Diabetes and the Heart
Amanda R. Vest
Leslie Cho
I. INTRODUCTION.
The presence of type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) confers a marked increase of risk of coronary artery disease (CAD) development. CAD accounts for as many as 80% of deaths among individuals with diabetes, compared with 30% in those without diabetes. The prevalence of T2DM, which correlates closely with overweight and obesity, has shown a sharp rise over recent decades. Consequently, the management of diabetes, in parallel with the management of nonglycemic CAD risk factors including hypertension, dyslipidemia, and obesity, has become a prime focus in both the primary and secondary prevention of cardiovascular events. Significant uncertainty remains regarding the impact of tight glucose control on future cardiovascular events and the optimal glucose-lowering drug regimen. The revascularization strategies best suited to individuals with diabetes are also an area of ongoing research.
II. EPIDEMIOLOGY
A. Epidemiology of diabetes
1. Diabetes has been described as a worldwide epidemic and is now one of the most common chronic diseases in both developed and developing nations. This rise in prevalence is driven partly by rising levels of obesity, physical inactivity, and
urbanization, coupled with the aging population and greater longevity for patients with diabetes due to advances in diabetes management. The International Diabetes Federation reported that there were 30 million individuals with diabetes worldwide in 1985. The most recent analysis of data suggests this had grown to 171 million adults over 20 years in 2000 (1). If the age-specific prevalence remains constant, there will be a projected doubling in global diabetes cases between 2000 and 2030, bringing the expected total to a staggering 366 million.
urbanization, coupled with the aging population and greater longevity for patients with diabetes due to advances in diabetes management. The International Diabetes Federation reported that there were 30 million individuals with diabetes worldwide in 1985. The most recent analysis of data suggests this had grown to 171 million adults over 20 years in 2000 (1). If the age-specific prevalence remains constant, there will be a projected doubling in global diabetes cases between 2000 and 2030, bringing the expected total to a staggering 366 million.
TABLE 45.1 List of Countries with the Highest Numbers of Estimated Cases of Diabetes for 2000 and 2030 | ||||||||||||||||||||||||||||||||||||
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2. The greatest burden of diabetes lies in developing countries, as illustrated in Table 45.1. India and China are notable for the exceptionally high prevalence in 2000 (31.7 and 20.8 million, respectively, compared with 17.7 million in the United States). The projected 2030 figures for individuals with diabetes are 79.4 million in India, 42.3 million in China, and 30.3 million in the United States (1). In developing countries, the majority of people with diabetes are in the 45- to 64-year age range. In contrast, the majority in developed countries are over 64 years of age.
3. T2DM was once considered to be a disease of adulthood, but it has recently been recognized with increased frequency in children and adolescents, particularly within some ethnic groups such as Native Americans (2). Ten years ago, 3% of new-onset diabetes in adolescents was type 2; currently, 45% of cases are designated T2DM (3). The onset of diabetes in the second decade of life coincides with the physiological occurrence of pubertal insulin resistance. Up to 75% of young people diagnosed with T2DM have a first- or second-degree relative with the condition.
4. Diabetes prevalence is higher in men than in women, but there are more women in total with diabetes. T2DM, in contrast to T1DM, is notable for its close association with conditions such as hypertension, dyslipidemia, and obesity, which further raises the impact of T2DM on the health outcomes of affected individuals.
5. In the United States, 95% of diabetes cases are T2DM, but T1DM has also shown increased incidence over recent years. The increase occurs largely in the youngest individuals (< 5 years) and those with moderate genetic susceptibility (4). A variety of environmental factors and the increasing incidence of childhood obesity are currently being studied as potential causes.
B. Spectrum of insulin resistance to T2DM
1. There is a continuum between the early pathological features of disordered glucose metabolism and T2DM.
TABLE 45.2 Criteria for the Diagnosis of Diabetes and Prediabetes | ||||||||||||||||||||||||||||||||||||
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a. A diagnosis of diabetes can be made on the basis of a fasting blood glucose ≥ 126 mg/dL (7.0 mmol/L) or a 2-hour plasma glucose of ≥ 200 mg/dL (11.1 mmol/L) during a 75-g oral glucose tolerance test. A HbA1c ≥ 6.5% has now been added to the ADA criteria for the diagnosis of diabetes. In the absence of unequivocal hyperglycemia, a positive result for any of these criteria should be confirmed on repeat testing. In the setting of classic hyperglycemic symptoms, a single random glucose ≥ 200 mg/dL is considered diagnostic (5). These diagnostic criteria are summarized in Table 45.2.
b. It is now recognized that the microvascular and macrovascular complications of diabetes are not limited only to individuals meeting the diagnostic criteria for established diabetes. The progression from normal glucose tolerance to T2DM involves intermediate stages of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), also collectively termed “prediabetes.” This pathological continuum arises from dysregulation of the balance between insulin sensitivity and insulin secretion.
c. There is usually a long phase of asymptomatic pathology prior to the development of overt T2DM. Longitudinal studies suggest that insulin resistance onset occurs 10 to 20 years prior to the diagnosis of diabetes and is the best predictor of whether an individual will develop T2DM later. Insulin resistance places pressure on the pancreatic β-cells to augment secretion of insulin and, therefore, promotes β-cell dysfunction. Once the β-cell is unable to compensate sufficiently for the peripheral insulin resistance state, progression to T2DM will ensue. The underlying etiology of T2DM is complex, with both environmental and genetic predisposing factors promoting insulin resistance and β-cell dysfunction.
d. The most notable epidemiological evidence regarding the impact of prediabetes states comes from the DECODE group. They have demonstrated that subjects without a diagnosis of diabetes have no threshold level of fasting or 2-hour postload glucose concentration above which the risk of all-cause or cardiovascular mortality death increased sharply. The relationship between 2-hour postload glucose and cardiovascular mortality was linear, with a continuum of risk extending into and below the prediabetes glucose range (6).
e. Current interpretations of data sets suggest that the cardiovascular effects of postprandial or postglucose challenge hyperglycemia are greater than those of IFG (7). During the prediabetes phase, the cardiovascular event rate is modestly increased. There is evidence for a higher mortality in individuals with IGT compared with those with IFG, which is independent of HbA1c or fasting blood glucose (8). The Emerging Risk Factors Collaboration found that individuals without a diagnosis of diabetes showed only a modest nonlinear correlation between fasting blood glucose and cardiovascular end points; postprandial glucose was not investigated.
f. There is evidence that the pathogenic effect of hyperglycemia on the endo-thelial cells already exists in the prediabetes stage.
2. The full transition from the early metabolic abnormalities of prediabetes to established diabetes probably occurs in about two-thirds of individuals.
a. There is interest in determining interventions that may decrease the likelihood of progression to diabetes or reduce the future cardiovascular event rate once diabetes occurs. The Diabetes Prevention Program Research Group randomly assigned 3,234 participants without diabetes, but with elevated fasting and postload glucose concentrations, to placebo versus metformin (850 mg twice daily) versus a lifestyle modification program promoting exercise and weight loss (9). The incidence of diabetes over an average follow-up of 2.8 years was 11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and lifestyle groups, respectively. The lifestyle intervention was significantly more successful in preventing diabetes than the metformin strategy. Also of note is the STOP-NIDDM trial, which randomized individuals with IGT to acarbose (which primarily affects postprandial glycemia) or placebo (10). Patients in the acarbose group were observed to have a lower rate of diabetes diagnosis than those receiving placebo. Furthermore, a lower rate of cardiovascular disease and hypertension over a 3.3-year mean follow-up period was reported in the acarbose group (11).
C. Impact of diabetes on heart disease
1. Both T1DM and T2DM confer significantly elevated risks of CAD, acute coronary syndromes, post—myocardial infarction (MI) complications, heart failure, and probably also sudden cardiac death. In addition, the incidences of peripheral arterial disease, stroke, and end-stage renal failure are elevated in individuals with diabetes. The cardiovascular complications of T2DM account for the majority of the socioeconomic burden of this chronic disease on both individuals and society.
a. As many as 80% of individuals with diabetes will die from cardiovascular causes. Per the Framingham Heart Study, the risk of CAD is doubled in men and tripled in women with diabetes, compared with age-matched subjects without diabetes.
b. In the modern era of drug-eluting stents and dual antiplatelet therapy, the mortality associated with CAD is falling overall. However, women with diabetes were observed to have a rise in CAD mortality in the period 1995 to 2003 (12).
c. More recently, the Emerging Risk Factors Collaboration undertook a large metaanalysis that demonstrated a twofold excess risk of outcomes such as coronary heart disease, coronary death, and nonfatal MI among individuals with established diabetes (13). They also found diabetes to be a third more strongly related to fatal than to nonfatal MI, possibly suggesting more severe manifestations of
coronary disease in those with diabetes. Hazard ratios (HRs) were particularly elevated for cardiovascular disease among individuals with diabetes who were female, younger, and non-smokers or had lower-than-average blood pressure.
coronary disease in those with diabetes. Hazard ratios (HRs) were particularly elevated for cardiovascular disease among individuals with diabetes who were female, younger, and non-smokers or had lower-than-average blood pressure.
d. Patients with diabetes present differently from those without diabetes and are much more likely to experience an acute coronary syndrome without chest pain, known as “silent ischemia.”
e. Various angiographic trials have demonstrated that patients with diabetes undergoing percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG) tend to have significantly more severe CAD, with a preponderance of multivessel disease and greater severity of lesions than those without diabetes. Despite the more severe plaque burden, diabetes correlates with lesser collateral vessel formation.
f. A particularly high risk is observed among individuals with T2DM following their first cardiovascular event. Indeed, there are multiple studies suggesting poorer outcomes following cardiovascular events, even with revascularization, for individuals with diabetes compared with those without. Cubbon et al. (14) reported that diabetes conferred a higher 30-day mortality after urgent PCI (9.4% patients with diabetes vs. 5.9% without diabetes, p < 0.001).
g. Post-MI complications and mortality in patients with diabetes correlate with post-MI ejection fraction and the presence of multivessel coronary disease. Cardiogenic shock is more common and more severe in post-MI patients with diabetes. The higher in-hospital mortality among the post—acute coronary syndrome (ACS) population with diabetes is largely related to the greater incidence of acute decompensated heart failure and to a lesser extent the increased risk of reinfarction and infarct extension.
h. The CAD mortality arising from T1DM has also been studied. Laing et al. reported a prospective study of 23,751 individuals with T1DM where subjects were followed for up to 29 years (15). As is typical of a T1DM cohort, the relatively young age correlated with a low event rate. However, their CAD risk was several times higher than that of a matched population without diabetes.
i. There is now sufficient literature to conclude that chronic hyperglycemia per se, rather than the associated cardiovascular risk factors, has a pathogenic role in the development of vascular disease in diabetes.
D. Risk factors for CAD in patients with diabetes
1. The risk factors that predispose individuals with diabetes to develop cardiovascular disease are the same as those that raise cardiovascular risks in those without diabetes. However, the prevalence of known major risk factors for CAD is generally amplified among persons with diabetes. Given the overall higher cardiovascular risk conferred, the benefits of tighter risk factor control may be greater in those with diabetes than those without. The potential gains of aspirin, attaining a normal body weight and nonsmoking status, tight blood pressure control, and aggressive lipid management in diabetes have been the subject of several recent trials.
2. a. Dyslipidemia
(1) This is one of the most profound risk factors among individuals with diabetes. Diabetes is associated with small, dense low-density lipoprotein (LDL) particle composition, increased levels of apolipoprotein B and E, low levels of high-density lipoprotein (HDL) cholesterol, and high triglyceride (TG) levels. These lipid composition abnormalities cluster with insulin resistance and abdominal adiposity and appear to induce endothelial dysfunction and an increased susceptibility to thrombosis.
(2) Lipid-lowering therapy is now a cornerstone of T2DM management. In the Scandinavian Simvastatin Survival Study (4S), there was a 55% reduction in cardiovascular events among subjects with diabetes and a 25% reduction in the CARE trial. The National Cholesterol Education Program
(NCEP) considers diabetes a CAD equivalent in its Adult Treatment Panel III guidelines. Hence, a target of < 100 mg/dL—with an optional goal of < 70 mg/dL—is recommended (16). Statins are considered first-line agents to achieve these targets. Niacin may be of use in elevating HDL levels. Bile acid binding resins (along with thiazides, estrogens, and glucocorticoids) may increase TG levels and therefore should be avoided where possible.
(NCEP) considers diabetes a CAD equivalent in its Adult Treatment Panel III guidelines. Hence, a target of < 100 mg/dL—with an optional goal of < 70 mg/dL—is recommended (16). Statins are considered first-line agents to achieve these targets. Niacin may be of use in elevating HDL levels. Bile acid binding resins (along with thiazides, estrogens, and glucocorticoids) may increase TG levels and therefore should be avoided where possible.
b. Hypertriglyceridemia
(1) Elevated fasting TG levels are characteristic of the lipid panel in diabetes and constitute an independent cardiovascular risk factor. Hyper-triglyceridemia correlates with abdominal adiposity.
(2) Fibrates have traditionally been considered an appropriate therapy to target hypertriglyceridemia and have often been added to statin therapy for this indication. The Helsinki Heart Study demonstrated the benefit of fibrates in a primary prevention trial to reduce cardiovascular end points (but not mortality), and the VA HDL Intervention Trial (VA-HIT) showed outcomes benefit in a secondary prevention setting. However, the lipid arm of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial did not demonstrate any benefit for subjects with T2DM in the addition of fenofibrate to simvastatin. The significant rhabdomyolysis risk with a fibrate and statin combination should also be considered.
c. Hypertension
(1) The prevalence of hypertension is increased in individuals with diabetes compared with those without. The presence of an elevated blood pressure serves as at least as strong a risk factor for CAD as it does for individuals without diabetes.
(2) There are multiple large trials supporting the benefit of blood pressure lowering in subjects with diabetes. In the UKPDS, lowering the blood pressure to a mean of 144/82 mm Hg (compared with 154/87 mm Hg) significantly reduced strokes, diabetes-related deaths, and heart failure, as well as microvascular complications. In that trial, there did not appear to be an outcome benefit between captopril and atenolol (17). However, several trials since have demonstrated the renal protective effects of angiotensin-converting enzyme (ACE) inhibitors (or angiotensin receptor antagonists) over alternate agents, which has firmly established them as the first-line antihypertensives in diabetes.
The Hypertension Optimal Treatment (HOT) trial demonstrated the benefit of a lower diastolic target. Among the 3,000 subjects with diabetes, but not in those without diabetes, the relative cardiovascular risk was significantly reduced in the ≤ 80 mm Hg group, compared with the ≤ 90 mm Hg group (18). Major guidelines suggest a target blood pressure in patients with diabetes of < 130/80 mm Hg. The ACCORD trial randomized subjects with diabetes to a target systolic blood pressure of < 120 mm Hg or < 140 mm Hg. The lower target group showed no difference in the primary cardiovascular outcomes end point but did have a significantly lower stroke rate; however, this was at the expense of significantly more adverse drug events and an increased risk of a creatinine rise of > 1.5 mg/dL (19). There is currently insufficient evidence to recommend ACE inhibitors in normotensive patients with diabetes without microalbuminuria.
d. Tobacco. There is evidence that smokers with diabetes have a markedly increased risk of MI and peripheral arterial disease. Lipid abnormalities and the development of atherosclerotic plaques appear to be promoted by smoking in the setting of diabetes.
e. Obesity
(1) The prevalence of obesity has more than doubled in the United States since 1980. Obesity and overweight are typically defined in terms of
body mass index (BMI), with overweight being 25 to 30 kg/m2, class I obesity 30 to 35 kg/m2, class II obesity 35 to 40 kg/m2, and class III obesity > 40 kg/m2. Waist circumference and waist-to-hip ratio better reflect abdominal adiposity and are more reliable predictors of CAD outcomes than BMI (20). Obesity is an important determinant of cardiovascular health and is associated with widespread alterations in cardiac and vascular structure and function. It has been shown to be an independent risk factor for the development of cardiovascular disease. T2DM correlates closely with obesity, especially central obesity.
body mass index (BMI), with overweight being 25 to 30 kg/m2, class I obesity 30 to 35 kg/m2, class II obesity 35 to 40 kg/m2, and class III obesity > 40 kg/m2. Waist circumference and waist-to-hip ratio better reflect abdominal adiposity and are more reliable predictors of CAD outcomes than BMI (20). Obesity is an important determinant of cardiovascular health and is associated with widespread alterations in cardiac and vascular structure and function. It has been shown to be an independent risk factor for the development of cardiovascular disease. T2DM correlates closely with obesity, especially central obesity.
(2) Caloric restriction, behavior modification, and increased physical activity form the basis of weight management programs. Unfortunately, sustained weight loss is difficult to achieve with these conservative measures. Several medications have been marketed for temporary assistance with weight loss.
(a) Sibutramine is a combined inhibitor of neuronal norepinephrine, serotonin, and, to a lesser degree, dopamine reuptake. It is a sympathomimetic and therefore increases heart rate and blood pressure, leading to concerns reading its cardiovascular safety profile. It has recently been withdrawn from the market in multiple countries including the United States.
(b) Ephedrine and ephedra alkaloids (“ma huang”) are sympathomimetic amines with a prolonged duration of action and increased peripheral effects. Due to safety concerns, ephedrine with or without caffeine and the ephedra alkaloids are not approved for treatment of obesity.
(c) Phentermine and diethylpropion are the only sympathomimetic drugs currently approved for the short-term treatment of obesity. Their use is not widespread.
(d) Orlistat is currently the only drug that is available for modulation of fat digestion. It inhibits pancreatic lipases, thus increasing the proportion of fat that is not completely hydrolyzed and is fecally excreted. The recommended prescription dose is 120 mg three times daily. A 60 mg over-the-counter version is available in some countries, including the United States. Major side effects include abdominal cramps, flatus, fecal incontinence, diarrhea, and oily stools; there is a rare association with severe liver injury.
Multiple trials have demonstrated a greater initial weight loss with orlistat, compared with placebo, and also slower weight regain in the longer term. In obese individuals with diabetes, orlistat not only promotes weight loss but also decreases A1c at 1 year in comparison with placebo (21).
(e) Other drugs that may have effects in supporting weight loss include antidepressants such as fluoxetine, sertraline, bupropion; anti-epileptics such as topiramate and zonisamide; and diabetes medications including metformin and the glucagonlike peptide (GLP) analogs.
(3) There is growing evidence regarding the beneficial effects of significant weight loss achieved by bariatric surgery on glucose metabolism. Bariatric surgery is generally restricted to individuals with BMI > 40 kg/m2 or BMI 35 to 40 kg/m2 with co-existing medical conditions such as diabetes, although the 2005 revision of the NIH consensus statement by the American Society for Bariatric Surgery expanded the indications to BMI 30 to 35 kg/m2 with comorbidities.
(a) Bariatric surgery options include malabsorptive procedures such as the Roux-en-Y gastric bypass (currently accounting for the majority of bariatric operations in the United States) and restrictive procedures such as laparoscopic adjustable gastric bands and sleeve gastrectomy. The most recent data from the Longitudinal Assessment of Bariatric Surgery Consortium show a 30-day mortality rate of < 1% (22).
(b) Weight loss post bariatric surgery is typically expressed in terms of “excess weight,” which refers to the difference between the actual and the ideal weights for an individual. Weight loss after malabsorptive bariatric surgery tends to reach a nadir at 12 to 18 months with an average of 70% excess body weight loss and a 35% decrease in BMI, with an approximate 10% weight regain in the following 10 years (23).
(c) A meta-analysis of 22,000 patients demonstrated that an average excess body weight loss of 61% was accompanied by significant improvements in T2DM, hypertension, dyslipidemia, and obstructive sleep apnea. Indeed, bariatric surgery has demonstrated an ability to completely reverse established diabetes in a large number of subjects. In the Swedish Obese Subjects Study (23), a prospective, nonrandomized, intervention trial of 4,047 obese subjects, 72% of individuals with diabetes who chose the bariatric surgery option showed reversal of their diabetes at 2 years, compared with 21% of those who followed a conservative weight loss regimen of diet and exercise. At 10 years follow-up, diabetes was reversed in 36% of the bariatric surgery group and 13% of the control group. In a smaller study of 165 obese patients with diabetes by Pories, 83% showed diabetes remission at a mean of 9.4 years (24). In the recent STAMPEDE trial, 150 patients with uncontrolled T2DM and a BMI between 27 and 43 kg/m2 were randomized to intensive medical therapy alone, versus medical therapy plus Roux-en-Y gastric bypass or sleeve gastrectomy. The proportion of patients with HbA1c ≤ 6.0% at 12 months was 12% in the medical therapy group, versus 42% in the gastric-bypass group (p = 0.002) and 37% in the sleeve-gastrectomy group (p = 0.008).
(d) There is growing evidence that there are both substantial modifications in the traditional CAD risk factors post bariatric surgery and that these risk modifications translate to a cardiovascular outcome benefit. The largest study of Framingham risk scores and actual cardiovascular events after gastric bypass involved 500 patients (without a control group) (25). At 1 year, the mean excess body weight loss was 68.7% ± 22%. The diabetes prevalence fell from 28% to 6% (p = 0.001). The average 10-year absolute cardiovascular event risk, as estimated from the Framingham data, was 5.4% at baseline. This reduced to 2.7% at 1 year postsurgery (p = 0.001). The actual rate of cardiovascular events observed in this cohort postoperatively was only 1%.
3. Multifactorial risk factor interventions should be targeted in all patients with diabetes, regardless of whether this is a primary or a secondary prevention strategy.
a. The Steno-2 trial randomized 160 patients with T2DM and microalbuminuria to intensive versus conventional therapy for a mean period of 7.8 years (26). The trial was designed to evaluate the effect on cardiovascular events of an intensified, targeted, multifactorial intervention comprising behavior modification and polypharmacologic therapy aimed at several modifiable risk factors in patients with T2DM.
b. The intensive management regimen included dietary fat restriction, 30 minutes of exercise three to five times per week, smoking cessation, ACE inhibitors or angiotensin receptor blocker administration irrespective of blood pressure, additional agents to target blood pressure < 130/80 mm Hg, 150 mg aspirin, stepwise glycemia management to target A1c < 6.5%, statins for hyperlipidemia, and fibrates for isolated hypertriglyceridemia. The intensive group achieved significantly lower blood pressure, HbA1c, LDL, and TGs. There was an absolute risk reduction of 20% in cardiovascular events.
c. The subjects were then followed up for a further mean of 5.5 years, at which point the primary end point of all-cause mortality was assessed (27).
Significant differences in blood pressure, A1c, LDL, and TGs were absent by this later follow-up point. The primary end point at 13.3 years was time to all-cause death, and an absolute risk reduction of 20% was found. Even beyond the period of tight risk factor control, the Kaplan-Meier curves for the first cardiovascular event continued to diverge. During the mean 13.3-year follow-up period, the mortality rate among the conventional therapy subjects was 50%, a finding that highlights the poor overall outcomes in patients with diabetes who are not intensively managed.
Significant differences in blood pressure, A1c, LDL, and TGs were absent by this later follow-up point. The primary end point at 13.3 years was time to all-cause death, and an absolute risk reduction of 20% was found. Even beyond the period of tight risk factor control, the Kaplan-Meier curves for the first cardiovascular event continued to diverge. During the mean 13.3-year follow-up period, the mortality rate among the conventional therapy subjects was 50%, a finding that highlights the poor overall outcomes in patients with diabetes who are not intensively managed.
d. This study established that there were long-term benefits to aggressive multifaceted risk factor management, and that tight glycemic control and treatment with aspirin, antihypertensives, and lipid-lowering drugs appeared to be additive. Therefore, current society and national guidelines stress the importance of a broad approach to targeting multiple cardiovascular risk parameters. This body of evidence is much more firmly established than that regarding any benefit from tight glycemic control as a single approach to reducing cardiovascular risk.
E. Metabolic syndrome
The term “metabolic syndrome” describes the clustering of several of these cardiovascular risk factors in association with impaired glucose metabolism. There are slightly differing diagnostic criteria established by the WHO (28), the AHA and IDF (29), and the NCEP (30). The 2009 joint AHA/IDF criteria are summarized in Table 45.3. The value of the concept of the metabolic syndrome may lie in the emphasis it has placed on considering the patient as a whole and also the concept of abdominal adiposity being the more relevant predictor of CAD than BMI. However, several commentators have recently challenged the relevance of the metabolic syndrome, as it appears that accounting for the presence of the metabolic syndrome does not serve as a stronger predictor of cardiovascular risk than the individual component parameters (31).
F. Role in pathology of atherosclerosis
1. Diabetes accelerates the atherosclerosis process. Autopsy series have revealed more diffuse coronary involvement, greater severity of vessel stenosis, and more severe left main disease in persons with diabetes, compared with those without. Similarly, adverse coronary anatomy findings have been observed in autopsy studies of patients with a history of childhood onset of T1DM who died before the age of 40 years. The pathophysiology of atherosclerosis in diabetes remains incompletely understood but is thought to involve the hyperglycemia, lipid abnormalities, and
dysfunctional endothelial and vascular smooth muscle function, coupled with a propensity for inflammation, thrombosis, and platelet activation.
dysfunctional endothelial and vascular smooth muscle function, coupled with a propensity for inflammation, thrombosis, and platelet activation.
TABLE 45.3 Joint AHA and IDF Criteria for the Diagnosis of the Metabolic Syndrome | ||||||||||||||||||
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2. It is recognized that the synthesis of nitric oxide (NO) by the vascular endothelium is reduced in subjects with diabetes. NO is among several key substances that maintain healthy endothelial function, which includes freedom from adhesion molecule activation, leukocyte diapedesis, platelet aggregation, and activation of thrombosis. However, the bioavailability of NO is adversely affected by hyperglycemia, high levels of free fatty acids, and insulin resistance. Current research reveals the impact of excessive oxidative stress (which can be induced by hyperglycemia, fatty acids, or insulin resistance) on NO production and also on the generation of advanced glycation end products, which are suspected to mediate various negative cellular effects in diabetes. Reactive oxygen species also activate protein kinase C with wide-ranging effects on cellular metabolism, including activation of the PI3K pathway, which has a role in mediating cell adhesion and migration. The ability of NO to act on vascular smooth muscle and cause vasodilation is reduced; endothelial cell dysfunction in diabetes is coupled with increased production of vasoconstrictors such as prostanoids and endothelin.
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