Cardiovascular outcomes in type 2 diabetes: the impact of preventative therapies

Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue: The Year in Diabetes and Obesity Cardiovascular outcomes in type 2 diabetes: the impact of preventative therapies Sophia Zoungas 1,2 and Anushka Patel 3 1 Diabetes Research Program, Cardiovascular Division, The George Institute for International Health, University of Sydney, Sydney, Australia. 2 School of Public Health, Monash University, Melbourne, Australia. 3 Cardiovascular Division, The George Institute for International Health, University of Sydney, Sydney, Australia Address for correspondence: Sophia Zoungas, The George Institute for International Health, King George V Building, Royal Prince Alfred Hospital, PO Box M201, Missenden Road, NSW 2050, Australia. szoungas@george.org.au The world is facing an unprecedented increase in type 2 diabetes. Most disability and premature mortality experienced by people with diabetes is related to cardiovascular disease. This review summarizes recent evidence about approaches for managing cardiovascular risk in patients with type 2 diabetes. While optimal blood pressure targets in people with diabetes remain uncertain, new data have demonstrated the benefits of routine blood pressure lowering in these patients, when administered without regard to initial blood pressure level. Other recent data indicate that blood pressure lowering treatment in patients with diabetes needs to be continued for ongoing benefit. The effects of intensive blood glucose lowering have been evaluated recently in a number of large trials, and individually these have failed to provide evidence of cardioprotection over a 4 5 year period. However, longer-term follow-up data suggest that there may be a delay in any such benefits becoming apparent. The benefits of statin therapy in preventing cardiovascular events in diabetic patients have been recently confirmed in a systematic overview of relevant trials; however, effects of fibrate therapy appear more limited. The role of antiplatelet agents remains unknown, as adequately powered trials of aspirin for the primary prevention of cardiovascular events in patients with diabetes have not yet been completed. Keywords: type 2 diabetes; cardiovascular disease; preventive therapies The prevalence of type 2 diabetes is rapidly rising worldwide. 1 Most disability and premature mortality in patients with diabetes is caused by vascular complications in particular, coronary artery disease and stroke. Indeed in 2010 in those aged 20 79 years, around 4 million deaths globally will be attributable to diabetes, with 50% of those due to cardiovascular disease. 1 Therefore, many approaches to improve clinical outcomes in patients have continued to focus on the prevention of cardiovascular events. In this review, we focus on the major strategies utilized for the delay or avoidance of cardiovascular events in patients with diabetes blood pressure lowering, blood glucose lowering, lipid modification, and antiplatelet therapy and provide a summary of the most recent evidence relating to the effects of these interventions. Blood pressure lowering A target blood pressure level of 130/80 mmhg or lower, using an initial regimen including an angiotensin converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB), is recommended by current hypertension guidelines for patients with diabetes. 2 While observational data showing a continuous association between blood pressure and cardiovascular risk suggests potential benefits of more intensive blood pressure lowering for people with diabetes, 3 direct randomized trial evidence about appropriate targets has been lacking. Debate about the relative benefits of particular therapeutic regimens for blood pressure lowering in diabetic patients is also ongoing. A number of major trials have recently addressed these issues. doi: 10.1111/j.1749-6632.2010.05837.x Ann. N.Y. Acad. Sci. 1212 (2010) 29 40 c 2010 New York Academy of Sciences. 29

ADVANCE The Action in Diabetes and Vascular Disease Prelerax and Diamicron MR Controlled-Evaluation (ADVANCE) trial was a factorial, randomized study of 11,140 individuals with type 2 diabetes from over 200 collaborating centers in 20 countries from Asia, Australasia, Europe, and North America. 4,5 Participants with either a history of macrovascular or microvascular disease, or at least one major risk factor for cardiovascular disease and any initial level of blood pressure and blood glucose, were randomly assigned to the fixed combination of the ACE inhibitor, perindopril and the thiazide diuretic, indapamide (4/1.25 mg) or matching placebo, and to intensive glucose control or standard guidelinebased glucose control. 4,5 The primary outcomes were composites of major cardiovascular (nonfatal acute myocardial infarction, nonfatal stroke, and cardiovascular death) and major microvascular events (new or worsening nephropathy and microvascular eye disease), analyzed jointly and separately. The average duration of follow-up was 4.3 years for the blood pressure lowering intervention, and 5.0 years for the glucose control intervention. 4,5 Importantly, in the blood pressure arm, ADVANCE was testing the effects of a strategy of routinely administering blood pressure lowering therapy to individuals with diabetes at high risk of a cardiovascular event, regardless of initial blood pressure level. This trial was not designed to evaluate different target blood pressure levels. The mean entry blood pressure of participants was 145/81 mmhg, with over 40% recording a blood pressure below 140/90 mmhg. 5 Over the course of active treatment, blood pressure was reduced by a mean of 5.6/2.2 mmhg compared to placebo. At the end of follow-up, the mean blood pressure achieved was 134.7/74.8 mmhg in the active treatment group and 140.3/77.0 mmhg in the placebo group. Active treatment reduced the risk of the combined composite primary outcome of major macrovascular and microvascular events by 9% (95% CI 0 to 17%, P = 0.043). Considered individually, the effect on major macrovascular events was of similar magnitude but not statistically significant (Fig. 1). Among those on active treatment, there was a 14% (2 to 25%; P = 0.025) reduction in all-cause mortality, driven by an 18% (2 to 32%; P = 0.027) reduction in cardiovascular mortality, as well as reductions in coronary events (14%; P = 0.02) and renal events (21%; P = 0.0001). There were no statistically significant reductions observed in cerebrovascular events or in microvascular eye disease. There was no evidence of heterogeneity in treatment effect in subgroups of participants defined by key baseline characteristics including baseline age, gender, history of cardiovascular disease, and use of blood pressure lowering therapy. In particular, the effects of the combination ACE inhibitor and diuretic treatment were similar across a range of initial blood pressure level and regardless of use of other concomitant preventive therapies (including other blood pressure lowering agents, statins and aspirin). The results of this part of the ADVANCE study point to the potential benefits of an alternative strategy for delivery of blood pressure lowering treatment, as opposed to traditional threshold and target-driven strategies where therapy is limited to patients with arbitrarily-defined hypertension and therefore potentially denied to a broader range of high-risk individuals with apparently normal blood pressure levels. The Action to Control Cardiovascular Risk in Diabetes The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was a factorial study of 10,251 individuals with type 2 diabetes from 77 centers in North America. 6 8 Participants with a HbA1c of 7.5% or more and aged 40 years of age or older with cardiovascular disease or 55 years of age or older with anatomical evidence of significant atherosclerosis, albuminuria, left ventricular hypertrophy, or at least two additional risk factors for cardiovascular disease (dyslipidemia, hypertension, smoking, or obesity) were randomized to intensive glucose control (aiming for HbA 1c levels 6.0%) or standard control (aiming for HbA 1c levels 7.0 7.9%). 7 Participants were also randomized to either a blood pressure lowering intervention (n = 4733) or lipid management intervention (n = 5518). 6,8 The aim of the blood pressure arm was to examine the effects of targeting different blood pressure levels (a systolic blood pressure target of 120 mmhg or less as compared to 140 mmhg or less). 6 As such, participants who had a systolic blood pressure between 130 and 180 mm Hg on three or fewer antihypertensive medications and no evidence of greater than 1.0 g per day of proteinuria or equivalent, were studied. The blood pressure lowering regimen was at 30 Ann. N.Y. Acad. Sci. 1212 (2010) 29 40 c 2010 New York Academy of Sciences.

Figure 1. Effects of routine blood pressure lowering and intensive glucose control on clinical outcomes in the ADVANCE trial. Per-Ind, Perindopril-indapamide. Black squares = point estimates (with area proportional to number of events); horizontal lines = 95% CI. the physician s discretion but included any class of drug therapy known to produce cardiovascular benefits (ACE inhibitor, ARB, diuretic, calcium channel blocker, or beta-blocker). The primary outcome was a composite of major cardiovascular events defined as nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death. 6 8 Secondary outcomes included all coronary events, all stroke events, and all-cause death, considered separately. The mean entry blood pressure was 139/76 mmhg with 87% of participants already taking some from of antihypertensive therapy. 6 Over a mean follow up of 4.7 years, intensive therapy achieved a systolic pressure of 119 mmhg as compared with 134 mmhg in the standard therapy group. Despite this very substantial difference in systolic blood pressure, intensive therapy did not result in a statistically significant reduction in major Ann. N.Y. Acad. Sci. 1212 (2010) 29 40 c 2010 New York Academy of Sciences. 31

Figure 2. Effects of intensive versus standard blood pressure control on major cardiovascular outcomes in the ACCORD trial (reproduced with permission from Cushman et al. 6 ). cardiovascular events (relative risk reduction [RRR], 12% 95% CI 6 to 27%, P = 0.20; Fig. 2). When the components of the composite outcome were considered separately, intensive therapy did significantly reduced all major strokes by 41% (95% CI 11 to 61%), but not all major coronary events (which included unstable angina) or cardiovascular death. There was no statistically significant effect of intensive therapy on all-cause mortality or heart failure. There was no evidence of heterogeneity in treatment effect in subgroups of participants defined by baseline age, gender, history of cardiovascular disease, and use of blood pressure lowering therapy. Much has been made of ACCORD being a negative trial with respect to the blood pressure lowering arm. However, notwithstanding the clear benefits of a more aggressive approach to blood pressure lowering for stroke, the confidence intervals around the estimates of effect size for other cardiovasculareventsdonotexcludemoderate(approximately one-quarter reduction) beneficial effects. The event rates in this trial were about one-half those anticipated, 6 resulting in a substantially underpowered study. The United Kingdom Prospective Diabetes Study Over a decade ago, the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that more intensive blood pressure lowering (with an ACE inhibitor or a beta-blocker based regimen) among newly diagnosed patients with type 2 diabetes and hypertension resulted in significant reductions in all diabetes-related endpoints, as well as cerebrovascular events and microvascular disease. 9 Subsequently, annual follow-up for an additional 6 years was undertaken for all study participants, without attempting to maintain therapies based on the original randomization. 10 As a result, the achieved blood pressure difference between randomized arms was no longer apparent within 2 years of the longer-term follow-up. The significant reductions in clinical events were also lost during the additional observational period, without the emergence of any new benefits (Fig. 3). A reasonable interpretation of these findings is that blood pressure reduction needs to be maintained in order for the long-term benefits of such treatment to continue. Other relevant trials While not restricted exclusively to patients with diabetes, the results of two other recent trials provide some evidence about the potential merits of different blood pressure lowering regimens in diabetic patients. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) included 25,620 patients at increased cardiovascular risk, of whom about 40% had diabetes. 11 Patients were randomized to ramipril alone, telmisartan alone, or both drugs. The mean blood pressure level at baseline was 142/82 mmhg, and compared to the ramipril alone group, blood pressure was reduced by 2.4/1.4 mmhg in the combination therapy group over the follow-up period. There was no difference in the incidence of the primary outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalized heart failure) between the ramipril-alone group and each of the other groups. As expected, participants randomized to telmisartan alone experienced less cough and angioedema than those allocated ramipril. However, symptoms of hypotension occurred more frequently in the telmisartan group (2.7%) and in the combination group (4.8%), compared with the ramipril alone group (1.7%). Renal dysfunction was observed more often in the combination group. There was no heterogeneity in treatment effects by diabetes status for the primary 32 Ann. N.Y. Acad. Sci. 1212 (2010) 29 40 c 2010 New York Academy of Sciences.

Interpretation of recent evidence Blood pressure lowering remains an important strategy for preventing cardiovascular events in patients with diabetes. Aggressive treatment, aiming for a systolic level <120 mmhg, appears to reduce the risk of stroke, but the effects on other cardiovascular outcomes is uncertain. A strategy of routine treatment, without regard to initial blood pressure level, reduced the risks of coronary events, cardiovascular death, and all-cause mortality. Importantly, the long-term observational follow-up of UKPDS confirms the need to maintain blood pressure lowering to realize ongoing benefits of treatment. Figure 3. Effects of tight versus less tight blood pressure control on any diabetes-related endpoint with long-term followup in the UKPDS (reproduced with permission from Holman et al. 10 ) The horizontal axis indicates the year of follow-up, with the hazard ratio (and 95% CI) indicated for each time point. outcome. In summary, the results of ONTARGET confirmed equivalence of the ACE inhibitor and the ARB, but provided no evidence of additional benefit from combination therapy. Another relevant trial is the Avoiding Cardiovascular Events through Combination Therapy to Patients Living with Systolic Hypertension trial. 12 Approximately 60% of the 11,506 high-risk patients with hypertension included in this study were diabetic. Participants were randomized to the ACE inhibitor, benazepril and the calcium channel blocker, amlodipine, or to benazepril, and the diuretic, hydrochlorothiazide (HCT). The mean blood pressure level at baseline was 145/80 mmhg. Over followup, a 0.9/1.1 mmhg lower blood pressure was observed in the benazepril/amlodipine group, compared with the benazepril/hct group. This study was stopped prematurely after a mean follow-up of 3 years, because of an observed 20% reduction in the primary outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for angina, resuscitation after cardiac arrest, and coronary revascularization) in the benazepril/amlodipine group compared with the benazepril/hct group. Again, there was no evidence of heterogeneity based on diabetes status. Blood glucose lowering While long-term cardioprotection with intensive glucose control has been clearly established for patients with type 1 diabetes, 13,14 the benefits in type 2 diabetes have been less certain. For many years, the most reliable evidence about the effects of more intensive glucose control in patients with type 2 diabetes was derived from the UKPDS. 15,16 While this study demonstrated benefits in reducing microvascular events with more intensive glucose control (HbA1c 7.0% vs. 7.9% at the end of follow-up), the findings were inconclusive with respect to cardiovascular events. Despite this, most clinical guidelines adopted recommended target levels for HbA1c of 6.5% or 7.0%, with the express purpose of preventing both microvascular and macrovascular events. The past two years have seen the completion of a number of new large studies that substantially add to the evidence base. ADVANCE As outlined above, ADVANCE was a factorial trial testing two interventions, one of which was intensive blood glucose control. 4 The glucose-lowering regimen for those randomized to intensive glucose control was based on the modified release sulphonylurea, gliclazide-mr, 30 120 mg daily; however, nonpharmacological approaches, other oral agents, and insulin were recommended to be added, as required, to achieve the target HbA1c of 6.5%. The choice of such additional treatments was left to the discretion of the responsible physician with a step wise up titration of oral therapy followed by introduction of basal insulin advocated. Participants randomized to standard guidelines-based glucose control were permitted to use sulphonylureas (other than gliclazide) and any other available glucoselowering therapy, including insulin. The mean entry HbA1c of participants was 7.5%, with 91% already receiving oral hypoglycemic agents. By the end of follow up of those in the intensive control group and standard control group, Ann. N.Y. Acad. Sci. 1212 (2010) 29 40 c 2010 New York Academy of Sciences. 33

Table 1. Effects of intensive versus standard glucose control in the ACCORD trial Intensive N (%) Standard N (%) HR (95% CI) P Primary 352 (6.86) 371 (7.23) 0.90 (0.78 1.04) 0.16 Secondary Mortality 257 (5.01) 203 (3.96) 1.22 (1.01 1.46) 0.04 Nonfatal MI 186 (3.63) 235 (4.59) 0.76 (0.62 0.92) 0.004 Nonfatal stroke 67 (1.31) 61 (1.19) 1.06 (0.75 1.50) 0.74 CVD death 136 (2.63) 94 (1.83) 1.35 (1.04 1.76) 0.02 CHF 152 (2.96) 124 (2.42) 1.18 (0.93 1.49) 0.17 92% and 59% were receiving sulphonylurea, 74% and 67% metformin, 40% and 24% insulin, and 17% and 11% thiazolidinediones. HbA1c was gradually reduced (over 3 years) with intensive glucose control to result in a mean HbA1c of 6.5% as compared to 7.3% in the standard arm, and produced an average difference during follow-up of 0.7% between the groups. Furthermore, the target HbA1c of 6.5% or less was achieved by 65% of those assigned intensive glucose control as compared to 29% of those assigned standard control. Intensive glucose control reduced the incidence of combined major cardiovascular and microvascular events by 10% (95% CI: 2 to 18%, P = 0.01). This was primarily due to a significant 21% reduction in the incidence of new or worsening nephropathy. There were no separately significant effects of intensive glucose control on any cardiovascular outcome or death (major cardiovascular events RRR 6%; 95% CI: -6 to 16%; P = 0.32; cardiovascular mortality, RRR 12%, 95% CI: 4 to 26, P = 0.12); or all cause mortality (RRR 7%; 95% CI: -6 to 17; P = 0.28; Fig. 1). The treatment effects were consistent across a range of participant subgroups defined by key baseline characteristics including duration of diabetes and prior history of cardiovascular or microvascular disease. ACCORD As previously outlined, all 10,251 participants in this trial were randomized to intensive glucose control (aiming for HbA 1c levels 6.0%) or standard control (aiming for HbA 1c levels 7.0 7.9%). 7 To achieve intensive glucose control, therapy was titrated monthly for 4 months and 2 monthly thereafter to achieve and maintain the proposed risk factor target. In the standard control group, therapy and targets were reviewed every 4 months. At study entry, the mean HbA1c of participants was 8.3%, with 34% already receiving insulin therapy. By the end of follow up of those in the intensive control group and standard control group, 87% and 74% were receiving secretagogues, 95% and 87% metformin, 77% and 55% insulin, and 92% and 58% thiazolidinediones. HbA1c was rapidly reduced (within 6 months) with intensive glucose control to achieve a median HbA1c of 6.4% as compared to 7.5% with standard control, representing a mean difference of 1.1%. After an average of 3.5 years follow-up, the trial was terminated prematurely, due to an increased risk of all-cause and cardiovascular mortality in the intensive control group (Table 1). There was no significant difference between the randomized groups in the incidence of the primary composite cardiovascular outcome (RRR 10%; 95% CI: 4 to 22%; P = 0.16). However, nonfatal myocardial infarction was significantly reduced with intensive glucose control (RRR 24%; 95% CI: 8 to 38%); P = 0.004). There was also some evidence of heterogeneity in the treatment effects across participant subgroups, with greater beneficial effects on the cardiovascular outcome in those with a lower entry HbA 1c level (P for heterogeneity = 0.03) and in those without a history of cardiovascular disease (P for heterogeneity = 0.04). The Veterans Affairs Diabetes Trial TheVeteransAffairsDiabetesTrial(VADT)wasalso designed to evaluate the effects of intensive glucose control in patients with type 2 diabetes albeit with substantially less power than the ADVANCE and ACCORD studies. 17 A total of 1,791 U.S. military veterans were randomized, with intensive glucose control resulting in a median HbA1c of 6.9%, as 34 Ann. N.Y. Acad. Sci. 1212 (2010) 29 40 c 2010 New York Academy of Sciences.

Figure 4. Effects of intensive versus standard glucose control on myocardial infarction in the UKPDS (reproduced with permission from Holman et al. 18 ) The horizontal axis indicates the year of follow-up, with the hazard ratio (and 95% CI) indicated for each time point. compared to 8.4% in the standard control group (mean difference 1.5%). The incidence of the primary outcome (myocardial infarction, stroke, cardiovascular death, heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischemic gangrene) was not significantly different between randomized groups. UKPDS In contrast to the findings of the BP arm of the UKPDS, long-term post-trial observational followup of the glucose-lowering arm demonstrated sustained, and in some cases newly emerged, reductions in clinical events associated with original randomization to intensive glucose control. 18 These benefits were observed despite convergence of HbA1c values within a year of post-trial monitoring. In addition to persistent benefits for microvascular events, a significant reduction in all-cause mortality became apparent at 10 years. Furthermore, the previously borderline nonsignificant 16% relative risk reduction in myocardial infarction observed at the end of the trial became statistically significant at 10 years follow-up (Fig. 4). Interpretation of recent evidence Assuming the finding of excess mortality in ACCORD was not a chance result, a number of other potential reasons for this observation could be considered. For example, the aggressive strategy for intensive glucose control utilized in ACCORD, with implementation of regimens using multiple oral agents and insulin, has been contrasted with that of ADVANCE, which used a much more incremental approach with progressive intensification over a long period. The effects of these different approaches are reflected in the substantially higher proportions of intensive control patients from ACCORD taking insulin (77%) and thiazolidinediones (92%), compared to those in ADVANCE (40% and 19%, respectively, by the end of followup). As a consequence of these differences, the decline in HbA1c occurred much more rapidly in ACCORD, compared to ADVANCE. Furthermore, the rate of severe hypoglycemia (using similar definitions) in ACCORD was sixfold greater than that in ADVANCE. While there was no weight gain among intensive glucose control patients in ADVANCE, those in ACCORD experienced an average 3.5 kg increase in weight over the duration of follow-up. Thus, the method of achieving intensive glucose lowering, rather than the target levels per se may be important. In this context, there has been much discussion about the potential adverse effects of thiazodinidiones in particular, although the design of these strategy trials precludes any reasonable analyses that might tease out the effects of individual drugs. While much focus of interest has been on the apparent increase in mortality with intensive glucose control reported in the ACCORD trial, the totality of evidence raises questions about the robustness of this finding. A recent meta-analysis of ADVANCE, ACCORD, VADT, and UKPDS, conducted by the investigators of these trials, concluded that intensive glucose control in patients with type 2 diabetes was associated with an overall modest one-tenth reduction in major cardiovascular events, primarily due to a 15% relative risk reduction of myocardial infarction (Fig. 5). 19 All-cause and cardiovascular mortality did not significantly differ between groups, with hazard ratios for intensive vs. standard glucose control of 1.04 (95% CI: 0.90 1.20) and 1.10 (95% CI: 0.84 1.42), respectively. In summary, the effects of blood glucose control have been addressed in a number of recently concluded clinical trials; individually, these have failed to provide clear evidence of cardioprotection with intensive glucose control over a 3 5 year period. However, when pooled together, significant benefits on major cardiovascular events and specifically acute myocardial infarction were evident. Moreover, long-term follow-up data suggest that such benefits may accrue over time and emerge many years Ann. N.Y. Acad. Sci. 1212 (2010) 29 40 c 2010 New York Academy of Sciences. 35

Figure 5. Pooled effects of more- versus less-intensive glucose control in major trials (reproduced with permission from Turnbull et al. 19 ). Black squares = point estimates (with area proportional to number of events); horizontal lines = 95% CI. later, indicating that better glycemic control could be cardioprotective over the lifespan of a patient with diabetes. Lipid modification The role of statins for the prevention of cardiovascular events is well established. Robust data related to the use of statins in patients with diabetes, have recently been published by the Cholesterol Treatment Trialists Collaboration. 20 This metaanalysis included 14 randomized trials of statin therapy, and clearly demonstrated that the proportionate benefits of statins in reducing all-cause mortality, vascular death, and cardiovascular events were similar among participants with diabetes (n = 18,686) and without diabetes (n = 71,370). The overview did not identify any subgroup of patients with diabetes where the treatment effects varied. The role of fibrates for prevention of cardiovasculareventsintype2diabetesislessclear.the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial published several years ago, randomized 9,795 patients with type 2 diabetes to fenofibrate or placebo. 21,22 The primary outcome, a composite of coronary death or nonfatal myocardial infarction, was not significantly different between randomized groups after an average of 5 years follow-up. This result reflected a significant 24% reduction in nonfatal myocardial infarction and nonsignificant increase in coronary death, associated with fenofibrate. The study was hampered by a substantial drop-in of statin therapy during follow-up that was greater in the placebo group. More recently, the lipid arm of the ACCORD trial has been reported. 8 In this part of the study, 5,518 patients concurrently taking open-label simvastatin were randomized to fenofibrate or placebo. After a mean follow-up period of 4.7 years, the incidence of the primary composite cardiovascular outcome was similar between randomized groups. Subgroup analysis suggested possible heterogeneity of treatment effects with beneficial effects of fibrates in patients with a baseline lipid profile of low HDL cholesterol and high triglycerides; however, the P value for interaction was of borderline significance. While FIELD and ACCORD represent the largest and most recent trials of fibrates in patients with diabetes, a number of smaller studies with agents other than fenofibrate have been conducted in populations with and without diabetes. A systematic overview of these trials indicated that fibrates were associated with modest but significant reductions in major cardiovascular events and coronary events, but there was no evidence of any reductions in cardiovascular death or all-cause mortality (Fig. 6). 23 36 Ann. N.Y. Acad. Sci. 1212 (2010) 29 40 c 2010 New York Academy of Sciences.

Figure 6. Pooled effects of fibrates on major cardiovascular outcomes (reproduced with permission from Jun et al. 23 ). Black squares = point estimates (with area proportional to number of events); horizontal lines = 95% CI. There was no heterogeneity of treatment effects when comparing trials of patients with diabetes with studies of patients without diabetes or mixed populations. Aspirin While the benefits of aspirin in diabetic patients with established cardiovascular disease is unequivocal, the role of antiplatelet agents for the primary prevention of cardiovascular events in patients with type 2 diabetes remains uncertain. 24 Two recent trials have attempted to address this question. However, both studies were substantially underpowered to reliably determine the effects of aspirin in this target population. The Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) randomly allocated 2,539 patients to low-dose aspirin on top of usual care or usual care without aspirin, with a median of 4.4 years follow-up. 25 In this open-label study, only 154 primary outcome events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and peripheral vascular events) occurred, with no significant difference between randomized groups (RRR 20%; 95% CI: 10 to 42%; P = 0.16). In a mixed population with type 1 and type 2 diabetes, the Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial randomized 1,276 patients with reduced anklebrachial pressure index but no established cardiovascular disease to low-dose aspirin or placebo. 26 After a median of 6.7 years follow-up, there was no difference between randomized groups in the primary outcome of coronary death, stroke death, nonfatal myocardial infarction, nonfatal stroke, or amputation above the ankle for critical limb ischemia. The trial failed to reach its recruitment target and the event rate was lower than anticipated, with post hoc analysis indicating only 70% power to detect a 25% relative-risk reduction from the intervention. In a factorial design, the trial also examined the effects of an antioxidant capsule on the same outcome, with no differences observed between randomized groups. Although both JPAD and POPADAD failed to demonstrate beneficial effects of aspirin in patients with diabetes, the low power in both studies limits any conclusions that can be drawn from their findings. The ongoing A Study of Cardiovascular Events in Diabetes (ASCEND) trial is likely to provide much more definitive evidence on the role of aspirin for the primary prevention of cardiovascular events in people with type 2 diabetes. 27 Multifactorial intervention While most clinical trials evaluate single interventions on cardiovascular outcomes, the effects of these treatments are generally found to be similar regardless of other preventative therapies that participants are taking. In the factorial trials such as ADVANCE and ACCORD, no clear evidence of interaction between treatment strategies has emerged. 6,8,28 Together, these findings indicate that the effects of therapeutic strategies are independent and thus benefits from their combined use should be additive. The Steno-2 study randomized 160 patient with type 2 diabetes and microalbuminuria to intensive multifactorial intervention (tight glucose control, use of renin angiotensin system blockers, Ann. N.Y. Acad. Sci. 1212 (2010) 29 40 c 2010 New York Academy of Sciences. 37

aspirin, and lipid lowering agents) or conventional therapy. 29 During the 7.8 year trial period, the risk of vascular complications was halved with multifactorial intervention, compared to standard care. The participants were observed for a further 5.5 years, during which time risk factor differences narrowed, but were persistent. 30 At the end of this observational period, all-cause mortality among intensively treated patients was less than one-half of that observed in the group previously assigned conventional therapy (Fig. 7). Conclusions While cardiovascular disease remains a dominant problem for patients with diabetes, a number of effective preventative strategies are available, with particularly beneficial effects from their combined use. Importantly, the absolute benefits of these treatments will be directly proportionate to the patient s baseline risk, suggesting that most benefit will accrue from more aggressive multifactorial intervention among those at highest risk. Although this review has highlighted some important gaps in our knowledge about cardiovascular risk factor modification in patients with diabetes, the greater challenge lies in effectively implementing existing evidence into routine clinical practice. As the global burden of diabetes continues to expand, developing, implementing, and evaluating new strategies to maximize this implementation is an increasing priority. Figure 7. Multifactorial risk factor management in the STENO trial (reproduced with permission from Gaede et al. 30 ). Panel A: Cumulative incidence curves for all-cause mortality, by treatment allocation; Panel B: Cumulative incidence curves for all cardiovascular events, by treatment allocation; Panel C: Numbers of cardiovascular events by type and treatment allocation. BOX 1: Risk factor modification in type 2 diabetes authors interpretation Blood pressure: Current recommendation for a target systolic blood pressure < 130 mmhg is reasonable based on current evidence, with likely particular benefits in reducing stroke and kidney disease. Blood glucose: Current recommendation for atargethba1c< 7.0% is reasonable if this can be achieved cautiously, with the expectation of reduced risks of kidney disease and probable modest reductions in myocardial infarction risk. Lipid modification: Statin therapy should be considered for all patients, while the addition of fibrates may lead to a modest reduction in nonfatal cardiovascular events, particularly among those with a pattern of atherogenic dyslipidemia. Aspirin: Routine use of low-dose aspirin should be considered in all patients with diabetes and cardiovascular disease or with an equivalent estimated cardiovascular risk 38 Ann. N.Y. Acad. Sci. 1212 (2010) 29 40 c 2010 New York Academy of Sciences.

(i.e. 5-year cardiovascular disease risk greater than 20%). The treatment effects of these interventions are independent and thus combined use will result in substantial benefits. Those patients with type 2 diabetes at highest risk will benefit the most in absolute terms, thus risk stratification is useful in influencing the intensity of preventative treatments. Acknowledgments Sophia Zoungas is supported by a Health Practitioner fellowship from the National Health and Medical Research Council of Australia and Royal Australasian College of Physicians. Anushka Patel is supported by a Senior Research Fellowship from the National Health and Medical Research Council of Australia. Conflicts of interest The authors declare no conflicts of interest. References 1. International Diabetes Federation, Diabetes Atlas 2009; 4th Ed. 2. Standards of medical care in diabetes 2009. Diabetes Care 2009;32(Suppl 1): S13 S61. 3. Adler, A.I., I.M. Stratton, H.A. Neil, et al. 2000. 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