Indian dyslipidaemia guidelines: Need of the hour

1. Introduction

At 75 years of independence, India is now among the fastest-growing and robust economies in the world. The country has also made enormous progress in the health sector. Life expectancy is more than 70 years, infant and under-five mortality rates are rapidly declining and many diseases have been vanquished.¹ Yet challenges remain. Non-communicable diseases (NCD) are the leading cause of death in the country contributing to 60 % of deaths. Cardiovascular diseases have overtaken infectious diseases and maternal, neonatal and childhood causes of death as the most important cause of disability and death in India.² The Indian State-Level Disease Burden Initiative reported that epidemiological transition index (ratio of maternal, neonatal and childhood conditions to noncommunicable disease deaths) has reversed in all the states of the country over the last 30 years.² As per Indian estimates, amongst NCD deaths, the largest proportion is attributable to CVD (48 %) followed by cancers (21 %). There is sufficient evidence that CVDs-both coronary artery disease (CAD) and strokes-occur much earlier in Indians than in developed countries of Europe and North America.³ The Global Burden of Disease (GBD) study has estimated that while death rates from CAD are declining in most developed countries, they are increasing in India and many developing countries of South Asia and Africa.⁴

2. Challenges unique to India

2.1. Higher and earlier risk

The Global Burden of Diseases study reported an age-standardised CVD death rate of 272/100,000 in India compared to the global average of 235/100,000 for the year 2019.⁴ Case-control and prospective studies have reported that CAD events occur almost a decade earlier in Indians: mean age of 52 years versus the global average of 62 years.^5,6 Of particular concern is that CVDs affect the most productive age groups (35–65 years). This has devastating consequences not only for the patient but also for the dependent family as well as society. To further complicate the situation, there are regional differences in CVD, within India.³ The rates of CVD are highest in the states of Kerala, Punjab, and Tamil Nadu. However, despite these regional variations, CVD is the leading cause of death in all parts of India, including less developed states and rural areas.³

The question is-why is there a higher and earlier risk of CVD in Indians? A variety of risk factors could be at play and include raised low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein (non-HDL) cholesterol, diabetes (or impaired glucose tolerance), hypertension, stress, abdominal obesity, and metabolic syndrome. A sedentary lifestyle, smoking/tobacco use, alcohol abuse, ambient and indoor pollution, unhealthy dietary patterns, and widely prevalent social determinants of health also add to burden of CVD. The diet in India is primarily vegetarian (high in vegetables, pulses, and grains) but incorporates high intake of saturated and trans-fats, refined carbohydrates, and unhealthy meats. However, it is difficult to define an average Indian diet as there are significant regional variations in dietary patterns.⁷ Indians generally have a high carbohydrate diet (65–75 %), which is likely the culprit for the raised triglycerides (TG) levels. Indians also have a higher prevalence of atherogenic dyslipidaemia (mix of high TG and small dense LDL particles with low HDL cholesterol) than the Western population due to physical inactivity, and a diet deficient in polyunsaturated fatty acids (PUFA).⁸ The preferred Indian style of cooking which involves the use of partially hydrogenated fats, reheated oils, and high-heat cooking leads to neo-formed contaminants (such as trans-fatty acids) and advanced glycation end-products which likely contribute to the higher and earlier risk of CVD in Indians.⁹ Clearly, larger and regional studies are required to evaluate the range of Indian dietary patterns so that critical links between diet and dyslipidaemia can be identified and appropriate guidelines developed.

2.2. Lipid abnormalities (Table 1)

Table 1.

Salient features of Indian dyslipidemia.

•Indians have a higher prevalence of dyslipidemia

ꞏLow HDL cholesterol is present in two-thirds of the adult population

ꞏLDL cholesterol >100 mg/dL and non-HDL cholesterol >130 mg/dL in half of population

ꞏRaised total cholesterol and triglycerides in more than one-third.

•In India the prevalence of various dyslipidemias has increased over the past 30 years. This is in contrast to developed countries where it is declining.

•Population levels of mean total cholesterol, LDL cholesterol and triglycerides are increasing.

•A high prevalence of atherogenic dyslipidemia and metabolic syndrome among Indians is an important feature.

•The propensity for dyslipidemia is noted at a younger age among Indians.

•Awareness and treatment of dyslipidemia is abysmally low in India. Control rates are unknown.

•Both genetic and lifestyle factors are important contributors to this early and increased prevalence of lipid abnormalities among Indians.

Dyslipidemias that are considered important in our population, based on case–control studies, are raised total, LDL and non-HDL cholesterol, triglycerides and lipoprotein(a) and low HDL cholesterol.^5,6,10,11 Metabolic non-communicable disease health report of India: the ICMR-INDIAB nationwide cross-sectional epidemiological study (ICMR-INDIAB-17)¹² on 113043 individuals (79506 from rural and 33537 from urban areas) showed the overall prevalence of dyslipidemia to be 81.2 %. Low HDL cholesterol accounted for most with a prevalence of 66.9 %. Both low HDL cholesterol and high TG were uniformly prevalent across India while high LDL cholesterol showed significant regional variability with the highest prevalence in the northern states, Kerala, Goa, and West Bengal. Prospective studies have reported a significant association of raised non-HDL cholesterol with the incident CVD and CAD in population-based as well as clinic-based cohorts.

In recent years, familial hypercholesterolemia (FH) with an estimated prevalence of >15 % in Indian youngsters unlike the global prevalence of 5–10 %, has been identified as another factor that predisposes Indians to CVD.¹³ Nearly 5 % of acute coronary syndromes in patients <60 years and about 20 % at age <45 years are attributed to familial heterozygous hypercholesterolemia (FHeH).¹⁴ It may be noted that dyslipidaemia patterns and characteristics amongst Indians and Caucasians are different.^11,15 For instance, Indians typically have high triglycerides and atherogenic dyslipidaemia (vide supra).¹⁵ Studies have reported that apolipoprotein B (ApoB) is significantly higher in Asian Indians than in Americans.¹⁵ Similarly, lipoprotein(a) [Lp(a)] which is one of the strongest genetic risk factor for premature CAD, is present in about 25 % of Indians and other South Asians compared to 20 % in Caucasians.¹⁶ This has been recommended as essential focus for CVD research in Indians. Of late, non-HDL cholesterol has emerged as an important CAD risk factor because it is the summation of all atherogenic lipid particles- LDL, intermediate-density lipoproteins and remnants.¹⁷ Non-HDL cholesterol >130 mg/dl is prevalent in more than 50 % of Indian populations in various epidemiological studies.¹⁸ Non-HDL cholesterol has the advantage over LDL cholesterol as it includes remnant cholesterol and is independent of triglyceride variability. Although low HDL cholesterol is presently considered a CAD risk marker and not a risk factor¹⁷, it is the most common form of dyslipidaemia in India and among emigrant South Asians.^15,16,18 More studies are required in our population because of its ubiquitousness and to evaluate the effects of clinical and therapeutic interventions.

2.3. Differences in drug pharmacokinetics

Statins, which are the cornerstone of hypercholesterolemia therapy, are reported to yield higher plasma levels (almost 1.5–2.3 times) when given in the same dose to different Asian ethnic groups, as compared to Caucasians.^19,20 This in turn makes Asians more susceptible to the adverse effects of statins. Statins also raise the risk of diabetes, which is of particular concern in our country with a high prevalence of metabolic syndrome and needs to be rigorously investigated.¹¹ There are suggestions that considering the risk of diabetes with statins, combination therapy with ezetimibe may be a better option.²¹ A clinical study compared low-dose vs high-dose atorvastatin (40 mg vs 80 mg) on LDL cholesterol in Indian patients with atherosclerotic dyslipidaemia.²² This study found that both doses of atorvastatin (40 mg and 80 mg) were equally efficacious in improving dyslipidaemia, a higher dose led to more myalgias. Thus, the benefit of the higher dose needs to be weighed against greater (observed) incidence of myalgia, risk of drug discontinuation, and (possibly avoidable) additional cost to the patient. To establish the correct dosage for the Indian population and CAD patients more and larger clinical trials are needed.

2.4. Poor awareness, treatment, and control

The India Heart Watch study reported that in urban middle-class populations²³, hypercholesterolemia awareness, treatment, and control rates in men and women respectively were, awareness 17.5 % and 13.2 %, treatment 7.5 % and 6.7 % and control 4.5 % and 3.7 %. These rates are much lower than in the US and Western European countries.²⁴ Researchers have also reported that prescriptions of statins and their dosage in primary and secondary clinic-based patients and in those nwith type 2 diabetes in India are suboptimal.^25,26

3. Call to action

These challenges and alarming statistics unique to India are of major concern and demand an urgent call to action with appropriate and uniform guidelines for screening, identification, categorisation, and treatment. While there are several global guidelines for the management of CAD^27,28, unfortunately, none of these are based on Indian data. Given that the disease characteristics and patterns in Indians are different, it is inconceivable that Western evidence-based medicine would be as effective for the Indian community.

Four major international guidelines are widely referred: American College of Cardiology/American Heart Association (ACC/AHA)²⁷, the Canadian Cardiovascular Society (CCS)²⁸, European Society for Cardiology/European Atherosclerosis Society (ECS/EAS)²⁹, and the National Institute for Health and Care Excellence (NICE)³⁰ guidelines. Despite commonalities, the guidelines differ in their risk calculator algorithms, lipid goals, and treatment strategies, based on their country-specific research data. Due to these differences and lack of clarity amongst cardiologists and physicians, as to which guidelines are best suited to the Indian patient, there is wide disparity in CVD risk calculation, lipid goals, and treatment plans. Given these differences, we must develop our guidelines that are tailor-made to suit our unique genetic, ethnic, and sociocultural fabric rather than be forced to rely on guidelines issued by the western countries based on evidence generated on their populations.

4. Knowledge gaps

However, the biggest challenge in developing our guidelines is a lack of large-scale prospective studies that define normal lipid values and their relationship with the development of CAD in Indians. While some Indian data is available, most are regional studies, which are not representative of the entire Indian population.³¹ Another major hurdle in lipid management in India has been the common use of non-standardised laboratories by physicians across the country, for both, patient management as well as generating research data.³² Studies have reported low prescription rates and adherence to statins among out-patients with CAD.^25,26 Studies that compare high vs low doses of statins, combination therapies with ezetimibe, and other non-statin drugs are also needed.

5. The first steps

Despite the gaps, it is heartening to note that given the large South Asian diaspora, many large international trials have begun to undertake sub-analyses based on ethnic groups, giving some valuable insights. In addition, in India, indigenous data regarding the epidemiology of various dyslipidemias including FH, statin efficacy, metabolism, dietary factors, regional variations, etc. is growing steadily. Lipid Association of India (LAI) has published consensus statements guided by an expert panel to adapt the Western guidelines to Indians.33, 34, 35, 36 The LAI guidelines have also focused on non-HDL cholesterol as a more valuable index of CAD risk in Indians and have recommended using non-HDL cholesterol as a co-primary target along with the primary target of LDL cholesterol lowering by statins. The present guidelines, supplement and complement the LAI consensus statement. In addition, we (a panel of experts) have adapted the 2019 ESC dyslipidaemia guideline recommendations to the Indian setting as they include some data on UK-based Indians.^29,37 However, as summarised by Menon et al, the absence of Indian guidelines has led to physicians basing treatment on individual preference, contributing to heterogeneity.³⁸ Further, the fact remains that these statements are based on trials, which do not have representative South Asian or Indian populations.

6. Limitations and opportunities

The enclosed consensus statement and executive summary³⁹ brings to the table, for the first time, guidelines customised for the Indian population. We concede, however, that in many instances, hard-core Indian data are not available and we have had to tweak the international guidelines with the help of expert opinions of the combined experience of top specialists in this field working in India. We hope that these guidelines will not only bring uniformity and clarity in the country regarding the management of dyslipidaemia but also promote and inspire researchers to fill in the gaps so that with subsequent revisions, these guidelines are further strengthened. For instance, an article in this issue discusses the European Atherosclerosis Society FH Studies Collaboration (FHSC), an observational study, which is attempting to address the global burden of FH.⁴⁰ About 87 National Lead Investigators from 74 countries (including India) are part of this global consortium, and their coordinating centre welcomes interest from potential new investigators and invites specialist clinicians to list their lipid clinics. This could be an excellent opportunity for Indian researchers to provide valuable insights into this nationally under-recognised, often misdiagnosed and inadequately treated condition. Randomised clinical studies are needed in India to define optimal strategies to manage dyslipidemias in our country as sub-studies of larger international clinical trials are not the best way to develop guidelines.⁴¹

7. Conclusions

Given the disparities in CAD and dyslipidaemia patterns in our country, evidence-based guidelines based on non-Indian studies should not be transplanted onto Indians without considering the ethnic, genetic as well as sociocultural, and economic diversities. These factors necessitate customised guidelines targeting aggressive and early screening and treatment, particularly of lipids which are a crucial and modifiable factor for triggering atherosclerotic CVD. With the present initiative, we have attempted to develop India-centric clinical practice guidelines for the management of dyslipidaemia building on the previous consensus statements. We believe that this special issue Indian Heart Journal on Clinical Practice Guidelines on Management of Dyslipidemia shall offer something for all healthcare professionals working in this field where dyslipidemia is commonly encountered, and questions and doubts are all-pervasive. For busy clinician the Executive Summary³⁹ could be adequate for providing the best care to their patients. Additionally, for those who have a keen research interest, each article is a goldmine of information especially regarding lacunae and gaps. They only need to identify their field of interest and engage in data generation of the Indians, for the Indians, and by the Indians. We hope more and more researchers will come forward and pick up an area of their interest and bit by bit plug the knowledge gaps so that in the not-so-distant future, we can develop clinical practice guidelines for the management of dyslipidaemia in the Indian patient that is based on evidence-informed data gathered from the Indian population.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.