Include references and avoid plagiarism when answering this, it is a graduate research NON-EXPERIMENTAL STUDY paper: Review the following attached articles that have been provided as example studies

Hypertension Diabetes mellitus Stroke Risk factors Lifestyle A B S T R A C T Background: Stroke is becoming a major challenge in healthcare systems, and this has necessitated the study of the various risk factors. As the number of people with hypertension, diabetes mellitus and obesity increases, the problem is expected to worsen. This review paper evaluates what can be done to eliminate or reduce the risk of stroke.

Objective: The aim of the research is to evaluate the risk factors for stroke. The paper also aims to understand how these risks can be handled to avoid incidences of stroke.

Method: Published clinical trials of stroke risk factors studies were recognised by a search of EMBASE and MEDLINE databases with keywords hypertension, blood pressure, diabetes mellitus, stroke or cardiovascular disease, or prospective study, and meta-analysis.

Results: The findings of this review are that the prevention of stroke starts with identifying risk factors for stroke, most of the patients diagnosed with stroke have various risk factors. Consequently, it is a very significant to identify all the risk factors for stroke as well as to teach the patient how to dominate them.

Conclusion: after summarising all the studies mentioned in the paper, it can be established that hypertension and diabetes mellitus are a stroke risk factors and correlated in patients with atherosclerosis.

© 2018 Diabetes India. Published by Elsevier Ltd. All rights reserved.

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577 2. Aim . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 578 3. Method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 578 3.1. Design and strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 578 3.2. Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 578 3.3. Ethical considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 578 4. Results and discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 578 4.1. Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 578 4.2. Diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 582 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583 6. Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583 1. Introduction There are diverse classifications of risk factors concerning strokes, traditional and new, such as hyperhomocysteinemia and hyperco- agulable state. There are also risk factors that are modifiable and non- modifiable. Cerebrovascular illnesses or diseases adhere to risk factors that are non-modifiable for sex-based orientation, age, race or * Corresponding author.

E-mail address: [email protected] (A. Alloubani).

https://doi.org/10.1016/j.dsx.2018.03.009 1871-4021/© 2018 Diabetes India. Published by Elsevier Ltd. All rights reserved. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 12 (2018) 577–584 Contents lists available at ScienceDirect Diabetes & Metabolic Syndrome: Clinical Research & Reviews journal homepa ge: www.elsev ier.com/locate/dsx ethnic groups, and genotype prior to the myocardial infarction, to the stroke and or TIA, in addition to modifiable risk factors such as diabetes, hypertension and hyperlipidemia [1]. There are also coronary artery diseases along with physical immobility, consump- tion of alcoholic beverages, cigarette smoking and obesity [2].

Atherosclerosis is a key pathomorphological method that narrows the arterial walls across the body and within the brain, leading to cerebrovascular disease. It is believed that atheroscle- rosis arises from chronic inflammation and damage to the arterial wall within the peripheral or coronary vascular system. As a reaction to endothelial inflammation and damage, oxidised lipids from LDL (low-density lipoproteins) particles gather in the endothelial region of the vessel wall [2]. The oxidation of these particles may be brought about by angiotensin II. Monocyte then infiltrates the arterial wall and differentiates into macrophages, which accumulate oxidised lipids to form foam cells. After their creation, foam cells encourage spread of macrophage and drawing of T-lymphocytes. These T-lymphocytes consequently bring about smooth muscle propagation within the arterial walls and build-up of collagen. This process results in the creation of a lipid dense atherosclerotic lesion with a fibrous cap. When this lesion ruptures, there is severe vascular infarction which ruptures, causing frequent bleeding in the plaque in diabetic patients (diabetic patients also have a greater perioperative risk of carotid endarterectomy).

Apart from atheroma creation, there is a greater proof of higher platelet adhesion, hypercoagulability, defected nitric oxide pro- duction and the higher creation of free radicals, in addition to altered calcium regulation in diabetic patients [3,4].

2. Aim The aim of this research paper is to evaluate the hypertension and diabetes mellitus as a risk factors associated with stroke.

Having understood the risk factors, the research evaluates how these risk factors have been handled in the past and what can be done in the future. The research aims to identify the major problems that have led to increased risks of stroke. This can help in recommending the steps that can be used to deal with the condition.

Based on the information available, it will be possible to offer a guide to people who are already facing high-risk factors, so that they can avoid the worst scenario of suffering a stroke.

Additionally, people who have not yet experienced risk factors can learn from this paper, steps that they can take to avoid increasing the risk of suffering from a stroke. The review will highlight gaps in healthcare that need to be closed to ensure that people receive better care and that mortalities resulting from stroke are reduced.

3. Method 3.1.

Design and strategy Published clinical trials of stroke risk factors studies were recognised by a search of EMBASE and MEDLINE databases with keywords hypertension; blood pressure; diabetes mellitus; stroke or cardiovascular disease; or prospective study; and meta-analysis.

Included are clinical trials involved patients with hypertension and diabetes mellitus as a predictive stroke risk factor. Date of birth or age, gender, blood pressure documented at baseline.

Randomised controlled trials of hypertension as a stroke risk factor published before 2016 were eligible for inclusion. Random studies distribution of participants to a stroke risk factors lowering drug or placebo; random distribution of participants to different stroke risk factors lowering drugs; and randomdistribution of participants to different stroke risk factors lowering targets were eligible. To decrease the risk of small- study effects [5], all studies were needed to have at least 1000 patient-years of follow-up in each study group.

Studies were involved if they were published or information were reachable before 2016, and if they provided information on inclusion criteria, regions and number of randomisation method, trial endpoints, duration of follow-up, trial interventions and methods of analyses. Results were independently extracted and summarised. Nevertheless, no further analyses were directed.

The first step was the selection of relevant references that could be used to complete the research. This was based on the information that the resources provide the background of the authors, the publisher and the year the references were published.

After selecting the needed references, the second step was to read through them and get the relevant information that could be useful for the research [6].

The research depended on primary sources that are reliable and address the issue of stroke risks in society. Various reputable organisations have completed research on the issue of stroke, and these resources are important for understanding the issue of stroke and its relationship with hypertension. Journal articles, books and websites were used in collecting reliable data published by authors in this field. Based on these sources, it was possible to make reductions as to how the problem of stroke affects society and how it can be handled.

3.2. Approach The sources were used in the literature review, where the various sources are critically evaluated to offer information about the topic. The findings from the sources were discussed and summarised in the tables to provide more information on the issue.

Based on such findings, it was possible to make conclusions and recommendations [7].

3.3. Ethical considerations This study was deemed IRB-exempt according to the university’s Human Subjects Protection guidelines since data were publicly available and individual patients were not identifiable. The research was based on ethical guidelines for carrying out research.

The references used in the research are well cited and referenced to avoid plagiarism. The sources are paraphrased to ensure that the research is not just a duplicate of the previous research. There are also no incidences where personal ideas that may be biased are included in the research as for facts. This ensures that the research is reliable, hence important to the various targeted users [6].

4. Results and discussion 4.1. Hypertension Hypertension is the most predominant modifiable risk factor for stroke with a prevalence of about thirty percent in developed nations. Hypertension is exposed more in elderly.

The Framingham Stroke Risk Profile (FSRP) was established to have better and more rapid assessment of stroke risk factors [8].

The developers of FSRP employed information from thirty-six years of follow-up within the Framingham Stroke cohort study then verified them from other cohorts. Sex-specific approxima- tions of the probability of stroke are offered by the FSRP with the help of clinical information [9]. Hypertension was found in the Framingham Heart Research Study concerning specialists who 578 A. Alloubani et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 12 (2018) 577–584 know about lifetime risks of hypertension. They did find around 90 percent for women and men who found to be non-hypertensive from about 55 up to 65 years old and the lived ages range from around 80 to 85 years old [10–12].

Presumably, there was a deduction in a meta-analysis of 1 million grown-ups that are enlisted in 61 observation studies and noted dynamic and direct inclination concerning to deaths brought about by the ischemic heart illness as well as stroke. It is systolic levels of blood pressure of 115 mm Hg low and of the diastolic base of about 75 mm Hg high’. A research study found that for each 20 mm Hg systolic and as well as 10 mm Hg diastolic rise in circulatory strains, the death ratios resulting from stroke and ischemic illness increased twofold. Nevertheless, it was recom- mended that around 10 mm Hg decrease in systolic pressure and as well as the 5 mm Hg decrease in diastolic blood pressure may prompt a forty percent reduction in the risk of death caused by stroke and a 30 percent reduction in ischemic heart illness and other vascular associated deaths [10 ,13].

Blood pressure in patients having diagnosed stroke was assessed by the United Kingdom transient ischemic attack (TIA) trial. It was found that there was a direct and consistent relation between recurrent strokes and blood pressure. The data showed that a five mmHg lower diastolic blood pressure was related to a decrease in stroke for around one-third [14 ,15].

Furthermore, there was 2003 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of high blood pressure or JNC – 7 that consider a category of hypertension. The new category did change the pressure of the blood of less than 12 0/ 80 mm Hg from the optimum down to what is standard, and prehyperten- sion was accessible for the systolic pressure of the blood of 12 0 up to 13 9 mm Hg and the diastolic pressure of the blood of 80 up to 89 mm Hg. This re-categorization was done to support modifications to lifestyles in the beginning phases of hypertension and decrease the occurrences of heart attack and stroke [16].

Changes in the lifestyle include dietary changes, which essentially involves consuming vegetables and fruits more (meta-analysis of 9 autonomous types of research has depicted that three to five servings every day decrease stroke risk for 0, 89) and eating less salt [17]. Further lifestyle changes include weight loss, aerobic activity and restricting alcohol intake. It is not suggested to undergo pharmacological treatment till systolic pressures increase to more than 14 0 mm Hg as well as diastolic increases to over 90 mm Hg brain perfusion. The significance of treating hypertension to decrease the stroke risk injuries is evident; however, the most optimal choice of antihypertensive medicine is not so evident [18].

It was depicted in the study of Heart Outcomes Prevention Evaluation (HOPE) that when angiotensin converting enzyme inhibitor (ACEI) Ramipril was used, there were better cardiovas- cular outcomes, further than its capacity to decrease blood pressure, which was not so intense in this trial (the mean decrease in systolic/diastolic blood pressure was 3/2 mm Hg) [9,19].

Consequently, The Losartan Intervention for the Endpoint reduction in hypertension (LIFE) study did assess impacts of Angiotensin Receptor Blocker (ARB) Losartan with the beta blocker, Atenolol toward cardiovascular-related failure, stroke and ‘myo- cardial infarction’ in patients that experienced hypertension and ‘left ventricular hypertrophy’. An evaluation demonstrates similar risk decline of 25% in fatal stroke and the backing of Losartan than Atenolol [20].

The foremost trial that was carried out only on patients diagnosed with a cerebrovascular disease or transient ischemic attack (TIA) was the perindopril protection against recurring stroke study (PROG- RESS). The patients with a background marked by a stroke were relegated to false treatment, perindopril alongside indapamide and a thiazide diuretic [21]. A normal blood pressure was noted as 147 /86 mm Hg, a combination of the indapamide the as well as perindopril produced a standard decrease in the blood pressure which is 12 /5 mm Hg and 43% reduction in relative risks of irregular stroke in opposition to perindopril that brought a simple decrease of 5/3 mm Hg in the blood pressure. The study did offer an increase to questions with respect to positive findings, and the findings indicate that ACEI and the thiazide [22,23]. The Study on Cognition and Prognosis in Elderly labelled as (SCOPE) that elderly patients experienced disconnected systolic hypertension and were risky into ARB antihypertensive treatment with Losartan and non-ARB treatment [10]. Notwithstanding, there was a comparable reduction in the blood pressure in ‘ARB arm (22/6 mm Hg)’ and ‘non-ARB arm (20/5 mm Hg)’ with 42 percent decrease in stroke risks. It is indicated through these findings that ACEI and ARB, particularly when mixed with a thiazide diuretic, may be better compared to other antihypertensive regimens in the secondary prevention of stroke (verified earlier findings of progress) [24,25].

It has been revealed by three randomized trials to compare the more severe blood pressure control against the less severe blood pressure control that the more severe blood pressure control was better at diminishing the magnitude of strokes, but mainly in diabetic patients and only affected diastolic blood pressures United Kingdom Prospective Diabetes Study (UKPDS) [26,27].

A thiazide diuretic chlorthalidone was found to be better than a calcium channel blocker (CCB) amlodipine, alpha-receptor antag- onist doxazosin, and angiotensin converting enzyme inhibitor (ACEI) lisinopril when avoiding one or main vascular conditions like stroke, in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) [28].

On Going Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) was assess the correlation between the ACEI ramipril against the ARB telmisartan and against the combination of both to decrease the chance of main vascular conditions in the patient with high risk [29,30].

The European Lacidipine Study on Atherosclerosis (ELSA) assessed the influence of lacidipine (calcium antagonist) cantered medication as well as the beta-blocker (atenolol) cantered remedy on the advancement and evolution of carotid atherosclerosis (measured in individuals with the highly severe condition). The initial inference of this research involved the degree of alteration in the wideness of the wall of the carotid artery, which was appraised with the help of a B- mode ultrasound (in the individuals who were on lacidipine IMT was decreased by forty percent in five years’ development phase) Valsartan Antihypertensive Long-term Use Evaluation (VALUE) research. The main objective of this research was to decide if the hypertension being treated with the treatment that was instigated with the angiotensin receptor blocker (ARB) valsartan would offer a decrease of 15 % in the possibility of cardiac condition and death, as compared to the blood pressure being controlled with the treatment of calcium channel blocker (CCB) amlodipine. Amlodipine decreased the possibility of stroke but not significantly [31,32].

For Secondary Prevention of the disease and mortality after stroke, the Eprosartan compared against Nitrendipine revealed that the potential prospective randomized controlled study (MOSES) displays that the individuals who have endured cerebrovascular conditions in the past, a medication cantered on eprosartan to reduce the blood pressure (BP) as compared to the nitrendipine is more affecting towards the repetition of cerebro- vascular conditions and cardiac related issues [33].

The SPS3 or the “Secondary Prevention of Small Subcortical Strokes Trial” did explore differentiating the different antiplatelet medicines to maintain a strategic distance from stroke in people by method for lacunar strokes is additionally looking at the impact of a diverse blood pressure mark, ‘systolic blood pressure less than150 mm Hg in contrast to targeted blood pressure <13 0 mm Hg [10 , 3 4 , 3 5]. A. Alloubani et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 12 (2018) 577–584 579 Table 1 Summary of the included Hypertension studies.

Year Study Participant Number of risk factors Findings 19 4 8 Framingham Heart Research Study5209 respondents (Men: 2336 Women: 2873) ages of 30 and 62 from the town of Framingham, MassachusettsHigh blood pressure, high blood cholesterol, smoking, obesity, diabetes, and physical inactivity. (blood triglyceride and HDL cholesterol levels, age, gender, and psychosocial issues)1960s Cigarette smoking increases risk of heart disease.

Increased cholesterol and elevated blood pressure increase risk of heart disease Exercise decreases risk of heart disease, and obesity increases it.

1970s Elevated blood pressure increases risk of stroke.

In women who are postmenopausal, risk of heart disease is increased, compared with women who are premenopausal.

Psychosocial factors affect risk of heart disease.

1980s High levels of HDL cholesterol reduce risk of heart disease.

1990s Having an enlarged left ventricle of the heart (left ventricular hypertrophy) increases risk of stroke.

Elevated blood pressure can progress to heart failure.

2000s So called “high normal blood pressure” increases risk of cardiovascular disease (high normal blood pressure is called prehypertension in medicine; it is defined as a systolic pressure of 12 0–13 9 mm Hg and/or a diastolic pressure of 80–89 mm Hg).

From 197 9 to 1985United Kingdom transient ischemic attack (TIA) aspirin trial2435 patient Treatment with aspirin 600 mg twice daily (n = 815), aspirin 300 mg once daily (n = 806) or placebo (n = 814).transient ischemic attack or minor ischemic strokeThere was no definite difference between responses to the 300 mg of aspirin and 120 0 mg daily doses, except that the lower dose was significantly less gastro toxic.

2006 Fruit and vegetable consumption and stroke:

meta-analysis of cohort studies257,551 individuals (4917 stroke events) with an average follow-up of 13 yearsEight studies, consisting of nine independent cohorts, met the inclusion criteria. Increased fruit and vegetable intake in the range commonly consumed is associated with a reduced risk of stroke Subgroup analyses showed that fruit and vegetables had a significant protective effect on both ischemic and hemorrhagic stroke.

Increased fruit and vegetable intake in the range commonly consumed is asso- ciated with a reduced risk of stroke.

19 97 Losartan Intervention for Endpoint reduction in hypertension (LIFE)9218 hypertensive patients Hypertension study is a double-blind, prospective, parallel group study designed to compare the effects of losartan with those of the beta-blocker atenolol on the reduction of cardiovascular morbidity and mortality.There was no significant difference between the losartan and atenolol treatment groups in adjusted relative risk of cardiovascular mortality, which was one of the primary endpoint components.

2001 perindopril protection against recurring stroke study (PROGRESS)6105 individuals’ active treatment (n = 3051) or placebo (n = 3054)“Randomized trial of a perindopril-based blood-pressure-lowering regimen” Blood- pressure-lowering regimen reduced the risk of stroke among both hypertensive and non-hypertensive individuals with a history of stroke or transient ischemic attack. Combination therapy with perindopril plus indapamide reduced blood pressure by 12/5 mm Hg and stroke risk by 43% (30–54).

Single-drug therapy reduced blood pres- sure by 5/3 mm Hg and produced no discernable reduction in the risk of stroke.

2000 Heart Outcomes Prevention Evaluation (HOPE)9297 high-risk patients, 55 years’ oldvascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low EF or heart failureRamipril, a long-acting angiotensin- converting–enzyme inhibitor, reduces the rates of death, myocardial infarction, stroke, revascularization, cardiac arrest, heart failure, complications related to diabetes, and new cases of diabetes in a broad spectrum of high-risk patients.

2002 The Antihypertensive and Lipid-Lowering Treatment To Prevent Heart Attack Trial (ALLHAT)33357 participants Antihypertensive treatment trial and the second largest lipid-lowering trial.

Participants were men and women aged 55 years or older who had stage 1 or stage 2 hypertension with at least 1 additional risk factor for CHD events. Thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive.

They should be preferred for first-step antihypertensive therapy. 580 A. Alloubani et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 12 (2018) 577–584 In individuals with a high-risk condition, the On-Going Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), is contrasting the ACEI ramipril against the ARB telmisartan against a blend of both to avoid main vascular episodes [30].

The telmisartan 80 mg with control in ACEI sensitive individuals is deliberated by the Telmisartan Randomized Assessment Study in ACE-intolerant Subjects with Cardiovascular Disease (TRANSCEND) [36] with similar risk elements and endings as ONTARGET.The influence of the medications of high blood pressure is restricted by the absence of knowledge in the individuals regarding high blood pressure (past research have revealed that only around 60% of the victims were conscious of suffering from high blood pressure), only a few of them acquire the standard applicable medication, while one-third of them are regulated to control the blood pressure (which is usually because of infrequent medication use). The instructions to handle high blood pressure to avoid stroke signifies that initial avoidance of stroke implies that the typical blood Table 1 (Continued) Year Study Participant Number of risk factors Findings 2008 On Going Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET)150,000 patients Telmisartan was equivalent to Ramipril in patients with vascular disease or high-risk diabetes and was associated with less angioedema.Telmisartan appears to have a benefit beyond blood pressure reduction that matches a representative ACEI, Ramipril, against major clinical events in high–CV risk patients.

2008 Telmisartan Randomized Assessment Study in ACE- intolerant Subjects with Cardiovascular Disease (TRANSCEND)5926 patients Telmisartan 80 mg/ day (n = 295) placebo n = 2972 5776 patients (out of a projected total of 6000 High-risk patients with coronary, peripheral, or cerebrovascular disease or diabetes with end-organ damage are being recruitedA randomized controlled trial Angiotensin- converting enzyme (ACE) inhibitors reduce major cardiovascular events 1. Cardiovascular death 2. Non-fatal myocardial infarction 3. Non-fatal stroke Mean blood pressure was lower in the Telmisartan group than in the placebo group Telmisartan was well tolerated in patients unable to tolerate ACE inhibi- tors.

Although the drug had no significant effect on the primary outcome of this study, which included hospitalizations for heart failure, it modestly reduced the risk of the composite outcome of car- diovascular death, myocardial infarction, or stroke.

2002 The European Lacidipine Study on Atherosclerosis (ELSA)2334 patients Hypertension The greater efficacy of lacidipine on carotid IMT progression and number of plaques per patient, despite a smaller ambulatory blood pressure reduction, indicates an ant atherosclerotic action of lacidipine independent of its antihypertensive action 2004 Valsartan Antihypertensive Long-term Use Evaluation (VALUE)15245 patients Aged 50 years or older with treated or untreated hypertension and high risk of cardiac events participated in a randomized, double-blind, parallel-group comparison of therapy based on valsartan or amlodipine. The baseline BP in the amlodipine group was 1.0/0.5 mm Hg higher than in the valsartan group.

Risk and disease factors were well balanced in the 2 monotherapy groups with exception of the LV strain pattern, which was more prevalent in the amlo- dipine group.

Monotherapy patients had significantly lower values in 11 of 15 demographic, risk, and disease categories.

Prevalence of smoking and coronary heart disease was higher, and there were fewer women in the monotherapy group.

2005 prospective randomized controlled study (MOSES)1405 well-defined high-risk hypertensives with cerebral event during the last 24 months Eprosartan Compared with Nitrendipine for Secondary Prevention (MOSES) study was the first to compare an angiotensin II type 1 receptor antagonist with a calci- um antagonist in secondary stroke pre- vention.

The combined primary end point was significantly lower in the Eprosartan group.

MOSES does reveal protective effects of Eprosartan over Nitrendipine in high- risk patients.

2012 The Secondary Prevention of Small Subcortical Strokes (SPS3) trial3000 patients Symptomatic small subcortical strokes and two levels of systolic blood pressure targets –‘intensive’ (<13 0 mm Hg) vs.

‘usual’ (130–14 9 mm Hg). Secondary Prevention of Small Subcor- tical Strokes will address several im- portant clinical and scientific questions by testing two interventions in patients with recent magnetic resonance imag- ing-defined lacunar infarcts, which are likely due to small vessel disease.

The results will inform the management of millions of patients with this common vascular disorder. A. Alloubani et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 12 (2018) 577–584 581 pressure must be fixed at a level less than 14 9 mm Hg/90 mmHg and less than 13 0 mm Hg/80 mmHg in diabetic patients [37].

The daily routine should be altered in a way to achieve the normal blood pressure marks, and in case this does not work, the patient should contemplate getting on medication. Presently, the blood pressure medication is suggested to all the sufferers of stroke or TIA. The normal blood pressure marks must be set after considering the age, sex and other conditions that the patient might be suffering from. The advantages are witnessed after a normal decrease in the blood pressure of around 10/5 mm Hg. The medication selected in based on the description of the sufferer, and in individuals prone to stroke, the ACEI and ARB to a diuretic are preferred, along with the information from the past examinations (AB/CD rule). In the individuals suffering from an acute case of precerebral artery stenosis, in the secondary prevention of stroke, if the high blood pressure is decreased, it should be initiated carefully [38,39]. Table 1 summarises all hypertension studies that included in this review.4.2. Diabetes mellitus Diabetes is a long-term chronic disease which needs constant medical care and treatment not only by doctors but also by patient knowledge about self-care to prevent critical secondary illness caused by diabetes. Diabetes is categorized according to previous diagnostic criteria which includes: DM type 1, DM type 2, illnesses of exocrine pancreas (cystic fibrosis), prediabetes (consistent high glucose level in fasting and impaired glucose tolerance), Diabetes because of genetic disorder of b cells of pancreas, secondary diabetes caused by drugs and chemicals and Gestational Diabetes Diagnosis of diabetes must be set up according to signs of diabetes and (Fasting plasma glucose, Glycosylated haemoglobin, Oral glucose tolerance tests). A large population of patients who faced strokes sooner or later has diabetes (16–24%).

People with diabetes have 1. 5–3 times chance of having strokes and high death rates compared to the common population with no diabetes. The main reason of metabolic abnormalities is due to Table 2 Summary of the included DM studies.

Year Study Participant Number of risk factors Findings 1995 Insulin Resistance Atherosclerosis Study (IRAS)Over 16 0 0 men and women were recruited from four geographic areas to represent a range of glucose tolerance (normal, impaired, and diabetic) and ethnicity (hispanic, non- Hispanic white, and African-American)Assess the relationships between insulin resistance, insulinemia, glycemia, other components of the insulin resistance syndrome, and prevalent cardiovascular disease (CVD) in a large multiethnic cohort.Improve association between insulin resistance and CVD, apart from the concomitant hyper insulinemia and related CVD risk factors.

2012 Stop Atherosclerosis in Native Diabetics Study (SANDS)499 people with type 2 diabetes age 40, without known CVD, were recruited for a randomized 3-year trialIntervention strategies to reduce CVD in diabetic individuals. Understanding the effects of intensive risk-factor reduction on atherosclerosis burden and cardiac function in diabetic individuals in all US populations and provide evidence for determining LDL and blood pressure treatment goals for diabetic patients.The baseline characteristics of the SANDS cohort are like those of a population based sample of American Indian diabetic men and women and closely resemble diabetic men and women of other ethnic groups. Results from this study can be used to identify appropriate targets for LDL-C and BP lowering in diabetic American Indians and diabetic patients in other ethnic groups.

1998 United Kingdom Prospective Diabetes study (UKPDS)510 2 patients with newly diagnosed type 2 diabetes. It ran for twenty years (1977 to 19 97 ) in 23 UK clinical sites.Randomised, multicentre trial of glycaemic therapies. Complications of type 2 diabetes, previously often regarded as inevitable, could be reduced by improving blood glucose and/or blood pressure control.Initial insulin therapy induced more hypoglycemic reactions and weight gain without necessarily providing better control, it may be reasonable to start with oral agents and change to insulin if goals for glycemic levels are not achieved.

1998 Study to Prevent Non-Insulin- Dependent Diabetes Mellitus (STOP NIDDM trial)1418 subjects diagnosed with impaired glucose tolerance (IGT)Diabetic patients taking acarbosa there was very low stroke incidenceScreening of a high-risk population yields one eligible subject per every 10 volunteers screened. This study should answer the question of whether acarbose can prevent or delay the progression of IGT to type 2 diabetes mellitus 2004 (Prospective pioglitazone Clinical Trial in macro Vascular Events (PROACTIVE trial)5238 patients have been randomized from 19 countries.Patients with type 2 diabetes managed with diet and/or oral blood glucose-lowering drugs that have a history of macrovascular disease. Pioglitazon reduces risk of stroke and cardiovascular risk in type 2 diabetic patients at high risk for strokeThe cohort of patients enrolled in PROactive is a typical type 2 diabetic population at high risk of further macrovascular events. The characteristics of this population are ideal for assessing the ability of pioglitazone to reduce the cardiovascular risk of patients with type 2 diabetes 2007 the UK Glucose Insulin in Stroke Trial (GIST-UK).933 patients were recruited Patients presenting within 24 h of stroke onset and with admission plasma glucose concentration between 6.0-17.0 mmol/LGKI infusions significantly reduced plasma glucose concentrations and blood pressure.

Hyperglycaemia after acute stroke is a common finding that has been associated with an increased risk of death.

2016 Insulin Resistance Intervention After Stroke Trial (IRIS)3936 subjects at approximately 17 0 hospitals in Australia, Canada, Germany, Israel, Italy, the United Kingdom (UK) and the US.Treatment with an approved antidiabetic drug at the prediabetic stage of insulin resistance (IR) improves outcomes in patients with cerebrovascular disease. After 5 years, pioglitazone-treated patients had 24% reduction in cardiovascular outcomes above and beyond a generally modern approach to secondary stroke prevention.Pioglitazone therapy was associated with reduced vascular events and new diabetes, and an increase in weight, oedema and bone fractures. Pioglitazone may add to the strategies for preventing further events in patients with stroke or transient ischaemic attack.

2004 The Collaborative Atorvastatin Diabetes Study (CARDS)2838 patients aged 40–75 years in 13 2 centers in the UK and Ireland were randomized to placebo (n = 1410 ) or atorvastatin 10 mg daily (n = 1428).Type 2 diabetes Multicenter randomized placebo-controlled trialAtorvastatin 10 mg daily is safe and efficacious in reducing the risk of first cardiovascular disease events, including stroke, in patients with type 2 diabetes without high LDL-cholesterol. 582 A. Alloubani et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 12 (2018) 577–584 proatherogenic risk factors-abnormal fat deposition in arteries, hypertension, hyperglycaemia (high blood glucose) also have 1.5- fold increased risk of strokes. Atherosclerotic changes in extracra- nial and intracranial vessels are caused due to insulin resistance by the cells and hyperinsulinemia which cause diabetes and not due to high glucose levels or other risk factors.

Diabetes vascular complications divided into microvascular complications (neuropathy, retinopathy and diabetic nephropathy) and macrovascular complications (stroke, peripheral artery disease and coronary vascular disease). There are solid indications of enlarged aggregation of platelet, hypercoagulability as well as raised free radical formation and altered calcium regulation in diabetic patients. Consequently, diabetes mellitus can fasten atherosclerosis even process in younger age. Table 2 summarises all diabetes mellitus studies included in this review.

Clinical evidence has proven the evidence of atherosclerosis (subclinical forms) while IRAS (The Insulin Resistance Atheroscle- rosis Study) provides that glucose uptake and diabetes not be linked with each other in an increase in intima-media thickness (IMT) [40].

Control in cerebrovascular risk factors (hypertension, hypolipo- proteinaemia) decrease the further thickening of IMT in patients who have diabetes as stated by SANDS proofs (The Stop Atherosclerosis in Native Diabetics Study). To lower strokes in a patient, UKPDS (United Kingdom Prospective Diabetes Study) states that change in the way of living and diabetic therapies is important a 1% decrease in HbA1c reduce the risk of strokes to 4%. While at early stages of diabetes mellitus, if glucose control (HbA1c = 7 mmol/L) with proper diet is ensured and per oral diabetic agents or insulin is taken than the risk of atherosclerosis is reduced [26,41] STOP NIDDM (Study to Prevent Non-Insulin-Dependent Diabe- tes Mellitus) lays evidence that stroke rates will reduce if patients take acarbose drugs (2/682 pts). Moreover, it is proposed that it was connected with a decrease in hypertension and cardiovascular disease [42,43].

Experimental research/control measures and use of insulin lowers the strokes by 41 % while PROACTIVE (Prospective Piogli- tazone Clinical Trial in macroVascular Events) provide evidence via double blinded experimental studies; 5238 patients, 34.5 months, 45 mg pioglitazone vs. placebo) in which pioglitazone lowers the chances of stroke in DM 2.

Hypoglycemia correction was confirmed as a significant parameter in acute stroke treatment. According to Meta-analyses have revealed (32 studies) that high glucose levels have dangerous consequences (6–8 mmol/L) and its control is more important as it results in raising 28 days’ death rate in non-diabetic (RR 3.1 CI 95% 2.5–3.8) and diabetic (RR 1. 3 CI 95% 0.5–3.4). According to Insulin Resistance Intervention after Stroke Trial (IRIS), Glucose Insulin in Stroke Trial-Pilot (GIST), Insulin in Acute Ischemic Stroke (INSULINFARCT), control of glucose levels and regulation of different metabolic factors can lead to the treatment of strokes in diabetic patients. 1/5 of diabetics are not able to respond to medicines like aspirins to reduce clotting which causes bleeding in them compared to normal populations [44].

The Collaborative Atorvastatin Diabetes Study (CARDS): 2838 patients with type 2 diabetes without increased cholesterol levelswere selected for this study to atorvastatin 10 mg/day against placebo group in the primary prevention of stroke and coronary artery disease. A significant reduction of 52% in the relative risk of stroke was observed in patients taking atorvastatin (RR 48%; 95% CI: 11–69%). Patients with coronary artery disease, hypertension or DM are suggested a cholesterol-lowering therapy. Also, Patients with a history of ischemic stroke might be favoured for control as they are undergoing on ‘statin treatment’ within the care facility [45]. Table 3 compares stroke risk factors for diabetic and nondiabetic patients.

5. Conclusion In conclusion, after summarising of all the studies mentioned in the paper, it can be established that hypertension and diabetes mellitus are a stroke risk factors and correlated in patients with atherosclerosis. The significance of primary, secondary prevention and monitoring of risk factors is also highlighted in this study. The risk factors for stroke can be eliminated if individuals change their lifestyles and engage in simple exercise every day. This can reduce hyperglycaemia levels and reduce blood pressure.

6. Limitations The research findings are limited to the articles that were selected for evaluation. There are many other researchers that have addressed the topic, and it would have been interesting to compare their findings to gain a greater understanding of the issue. Since there is not the time to study all the relevant resources, only the selected resources shaped the findings of this research.

References [1] Arboix A. Cardiovascular risk factors for acute stroke: risk profiles in the different subtypes of ischemic stroke. World J Clin Cases 20153(5), doi:http:// dx.doi.org/10.12998/wjcc.v3.i5.418.

[2] LaRosa J, Grundy S, Waters D. Statin therapy after stroke or transient ischemic attack. N Engl J Med 2006;355(22):2368–71, doi:http://dx.doi.org/10.1056/ NEJMc062456.

[3] Demarin V, Lovren9 ci c-Huzjan A, Trkanjec Z, Vukovi c V, Vargek Solter V, Šeri c V, et al. Recommendations for stroke management 2006 update. Acta Clin Croat 2006;45(3):219–85.

[4] Spiess BD, Horrow J, Kaplan JA. Transfusion Medicine and Coagulation Disorders. Philadelphia: Saunders Elsevier; 2006, doi:http://dx.doi.org/ 10.1016/B978-1-4160-3786-6.10024-5.

[5] Gluud L, Thorlund K, Gluud C, Woods L. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses.

Ann Intern Med 2008149(8). . Accessed 17 April 2017 http://cat.inist.fr/?

aModele=afficheN&cpsidt=21778685.

[6] Research Arora H. Methodology: a step-by-step guide for beginners. Abhigyan 2011;29(3):62–4.

[7] Brink H, Van WC, Van RG. In: Brink H, Van der Walt C, Van Rensburg G, editors.

Fundamentals of Research Methodology for Health Care Professionals. Kenwyn:

Juta: Google Books; 2018. . Published 2007 https://books.google.com.sa/books?

hl=en&lr=&id=YZnPYoA4Jk0C&oi=fnd&pg=PA1&dq=Fundamentals+of +research+methodology+for+health+care+professionals.+Kenwyn:+Juta.

&ots=9UGjyItF_T&sig=1tCkTrpJf9ni3qcnoizBLXCY-IU&redir_esc=y#v= onepage&q&f=false.

[8] Seshadri S, Debette S. Risk Factors for Cerebrovascular Disease and Stroke.

Oxford University Press; 2016. . Accessed 16 October 2016 https://books.

google.com/books?hl=en&lr=&id=HVlxCwAAQBAJ&oi=fnd&pg=PP1&dq=Risk +Factors+for+Cerebrovascular+Disease+and+Stroke&ots=s2- 3e0V3tW&sig=KecSH6HNoXAVkPyHKMbIZe3zyYs. Table 3 Patients diagnosed with Diabetes.

Stroke Patients diagnosed with Diabetes Patient without Diabetes Hemorrhagic or Ischemic stroke 20% persons were alive 40% persons were alive Lacunar stroke Common Not common Infratentorial stroke Common Not common Risk for stroke at the age more than 55 Increase Decrease relative risk women/men Women more than men Women less than men A. Alloubani et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 12 (2018) 577–584 583 [9] Romero JR, Morris J, Pikula A. Review Stroke prevention: modifying risk factors. Ther Adv Cardiovasc Dis 2008;2(4):287–303, doi:http://dx.doi.org/ 10.1177/1753944708093847.

[10] Acharya T, Huang J, Tringali S, Frei CR, Mortensen EM, Mansi IA. Statin use and the risk of kidney disease with long-term follow-Up (8.4-Year study). Am J Cardiol 2016;117(4):647–55, doi:http://dx.doi.org/10.1016/j.amjcard.2015.11.031.

[11] Lionakis N, Mendrinos D, Sanidas E, Favatas G, Georgopoulou M. Hypertension in the elderly. World J Cardiol 2012;4(5):135–47, doi:http://dx.doi.org/ 10.4330/wjc.v4.i5.135.

[12] Afifi RM, Omar SR, El. Eaggal AA. A community screening plan for the prevalence of some chronic diseases in specified adult populations in Saudi Arabia-II: pre-hypertension and hypertension. Int J Biomed Res 2013;4(5):205, doi:http://dx.doi.org/10.7439/ijbr.v4i5.258.

[13] Lewington S, Clarke R, Qizilbash N, et al. Prospective Studies Collaboration, Age-specific relevance of usual blood pressure to vascular mortality: a meta- analysis of individual data for one million adults in 61 prospective studies. The Lancet 2002;360(9349):1903–13 , doi:http://dx.doi.org/10.1016/S0140-6736 (02)11911-8.

[14] Rodgers A, MacMahon S, Gamble G, Slattery J. Blood pressure and risk of stroke in patients with cerebrovascular disease. BMJ 1996. . Accessed October 19 , 2016 http://www.bmj.com/content/313/7050/147.short.

[15] Sacco RL, Adams R, Albers G, Alberts MJ, Benavente O, Furie K, et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack. Stroke 200637(2).

[16] Chobanian A, Bakris G, Black H, Cushman W. Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. Natl Hear Lung, Blood Inst 2003. . Accessed 19 October 2016 http://www.nhlbi.nih.gov/files/docs/guidelines/jnc7full.pdf.

[17] He FJ, Nowson CA, MacGregor GA. Fruit and vegetable consumption and stroke: meta-analysis of cohort studies. Lancet (London, England) 2006;367 (9507):320–6, doi:http://dx.doi.org/10.1016/S0140-6736(06)68069-0.

[18] Ravenni R, Jabre JF, Casiglia E, Mazza A. Primary stroke prevention and hypertension treatment: which is the first-line strategy? Neurol Int. 20113(2), doi:http://dx.doi.org/10.4081/ni.2011.e12.

[19] Sleight P. The HOPE study (Heart outcomes prevention evaluation). J Renin Angiotensin Aldosterone Syst 2000;1(1):18–20, doi:http://dx.doi.org/10.3317/ jraas.2000.002.

[20] Dahlöf B, Devereux R, Faire D, Fyhrquist F, Hedner T, Ibsen H, et al. The losartan intervention for endpoint reduction (LIFE) in hypertension study: rationale, design, and methods. the LIFE study group. Am J Hypertens 1997;10(7 Pt. 1) 705–13 . . Accessed 30 October 2016 http://www.ncbi.nlm.nih.gov/pubmed/ 9234823.

[21] PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet 2001;358(9287):1033–41, doi:

http://dx.doi.org/10.1016/S0140-6736(01)06178-5.

[22] Ratnasabapathy Y, Lawes CMM, Anderson CS. The perindopril protection against recurrent stroke study (PROGRESS): clinical implications for older patients with cerebrovascular disease. Drugs Aging 2003;20(4)241–51. .

Accessed 16 October 2016 http://www.ncbi.nlm.nih.gov/pubmed/12641480.

[23] Daskalopoulou S, Daskalopoulos M, Perrea D, Nicolaides A, Liapis C. Carotid artery atherosclerosis: what is the evidence for drug action? Curr Pharm Des 2007;13(11):1141–59, doi:http://dx.doi.org/10.2174/138161207780619019.

[24] Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B, et al. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens 2003;21(5):875–86, doi:http://dx.doi.org/10.1097/01.hjh.0000059028.82022.89.

[25] Trenkwalder P. The study on COgnition and prognosis in the elderly (SCOPE)– recent analyses. J Hypertens Suppl 2006;24(1):S107–14 , doi:http://dx.doi.org/ 10.1097/01.hjh.0000220415.99610.22.

[26] Holman R, Cull C, Fox C. United Kingdom prospective diabetes study (UKPDS) 13 : relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly. Br Med J 1995. . Accessed 20 October 2016 http://search.proquest.com/openview/ 0d99293421472d81ca6de5fcbc08ee80/1?pq-origsite=gscholar&cbl=40566.

[27] Alva ML, Gray A, Mihaylova B, Leal J, Holman RR. The impact of diabetes- related complications on healthcare costs: new results from the UKPDS (UKPDS 84). Diabetic 2015;32(4):459–66. http://onlinelibrary.wiley.com/doi/ 10.1111/dme.12647/full.

[28] ALLHAT Officers, Coordinators for the ALLHAT Collaborative Research Group.

The antihypertensive and lipid-Lowering treatment to prevent heart attacktrial. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT-LLT). JAMA 2016;288(23):459–66. http://www.ncbi.nlm.nih.gov/pubmed/12479764.

[29] The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358(15):1547–59, doi:http://dx.

doi.org/10.1056/NEJMoa0801317.

[30] Liebson PR, Amsterdam EA. Ongoing telmisartan alone and in combination with ramipril global endpoint trial (ONTARGET): implications for reduced cardiovascular risk. Prev Cardiol 2009;12(1)43–50. . Accessed 25 October 2016 http://www.ncbi.nlm.nih.gov/pubmed/1930169.

[31] Zanchetti A, Bond MG, Hennig M, Neiss A, Mancia G, Dal Palù C, et al. Calcium antagonist lacidipine slows down progression of asymptomatic carotid atherosclerosis: principal results of the European Lacidipine Study on Atherosclerosis (ELSA), a randomized, double-blind, long-term trial.

Circulation 2002;106(19)2422–7. . Accessed 26 October 2016 http://www.

ncbi.nlm.nih.gov/pubmed/12417537.

[32] Mancia G, Grassi G, Redon J. Manual of Hypertension of the European Society of Hypertension. CRC Press; 2014. . Accessed 3 November 2016 https://books.

google.com/books?hl=en&lr=&id=sTncBQAAQBAJ&oi=fnd&pg=PP1&dq= Manual+of+Hypertension+of+the+European+Society+of+Hypertension, +Second+Edition&ots=JnImld_P-Z&sig=teDi_RLqV1MHbWmZR0zHADDp5QY.

[33] Schrader J, Lüders S, Kulschewski A, Hammersen F, Plate K, Berger J, et al.

Morbidity and mortality after stroke, eprosartan compared with nitrendipine for secondary prevention: principal results of a prospective randomized controlled study (MOSES). Stroke 2005;36(6):1218–24, doi:http://dx.doi.org/ 10.1161/01.STR.0000166048.35740.a9.

[34] Benavente OR, White CL, Pearce L, Pergola P, Roldan A, Benavente MF, et al. The secondary prevention of small subcortical strokes (SPS3) study. Int J Stroke 2011;6(2):164–75, doi:http://dx.doi.org/10.1111/j.1747-4949.2010.00573.x.

[35] Graves JW, White CL, Szychowski JM, Pergola PE, Benavente OR, Coffey CS, et al.

Predictors of lowering SBP to assigned targets at 12 months in the Secondary Prevention of Small Subcortical Strokes study. J Hypertens 2012;30(6):1233– 40, doi:http://dx.doi.org/10.1097/HJH.0b013e328353968d.

[36] Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators, Yusuf S, Te o K, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet (London, England) 2008;372(9644):1174– 83, doi:http://dx.doi.org/10.1016/S0140-6736(08)61242-8.

[37] Rundek T, Sacco RL. Risk factor management to prevent first stroke. Neurol Clin 2008;26(4)1007–45, doi:http://dx.doi.org/10.1016/j.ncl.2008.09.001 ix.

[38] Appleton JP, Sprigg N, Bath PM. Blood pressure management in acute stroke.

Stroke Vasc Neuro 1 2016;e000020:72–82, doi:http://dx.doi.org/10.1136/svn- 2016-000020.

[39] Shimada K. SY 08-2 hypertension management for secondary prevention of stroke. J Hypertens 2016;34:e183, doi:http://dx.doi.org/10.1097/01.hjh.

0000500397.25140.82.

[40] Wagenknecht LE, Mayer EJ, Rewers M, Haffner S, Selby J, Borok GM, et al. The insulin resistance atherosclerosis study (IRAS). Ann Epidemiol 1995;5(6):464– 72, doi:http://dx.doi.org/10.1016/1047-2797(95)00062-3.

[41] UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352 (9131):837–53, doi:http://dx.doi.org/10.1016/S0140-6736(98)07019-6.

[42] Nishimura R. The study TO prevent non-Insulin dependent diabetes mellitus trial (acarbose). Nihon Rinsho 2005;63:478–82. http://europepmc.org/ abstract/med/15779425.

[43] Chiasson J-L, Gomis R, Hanefeld M, Josse RG, Karasik A, Laakso M. The STOP- NIDDM Trial: an international study on the efficacy of an a-glucosidase inhibitor to prevent type 2 diabetes in a population with impaired glucose tolerance: rationale, design, and preliminary screening data. Diabetes Care 199821(10). http://care.diabetesjournals.org/content/21/10/1720.short.

[44] Bath P, Appleton J, Sprigg N. The Insulin Resistance Intervention after Stroke trial: a perspective on future practice and research. Int J 2016;11(7):741–3.

http://journals.sagepub.com/doi/abs/10.1177/1747493016660099.

[45] Colhoun H, Betteridge D, Durrington P, Hitman G. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised. Lancet 2004;364(9435):685–96. http://www.sciencedirect.com/science/article/pii/ S0140673604168955. 584 A. Alloubani et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 12 (2018) 577–584