R3i Editorial

The developed world has seen substantial improvement in the management of cardiovascular disease (CVD), particularly in the acute setting. Indeed, in Western and Central Europe, these gains in cardiovascular health have been sufficient to counteract demographic forces.¹ The situation in economically emerging regions is, however, less promising. Increasingly, the vast majority of deaths due to CVD occur here, usually at younger ages than in developed countries, with a correspondingly greater impact on the burden of CVD, both in terms of the individual and societal cost.

Adoption of a Westernized diet and sedentary lifestyle, fuelled by greater urbanization and socioeconomic improvement, has been a major driver of this escalation in CVD in developing regions. Thus, it is not surprising that in India, one of the major economies of the future, obesity was reported to be nearly 3 times more prevalent in urban areas than in rural regions,² contributing to exponential increases in diabetes and cardiometabolic disease prevalence. Already by 2015, India and China topped the league table for the number of people with diabetes. By 2040, it is anticipated that these countries will be joined by others in Asia, as well as representation from those in the Middle East and South America.³

Targeting elevated low-density lipoprotein cholesterol (LDL-C) is undoubtedly the cornerstone for lipid-lowering approaches to prevent CVD. Yet where insulin resistant states are prevalent, other lipid abnormalities also merit therapeutic intervention. Notably, atherogenic dyslipidaemia, the combination of elevated triglycerides (a marker for triglyceride-rich lipoproteins and their remnants) and low high-density lipoprotein (HDL-C), is a dyslipidaemic profile commonly associated with type 2 diabetes, perhaps more so in developing than developed regions, and contributes to non-LDL-related risk for CVD.(4-7) As highlighted in this month’s Focus report,⁸ in the dyslipidaemia Residual and Mixed Abnormalities IN spite of Statin therapy (REMAINS) study of 474 patients hospitalized for an acute coronary syndrome, nearly half had low HDL-C, one in 5 had elevated triglycerides and about 1 in 8 had atherogenic dyslipidaemia, irrespective of LDL-C levels. The underlying reasons why atherogenic dyslipidaemia is more prevalent in South Asians may relate to underlying differences in diet, specifically carbohydrate and saturated fat intake, body composition, insulin sensitivity, as well as in the capacity to store fatty acids in subcutaneous adipose tissue, resulting in intra-abdominal or ectopic fat accumulation, which in turn promotes adverse effects on inflammation and glucose metabolism, contributing to increased cardiovascular risk.(9.10) Additionally, the activity of cholesteryl ester transfer protein (CETP) may play a role in the underlying pathogenesis of atherogenic dyslipidaemia among South Asians.¹¹

Irrespective of the underlying cause, it is clear that, as shown by studies in the US and Europe, statin therapy alone is inadequate for management of atherogenic dyslipidaemia. Added to this, the REMAINS study showed that high dose atorvastatin therapy although effective in management of elevated LDL-C levels had no effect on atherogenic dyslipidaemia.⁸

Early prevention and control of dyslipidaemia is of paramount importance to reduce the risk of CVD. It is clear that there is a gap in recognizing and managing atherogenic dyslipidaemia appropriately in developing countries so as to reduce the associated residual cardiovascular risk. The Residual Risk Reduction Initiative joins with other experts ^12,13 in highlighting the need for urgent action to develop local guidelines for the diagnosis and management of residual non-LDL dyslipidaemia that are specific to each region. Education of the public and healthcare professionals is also key.

It has taken over 20 years since the first report of the 4S study to develop novel agents that are effective in lowering elevated LDL-C levels in patients on statin therapy. Yet while LDL-C is clearly the priority lipid target in CVD prevention, it is important that clinicians are not blinded to the need to identify and treat non-LDL lipid abnormalities that also contribute to cardiovascular risk. We look forward to new initiatives aimed at addressing the unmet clinical need of lipid-related residual cardiovascular risk. While we have made some inroads,¹⁴ there is still clearly much to learn.

References
1. Roth GA, Forouzanfar MH, Moran AE et al. Demographic and epidemiologic drivers of global cardiovascular mortality. N Eng J Med 2015;372:1333-41.
2. Siddiqui ST, Kandala NB, Stranges S. Urbanisation and geographic variation of overweight and obesity in India: a cross-sectional analysis of the Indian Demographic Health Survey 2005-2006. Int J Public Health 2015;60:717-26.
3. IDF Diabetes Atlas. 7th Edition, 2015. http://www.diabetesatlas.org/resources/2015-atlas.html
4. Guptha S, Gupta R, Deedwania P et al. Cholesterol lipoproteins and prevalence of dyslipidemias in urban Asian Indians: a cross sectional study. Indian Heart J 2014;66:280–8.
5. Raal FJ, Blom DJ, Naidoo S et al. Prevalence of dyslipidaemia in statin-treated patients in South Africa: results of the DYSlipidaemia International Study (DYSIS). Cardiovasc J Afr 2013;24:330-8.
6. Karthikeyan G, Teo K.K., Islam S. Lipid profile, plasma apolipoproteins, and risk of a first myocardial infarction among Asians: an analysis from the INTERHEART study. J Am Coll Cardiol 2009;53:244–53.
7. Gehani AA, Al-Hinai AT, Zubaid M et al. INTERHEART Investigators in Middle East. Association of risk factors with acute myocardial infarction in Middle Eastern countries: the INTERHEART Middle East study. Eur J Prev Cardiol 2014; 21:400-10.
8. Jaywant SV, Singh AK, Prabhu MS, Ranjan R. Statin therapy/lipid lowering therapy among Indian adults with first acute coronary event: The dyslipidemia Residual and Mixed Abnormalities IN spite of Statin therapy (REMAINS) study. Indian Heart J 2016;68:646-54.
9. Sniderman AD, Bhopal R, Prabhakaran D et al. Why might South Asians be so susceptible to central obesity and its atherogenic consequences? The adipose tissue overflow hypothesis. Int J Epidemiol 2007;36:220–5.
10. Anand SS, Tarnopolsky MA, Rashid S et al. Adipocyte hypertrophy, fatty liver and metabolic risk factors in South Asians: the Molecular Study of Health and Risk in Ethnic Groups (mol-SHARE). PLoS One 2011;6⁷:e22112.
11. Rashid S, Sniderman A, Melone M et al. Elevated cholesteryl ester transfer protein (CETP) activity, a major determinant of the atherogenic dyslipidemia, and atherosclerotic cardiovascular disease in South Asians. Eur J Prev Cardiol 2015;22:468-77.
12. Al Rasadi K, Almahmeed W, AlHabib KF et al. Dyslipidaemia in the Middle East: Current status and a call for action. Atherosclerosis 2016;252:182-7.
13. Mishra S, Chaturvedi V. Are western guidelines good enough for Indians? My name is Borat. Indian Heart J 2015;67:85–9.
14. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol;13:26.