**8. Clinical trials on prevention strategies and therapeutic approaches for diabetic vasculopathy**

Growth of overweight and obese population due to diet and life-style changes worldwide correlates with the global T2DM epidemic [144]. However, majority of the studies focusing on diabetes prevention were not designed to assess CV outcomes [145]. There is a need for studies to explore the effect of exercise and diet on quality of life, morbidity, and mortality, with a special focus on CV outcomes.

Clinical trials examining the effect of *intensive glucose control* on CVD did not report consistency in beneficial effects of intensive glycemic control on CV events [146–149]. Although the risk of microvascular complications was reduced with strict glucose control in T2DM patients, its beneficial effects on CVD prevention or reduction remain ambiguous [150–152]. Data from UKPDS 34 (the United Kingdom Prospective Diabetes Study) suggested a protective effect of improved glucose control on CVD, CV mortality, and all-cause mortality [146]. However, a number of large randomized, controlled trials have reported conflicting results. ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) [147], VADT (Veterans Affairs Diabetes Trial) [153], and NAVIGATOR (Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research) [154] showed no effect of intensive glucose control on major CV events. However, ACCORD (Action to Control Cardiovascular Disease in Diabetes) [149] demonstrated an increased risk of death from CV causes and total mortality associated with intensive glucose control. In the PROactive (Prospective Pioglitazone Clinical Trial in Macrovascular Events) study [155], patients treated with pioglitazone had a significant 16% reduction in mortality, non-fatal myocardial infarction, and stroke. Further research is needed to examine effect of pharmacological approaches for the management of hyperglycemia on CVD.

Diabetic vasculopathy can be improved by *lowering blood pressure* with antihypertensive drugs which have antiatherogenic effects, e.g., ACE inhibitors, angiotensin II receptor blockers, beta-blockers, and calcium channel blockers. Randomized controlled trials like UKPDS [33, 127], HOT (Hypertension Optimal Treatment) [156], SHEP (the Systolic Hypertension in the Elderly Program) [157–159], Syst-EUR (Systolic Hypertension in Europe) [158–161], HOPE (Heart Outcomes Prevention Evaluation) [162], LIFE (Losartan Intervention For Endpoint Reduction in Hypertension) [163], and ALLHAT (the Anti-hypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) [164] have found beneficial effects of adequately controlling blood pressure in improving CV outcomes, specifically, for stroke, when aggressive blood pressure targets are met [33, 156, 165, 166].

*Dyslipidemia* plays a significant role in CV complications in T2DM. Dyslipidemia comprises elevated total cholesterol and LDL cholesterol, decreased HDL cholesterol, and high triglyceride levels [74, 75]. Lowering LDL cholesterol reduces the risk of major vascular events in T2DM patients [167]. Randomized clinical trials in T2DM have consistently shown that statins significantly reduce the risk of major primary and secondary CVD endpoints. Clinical trials of fibrate therapy have shown mixed results.

Clinical trials e.g. CARDS (the Collaborative Atorvastatin Diabetes Study) [168], LIPID (Longterm Intervention with Pravastatin in Ischemic Disease) [169], 4S (Scandinavian Simvastatin Survival Study) [170] and HPS (the Heart Protection Study) [171], demonstrated that statin significantly reduced the incidence of stroke in diabetic patients.

Subgroup analysis of the Helsinki Heart Study [136], and VA-HIT (Veterans Affairs Highdensity lipoprotein Intervention Trial) [172, 173] provided evidence for the potential benefit of fibrate therapy in reducing CVD in T2DM. However, FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study [174] failed to show similar benefits. The lipid arm of the ACCORD study examined combination therapy of statin and fibrate and failed to support the effectiveness to reduce CV risk as compared with statin alone [175].

*Antiplatelet drugs* reduce the risk of CV events in T2DM patients. Currently, aspirin is widely recommended for primary prevention of CV events in T2DM patients and is the main drug under investigation to reduce the risk of CVD [176]. Aspirin reduces the risk of serious vascular events in high risk patients by about 25% and also prevents the recurrence of angina, heart attack and stroke. Aspirin is routinely given for primary prevention of CV events in T2DM patients as all major guidelines recommend such preventive use that is based on evidence gathered from clinical trials of high-risk patients [177, 178]. However, the POPADAD (Prevention of Progression of Arterial Disease and Diabetes) trial [179] demonstrated that aspirin failed to prevent a first CV event or death in T2DM patients, which contradicts the recommendations by many guidelines. The POPADAD trial recommended that aspirin should be used for secondary prevention of CVD in patients with T2DM. The JPAD (Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes) trial examined the efficacy of low-dose aspirin for the primary prevention of atherosclerotic events in T2DM patients and found that low-dose aspirin when used for primary prevention did not reduce the risk of CV events [180].

In a subgroup analysis of the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events) study, patients with T2DM taking clopidogrel seem to derive enhanced benefit from clopidogrel compared with aspirin [181, 182]. The subgroup analysis of PRISMPLUS (Platelet Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms) trial showed that triple therapy (aspirin, heparin, tirofiban) significantly reduced the incidence of myocardial infarction or death as compared with aspirin plus heparin [183].

### **9. Conclusion and recommendations**

increases cAMP concentration in platelets by inhibiting phosphodiesterase enzyme, and the increased cAMP levels inhibit activation of cytoplasmic second messengers. Dipyridamole also promotes prostacyclin release and inhibits thromboxane A2 synthesis. Glycoprotein IIb/

**8. Clinical trials on prevention strategies and therapeutic approaches for** 

Growth of overweight and obese population due to diet and life-style changes worldwide correlates with the global T2DM epidemic [144]. However, majority of the studies focusing on diabetes prevention were not designed to assess CV outcomes [145]. There is a need for studies to explore the effect of exercise and diet on quality of life, morbidity, and mortality, with

Clinical trials examining the effect of *intensive glucose control* on CVD did not report consistency in beneficial effects of intensive glycemic control on CV events [146–149]. Although the risk of microvascular complications was reduced with strict glucose control in T2DM patients, its beneficial effects on CVD prevention or reduction remain ambiguous [150–152]. Data from UKPDS 34 (the United Kingdom Prospective Diabetes Study) suggested a protective effect of improved glucose control on CVD, CV mortality, and all-cause mortality [146]. However, a number of large randomized, controlled trials have reported conflicting results. ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) [147], VADT (Veterans Affairs Diabetes Trial) [153], and NAVIGATOR (Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research) [154] showed no effect of intensive glucose control on major CV events. However, ACCORD (Action to Control Cardiovascular Disease in Diabetes) [149] demonstrated an increased risk of death from CV causes and total mortality associated with intensive glucose control. In the PROactive (Prospective Pioglitazone Clinical Trial in Macrovascular Events) study [155], patients treated with pioglitazone had a significant 16% reduction in mortality, non-fatal myocardial infarction, and stroke. Further research is needed to examine effect of pharmacological approaches for the management of hyperglycemia on CVD.

Diabetic vasculopathy can be improved by *lowering blood pressure* with antihypertensive drugs which have antiatherogenic effects, e.g., ACE inhibitors, angiotensin II receptor blockers, beta-blockers, and calcium channel blockers. Randomized controlled trials like UKPDS [33, 127], HOT (Hypertension Optimal Treatment) [156], SHEP (the Systolic Hypertension in the Elderly Program) [157–159], Syst-EUR (Systolic Hypertension in Europe) [158–161], HOPE (Heart Outcomes Prevention Evaluation) [162], LIFE (Losartan Intervention For Endpoint Reduction in Hypertension) [163], and ALLHAT (the Anti-hypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) [164] have found beneficial effects of adequately controlling blood pressure in improving CV outcomes, specifically, for stroke, when

*Dyslipidemia* plays a significant role in CV complications in T2DM. Dyslipidemia comprises elevated total cholesterol and LDL cholesterol, decreased HDL cholesterol, and high

aggressive blood pressure targets are met [33, 156, 165, 166].

IIIa receptor antagonists inhibit the final common pathway for platelet aggregation.

**diabetic vasculopathy**

80 Recent Trends in Cardiovascular Risks

a special focus on CV outcomes.

CV complications are the major causes of morbidity and mortality in patients with T2DM. Macrovascular complications are more common, and most diabetic patients develop or die of macrovascular diseases, predominantly by developing CVD.

The initiators of vasculopathy that ultimately develop into long-term complications can be controlled and avoided by strict glycemic control, maintaining normal lipid profiles, regular physical exercise, adopting a healthy lifestyle and pharmacological interventions. Studies have shown that lifestyle interventions help in prevention and reduction of CV risk factors; however, there is a lack of studies investigating effects of lifestyle modifications on long-term CV outcomes that need to be addressed. Similarly, because the intensive glycemic control in T2DM patients did not show consistent beneficial effects on CV events, such a strict glycemic control needs to be revisited. Contrary to the disappointing results of intensive glucose control in prevention of CVD, intensive control of blood pressure using anti-hypertensive drugs, normalization of lipid profiles using lipid-lowering agents, and prevention of atherosclerosis and vascular thrombosis with antiplatelet therapy have been found to be beneficial.

Health promotion and patient education should be given priority to combat CV complications in T2DM patients. A multidisciplinary approach involving patients, health professionals, and researchers should be undertaken to reduce the incidence and prevalence of T2DM and CVD, and improve the quality of life and well-being of patients.

### **Author details**

Sayeeda Rahman1 , Md. Anwarul Azim Majumder2 \*, Russell Kabir3 , Mainul Haque4 , Subir Gupta2 , Sana Mohammad Yasir Arafat5 , Nkemcho Ojeh2 and Prasad Dalvi6

\*Address all correspondence to: azim.majumder@cavehill.uwi.edu

1 Department of Clinical Sciences, Faculty of Life Sciences, School of Medical Sciences, University of Bradford, UK

2 Faculty of Medical Sciences, The University of the West Indies, Cave Hill Campus, Barbados, West Indies

3 Department for Allied and Public Health, Faculty of Medical Sciences, Anglia Ruskin University, Chelmsford, Essex, UK

4 Faculty of Medicine and Defense Health, National Defense University of Malaysia, Kuala Lumpur, Malaysia

5 Department of Psychiatry, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh

6 Lake Erie College of Osteopathic Medicine, Bradenton, Florida, USA

### **References**

[1] Stemmer EA. Diabetes mellitus and vascular disease. In: Aronow WS, Stemmer EA, Wilson SE, editors. Vascular Disease in the Elderly. Armonk: Futura; 1997. pp. 199-220


The initiators of vasculopathy that ultimately develop into long-term complications can be controlled and avoided by strict glycemic control, maintaining normal lipid profiles, regular physical exercise, adopting a healthy lifestyle and pharmacological interventions. Studies have shown that lifestyle interventions help in prevention and reduction of CV risk factors; however, there is a lack of studies investigating effects of lifestyle modifications on long-term CV outcomes that need to be addressed. Similarly, because the intensive glycemic control in T2DM patients did not show consistent beneficial effects on CV events, such a strict glycemic control needs to be revisited. Contrary to the disappointing results of intensive glucose control in prevention of CVD, intensive control of blood pressure using anti-hypertensive drugs, normalization of lipid profiles using lipid-lowering agents, and prevention of atherosclerosis

and vascular thrombosis with antiplatelet therapy have been found to be beneficial.

and CVD, and improve the quality of life and well-being of patients.

, Md. Anwarul Azim Majumder2

\*Address all correspondence to: azim.majumder@cavehill.uwi.edu

6 Lake Erie College of Osteopathic Medicine, Bradenton, Florida, USA

, Sana Mohammad Yasir Arafat5

**Author details**

82 Recent Trends in Cardiovascular Risks

Sayeeda Rahman1

versity of Bradford, UK

versity, Chelmsford, Essex, UK

Gupta2

West Indies

Lumpur, Malaysia

**References**

Health promotion and patient education should be given priority to combat CV complications in T2DM patients. A multidisciplinary approach involving patients, health professionals, and researchers should be undertaken to reduce the incidence and prevalence of T2DM

, Nkemcho Ojeh2

1 Department of Clinical Sciences, Faculty of Life Sciences, School of Medical Sciences, Uni-

2 Faculty of Medical Sciences, The University of the West Indies, Cave Hill Campus, Barbados,

3 Department for Allied and Public Health, Faculty of Medical Sciences, Anglia Ruskin Uni-

4 Faculty of Medicine and Defense Health, National Defense University of Malaysia, Kuala

5 Department of Psychiatry, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh

[1] Stemmer EA. Diabetes mellitus and vascular disease. In: Aronow WS, Stemmer EA, Wilson SE, editors. Vascular Disease in the Elderly. Armonk: Futura; 1997. pp. 199-220

\*, Russell Kabir3

and Prasad Dalvi6

, Mainul Haque4

, Subir


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