Screening and Diagnosis of Cardiovascular Disease

It has long been observed that patients with diabetes are at increased risk for macrovascular complications, particularly coronary heart disease and myocardial infarction.[1] Cardiovascular disease (CVD) remains the major cause of death in patients with diabetes. The incidence and prevalence of CVD in patients with diabetes continues to increase. Additionally, people with diabetes experience higher fatality rates, as compared with people who do not have diabetes.[2] In fact, epidemiological studies have shown a 2- to 4-fold increase in coronary artery disease (CAD) among people with diabetes.[1]

Approximately 65% of deaths related to diabetes involve stroke or heart disease.[3] Although the link between diabetes and CVD is well established and widely recognized, the underlying pathophysiology of hyperglycemia’s direct influence on cardiovascular risk is less clear.[1] The main goal of this article is to explore the underlying risk factors of diabetes pertaining to an increased risk of CVD. Emphasis will be placed on the importance of identifying risk factors and early screening techniques, which allows for early detection and initiation of therapeutic advances, hopefully resulting in decreased rates for morbidity and mortality.

Risk factors for CVD

Hyperglycemia, hypertension, and obesity are several common characteristics of type 2 diabetes and are all associated with an increased risk of CVD.[4] Table 1 identifies the major risk factors for CVD and, generally speaking, these risk factors contribute to atherosclerosis, which is the leading cause of CVD. In addition, patients with diabetes should have a complete assessment of other risk factors for CVD, especially the association of various metabolic and hemodynamic abnormalities now referred to as the metabolic syndrome, formerly known as “syndrome X.”[4] The risk for CAD and stroke is increased 3-fold in patients with this syndrome.[5] The definition of metabolic syndrome according to the National Cholesterol Education Program's Adult Treatment Panel III (ATP III) guidelines is indicated in Table 2.

Table 1. Risk factors for CVD[6]

Cigarette smoking

Hypertension (BP >140/90 mm Hg or on antihypertensive medication)

Low HDL cholesterol (<40mg/dL)*

Family history of premature CAD (CAD in male first-degree relative <55 years; CAD in female first-degree relative <65 years) OR Diagnosed with diabetes†

Age men >45 years women > 55 years

*HDL cholesterol ≥ mg/dL is considered a “negative” risk factor; its presence removes one risk factor from the total count...

†In ATP III, diabetes is regarded as a CAD risk equivalent.

Table 2. ATP III definition of metabolic syndrome[6]

Abdominal obesity (waist circumference) >102 cm (>40 in) in men >88 cm (>35 in) in women

Hypertension BP >130/85 mm Hg

High triglycerides >150 mg/dL

Low HDL cholesterol <40 mg/dL in men <50 mg/dL in women

Fasting plasma glucose >110 mg/dL

Metabolic syndrome = Three or more criteria

Hypercholesterolemia

Atherosclerosis has been profoundly implicated in the development of CVD, and the main contributor to plaque formation is cholesterol. Blood cholesterol levels should be determined by a screening test called lipid analysis (or lipid profile), which measures the levels of low-density lipoproteins (LDL), high-density lipoproteins (HDL), and triglycerides (TG), as well as the total blood cholesterol levels. If LDL is too high or HDL is too low, a medically derived treatment program should be instituted to achieve goal cholesterol levels, which are determined either through the presence of CVD risk factors or in the case of diabetes (Table 3), a preset goal proven to decrease CVD complications. Current accepted classifications of blood cholesterol levels are indicated in Table 4. The ADA recommendations for lipid assessment are indicated in Table 5.

Table 3. ATP III LDL modifications based on risk factor assessment[6]

Risk Category	LDL Goal (mg/dL)
CAD and CAD risk equivalents (diabetes)	<100 (optional goal <70)*
Multiple (2+) risk factors	<130 or (optional goal <100)†
Zero to one risk factor	<160

*LDL goal of <70 mg/dL is a reasonable therapeutic option in patients at very high risk for CVD (diabetes plus CVD). Recommendation based on new clinical trial evidence.[7]

† LDL goal of <100 mg/dL is a reasonable therapeutic option in patients at moderately high risk for CVD (2+ risk factors and 10-year risk 10% to 20%). Recommendation based on new clinical trial evidence.[7]

Table 4. ATP III classification of LDL, Total, and HDL cholesterol (mg/dL)[6,7]

LDL cholesterol <70* <100 100-129 130-159 160-189 ≥190	Therapeutic option in very high-risk populations Optimal Near optimal/above optimal Borderline high High Very high
Total Cholesterol <200 200-239 ≥240	Desirable Borderline high High
HDL cholesterol <40 ≥60	Low High

*LDL goal of <70 mg/dL is a reasonable therapeutic option in patients at very high risk for CVD (diabetes plus CVD). Recommendation based on new clinical trial evidence.[7]

Table 5. ADA recommendations on lipid assessment [8,9]

Population	Initial	Follow-up
Adults (Type 2 diabetes) Adults low-risk lipid values          --LDL--  <100 mg/dL          --HDL-- >40 mg/dL (men) >50 mg/dL(women)          --TG--  <150 mg/dL	At diagnosis	Annual testing, more often if needed to achieve goals Repeat lipid assessments every 2 years
Children > 2 years Type 1 diabetes Type 2 diabetes	Initial assessment after diagnosis and when glucose control has been established Begin prior to puberty, if positive family history of CVD and at puberty, if family history is known and is negative Begin at diagnosis, regardless of pubertal status	If lipid values are considered low risk, repeat lipid profile every 2-5 years based on CVD risk status

Blood cholesterol levels for type 1 and type 2 diabetes differ. Patients with well-controlled type 1 diabetes have LDL levels comparable to those of the general population; their HDL cholesterol levels are normal or higher than those of the general population.[10,11] In contrast, patients with type 2 diabetes generally have elevated LDL and TG levels; their HDL levels are lower.[12] Type 2 patients will generally comprise the majority of patients undergoing pharmacologic treatment for high cholesterol. However, lipoproteins in type 1 diabetes have an adverse effect on diabetic nephropathy and retinopathy and should not be overlooked.[13]

Hyperglycemia

The causal relationship between hyperglycemia and microvascular disease, as well as the delay or prevention of microvascular complications by improved glycemic control, is well established. However, the relationship between hyperglycemia and macrovascular disease is less clear. Patients with Type 1 diabetes experience hyperglycemia related to insulin deficiency rather than insulin resistance, and the risk of cardiovascular mortality increases 3- to 6-fold, as compared with the general population.[14] Patients who have a deficiency in insulin sensitivity have a 5-fold increase in risk; and those with both insulin resistance and decreased insulin sensitivity have a 20-fold increase in CVD risk.[12] Growing evidence suggests hyperglycemia even in the nondiabetic range could be associated with increased risk of CVD.[1] Currently, there is a great deal of interest in determining hyperglycemia’s direct effect on CVD. Several studies have indicated that decreasing blood glucose levels correlate with decreased CVD risk; however, not all are statistically significant. The UKPDS determined that achieving a median A1C of 7% compared with conventional treatment A1C of 7.9% over a median of 10 years resulted in a 16% reduction in myocardial infarction, but did not reach statistical significance (P = 0.052).[15] It has also been postulated that postprandial glycemia may be a stronger indicator of increased CVD risk.[16] Results from the Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) study suggest fasting glucose levels have less impact on prediction of cardiovascular risk compared with the 2-hour glucose levels.[17] A more recent meta-analysis showed that a 2-hour glucose level of 140 mg/dL was associated with a 58% increase risk of CVD.[18] The glucose level at the time of myocardial infarction if exceeding 6 to 8 mmol/L has been demonstrated to correlate with a 4-fold increase in mortality.[19] Based on all of these findings, it is imperative that screening for glucose control be performed regularly. Table 6 indicates the current goals for glucose control. The ADA recommends performing A1C tests at least twice a year in patients achieving targets and quarterly in patients whose therapy has changed and in patients who are not achieving glycemic goals.[9]

Table 6. Blood glucose goals [9]

	ADA	AACE	AADE	IDF/WHO
A1C	<7.0%*	≤6.5%	<7.0%	<7.0%
Fasting/Preprandial (plasma equivalent)	90-130 mg/dL	<110 mg/dL	90-130 mg/dL	90-130 mg/dL
Postprandial	<180 mg/dL	<140 mg/dL	<180 mg/dL	<160 mg/dL

*More stringent goals (A1C<6%) may further reduce complications at the cost of increased risk of hypoglycemia.

Hypertension

Hypertension (BP >140/90 mm Hg) is present in the majority of patients with diabetes, depending on their age, ethnicity and obesity. Hypertension is a major risk factor for the development of CVD, retinopathy and nephropathy.[9] In type 1 patients, hypertension is often the result of underlying nephropathy, whereas in type 2 diabetes, it is likely to be part of the metabolic syndrome associated with increased risk of CVD.[20] According to epidemiologic evidence, blood pressure >115/75 mmHG increases a diabetes patient's cardiovascular event rate and mortality risk.[9] Post hoc analysis of the UKPDS data determined that every 10 mm Hg drop in systolic blood pressure was associated with a significant 11% reduction in myocardial infarction (P<0.0001).[21] Moreover, patients assigned to the lowest blood pressure goal in UKPDS experienced the lowest number of cardiovascular events and cardiovascular mortality. Based on these and other findings, the ADA recommends that adults with diabetes achieve a blood pressure goal of <130/80 mmHg.[9] For pregnant women with diabetes and chronic hypertension, the goal is 110-129/65-79.[9] 

In an effort to diagnose hypertension early, the ADA also recommends routine blood pressure screenings to occur at each routine office visit. Patients found to have blood pressure ≥130 mm Hg systolic or ≥80 mm Hg diastolic should have blood pressure confirmed on a separate day.[9]

Conclusion

Compared with nondiabetic individuals, patients with diabetes possess an increased risk not only for sustaining cardiovascular events but also for poorer outcomes associated with CVD, marked by significantly increased mortality. Despite the need to engage in aggressive cardiovascular risk management in patients with diabetes, current practice falls short of achieving treatment targets in most patients. Effective and timely screening methods could help identify patients at risk of developing CVD as well as initiate early therapy for patients who have been identified as high risk. Several screening methods are abundantly available and inexpensive; however, the results can be profound. An overview of the screening assessments recommended by the ADA is summarized in Table 7.

Table 7. Summary of screening recommendations by the ADA [8,9]

Type of Assessment	Population	Initial	Follow-up
Lipid Assessment	Adults (type 2 diabetes) Adults low-risk lipid values --LDL-- <100 mg/dL   --HDL-- >40 mg/dL (men) >50 mg/dL (women)   --TG--  <150 mg/dL Children >2 years Type 1 diabetes Type 2 diabetes	At diagnosis                     Initial assessment after diagnosis and when glucose control has been established     Begin prior to puberty, if positive family history of CVD and at puberty, if family history is known and is negative   Begin at diagnosis, regardless of pubertal status	Annual testing, more often if needed to achieve goals Repeat lipid assessments every 2 years If lipid values are considered low risk, repeat lipid profile every 2-5 years based on CVD risk status
Blood Pressure Assessment	Adults and children	At diagnosis	Each routine diabetes visit
Glucose Assessment	Adults and children: Achieving treatment goals Therapy changed or not meeting glycemic goals	At diagnosis	Perform A1C at least twice/year   Perform A1C quarterly

References

1. Lteif AA, Mather KJ, Clark CM. Diabetes and heart disease. An evidence-driven guide to risk factors management in diabetes. Cardiol in Rev. 2003;11:262-274.
2. Miettinen H, Lehto S, Salomma V, et al. Impact of diabetes on mortality after the first myocardial infarction. The FINMONICA Myocardial Infarction Register Study Group. Diabetes Care. 1998;21:69-75.
3. American Diabetes Association. Diabetes: Heart Disease and Stroke. Available at: http://www.diabetes.org/diabetes-heart-disease-stroke.jsp. Accessed June, 2006.
4. Nesto RW. Correlation between cardiovascular disease and diabetes mellitus:current concepts. Am J Med. 2004;116:11S-22S.
5. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care. 2001;24:683-689.
6. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.
7. Grundy SM, Cleeman JI, Merz CNB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239.
8. American Diabetes Association. Management of dyslipidemia in children and adolescents with diabetes. Diabetes Care. 26:2194-2197.
9. American Diabetes Association. Standards of medical care in diabetes-2006. Diabetes Care. 2006;29(suppl 1):S4-S42.
10. Winocour PH, Durrington PN, Ishola M, Anderson DC.Lipoprotein abnormalities in insulin-dependent diabetes mellitus. Lancet. 1986;1:1176-1178.
11. Colhoun HM, Rubens MB, Underwood SR, Fuller JH. The effect of type 1 diabetes mellitus on the gender difference in coronary artery calcification. J Am Coll Cardiol. 2000;36:2160-2167.
12. Bloomgarden ZT. Macrovascular complications of diabetes. Available at: http://www.medscape.com/viewarticle/413043?src=search.
13. Chaturvedi N, Fuller JH, Taskinen MR. Differing associations of lipid and lipoprotein disturbances with the macrovascular and microvascular complications of type 1 diabetes. Diabetes Care. 2001;24:2071-2077.
14. Laing SP, Swerdlow AJ, Slater SD, et al. The British diabetic association cohort study. I: all-cause mortality in patients with insulin-treated diabetes mellitus. Diabetes Med. 1999;16:459-465.
15. UKPDS Group. Intensive blood-glucose control with sulphonylureas and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853.
16. Barzilay JI, Spiekerman CF, Wahl PW, et al. Cardiovascular disease in older adults with glucose disorders: comparison of American Diabetes Association criteria for diabetes mellitus with WHO criteria. Lancet. 1999;354:622-625.
17. European Diabetes Epidemiology Group. Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe: glucose tolerance and mortality: comparison of WHO and ADA diagnostic criteria: the DECODE study group. Lancet. 1999;354:617-621.
18. Coutinho M, Gerstein HC, Wang Y, Yusuf S. The relationship between glucose and incident cardiovascular mortality in the Hoorn population : the Hoorn Study. Diabetologia. 1999;42:926-931.
19. Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systemic overview. Lancet. 2000;355:773-778.
20. Bakris GL. The importance of blood pressure control in the patient with diabetes. Am J Med. 2004;116:30S-38S.
21. Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with macrovascular and microvascular complications in type 2 diabetes (UKPDS 36). BMJ. 2000;321:412-419.