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ABSTRACT

The link between type 2 diabetes and cardiovas-cular disease has been amply demonstrated in numerous studies. People with diabetes have a higher risk for cardiovascular events and higher mortality rates from cardiovascular causes than people who do not have diabetes. However, dia-betes develops over time, preceded by several years of gradually worsening insulin resistance. Ideally, persons at risk for diabetes should be identified at this time, when strategies to prevent type 2 diabetes and its cardiovascular complica-tions are most likely to be successful. This article reviews the evidence linking diabetes to cardio-vascular disease, discusses the role of insulin resistance and hyperinsulinemia in the progres-sion from normoglycemia to diabetes, and explores the association of insulin resistance, dia-betes, and cardiovascular risk. It also addresses why normalization of glucose, blood pressure, and lipid levels is crucial in the prevention of or delaying the progression to diabetes and cardio-vascular disease.

(Adv Stud Med.2006;6(10A):S921-S925)

H

istorically, diabetes has been consid-ered a blood glucose disease with hyperglycemia as its cardinal symp-tom. However, considerable evidence indicates that diabetes is also a car-diovascular disease in which hyperglycemia is a symp-tom, but not the underlying issue. Because both diabetes and cardiovascular disease develop over the course of years, nurse practitioners, physician assis-tants, and other healthcare professionals involved in primary care are in an excellent position to detect these diseases in their early stages and prevent or delay dis-ease progression.

IMPACT OFATHEROSCLEROSIS ANDDIABETES

The relationship between diabetes and cardiovas-cular disease, particardiovas-cularly atherosclerosis, is amply demonstrated by recent mortality and morbidity sta-tistics. Approximately 80% of all mortality in persons with diabetes is due to atherosclerosis, with coronary atherosclerosis accounting for 75% of the total and cerebral or peripheral vascular disease accounting for the remainder.1 Atherosclerosis also accounts for over 75% of all hospitalizations for diabetic complications, w h e reas card i ovascular complications account for approximately 50% of the costs of inpatient diabetes care.1In fact, the link between atherosclerosis and dia-betes is so strong that the National Cholestero l Education Program (NCEP) designated diabetes as a “coronary artery disease risk equivalent,” meaning that a person with diabetes and a person who has already had a heart attack have the same risk for death from a cardiovascular cause.2

The influence of diabetes on risk for cardiovascular disease had been demonstrated in many studies prior to the NCEP report, including the East-West Study,

THE LINK BETWEEN TYPE 2 DIABETES

AND CARDIOVASCULAR DISEASE

*

Thomas G. Bartol, NP, CDE†

*Based on a presentation at a symposium held at the 2006 National Conference of the American Academy of Nurse Practitioners, Grapevine, Texas, on June 24, 2006.

Family Nurse Practitioner, Richmond Area Health Center, Richmond, Maine; Adjunct Faculty, Husson College School of Nursing, Bangor, Maine.

Address correspondence to: Thomas G. Bartol, NP, CDE, 310 Meadow Hill Road, Manchester, ME 04351. E-mail: bartol@gwi.net.

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which examined the incidence of fatal and nonfatal myocardial infarction (MI) over 7 years in 1059 patients with diabetes and 1373 nondiabetic patients.3 The study found that the chance of having an MI over 7 years was 1 in 30 among patients without diabetes and no prior history of MI, but 1 in 5 with a previous MI. By comparison, the chance was slightly higher than 1 in 5 among patients with diabetes but no prior MI, and 1 in 2, or 50%, in those with diabetes and a previous MI. Moreover, the risk was slightly higher than 50% in women with diabetes who had previous-ly had an MI.

Aside from increasing the risk for a card i ova s c u l a r e vent, diabetes has a considerable impact on ove r a l l health and surv i val. Largely because of its chronic com-plications, including athero s c l e rosis, diabetes is the sev-enth leading cause of death in the United States, and accounts for more deaths annually than breast cancer or AIDS.1Diabetes also decreases life expectancy by 15 ye a r s .1 Mo re ove r, Census Bu reau data indicate that Caucasian children born in the year 2000 have a 1 in 3 chance of developing diabetes in adulthood, where a s c h i l d ren in high-risk ethnic gro u p s — A f r i c a n American, Na t i ve American, Asian American, Pa c i f i c Is l a n d e r, and Hispanic American—have a 50% risk.4

Against this backdrop, clinicians must keep dia-betes risk in mind in all patients, especially those at risk for cardiovascular disease or those with a history of a cardiac event. These patients require further evalua-tion and then appropriate intervenevalua-tion or referral. PATHOPHYSIOLOGY OFTYPE2 DIABETES

The pathophysiology of type 2 diabetes involves 3 major underlying defects that help to explain how pre-diabetes pro g resses to pre-diabetes and how pre-diabetes increases the risk for cardiovascular disease: insulin resistance, increased hepatic glucose output, and decreased pancreatic insulin secretion.

INSULINRESISTANCE

Insulin resistance, which is present in approximate-ly 92% of people with type 2 diabetes, is a defect in insulin utilization that precedes the manifestations of type 2 diabetes, often by 5 to 10 years or more.5Insulin resistance occurs primarily in fat and muscle cells and, to a lesser extent, in liver cells. The normal glucose-lowering effect of insulin on these cells is blunted by poor insulin utilization, resulting in a significant

increase in insulin-mediated glucose uptake and mild-ly elevated glucose levels. The pancreas, which “works” at approximately 5% of its capacity to maintain glu-cose homeostasis in normal individuals, responds to the rise in blood glucose by providing incre a s e d insulin, resulting in hyperinsulinemia and normo-glycemia. Over time, the insulin resistance progresses and the pancreas produces increasing amounts of insulin to maintain normoglycemia.

As long as the pancreas can produce enough insulin, blood glucose will remain at normal levels. In fact, blood glucose levels in people with hyperinsu-linemia are normal because the pancreas is working overtime to maintain homeostasis. However, when the p a n c reas can no longer maintain normoglyc e m i a , blood glucose levels start to rise, resulting in a relative insulin deficiency and the prediabetic state. Insulin production begins to drop off and blood glucose levels increase, eventually leading to diabetes. When most people are first diagnosed with type 2 diabetes, they are producing more than the average amount of insulin, but they have a relative insulin deficiency because the amount of insulin produced is no longer adequate to maintain normoglycemia.

Changes in insulin and glucose levels over time, from normoglycemia through insulin resistance and impaired glucose tolerance to diabetes, are shown in Figure 1. In years past, most cases of diabetes were diagnosed when glucose levels had been elevated for several years. Although more people are now identified

F i g u re 1. Glucose and Insulin Changes in the P ro g ression from Normoglycemia to Type 2 Diabetes

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at earlier stages along the spectrum, the goal is to inter-vene with preventive measures when insulin levels begin to rise but glucose levels remain normal.

Hyperinsulinemia stimulates fat storage, increases appetite, increases sodium reabsorption in the kidneys, decreases fibrinolysis, and is associated with vascular inflammation and endothelial dysfunction. Moreover, a study investigating hyperinsulinemia in men found that a high fasting insulin level was an independent predictor of ischemic heart disease, regardless of lipid levels, smoking, and hypertension.6Clinical markers of hyperinsulinemia include high triglyceride and low high-density lipoprotein cholesterol levels, elevated blood pressure, and central obesity. These markers can be used to identify which patients to target for early treatment of insulin resistance and prevention of type 2 diabetes.

INCREASEDHEPATICGLUCOSEOUTPUT

A second defect underlying type 2 diabetes is increased hepatic glucose output, which results in increased glycogen production and gluconeogenesis, and fasting hyperglycemia due to hepatic insulin resis-tance. In this scenario, the liver produces extra glucose, typically in the fasting state. This explains why some people with a blood glucose level of 160 mg/dL after supper will have a fasting glucose level of 220 mg/dL the next morning.

DECREASEDPANCREATICINSULINSECRETION

The third defect underlying type 2 diabetes is decreased secretion of insulin from the pancreas. Prior to the onset of diabetes, the pancreas increas-es insulin output to maintain normoglyc e m i a . Eventually, the pancreas can no longer continue producing such high amounts of insulin and, as insulin levels begin to decrease, glucose levels start to rise. The absolute insulin level is still above nor-mal, but there is a relative insulin deficiency. As glu-cose levels rise, they impair β-cell production of insulin, resulting in further insulin deficiency and h y p e r g l yc e m i a .

INSULINRESISTANCE, DIABETES, ANDCARDIOVASCULARRISK

In addition to being a coronary artery disease risk equivalent, diabetes is associated with several well-recognized risk factors for cardiovascular

dis-ease, including lipid abnormalities and hypertension. However, insulin resistance is also associated with a number of risk factors for card i ovascular disease (Table), including the highly atherogenic form of small, dense, low-density lipoprotein (LDL) choles-terol known as Pattern B.7Although elevated levels of LDL cholesterol in any patient increase the risk for

Figure 2. Association of Insulin Resistance,Type 2 Diabetes, and Card i ovascular Disease

HDL-C = high-density lipoprotein cholesterol; PAI-1 = plasminogen activator inhibitor-1; S, D LDL = small, dense low-density lipoprotein; TG = triglycerides.

Reprinted with permission from Hsueh and Law. Am J Cardiol.2003;92:3J-9J.9

Ta b l e. C a rd i ovascular Risk Factors Associated with Insulin Resistance

HDL = high-density lipoprotein; LDL = low-density lipoprotein. Data from McFarlane et al. J Clin Endocrinol Metab. 2001;86:713-718.7

• Elevated blood pressure • Hyperinsulinemia

• Low HDL cholesterol levels • Elevated triglyceride levels

• Small, dense LDL cholesterol particles • Increased apolipoprotein B levels • Endothelial dysfunction

• Increased fibrinogen levels

• Increased levels of plasminogen activator inhibitor-1 • Increased levels of C-reactive protein and other

inflammatory markers • Increased blood viscosity • Microalbuminuria

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atherosclerosis, Pattern B is particularly atherogenic because of its small, dense LDL particles containing large amounts of triglyceride apolipoprotein B (apo B), being more easily oxidized, and having decreased clearance due to a decreased affinity for hepatic LDL-receptors.8 By contrast, LDL cholesterol with larger, m o re buoyant LDL particles containing smaller amounts of apo B is less atherogenic.

The association of insulin resistance, type 2 diabetes, and card i ovascular disease is illustrated in Fi g u re 2.9 Insulin resistance is present well before the manifesta-tions of type 2 diabetes appear. Insulin resistance and its resultant hyperinsulinemia are the first steps of the p rocess, and they continue to be present throughout the p ro g ression from normoglycemia to type 2 diabetes.

A timeline of the natural history of the pro g re s s i o n of prediabetes to type 2 diabetes is shown in Fi g u re 3 .1 0 - 1 2 Insulin resistance and prediabetes may occur 5 to 10 years or more before type 2 diabetes is diag-nosed. The onset of microvascular complications can occur several years before the diagnosis of type 2 dia-betes. Im p o rt a n t l y, the onset of macrovascular com-plications may occur even earlier. Thus, it is i m p o rtant to assess patients for diabetes and its pre-cursors early in order to try to pre vent these chro n i c complications from occurring.

IMPACT OFDIABETES ANDMULTIPLERISKFACTORS

As demonstrated in the Nurses’ Health Study, which followed more than 117 000 women for 20 years, both diabetes and prediabetes significantly i n c reased the risk of card i ovascular disease.1 3 Compared to women who did not develop diabetes during the study (relative risk = 1), those who did develop diabetes were at substantially higher risk to suffer an MI or stroke. The relative risk was 2.82 prior to the diagnosis, 3.71 after the diagnosis of diabetes, and 5.02 if diabetes was present at baseline.

Similarly, the Multiple Risk Factor Intervention Trial, which followed nearly 348 000 men for an aver-age of 12 years, demonstrated that the presence of ele-vated total cholesterol, hypertension, and/or smoking increased the risk of death from a cardiovascular cause in people with and without diabetes.14Although death rates rose in people without diabetes with the addition of each of the 3 risk factors, the increases were even more pronounced in those with diabetes. Death rates were 2 times higher in people with diabetes who had 1 risk factor than in those who had none of the 3 risk

factors, 3 times as high in people with diabetes who had 2 risk factors, and 4 times higher in people with diabetes who had all 3 of the risk factors.

The findings of both studies underscore the impact of diabetes on cardiovascular risk and the need for aggressive intervention to reduce their cardiovascular risk factors.

TREATINGDIABETES ANDPREDIABETES

Treatment of individuals with prediabetes and those with type 2 diabetes re q u i res intervention to reduce risk factors that contribute to diabetes and car-d i ovascular car-disease. Mo t i vating patients to change d i e t a ry habits, develop a regular exe rcise program, and maintain an optimal weight are our first priority. Eve n small changes in diet, a modest increase in exe rcise or physical activity, or weight loss can be significant in l owering glucose and blood pre s s u re, and normalizing lipid levels. T h ree interventional trials have show n that patients randomized to intensive lifestyle inter-venton had a significantly reduced risk of deve l o p i n g type 2 diabetes.15-17 Drug therapies to control glucose, blood pre s s u re, and lipids should be initiated when n e c e s s a ry, and all patients with diabetes should take at least 81 mg of aspirin each day to lower their risk for c a rd i ovascular disease.

Figure 3. Natural History of the Progression of Prediabetes to Type 2 Diabetes

Reprinted with permission from Steven V. Edelman, MD. Figure from Ramlo-Halsted and Edelman. Prim Care Clin North Am.1998;26:771-789.11

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CONCLUSIONS

Diabetes is not merely a blood glucose disease, but a cardiovascular disease in which hyperglycemia is a symptom. Indeed, the influence of diabetes on cardio-vascular disease is considerable, with studies showing a higher incidence of cardiovascular events and increased mortality from cardiovascular causes in persons with diabetes.

Diabetes develops over time, as does cardiovascular disease, thus affording healthcare professionals the opportunity to intervene with appropriate preventive measures. Diabetes, for example, is preceded by insulin resistance and hyperinsulinemia, both of which are associated with cardiovascular risk factors such as obe-sity, hypertension, lipid abnormalities, and endothelial dysfunction. Without intervention, insulin resistance progresses to impaired glucose tolerance and type 2 diabetes, which further increases the risk for cardiovas-cular disease.

The goal is to identify people at risk before they develop diabetes and to help them normalize their glu-cose, blood pressure, and lipid levels. Weight loss, lifestyle modification, and reduction of cardiovascular risk factors are keys to intervention.

REFERENCES

1. American Diabetes Association. Facts and Figures. Available at: h t t p : / / w w w. d i a b e t e s . o rg / m a i n / a p p l i c a t i o n / c o m m e rc e w f ? o r igin=*jsp&event=link(B1). Accessed September 13, 2006. 2. Expert Panel on Detection, Evaluation, and Treatment of High

Blood Cholesterol in Adults. Executive Summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol (Adult Treatment Panel III). J A M A. 2001;285:2486-2497.

3. Haffner SM, Lehto S, Ronnemaa T, et al. Mortality from coro-nary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with or without prior myocardial infarc-tion. N Engl J Med. 1998;339:229-234.

4. Venkat Narayan KM, Boyle JP, Thompson TJ, et al. Lifetime risk for diabetes mellitus in the United States. J A M A. 2003;290:1884-1890.

5. Haffner SM, Miettinen H. Insulin resistance implications for type II diabetes and coronary heart disease. Am J Med. 1997;103:152-162.

6. Desprès JP, Lamarch B, Mauriege P, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med. 1996;334:952-967.

7. McFarlane SI, Banerji M, Sowers JR. Insulin resistance and cardiovascular disease. J Clin Endocrinal Metab. 2001; 86:713-718.

8. Sniderman AD, Scantlebury T, Cianflone K. Hypertriglycer-idemic hyperapob: the unappreciated atherogenic dys-lipoproteinemia in type 2 diabetes mellitus. Ann Intern Med. 2001;135:447-459.

9. Hsueh WA, Law R. The central role of fat and effect of per-oxisome proliferator-activated receptor-gamma on progres-sion of insulin resistance cardiovascular disease. Am J Cardiol. 2003;92:3J-9J.

10. UK Prospective Diabetes Study (UKPDS). VIII. Study design, p ro g ress and perf o rmance. D i a b e t o l o g i a. 1991;34:877-890. 11. Ramlo-Halsted BA, Edelman SV. The natural history of type 2

diabetes. Prim Care Clin North Am. 1998;26:771-789. 12. Edelman SV, Henry RR. Diagnosis and Management of Type

2 Diabetes. 5th edition. Greenwich, Conn; Professional Communications, Inc.; 2002.

13. Hu FB, Stampfer MJ, Haffner SM, et al. Elevated risk of car-diovascular disease prior to clinical diagnosis of type 2 dia-betes. Diabetes Care. 2002;25:1129-1134.

14. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial.

Diabetes Care. 1993;16:434-444.

15. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose toler-ance. The Da Qing IGT and Diabetes Study.Diabetes Care. 1997;20:537-544.

16. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343-1350.

17. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.

References

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