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World J Clin Cases. Sep 16, 2014; 2(9): 415-421
Published online Sep 16, 2014. doi: 10.12998/wjcc.v2.i9.415
Subclinical cardiovascular disease in type 2 diabetes mellitus: To screen or not to screen
Juan J Chillarón, Juana A Flores-Le Roux, David Benaiges, Juan Pedro-Botet, Department of Endocrinology and Nutrition, Hospital del Mar, Passeig Marítim 25-29, 08003 Barcelona, Spain
Juan J Chillarón, Juana A Flores-Le Roux, David Benaiges, Juan Pedro-Botet, Institut Municipal d´Investigacions Mèdiques, Passeig Marítim 25-29, 08003 Barcelona, Spain
Juan J Chillarón, Juana A Flores-Le Roux, David Benaiges, Juan Pedro-Botet, Departament de Medicina, Universitat Autònoma de Barcelona, 08193 Cerdanyola (NOT Sardañola) del Vallés, Barcelona, Spain
Author contributions: All the authors contributed to this paper.
Correspondence to: Dr. Juan J Chillarón, Department of Endocrinology and Nutrition, Hospital del Mar, Passeig Marítim, 25-29, 08003 Barcelona, Spain.
Telephone: +34-93-2483902 Fax: +34-93-2483337
Received: March 26, 2014
Revised: April 30, 2014
Accepted: July 12, 2014
Published online: September 16, 2014


The prevalence of type 2 diabetes mellitus (T2DM) has risen in recent decades, and cardiovascular disease remains the leading cause of death in this population. Several clinical trials have demonstrated the benefit of tight control of risk factors on the incidence and mortality of cardiovascular disease. However, in clinical practice, few patients achieve the therapeutic goals. The current diagnostic procedures for subclinical cardiovascular disease in T2DM patients have not been shown to improve prognosis or mortality, probably because they do not categorize cardiovascular risk. Thus, clinical practice guidelines do not systematically recommend screening for subclinical atherosclerosis in these patients, although it is known that patients with extra-coronary atherosclerosis, microangiopathy and poorly-controlled cardiovascular risk factors are at high risk for cardiovascular disease. Improvements in the reliability of diagnostic tests, with fewer side effects and better cost efficiency, may better help to stratify cardiovascular risk in this group of patients, and further evaluation on this topic should be considered.

Key Words: Cardiovascular disease, Type 2 diabetes mellitus, Cardiovascular risk

Core tip: The prevalence of type 2 diabetes mellitus (T2DM) has risen in recent decades, and cardiovascular disease remains the leading cause of death in this population. Several clinical trials have demonstrated the benefit of tight control of risk factors on the incidence and mortality of cardiovascular disease. The current diagnostic procedures for subclinical cardiovascular disease in T2DM patients have not been shown to improve prognosis or mortality, probably because they do not categorize cardiovascular risk. Improvements in the reliability of diagnostic tests, with fewer side effects and better cost efficiency, may better help to stratify cardiovascular risk in this group of patients, and further evaluation on this topic should be considered.


The prevalence of type 2 diabetes mellitus (T2DM) is rising dramatically in industrialized countries[1]. According to the National Health and Nutritional Examination Survey, 19.7 million Americans had diagnosed diabetes, representing 8.3% of the adult population, and an additional 8.2 million were undiagnosed[2]. In Europe, population studies report a T2DM prevalence of 13.8%, although many cases are undiagnosed[3]. Cardiovascular disease is the leading cause of mortality and morbidity in this specific population and is responsible for most of the increased health care costs[4]. Traditionally, T2DM has been considered a coronary risk equivalent[5]. Although this topic is the subject of debate[6-10], there is unanimous agreement that strict control of cardiovascular risk factors in T2DM patients reduces the incidence of cardiovascular disease[11].

T2DM is often associated with several other cardiovascular risk factors. Therefore, cardiovascular prevention in these patients should be multifactorial. Studies assessing the impact of multifactorial risk factor intervention obtained substantial improvements compared with those evaluating single risk factor interventions[12,13].

The effectiveness of a multifactorial intervention was demonstrated in the Steno-2 study, where patients with T2DM and microalbuminuria were randomized to intensive or conventional multifactorial intervention over 7.8 years. A target-driven, long-term, intensified intervention aimed at multiple risk factors, particularly through low-density lipoprotein (LDL) cholesterol lowering and blood pressure control, achieved a 50% reduction in vascular events in this specific population[11].

In addition, many of the benefits of controlling risk factors in patients with T2DM disappear when control ceases, at a similar rate as the benefits ​​are obtained[13-15]. For example, in the UKPDS study, patients with newly-diagnosed T2DM who presented an increase in blood pressure levels during follow-up almost immediately had an increase in the risk of cardiovascular episodes[14]. Furthermore, intravascular ultrasound studies have shown that coronary atherosclerosis regression is more difficult to attain in patients with diabetes than in those without[16], and therefore prevention and early treatment of the disease are essential.

The proportion of patients achieving therapeutic goals in cardiovascular risk factors in clinical practice[17] is very low, mainly in those at high cardiovascular risk, as is the case of patients with T2DM. In this respect, only 28% of T2DM patients reach a blood pressure level < 140/90 mm​​Hg, and 22% less than 130/90 mmHg. Of greater concern is the fact that among known hypertensive patients, 40% did not follow a specific therapeutic strategy. Regarding lipid goals, only 35% of T2DM patients reached on LDL cholesterol concentration below 100 mg/dL. Another alarming fact is that 62% of patients requiring lipid-lowering therapy do not receive pharmacologic treatment[18].

Given the poor risk factor control in clinical practice, it is essential to evaluate strategies for early diagnosis of cardiovascular disease in T2DM patients, especially since the disease is often asymptomatic and has worse prognosis in these subjects than in non-diabetics[19]. A substantial percentage of patients with T2DM have silent myocardial ischemia, and these patients are at greater risk for cardiovascular events[20]. Therefore, the diagnosis of silent coronary disease may help to identify subjects at very high risk and consequently aid the implementation of more aggressive risk reduction strategies in this subgroup of patients.

Recent American Diabetes Association (ADA) guidelines[17] recommend only advanced or invasive cardiac tests in the presence of typical or atypical symptoms or abnormal baseline electrocardiogram (ECG). The rationale for not indicating screening tests in asymptomatic patients at high cardiovascular risk is simply because these patients are already supposed to be being treated to attain strict metabolic goals, although as previously stated, this is not so in the majority of cases[18]. Moreover, we must take into account that technologic progress renders diagnostic techniques increasingly sensitive and less invasive and thus their applicability may vary in the short-mid term. Therefore, we considered it of interest to carry out a review of factors that may predispose to silent cardiovascular disease in T2DM and of diagnostic tests that can be considered in selected cases.


The expert consensus published by the ADA in 2007[21] defines asymptomatic T2DM patients as being at high risk for myocardial ischemia if they display any of the characteristics shown in in Tables 1 and 2.

Table 1 Clinical characteristics of diabetic patients with increased risk of coronary heart disease.
Evidence of other atherosclerotic vascular disease
Renal disease
Abnormal resting electrocardiogram
Diabetes complications including autonomic neuropathy
Age > 45 yr
Male sex
Traditional risk factors
Blood pressure
Abdominal obesity
Novel cardiac risk factors
C-reactive protein
Table 2 Key messages.
Cardiovascular disease is the leading cause of mortality in patients with T2DM
Control of cardiovascular risk factors has been shown to significantly reduce the incidence of cardiovascular disease in T2DM patients
Control level of cardiovascular risk factors in patients with T2DM in clinical practice is poor
Systematic screening of cardiovascular disease has not been shown to improve the prognosis of patients with T2DM
In patients with atypical symptoms or ECG abnormalities, cardiovascular disease screening is warranted
Evidence of other atherosclerotic vascular disease

Atherosclerosis is a systemic process, and patients with T2DM have a greater atherosclerotic burden at any level of the arterial tree[22,23]; therefore, involvement of only one vascular territory is highly unlikely.

Screening for peripheral arterial disease (PAD) is widely accepted and has been extensively implemented in clinical practice. Thus, patients diagnosed with T2DM require an annual evaluation of their feet, including inspection, examination of sensitivity and palpation of pedal pulses and a questionnaire addressed to identify intermittent claudication. Periodic determination of the ankle-brachial index is also recommended[17]. Ninety per cent of patients with established PAD have coronary atherosclerosis on angiography[24]. In accordance with this observation, the presence of PAD is a predictor of symptomatic coronary artery disease, with a relative risk of 6.6 (95%CI: 2.9-15)[25]. Studies in patients who have suffered a stroke showed an 18%-38% prevalence of asymptomatic heart disease[26-28]. Thus, patients with extra-coronary atherosclerosis are at high risk of coronary involvement, and therefore screening strategies should be considered along with aggressive treatment of cardiovascular risk factors.


Microalbuminuria and chronic kidney disease are clearly associated with cardiovascular disease. The incidence of coronary heart disease or cardiac death 5 years after kidney failure diagnosis is 40%[29], and the age-adjusted hazard ratio for the development of coronary heart disease is 1.66 (95%CI: 1.24-1.92) when microalbuminuria is present, and may rise to 2.84 (95%CI: 1.80-4.46) in the case of macroalbuminuria[30]. Although the pathophysiologic explanation for this association is not fully understood, factors associated with the development of microalbuminuria or renal failure, such as a nocturnal rise in blood pressure, increased lipoprotein(a) and homocysteine levels or elevation of inflammatory markers and insulin resistance could play a role.

In any event, multiple observational studies confirmed this association, and thus patients with T2DM and any renal impairment stage should be considered at high risk for asymptomatic coronary artery disease.


Baseline ECG is a rapid, cheap, simple and accessible method of screening for coronary heart disease. The finding of pathologic Q waves, ST-segment changes or left bundle branch block requires further testing to evaluate coronary artery disease in these patients, who should no longer be classified as “asymptomatic”. Unfortunately, the number of cases detected with a baseline ECG alone is very low.

The exercise stress test is widely available in most hospitals and provides useful information regarding the ST-segment abnormalities suggestive of ischemia, although it does not constitute a very powerful marker of prevalent or incident coronary heart disease[28,31]. In patients with T2DM, sensitivity for detecting coronary artery disease is 47% and specificity 81%[32]. In addition to low sensitivity, the exercise stress test may have a limited role in diabetic patients who are typically deconditioned, overweight and possibly ataxic from peripheral neuropathy. In some studies, over 50% of subjects are not able to complete the exercise stress test[33].

Exercise capacity is probably a more relevant factor, since decreased exercise capacity has been linked to increased mortality and cardiovascular events in healthy people[34] and in patients with T2DM, with an odds ratio for coronary heart disease of 2.21 (95%CI: 1.41-3.46)[35].

Autonomic neuropathy

Systematic screening for autonomic neuropathy at the time of T2DM diagnosis[17] is recommended; however, it is probably the most underdiagnosed chronic complication of diabetes. It is usually associated with other microvascular complications such as retinopathy or nephropathy, and its major clinical manifestations include resting tachycardia, exercise intolerance, orthostatic hypotension, constipation, gastroparesis, erectile dysfunction, sudoriparous dysfunction and hypoglycemia unawareness. In patients with at least one microvascular complication it may be indicated to perform a Valsalva or deep breathing test to assess the presence of cardiac autonomic neuropathy.

Since 1962, it has been assumed that patients with T2DM may have coronary episodes with few or no symptoms, and this has been attributed, at least in part, to possible cardiac denervation due to neuropathy[36]. As previously mentioned, the presence of diabetic autonomic neuropathy is a significant predictor of coronary ischemia[37]; conversely, between 65% and 92% of diabetic patients with myocardial ischemia have autonomic neuropathy[38,39]. Thus, in all T2DM patients, but especially those with other cardiovascular risk factors, it is important to perform routine screening for autonomic neuropathy. Patients with diabetic autonomic neuropathy should undergo cardiac evaluation before initiating more intense physical activity than their usual.


As in other microangiopathic complications, the presence of retinopathy is also related to the incidence of coronary artery disease in these patients[40,41]. In this regard, after adjusting for age, body mass index, waist circumference, smoking status, lipids, glycosylated hemoglobin, T2DM duration and treatment, the odds ratio for the development of heart disease was 3.75 (95%CI: 2.0-7.4) in men and 3.81 (95%CI: 2.2-7.3) in women with proliferative retinopathy or who had received laser therapy[41]. Statistical significance was also maintained after adjustment for the presence of hypertension and nephropathy. In accordance with these results, the relative risk for the prevalence of symptomatic coronary artery disease in patients with established retinopathy was 1.98 (95%CI: 1.44-2.74)[42].

Traditional risk factors

Typically, patients with T2DM have other classic associated cardiovascular risk factors such as hypertension or dyslipidemia which increase their cardiovascular risk. Therapeutic intervention for these factors contributes to a reduction in vascular risk[11]; however, previous studies demonstrated that in clinical practice it is very difficult to achieve the therapeutic goals for these risk factors recommended by clinical guidelines[18].

On the other hand, previous studies suggested that traditional cardiac risk factors are not associated with abnormal stress tests in asymptomatic diabetic patients[37]. The Detection of Ischemia in Asymptomatic Diabetics (DIAD) study concluded that markedly abnormal myocardial perfusion results occurred with equal frequency among patients with two or more and less than two risk factors.Thus, the presence or absence of major cardiovascular risk factors is not a suitable parameter to determine which T2DM patients require screening for asymptomatic coronary artery disease.


No validated algorithm for the screening of asymptomatic coronary artery disease in T2DM patients has been established. In this respect, choice of the diagnostic procedure will depend on the available scientific evidence, experience in each center and degree of coronary heart disease suspicion, based on the variables mentioned previously. The scientific evidence on the available diagnostic procedures for coronary heart disease: echocardiography, myocardial perfusion imaging and computed tomography for coronary calcium, will be reviewed.


Resting echocardiogram is not routinely recommended in normotensive patients since its sensitivity and specificity for coronary heart disease detection are low[43]. Severe changes in contractility are more typical of the acute phase of myocardial infarction; moreover, segmental wall abnormalities do not exclusively constitute an ischemic etiology, since they may also be present in patients with non-ischemic heart diseases.

Therefore, resting or stress echocardiography after exercise or dobutamine is not routinely recommended in asymptomatic T2DM patients since no studies have provided data on its benefits. The usefulness of this test is limited to patients with known coronary heart disease ​​to assess reversible ischemia, myocardial viability and risk stratification.

Myocardial perfusion imaging

Single-photon emission computed tomography after exercise or pharmacologic administration is one of the most widely performed screening tests in asymptomatic T2DM patients. The presence of a fixed or reversible perfusion defect is associated with a three-fold increased risk for cardiovascular episodes in patients over 60 years of age[44]. In the DIAD study, participants with type 2 diabetes and no symptoms of CAD were randomly assigned to be screened with adenosine-stress radionuclide myocardial perfusion imaging (MPI) or not to be screened and be prospectively followed for a mean period of 5 years. Patients with a normal/low-risk scan showed an annual cardiovascular event incidence of 0.4% compared with 2.4% in those with a moderate to large perfusion defect[45]. Therefore, if the benefits of this test, which is minimally invasive and of acceptable cost are considered, it should probably be recommended as a first-line diagnostic procedure for silent myocardial ischemia in T2DM patients.

Computed tomography

The use of Multi-detector computed tomography (CT) as a noninvasive assessment of the coronary artery tree is becoming more frequent in addition to angiographic methods in patients with or without T2DM diabetes who have had an acute myocardial infarction.

In asymptomatic patients or in those with mild symptoms the assessment of coronary artery calcium (CAC) is most commonly used, which is a specific marker of atherosclerosis. It can be visualized and measured noninvasively by computed tomography. The quantity of calcium within coronary arteries is typically scored as the area affected on the scan, multiplied by a weighting factor depending on the Hounsfield unit density of the calcium deposits[46]. Given the radiation exposure, careful patient selection for this test is mandatory. Coronary calcification in men < 40 years of age and in women < 50 years of age is infrequent; therefore, CT scanning is generally not recommended in these age groups. Several studies have shown the coronary artery calcium score to be valuable in identifying patients at high risk of inducible myocardial ischemia[47,48]. These studies consistently observed that the likelihood of ischemia in patients with a calcium score ≤ 100 is negligible, whereas the probability of inducible ischemia in those with a score of ≥ 400 is relatively high, even in oligoasymptomatic patients[49].

The presence of CAC is predictive for future cardiovascular events in both asymptomatic diabetic individuals and in nondiabetic subjects. However, for every increase in CAC, there is a greater increase in the mortality rate for diabetic than for nondiabetic subjects[50]. Moreover, diabetic patients with low CAC scores (Agatston Score ≤ 10) had a low prevalence of inducible myocardial ischemia and a low cardiovascular event rate[49,50]. Therefore, assessment of CAC might be useful in identifying diabetic individuals with a low risk of silent myocardial ischemia. Nevertheless, the use of CAC scoring for risk stratification in asymptomatic diabetic patients is not currently endorsed by the ADA recommendations[17] since there is insufficient evidence of the long-term benefits of early diagnosis.


Despite all this evidence, the possible benefits of early detection of cardiovascular disease in asymptomatic T2DM patients have not been confirmed in randomized trials. In the DIAD study, the cardiac event rates were not significantly reduced by MPI screening for myocardial ischemia[45]. Additionally, observational studies have shown that, on occasions, alterations in the coronary arteries of these patients can become spontaneously reversible[51]. Finally, studies comparing intensive medical treatment with revascularization procedures showed similar results[52,53]. Therefore, from a clinical and cost-benefit point-of-view, there is not enough evidence at present to recommend screening in these patients.

However, it should be taken into account that these studies were conducted in asymptomatic patients diagnosed early with cardiovascular disease. Therefore, both patient compliance and the intensity of monitoring by the physician were higher than those observed in real life, and this fact may have influenced the results. On the other hand, the DIAD study found a six-fold increased incidence of cardiac events in patients with moderate to large perfusion defects compared to those with a normal/low-risk scan[45], which supports the hypothesis that screening for asymptomatic coronary disease can be useful even though the low prevalence could have influenced the statistical power to demonstrate the possible benefits, including cost-benefit.


In the absence of categorical scientific evidence to date, the sequence of tests to be performed in high-risk patients is not established. In this sense, after performing a baseline ECG, the availability of technical and financial resources, and experience in each center can play a role in choosing the most appropriate diagnostic management. Overall, the most common recommendation is to start with a resting ECG and then a myocardial perfusion imaging by SPECT, although the increasingly widespread and cheap use of multi-detector CT can change this trend in the coming years.


Systematic screening for cardiovascular disease in asymptomatic patients with T2DM is not recommended since there is insufficient evidence at present that the benefits of early detection outweigh the costs and side effects of the different diagnostic tests. However, as mentioned previously, this situation may change in the near future given the advances in reliability and efficiency of the different diagnostic tests.

Professionals responsible for the medical care of patients with T2DM should focus on optimizing the control of cardiovascular risk factors and evaluate, only in selected cases, the need to further investigate the presence of cardiovascular disease.


We thank Miss Christine O’Hara for review of the English version of the manuscript.


P- Reviewer: Okumura K, Toro R, Vasarhelyi B, Wan Y S- Editor: Song XX L- Editor: A E- Editor: Lu YJ

1.  Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27:1047-1053.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9344]  [Cited by in F6Publishing: 10055]  [Article Influence: 529.2]  [Reference Citation Analysis (1)]
2.  Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox CS, Franco S. Executive summary: heart disease and stroke statistics--2014 update: a report from the American Heart Association. Circulation. 2014;129:399-410.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1070]  [Cited by in F6Publishing: 1143]  [Article Influence: 127.0]  [Reference Citation Analysis (0)]
3.  Soriguer F, Goday A, Bosch-Comas A, Bordiú E, Calle-Pascual A, Carmena R, Casamitjana R, Castaño L, Castell C, Catalá M. Prevalence of diabetes mellitus and impaired glucose regulation in Spain: the Study. Diabetologia. 2012;55:88-93.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 714]  [Cited by in F6Publishing: 525]  [Article Influence: 47.7]  [Reference Citation Analysis (0)]
4.  Hogan P, Dall T, Nikolov P. Economic costs of diabetes in the US in 2002. Diabetes Care. 2003;26:917-932.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 993]  [Cited by in F6Publishing: 1061]  [Article Influence: 53.1]  [Reference Citation Analysis (0)]
5.  Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229-234.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4846]  [Cited by in F6Publishing: 5023]  [Article Influence: 200.9]  [Reference Citation Analysis (0)]
6.  Cano JF, Baena-Diez JM, Franch J, Vila J, Tello S, Sala J, Elosua R, Marrugat J; Marrugat J; REGICOR and GEDAPS Investigators. Long-term cardiovascular risk in type 2 diabetic compared with nondiabetic first acute myocardial infarction patients: a population-based cohort study in southern Europe. Diabetes Care. 2010;33:2004-2009.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 43]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
7.  Evans JM, Wang J, Morris AD. Comparison of cardiovascular risk between patients with type 2 diabetes and those who had had a myocardial infarction: cross sectional and cohort studies. BMJ. 2002;324:939-942.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 281]  [Cited by in F6Publishing: 289]  [Article Influence: 13.8]  [Reference Citation Analysis (0)]
8.  Lee CD, Folsom AR, Pankow JS, Brancati FL; Atherosclerosis Risk in Communities [ARIC] Study Investigators. Cardiovascular events in diabetic and nondiabetic adults with or without history of myocardial infarction. Circulation. 2004;109:855-860.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 193]  [Cited by in F6Publishing: 207]  [Article Influence: 10.9]  [Reference Citation Analysis (0)]
9.  Pajunen P, Koukkunen H, Ketonen M, Jerkkola T, Immonen-Räihä P, Kärjä-Koskenkari P, Kuulasmaa K, Palomäki P, Mustonen J, Lehtonen A. Myocardial infarction in diabetic and non-diabetic persons with and without prior myocardial infarction: the FINAMI Study. Diabetologia. 2005;48:2519-2524.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 41]  [Cited by in F6Publishing: 33]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
10.  Natarajan S, Liao Y, Sinha D, Cao G, McGee DL, Lipsitz SR. Sex differences in the effect of diabetes duration on coronary heart disease mortality. Arch Intern Med. 2005;165:430-435.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 83]  [Cited by in F6Publishing: 85]  [Article Influence: 4.7]  [Reference Citation Analysis (0)]
11.  Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383-393.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3042]  [Cited by in F6Publishing: 3220]  [Article Influence: 161.0]  [Reference Citation Analysis (0)]
12.  Yusuf S. Two decades of progress in preventing vascular disease. Lancet. 2002;360:2-3.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 253]  [Cited by in F6Publishing: 271]  [Article Influence: 12.9]  [Reference Citation Analysis (0)]
13.  Stratton IM, Cull CA, Adler AI, Matthews DR, Neil HA, Holman RR. Additive effects of glycaemia and blood pressure exposure on risk of complications in type 2 diabetes: a prospective observational study (UKPDS 75). Diabetologia. 2006;49:1761-1769.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 248]  [Cited by in F6Publishing: 212]  [Article Influence: 12.5]  [Reference Citation Analysis (0)]
14.  Gaede P, Pedersen O. Intensive integrated therapy of type 2 diabetes: implications for long-term prognosis. Diabetes. 2004;53 Suppl 3:S39-S47.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 76]  [Cited by in F6Publishing: 78]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
15.  Vaag AA. Glycemic control and prevention of microvascular and macrovascular disease in the Steno 2 study. Endocr Pract. 2006;12 Suppl 1:89-92.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 32]  [Cited by in F6Publishing: 32]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
16.  Nicholls SJ, Tuzcu EM, Kalidindi S, Wolski K, Moon KW, Sipahi I, Schoenhagen P, Nissen SE. Effect of diabetes on progression of coronary atherosclerosis and arterial remodeling: a pooled analysis of 5 intravascular ultrasound trials. J Am Coll Cardiol. 2008;52:255-262.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 228]  [Cited by in F6Publishing: 202]  [Article Influence: 13.5]  [Reference Citation Analysis (0)]
17.  American Diabetes Association. Standards of medical care in diabetes--2014. Diabetes Care. 2014;37 Suppl 1:S14-S80.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2830]  [Cited by in F6Publishing: 3235]  [Article Influence: 359.4]  [Reference Citation Analysis (0)]
18.  Navarro-Vidal B, Banegas JR, León-Muñoz LM, Rodríguez-Artalejo F, Graciani A. Achievement of cardiometabolic goals among diabetic patients in Spain. A nationwide population-based study. PLoS One. 2013;8:e61549.  [PubMed]  [DOI]  [Cited in This Article: ]
19.  Jouven X, Lemaître RN, Rea TD, Sotoodehnia N, Empana JP, Siscovick DS. Diabetes, glucose level, and risk of sudden cardiac death. Eur Heart J. 2005;26:2142-2147.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 166]  [Cited by in F6Publishing: 178]  [Article Influence: 9.9]  [Reference Citation Analysis (0)]
20.  Cosson E, Nguyen MT, Chanu B, Banu I, Chiheb S, Balta C, Takbou K, Valensi P. Cardiovascular risk prediction is improved by adding asymptomatic coronary status to routine risk assessment in type 2 diabetic patients. Diabetes Care. 2011;34:2101-2107.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 35]  [Cited by in F6Publishing: 35]  [Article Influence: 2.9]  [Reference Citation Analysis (0)]
21.  Bax JJ, Young LH, Frye RL, Bonow RO, Steinberg HO, Barrett EJ. Screening for coronary artery disease in patients with diabetes. Diabetes Care. 2007;30:2729-2736.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 184]  [Cited by in F6Publishing: 189]  [Article Influence: 11.8]  [Reference Citation Analysis (0)]
22.  Nicholls SJ, Tuzcu EM, Crowe T, Sipahi I, Schoenhagen P, Kapadia S, Hazen SL, Wun CC, Norton M, Ntanios F. Relationship between cardiovascular risk factors and atherosclerotic disease burden measured by intravascular ultrasound. J Am Coll Cardiol. 2006;47:1967-1975.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 120]  [Cited by in F6Publishing: 104]  [Article Influence: 6.1]  [Reference Citation Analysis (0)]
23.  Gorter PM, Visseren FL, Algra A, van der Graaf Y; SMART Study Group. The impact of site and extent of clinically evident cardiovascular disease and atherosclerotic burden on new cardiovascular events in patients with Type 2 diabetes. The SMART study. Diabet Med. 2007;24:1352-1360.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 16]  [Cited by in F6Publishing: 17]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
24.  Golomb BA, Dang TT, Criqui MH. Peripheral arterial disease: morbidity and mortality implications. Circulation. 2006;114:688-699.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 355]  [Cited by in F6Publishing: 369]  [Article Influence: 21.7]  [Reference Citation Analysis (0)]
25.  Criqui MH, Langer RD, Fronek A, Feigelson HS, Klauber MR, McCann TJ, Browner D. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med. 1992;326:381-386.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1889]  [Cited by in F6Publishing: 1937]  [Article Influence: 62.5]  [Reference Citation Analysis (0)]
26.  Ahn SS, Nam HS, Heo JH, Kim YD, Lee SK, Han KH, Choi BW, Kim EY. Ischemic stroke: measurement of intracranial artery calcifications can improve prediction of asymptomatic coronary artery disease. Radiology. 2013;268:842-849.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 18]  [Cited by in F6Publishing: 18]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
27.  Calvet D, Touzé E, Varenne O, Sablayrolles JL, Weber S, Mas JL. Prevalence of asymptomatic coronary artery disease in ischemic stroke patients: the PRECORIS study. Circulation. 2010;121:1623-1629.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 110]  [Cited by in F6Publishing: 114]  [Article Influence: 8.8]  [Reference Citation Analysis (0)]
28.  Amarenco P, Lavallée PC, Labreuche J, Ducrocq G, Juliard JM, Feldman L, Cabrejo L, Meseguer E, Guidoux C, Adraï V. Prevalence of coronary atherosclerosis in patients with cerebral infarction. Stroke. 2011;42:22-29.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 111]  [Cited by in F6Publishing: 118]  [Article Influence: 9.1]  [Reference Citation Analysis (0)]
29.  Mann JF, Gerstein HC, Pogue J, Bosch J, Yusuf S. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med. 2001;134:629-636.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 977]  [Cited by in F6Publishing: 1034]  [Article Influence: 47.0]  [Reference Citation Analysis (0)]
30.  Yuyun MF, Khaw KT, Luben R, Welch A, Bingham S, Day NE, Wareham NJ. A prospective study of microalbuminuria and incident coronary heart disease and its prognostic significance in a British population: the EPIC-Norfolk study. Am J Epidemiol. 2004;159:284-293.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 75]  [Cited by in F6Publishing: 79]  [Article Influence: 4.2]  [Reference Citation Analysis (0)]
31.  Gianrossi R, Detrano R, Mulvihill D, Lehmann K, Dubach P, Colombo A, McArthur D, Froelicher V. Exercise-induced ST depression in the diagnosis of coronary artery disease. A meta-analysis. Circulation. 1989;80:87-98.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 524]  [Cited by in F6Publishing: 545]  [Article Influence: 16.0]  [Reference Citation Analysis (0)]
32.  Lee DP, Fearon WF, Froelicher VF. Clinical utility of the exercise ECG in patients with diabetes and chest pain. Chest. 2001;119:1576-1581.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 38]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
33.  Vanzetto G, Halimi S, Hammoud T, Fagret D, Benhamou PY, Cordonnier D, Denis B, Machecourt J. Prediction of cardiovascular events in clinically selected high-risk NIDDM patients. Prognostic value of exercise stress test and thallium-201 single-photon emission computed tomography. Diabetes Care. 1999;22:19-26.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 90]  [Cited by in F6Publishing: 96]  [Article Influence: 4.0]  [Reference Citation Analysis (0)]
34.  Kodama S, Saito K, Tanaka S, Maki M, Yachi Y, Asumi M, Sugawara A, Totsuka K, Shimano H, Ohashi Y. Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: a meta-analysis. JAMA. 2009;301:2024-2035.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1966]  [Cited by in F6Publishing: 1964]  [Article Influence: 140.3]  [Reference Citation Analysis (0)]
35.  Lyerly GW, Sui X, Church TS, Lavie CJ, Hand GA, Blair SN. Maximal exercise electrocardiography responses and coronary heart disease mortality among men with diabetes mellitus. Circulation. 2008;117:2734-2742.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 29]  [Cited by in F6Publishing: 31]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
36.  Bradley RF, Schonfeld A. Diminished pain in diabetic patients with acute myocardial infarction. Geriatrics. 1962;17:322-326.  [PubMed]  [DOI]  [Cited in This Article: ]
37.  Wackers FJ, Young LH, Inzucchi SE, Chyun DA, Davey JA, Barrett EJ, Taillefer R, Wittlin SD, Heller GV, Filipchuk N. Detection of silent myocardial ischemia in asymptomatic diabetic subjects: the DIAD study. Diabetes Care. 2004;27:1954-1961.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 578]  [Cited by in F6Publishing: 606]  [Article Influence: 31.9]  [Reference Citation Analysis (0)]
38.  Murray DP, O’Brien T, Mulrooney R, O’Sullivan DJ. Autonomic dysfunction and silent myocardial ischaemia on exercise testing in diabetes mellitus. Diabet Med. 1990;7:580-584.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 42]  [Cited by in F6Publishing: 44]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
39.  O’Sullivan JJ, Conroy RM, MacDonald K, McKenna TJ, Maurer BJ. Silent ischaemia in diabetic men with autonomic neuropathy. Br Heart J. 1991;66:313-315.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 44]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
40.  Cheung N, Wang JJ, Klein R, Couper DJ, Sharrett AR, Wong TY. Diabetic retinopathy and the risk of coronary heart disease: the Atherosclerosis Risk in Communities Study. Diabetes Care. 2007;30:1742-1746.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 176]  [Cited by in F6Publishing: 182]  [Article Influence: 11.4]  [Reference Citation Analysis (0)]
41.  Targher G, Bertolini L, Zenari L, Lippi G, Pichiri I, Zoppini G, Muggeo M, Arcaro G. Diabetic retinopathy is associated with an increased incidence of cardiovascular events in Type 2 diabetic patients. Diabet Med. 2008;25:45-50.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 64]  [Cited by in F6Publishing: 66]  [Article Influence: 4.4]  [Reference Citation Analysis (0)]
42.  Kawasaki S, Misawa H, Tamura Y, Kondo Y, Satoh S, Hasegawa O, Kato S, Terauchi Y. Relationship between coronary artery disease and retinopathy in patients with type 2 diabetes mellitus. Intern Med. 2013;52:2483-2487.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Cited by in F6Publishing: 4]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
43.  Greenland P, Alpert JS, Beller GA, Benjamin EJ, Budoff MJ, Fayad ZA, Foster E, Hlatky MA, Hodgson JM, Kushner FG. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2010;56:e50-103.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 935]  [Cited by in F6Publishing: 1017]  [Article Influence: 84.8]  [Reference Citation Analysis (0)]
44.  Valensi P, Pariès J, Brulport-Cerisier V, Torremocha F, Sachs RN, Vanzetto G, Cosson E, Lormeau B, Attali JR, Maréchaud R. Predictive value of silent myocardial ischemia for cardiac events in diabetic patients: influence of age in a French multicenter study. Diabetes Care. 2005;28:2722-2727.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 83]  [Cited by in F6Publishing: 84]  [Article Influence: 4.7]  [Reference Citation Analysis (0)]
45.  Young LH, Wackers FJ, Chyun DA, Davey JA, Barrett EJ, Taillefer R, Heller GV, Iskandrian AE, Wittlin SD, Filipchuk N. Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes: the DIAD study: a randomized controlled trial. JAMA. 2009;301:1547-1555.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 609]  [Cited by in F6Publishing: 619]  [Article Influence: 44.2]  [Reference Citation Analysis (0)]
46.  Nasir K, Budoff MJ, Post WS, Fishman EK, Mahesh M, Lima JA, Blumenthal RS. Electron beam CT versus helical CT scans for assessing coronary calcification: current utility and future directions. Am Heart J. 2003;146:969-977.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 64]  [Cited by in F6Publishing: 67]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
47.  Berman DS, Wong ND, Gransar H, Miranda-Peats R, Dahlbeck J, Hayes SW, Friedman JD, Kang X, Polk D, Hachamovitch R. Relationship between stress-induced myocardial ischemia and atherosclerosis measured by coronary calcium tomography. J Am Coll Cardiol. 2004;44:923-930.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 315]  [Cited by in F6Publishing: 338]  [Article Influence: 17.8]  [Reference Citation Analysis (0)]
48.  He ZX, Hedrick TD, Pratt CM, Verani MS, Aquino V, Roberts R, Mahmarian JJ. Severity of coronary artery calcification by electron beam computed tomography predicts silent myocardial ischemia. Circulation. 2000;101:244-251.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 245]  [Cited by in F6Publishing: 266]  [Article Influence: 11.6]  [Reference Citation Analysis (0)]
49.  Anand DV, Lim E, Hopkins D, Corder R, Shaw LJ, Sharp P, Lipkin D, Lahiri A. Risk stratification in uncomplicated type 2 diabetes: prospective evaluation of the combined use of coronary artery calcium imaging and selective myocardial perfusion scintigraphy. Eur Heart J. 2006;27:713-721.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 278]  [Cited by in F6Publishing: 297]  [Article Influence: 17.5]  [Reference Citation Analysis (0)]
50.  Raggi P, Shaw LJ, Berman DS, Callister TQ. Prognostic value of coronary artery calcium screening in subjects with and without diabetes. J Am Coll Cardiol. 2004;43:1663-1669.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 431]  [Cited by in F6Publishing: 355]  [Article Influence: 18.7]  [Reference Citation Analysis (0)]
51.  Wackers FJ, Chyun DA, Young LH, Heller GV, Iskandrian AE, Davey JA, Barrett EJ, Taillefer R, Wittlin SD, Filipchuk N. Resolution of asymptomatic myocardial ischemia in patients with type 2 diabetes in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study. Diabetes Care. 2007;30:2892-2898.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 102]  [Cited by in F6Publishing: 102]  [Article Influence: 6.4]  [Reference Citation Analysis (0)]
52.  Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ, Knudtson M, Dada M, Casperson P, Harris CL. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356:1503-1516.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3259]  [Cited by in F6Publishing: 3344]  [Article Influence: 209.0]  [Reference Citation Analysis (0)]
53.  BARI 2D Study Group; Frye RL, August P, Brooks MM, Hardison RM, Kelsey SF, MacGregor JM, Orchard TJ, Chaitman BR, Genuth SM, Goldberg SH, Hlatky MA, Jones TL, Molitch ME, Nesto RW, Sako EY, Sobel BE. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med. 2009;360:2503-2515.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1392]  [Cited by in F6Publishing: 1443]  [Article Influence: 103.1]  [Reference Citation Analysis (0)]