Published on

  • Be the first to comment

  • Be the first to like this

No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide


  1. 1. Review S7Blood pressure control, risk factors and cardiovascularprognosis in patients with diabetes: 30 years of progressJean-Jacques Mourad and Sylvain Le JeuneHypertension is a major co-morbidity for type 2 diabetes, and patients with type 2 diabetes in the Steno-2 study.an important modifiable risk factor for vascular events. Nevertheless, the major coronary event risk remains high inTherefore, treatment of diabetes and its risk factors is type 2 diabetes patients, and the results of the ADVANCEimportant to minimize complications, and much progress trial provided a step forward in treatment.has been made over the past 30 years. The UKPDS trial J Hypertens 26 (suppl 3):S7–S13 Q 2008 Wolters Kluwershowed that intensive glycaemic and blood pressure control Health | Lippincott Williams & Wilkins.reduced the risk of vascular events. In the HOT study, the Journal of Hypertension 2008, 26 (suppl 3):S7–S13addition of aspirin to patients with diabetes and controlledhypertension decreased the risk of myocardial infarction. Keywords: diabetes mellitus, hypertension, risk factors, treatmentBlood pressure control with angiotensin-converting enzyme Hypertension Unit, Avicenne University Hospital (AP-HP) and Paris 13 Universityinhibitors in MICRO–HOPE also showed significant (EA 3412), 93000 Bobigny, Francereductions in the risk of vascular complications, and blockers Correspondence to Jean-Jacques Mourad, Avicenne University Hospital,of the renin–angiotensin system produced substantial renal 125 route de Stalingrad, 93009 Bobigny Cedex 09, Franceprotective effects in patients with hypertension and diabetes. E-mail: jean-jacques.mourad@avc.aphp.frStatin therapy in the HPS and CARDS studies was effective in Sponsorship: Funding for preparation of this paper was provided by Servier.the primary prevention of cardiovascular disorders. Finally, an Conflicts of interest: J-J.M. has undertaken consultancies for almost allintensive multifactorial intervention achieved sustained pharmaceutical companies that develop antihypertensive medications, includingreduction in the risk of vascular complications and death in Servier.Diabetes and hypertension: risk factors In particular, hypertension is a major co-morbid conditionfor cardiovascular disease for diabetes, and an important risk factor for the devel-Diabetes mellitus is a major global health problem, with a opment of cardiovascular and renal disease in patientsprevalence of approximately 246 million individuals world- with diabetes. In an observational study of the UKPDSwide [1]. By 2025, this number is predicted to increase to trial [5], a continuous positive correlation was seenapproximately 350 million people, particularly in develop- between systolic blood pressure and the occurrence ofing regions of the world, an increase of more than 50%. macrovascular and microvascular events (Fig. 2). More-Patients with diabetes are at an increased risk of developing over, it is estimated that 68% of coronary events globallymacrovascular (e.g. cardiovascular disease) and microvas- are attributable to diabetes or hypertension [6]. Thecular (e.g. nephropathy and retinopathy) complications, coexistence of hypertension and diabetes provides anwhich result in a significant decrease in life expectancy. In a additive increase in the risk of vascular events. Therecent retrospective analysis [2], the life expectancy of men ¨ Swedish Goteborg study, which followed 754 men withand women with diabetes aged 50 years or older was hypertension for at least 25 years, found that men withdecreased by 7.5 and 8.2 years, respectively, compared both conditions had a 66% greater risk of stroke orwith equivalent non-diabetic individuals. The occurrence myocardial infarction compared with men with hyperten-of macrovascular complications is more common, cardio- sion alone [7]. The strong association between diabetesvascular disease being responsible for up to 80% of the total and other cardiovascular risk factors emphasizes the needmortality in patients with type 2 diabetes [3]. A marked for comprehensive, integrated therapeutic managementincrease in microvascular complications is also seen, how- programmes to reduce the risk of complications andever, with 75% of patients with diabetes from the UK increase life expectancy. Significant progress in the mana-Prospective Diabetes Study (UKPDS) having a renal event gement of diabetes has been made over the past 30 years,over a 20-year period (Fig. 1) [4]. largely as a result of the numerous studies that have demonstrated the importance of specific drug interven-Diabetes is associated with a number of cardiovascular tions, the need to combine drug treatment with closerisk factors, which include hypertension, dyslipidaemia, monitoring, and the aggressive treatment of any co-hypercholesterolaemia and abnormalities in fibrinolysis. existing cardiovascular risk factors. The major advances0263-6352 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/01.hjh.0000334072.97080.33Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
  2. 2. S8 Journal of Hypertension 2008, Vol 26 (suppl 3) Fig. 1 100 Proportion of patients (%) 80 Any renal event 60 Microalbuminuria 40 Reduced creatinine clearance 20 Macroalbuminuria Doubling of serum creatinine 0 5 10 15 20 Years after randomization Proportion of patients with renal events during the follow-up of UKPDS (4031 patients followed during 20 years). Reproduced with permission from The American Diabetes Association [4]. Copyright # 2006 American Diabetes Association. in the treatment and understanding of diabetes of the explore the effects of intensive blood glucose control on past 30 years are reviewed in this article. the development of complications in patients with type 2 diabetes. In 1991 the scope of the trial was broadened to 30 years of progress in diabetes: from UKPDS examine the effects of intensive blood pressure control. to ADVANCE The UKPDS is one of the longest and largest clinical trials Glycaemic and blood pressure control in UKPDS ever conducted. When it commenced in 1977 it aimed to The primary part of diabetes care is the control of blood glucose levels. It is clear that tight glycaemic control slows Fig. 2 the progression of microvascular disease, but it remains uncertain if intensive glycaemic control alone has a 50 beneficial effect on major vascular events. In UKPDS 33 the difference in the incidence of macrovascular events between the intensive glycaemic control group (fasting Adjusted incidence per 1000 person years (%) plasma glucose <6 mmol/l) and the conservative therapy 40 group was only of borderline significance (Fig. 3a) [8]. However, a subsequent analysis of data from the UKPDS trial [9] revealed that each 1% reduction in mean haemo- globin A1c was associated with significant reductions in the 30 incidence of myocardial infarction (14%; P < 0.0001) and stroke (12%; P ¼ 0.035). Intensive control was highly effective for the prevention of microvascular events. After 10 years of follow-up, haemoglobin A1c in the intensive 20 treatment group was reduced by 11% relative to the conservative group, resulting in a 25% reduction in the relative risk (RR) of microvascular events [RR 0.75; 95% 10 confidence interval (CI) 0.60–0.93; P ¼ 0.0099). In con- trast, there was no significant change in the risk of stroke, although a trend towards significance was seen with the risk of myocardial infarction (RR 0.84; 95% CI 0.71–1.00; 0 P ¼ 0.052) [8]. It is, however, plausible that a longer period 110 120 130 140 150 160 170 of observation would lead to a significant benefit in terms of macrovascular events. The relatonship between mean systolic blood pressure (mmHg) and the incidence of myocardial infarction or microvascular events in the The American Diabetes Association and the American UKPDS trial. & Myocardial infarction; microvascular endpoints. Reproduced with permission from Adler et al. [5]. Association of Clinical Endocrinologists currently recom- mend maintaining haemoglobin A1C at less than 7% orCopyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
  3. 3. Blood pressure control and cardiovascular prognosis in diabetes Mourad and Le Jeune S9Fig. 3(a) Proportion of patients with events during the follow-up of UKPDS 33 [8]; 3867 patients with diabetes over 10 years. Conventional group(haemoglobin A1c 7.9%); intensive group (haemoglobin A1c 7%). (b) Proportion of patients with events during the follow-up of UKPDS 38 [14];3867 patients with diabetes over 10 years. Conventional group (154/87 mmHg); intensive group (144/82 mmHg).less than 6.5%, respectively [10,11]. Blood pressure vascular events, but also prevents or reduces microvas-lowering has been shown to reduce the incidence of cular complications. In the UKPDS trial, the use of anstroke and myocardial infarction in the general popu- ACE inhibitor or a beta-blocker reduced the risk oflation [12], and improve symptoms associated with microvascular, and some macrovascular events [14].microalbuminuria and overt nephropathy in patients with The Heart Outcomes Prevention Evaluation (HOPE)type 1 diabetes [13]. Therefore, strict blood pressure trial published in 2000 [15] demonstrated a decrease incontrol is important in patients with diabetes, especially the risk of both macro- and microvascular events with thein those with co-morbid hypertension. In UKPDS 38 [14], use of an ACE inhibitor (ramipril) in patients at high riskintensive treatment with tight blood pressure control of a cardiovascular event. The diabetic subgroup of the(target blood pressure <150/85 mmHg) using the angio- HOPE trial (MICRO–HOPE) [16] also showed thattensin-converting enzyme (ACE) inhibitor captopril or ramipril significantly reduced the risk of the compositethe beta-blocker atenolol significantly reduced the risk of primary endpoint of myocardial infarction, stroke andmicrovascular events (RR 0.63; 95% CI 0.44–0.89; cardiovascular mortality by 25% (P ¼ 0.0004), comparedp ¼ 0.0092), but not myocardial infarction, compared with placebo; the risk reduction for each of these indi-with conservative therapy using less intensive blood vidual outcomes was found to be significant (Fig. 4). Inpressure control (blood pressure <180/105 mmHg) addition, the risk of overt nephropathy was reduced by(Fig. 3b). The risk of stroke was also significantly reduced 24% in the ramipril group (P ¼ 0.027). The results ofin the intensive group (RR 0.56; 95% CI 0.35–0.89; MICRO–HOPE further reinforced the importance ofp ¼ 0.013); this outcome is in agreement with an earlier blood pressure control for the therapeutic managementmeta-analysis, which showed a stroke risk reduction of of patients with diabetes, and clearly demonstrated42% [12]. the benefits of ACE inhibitors in this population, for the reduction of cardiovascular and renal disease. MoreBlood pressure control in MICRO–HOPE recently, the Antihypertensive and Lipid-LoweringBlockade of the renin–angiotensin–aldosterone system Treatment to Prevent Heart Attack Trial (ALLHAT)by ACE inhibitors or angiotensin II receptor blockers [17] showed that the risk of cardiovascular events was(ARB) not only treats hypertension and reduces cardio- decreased with the thiazide-type diuretic chlorthalidoneCopyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
  4. 4. S10 Journal of Hypertension 2008, Vol 26 (suppl 3) Fig. 4 Proportion of patients with diabetes with events during the follow-up of the MICRO–HOPE study; 3577 patients with diabetes with a follow-up of more than 4.5 years (60% of patients had coronary events). Placebo group (142/79 mmHg); ramipril group (142/80 mmHg) [16]. compared with the ACE inhibitor lisinopril in patients with with diabetes, probably as a result of the smaller dia- hypertension with or without diabetes. As a result, thiazide betic patient sample size [11,23]. Furthermore, aspirin diuretics are one of the recommended first-line therapies had no substantial effects on stroke and mortality in in patients with hypertension and diabetes, without overt patients either with or without diabetes. The real nephropathy, with ACE inhibitors one of the leading degree of efficacy of aspirin for the prevention of options for add-on treatment [18]. cardiovascular events in patients with diabetes thus remains uncertain, and additional specific trials of Blood pressure control and aspirin therapy in HOT aspirin administration in patients with diabetes are The effectiveness of tight blood pressure control for the required. Certainly, evidence indicating that diabetes prevention of macrovascular events was further shown in is a prothrombotic condition continues to accumulate. A a diabetic subgroup of the Hypertension Optimal Treat- recent review [24] reported that insulin resistance ment (HOT) trial [19]. In HOT, patients randomly is accompanied by the loss of control of platelet acti- assigned to antihypertensive treatment with a diastolic vation and increased levels of a variety of coagulation blood pressure goal of less than 80 mmHg had a 51% factors and the fibrinolytic inhibitor, plasminogen acti- reduction in major cardiovascular events compared with vator inhibitor 1. As diabetes develops, the fibrin struc- those randomly assigned to a diastolic blood pressure ture/function of fibrinogen is altered, resulting in a target of less than 90 mmHg. The current blood press- reduction in permeability, clot lysis and enhanced clot ure target of 130/80 mmHg recommended for patients rigidity. These haemostatic abnormalities generate a with hypertension and diabetes in all major guidelines prothrombotic phenotype, suggesting the importance [10,11,18] has been heavily influenced by these land- of antithrombotic therapy as a prevention strategy in mark studies. Before the publication of these studies patients with diabetes. Current American Diabetes ‘fair’ or ‘acceptable’ blood pressure levels for individuals Association guidelines recommend the use of aspirin with diabetes were as high as 160/95 mmHg or less therapy in patients with diabetes who have a history [20]. (secondary prevention) or are at risk (primary preven- tion) of cardiovascular disease [10]. Clinical trials have also shown that aspirin reduces the incidence of stroke and myocardial infarction in patients Renal protection in IDNT with a history of cardiovascular disease [21,22]. The Diabetic nephropathy is a common complication of HOT trial showed that the addition of low-dose aspirin diabetes, which results in a decline in renal function to antihypertensive treatment reduced major cardiovas- and consequent progression to end-stage renal disease cular events by 15% (P ¼ 0.03) and myocardial infarc- (ESRD) in the absence of specific intervention. Arterial tion by 36% (P ¼ 0.001), compared with placebo, in blood pressure also plays an important role in the devel- patients with treated hypertension [19]. A separate opment of renal damage; hypertension appears to be a subgroup analysis showed that although aspirin statisti- determining factor of progression to ESRD. Therefore, cally significantly reduced the risk of major cardiovas- the tight control of hypertension is essential to reduce cular events and myocardial infarction in patients with- the risk of development and progression of diabetic out diabetes it did not show such an effect in patients nephropathy.Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
  5. 5. Blood pressure control and cardiovascular prognosis in diabetes Mourad and Le Jeune S11As described above, the use of ACE inhibitors in both the or greater [28]. Daily treatment with simvastatin was foundUKPDS and MICRO–HOPE studies reduced the risk of to reduce significantly the incidence of major coronarymicrovascular events. In the Irbesartan Diabetic Nephro- (27%) and vascular (22%; both p < 0.0001) events, includ-pathy Trial (IDNT) [25], the renoprotective effects of the ing stroke (24%; p ¼ 0.01), compared with placebo afterARB irbesartan were demonstrated in patients with hy- 4.8 years of follow-up. This risk reduction in majorpertension with nephropathy caused by type 2 diabetes. vascular events was also seen in diabetic patients withAfter 2.6 years of follow-up, the risk of a doubling of the hypertension within the HPS population. The Collabora-serum creatinine concentration was decreased by 33% tive Atorvastatin Diabetes Study (CARDS) [29] showed(p ¼ 0.003) and 37% (p < 0.001) in irbesartan and amlodi- that atorvastatin effectively reduced the risk of cardio-pine recipients, respectively, compared with placebo vascular events, including acute coronary events and(Fig. 5). Moreover, the relative risk of ESRD was 23% stroke, in patients with type 2 diabetes without elevatedlower in the irbesartan group compared with either the LDL-cholesterol levels and with no previous history ofplacebo or amlodipine groups; this was found to be margin- cardiovascular disease (Fig. 6). After a follow-up period ofally significant (both p ¼ 0.07). An analysis [26] of the 3.9 years, the risk of a major cardiovascular event wascardiovascular endpoints that were reported in the IDNT significantly reduced in the atorvastatin group comparedstudy failed to show a cardioprotective effect with irbe- with the placebo group [hazard ratio (HR) 0.63; 95% CIsartan; no difference in the cardiovascular event rates were 0.48–0.83; p ¼ 0.001]. This outcome was driven by signi-seen between the irbesartan, placebo and amlodipine ficant reductions in the risk of acute coronary eventsgroups (29.7%, 32.5% and 28.3% of patients, respectively). (HR 0.64; 95% CI 0.45–0.91) and stroke (HR 0.52; 95% CI 0.31–0.89).Lipid-lowering therapy: HPS and CARDSThe increased risk of cardiovascular morbidity and The results of HPS and CARDS established the effec-mortality in patients with diabetes emphasizes the need tiveness of statin therapy for the primary prevention offor aggressive lowering of all modifiable risk factors. In macrovascular events in patients with diabetes regardlessthese individuals, low-density lipoprotein (LDL) choles- of cholesterol levels, and statins have become the first-terol is a strong predictor of coronary heart disease as in choice agent for primary prevention in these patients.the general population. Plasma concentrations of total Those studies also emphasized the need for tight controland LDL-cholesterol in patients with diabetes are, how- of the multiple risk factors present in patients withever, typically similar to those in the general population, diabetes.which may explain the low prescription rates of lipid-lowering therapies for patients with diabetes in the past Multifactorial intervention and mortality: Steno-2[27]. Trials of intensified interventions for single risk factors in patients with type 2 diabetes, which include UKPDS andTwo major studies have demonstrated the benefits of CARDS, have demonstrated efficacy in reducing thestatins for the prevention of macrovascular events in development and progression of both micro- and macro-patients with diabetes, which has led to the wide use of vascular complications. On the basis of these findings,this lipid-lowering therapy in such individuals. The Heart treatment guidelines were modified to recommend anProtection Study (HPS) included almost 6000 patients intensified multifactorial approach to the treatment ofwith diabetes and total cholesterol levels of 3.5 mmol/l type 2 diabetes.Fig. 5 End stage of renal disease p = 0.003 Doubling of creatinine p = 0.07 Cardiovascular events NS 0 10 20 30 % patientsProportion of patients with events during the follow-up of the IDNT study; 1715 patients with hypertension and proteinuria (>900 mg/24 h, creatinine1–3 mg/dl) with a follow-up of more than 2.6 years. Placebo group (144/80 mmHg); irbesartan group (141/78 mmHg) [25].Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
  6. 6. S12 Journal of Hypertension 2008, Vol 26 (suppl 3) Fig. 6 Proportion of patients with events during the follow-up of the CARD study; 2838 patients with diabetes with one or more other risk factor (hypertension, retinopathy, albuminuria, smoking). Placebo group; atorvastatin group [29]. The Steno-2 study was designed to evaluate the effect on assessed the effects of fixed combination therapy, using cardiovascular disease of multiple drug combination an ACE inhibitor and a diuretic, on vascular disease in a therapy and behavioural modification, aimed at several large, diverse population of patients with type 2 diabetes. modifiable risk factors in type 2 diabetes patients with ADVANCE also evaluated the effects of intensive microalbuminuria [30,31]. After a mean follow-up of glycaemic control with a gliclazide-based antihypergly- 13.3 years, significant reductions in the risk of death from caemic and standard glycaemic control on the same any cause (HR 0.54; 95% CI 0.32–0.89; P ¼ 0.02), the risk outcomes. The results of the blood pressure arm of the of death from cardiovascular causes (HR 0.43; 95% CI ADVANCE trial discussed in more detail later in this 0.19–0.94; P ¼ 0.04) and the risk of a cardiovascular event supplement provide a clear step forward for the routine (HR 0.41; 95% CI 0.25–0.67; P < 0.001) were demons- treatment of patients with diabetes. trated with intensive therapy versus conventional therapy [30]. In addition, significantly fewer patients in Acknowledgements the intensive versus the conventional therapy groups The authors would like to thank Max Chang, Wolters developed diabetic retinopathy (RR 0.57; 95% CI Kluwer Health, for his assistance in the writing and 0.37–0.88; P ¼ 0.01) or diabetic nephropathy (RR 0.4; editing of this manuscript. 95% CI 0.25–0.77; P ¼ 0.004), and significantly fewer progressed to ESRD (one versus six; P ¼ 0.02). References 1 International Diabetes Federation. Diabetes atlas, 3rd ed. 2006 1 November 2007. Available from: http://www.eatlas.idf.org/webdata/docs/ Therefore, an intensive multi-focused treatment regimen At%20a%20glance_lg.jpg. Accessed: August 2008. is capable of producing a sustained reduction in the risk of 2 Franco OH, Steyerberg EW, Hu FB, Mackenach J, Nusselder W. Associations of diabetes mellitus with total life expectancy and life vascular complications and death in at-risk patients with expectancy with and without cardiovascular disease. Arch Intern Med type 2 diabetes. 2007; 167:1145–1151. 3 ¨ ¨ ¨ ¨ Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic Where do we go from here? subjects with and without prior myocardial infarction. N Engl J Med 1998; Progress over the past 30 years has seen marked improve- 339:229–234. ments in the management of patients with diabetes. The 4 Retnakaran R, Cull CA, Thorne KI, Alder AI, Holman RR, UKPDS Study Group. Risk factors for renal dysfunction in type 2 diabetes: UK Prospective studies discussed above demonstrate the importance of Diabetes Study 74. Diabetes 2006; 55:1832–1839. managing the multiple risk factors associated with dia- 5 Adler AI, Stratton IM, Neil HA, Yudkine JS, Matthews DR, Cull CA, et al. Association of systolic blood pressure with macrovascular and betes not just blood glucose levels. Despite a substantial microvascular complications of type 2 diabetes (UKPDS 36): prospective absolute reduction in the risk of events in clinical trials observational study. BMJ 2000; 321:412–419. conducted over the past 30 years, however, the risk of a 6 Danaei G, Lawes CM, Vander Hoorn S, Murray CJ, Ezzati M. Global and regional mortality from ischaemic heart disease and stroke attributable to major coronary event is still increased more than twofold higher-than-optimum blood glucose concentration: comparative risk in an ageing population of individuals with diabetes, assessment. Lancet 2006; 368:1651–1659. compared with those without diabetes [32]. Therefore, 7 Almgren T, Wilhelmsen L, Samuelsson O, Himmelmann A, Rosengren A, Andersson OK. Diabetes in treated hypertension is common and carries a further clinical trials are needed to challenge current high cardiovascular risk: results from a 28-year follow-up. J Hypertens treatment guidelines and change clinical practice in an 2007; 25:1311–1317. attempt to close this gap [18]. The Action in Diabetes and 8 UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional Vascular disease: preterAx and diamicroN-MR Con- treatment and risk of complications in patients with type 2 diabetes trolled Evaluation (ADVANCE) is one such study, which (UKPDS 33). Lancet 1998; 352:837–853.Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
  7. 7. Blood pressure control and cardiovascular prognosis in diabetes Mourad and Le Jeune S13 9 Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, et al. 30 Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a Association of glycaemia with macrovascular and microvascular multifactorial intervention on mortality in type 2 diabetes. N Engl J Med complications of type 2 diabetes (UKPDS 35): prospective observational 2008; 358:580–591. study. BMJ 2000; 321:405–412. 31 Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O.10 American Diabetes Association. Standards of medical care in diabetes – Multifactorial intervention and cardiovascular disease in patients with type 2 2007. Diabetes Care 2007; 30 (Suppl. 1):S4–S41. diabetes. N Engl J Med 2003; 348:383–393.11 Zanchetti A. Aspirin and antiplatelet drugs in the prevention of 32 Booth GL, Kapral MK, Fung K, Tu JV. Relation between age and cardiovascular complications of diabetes. In: Mogensen C, editor. cardiovascular disease in men and women with diabetes compared with Pharmacotherapy of diabetes: new developments. Improving life and non-diabetic people: a population-based retrospective cohort study. prognosis for diabetic patients. London: Springer; 2007 . pp. 211–218. Lancet 2006; 368:29–36.12 Collins R, MacMahon S. Blood pressure, antihypertensive drug treatment and the risks of stroke and of coronary heart disease. Br Med Bull 1994; 50:272–298.13 Parving HH, Andersen AR, Smidt UM, Hommel E, Mathiesen ER, Svendsen PA. Effect of antihypertensive treatment on kidney function in diabetic nephropathy. BMJ (Clin Res Ed) 1987; 294:1443–1447.14 UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317:703–713.15 Yusuf S, Sleight P, Pogue J, Bosh J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000; 342:145–153.16 Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO–HOPE substudy. Lancet 2000; 355:253–259.17 ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288:2981–2997.18 Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289:2560–2572.19 ¨ Hansson L, Zanchetti A, Carruthers SG, Dahlof, Elmfeldt D, Julius S, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998; 351:1755–1762.20 Alberti KG, Gries FA, Jewell J, Krans HM. A desktop guide for the management of non-insulin-dependent diabetes mellitus (NIDDM): an update. European NIDDM Policy Group. Diabet Med 1994; 11:899–909.21 The SALT Collaborative Group. Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. Lancet 1991; 338:1345–1349.22 Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy – I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308:81–106.23 ¨ ´ Zanchetti A, Hansson L, Dahlof B, Julius S, Menard J, Warnold I, et al. Benefit and harm of low-dose aspirin in well-treated hypertensives at different baseline cardiovascular risk. J Hypertens 2002; 20:2301–2307.24 Grant PJ. Diabetes mellitus as a prothrombotic condition. J Intern Med 2007; 262:157–172.25 Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345:851–860.26 Berl T, Hunsicker LG, Lewis JB, Pfeffer MA, Porush JG, Roleau JL, et al. Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephropathy. Ann Intern Med 2003; 138:542–549.27 Saydah SH, Fradkin J, Cowie CC. Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. JAMA 2004; 291:335–342.28 Collins R, Armitage J, Parish S, Sleigh P, Peto R, Heart Protection study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol- lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003; 361:2005–2016.29 Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004; 364:685–696.Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.