Understanding how twice-a-year Inclisiran therapy can transform cholesterol management, and the challenges facing adoption of this new drug

 For decades, cholesterol-lowering medications like statins have been the go-to solution for managing heart health. However, a newer, lesser-known drug promises to dramatically lower LDL (low-density lipoprotein) cholesterol with just two doses a year. Inclisiran, an innovative medication that claims to change the way we think about cholesterol management, is said to be unlike traditional pills taken daily. It harnesses the power of gene silencing technology to target cholesterol production at its root – offering a novel approach for those struggling with high cholesterol, especially individuals with diabetes, coronary artery disease, or obesity.

To understand the full scope of this medication – its effectiveness, risks, and who stands to benefit the most — indianexpress.com spoke to leading cardiologists, diabetologists, and endocrinologists. Their insights paint a fascinating picture of how Inclisiran could revolutionise treatment, particularly for high-risk individuals with sedentary lifestyles or a genetic predisposition to high cholesterol.

But does it truly live up to the hype? And what should patients know before considering it?

Understanding Inclisiran

At its core, Inclisiran employs a revolutionary approach to managing cholesterol levels. Unlike traditional medications, it targets the cause of cholesterol accumulation in the bloodstream. This sophisticated mechanism operates at the genetic level, offering a fundamentally different approach to cholesterol management.

Dr Kalyan Kumar Gangopadhyay, endocrinologist at the Calcutta Medical Research Institute (CMRI), breaks down this complex mechanism: “There is a protein called PCSK9 that destroys LDL receptors in the liver. If the LDL receptors are reduced, then the LDL cholesterol in the blood accumulates, promoting heart attack and stroke.”

Inclisiran’s specialty lies in its targeted approach. Dr A Sharda, consultant endocrinologist and diabetologist at Manipal Hospital, Millers Road, Bengaluru elaborates, “It uses a unique technique called small interfering RNA (siRNA) to silence the PCSK9 gene, which results in more consistent, long-term reduction in LDL. Additionally, Inclisran’s mechanism of action also bypasses statin intolerance, another prevalent issue, also seen in individuals with diabetes.”

Clinical efficacy

The effectiveness of Inclisiran has been demonstrated through extensive clinical research. The medication has consistently shown remarkable results in reducing LDL cholesterol levels, particularly in combination with existing treatments.

Dr Manoj Chawla, consultant diabetologist at PD Hinduja Hospital, highlights the impressive clinical outcomes: “In clinical trials conducted so far, Inclisiran showed effective and sustained LDL-C reduction of ~53 per cent, and more robust reduction of up to ~57 per cent has been observed in the Asian population.” This finding is particularly relevant in the Indian context.

To put these numbers in perspective, Dr Gangopadhyay explains: “35 mg reduction in LDL cholesterol reduces the occurrence of stroke and heart attack by about 25 per cent, and Inclisiran reduces LDL cholesterol by more than 50 per cent.” He emphasises that this reduction comes “on top of the highest possible dose” of traditional statin therapy, making it a great option for patients who need additional cholesterol management.

Transforming treatment protocols

Inclisiran’s dosing schedule represents a paradigm shift in chronic disease management. The medication requires only two injections per year after the initial dosing period, as opposed to daily medications or monthly injections.

Dr Harshitha Boyareddigari, consultant, diabetes and endocrinology at Manipal Hospital, Sarjapur, underlines this advantage: “Inclisran has overcome the challenge of frequent injections seen with PCSK9 inhibitor.” The simplified dosing schedule addresses one of the most significant challenges in chronic disease management: patient compliance.

The impact of this convenient dosing schedule extends beyond mere convenience. Dr Sharda notes that “the convenience of fewer injections makes Inclisiran a desirable choice for people with polypharmacy (simultaneous use of multiple medicines),” highlighting the relevance for patients with several chronic conditions.

Inclisiran offers solutions to several challenges commonly encountered with traditional cholesterol medications. Dr Gautam Swaroop, cardiologist at Tender Palm Hospital, Lucknow, says, “Inclisiran has shown durable and potent LDL-C reductions of >50% levels with good safety and tolerability.”

Special applications in high-risk populations

A significant advantage is its effectiveness in patients who struggle with conventional treatments. Dr Viveka Kumar, cardiologist at Max Hospital, Delhi, points out that this medication is particularly beneficial for specific patient groups, including “patients with familial hypercholesterolemia or those who cannot achieve target LDL levels with statins alone, patients with established coronary artery disease, and patients who experience side-effects from traditional cholesterol-lowering medications.”

Dr Palleti Siva Karthik Reddy, consultant, internal medicine at Koshys Hospital, Bengaluru, states that inclisran’s twice-yearly dosing simplifies treatment adherence, “addressing a common issue for patients with chronic conditions.” This is particularly beneficial for obese, sedentary patients who may struggle with maintaining daily medication routines. It also reduces the potential for side effects related to daily statins, such as myopathy or liver enzyme elevation.

Diabetologist Dr Chawla adds that lipid-lowering therapy (LLT) plays a crucial role in managing patients with diabetes and atherosclerotic cardiovascular disease. However, when conditions like statin intolerance limit the use of traditional LLT, Inclisiran emerges as a promising alternative.

Implementation challenges

Despite its promising benefits, several important considerations need to be addressed for widespread adoption of Inclisiran. “The biggest disadvantage is the high cost, which is prohibitively expensive for most patients,” Dr Gangopadhyay says.

Concurring, Dr Reddy states that Inclisran “may not be feasible for all patients” for this reason. “Additionally, biannual injections may lead to a false sense of security, with patients potentially neglecting lifestyle modifications crucial for long-term health improvement,” he says.

Dr Boyareddigari calls for more comprehensive real-world data. “We need to see whether it is as efficacious as PCSK9 inhibitors. We also need to see what its effect is on triglyceride levels, and understand what are its side-effects when used in a real-world setting that could not be seen in clinical trials.”

The successful implementation of Inclisiran therapy requires careful consideration of healthcare infrastructure. Dr Chawla stresses that while the medication offers significant advantages, its integration into existing treatment protocols must be carefully managed. The need for healthcare provider training and establishing proper administration protocols are important considerations for widespread adoption.

The safety profile of Inclisiran has been encouraging in clinical trials. Dr Viveka Kumar notes that compared to statins, “Inclisiran has a favourable safety profile with fewer side effects.” However, monitoring is still required. Healthcare providers should watch for localised reactions at injection sites and maintain regular follow-up with patients to ensure optimal outcomes.

Future implications and potential impact

Looking ahead, the potential impact of Inclisiran on cardiovascular health management appears significant. Dr Sharda suggests that “in the long run, Inclisiran may offer a more thorough method of controlling cholesterol, addressing the shortcomings of conventional treatments and giving patients a greater possibility of lowering cardiovascular events.”

“Inclisiran is likely to reshape current lipid-lowering treatment strategies in atherosclerotic cardiovascular disease (ASCVD) as well as diabetes in India,” notes Dr Chawla. According to him, it is a valuable add-on for patients who face challenges with adherence or experience adverse effects with existing therapies. Its potential to be used in combination with existing LLT therapies further expands its impact on reducing ASCVD and diabetes-related morbidity and mortality.

“The use of Inclisran must be carefully considered alongside lifestyle interventions, cost, and patient-specific factors. While it provides significant benefits in lipid control, its broader impact on overall health outcomes depends on how it is integrated into a comprehensive care plan,” concludes Dr Reddy.

The medication’s ability to maintain sustained cholesterol reduction with minimal dosing requirements, combined with its favourable safety profile, positions it as a valuable addition to the cardiovascular treatment arsenal. As real-world data continues to accumulate and if cost barriers can be addressed, Inclisiran may indeed fulfil its promise of transforming cholesterol management in India and globally.