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Diabetes and vascular disease:

Pathophysiology, clinical consequences, and
medical therapy: Part II
Article in European Heart Journal August 2013

DOI: 10.1093/eurheartj/eht142
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European Heart Journal Advance Access published April 26, 2013
European Heart Journal REVIEW

doi:10.1093/eurheartj/eht142
Clinical update
Diabetes and vascular disease: pathophysiology,

clinical consequences, and medical therapy: part II
Joshua A. Beckman 1*, Francesco Paneni 2,3, Francesco Cosentino 2,4,
and Mark A. Creager 1
1
Cardiovascular Division, Brigham and Womens Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA; 2Cardiology and Cardiovascular Research, University of
Zurich, Zurich, Switzerland; 3IRCCS Neuromed, Pozzilli, Italy; and 4Cardiology, Department of Clinical and Molecular Medicine, University of Rome Sapienza, Rome, Italy
Downloaded from http://eurheartj.oxfordjournals.org/ at Universitaet Zuerich on May 9, 2013

Received 14 September 2012; revised 28 February 2013; accepted 26 March 2013
In part II of this review, we describe the epidemiology and clinical consequences of vascular disease in patients with diabetes, and discuss the ef-
ficacy of risk factor modification and antiplatelet treatment. Specifically, evidence-based cardiovascular therapies are discussed through novel
clinical insights on management of hyperglycaemia, hypertension, dyslipidaemia as well as platelet dysfunction. Recent trends in the incidence
and outcomes of vascular disease in diabetes suggest that timely and effective implementation of therapies is making a favourable impact.
-----------------------------------------------------------------------------------------------------------------------------------------------------------
Keywords Diabetes Vascular disease Medical therapy
but continue to increase in Asia and Africa, making clear the global
Introduction nature of the problem.13 16
Diabetes and vascular disease are intimately linked and share patho- Recently, investigators have identified subsets of patients with dia-
physiological features as examined in Part I of this review. In this betes at the highest risk. In a meta-analysis of 29 clinical trials that
section, we review the epidemiology and clinical consequences of included at least 1000 patients with diabetes, two factors were
vascular disease in patients with diabetes, and discuss the efficacy noted to identify a higher risk cohort within the diabetes population:
of risk factor modification and antiplatelet treatment. Since the the presence of cardiovascular disease and the presence of protein-
reviews published on this topic by the authors previously,1,2 contem- uria.17 Cardiovascular disease increased the rate of all-cause death
porary trends in the incidence and outcomes of vascular disease in nearly three-fold and the rate of cardiovascular death nearly five-fold
diabetes suggest that timely and effective implementation of therap- in subjects with diabetes. These results are in concordance with
ies is making a favourable impact. another systematic review of large trials in patients with diabetes,
demonstrating the association of renal disease, measured either by
Epidemiology of diabetes and the function or presence of proteinuria with increased mortality.18
atherosclerosis Coronary heart disease

In the late 1990s and early 2000s, there was a marked increase in the The impact of diabetes on atherosclerosis is best documented in
rate of obesity and diabetes across the globe.3 These changes were terms of its association with coronary heart disease and cardiovascu-
observed and reported in the United States,4 Europe,5,6 Africa,7 lar events. Several studies make clear that patients with diabetes are
China,8,9 and India.10 In 1997, Amos et al. 11 predicted the worldwide several-fold more likely to develop myocardial infarction than
burden of diabetes would increase from 124 to 221 million people in matched subjects without diabetes. In a seminal Finnish study, the
2010, with particular gains in Asia and Africa. In retrospect, these pre- presence of diabetes increased the 7-year risk of myocardial infarc-
dictions now seem optimistic as the World Health Organization esti- tion and death in older subjects.19 It was from this study that the
mates a current worldwide prevalence of 346 million patients with concept of diabetes as a coronary heart disease risk-equivalent
diabetes12 (Figure 1). Evidence suggests that the rates of obesity began, and culminated in its coronation as a high-risk cardiovascular
and diabetes may be leveling off in Europe and the United States state requiring secondary prevention level care as recommended in
* Corresponding author. Tel: +1 617 525 7053, Fax: +1 617 232 2749, Email: jbeckman@partners.org
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: journals.permissions@oup.com
Page 2 of 13 J.A. Beckman et al.

Figure 1 Worldwide prevalence of diabetes mellitus in persons aged 20 79 years. The prevalence of diabetes is high. Colours indicate percent
prevalence in respective nations. Source: Diabetes Atlas 5, International Diabetes Federation. Permission granted by the International Diabetes Fed-
eration.
the Adult Treatment Panel III of the National Cholesterol Education

Program several years later.20 More recent evidence, however, sug-
gests that although diabetes increases the risk of coronary heart
disease, it may not reach risk-equivalence for adverse cardiovascular
outcomes. In a Danish population study, the risk of adverse cardiovas-
cular events (composite of myocardial infarction, stroke, or cardio-
vascular death) was lower in both men and women with diabetes
and no prior myocardial infarction than in non-diabetic men and
women with prior myocardial infarction.21 Bulugahapitiya et al. 22
reviewed 13 studies, comprising 45 108 patients with follow-up
ranging from 5 to 25 years. In this meta-analysis, patients with dia-
betes had a 43% lower risk of developing coronary heart disease
events than patients without diabetes but with previous myocardial in- Figure 2 Insulin resistance in patients referred for cardiac evalu-
farction. The lesser cardiovascular risk found in the meta-analysis as ation. Results of oral glucose tolerance testing in a survey of 4196
non-diabetic patients referred to a cardiologist for coronary
compared with previous studies, may be attributed, in part, to the
artery disease (2107 for an acute cardiac problem and 2854 for
lower glucose threshold used for the diagnosis of diabetes, such that
an elective evaluation) from 110 centres in 25 countries. More
a relatively less sick population now carried the same diagnosis.23
than half of all patients with coronary artery disease, when present-
Nonetheless, patients with diabetes still carry a significantly increased ing with an acute or chronic cardiac condition, have evidence of
risk of coronary heart disease compared with patients without it. insulin resistance, even after excluding patients with known dia-
Despite the lack of risk equivalency, the relevance of diabetes to betes. IGT, Impaired glucose tolerance. Adapted from Bartnik
atherosclerosis has been made clear through another observation: et al.25
a majority of patients with coronary heart disease have insulin resist-
ance or frank diabetes. Norhammar et al. 24 studied 181 consecutive
patients admitted to coronary care units with acute myocardial in- and a majority of these patients were subsequently found to have dia-
farction and glucose of ,11.1 mmol/L. Despite specifically excluding betes, impaired glucose tolerance, or impaired fasting glucose
subjects with known diabetes, oral glucose tolerance testing (OGTT) (Figure 2). Using OGTT, 18% of subjects were newly diagnosed
at discharge showed that 35% of subjects had impaired glucose toler- with diabetes, 32% had impaired glucose tolerance, and 5% had
ance and 31% had previously undiagnosed diabetes. These results impaired fasting glucose. The results have been replicated in
were confirmed in the much larger Euro Heart Survey performed non-European populations as well.26
in 110 medical centres in 25 nations.25 In Euro Heart, 4961 subjects Even in recent clinical trials, adverse events associated with symp-
with coronary artery disease but no known diabetes were enrolled, tomatic coronary heart disease are higher in patients with diabetes
Diabetes and vascular disease Page 3 of 13
than in patients without it. In the Metabolic Efficiency With Ranola- Stroke
zine for Less Ischemia in Non-ST-Elevation Acute Coronary Diabetes also contributes significantly and increasingly to the burden
Syndromes6-TIMI 36 trial of 6560 patients with non-ST-segment ele- of stroke.44,45 In the INTERSTROKE case control study, performed
vation myocardial infarction, subjects with diabetes had higher rates in 22 nations, diabetes increased the rate of stroke by 35% when com-
of the composite endpoint of cardiovascular death, myocardial in- paring the top to the bottom tertile, and was associated with 5% of
farction, or recurrent ischaemia.27 In the Trial to Assess Improve- the population attributable risk for stroke.46 The Emerging Risk
ment in Therapeutic Outcomes by Optimizing Platelet Inhibition Factors Collaboration analysed 698 782 people from 102 prospect-
With Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON- ive studies, finding that diabetes was associated with a 2.27-fold in-
TIMI 38),28 of 13 608 subjects with acute coronary syndromes, prasu- crease in the risk of ischaemic stroke and 56% excess rate of
grel lowered adverse event rates, but patients with diabetes still had haemorrhagic stroke.47 Following a stroke, diabetes attenuates cog-
higher levels of myocardial infarction, cardiovascular death, and stent nitive recovery,48 limits functional outcome,49 and increases mortal-
thrombosis than patients without diabetes. In a Danish study of 3655 ity.50 Diabetes increases the risk of recurrent stroke as well. In the Life
consecutive patients with ST-segment elevation myocardial infarc- Long After Cerebral ischemia (LiLAC) cohort study, diabetes
tion treated with percutaneous coronary intervention, diabetes increased the risk of recurrent fatal and non-fatal stroke more than
was associated with a more than two-fold increase in the rate of myo- two-fold.51
cardial infarction and all-cause mortality over 3 years of follow-up.29 Identification and implementation of effective therapies have

Diabetes worsens outcomes after coronary revascularization as well, begun to reduce the risk of stroke in diabetes. In Finland, both the
with higher rates of stent thrombosis, both early and late,30 33 and population attributable risk of stroke and prognosis after stroke are
mortality after coronary artery bypass grafting.34,35 In a prospective decreasing over time in patients with diabetes.52,53 Improvements
cohort study of more than 36 000 patients, those with diabetes had in control of hypertension, dyslipidaemia, and treatment of diabetes
a 25% excess mortality compared with those without.36 Complica- have been demonstrated as well in the NHANES survey,54 and are
tions of diabetes, like renal failure, further increase the rate of likely contributing to more favourable outcomes and a lower rate
adverse events when compared with diabetes alone. of recurrence. Data showing better outcome of stroke overall are
Over the last decade, both the recognition by the medical com- not uniform, however.45,55 For example, Harmsen et al. 55 reported
munity of the impact of diabetes on atherosclerosis and the efforts a tripling in the incidence of diabetes in patients with stroke, but no
to modify the increased risk have improved.37 In Sweden, risk factor change in stroke incidence and mortality in Gothenburg, Sweden
modification has improved in this cohort even years after diagnosis. between 1987 and 2006.
Fharm et al. 38 evaluated 19 382 diabetic patients in cross-sectional
surveys from 2003 to 2008 as well as a subgroup of 4293 patients
followed individually from the year of diagnosis to a mean 2.6 years of Peripheral artery disease
follow-up. They found that treatment goals for HbA1c, blood pres- Increasing rates of diabetes also have implications for the prevalence
sure, total cholesterol, and LDL cholesterol improved over the 5 and prognosis of peripheral artery disease. In the German Epidemio-
years of cross-sectional analysis and were achieved ultimately in logical Trial on Ankle Brachial Index (GETABI), which screened 6880
78.4, 65.5, 55.6, and 61.0% of patients, respectively. The results consecutive primary care patients aged 65 years or older, 1743
were similar in the National Health and Nutrition Surveys (25.3%) had diabetes.56 In the entire cohort, the prevalence of
(NHANES) over the 19982008 time period. Significant improve- PAD, defined by an abnormal ankle brachial index, was 19.8% for
ments were seen in the control of HbA1c (37.055.2%), blood pres- men and 16.8% for women.57 Compared with patients without dia-
sure (35.251.0%), and low-density lipoprotein-cholesterol (LDL-C; betes, patients with diabetes had a higher prevalence of PAD, (26.3
32.552.9%).39 vs. 15.3%) and intermittent claudication (5.1 vs. 2.1%).56 The rate
As a result of better available medical therapy and more pervasive of PAD in patients with diabetes also increases with age, as it does
use of these therapies, the risk of myocardial infarction in the patients in non-diabetic persons. In a multicentre cross-sectional study of
with diabetes has diminished. Using the United Kingdom Prospective patients older than 70 years with diabetes, 71% had PAD when
Diabetes Study risk calculator, the estimated 10-year risk for coron- detected by abnormal ankle brachial index.58
ary heart disease decreased from 21.1% in 1999 2000 to 16.4% in Diabetes increases the incidence of critical limb ischaemia (CLI)
20072008.40 The impact of therapy may even extend to mortality. four-fold in patients with peripheral artery disease (Figure 3).59 More-
Gregg et al. 41 compared 3-year death rates of four consecutive na- over, in diabetic patients with CLI, 50% will develop CLI in the contra-
tionally representative samples from the National Health Interview lateral limb within 5 years.60 Also, results of revascularization,
Surveys linked to National Death Index (19971998, 19992000, whether percutaneous or surgical, are worse in patients with dia-
20012002, and 2003 2004) of US adults aged 18 years and betes, and there is a higher rate of cardiovascular morbidity asso-
older. Among the individuals with diabetes, the cardiovascular ciated with the procedure.61
death rate declined by 40% and all-cause mortality declined by 23% It is not established whether aggressive risk factor modification
when comparing the earliest and latest time periods. Reductions in decreases the risk of PAD in patients with type 2 diabetes. In 1533
mortality, however, were not noted in the Framingham population patients with type 2 diabetes randomized to intensive risk factor
when pre-1976 and pre-2001 time periods were compared.42 The control or standard therapy, there was no difference after 6 years
difference in findings may reflect the routine incorporation of in the prevalence of peripheral artery disease.62 Despite this, most
statins into therapy of patients with diabetes after the Heart Protec- data suggest that the rate of complications, and specifically diabetes-
tion Study43 was released in 2002. related amputation, declined over the last decade.63 65 Using the
was a significant 22% increase in all-cause mortality in the intensively

treated group. A second large trial also failed to find any cardiovascu-
lar benefit to intensive control. In the Action in Diabetes and Vascular
Disease: Preterax and Diamicron Modified Release Controlled
Evaluation (ADVANCE) trial,71 11 140 patients with type 2 diabetes
were randomized to standard glucose control or intensive glucose
control (Hgb A1c ,6.5%). Intensive glucose control did not reduce
major macrovascular events, death from cardiovascular causes, or
death from any cause. A smaller, Veterans Affairs-based trial of more
poorly controlled subjects with type 2 diabetes also demonstrated
lack of efficacy with intensive control of hyperglycaemia.72 A
meta-analysis of 33 040 subjects from the five trials commonly asso-
Figure 3 Incidence of ischaemic ulceration in a cohort of patient
ciated with tight vs. conventional control of glucose showed a 17%
with intermittent claudication. A total of 1244 men with claudica-
reduction in myocardial infarction without improvement in stroke or
tion were followed for a mean of 45 months. Over the follow-up
period, men with diabetes were at a four-fold risk of ulceration all-cause mortality rates.73 However, caution is required in the inter-
for every level of reduction in ankle perfusion pressure compared pretation of these data: the intensive treatment goal of UKPDS was

with men without diabetes. DM, diabetes; ABI, ankle brachial the same as the conventional goal of the more recent trials; the PRO-
index. Adapted from Aquino et al.59 spective pioglitAzone Clinical Trial In macroVascular Events (PRO-
active), also included in this meta-analysis, compared the addition of
a thiazolidinedione with placebo in patients with established athero-
National Hospital Discharge Survey and National Health Interview sclerosis and was not specifically a study of more vs. less intensive
Survey Data, Li et al. 66 showed a decrease in the age-adjusted non- therapy74; and the ACCORD actually showed a mortality hazard. As
traumatic lower extremity amputation rate per 1000 persons in a result of these studies, the American Heart Association, American
patients with diabetes from 11.2 in 1996 to 3.9 in 2008. Despite College of Cardiology, and American Diabetes Association concluded
this reduction, the rate of non-traumatic lower extremity amputation that a Hgb A1c goal of 7% should be maintained, and the decision to
remains nearly eight-fold higher in patients with diabetes compared pursue tighter control could be made on an individual basis.75
with those without it. In contrast to the failure of targeting a glucose level, targeting the
mechanism of hyperglycaemia may yield better therapeutic out-
comes. Improving insulin sensitivity, rather than insulin levels, is a
Treatment of atherosclerosis strategy that has undergone study. The biguanide metformin has
in diabetes demonstrated efficacy when compared with insulinotropic sulfony-
lureas. In UKPDS, among subjects with .120% of ideal body
Advances in therapy have led to significant reductions in morbidity weight, metformin was associated with a 42% reduction in diabetes-
and mortality for patients with diabetes (Table 1). The primary related death and 36% reduction in all-cause mortality.68 The results
focus of these treatments is the modification of risk factors for cardio- were difficult to interpret, for in the same study the addition of met-
vascular disease (Figure 4). formin to a sulfonylurea was associated with an increase in mortality.
In the 10-year follow-up of UKPDS, despite a lack of difference in gly-
Hyperglycaemia cosylated haemoglobin between the metformin and sulfonylurea
The potential role of glucose-lowering therapies in reducing cardio- arms in the 5 years after the initial study ended, metformin-treated
vascular events has been studied for more than two decades. Several patients had a 33% reduction in myocardial infarction and 27% reduc-
factors suggest that elevated glucose levels would be an important tion in death from any cause, both significantly more than that in the
therapeutic target. First, there is increased risk of cardiovascular patients in the sulfonylurea arm.76 The value of metformin has been
events with the very earliest signs of increased glucose levels, even supported in other studies as well. In the 19 691 diabetic patients with
those below the threshold for a diagnosis of diabetes.67 Early work in the Reduction of Atherothrombosis for Continued Health
with glucose-lowering therapies came tantalizingly close to demon- (REACH) Registry, those treated with metformin had a 24% reduc-
strating a reduction in cardiovascular events. In the United tion in mortality compared with those not treated with metformin.77
Kingdom Prospective Diabetes Study (UKPDS), there was a near In a nationwide Danish study, patients treated with an insulin secreta-
statistically significant reduction in myocardial infarction68,69 with gogue, suffered a 19 32% increase in all-cause mortality compared
tight glucose control. The close results prompted several other with those treated with metformin.78 The results were similar
investigations to definitively answer the question. In The Action to whether or not the study subjects had a previous myocardial infarc-
Control Cardiovascular Risk in Diabetes (ACCORD) Study, 10 251 tion. It is because of results like these that metformin is the recom-
patients (mean age, 62.2 years) with a median glycosylated haemoglo- mended first hypoglycaemic agent to be used in patients with type
bin level of 8.1% were randomly assigned to intensive therapy [a 2 diabetes.79 The thiazolidinediones, however, have a mixed
haemoglobin (Hgb) A1c ,6.0%] or standard therapy (a Hgb A1c record of success in terms of cardiovascular outcomes. In the (PRO-
of 7.0 7.9%).70 Although there was a non-significant 10% trend in ACTIVE) trial, pioglitazone missed its primary cardiovascular end-
the reduction of the primary endpoint (non-fatal myocardial infarc- point (composite of all-cause mortality, non-fatal MI, stroke, acute
tion, non-fatal stroke, or death from cardiovascular causes), there coronary syndrome, revascularization, and amputation) when
Table 1 Evidence for cardiovascular therapies in patients with diabetes mellitus
Condition supporting literature

...............................................................................................................................................................................
Hyperglycaemia
In patients with diabetes
The use of metformin to lower Hgb A1c to ,7% in the prevention of cardiovascular disease events is UKPDS76
likely of value.
The use of hypoglycaemic medications to achieve a target Hgb A1c of 66.5% to reduce cardiovascular ACCORD70 ADVANCE96
events is not beneficial and may be harmful when compared with a target of 7%.
Hypertension
Blood pressure should be reduced to ,140/90 mmHg in all risk settings. ALLHAT92
Patients with CHD, CVD, or PAD should receive an antagonist of the reninangiotensin system. ALLHAT92 HOPE95 VALUE104
ONTARGET108
Blood pressure should not be routinely lowered to a target of ,120/80 mmHg. ACCORD-Blood Pressure91
Acceptable initial agents in the treatment of uncomplicated hypertension include beta-adrenergic blockers, ALLHAT92

thiazide diuretics, and dihydropiridine calcium-channel blockers.
The use of alpha adrenergic blockers as initial therapy in uncomplicated hypertension is not recommended. ALLHAT92
Dyslipidaemia
All patients, with or without a history of atherosclerotic vascular disease, should be treated with statins. HPS43 CARDS118
Routine administration of fibrates or long-acting niacin in addition to therapy with statins is not useful. ACCORD-Lipid129 AIM-HIGH131
The use of fibrates may be effective in selected patients who manifest an HDL ,34 mg/dL and triglycerides SACKS130 FIELD127
.204 mg/dL.
Antiplatelet therapy
The use of aspirin in the treatment of acute coronary syndromes and in the prevention of recurrent coronary ISIS-2141 AntiplateletTrialists
syndromes has been established. Collaboration137
The use of P2Y12 inhibitors in the treatment of acute coronary syndromes in addition to aspirin for the CURE145 TRITON28
prevention of recurrent coronary syndromes is established.
P2Y12 inhibitors are superior to aspirin as monotherapy in patients with atherosclerotic vascular disease. CAPRIE142
The value of aspirin in the primary prevention of atherosclerotic vascular disease is unclear. JPAD138 POPADAD139
compared with placebo, but showed benefit in its composite second- fatty acid oxidation inhibitor, it improves glucose utilization and has
ary endpoint (all-cause mortality, non-fatal MI, and stroke),74 while consistently performed as a hypoglycaemic agent.82,83 Despite the
rosiglitazone has been associated with an increase in myocardial in- glucose-lowering capability, patients with diabetes do not gain
farction but not all-cause mortality.80 extra function or improved cardiovascular outcomes with ranola-
Several other hypoglycaemic medications are commonly zine. Current guidelines do not support the use of these agents to
employed for diabetes, but lack enough data to recommend their improve cardiovascular outcomes in patients with diabetes.79 More-
use as treatments to reduce cardiovascular events. Acarbose, an over, the safety requirements for the approval of hypoglycaemic
alpha glucosidase inhibitor, reduced the rate of myocardial infarction agents for type 2 diabetes has undergone scrutiny and now faces a
by 91% and a composite of cardiovascular events (myocardial infarc- higher threshold at the Food and Drug Administration in the
tion, new angina, revascularization, cardiovascular death, congestive United States.84
heart failure, cerebrovascular events, and peripheral vascular
disease) by 49% in subjects with impaired glucose tolerance in the Hypertension
STOP-Noninsulin Dependent Diabetes (NIDDM) trial.81 However, Treatment of hypertension was the first among the therapies of the
cardiovascular risk reduction with acarbose has not been reported comorbidities of patients with diabetes to reduce mortality. In
in patients with diabetes. Neither incretin mimetics, dipeptidyl pep- UKPDS, 1148 hypertensive patients with diabetes were randomly
tidase (DPP)-4, nor sodium glucose co-transporter-2 (SGLT2) inhi- allocated to tight (more intensive) or standard blood pressure
bitors have any clinical trial data demonstrating cardiovascular control.85 Followed for 8.4 years, patients in the tight control arm
event reduction. had a significantly lower blood pressure (144/82 mmHg) compared
Ranolazine, a partial fatty acid oxidation inhibitor, improves func- with those in the standard control arm (154/87 mmHg) and had a
tional capacity in patients with stable angina and has been shown to 44% reduction in stroke and a 32% reduction in diabetes-related
improve exercise tolerance similarly in patients with and without dia- death. The choice of first agent, beta-adrenergic blocker or
betes82 but does not reduce cardiovascular outcomes.27 As a partial angiotensin-converting enzyme inhibitor, made no difference in the

Figure 4 Comprehensive anti-atherosclerotic therapy in diabetes. The pathophysiology of diabetes-related atherogenesis is broad and requires a
comprehensive medical strategy to attenuate its progress. Improvements in dyslipidaemia, insulin resistance, hypertension, and platelet activation all
have a role in the care of patients with diabetes to minimize the complications of atherosclerosis. Statin therapy provides important risk reduction to
diabetic patients with and without diagnosed atherosclerosis. Improvement in glycaemia reduces the rate of myocardial infarction while metformin-
mediated improvements in insulin sensitivity provide long-term reductions in cardiovascular death. Antiplatelet therapy including aspirin and
thienopyridines have a definitive role in patients with atherosclerosis and a nuanced, individualized role in patients without a diagnosis of previous
myocardial infarction, stroke, or peripheral artery disease. Treatment of hypertension significantly reduces stroke and death. With the diagnosis of
atherosclerosis, antagonists of the renin angiotensin system may play a heightened role.
outcomes, likely because the majority of patients required more than patients with diabetes have their blood pressure controlled to 130/
one anti-hypertensive agent.85 Interestingly, the efficacy of treatment 80 mmHg or lower, although the report admitted that available data
of hypertension is not as durable as treatment of hyperglycaemia with are somewhat sparse to justify the low target.
metformin. Whereas the benefit of metformin in the first 5 years of The rationale of the Action to Control Cardiovascular Risk in Dia-
treatment persisted and increased over time,76 the benefit of tight betes (ACCORD) trial was to determine with definitive clinical trial
control of blood pressure did not persist once UKPDS had com- evidence whether a more aggressive systolic blood pressure target of
pleted.86 The results suggest that the aggressive treatment of blood ,120 mmHg was superior to a systolic blood pressure target of
pressure must be ongoing for the benefit to be maintained. ,140 mmHg.90 In ACCORD, 4733 patients were enrolled and the
There is general agreement about the benefits of optimal blood goals were achieved: at 1 year, the intensive arm had a mean systolic
pressure control, but not about the definition of optimal. Clinical blood pressure of 119.3 mmHg and the standard group had a blood
trials that were reported around the time of UKPDS provided pressure of 133.5 mmHg.91 After a mean follow-up of 5 years, there
some clue as to the appropriate goal level. In the Hypertension was no significant difference in the primary outcome (non-fatal myo-
Optimal Treatment (HOT) trial, 18 790 patients with diastolic cardial infarction, non-fatal stroke, or death from cardiovascular
blood pressure between 100 and 115 mmHg were randomly causes), death from any cause, or major coronary disease event.
assigned to treatment sufficient to achieve a diastolic blood pressure However, there was a significant 40% reduction in stroke. Also, a sig-
of 90, 85 or 80 mmHg.87 In the patients with diabetes, there was a 51% nificant increase in medication-related adverse events was noted.
reduction in major cardiovascular events in the 80 mmHg target group Subjects in the tight arm required 3.4 medications to achieve the
compared with the 90 mmHg target group. Similarly, in the Appropri- target compared with 2.1 medications in the standard group. We
ate Blood Pressure Control in Diabetes (ABCD) trial, 470 patients with await JNC 8 for any change in the recommended target of 130/
diabetes were randomized to a target diastolic blood pressure of 80 80 mmHg in patients with diabetes.
89 mmHg or a diastolic of 75 mmHg.88 Although cardiovascular events The preferred class of anti-hypertensive in patients with diabetes
did not differ between groups, all-cause mortality was lower in the merits consideration. The choice of agent may be predicated on
more aggressively treated group. Thus, in the Seventh Report of the the presence of complications of diabetes. In the absence of compli-
Joint National Committee (JNC) on Prevention, Detection, Evaluation, cations, ALLHAT, the Antihypertensive and Lipid-Lowering Treat-
and Treatment of High Blood Pressure,89 it was recommended that ment to Prevent Heart Attack Trial, demonstrated no difference in
the primary outcome of fatal coronary heart disease or non-fatal or the combination. After a median 56 months of follow-up, there
myocardial infarction among the chlorthalidone, amlodipine, and lisi- was no difference among the groups in the primary outcome of
nopril arms in patients with diabetes.92 Thus, if the primary goal of death from cardiovascular cause, myocardial infarction, stroke, or
treatment is the reduction of blood pressure, then a thiazide diuretic, hospitalization for heart failure in the entire cohort and diabetic sub-
dihydropyridine calcium-channel blocker, or angiotensin-converting group.
enzyme inhibitor (ACE-I) are acceptable first choices. b-adrenergic Inhibitors of the mineralocorticoid receptor have been studied in
antagonists should not be considered as first-line agents for treating large trials in patients with congestive heart failure and left-ventricular
hypertension in most patients. A meta-analysis of 12 studies evaluat- dysfunction after myocardial infarction. In the Randomized Aldac-
ing 94 492 patients found that b-adrenergic blocker therapy was tone Evaluation Study (RALES) trial of patients with severe systolic
associated with a 22% increased risk for new-onset diabetes, and a heart failure, spironolactone reduced mortality by 30% in patients
15% increased risk of stroke compared with non-diuretic anti- with and without diabetes.109,110 Two trials have evaluated the use
hypertensive agents.93 In contrast, b-adrenergic blocker therapy is of eplerenone in patients with reduced left-ventricular systolic func-
recommended for 3 years after myocardial infarction and in the tion, one in patients with mild heart failure and the other in patients
setting of left-ventricular dysfunction, with or without heart failure. after myocardial infarction. In both trials, eplerenone reduced mor-
Moreover, b-adrenergic blocker therapy, titrated to full dose, is tality compared with placebo, and patients with diabetes received
recommended for the treatment of stable angina.94 the same benefit as those without diabetes.111,112

If the goal is secondary prevention of atherosclerotic events, Recent trials, however, have cast doubt on the perceived superior-
antagonists of the reninangiotensin system take precedence ity of renin angiotensin antagonists in patients with diabetes. In the
because of the possible benefits beyond blood pressure lowering. Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes
The efficacy of ACE-I therapy has been demonstrated in several Research (NAVIGATOR) trial, 9306 subjects with impaired glucose
large clinical trials. In the Heart Outcomes Prevention Evaluation tolerance and established cardiovascular disease were randomized
(HOPE) study, 9297 subjects with atherosclerosis or diabetes and to valsartan or placebo and followed for 5 years. Despite a 2.8/
a cardiovascular risk factor were randomly allocated ramipril or 1.4 mmHg difference in blood pressure between the groups, there
placebo.95 The diabetic subgroup showed significant reductions in was no difference in death, myocardial infarction, stroke, and revas-
MI, stroke, and death, despite a baseline blood pressure of 139/ cularization.113 Similarly, in the Prevention Regimen for Effectively
79 mmHg prior to treatment. The ADVANCE trial enrolled 11 140 Avoiding Second Strokes (PRoFESS) trial, telmisartan failed to
subjects with diabetes, irrespective of blood pressure, and randomly reduce stroke and major cardiovascular events in diabetic patients
allocated the subjects to perindopril and indapamide or matching with recent stroke when compared with placebo.114 In contrast,
placebo.96 With a drop of 5.6 mmHg in systolic blood pressure, the the ACCOMPLISH trial in which 60% of patients had diabetes
perindopril and indapamide combination reduced all vascular showed that treatment with the ACE-I benzapril in combination
events, but not cardiovascular events alone. In the EUropean trial with amlodipine significantly reduced cardiovascular events.115 For
on Reduction Of cardiac events with Perindopril (EUROPA) trial of now, the usefulness of ACE-I and ARB in diabetic patients with myo-
patients with stable coronary artery disease, perindopril reduced cardial infarction remains clear, but the preferential role in other set-
the composite endpoint of cardiovascular mortality, MI, or cardiac tings less so.
arrest, similarly in those with and without diabetes.97 Interestingly,
when the 1502 diabetic subjects of EUROPA were evaluated inde- Dyslipidaemia
pendently, no benefit could be demonstrated, likely suggesting inad- The cornerstone of lipid management in diabetes is the
equate power in this sized sample.98 In other trials of secondary hydroxymethylglutaryl-CoA reductase inhibitors (statins). The land-
prevention after a cardiovascular event, ACE inhibition has been mark Heart Protection Study established the role of statins in the treat-
shown to reduce recurrent stroke in diabetic patients with previous ment of patients with diabetes.116 In the 5963 subjects with diabetes
stroke or TIA99 and reduce mortality in diabetic patients after myo- and no cardiovascular disease, there were significant reductions in
cardial infarction.100 102 Angiotensin receptor blockers (ARBs) have first non-fatal myocardial infarction or death, major coronary events,
similar efficacy to ACE-I after myocardial infarction. In the Valsartan in stroke, and revascularization in the group treated with simvastatin
Acute Myocardial Infarction Trial,103 valsartan was as effective as cap- compared with the group treated with placebo. These benefits were
topril for the primary endpoint of total mortality in the subgroup of recapitulated with atorvastatin in Anglo-Scandinavian Cardiac Out-
diabetic patients with myocardial infarction complicated by left- comes Triallipid-lowering arm117 and the Collaborative Atorvasta-
ventricular systolic dysfunction.104 In the Losartan Intervention For tin Diabetes Study.118 Statins have an even more profound effect in
Endpoint reduction in hypertension study,105 losartan was found to diabetic subjects preventing recurrent myocardial infarction and a
be superior to atenolol in diabetic patients with end-organ damage similar benefit in preventing stroke compared with patients without
for the primary composite endpoint of cardiovascular death, MI, diabetes.119 121 Thus, patients with diabetes should be treated with
and stroke,106 and in the Valsartan Antihypertensive Long Term a statin. The one exception may be in patients with renal failure, as
Use Evaluation (VALUE), valsartan was equivalent to amlodipine statins have failed to show efficacy consistently is in diabetic patients
for the endpoint of cardiovascular morbidity and mortality in hyper- undergoing haemodialysis.122,123 Moreover, high-dose more potent
tensive diabetic patients.107 The Ongoing Telmisartan Alone and in statins have been shown to be superior to a lower dose of the same
Combination with Ramipril Global Endpoint Trial (ONTARGET)108 medication or less-potent statins in two clinical trials, indicating that
enrolled 25 620 patients with vascular disease or diabetes with a high dose of a more potent statin therapy should be used in standard
end-organ damage and randomized them to ramipril, telmisartan, practice.124,125
The usefulness of other lipid modification agents, alone or in add- stroke, and peripheral artery disease). Similarly, in the Prevention
ition to statins, in patients with diabetes is not established. Early work of Progression of Arterial Disease and Diabetes (POPADAD) trial,
with fibric acid derivatives alone demonstrated a similar reduction in 1276 adults with type 2 diabetes and an anklebrachial index of
cardiovascular events in patients with and without diabetes in the ,1.0 were randomized to daily aspirin or placebo.139 In this study,
Veterans Affairs High-Density Lipoprotein Cholesterol Intervention there was no significant difference in the composite outcome of
Trial,126 but more recent data have been less compelling. The Feno- death from coronary heart disease or stroke, non-fatal myocardial in-
fibrate Intervention and Event Lowering in Diabetes (FIELD) trial ran- farction or stroke, or above ankle amputation for critical limb ischae-
domized 9795 patients with type 2 diabetes to fenofibrate or mia; or any of its individual components. A meta-analysis of aspirin
placebo,127 but was unable to show a reduction in the primary treatment in only the diabetic subjects in large primary prevention
outcome of coronary events. The lack of efficacy was posited to an studies demonstrated a trend towards a 10% reduction in the cardio-
unequal distribution of statin usage. The use of fenofibrate was asso- vascular disease events.140 Based on the limited data and small, if any
ciated with a reduction in minor amputation,128 although interpret- benefit, the American Diabetes Association, American Heart Associ-
ation of a secondary endpoint without a positive primary endpoint ation, and American College of Cardiology Foundation recommend
should be done with caution. The use of a fibrate in supplement to the use of low-dose aspirin in diabetic patients with a cardiovascular
statin therapy for all subjects with diabetes was studied in the disease risk of .1% per year based on diabetes-based risk calculators
ACCORD Lipid trial.129 In this trial of 5518 patients, all patients like the UKPDS Risk Engine (http://www.dtu.ox.ac.uk/riskengine/

received open label simvastatin and were randomized to fenofibrate index.php) or American Diabetes Association Risk Assessment
or placebo. After a mean follow-up of nearly 5 years, despite signifi- Tool (http://www.diabetes.org/phd).140 Thus, diabetes alone is not
cantly lower triglyceride and higher high-density lipoprotein (HDL) enough to warrant low-dose aspirin therapy, but use of aspirin may
levels in the fenofibrate arm, there was no difference in the rate of be acceptable when the cardiovascular risk surmounts the 1% per
major fatal or non-fatal cardiovascular events, stroke, or death. year needed to gain the small benefit of aspirin in primary prevention.
Based on this trial, routine use of a fibrate in addition to statin In patients with acute coronary syndromes aspirin significantly
therapy is not warranted. Some have suggested that fibrates may reduced the rate of reinfarction, stroke, and death.141 More potent
have value in patients with high triglyceride and low HDL levels,130 than aspirin, the P2Y12 inhibitors, have been studied in secondary
but this remains to be proved prospectively. Similarly, niacin has yet prevention, both in the acute phase of coronary syndromes and
to find a treatment niche when statins are in use. In the Atherothrom- stroke and during stable chronic follow-up. In the Clopidogrel vs.
bosis Intervention in Metabolic Syndrome with Low HDL/High Tri- Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, 19 185
glycerides: Impact on Global Health Outcomes (AIM-HIGH) trial, patients with coronary artery disease, cerebrovascular disease, or
3414 patients with established vascular disease on a statin with low peripheral artery disease were randomized to aspirin or clopido-
HDL and high triglycerides were randomized to extended release grel.142 A modest 0.5% absolute annual risk reduction was noted.
niacin or placebo.131 Niacin treatment significantly increased HDL, In the diabetic subgroup of 1952 patients, the absolute risk reduction
lowered triglyceride, and lowered LDL levels, but there was no differ- was 2.1%, significantly larger than in subjects without diabetes.143
ence in the composite of death from coronary heart disease, non- However, in The Clopidogrel for High Atherothrombotic Risk and
fatal myocardial infarction, ischaemic stroke, hospitalization for an Ischemic Stabilization, Management, and Avoidance (CHARISMA)
acute coronary syndrome, or symptom-driven coronary or cerebral trial of patients with established atherosclerosis or multiple risk
revascularization or any of the individual components in the entire factors for atherosclerosis, the addition of clopidogrel to aspirin
cohort and diabetic subgroup. For now, the addition of a second was no more effective than aspirin alone in the prevention of the
lipid modifying medication may be made on an individual basis, but composite endpoint of cardiovascular death, MI, and stroke.144 Fol-
cannot be recommended for all patients with diabetes. lowing acute coronary syndromes, there is evidence that greater anti-
platelet inhibition provides more benefit for patients with diabetes.
Antiplatelet therapy The Clopidogrel in Unstable Angina to Prevent Recurrent Events
The benefit of antiplatelet therapy in patients with diabetes but (CURE) trial demonstrated benefit in reducing the composite of car-
without evident atherosclerosis has become less clear with time. diovascular death, non-fatal MI, and stroke with the addition of clopi-
The current recommendation by the US Preventive Services Task dogrel to aspirin in both non-diabetic and diabetic patients with acute
Force and the American College of Chest Physicians is low-dose coronary syndrome.145 In TRITON-TIMI 38 trial, patients with acute
aspirin for primary prevention in all patients.132,133 This recommen- coronary syndromes undergoing percutaneous revascularization
dation is largely based on meta-analyses of many primary prevention were randomly allocated to clopidogrel or prasugrel. The benefit
trials showing a small benefit of aspirin in the reduction of non-fatal associated with the more potent prasugrel was significantly greater
myocardial infarction (about five events per 10 000 patients) offset for subjects with diabetes than those without diabetes, despite no
by a similar increase in gastrointestinal hemorrhage (three events excess bleeding.28 In the Targeted Platelet Inhibition to Clarify the
per 10 000 patients).134 137 However, the data in diabetic patients Optimal Strategy to Medically Manage Acute Coronary Syndromes
in particular is not compelling. Two recent trials enrolled only (TRILOGY ACS) trial, patients randomized to prasugrel had a
patients with diabetes and found no benefit. The Japanese Primary lower rate of recurrent events than those randomized to clopidogrel.
Prevention of Atherosclerosis with Aspirin for Diabetes (JAPAD) In contrast to TRITON-TIMI 38, the patients with diabetes did not
Trial included 2539 patients with diabetes and no history of athero- have a better result than those without diabetes.146 Another novel
sclerotic disease.138 There was a non-significant 20% reduction in P2Y12 inhibitor, ticagrelor, was tested in patients with acute coron-
atherosclerotic events (fatal and non-fatal MI, fatal and non-fatal ary syndromes and compared with clopidogrel in the Platelet
Inhibition and Patient Outcomes (PLATO) trial. In Plato, ticagrelor physician determined the appropriate strategy. Over the course of
was superior to clopidogrel and showed a significant reduction in 5 years of follow-up, there was no difference in survival between
mortality, but the benefit for subjects with diabetes was not different the medical therapy and revascularization arms in total, or by type.
from the cohort as a whole.147,148 Further work is needed to clarify In a secondary outcome, the patients in the coronary artery bypass
these differences among agents and their interaction with diabetes. portion of the study who underwent surgery had a significantly
lower rate of major cardiovascular events (death, MI, or stroke)
The benefit of risk modification in than those allocated to medical therapy. This may have resulted
because the patients in the bypass arm had more triple vessel coron-
aggregate
ary artery disease (52.4 vs. 20.3%). The Future Revascularization
Modifications of each of the risk factors brings reductions in cardio-
Evaluation in Patients with Diabetes Mellitus: Optimal Management
vascular adverse events. Intensive modification of every risk factor
of Multivessel Disease (FREEDOM) trial compared the outcomes
provides additive benefits. In the Steno-2 trial, 160 patients with
in 1900 diabetic subjects with multivessel coronary disease randomly
type 2 diabetes were randomized to intensive therapy or convention-
assigned to percutaneous coronary intervention or coronary artery
al therapy and followed for up to 13 years.149 Intensive therapy was
bypass grafting and followed for a median of 3.8 years.154 Subjects
defined as haemoglobin A1c ,6.5%, total cholesterol ,175 mg/
who underwent surgical bypass had an absolute 7.9% reduction in
dL, fasting serum triglycerides ,150 mg/dL, systolic blood pressure
the primary outcome of death, non-fatal myocardial infarction, and
,130 mmHg, diastolic blood pressure ,80 mmHg, use of low-dose

non-fatal stroke. Indeed, the reduction in death from any cause was
aspirin, and treatment with renin angiotensin antagonist. Intensive
significant by itself, with a 5.4% absolute reduction in all-cause mor-
therapy significantly reduces cardiovascular and total mortality com-
tality. Thus, in patients with diabetes and multivessel disease who
pared with standard treatment. Thus, intensive therapy of all the risk
require revascularization, coronary artery bypass surgery is pre-
factors for atherosclerosis is life extending and should be pursued.
ferred over percutaneous coronary intervention.
Indeed, intensive medical therapy is so effective, that investigation
for coronary artery disease in asymptomatic patients is unnecessary.
In the Detection of Ischemia in Asymptomatic Diabetics (DIAD) Conclusion
study, 1123 subjects with type 2 diabetes were randomly assigned
Diabetes is a risk multiplier in atherosclerosis. It increases the risk of
to adenosine stress radionuclide myocardial perfusion imaging or
developing atherosclerosis, the incidence of complications of athero-
no screening.150 Over nearly 5 years of follow-up, there was a cumu-
sclerosis, and is associated with poorer outcomes from these events.
lative cardiac death or non-fatal myocardial infarction rate of 2.9%,
Health care professionals now have the benefit of a wide variety of
without difference between the two groups. Thus, aggressive use
clinical trial data supporting specific treatments and targets for
of risk modifying therapies remains the mainstay of therapy. On the
patients with diabetes. These include lipid-lowering therapy with
other hand, intensive treatment of risk factors, namely hypertension
statins, blood pressure control, and antiplatelet therapy in patients
and hyperglycaemia may also associate with increased cardiovascular
with increased cardiovascular risk scores. Hyperglycaemia should
events in the diabetic population.70,151 Hence, a cautious approach
be treated to a target glycosylated haemoglobin of 7%, with
should be implemented when considering individual therapeutic
therapy that includes an agent that improves insulin sensitivity, such
targets in this setting.
as metformin. Optimal medical treatment, including risk factor modi-
fication, antiplatelet therapy, and antianginal medications is the pre-
Coronary revascularization ferred approach for most patients with diabetes and stable
The role of revascularization in diabetes has evolved over the recent coronary artery disease. Over the last decade, aggressive application
years. The Clinical Outcomes Utilizing Revascularization and Aggres- of these therapies by care providers has reduced the rate of cardio-
sive Drug Evaluation (COURAGE) trial included 2287 patients with vascular events in patients with diabetes, ameliorating outcomes in
significant stable coronary artery disease and compared the out- this population. Despite these improvements, the risk of adverse car-
comes of optimal medical therapy (OMT) with and without percu- diovascular outcomes remains significantly higher in patients with
taneous coronary intervention (PCI).152 Over a median 4.6 years of diabetes than those without diabetes. Understanding the pathophysi-
follow-up, the addition of PCI to OMT did not reduce death and ology of vascular disease in diabetes, as reviewed in Part I of this
MI compared with OMT alone, either in the entire cohort or the sub- review will facilitate discovery of beneficial treatments for diabetic
group with diabetes. Thus, in most patients with stable coronary patients to reduce this gap in morbidity and mortality.
artery disease, who have preserved left-ventricular function and
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Diabetes and vascular disease:

Article in European Heart Journal August 2013

Joshua Beckman Francesco Paneni

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European Heart Journal REVIEW

Diabetes and vascular disease: pathophysiology,

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atherosclerosis Coronary heart disease

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the Adult Treatment Panel III of the National Cholesterol Education

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was a significant 22% increase in all-cause mortality in the intensively

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Table 1 Evidence for cardiovascular therapies in patients with diabetes mellitus

Condition supporting literature

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