Journal of Taibah University Medical Sciences (2016) 11(4), 330e338

Taibah University

Journal of Taibah University Medical Sciences

www.sciencedirect.com

Review Article

Coronary artery disease and diabetes mellitus

Mansour M. Al-Nozha, FACC a, *, Hussein M. Ismail, MD b and
Omar M. Al Nozha, MD a
a
Department of Medicine, School of Medicine, Taibah University, Almadinah Almunawwarah, KSA
b
Cardiology Department, School of Medicine, Suez Canal University, Ismailia, Egypt

Received 4 October 2015; revised 27 March 2016; accepted 28 March 2016; Available online 2 May 2016

‫ﻟﻤﻠﺨﺺ‬ prevalence of DM and CAD is growing primarily due to

the rising prevalence of obesity. The rapidly changing life
‫ ﻫﻨﺎﻙ ﻋﻼﻗﺔ ﻭﻃﻴﺪﺓ ﺑﻴﻦ ﻣﺮﺽ ﺍﻟﺴﻜﺮﻱ ﻭﻣﺮﺽ ﺍﻟﺸﺮﺍﻳﻴﻦ‬:‫ﺃﻫﺪﺍﻑ ﺍﻟﺒﺤﺚ‬ style, especially in developing countries, plays major role
‫ ﻭﻻ ﺗُـﻌﺪ ﺍﻹﺻﺎﺑﺔ ﺑﻤﺮﺽ ﺍﻟﺴﻜﺮﻱ ﻣﺠﺮﺩ ﻋﺎﻣﻞ ﺧﻄﻮﺭﺓ ﻟﻺﺻﺎﺑﺔ‬.‫ﺍﻟﺘﺎﺟﻴﺔ‬ in the occurrence of these diseases.
‫ ﻭﺇﻧﻤﺎ ﺗﻌﺘﺒﺮ ﻣﺴﺎﻭﻳﺔ ﻟﻤﻦ ﻫﻮ ﻓﻌﻼ ﻣﺼﺎﺏ ﺑﺄﻣﺮﺍﺽ‬٬‫ﺑﺄﻣﺮﺍﺽ ﺍﻟﺸﺮﺍﻳﻴﻦ ﺍﻟﺘﺎﺟﻴﺔ‬
‫ ﻭُﻳﻌﺰﻯ ﺫﻟﻚ ﺑﺎﻟﺪﺭﺟﺔ ﺍﻷﻭﻟﻰ‬٬‫ ﻧﺴﺐ ﺍﻧﺘﺸﺎﺭ ﺍﻟﻤﺮﺿﻴﻦ ﻓﻲ ﺍﺯﺩﻳﺎﺩ‬.‫ﺍﻟﺸﺮﺍﻳﻴﻦ ﺍﻟﺘﺎﺟﻴﺔ‬ Methods: We performed a literature review to summarize
‫ ﻻﺳﻴﻤﺎ ﻓﻲ ﺍﻟﺪﻭﻝ‬٬‫ ﻭﻳﻠﻌﺐ ﺍﻟﺘﻐﻴﺮ ﺍﻟﺴﺮﻳﻊ ﻓﻲ ﻧﻤﻂ ﺍﻟﺤﻴﺎﺓ‬.‫ﺇﻟﻰ ﺯﻳﺎﺩﺓ ﺍﻧﺘﺸﺎﺭ ﺍﻟﺴﻤﻨﺔ‬ and explore the relationship between CAD and DM with
.‫ ﺩﻭﺭﺍ ﺭﺋﻴﺴﺎ ﻓﻲ ﺍﻹﺻﺎﺑﺔ ﺑﺎﻟﻤﺮﺿﻴﻦ‬٬‫ﺍﻟﻨﺎﻣﻴﺔ‬ a special focus on Arab countries in terms of risk factors
and prevalence. We suggest future directions to prevent
‫ ﻗﻤﻨﺎ ﺑﺪﺭﺍﺳﺔ ﺍﺳﺘﺮﺟﺎﻋﻴﺔ ﻟﻸﺩﺑﻴﺎﺕ ﺑﻬﺪﻑ ﺗﻠﺨﻴﺺ ﻭﺍﺳﺘﻜﺸﺎﻑ‬:‫ﻃﺮﻕ ﺍﻟﺒﺤﺚ‬ escalation in the incidence of DM and CAD in Arab
‫ ﻣﻊ ﺗﺮﻛﻴﺰ ﺧﺎﺹ ﻋﻠﻰ‬،‫ﺍﻟﻌﻼﻗﺔ ﺑﻴﻦ ﻣﺮﺽ ﺍﻟﺴﻜﺮﻱ ﻭﺃﻣﺮﺍﺽ ﺍﻟﺸﺮﺍﻳﻴﻦ ﺍﻟﺘﺎﺟﻴﺔ‬ countries.
‫ ﻛﻤﺎ ﻧﻘﺘﺮﺡ ﺍﺗﺠﺎﻫﺎﺕ‬.‫ﺍﻟﺪﻭﻝ ﺍﻟﻌﺮﺑﻴﺔ ﻓﻲ ﻣﺎ ﻳﺨﺺ ﻋﻮﺍﻣﻞ ﺍﻟﺨﻄﻮﺭﺓ ﻭﻧﺴﺒﺔ ﺍﻻﻧﺘﺸﺎﺭ‬
.‫ﻣﺴﺘﻘﺒﻠﻴﺔ ﻟﻤﻨﻊ ﺍﻟﺰﻳﺎﺩﺓ ﻓﻲ ﺍﻧﺘﺸﺎﺭ ﺍﻟﻤﺮﺿﻴﻦ ﻓﻲ ﺍﻟﺪﻭﻝ ﺍﻟﻌﺮﺑﻴﺔ‬ Conclusion: An important part of any preventive pro-
gram for CAD should include clear prevention strategies
‫ ﻳﺠﺐ ﺃﻥ ﻳﺸﺘﻤﻞ ﺃﻱ ﺑﺮﻧﺎﻣﺞ ﻭﻗﺎﺋﻲ ﻷﻣﺮﺍﺽ ﺍﻟﺸﺮﺍﻳﻴﻦ ﺍﻟﺘﺎﺟﻴﺔ ﻋﻠﻰ‬:‫ﺍﻻﺳﺘﻨﺘﺎﺟﺎﺕ‬ for DM and other associated metabolic risk factors, such
‫ ﻭﻏﻴﺮﻩ ﻣﻦ ﻋﻮﺍﻣﻞ ﺍﻟﺨﻄﻮﺭﺓ ﺍﻷﻳﻀﻴﺔ‬،‫ﺍﺳﺘﺮﺍﺗﻴﺠﻴﺎﺕ ﻟﻠﻮﻗﺎﻳﺔ ﻣﻦ ﻣﺮﺽ ﺍﻟﺴﻜﺮﻱ‬ as obesity. Preventive measures, such as physical exercise
‫ ﻛﻤﺎ ﻳﻨﺒﻐﻲ ﺍﻟﺘﺸﺠﻴﻊ ﻋﻠﻰ ﺍﻹﺟﺮﺍﺀﺍﺕ ﺍﻟﻮﻗﺎﺋﻴﺔ ﻣﺜﻞ‬.‫ﺍﻟﻤﺼﺎﺣﺒﺔ ﻟﻪ ﻣﺜﻞ ﺍﻟﺴﻤﻨﺔ‬ in high-risk groups, at the population level should be
.‫ﺍﻟﺘﻤﺎﺭﻳﻦ ﺍﻟﺮﻳﺎﺿﻴﺔ ﻓﻲ ﺍﻟﻔﺌﺎﺕ ﺍﻟﻤﺠﺘﻤﻌﻴﺔ ﺍﻟﻤﻌﺮﺿﺔ ﻟﻺﺻﺎﺑﺔ‬ encouraged.
‫ ﺍﻟﻌﺎﻟﻢ ﺍﻟﻌﺮﺑﻲ؛ ﻣﺮﺽ ﺍﻟﺴﻜﺮﻱ؛ ﺍﻟﺴﻤﻨﺔ؛ ﺃﻣﺮﺍﺽ ﺍﻟﺸﺮﺍﻳﻴﻦ‬:‫ﺍﻟﻜﻠﻤﺎﺕ ﺍﻟﻤﻔﺘﺎﺣﻴﺔ‬ Keywords: Arab world; Coronary artery disease; Diabetes
‫ﺍﻟﺘﺎﺟﻴﺔ؛ ﺍﻟﺘﻤﺎﺭﻳﻦ ﺍﻟﺮﻳﺎﺿﻴﺔ‬ mellitus; Obesity; Physical exercise

Ó 2016 The Authors.

Abstract Production and hosting by Elsevier Ltd on behalf of Taibah
University. This is an open access article under the CC BY-
Objectives: Diabetes mellitus (DM) and coronary artery NC-ND license (http://creativecommons.org/licenses/by-nc-
disease (CAD) are closely related. DM is a risk factor for nd/4.0/).
CAD, but it is also equivalent to established CAD. The

Introduction
* Corresponding address: Department of Medicine, School of
Medicine, Taibah University, P. O. Box: 30088, Almadinah
Almunawwarah, 41477, KSA. Coronary artery disease (CAD) is a major cause of death
E-mail: [email protected] (M.M. Al-Nozha) in Western countries, and it is becoming a major cause of
Peer review under responsibility of Taibah University. death in developing countries. This increase may be due to the
rising prevalence of many CAD risk factors, such as diabetes,
which is one of the most important of these risk factors. The
prevalence of diabetes is increasing globally, and it has
Production and hosting by Elsevier
reached pandemic levels in the Middle East and worldwide.1
1658-3612 Ó 2016 The Authors.
Production and hosting by Elsevier Ltd on behalf of Taibah University. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/). http://dx.doi.org/10.1016/j.jtumed.2016.03.005
 M.M. Al-Nozha et al. 331

The prevalence of diabetes in patients with CAD is up to oxidative stress was higher in the CAD and DM group
50% in many countries.2 The impact of tighter control of despite statin therapy. These results highlighted the impor-
diabetes on cardiovascular morbidity and mortality has been tance of oxidative stress.19
controversial with conflicting results, which attracted special
attention in current diabetes management guidelines. The Diabetes as a risk factor for CAD
measurement of this impact remains an active area of research.

Diabetes and atherosclerosis The prevalence of DM is increasing globally, and the

International Diabetes Federation (IDF) estimated that
there were 387 million people with DM in 2013, and this
Type 2 diabetes mellitus (DM) is a strong risk factor for
incidence is expected to rise to 592 million by 2035. An
CAD, and experts consider DM an equivalent to established
estimated 1 in 10 people have DM in the Middle East and
CAD risk.3 Patients with diabetes have 2- to 4-fold greater
North Africa (MENA) region.20 Six of the top ten countries
risk of developing CAD than non-diabetic patients.4,5
with a high estimated prevalence of DM were Arab countries
Diabetic patients exhibit an increased risk for develop-
in the 2011 IDF global estimate: Kuwait, Lebanon, Qatar,
ment of atherosclerotic CAD for many reasons, including
KSA, Bahrain and United Arab Emirates.21 Three of the
metabolic factors, like hyperglycaemia, dyslipidemia and
top 10 countries with a high estimated prevalence of DM
insulin resistance, which lead to endothelial cell, vascular
were Arab countries in the updated 2014 IDF estimate:
smooth muscle dysfunction,6,7 impaired platelet function
KSA, Kuwait and Qatar.20 (Table 1 and 2).
and abnormal coagulation.8 Diabetic patients tend to
The overall prevalence of DM was 23.7%, (26.2% in
exhibit other risk factors for CAD, like hypertension and
males & 21.5% in females) in a study of the prevalence of
obesity. Patients with diabetes have lipid-rich atheroscle-
diabetes in KSA,22 which was part of the Coronary Artery
rotic plaques, which are more vulnerable to rupture than the
Disease in Saudis Study (CADISS),23 and the impaired
plaques seen in non-diabetic patients.9,10 Yoo et al. described
fasting blood glucose was 14.1% for males and females
an overall increase in atherosclerotic burden and a 3.5-fold
combined. A total of 27.9% of diabetics were unaware of
higher risk of coronary stenosis that was independent of
having diabetes,22 and 34% of diabetic patients were
other cardiovascular risk factors in diabetic patients.11
hypertensive compared to 21.4% without DM
Inflammation plays an important role in atherosclerosis.
(P < 0.001).24 These factors further contribute to the risk
Inflammation activation in type 2 DM results from obesity
of CAD in the KSA population.
and insulin resistance, in which an acute phase reaction
CADISS is a national community-based study that
occur, and a large number of inflammatory and pro-
examined 17,232 KSA subjects aged 30e70 years from
inflammatory cytokines are released from adipose tissue.12
randomly selected households. The primary objective was to
Endothelial dysfunction is generally present in diabetic
estimate the prevalence of CAD and its risk factors in KSA.
patients with CAD, as evidenced by high levels of
The overall prevalence of CAD was 5.5% (6.6% in males,
endothelin 1 and low levels of nitric oxide.13 Vascular
4.4% in females).23
endothelial (VE)-cadherin was identified recently as an
The prevalence of type 2 DM in KSA is expected to rise
updated marker of endothelial function that is well-
because of the high prevalence of obesity. The overall prev-
correlated with endothelin 1 in diabetic patients with CAD.14
alence of obesity was 35.6% in CADISS with a higher
Enhanced thrombus formation occurs in type 2 DM
prevalence in females (44%) compared to males (26.4%)
because of increased platelet activity and blood coagula-
(P < 0.0001).25
bility.15 Pathological alterations in fibrinogen and
Another important factor in the high prevalence of DM in
plasminogen activation inhibitors are primarily relevant for
KSA is the high prevalence of physical inactivity, with an
the short-term incidence of cardiovascular events in pa-
overall prevalence of 96.1% (98.1% in females vs. 93.9% in
tients with type 2 DM.16
males) (P < 0.001).26
Notably, not all diabetic patients develop cardiovascular
The prevalence of metabolic syndrome in KSA is also
disease despite the presence of the same risk factors. How-
very high (39.3%), and it is higher in females (42%)
ever, recent studies focused on biomarkers of CVD in dia-
betic patients, such as serum phospholipids and their role in
the progression of CVD. Beatriz Garcı́a-Fontana and col- Table 1: The adjusted prevalence of diabetes in some Arab
leagues recently found low serum levels of 4 phospholipids in counties in 2011 [adopted from Top 10 countries/territories for
diabetic patients with CVD compared to diabetic patients prevalence (%) of people with diabetes (20e79 years), 2011
without CVD.17 and 2030a].
A recent study found a new biomarker in type 2 DM
Country The adjusted Rank in top 10
complicated with CAD that was significantly elevated and prevalence (%) countries for
positively correlated with the degree of CAD stenosis. This prevalence
new biomarker is called Osteonectin Secreted Protein Acidic
Kuwait 20.7 3
and Rich in Cysteine (SPARC). The mechanism by which
Qatar 19.8 5
SPARC may cause CAD development requires further
KSA 19.6 6
research.18 Lebanon 19.6 7
Palazhy et al. evaluated oxidative stress in CAD patients Bahrain 19.5 8
on statins in a cross-sectional study of 3 groups: Group 1, United Arab of Emirates 18.8 10
healthy control; Group 2, patients with DM and CAD on a
Adopted from The IDF Diabetes Atlas 201121.
statins; Group 3, only diabetic patients. They found that
332 Coronary artery disease and diabetes

controls from the Middle East. Subgroup analysis of the

Table 2: Top 10 countries/territories for prevalencea (%) of
Middle East group revealed a diabetes prevalence of
people with diabetes (20e79 years), 2013 and 2035b.
approximately 15%, hypertension was present in approxi-
2013 2035 mately 9%, and current smokers included approximately
Country/territory % Country/territory % 45% of cases. Dyslipidemia and abdominal obesity were
present in 70% and 25% of cases, respectively.32
Tokelau 37.5 Tokelau 37.9
Federated States 35.0 Federated States 35.1 The Gulf Registry of Acute Coronary Events (Gulf
of Micronesia of Micronesia RACE) is the first multi-national acute coronary syndrome
Marshall Islands 34.9 Marshall Islands 35 registry in the Middle East. These investigators studied pa-
Kiribati 28.8 Kiribati 28.9 tients with in the United Arab Emirates, Kuwait, Bahrain,
Cook Islands 25.7 Cook Islands 25.7 Oman, Qatar and Yemen. A total of 1484 ACS patients were
Vanuatu 24.0 KSA 24.5 recruited. Myocardial infarction formed the majority of
KSA 24.0 Vanuatu 24.2 cases (approximately 69%), and DM prevalence was rela-
Nauru 23.3 Nauru 23.3 tively high (38%). Hypertension was present in 46% of the
Kuwait 23.1 Kuwait 23.2
study population, hyperlipidaemia in 31%, and smoking in
Qatar 22.9 Qatar 22.8
45%.33
a
Comparative prevalence. The Second Gulf Registry of Acute Coronary Events
b
Adopted from The IDF Diabetes Atlas 201420. (Gulf RACE 2) is a registry studying the effects of DM and
new-onset hyperglycaemia on cardiovascular outcomes in
ACS patients from Arabian Gulf countries. More than 7000
compared to males (37.2%). The prevalence of DM in pa- patients were recruited from 6 Arabian Gulf countries: KSA,
tients with metabolic syndrome was 67.8% compared to Bahrain, Qatar, Oman, United Arab Emirates, and Yemen.
15.7% in DM patients without metabolic syndrome.27 The prevalence of DM was high; 49.2% of the study patients
A recent cross-sectional community-based Indian study had been diagnosed previously with DM (23% on insulin,
published in January 2016 estimated the prevalence of CAD and 76% treated with oral anti-diabetic agents and/or diet
and its risk factors and found that the age-adjusted preva- control). New-onset hyperglycaemia was estimated at 8.8%.2
lence of definite CAD was 3.5% in the entire study popula- The DM prevalence reported in Gulf RACE 2 was very
tion, 4.8% in males, and 2.6% in females. DM was found in high compared to the Western data in the Global Registry of
15% of the population, hypertension in 28%, smoking in Acute Coronary Events (GRACE) registry (approximately
28%, and overweight or obesity in 59%.28 24%)34 and the Asian data found in treatment and outcomes
A recent study investigated the prevalence of CAD risk of ACS in an Indian registry (about 30%).35
factors in 1056 healthy adults in Brazil and found that the Hersi et al. examined the gender difference between pa-
prevalence of DM was 11%, systemic hypertension was 40%, tients with ACS from 17 participating centres in KSA. More
family history of CAD was 50%, smoking was 23%, dysli- than 5000 patients were recruited, and the prevalence of DM
pidemia was 43%, and overweight/obesity was 68%.29 in the entire study population was even higher at 58%, 73%
in the female subgroup, and 41% in the male subgroup.36
Diabetes in CAD patients Mobeirek and co-workers found a relatively high preva-
lence of risk factors in the SPACE registry (the KSA Patients
Several studies in the Arabian Gulf region had limitations Admitted with acute Coronary syndromes registry) in KSA:
because a large proportion of expatriates were included in DM (57%), overweight or obesity (72%), hypertension
the population. This inclusion was reflected in the results that (56.6%), dyslipidemia (42%), and smoking (32.4%).37
revealed a similar prevalence in their country of origin. A total of 16,736 patients with acute coronary syndrome
Therefore, we excluded many of these studies from the cur- were studied in a 20-year registry (1991 to the end of 2010)
rent review. from Hamad Medical Corporation (HMC) in Qatar. This
The World Health Organization (WHO) initiated a cross- centre provides medical services to different ethnicities in the
sectional study, the Prevention of Recurrences of Myocardial area, and the results should be interpreted carefully. The
Infarction and Stroke (WHO-PREMISE), of 10,000 patients prevalence rates of DM were 65.7% and 37.4% in females
in 10 countries, primarily the Middle East, which exhibits and males, respectively, and hypertension prevalence was
coronary heart disease in approximately 85% of the popu- estimated as 68.1% in females and 36.5% in males.38
lation and cerebrovascular disease (CVD) in approximately Abdelmoneim and colleagues published the results of
15%. The working group found a high prevalence of some their cross-sectional observational study of the demographic
risk factors, and DM was found in approximately one third of ACS in Egypt in 2014. They studied 795 ACS patients
of the patients (31.5%).30 divided into 2 groups: group 1 (270 patients), ST segment
National data from Lebanon are scarce. The Lebanese Elevation Myocardial Infarction (STEMI) and group 2 (525
Interventional Registry provided data of the cardiovascular patients), Unstable Angina/Non-ST Segment Elevation
risk factors of patients who presented for coronary angiog- Myocardial Infarction (UA/NSTEMI). The prevalence of
raphy. The risk factors included DM (29%), hypertension DM in these groups was 34% and 45%, respectively. Other
(60%), smoking (50%), and dyslipidemia (29%).31 reported risk factors in these groups were hypertension (33%
The INTERHEART study is a case-control study of and 59%, respectively), dyslipidemia (29% and 39%,
modifiable risk factors in acute myocardial infarction pa- respectively), smoking (51% and 38%, respectively), family
tients. The investigators studied 15,152 patients and 14,820 history (16% and 7%, respectively), and male gender (72%
controls, which included more than 1500 patients and 1700 and 64%, respectively).39
 M.M. Al-Nozha et al. 333

Another Egyptian study recruited 142 patients with adenosine-stress myocardial perfusion imaging screening. A
STEMI and classified patients into 2 groups according to total of 358 patients underwent repeat adenosine-stress
waist circumference. The prevalence of diabetes was (53/142) myocardial perfusion imaging 3 years after the first evalua-
37.3% in the entire study population. The prevalence of other tion. Fifty-six of the 71 patients with abnormal studies dur-
risk factors was hypertension 41.5%, current smoking 49.3%, ing the initial evaluation (79%) had resolution of ischaemia
and family history of coronary artery disease 16.2%.40 on the myocardial perfusion scan after 3 years. Fifteen (21%)
Jain et al. (2015) investigated the risk factors for post- patients had abnormal studies at follow up. There were more
myocardial infarctions and assessed coronary artery anat- patients using aspirin, statins, and angiotensin-converting
omy using coronary angiography. They found that the enzyme inhibitors (ACEIs) at the 3-year follow up than the
prevalence of DM was 28.2%, hypertension was 31.4%, initial evaluations. This increase supports the evidence that
dyslipidemia was 37.5%, and current smoker was 44.9%.41 silent myocardial ischaemia may resolve over time with
OMT. This result undermines the strategy of routine
Screening of diabetic patients for CAD aggressive screening of asymptomatic diabetic patients and
emphasises the importance of the use of evidence-based
OMT for high-risk patients.49 The benefits of newer non-
The 2015 American Diabetes Association (ADA) rec-
invasive CAD screenings, such as computed tomography
ommendations suggest that diabetic patients who are can-
angiography, are not well established, and their use as a
didates for advanced investigations that may include
routine screening tool in asymptomatic diabetic patients may
coronary angiography are patients with cardiac symptoms
lead to undue radiation exposure and interventional
(either typical or atypical) or patients with abnormal resting
procedures.42
electrocardiogram (ECG). Routine screening of asymptom-
atic patients is not recommended42 because high-risk diabetic
Management of CAD in diabetes
patients for CAD should receive optimal medical therapy
(OMT) to reduce the incidence of cardiovascular events, even
if they are asymptomatic. A large body of evidence confirms Reduction of diabetic macrovascular disease
that OMT provides similar benefits as percutaneous coro-
nary intervention (PCI) in stable CAD. This evidence came Diabetics are at increased risk of developing cardiovas-
from 2 landmark trials: the first trial, the Clinical Outcomes cular disease and total death compared to non-diabetics.50,51
Utilizing Revascularization and Aggressive Drug Evaluation The United Kingdom Prospective Diabetes Study
(COURAGE) trial43; and the second trial, the “Bypass (UKPDS) is a landmark study of modifiable risk factors in
Angioplasty Revascularization Investigation 2 Diabetes” more than 3000 type 2 diabetics: increased levels of low-
(BARI 2D) Trial.44 density lipoprotein (LDL) cholesterol, low levels of high-
Other studies also demonstrate that the coronary artery density lipoprotein (HDL) cholesterol, hypertension, and
calcium score (CACS) provides refined risk stratification for smoking. The median follow-up period was approximately 8
high-risk patients,45 but coronary computed tomography years. Coronary artery disease was significantly associated
angiography (CCTA) provides a more detailed assessment with these risk factors.52
of subclinical CAD and had a better prognostic value than Reduction of macrovascular complications in type 2 DM
CACS.46 was confirmed using good blood pressure control, but tight
The Detection of Ischemia in Asymptomatic Diabetics glycaemic control was not conclusively demonstrated as
(DIAD) study assessed cardiac autonomic neuropathy in beneficial.53 Intensive glycaemic control in type 1 DM
1119 asymptomatic type 2 DM patients using autonomic demonstrated long-term benefits on macrovascular compli-
heart rate, blood pressure, and heart rate variability. Cardiac cations and mortality in the Diabetes Control and Compli-
autonomic neuropathy predicted adverse cardiac events in cations Trial/Epidemiology of Diabetes Interventions and
8.4% of the studied population who developed symptomatic Complications (DCCT/EDIC) study.54
cardiac disease during the 5 years of follow-up.47 A meta-analysis on cardiovascular risk reduction found
The COURAGE trial examined 2287 patients with stable that smoking cessation was the most important intervention
CAD with objective evidence of ischaemia who were rand- in reducing mortality compared to other interventions. This
omised to PCI with OMT versus OMT alone. The primary study concluded that smoking cessation may prolong life in a
outcome endpoint was a composite of death from any cause 45-year-old male diabetic patient for a mean of 3 years and a
and non-fatal myocardial infarction. There was no signifi- mean of 4 years in non-diabetic male patients.55
cant difference in the primary outcome at the mean follow- The Veteran Affairs Diabetes Trial (VADT) demon-
up of 4.6 years. Therefore, the addition of early PCI to strated in its extended follow-up arm that intensive glycaemic
OMT did not reduce the long-term risk of death or control group had a significant lower risk of primary out-
myocardial infarction (MI) in COURAGE patients regard- comes compared to the standard therapy group. The abso-
less of diabetes status.48 The BARI-2D trial examined the lute risk reduction was 8.6 major cardiovascular events per
coronary revascularization using PCI or Coronary Artery 1000 person-years. However, there was no reduction in car-
Bypass Grafting (CABG) versus intensive medical therapy in diovascular mortality or total mortality.56 These researchers
patients with type 2 diabetes. The research group found no found a 17% relative risk reduction in the rate of
significant difference in the all-cause mortality or the com- cardiovascular events in the intensive medical therapy
posite endpoints of death, MI or stroke (BARI-2D trial).44 group. The results of the follow up study of the Action to
A total of 1123 diabetic patients were recruited in the Control Cardiovascular Risk in Diabetes blood pressure
DIAD study, and 522 patients were randomised for trial (the ACCORD trial) exhibited a similar result with
334 Coronary artery disease and diabetes

fewer non-fatal cardiovascular events, and the conclusion such as a significant rise in serum creatinine of more than
from the extended follow-up arm was not very different from 1.5 mg/dl, hyperkalemia, hypotension, and syncope.64
the original trial, especially that the overall mortality A meta-analysis of ACCORD-BP, Appropriate Blood
remained higher in the intensive glycaemic control group.57 Pressure Control in NIDDM Trial (ABCD), and The Hy-
pertension Optimal Treatment (HOT) trials reported that
Use of anti-platelet drugs in DM intensive BP control in diabetic patients significantly reduced
the risk of stroke but failed to reduce the incidence of
The recent recommendations of American Diabetes As- myocardial infarction or total mortality.65
sociation (ADA) published in 2015 suggest aspirin (75e The JNC-8 in white adult (>18 years) patients suggested
162 mg) for secondary prevention of CAD and primary that the initial antihypertensive regimen should include
prevention in patients with high cardiovascular risk, with an thiazide diuretic, a calcium channel blocker (CCB), and
estimated 10-year risk of more than 10%. This group in- ACEI or angiotensin receptor blockers (ARBs). However,
cludes males older than 50 years or females older than 60 the initial treatment in black adult (>18 years) patients
years with one or more of the following risk factors: hyper- should include a thiazide diuretic or CCB. ACEI or ARB
tension, dyslipidemia, family history of cardiovascular dis- should be included in the treatment of patients with chronic
ease, smoking, and albuminuria.42 Clopidogrel is indicated kidney disease (CKD), regardless of diabetes status or
for patients with cardiovascular disease and documented race62.
aspirin allergy.58 The Heart Outcomes Prevention Evaluation (HOPE) trial
investigated a total of 9297 patients with diabetes or evidence
Blood pressure control of vascular disease (high-risk group) and randomised pa-
tients to ramipril or placebo control groups. Ramipril
significantly reduced the primary endpoint of myocardial
The UKPDS confirmed in early 1998 that tight treatment
infarction, stroke or death from cardiovascular disease.66
of hypertension in diabetic patients was associated with
better outcomes than less tight control. The mean achieved
Statins in DM
BP was 144/82 mmHg in the tight control group versus 154/
87 mmHg in the less tight control group. The tight BP con-
trol arm exhibited a risk reduction of 24% in any related DM A meta-analysis of 14 randomised trials of statins
endpoints, 32% in diabetes-related death, 44% in strokes, involved 18,686 diabetic patients who were followed up for
and 37% in microvascular complications.59 4.3 years. There was a 9% proportional reduction in all-
The Action in Diabetes and Vascular disease: PreterAx cause mortality and 13% reduction in vascular mortality
and DiamicroN MR Controlled Evaluation (ADVANCE) for each one mmol/l reduction of LDL-cholesterol.67
trial demonstrated that major macrovascular and micro- The ADA standard of medical care of diabetes in 2015
vascular events were reduced significantly in the active BP states that diabetic patients aged >40 years should receive
intervention arm (a single pill, fixed-dose combination of moderate intensity statins with life-style modifications, but
perindopril and indapamide), and this result was associated high-dose statins are indicated in patients with cardiovas-
with reductions in all-cause mortality and cardiovascular cular diseases or other risk factors.42 Cannon and colleagues
mortality. A blood pressure of 136/73 mmHg was the level investigated an intensive lipid-lowering regimen (atorvasta-
attained in the active treatment arm.60 Reductions in all- tin 80 mg/day) versus a moderate regimen (pravastatin
cause mortality and cardiovascular mortality was attenu- 40 mg/day) in 4162 ACS patients. The high-intensity regimen
ated in the 6-year follow-up of the ADVANCE-BP study, of atorvastatin provided significantly greater protection
but it continued to be significant.61 against death and cardiovascular events compared to the
Several of the major guidelines for the management of moderate regimen of pravastatin after a 2-year follow up.68
hypertension, including the Eighth Joint National Commit- There is scarce data on the use of statins in diabetics under
tee (JNC-8)62 and the European Societies of Hypertension the age of 40 years, and the current recommendations do
and Cardiology (ESH/ESC),63 suggested that the goal of not indicate statin use for diabetic patients below 40 years
blood pressure control in diabetics should be less than 140/ of age without overt cardiovascular disease or other risk
90 mmHg. Previous guidelines recommended blood factors.42
pressure control to less than 130/80 mmHg.
The Action to Control Cardiovascular Risk in Diabetes Coronary revascularization in diabetics
blood pressure trial Blood Pressure (ACCORD-BP) arm
recruited a total of 4733 patients who were randomly Selection of the optimal method of coronary revascular-
assigned to intensive (systolic BP goal below 120 mmHg) isation for diabetic patients often requires a multidisciplinary
versus standard (systolic BP goal below 140 mmHg) blood team meeting (i.e., a heart team). The Bypass Angioplasty
pressure control and followed up to 4.7 years. There was a Revascularization Investigation 2 Diabetes (BARI 2D) trial
statistically significant reduction in the annual incidence of was a landmark trial that addressed the treatment of diabetic
stroke (total stroke and non-fatal stroke) in the intensive BP patients with stable CAD. A total of 2368 patients with type
control group, but there was no significant difference be- 2 DM and stable CAD were enrolled and randomised to a
tween the two groups in the primary composite endpoint of revascularization, coronary artery bypass graft (CABG) or
non-fatal MI, non-fatal stroke or death from cardiovascular PCI group, according to individual physician’s preference,
causes. There was also no difference in all-cause mortality. plus intensive medical therapy (IMT) versus IMT alone. The
Serious side effects were reported in the intensive BP arm, primary endpoints were the rate of death and the composite
 M.M. Al-Nozha et al. 335

cardiovascular events of death, MI or stroke. There was no confirmed the initial results of the original study.75 The
significant difference in the primary endpoints at the 5-year FDA recently eliminated the Risk Evaluation and
follow-up. The cardiovascular events were significantly Mitigation Strategy (REMS) for rosiglitazone and
lower in the CABG subgroup compared to the medical rosiglitazone-containing hypoglycaemic agents in 2015 and
treatment group, but mortality was not significant. There stated “The REMS is no longer necessary to ensure that the
was no significant difference in the risk of death and the benefits of rosiglitazone medicines outweigh their risks”.76
cardiovascular events between the PCI group plus IMT and Many concerns were raised about other agents and classes
IMT alone.44 intended to treat hyperglycaemia following the rosiglitazone
Diabetic patients are at an increased risk of progressive story. These concerns triggered a series of trials on newer
coronary artery disease and coronary artery re-stenosis after classes and agents and changed the process of approving
stent implantation. The predictors of coronary artery re- new anti-diabetic agents, at least by the U.S. FDA.
stenosis are small vessel coronary artery, long lesion, and
lower body mass index.69,70 Conclusion and recommendations
Drug-eluting stents (DES) are used preferentially used
over bare metal stents (BMS) in diabetic patients because
DES significantly reduce the incidence of re-stenosis and Diabetes is a very important major risk factor for CAD,
target vessel revascularisation (TVR). Bangalore and col- and it is becoming a global health problem with increasing
leagues published a meta-analysis of 42 trials with more than prevalence in a pandemic form. Many Arab countries,
22,000 patient-years of follow up and found that DES especially the Arabian Gulf region, are at the top of the in-
significantly reduced the TVR compared to BMS (37e69%, ternational prevalence list. However, many Arab countries
respectively). There was no increased risk of any safety do not possess updated prevalence data from the community
outcomes in the DES group, such as death, MI, or stent or maintain a registry of DM, CAD or other DM compli-
thrombosis.71 cations. Therefore, there is a great need to collect these data
The recent 5-year follow-up of (TAXUS Drug-Eluting in all Arab countries.
Stent Versus Coronary Artery Bypass Surgery for the There is an urgent need for interventions at the population
Treatment of Narrowed Arteries) SYNTAX trial investi- level and in high-risk groups to reduce the incidence of DM
gated the cause of death following PCI versus CABG in by promoting physical activity and controlling the obesity
complex CAD. Most death after PCI was due to a cardio- epidemic. The prevalence of CAD will continue to rise in these
vascular cause (67%), and myocardial infarction death countries if no action is taken to control DM and other risk
accounted for approximately 29%. Post-CABG deaths factors for CAD, like hypertension and dyslipidemia.
included 49% due to cardiovascular cause. The cumulative International agencies, such as the WHO, IDF, ADA,
incidence rates of all-cause death were not significantly European Association for the Study of Diabetes (EASD),
different between CABG and PCI, but cardiovascular and American College of Cardiology (ACC) and the European
cardiac deaths were significantly higher in PCI group. A Society of Cardiology (ESC), should play an active role to
difference between PCI and CABG in MI mortality was assist Arab countries to establish basic data and registries
found in diabetic patients, three-vessel CAD, and high and the promotion of health interventional programs to ul-
SYNTAX score. It was concluded that treatment with PCI timately control the rising incidence of DM and CAD.
versus CABG was an independent predictor of cardiac death All efforts, governmental and non-governmental,
in patients with complex CAD (hazard ratio: 1.55; 95% including all health organisations and scientific societies,
confidence interval: 1.09 to 2.33; P ¼ 0.045).72 should come together locally in each country to combat this
epidemic of DM and CAD instead of individual scattered
efforts. We need uniformed programs at the national level to
Anti-diabetic agents and the risk of cardiovascular events win this battle.

The hypothesis linking anti-diabetic agents with cardio- Conflict of interest

vascular disease is not new. The 2007 meta-analysis that
linked rosiglitazone to increased cardiovascular risk and the The authors have no conflict of interest to declare.
possibility of increasing cardiac events further added to this
concern.73 The decision of the Food and Drug
Authors’ contributions
Administration (FDA) in the United States (U.S.) to
restrict the use of rosiglitazone because of this postulated
link resulted from this study. The chairman of the same All authors contributed equally in both reviewing avail-
committee from the U.S. FDA wrote a perspective paper in able evidence and writing up this manuscript.
the New England Journal of Medicine (NEJM) to explain
the process of the FDA decision and announcement, and he References
clarified his personal opinion about this decision, which
further added to this debate and controversy.74 The FDA
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