Blog Archive

Friday 16 May 2008

Prediabetes & Atherosclerosis: What’s the Connection?

The Nurse Practitioner
Prediabetes & Atherosclerosis: What’s the Connection?
Author(s):

Douaihy, Katharine MSN, CRNP, CDE, BC-ADM

Issue:
Volume 30(6), June 2005, pp 24-35
Publication Type:
[DIABETES CARE]
Publisher:
© 2005 Lippincott Williams & Wilkins, Inc.
Institution(s):
ABOUT THE AUTHOR
Katharine Douaihy is an Assistant Professor of Nursing, Wilkes University, a Nurse Practitioner in a private practice of endocrinology, and a doctoral student at Widener Univesity, Chester, PA.
AUTHOR DISCLOSURE
The author has disclosed that she has no significant relationship or financial relationship with any commercial companies mentioned in this continuing education activity.

Type 2 diabetes is a progressive, chronic disease affecting 18.2 million people in the United States, or 6.2% of the population. 1 Another 5.2 million individuals are unaware that they have the disease. 1 Presently, 41 million individuals between 40 and 74 years of age are facing a clinical diagnosis of type 2 diabetes. 1 These individuals have blood glucose levels that are above normal but do not meet the criteria for the clinical diagnosis of diabetes. Abnormalities in glucose homeostasis may be present for years if not decades before a clinical diagnosis of type 2 diabetes has been met.


Graphic
[Help with image viewing]
[Email Jumpstart To Image] 		FIGURE. No caption available.

The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus recognized these individuals as an intermediary group who are referred to as having prediabetes, formerly referred to as borderline or asymptomatic diabetes. 2 Prediabetes has two components: impaired glucose tolerance and impaired fasting glucose, both of which precede the development of type 2 diabetes.

Many individuals are unaware of any anomaly in glucose homeostasis and are often diagnosed with type 2 diabetes at the time of a cardiovascular event. A number of studies revealed that an acute myocardial infarction may be the initial presentation of overt diabetes in some individuals. 3,4 In a prospective study by Norhammar, Tenerz, Nilsson, et. al., out of 3,181 patients with an acute myocardial infarction and no previous history of diabetes, 35% were found to have impaired glucose tolerance at hospital discharge and 40% had this condition 3 months later. A metaanalysis of 20 studies that included 100,000 people revealed a curvilinear increase in the risk for a cardiovascular event with increasing glucose intolerance. 4

These individuals have other abnormalities that form metabolic syndrome, also known as insulin resistance syndrome and metabolic syndrome X. Each component of metabolic syndrome is a risk factor for cardiovascular disease, contributing to the high incidence of this condition among individuals with type 2 diabetes. Adults with diabetes have a two to four times higher incidence of death related to cardiovascular disease, making it the leading cause of death among the type 2 diabetes population. 1 The incidence of cardiovascular disease does not depend on the duration of type 2 diabetes, which suggests that a prediabetic state may determine the onset of coronary heart disease. 5 The onset of macrovascular complications can begin years or even decades earlier. Therefore, a much more multifactorial approach in the early stages of pre-diabetes is warranted. Such an approach includes lifestyle modifications and aggressive treatment of abnormal glucose and lipids.

This article provides an overview of prediabetes as the first step on the road to developing overt type 2 diabetes. An understanding of the pathogenesis of type 2 diabetes is imperative to assist the clinician in screening for and formulating an effective treatment plan that reflects each pathologic state of the disease. The opportunity to prevent macrovascular complications will be introduced, which includes the link between prediabetes and atherosclerosis, the identification of new targets for treatment, and guidelines for treatment of this progressive disease process.

Metabolic Syndrome

Metabolic syndrome is a constellation of metabolic disorders. This syndrome is associated with insulin resistance, affecting insulin’s action on glucose uptake in muscle and fat as well as the suppression of liver glucose output. Genetic predisposition and acquired factors such as obesity and physical inactivity lead to insulin resistance and metabolic syndrome. Characteristics of this syndrome include abdominal obesity, atherogenic dyslipidemia (low, high-density lipoprotein [HDL], high triglycerides, small, dense low-density lipoprotein [LDL] particles), elevated blood pressure, prothrombotic state, and proinflammatory state. 6 The Adult Treatment Panel III (ATP-III) has placed increased emphasis on metabolic syndrome and established criteria for diagnosis. According to ATP-III, metabolic syndrome is identified by the presence of three or more components (see Table: “ATP-III Criteria for Metabolic Syndrome”).


Graphic
[Help with image viewing]
[Email Jumpstart To Image] 		TABLE. ATP-III Criteria for Metabolic Syndrome

Insulin resistance is a complex cellular abnormality affecting multiple organ systems. The link between insulin resistance and atherogenic dyslipidemia, hypertension, prothrombotic state, and glucose intolerance is multifaceted and may be mediated through multiple metabolic pathways. 7

One of the most important phenomena related to type 2 diabetes under investigation is obesity, and in particular, visceral adiposity. Fat has very important effects on metabolism. The best correlation shown by research reveals a decrease in insulin sensitivity associated with central abdominal fat. 8 The effect of fatty acids on insulin action has been reported in the literature. 10,11 Fatty acids have direct effects on insulin action by blocking the promotion of glucose uptake into muscle and enhancing gluconeogenesis in the liver. Both actions tend to cause hyperglycemia and contribute to hyperinsulinemia. Hyperinsulinemia is another anomaly found in metabolic syndrome that results from insulin resistance. This is a marker of low insulin sensitivity and is an independent risk factor for ischemic heart disease. 9

The adipose tissue and liver are considered the endocrine organs most affected by insulin resistance. 10,12 Visceral fat contributes to an increased fatty acid flux to the liver. 11 In turn, the liver stimulates the synthesis of a triglyceride-rich lipoprotein called very low-density lipoprotein (VLDL), resulting in lower HDL. Adipose tissue also plays a central role in insulin resistance because it releases proinflammatory cytokines, tumor necrosis factor-[alpha] (TNF- [alpha]), plasminogen activator inhibitor-1, and interleukin-6. 12,13 The release of proinflammatory cytokines elicits higher C-reactive protein (CRP) levels, which have been implicated as a risk for coronary heart disease. Thus, inflammation may contribute to both metabolic syndrome and atherosclerosis. Therefore, the release of potentially arthrogenic factors into the circulation has led researchers to consider obesity as a central component of metabolic syndrome.

Insulin resistance has a stimulatory effect on the beta cells of the pancreas, accelerating the decrease in insulin secretion and hastening the onset of glucose intolerance. 7,14 Therefore, insulin resistance may first be seen as impaired glucose tolerance or impaired fasting glucose, both of which are referred to as prediabetes. In the presence of abdominal obesity or signs of insulin resistance, clinicians need to consider prediabetes or overt diabetes.

Natural History of Type 2 Diabetes

Type 2 diabetes is characterized by impaired insulin action (insulin resistance) and an insulin secretory defect as a result of impaired beta cell functioning. Initially, insulin resistance causes an increase in insulin secretion from the beta cells of the pancreas. This compensatory mechanism results in euglycemia with elevated fasting and/or postprandial serum insulin levels. Over time, the beta cells continue to compensate by increasing insulin levels, resulting in hyperinsulinemia, and keeping blood glucose normalized for up to 7 years. 14 Over time, the beta cells exhaust and a mild postprandial hyperglycemia, referred to as impaired glucose tolerance (IGT), develops. Impaired glucose tolerance is defined as a postprandial blood glucose between 140 to 199 mg/dL. 2 As insulin resistance increases and beta cell insulin production decreases with time, more global defects in insulin secretion occur, resulting in impaired fasting glucose (IFG). Impaired fasting glucose is defined as fasting plasma glucose between 100 mg/dL and 125 mg/dL. 2

The United Kingdom Prospective Diabetes Study (UKPDS), a landmark study of 5,102 patients with newly diagnosed type 2 diabetes revealed a decrease in insulin secretion, and that diabetes develops and progresses because there is a loss of beta cell functioning. 15 The study revealed that at the time of diagnosis, patients had already lost one-half of their beta cell function. 15 In addition, beta cell function continued to decline during the UKPDS, which accounted for the progression or deterioration of diabetes. It is important to consider that the treatments that were used in the UKPDS did not help the pancreas survive longer. At the time of the UKPDS, it was speculated that the decline in beta cell function was related to some programmed abnormality or response to the pancreas that could not be recovered in the study.

Three potential causes for beta cell dysfunction have been hypothesized. The first is glucose toxicity from chronic hyperglycemia, causing an increase in insulin demands and resulting in a depletion of insulin secretory granules of the beta cells. 14,16 Lipotoxicity has also been considered a potential cause of beta cell dysfunction. With lipotoxicity, the beta cells may become injured from the accumulation of fatty acids and their metabolic products, which has been observed among individuals with insulin resistance and IGT. 14,16 Variations in free fatty acid levels are necessary for beta cells to function normally, however, prolonged increases in these levels have a negative impact on the conversion of proinsulin to insulin, resulting in decreased insulin output. 14,16 Lastly, a reduction in beta cell mass can cause dysfunction; this has been observed in those with IGT and type 2 diabetes. 14,16 The exact cause of reduced beta cell mass remains unknown.

A measurable change in the pulsatile secretory pattern of insulin release before overt diabetes or even IGT develops has been observed in individuals with insulin resistance. 14 In individuals without diabetes, insulin is released in 8- to 10-minute pulses and long oscillations. 14 In prediabetes and overt diabetes, the pulsed pattern is disrupted. The loss of pulsatility can contribute to insulin resistance. 14 The decline in insulin levels and the inhibitory effects of insulin eventually result in an increase in hepatic glucose output. 17 The prediabetic state of IGT and/or IFG precedes the development of overt type 2 diabetes (fasting plasma glucose > 126 mg/dL) by years or even decades (see Figure: “The Natural History of Type 2 Diabetes”).


Graphic
[Help with image viewing]
[Email Jumpstart To Image] 		FIGURE. The Natural History of Type 2 Diabetes
Epidemiology of Atherosclerosis in Prediabetes

Coronary heart disease occurs more often in those with diabetes than in the general population; approximately 65% of deaths due to heart disease are among people with diabetes. 1 It has been estimated that in the U.S., diabetes and IGT account for about 14% of cardiovascular disease in Caucasians and as much as 50% to 80% in Native Americans. 18 Given the rising incidence of obesity in this country, these proportions are likely to increase.

As previously discussed, acute myocardial infarction may be the initial presentation of either IGT or overt diabetes. The Insulin Resistance Atherosclerosis Study and others have revealed that insulin resistance is associated with atherosclerosis as defined by intima-media thickening of the carotid arteries. 8,19–21 In a subsequent prospective study of 6,800 Finnish subjects without a history of type 2 diabetes who were followed for 7 to 10 years, each one standard deviation increase in 2 hour glucose increased the hazard ratio for both coronary events and cardiovascular mortality. 4,22 These findings, as well as other studies of patients with acute myocardial infarctions who were previously undiagnosed with type 2 diabetes, suggest that atherosclerosis starts in the prediabetic state.

Pathogenesis of Atherosclerosis in Prediabetes

Both atherosclerosis and prediabetes are systemic and complex processes involving multiple organs and metabolic pathways. As discussed earlier, each component of metabolic syndrome promotes the development of atherosclerosis. The initial offense is insulin resistance at the level of the fat cells, causing an increased intracellular decomposition of triglycerides and release of free fatty acids into the circulation. 10 Elevated free fatty acids from insulin resistant adipose tissue invade the liver, causing it to stimulate the production and secretion of VLDL. The increased secretion of VLDL results in hypertriglyceridemia.

In addition, the VLDL exchanges cholesteryl esters—transfer proteins—from HDL and LDL for VLDL. This exchange leads to low HDL and increases small, dense LDL particles. 10 Apoprotein A-I (ApoA-I), the second major lipoprotein of HDL, is involved with assembly of HDL, removal of excess cholesterol from cells, and transportation of cholesterol from peripheral tissues to the liver. ApoA-I is referred to as the “reverse cholesterol transporter.” This ApoA-I can dissociate from triglyceride-enriched HDL and can be filtered by the kidney and degraded by the renal tubular cells, thus reducing the availability of HDL for reverse cholesterol transport. 10 The triglyceride-rich LDL undergoes lipolysis and becomes smaller and denser. The low levels of HDL and small, dense LDL particle size are each independent risk factors for cardiovascular disease.

Sequentially, circulating risk factors such as dyslipidemia lead to endothelium injury in the arterial walls. Injury to the endothelium results from an alteration in permeability and the induction of circulating cytokines released by the adipose tissue and liver. Therefore, the proimflammatory state is included in the ATP-III criteria for metabolic syndrome.

Low density lipoprotein is clearly very important for atherosclerosis. Clinical trials have shown that by lowering the burden of LDL cholesterol, cardiovascular mortality is decreased. As the burden of LDL is lowered, the amount that becomes trapped in the vessel wall is also lowered, and the trapped LDL becomes oxidized through different processes. This process of oxidation, however, is increased in insulin resistance, leading to an increase in oxidized LDL in the vessel wall. 7,12 This is measured by small, dense LDL cholesterol as a marker of the particle of cholesterol that is more easily oxidized because it has larger levels of apolipoprotein B.

In addition to the LDL, the macrophage becomes important. The macrophage devours the oxidized LDL cholesterol, and rather than taking cholesterol out of the vessel wall, it breaks down into foam cells. These foam cells are so lipid-laden that they stick to the vessel wall, and as they accumulate, begin to form a fatty streak. That is the first important change in the vessel wall—the first marker—lesion of an atherosclerotic plaque. Smooth muscle cells start to migrate into the area and form a fibrous cap. These foam cells often die, leaving a necrotic lipid core, and a more advanced atherosclerotic plaque develops. 7,12 As the endothelium is damaged, monocytes stick to the vessel wall due to an increased expression of adhesion molecules. This is a critical step in leukocytes adhering and entering the vessel wall. As the process of vascular injury proceeds, macrophage chemoattractant protein-1 (MCP-1) is increased and secreted from the endothelial cells and the vascular smooth muscle cells. 12 The monocytes become differentiated and activated, and now become active macrophages to take up oxidized LDL cholesterol. 12

In addition, T-lymphocytes encounter signals that cause them to amplify inflammatory cytokines such as tumor necrosis factor-[alpha] (TNF-[alpha]), which can stimulate macrophages as well as vascular endothelial cells. In particular, adipose tissue has emerged as a complex secretor of inflammatory cytokines, including TNF-[alpha]. 11 The pre-diabetes state has many similar abnormalities, leading to the onset of atherosclerosis long before the clinical diagnosis of type 2 diabetes is made.

Screening and Therapeutic Targets for Prediabetes

In 2001, the National Institutes of Health completed the Diabetes Prevention Program (DPP), a trial investigating the most effective ways of preventing type 2 diabetes in those with prediabetes who are overweight. 23 Nondiabetic individuals (n = 3,234) with elevated fasting and postprandial blood plasma glucose were randomized to receive a placebo, metformin (Glucophage) (850 mg twice daily), or a lifestyle modification program with the goal of 7% weight loss and exercise 150 minutes/week, and were followed for an average of 2.8 years. 23 The lifestyle intervention reduced the incidence of diabetes by 58% and the metformin group reduced the incidence by 31% when compared with the placebo group. 23 Based on the results of the DPP, the American Diabetes Association (ADA) proposed screening recommendations for prediabetes. The ADA recommends screening individuals >= 45 years of age, especially overweight individuals (body mass index [BMI] >= 25 kg/m2) as part of their healthcare visit (see Table: “Routine Screening Recommendations for Prediabetes”). 24 In addition, individuals who are <>= 250 mg/dL), history of gestational diabetes, and polycystic ovarian syndrome. Asian Americans may be screened at lower levels of BMI (23 kg/m2).


Graphic
[Help with image viewing]
[Email Jumpstart To Image] 		TABLE. Routine Screening Recommendations for Prediabetes

Fasting plasma glucose or random glucose tolerance test (OGTT) should be performed for screening. 24,25 Although not a common screening practice or recommended by the ADA, serum insulin levels obtained each time plasma glucose is drawn during an OGTT may assist in evaluating hyperinsulinemia. Individuals diagnosed with prediabetes (IGT or IFG) should be monitored for the development of diabetes every 1 to 2 years. 24 Target blood glucose goals are the same for those with overt diabetes; 90 to 130 mg/dL for fasting blood glucose and less than 180 mg/dL for 2-hour postprandial blood glucose. 2

Once diagnosed with prediabetes, additional testing is essential for the prevention of macrovascular complications. Laboratory tests include lipid profile and direct LDL. Other variables recognized within the National Cholesterol Education Program Adult Treatment Panel III Guidelines, but not included in setting LDL goals, may be considered by the clinician in determining the intensity or aggressiveness of lipid-modifying interventions. 6,26 One such test is lipoprotein (a) to determine the LDL particle size, which may assist in guiding the treatment regimen. 26 For example, a pattern B LDL refers to a small, dense LDL particle size, which is a risk factor for atherosclerosis. If an individual has an LDL of 90 mg/dL, which is within goal according to ADA recommendations (< linkindex="102" class="fulltext-RA" href="http://ovidsp.uk.ovid.com/spa/ovidweb.cgi#86">26

Another laboratory test is a high-sensitivity C-reactive protein (CRP) since inflammation plays a role in the pathogenesis of diabetes and atherosclerosis. 26 A statement by the American Heart Association (AHA) identifies the measurement of high-sensitivity CRP as the most useful when compared to markers such as cytokines, adhesion molecules, and acute-phase reactants. 27 Reports indicate that high-sensitivity CRP is an independent risk factor for coronary heart disease (CHD). 28 Although not recommended for all patients, measurement is reserved for individuals who may benefit from more aggressive therapy, such as those with prediabetes. 26

A 2004 update to the NCEP-ATP III advises health-care providers to consider more intensive LDL targets and treatment options for those at high and moderately high risk for cardiovascular events. 26 These options included setting lower treatment goals for LDL cholesterol and initiating cholesterol-lowering drug therapy at lower LDL thresholds. 26

The update is based on a review of five major clinical trials of statin therapy conducted since the 2001 release of NCEP ATP III guidelines. 26 These include the Heart Protection Study, 29,30 the Prospective Study of Pravastatin in the Elderly at Risk, 29,31 Antihyhpertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial – Lipid Lowering Trial, 29,32 Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering, 29,33 and the Pravastatin or Atorvastatin Evaluation and Infection –Thrombolysis in Myocardial Infarction 22 Trial. 29,34 The update is endorsed by the National Heart, Lung, and Blood Institute, The American College of Cardiology, and the AHA.

According to the ATP III, individuals are placed into three risk categories: (1) high and very high risk—those with CHD or CHD risk equivalent; (2) moderately high-risk—those with multiple (two or more) risk factors for CHD (smoking, hypertension), and (3) low-to-moderate risk—zero to one risk factor. 26 Coronary heart disease risk equivalents include noncoronary forms of clinical atherosclerotic disease, diabetes, and multiple (2+) CHD risk factors within 10-year risk for CHD greater than 20%. 26 In addition, the presence of metabolic syndrome is believed to increase an individual’s risk for CHD at any level of LDL cholesterol. 35 Thus, those with prediabetes are considered to have CHD risk equivalents, and all individuals with CHD or CHD risk equivalents can be referred to as high-risk, while those with prediabetes or diabetes plus cardiovascular disease are considered to be at very high risk. 26 Target LDL cholesterol levels for individuals with prediabetes are the same as for those with diabetes, which is considered a CHD risk equivalent. According to the updated ATP III recommendations, the goal for high-risk patients remains an LDL of < linkindex="119" class="fulltext-RA" href="http://ovidsp.uk.ovid.com/spa/ovidweb.cgi#86">26 It is also recommended that those with LDL 100 to 120 mg/dL receive cholesterol-lowering medication. 26 High-density lipoprotein cholesterol target is > 40 mg/dL for men and > 50 mg/dL for women; the target for triglycerides is < linkindex="121" class="fulltext-RA" href="http://ovidsp.uk.ovid.com/spa/ovidweb.cgi#62">2,6

ATP III continues to place major emphasis on lifestyle modifications as an essential modality in clinical management for those at risk for cardiovascular disease. 26,35 The approach was designed to achieve risk reduction through both LDL lowering and metabolic syndrome management. 26,35 Therefore, when lipid-lowering medications are considered, the importance of lifestyle changes should be reemphasized.

Management of Prediabetes
Lifestyle Modification

Two well-controlled studies on the prevention of diabetes revealed that changes in lifestyles of high-risk individuals could prevent type 2 diabetes. 23,36 The Finnish study investigated the feasibility and effects of lifestyle modifications to prevent or delay the onset of type 2 diabetes. 36 Subjects were randomized into a control group and an intervention group. The intervention group received seven sessions of nutritional counseling during the first year and every 3 months for the remainder of the study. 36 In addition, the group received individualized exercise plans with half of the subjects receiving supervised individual training sessions. 24,36 The average weight loss in the “moderate exercise” (30 min/day) intervention group was 9.2 lb at 1 year, 7.7 lb after 2 years, and 4.6 lb after 5 years. 24,36

In the DPP, individuals in the lifestyle modification group met with a case manager on a regular basis and received weekly-supervised exercise sessions. 23,24,36 Participants lost approximately 12 lb at 2 years and 9 lb at 3 years. 23,24,36 Although subjects in both studies lost only a modest amount of weight, both studies revealed that diabetes could be prevented with lifestyle modifications.

The recommended goals set forth by the ADA and the National Institute of Diabetes and Digestive and Kidney Disease include a modest weight loss of 5% to 10% and modest exercise of 30 minutes daily. 24 As the studies have shown, increased exercise can have a major impact on weight, blood glucose levels, and overall health of an individual. Although weight loss is difficult to achieve, it is imperative for healthcare providers to reinforce the importance of weight loss and exercise not only to those with prediabetes in an effort to prevent diabetes, but also to all overweight or sedentary individuals. Even modest weight loss and exercise can have significant effects on metabolic factors.

Pharmacologic Therapy

The DPP and STOP-NIDDM prevention studies utilized pharmacologic agents as interventions for the prevention of diabetes. In the DPP, the biguanide metformin reduced the incidence of diabetes by 31%. 23,37,38 The STOP-NIDDM utilized the alpha-glucosidase inhibitor acarbose (Precose), which was shown to decrease the risk of diabetes by one-third. 38 The DPP study showed that metformin was effective in reducing the risk of type 2 diabetes in patients with IGT, although less effective than lifestyle modifications. Metformin reduced the rate of progression to diabetes in men and women of all ethnic groups but was nearly ineffective in older patients (>= 60 years of age) and those who were less overweight (BMI < class="fulltext-SP">2). The dosage of metformin in the DPP study was 850 mg twice daily. An individual with prediabetes may benefit from the initiation of a lower dose of 500 mg daily with a weekly upward titration in an effort to minimize gastrointestinal side effects. An additional benefit to metformin is the positive effects this drug has on triglycerides and weight.

The STOP-NIDDM trial randomized patients with IGT to receive acarbose 100 mg 3 times daily or a placebo. 38 When compared to the placebo, the acarbose group had a significantly lower risk of diabetes. However, 19% of the patients receiving acarbose withdrew from the trial because of gastrointestinal side effects. 38 Therefore, those with IGT would benefit with acarbose 100 mg premeal, but need to be aware of the potential for gastrointestinal symptoms such as nausea and flatulence.

In a double-blind, placebo-controlled randomized study in Hispanic women with a history of gestational diabetes, a thiazolidinedione (TZD), troglitazone (Rezulin), which was later withdrawn from the market following reports of liver toxicity, delayed or prevented the onset of diabetes. 39 The TZD study also revealed that these insulin-sensitizing agents may be associated with the preservation of beta cell function, thereby improving insulin resistance. Pioglitazone (Actos) and rosiglitazone (Avandia) are currently available TZDs. One major disadvantage of TZDs is it can cause fluid retention. Therefore, this class of medications should be avoided in those with a history of congestive heart failure (CHF). Patients who have a history of CHF and are on a TZD need to be watched closely for worsening signs and symptoms of heart failure.

Treatment of dyslipidemia in those with prediabetes is the same as for those with diabetes. Extensive data has demonstrated the effectiveness of HMG-CoA reductase inhibitors (statins) in decreasing atherogenic events by lowering LDL levels. The Heart Protection Study showed that diabetic patients without a history of myocardial infarction but with mildly elevated LDL levels had decreased cardiovascular events with a statin. 26,30

HMG-CoA reductase inhibitors are preferred by the ADA for treatment of elevated LDL. 2 This class of drugs is also beneficial for those with prediabetes who have an elevated CRP and/or pattern B LDL. The link between prediabetes and atherosclerosis warrants aggressive lipid treatment for prevention of atherogenic events.

Implications for Clinical Practice

Medical professionals have focused on the late manifestations of progressive and chronic diseases, type 2 diabetes, and atherosclerosis. Research has shown that interventions are initiated too late for a majority of individuals. Prediabetes is a pathologic condition which affords the clinician the opportunity to prevent macro-vascular complications. Identification of those with IGT or IFG allows healthcare professionals to aggressively pursue lifestyle and diet changes that might prevent not only macrovascular complications but also the progression to type 2 diabetes. In a healthcare arena where prevention is emphasized, increased attention to the stages that precede type 2 diabetes is imperative for preventing atherosclerosis in individuals moving toward the clinical diagnosis of diabetes.

REFERENCES

1. American Diabetes Association. National diabetes fact sheet. http://www.diabetes.org/diabetes-statistics/national-diabetes-fact-sheet.jsp.2002 . [Context Link]

2. American Diabetes Association. American diabetes association: clinical practice recommendations. Diabetes Care 2004;27(S1):S1–S9. [Context Link]

3. Norhammar A, Tenerz A, Nilsson G, et. al: Glucose metabolism in patients with acute myocardial infarction, and no previous diagnosis of diabetes mellitus: A prospective study. Lancet 2002;359:2140–52. Bibliographic Links [Context Link]

4. Coutinho M, Gerstein HC, Wang Y, et al: The relationship between glucose and incident coronoary heart disease and cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care 1999; 22: 233–238. Bibliographic Links [Context Link]

5. Haffner SM: Impaired glucose tolerance, insulin resistance and cardiovascular disease. Diabetic Medicine 1997; 14: S12–S18. Bibliographic Links [Context Link]

6. National Cholesterol Education Program, National Heart, Lung, and Blood Institute, National Institutes of Health. 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). National Institutes of Health Publication 2002. [Context Link]

7. Grundy SM: Hypertrigyceridemia, insulin resistance, and the metabolic syndrome. Am J Cardiol 1999;83:25F–29F. [Context Link]

8. Rewers M, Zaccaro D, D’Agostino R, et al: Insulin sensitivity, insulinemia, and coronary artery disease: the insulin resistance atherosclerosis study. Diabetes Care 2004;27 (3):781–7. Bibliographic Links [Context Link]

9. Despres JP, Lamarche B, Mauriege P, et.al: Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996;334: 952–7. Bibliographic Links [Context Link]

10. Ginsberg HN: Insulin resistance and cardiovascular disease. J Clin Invest 2000;106 (4):453–58. Bibliographic Links [Context Link]

11. Kahn BB, Flier, JS. Obesity and insulin resistance. J. Clin Invest 2000; 106(4):473–81. [Context Link]

12. Libby P, Ridker PM, Masseri A: Inflammation and atherosclerosis. Circulationn 2002;105:1135–43. [Context Link]

13. Frohlich M, Imhof A, Berg G, et al: Association between c-reactive protein and features of the metabolic syndrome. Diabetes Care 2000;23(12):1835–9. Bibliographic Links [Context Link]

14. Buchanan TA: Pancreatic beta-cell loss and preservation in type 2 diabetes. Clinical Ther 2003;25 (Supp B):B33–B45. [Context Link]

15. United Kingdom Prospective Diabetes Study Group. UKPDS: Intensive blood glucose control with sulfphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet 1998;352: 837–51. [Context Link]

16. Polonsky KS: Evolution of beta-cell dysfunction in impaired glucose tolerance and diabetes. Experimental Clinical Endocrinology and Diabetes 1999; 107 (S4): S124–S127. [Context Link]

17. Ramlo-Halsted BA, Edelman SV: The natural history of type 2 diabetes: Implications for clinical practice. Primary Care 1999;26(4):771–89. Bibliographic Links [Context Link]

18. Harris MI, Flegal KM, Cowie CC, et al: Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. The third national health and nutrition examination survey, 1988–1994. Diabetes Care 1998;21:518. Bibliographic Links [Context Link]

19. Howard G, O’Leary DH, Zaccaro D, et al: Insulin sensitivity and atherosclerosis. Circulation 1996;93:1809–17. [Context Link]

20. Watarai T, Yamasaki Y, Ikeda M, et al: Insulin resistance contributes to carotid arterial wall thickness in patients with non-insulin dependent-diabetes mellitus. Endocrin J 1999;46:629–38. [Context Link]

21. Wohlin M, Sundstrom J, Arnlov J, et al: Impaired insulin sensitivity is an independent predictor of common carotid intima-media thickness in a population sample of elderly men. Atherosclerosis 2003;170:181–5. Bibliographic Links [Context Link]

22. Qiao Q, Pyorala K, Pyorala M, et. al. Two-hour glucose is better risk predictor for incident coronary heart disease and cardiovascular mortality than fasting glucose. Eur Heart J 2002;23:1267–78. Bibliographic Links [Context Link]

23. Knowler WC, Barrett-Connor E, Fowler SE, et al: Reduction in the incidence of type 2 diabetes with lifestyle intervention on metformin. N Engl J Med 2002;346: 393–403. [Context Link]

24. American Diabetes Association, National Institute of Diabetes and Digestive and Kidney Diseases. American diabetes association: Clinical practice recommendations Prevention or delay of type 2 diabetes. Diabetes Care 2004;27(S1):S47–S54. [Context Link]

25. American Diabetes Association. Diagnosis and Classification of Diabetes Mellitus. American diabetes association: Clinical practice recommendations Diabetes Care 2004; 27(S1): S5–S10. [Context Link]

26. Talbert RL: Role of the national cholesterol education program adult treatment panel III. Guidelines in managing dyslipidemia. Niacin in the treatment of dyslipidemia: insight from Adult treatment panel III; Symposium. American Journal of Health-System Pharmacy 2003;60 (13) (S2):S3–S8. [Context Link]

27. Pearson TA, Mensah GA, Alexander RW, et. al: Triglyceride concentration and ischemic heart disease: An eight-year-follow-up in the Copenhagen male study. Circulation 1998; 97:1029–36. [Context Link]

28. Ridker PM, Rifai N, Rose L, et al: Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002;347:1557–65. Bibliographic Links [Context Link]

29. Grundy SM, Cleeman JI, Bairey Merz CN, et al: NCEP Report: Implications of recent clinical trials for the national cholesterol education program adult treatment panel III guidelines. Circulation 2004;110:227–39. Bibliographic Links [Context Link]

30. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo- controlled trial. Lancet 2002;36 (9326):7–22. [Context Link]

31. Shepherd J, Blauw GJ, Murphy MB, et al: PROSPER study group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial. Prospective study of Pravastatin in the elderly at risk. Lancet 2002;360:1623–30. Bibliographic Links [Context Link]

32. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The antihypertensive and lipid-lowering treatment to prevent heart attack trial. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALL-HAT-LLT). JAMA 2002;288:2998–3007. Bibliographic Links [Context Link]

33. Sever PS, Dahlof B, Poulter NR, et al: ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the angloscandinavian cardiac outcomes trial-lipid lowering arm (ASCOT-LLA): a multicentre randomized controlled trial. Lancet 2003; 361:1149–58. [Context Link]

34. Cannon CP, Braunwald E, McCabe CH, et al: Pravastatin or atorvastatin evaluation and infection therapy-thrombolysis in myocardial infarction 22 investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495–504. [Context Link]

35. Fruchart JC, Nierman MC, Stroes ESG, et al: Atherosclerosis: evolving vascular biology and clinical implications. New risk factors for atherosclerosis and patient risk assessment. Circulation 2004;109:III-15–III-19. [Context Link]

36. Tuomilehto J, Lindström MS, Eriksson JG, et al: Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J of Med 2001;344 (18):1343–50. Bibliographic Links [Context Link]

37. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346(6):393–403. Bibliographic Links [Context Link]

38. Chiasson JL, Josse RG, Gomis R, et al, for the STOP-NIDDM Trial Research Group. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomized trail. Lancet 2002;359:2072–7. Bibliographic Links [Context Link]

39. Buchanan TA, Xiang AH, Peters RK, et al: Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high risk Hispanic women. Diabetes 2002;53: 2796–803. [Context Link]


Posted by at

No comments:

Post a Comment

Subscribe to: Post Comments (Atom)