Cardiovascular disease (CVD) is considered the most common cause of death in the Arabian Gulf accounting for up to 45% of all mortalities.1 Risk factors for CVD, like dyslipidemia and smoking, are prevalent in young Arab populations. The Gulf Registry of Acute Coronary Events (Gulf RACE)2 and the INTERHEART3 studies have shown that the first presentation of acute myocardial infarction (AMI) in this population is 10–12 years earlier than in their Western counterparts.3

The presence of high low-density lipoprotein (LDL-C) levels is a strong independent risk factor for CVD in several populations worldwide.4 Therefore, LDL-C is accepted by several guidelines to be the primary target of cholesterol-lowering therapy.5-9 However, in the Arabian Gulf, a significant proportion of patients on lipid-lowering drugs (LLDs), mainly those considered to be in the high and very high-risk groups for CVD, are not at their recommended therapeutic LDL-C targets. This was evident from the Centralized pan-Middle East Survey on the undertreatment of hypercholesterolemia (CEPHEUS), which was conducted in 5,276 patients in six Arabian Gulf countries on LLDs. The LDL-C goal was attained in 91.1% of low-risk, 52.7% of high-risk, and 32.0% of very high-risk category patients.10 In a study conducted in 160 dyslipidemic patients in Oman the LDL-C goal was achieved in only 43% of high-risk, 50% of moderate risk, and 90% of low-risk patients.11

There is a high prevalence of diabetes mellitus (DM) and metabolic syndrome (MetS) in the Arabian Gulf in patients with acute coronary syndrome (ACS).12,13 Atherogenic dyslipidemia in these populations is characterized by high triglyceride (TG), low high-density lipoprotein cholesterol (HDL-C), and elevated levels of small, dense LDL particles.14 Patients with these pro-atherogenic lipoproteins remain at a higher risk for residual cardiovascular disease despite attaining optimal LDL-C targets.15,16 In the Gulf RACE survey, 62% of patients with ACS had low HDL-C. This figure was the highest reported in studies on ACS in the region, which ranged from 28% to 57%.17 Moreover, in this study, in-hospital mortality and cardiogenic shock were significantly associated with low levels of HDL-C. Other predictors of low HDL-C levels were a higher body mass index (BMI), prior myocardial infarction, DM, smoking, and renal impairment.17 Despite the lack of evidence from clinical trials on the benefit of raising HDL-C levels to reduce CVD events,18 low HDL-C remains a target for intervention, but mainly through lifestyle therapies especially exercise19 and smoking cessation.20

Beyond LDL-C, both non-HDL-C and apolipoprotein B (ApoB) are considered important lipid markers for not only LDL particles but also for TG-rich lipoprotein concentrations, CVD risk prediction, and monitoring the efficacy of LLDs especially in patients with DM and MetS.21,22 Both markers can be measured in the non-fasting state, but non-HDL-C is usually calculated by substracting the HDL-C concentration from the total cholesterol concentration. ApoB, however, is directly measured making the non-HDL-C a more preferable marker for monitoring lipid targets particularly in terms of cost. Patients with high non-HDL-C levels remained at an increased risk for cardiovascular events despite achieving low LDL-C levels23 and, therefore, several guidelines recommend non-HDL-C as an additional therapeutic target particularly in patients with high triglyceride after reaching their primary LDL-C target.5-9 However, in the Arabian Gulf, a large proportion of patients on LLDs in the high and very high-risk groups for CVD are not at their recommended therapeutic non-HDL-C and ApoB targets. In the CEPHEUS study,24 which included 5,276 patients on LLDs in six Arabian Gulf countries, non-HDL-C and ApoB targets were achieved in 36% and 38% of patients, respectively, in the very high-risk group compared to 58% and 51% of patients, respectively, in the high-risk patients. Factors associated with not meeting targets included patients in the high-risk categories, not receiving optimum doses of statins, treating physicians not adhering to international guidelines, and difficulties with patient compliance.24 Similarly, in a study conducted in Oman in 94 dyslipidemic patients taking LLDs found that the non-HDL-C target was achieved in 53% of patients and ApoB in only 39% of patients in the overall group.25

Another underdiagnosed and undertreated type of dyslipidemia in the Arabian Gulf is familial hypercholesterolemia (FH), which is a common genetic cause of premature coronary heart disease (CHD) due to lifelong elevated plasma LDL-C levels.26,27 There are a few reports on the molecular characteristics of FH in the Middle East and the Arabian Gulf.28-33 A systematic review to identify all FH-related mutations reported in the Middle East and in Western populations identified only 57 mutations in 17 Middle East and North Africa (MENA) countries compared to over 500 mutations in three Western nations.34 The predicted prevalence of FH in the Arabian Gulf could be between 52,277 to 130,693 patients for heterozygous familial hypercholesterolemia (HeFH) (based on a rate of 1:200–500) and 87 to 163 patients for homozygous familial hypercholesterolemia (HoFH) (based on a rate of 1:300,000–600,000). These calculations are based on the National Centre for Statistical Information (NCSI) 2010–2015 census.35 The FH numbers in the region could be higher than predicted due to high consanguinity in the Arabian Gulf.36 The prevalence of FH in the Gulf Countries is unknown due to lack of national registries and genetic screening for FH.34,37,38

There is suboptimal management of dyslipidemia across the Arabian Gulf countries. More aggressive treatment management is required which would include aggressive lifestyle modifications, adherence to international guidelines for lipid management, and the use of optimal lipid lowering therapies.

references

1. Husseini A, Abu-Rmeileh NM, Mikki N, Ramahi TM, Ghosh HA, Barghuthi N, et al. Cardiovascular diseases, diabetes mellitus, and cancer in the occupied Palestinian territory. Lancet 2009 Mar;373(9668):1041-1049.
2. Zubaid M, Rashed WA, Almahmeed W, Al-Lawati J, Sulaiman K, Al-Motarreb A, et al. Management and outcomes of Middle Eastern patients admitted with acute coronary syndromes in the Gulf Registry of Acute Coronary Events (Gulf RACE). Acta Cardiol 2009 Aug;64(4):439-446.
3. Gehani AA, Al-Hinai AT, Zubaid M, Almahmeed W, Hasani MR, Yusufali AH, 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 Apr;21(4):400-410.
4. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003 Jun;326(7404):1423.
5. Grundy SM. Low-density lipoprotein, non-high-density lipoprotein, and apolipoprotein B as targets of lipid-lowering therapy. Circulation 2002 Nov;106(20):2526-2529.
6. Brunzell JD, Davidson M, Furberg CD, Goldberg RB, Howard BV, Stein JH, et al; American Diabetes Association; American College of Cardiology Foundation. Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care 2008 Apr;31(4):811-822.
7. Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, et al; European Association for Cardiovascular Prevention & Rehabilitation; ESC Committee for Practice Guidelines (CPG) 2008-2010 and 2010-2012 Committees. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011 Jul;32(14):1769-1818.
8. Expert Dyslipidemia Panel of the International Atherosclerosis Society Panel members. An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia–full report. J Clin Lipidol 2014 Jan-Feb;8(1):29-60.
9. Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays HE, Jones PH, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 - executive summary. J Clin Lipidol 2014 Sep-Oct;8(5):473-488.
10. Arafah M, Al-Hinai AT, Al Mahmeed W, Al-Rasadi K, Al Tamimi O, Al Herz S, et al. Centralized pan-Middle East Survey on the undertreatment of hypercholesterolemia: results from the CEPHEUS study in Arabian Gulf countries. Angiology 2014 Nov;65(10):919-926.
11. Al-Siyabi K, Farhan H, Al-Rasadi K, Al-Salhi A, Al-Hinai AT, Al-Zakwani I. Safety of simvastatin and goal attainment for low-density lipoprotein cholesterol in sultan qaboos university hospital. Oman Med J 2010 Oct;25(4):264-268.
12. Thalib L, Zubaid M, Rashed W, Suwaidi JA, Almahmeed W, Alozairi E, et al. Impact of diabetic status on the hyperglycemia-induced adverse risk of short term outcomes in hospitalized patients with acute coronary syndromes in the Middle East: findings from the Gulf registry of Acute Coronary Events (Gulf RACE). Clin Med Res 2011 Mar;9(1):32-37.
13. Al Suwaidi J, Zubaid M, El-Menyar AA, Singh R, Rashed W, Ridha M, et al. Prevalence of the metabolic syndrome in patients with acute coronary syndrome in six middle eastern countries. J Clin Hypertens (Greenwich) 2010 Nov;12(11):890-899.
14. Al-Rasadi K, Sulaiman K, Panduranga P, Al-Zakwani I. Prevalence, characteristics, and in-hospital outcomes of metabolic syndrome among acute coronary syndrome patients from Oman. Angiology 2011 Jul;62(5):381-389.
15. Fruchart JC, Sacks FM, Hermans MP, Assmann G, Brown WV, Ceska R, et al; Residual Risk Reduction Initiative (R3I). The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patient. Diab Vasc Dis Res 2008 Nov;5(4):319-335.
16. Hermans MP, Fruchart J-C. Reducing Residual Vascular Risk in Patients with Atherogenic Dyslipidemia: Where do we go from here? Clin Lipidol 2010;5:811-826.
17. Al-Rasadi K, Al-Zakwani I, Zubaid M, Ali A, Bahnacy Y, Sulaiman K, et al. Prevalence, Predictors, and Impact of Low High-Density Lipoprotein Cholesterol on in-Hospital Outcomes Among Acute Coronary Syndrome Patients in the Middle East. Open Cardiovasc Med J 2011;5:203-209.
18. Keene D, Price C, Shun-Shin MJ, Francis DP. Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients. BMJ 2014;349:g4379.
19. Tanasescu M, Leitzmann MF, Rimm EB, Willett WC, Stampfer MJ, Hu FB. Exercise type and intensity in relation to coronary heart disease in men. JAMA 2002 Oct;288(16):1994-2000.
20. Mons U, Müezzinler A, Gellert C, Schöttker B, Abnet CC, Bobak M, et al. Impact of smoking and smoking cessation on cardiovascular events and mortality among older adults: meta-analysis of individual participant data from prospective cohort studies of the CHANCES consortium. BMJ 2015 Apr;350:h1551.
21. Boekholdt SM, Arsenault BJ, Mora S, Pedersen TR, LaRosa JC, Nestel PJ, et al. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA 2012 Mar;307(12):1302-1309.
22. Sniderman AD, Williams K, Contois JH, Monroe HM, McQueen MJ, de Graaf J, et al. A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B as markers of cardiovascular risk. Circ Cardiovasc Qual Outcomes 2011 May;4(3):337-345.
23. Kastelein JJ, van der Steeg WA, Holme I, Gaffney M, Cater NB, Barter P, et al; TNT Study Group; IDEAL Study Group. Lipids, apolipoproteins, and their ratios in relation to cardiovascular events with statin treatment. Circulation 2008 Jun;117(23):3002-3009.
24. Al-Rasadi K, Al-Zakwani I, Al Mahmeed W, Arafah M, Al-Hinai AT, Shehab A, et al. Therapeutic lipid target achievements among high and highest risk patients: results from the CEPHEUS study in the Arabian Gulf. Curr Med Res Opin 2014 Dec;30(12):2429-2435.
25. Al-Waili K, Al-Zakwani I, Al-Dughaishi T, Baneerje Y, Al-Sabti H, Al-Hashmi K, et al. Comparison of therapeutic lipid target achievements among high-risk patients in Oman. Angiology 2014 May;65(5):430-435.
26. Goldstein JK. Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The Metabolic & Molecular Bases of Inherited Disease. 8th ed. McGraw-Hill, Inc; New York: 2001. p. 2863-2913.
27. Austin MA, Hutter CM, Zimmern RL, Humphries SE. Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. Am J Epidemiol 2004 Sep;160(5):407-420.
28. Al-Hinai AT, Al-Abri A, Al-Dhuhli H, Al-Waili K, Al-Sabti H, Al-Yaarubi S, et al. First case report of familial hypercholesterolemia in an Omani family due to novel mutation in the low-density lipoprotein receptor gene. Angiology 2013 May;64(4):287-292.
29. Al-Waili K, Al-Zidi WA, Al-Abri AR, Al-Rasadi K, Al-Sabti HA, Shah K, et al. Mutation in the PCSK9 Gene in Omani Arab Subjects with Autosomal Dominant Hypercholesterolemia and its Effect on PCSK9 Protein Structure. Oman Med J 2013 Jan;28(1):48-52.
30. Al-Rasadi K, Al-Waili K, Al-Zidi WA, Al-Abri AR, Al-Hinai AT, Al-Sabti HA, et al. Low-density lipoprotein receptor gene mutation analysis and structure-function correlation in an Omani arab family with familial hypercholesterolemia. Angiology 2014 Nov;65(10):911-918.
31. Al-Rasadi K, Al-Waili K, Al-Sabti HA, Al-Hinai A, Al-Hashmi K, Al-Zakwani I, et al. Criteria for Diagnosis of Familial Hypercholesterolemia: A Comprehensive Analysis of the Different Guidelines, Appraising their Suitability in the Omani Arab Population. Oman Med J 2014 Mar;29(2):85-91.
32. Shawar SM, Al-Drees MA, Ramadan AR, Ali NH, Alfadhli SM. The Arabic allele: a single base pair substitution activates a 10-base downstream cryptic splice acceptor site in exon 12 of LDLR and severely decreases LDLR expression in two unrelated Arab families with familial hypercholesterolemia. Atherosclerosis 2012 Feb;220(2):429-436.
33. Al-Allaf FA, Athar M, Abduljaleel Z, Taher MM, Khan W, Ba-Hammam FA, et al. Next generation sequencing to identify novel genetic variants causative of autosomal dominant familial hypercholesterolemia associated with increased risk of coronary heart disease. Gene 2015 Jul;565(1):76-84.
34. Bamimore MA, Zaid A, Banerjee Y, Al-Sarraf A, Abifadel M, Seidah NG, et al. Familial hypercholesterolemia mutations in the Middle Eastern and North African region: a need for a national registry. J Clin Lipidol 2015 Mar-Apr;9(2):187-194.
35. National Centre for Statistical Information (NCSI). Available at: http://www.ncsi.gov.om/NCSI_website/N_default.aspx. Accessed on March 5, 2015.
36. el-Hazmi MA, al-Swailem AR, Warsy AS, al-Swailem AM, Sulaimani R, al-Meshari AA. Consanguinity among the Saudi Arabian population. J Med Genet 1995 Aug;32(8):623-626.
37. Al-Ashwal A, Alnouri F, Sabbour H, Al-Mahfouz A, Al-Sayed N, Razzaghy-Azar M, et al. Identification and treatment of patients with homozygous familial hypercholesterolaemia: information and recommendations from a Middle East advisory panel. Curr Vasc Pharmacol 2015;13(6):759-770.
38. Vallejo-Vaz AJ, Kondapally Seshasai SR, Cole D, Hovingh GK, Kastelein JJ, Mata P, et al. Familial hypercholesterolaemia: A global call to arms. Atherosclerosis 2015 Nov;243(1):257-259.