended LDL-C target of <55 mg/dl (<1.4 mmol/l). Combination therapy with high-intensity statins, especially when PCSK9 inhibitors are added, significantly enhances LDL-C reduction and improves goal attainment. Furthermore, in patients with LDL-C levels >135 mg/dl (>3.5 mmol/l), combination therapy with oral LLTs alone may not achieve the target LDL-C goal. This underscores the need for an early and proactive combination therapy strategy rather than a stepwise escalation approach, ensuring timely and effective LDL-C lowering in very-high-risk patients.
Panellists emphasised that further treatment should be tailored based on multiple factors, including CV risk level, baseline LDL-C levels, age and life expectancy, diabetes status, renal function (eGFR), familial hypercholesterolaemia, history of gout or hepatic dysfunction, potential drug–drug interactions and medication compliance issues, which vary on a case-by-case basis.
Shared Decision-making in Lipid Management
A shared decision-making approach, in which patients actively participate in their treatment decisions, has been shown to improve adherence to LLT and enhance patient engagement.25 Educating patients about ASCVD risk, the importance of LDL-C reduction and available treatment options fosters better understanding and adherence.25 Conversations with patients should address not just LDL-C targets but also treatment costs, side-effect concerns, comorbidities and lifestyle modifications to ensure sustainable, long-term adherence.25 Table 2 presents the results of expert polling on key challenges and considerations in LLT adherence. It includes responses of the experts on clinical practice related to adherence.
While the primary objective of this expert opinion manuscript is to provide practical pharmacological treatment guidance for managing LDL-C in very-high-risk Indian patients, we fully acknowledge that non-pharmacological factors including diet, physical activity, patient and physician education, play a critical role in lipid control and overall CV risk reduction. While this expert opinion emphasises what needs to be done from a cardiologist’s perspective, strategies involving patients, physicians and health systems, as cited in the article by Bansal et al., can further help in improving adherence.26
Conclusion
Failure to achieve guideline-recommended LDL-C targets remains a major challenge in real-world clinical practice, primarily due to poor patient adherence and delayed therapy escalation. Despite the availability of effective LLTs, many patients remain above target for prolonged periods, increasing their risk of recurrent CV events. A simplified approach to lipid management is essential to bridge the gap between guidelines and clinical practice. The expert panel emphasised the importance of early and intensive lipid-lowering using combination therapy. The panel strongly supported the use of dual therapy with high-intensity statins and ezetimibe as an initial strategy, which can help achieve LDL-C goals in approximately 60% of patients. In another 30% of cases, PCSK9 inhibitors may be required to further reduce LDL-C levels. For very-high-risk patients, including young individuals with recurrent CV events, aggressive treatment with combination therapies should be prioritised to achieve LDL-C targets of <55 mg/dl (<1.4 mmol/l). In ACS patients, the panel recommended a triple-drug regimen of high-intensity statins, ezetimibe and BA before considering PCSK9 inhibitors if LDL-C targets are unmet. The panel members agreed that a triple-drug combination is potent and should be implemented in patients who require faster goal attainment. Additionally, injectable therapies such as inclisiran may offer a practical solution for patients requiring consistent LDL-C control and in patients who fail to achieve the desired LDL-C goal with dual or triple combination therapy, particularly in those with adherence challenges or infrequent follow-up. The panel also advocated shared decision-making to optimise LLT adherence and improve long-term CV outcomes. By adopting a holistic, simplified and risk-adherence-based patient-centric approach, Indian clinicians can optimise LDL-C management, reduce the burden of ASCVD and improve long-term CV outcomes in this vulnerable patient population.