INTRODUCTION
Behavioral Objectives
Certifications
CV
RISK AND DIABETES
Prevalence of CVD in
Diabetes
Poor
Diabetes Control
Hyperinsulinemia, Insulin Resistance, and CVD
Hypertension
MANAGING
CARDIAC RISKS
Blood Pressure Control
Smoking
Cessation
SUMMARY
REFERENCES
TABLES
Table 1
Table 2
Table 3
Table 4
Table 5
Table 6
Table 7
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This Continuing Education module provided through an unrestricted
educational grant by Takeda Pharmaceuticals America / Eli Lilly and Company.
Managing Cardiovascular Risk in Type 2 Diabetes Mellitus
Karissa Y. Kim, PharmD
Dr. Kim is a Clinical Assistant Professor at Temple University School of Pharmacy and a Clinical Pharmacist in Ambulatory Care at the Philadelphia VA Medical Center
Cardiovascular disease (CVD) is the leading cause of death in adults with diabetes. The risk of CVD is two to three times greater in diabetics than nondiabetics. At the time of diagnosis of diabetes, more than 50% of patients already have evidence of CVD. Furthermore, diabetics who suffer a
myocardial infarction (MI) have a higher fatality rate than nondiabetic
patients.1 Because CVD is a major cause of morbidity and mortality in this population, pharmacists in order to counsel diabetics should know how to identify major risk factors that contribute to CVD in type 2 diabetics and to delineate components of comprehensive cardiovascular risk reduction.
Approximately 16 million Americans have diabetes mellitus.2 The two most common forms of diabetes are type 1 (insulin-dependent diabetes mellitus) and type 2 (non-insulin-dependent diabetes mellitus)
(Table 1).
Approximately 5% to 10% of diabetics have type 1 diabetes. Type 1 diabetes usually has a sudden onset and occurs in patients younger than 30 years of age. The pathogenesis of type 1 diabetes includes autoimmune mediated beta-cell destruction that leads to an absolute insulin deficiency. Patients present with moderate-to-severe symptoms of polydipsia, polyuria, fatigue, and weight loss; these symptoms progress relatively rapidly. Exogenous insulin therapy is necessary for treatment.
Table 1. Comparison of Type 1 and Type 2 Diabetes
The onset of type 2 diabetes, which occurs in approximately 90% of diabetics, is gradual and usually occurs later in life, such as in patients older than 40 years of age. The pathogenesis of type 2 diabetes is hallmarked by insulin resistance (decreased sensitivity to insulin), beta-cell dysfunction (defects in insulin secretion in the pancreas), and increased hepatic glucose output (excessive glucose production by the liver). Patients are often asymptomatic or present with mild polyuria and fatigue. Because many patients are asymptomatic, type 2 diabetes is often diagnosed on routine examination. Lifestyle modifications and
medications, such as sulfonylureas, thiazolidinediones, biguanides, and insulin, can help patients with type 2 diabetes control their disease.
Poorly controlled diabetes can lead to both acute and chronic complications
(Table 2). Acute metabolic complications include diabetic ketoacidosis, hyperglycemic hyperosmolar nonketotic syndrome, and hypoglycemia. Chronic complications can be classified as microvascular or macrovascular. Microvascular (small-vessel) complications of diabetes include retinopathy, nephropathy, and neuropathy. Macrovascular (large-vessel) complications of diabetes include coronary artery disease, stroke or transient ischemic attacks, and peripheral vascular disease (PVD). Macrovascular complications, such as CVD, are a major cause of morbidity and mortality.
Table 2. Complications of
Diabetes
Diabetes is an independent risk factor for CVD.3 The prevalence of CVD is significantly higher in diabetics than in nondiabetics. Based on the 1989 U.S. National Health Interview Survey, 14% of diabetic patients between the ages of 45 and 65 years and 20% of those older than 65 years of age reported
CVD.4 Furthermore, when diabetics have CVD, their prognosis is worse. For example, a study by Haffner et al indicated that the number of deaths from cardiovascular causes was significantly higher in diabetic
patients.5
Intervention trials have evaluated the relationship between effective diabetes control and microvascular and macrovascular complications. The Diabetes Control and Complications Trial6 in type 1 diabetics and the United Kingdom Prospective Diabetes Study
(UKPDS)7 in type 2 diabetics examined the effect of maintaining near-normal glucose levels on those complications. Both studies showed that good glycemic control prevented the development and progression of microvascular complications such as nephropathy and retinopathy. The relationship between hyperglycemia and CVD was not
unequivocally proved. There was a reduction in macrovascular events in both of these trials, but it was not statistically significant.
Observational studies among diabetics have also investigated the relationship between hyperglycemia and the development of CVD and also could not prove a clear correlation between the degree of hyperglycemia and CVD occurrence.
Hyperinsulinemia (high levels of insulin) and insulin resistance (a resistance to the action of insulin) have been reported as risk factors for CVD in diabetics. Current thought is that hyperinsulinemia may be an independent risk factor that promotes atherogenesis. Insulin resistance also has a predictive value for CVD and may also promote atherosclerosis. Patients with type 2 diabetes are often insulin-resistant and present with the insulin resistance syndrome or syndrome X. Insulin resistance syndrome is the clustering of glucose intolerance, central obesity, dyslipidemia, hypertension, and increased prothrombotic and antifibrinolytic factors in an individual. The presence of this syndrome may increase the risk for atherosclerotic vascular disease.
Hypertension is a major risk factor for CVD, and its prevalence is at least twofold higher in diabetics than nondiabetics. The increased CVD risk in diabetics may be as a result of the coexistence of hypertension and diabetes. Furthermore, diabetics with hypertension have a greater risk of CVD mortality (almost threefold) than do nondiabetics across all blood pressure levels according to the Multiple Risk Factor Intervention Trial (MRFIT).8 The presence of hypertension and diabetes also increases the risk of microvascular complications such as nephropathy.
Type 2 diabetics often have an abnormal lipid profile, which is another major risk factor for CVD. Although diabetics’ total cholesterol and low-density lipoprotein (LDL) cholesterol values are similar to nondiabetics, their triglyceride (TG) levels are higher and their high-density lipoprotein (HDL) cholesterol levels are lower. This is often referred to as diabetic
dyslipidemia.9 Although the prevalence of hypercholesterolemia is not increased in diabetics, the MRFIT trial demonstrated that at each cholesterol level, coronary heart disease (CHD) mortality rates were threefold to fourfold higher in diabetics than in
nondiabetics.8 High levels of LDL and low levels of HDL are major risk factors for CVD; similarly, hypertriglyceridemia is now thought to be an independent risk factor for
CVD.10
Procoagulant State
Diabetics often exhibit a procoagulant state, and abnormalities in platelet function, coagulation, and fibrinolysis have been described in these
patients.1 These abnormalities may predispose diabetics to thrombosis and cardiovascular events.
Renal disease is a major complication of uncontrolled diabetes and has been reported to be a risk factor for CVD. Furthermore, microalbuminuria (the spilling of 30 to 300 grams/day of albumin in urine) is a marker of kidney damage. Microalbuminuria is a strong predictor of CVD mortality and
morbidity.11
Smoking is a major risk factor for CVD and is the leading avoidable cause of mortality. As with cholesterol values and blood pressure, the MRFIT study showed that diabetics who smoke have a two-fold to fourfold higher rate of cardiovascular
death.8 The combination of smoking and diabetes seems to increase the development of macrovascular complications.
Smoking may also increase the risk of microvascular complications.12 For example, smoking increases the risk of nephropathy and microalbuminuria. Peripheral neuropathy risk is also increased in smokers.
Diabetics are at an increased risk for CVD; this may be as a result of the interaction of several factors, including insulin resistance, hyperinsulinemia, procoagulant state, renal disease, and the presence of other major cardiovascular risk factors such as hypertension, dyslipidemia, and cigarette smoking. To ameliorate CVD in diabetics, the above major risk factors must be identified and managed. The following discussion will address these factors.
Insulin resistance and hyperinsulinemia contribute to the pathogenesis of type 2 diabetes and are risk factors for macrovascular disease. However, no studies have been conducted to show whether there is a relationship between the drugs that modify such factors and the reduction of cardiovascular risk.
Studies have proved that tight glycemic control reduces microvascular complications. Current thought is that some antidiabetic agents currently on the market may also modify macrovascular risk factors, but this potential indication remains under investigation. In the UKPDS, monotherapy with the biguanide metformin (Glucophage) in obese patients showed a reduction in a macrovascular complication (ie, 39% reduced incidence of MI) compared with conventional
treatment.13 Metformin has been found to reduce body weight by 1 to 2 Kg, reduce TG by 4% to 5%, and decrease LDL by 4% to
5%.14 Some hypothesize that the benefit of metformin is as a result of its ability to modify CVD risk factors, independent of its antidiabetic action. However, when metformin was added in sulfonylurea-treated patients, mortality was increased. The reasons for this discrepancy are unknown.
Thiazolidinediones (TZDs) such as pioglitazone (Actos) and rosiglitazone (Avandia) may modify CVD factors as well. Those drugs reduce TG by 15% to 20% and increase HDL by 10%. LDL may increase with
rosiglitazone14; data suggest that pioglitazone does not raise LDL and its effect on LDL is comparable to
placebo.15 Metformin and TZDs also reduce insulin levels and insulin resistance, which as noted earlier may modify cardiovascular risk. TZDs may also have the potential to reduce blood pressure. However, patients on TZDs often gain weight. Until trials evaluating the clinical significance of these effects on CVD are conducted, it is premature to recommend that metformin or TZDs should be used to modify cardiovascular risk in diabetics.
a-glucosidase inhibitors such as acarbose (Precose) and miglitol (Glyset) do not modify cardiovascular risk factors. They have neutral effects on weight, lipids, and insulin. On the other hand, insulin, sulfonylureas, and meglitinides (repaglinide [Prandin]) deleteriously modify cardiovascular risk factors by increasing body weight and insulin levels. All of these agents increase body weight and insulin levels.
Table 3 summarizes the effects of antidiabetic agents in modifying macrovascular risk factors.
Table 3. Effects of Antidiabetic Agents
in Modifying Cardiovascular Risk Factors14
Studies have shown that treating hypertension has numerous benefits, such as reducing overall mortality; reducing deaths from stroke, CVD events, and MI; and delaying the progression of renal disease in both diabetics and non-diabetics. The Systolic Hypertension in Elderly Program (SHEP) study evaluated the effect of low-dose diuretic therapy (chlorthalidone) on the rate of stroke in elderly patients with isolated systolic hypertension. A post-hoc analysis evaluating major CVD outcomes in diabetics and nondiabetics from SHEP showed that major cardiovascular events, stroke, nonfatal MI, fatal CHD, major coronary events, and all-cause mortality were lower in diabetics treated for
hypertension.16 Absolute risk reduction with treatment was twice as high for diabetics than for nondiabetics. The Systolic Hypertension in Europe Trial examined the effects of a calcium-channel blocker in isolated systolic hypertension, looking at the incidence of stroke as the primary end point. A post-hoc analysis of this trial performed to determine the outcomes in diabetics indicated that active treatment in diabetics reduced overall mortality by 55%, mortality from cardiovascular causes by 76%, all cardiovascular events by 69%, and stroke by
73%.17
The Sixth Report of the Joint National Commission on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) recommends treating diabetic patients with even high-normal blood pressure (defined as blood pressure 130 to 139/85 to 89 mm
Hg).18 Drug therapy and lifestyle modifications, such as sodium restriction, limiting alcohol intake, and weight loss, should be implemented concomitantly.
Hypertension must be treated to target values. Aggressive blood pressure reduction is associated with a reduced rate of progression of renal disease and a decreased incidence of cardiovascular
events.19,20 UKPDS 38 examined the effect of blood pressure control on macrovascular and microvascular
complications.21 Approximately 1,100 patients were randomized to either tight control of blood pressure (<150/85) or less tight control of blood pressure (<180/105). The tight control group utilized captopril and atenolol; the less tight control group used other antihypertensives for blood pressure control. The tight control group had a 24% reduction in the risk of developing any end point related to diabetes, a 32% reduction in the risk of mortality from diseases substantially increased by diabetes (two thirds of which were CVD), a 44% reduction in stroke, and a 37% reduction in microvascular disease.
In the Hypertension Optimal Treatment (HOT) study, which evaluated the effects of intensive blood pressure lowering, three diastolic blood pressure targets
(90, 85, and 80 mm Hg) were utilized with approximately 6,000 patients enrolled in each
group.22 The main antihypertensive used was felodipine (Plendil). In the diabetic subgroup, major cardiovascular events and cardiovascular mortality rates were lower in the group with the lowest target diastolic blood pressure
(p for trend = 0.05 and 0.016, respectively). Thus, aggressive blood pressure lowering is recommended for diabetics. The blood pressure goal for diabetics is <130/85 mm Hg, according to the JNC VI report. For those with significant proteinuria (urinary protein >1 gram /24-hr period), a lower target of
125/75 mm Hg is recommended.
Although all of the antihypertensive agents currently on the market adequately control blood pressure, there are several that are preferred for use in diabetes
(Table 4).
Table 4. Antihypertensive Agents of Choice in
Diabetes18
Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce proteinuria and delay the progression of diabetic nephropathy in normotensive type 1 diabetics with proteinuria (either micro or macro). In those with type 1 diabetes, hypertension, and proteinuria, there is compelling evidence for the use of ACE inhibitors as first-line agents. Because renoprotective effects of ACE inhibitors in type 2 diabetics have also been shown, it is reasonable to use ACE inhibitors as first-line agents in type 2 diabetics with
proteinuria.23 Angiotensin II receptor antagonists may be considered for use in those patients who do not tolerate ACE inhibitors.
In addition to their renoprotective effect, ACE inhibitors may have cardiovascular benefits. The Heart Outcomes Prevention Evaluation study evaluated the effect of the ACE inhibitors ramipril on cardiovascular events in high-risk
patients.24 Men and women with a history of CVD, stroke, peripheral vascular disease (PVD), or diabetes plus one other cardiovascular risk factor, such as hypertension or hyperlipidemia, were eligible. Approximately 9,000 patients randomly received either ramipril with or without vitamin E or placebo with or without vitamin E. A significant reduction in the primary end point (composite of MI, stroke, or death from cardiovascular causes) was observed in the ramipril group, regardless of the use of vitamin E. The relative risk reduction was 0.78 (95% CI, 0.70 to 0.86). In the subset with diabetes, the benefits were similar. That study suggests, because ACE inhibitors blunt the renin-angiotensin-aldosterone system, these drugs may prevent cardiovascular events.
Other preferred antihypertensive agents are calcium-channel blockers and low-dose diuretics because they do not alter glucose homeostasis or lipid profiles. Calcium-channel blockers, such as diltiazem and verapamil, may also provide renoprotective effects. Beta blockers may mask symptoms of hypoglycemia and can prolong hypoglycemia; however, they are effective antihypertensive agents that can be used when their benefits outweigh the potential risks in this population, especially in those with prior MI history, because they can reduce mortality and prevent
reinfarction.
Because microalbuminuria and renal disease predict CVD, renal disease must be prevented. Controlling hypertension (if present) and diabetes will prevent the development of renal disease and therefore must be stressed. For patients with existing renal disease, good control of diabetes and blood pressure may slow the progression of renal disease. ACE inhibitors are also renoprotective and should be utilized if not contraindicated.
Another priority in cardiac risk reduction is treating dyslipidemia. Although no full-scale clinical trials have been conducted to evaluate the effect of lipid-lowering therapy specifically in diabetic patients, subgroup analyses of diabetics from large trials examining LDL reduction have been conducted. In the Scandinavian Simvastatin Survival Study, which evaluated the mortality benefits of simvastatin therapy in 4,444 patients with established CHD, 202 also had diabetes. In the subgroup analysis of those patients, a risk reduction of 55% (95% CI, 24% to 73%) was shown for major CHD events and 37% (95% CI, 8% to 57%) for any atherosclerotic event. Total mortality was reduced 43% in diabetic patients (95% CI, –8% to 70%) and 29% in nondiabetic patients (95% CI, 13% to
42%).25 The reduction in mortality in the diabetic subset was not statistically significant. A post-hoc analysis was conducted on the diabetic subset of patients (14% of 4,159 study
participants) in the Cholesterol and Recurrent Events
trial.26 The analysis indicated a significant 25% reduction of risk of coronary events such as death, nonfatal MI, coronary bypass surgery, and angioplasty in the diabetic subset of patients.
Although the benefits of LDL reduction have been extensively studied, the benefits of drug therapy to reduce hypertriglyceridemia and to raise HDL as primary prevention need further evaluation by clinical trials.
The American Diabetes Association (ADA)27 and the National Cholesterol Education Program (NCEP) expert panel recommend treatment of diabetic
dyslipidemia.28 The ADA recommends aggressive treatment: any diabetic with LDL levels greater than 100 mg/dL should be treated with either dietary modification or drug therapy, with target LDL levels at less than 100 mg/dL. For diabetics with CHD, PVD, or CVD, who have an LDL level greater than 100 mg/dL, drug therapy is recommended. Diabetics without these conditions can defer drug treatment until their LDL level is 130 mg/dL or higher. The NCEP guidelines reserve such aggressive treatment only for those with evidence of
atherosclerosis, regardless of the presence of diabetes. If TGs are elevated, treatment should be considered. Those with severe hypertriglyceridemia (higher than 1,000 mg/dL) should be treated to reduce the risk of pancreatitis. If TG levels are above 400 mg/dL, the ADA strongly suggests drug treatment. Those with borderline TG (200 to 400 mg/dL) should be treated based on the clinician’s judgment. The ADA recommends a goal TG level of less than 200 mg/dL. Drug treatment to solely raise HDL is currently controversial. Nonpharmacologic interventions such as exercise and smoking cessation should be undertaken to raise HDL values.
Choosing a lipid-lowering agent is dependent on the lipid profile (Table
5). If the main concern is LDL cholesterol, statin drugs are first-choice agents because of their superior efficacy. Bile acid sequestrants (cholestyramine and colestipol) and fenofibrate (Tricor) are second-line agents.
Table 5. Treatment of Diabetic Dyslipidemia in
Adults27
Because poor diabetes control raises TG levels, the first priority for those with hypertriglyceridemia is good glycemic control. If additional intervention is needed, fibric acid derivatives are drugs of choice. Niacin is also effective in lowering TG, but this agent is relatively contraindicated in diabetics because it can cause hyperglycemia. Statins, such as atorvastatin (Lipitor) and high-dose simvastatin (Zocor) may also reduce TG.
To treat combined hyperlipidemia (increased LDL and increased TG), good glycemic control and high-dose statin therapy are recommended. Other pharmacotherapeutic alternatives include the use of bile-acid binding resin and fibrate, a statin and fibrate, or statin and niacin. The use of the combination of statin and fibrate or statin and niacin should be reserved for cases in which the benefits outweigh the risk because those combinations may increase the risk of myopathy and rhabdomyolysis. Close monitoring is essential when these combinations are used. Fluvastatin (Lescol) and pravastatin (Pravachol) may be safer when used together with niacin or fibrate.
Patients with diabetes often exhibit a procoagulant state. Thus, cardiac risk reduction using aspirin, an antiplatelet agent, has been evaluated. The Early Treatment Diabetic Retinopathy Study, a multicenter, randomized trial in 3,711 participants, evaluated the effects of photocoagulation and aspirin 650 mg daily on diabetic
retinopathy.29 Data were also collected on the cardiovascular effects of aspirin. Approximately half of the participants had a history of CVD. Although a reduction in relative rates of death from all causes, cardiovascular death, and fatal or nonfatal MI were shown with aspirin, these reductions were not statistically significant. The relative risk for MI in the first 5 years was significantly lowered by aspirin 0.72 (CI 0.55 to 0.95).
A meta-analysis of 145 prospective controlled trials of antiplatelet therapy in patients with a history of CVD, PVD, and stroke estimated that approximately
40 vascular events can be prevented per 1,000 diabetics who are treated with aspirin for secondary
prevention.30 The use of aspirin for primary prevention has also been evaluated. The HOT study, which looked at aspirin prophylaxis as well, showed that aspirin significantly reduced major cardiovascular events by 36% and all MI by
30%.22
 
The ADA recommends the use of aspirin as secondary prevention in those with macrovascular
disease.31 Other antiplatelet agents, such as clopidogrel (Plavix) and ticlopidine (Ticlid), are alternatives for those with aspirin allergy. High-risk men and women should receive aspirin as well. The doses of enteric-coated aspirin 81 to 325 mg daily are recommended. Enteric-coated preparations are recommended because they are less likely to cause stomach
irritation.31
Smoking cessation decreases the risk of CVD, stroke, cancer, and lung disease. Only about half of diabetics are advised to quit
smoking.32 All smokers should be encouraged to quit smoking. The message to stop smoking should be delivered consistently and repeatedly by all health care providers. Even minimal intervention lasting less than 3 minutes and consisting of a strong, personalized recommendation to quit is effective in increasing cessation
rates.33
Pharmacotherapeutic options to assist in smoking cessation are numerous
(Table 6). The use of nicotine replacement and anti-depressant therapy have been shown to enhance cessation rates. One study showed superiority of the antidepressant bupropion to nicotine replacement
therapy.34 Behavior counseling is also an integral component to successful cessation. Because some forms of nicotine replacement therapy are available over the counter, opportunities for pharmacists in this area are tremendous. Product selection, dosing, and counseling are potential areas to discuss with patients. Weight gain is a real concern for those who quit smoking using nicotine replacement therapy. Pharmacists should inform patients of this potential and reaffirm the health benefits of cessation.
Table 6. Pharmacotherapy for Smoking
Cessation33
CVD is the leading cause of death in diabetics, accounting for approximately 65% of all deaths. A comprehensive cardiac risk assessment should be conducted and major risk factors must be managed.
Table 7 summarizes components of cardiac risk reduction in diabetics.
Aggressive blood pressure control, modifying diabetic dyslipidemia, promoting smoking cessation, and prophylactic anti-platelet therapy are major areas to be addressed. Pharmacists can have a significant impact in the area of cardiac risk reduction by identifying diabetic patients and evaluating their risk factors for CVD. Educating patients about the goals of treatment, counseling patients on expected outcomes of therapy, assisting patients in smoking cessation, and ensuring the use of antiplatelet agents can be areas of focus.
Table 7.
Comprehensive Guide to Cardiac Risk Reduction
for Patients with Diabetes
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2. Kenny SJ, Aubert RE, Geiss LS. Prevalence and Incidence of Non-Insulin-Dependent Diabetes. In Harris (ed): Diabetes in America, ed 2. Bethesda, MD, National Institutes of Health.
3. Grundy SM, Benjamin IJ, Burke GL, et al. Diabetes and cardiovascular disease: a statement for healthcare professionals form the American Heart Association. Circulation 1999;100:1134-1146.
4. Wingard DL, Barrett-Connor E: Heart disease and diabetes. In Harris (ed): Diabetes in America, ed 2. Bethesda, MD, National Institutes of Health.
5. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Markku L. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229-234.
6. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term compliations in insulin-dependent diabetes mellitus. N Engl J Med. 1993:329:977-86.
7. United Kingdom Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-53.
8. Stamler J, Vacaro O, Neaton O, etal. Diabetes, other risk factors and 12 year cardiovascular mortality for men screened in teh Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16:434-444.
9. Kreisberg RA. Diabetic dyslipidemia. Am J Cardiol 1998;82:76U-73U.
10. Bohannon NJ. Coronary artery disease and diabetes. Postgrad Med 1999;105:66-80.
11. Dineen SF, Gerstein HC. The association of microalbuminuria and mortality in non-insulin-dependent diabetes mellitus: a systematic overview of the literature. Arch Intern Med 1997;157:1413-1418.
12. Haire-Joshu D, Glasgow RE, Tibbs TL. Smoking and diabetes. Diabetes Care 1999;22:1887-1898.
13. United Kingdom Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-865.
14. Lebovitz HE. Effects of oral antihyperglycemic agents in modifying macrovascular risk factors in type 2 diabetes. Diabetes Care 1999;22:C41-C43.
15. Takeda Pharmaceuticals America, Inc. Actos (pioglitazone) package insert. Lincolnshire, IL 60069
16. Curb JD, Pressel SL, Cutler JA, et al. Effect of diuretic-based antihypertensive treatment on cardiovascular disease in risk in older diabetic patients with isolated systolic hypertension. JAMA 1996;276:1886-1892.
17. Tuomilehto J, Rastenyte D, Birkenhager WH, et al. Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. N Engl J Med 1999;340:677-684.
18. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, And Treatment of High Blood Pressure. Arch of Inter Med. 1997; 157: 2413-2439.
19. Cooper ME, Johnston CI. Optimizing treatment of hypertension in patients with diabetes. JAMA 2000;283: 3177-3179.
20. Deedwania PC. Hypertension and diabetes. Arch Intern Med 2000;160:1585-1594.
21. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;7160:703-713.
22. Hansson L, Zanchetti AZ, Dahlof B. et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998;351:1755-1762.
23. Ravid M, Brosh D, Levi Z, Bar-Dayan Y, Ravid D, Rachmani R. Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus. Ann Intern Med 1998;128:982-988.
24. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:145-153.
25. Pyorala K. Pedersen TR. Kjekshus J. Faergeman O. Olsson AG. Thorgeirsson G. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care 1997; 20:614-620.
26. Goldberg RB, Mellies MJ, Sacks FM, et al. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels. Subgroup analyses in teh cholesterol and recurrent events (CARE) trial. Circulation 1998;98:2513-2519.
27. American Diabetes Association. Management of Dyslipidemia in adults with diabetes. Diabetes Care 2000;23:S57-S60.
28. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the second report of the national cholesterol education program (NCEP) expert pnael on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel II). JAMA 1993;269:3015-3023.
29. ETDRS Investigators. Aspirin effects on mortality and morbidity in patients with diabetes mellitus. JAMA 1992;268:1292-1300.
30. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of anti-platelet therapy---I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994:308:81-106.
31. American Diabetes Associaton. Aspirin therapy in diabetes. Diabetes Care 2000;23:S61-S62.
32. American Diabetes Association. Smoking and diabetes. Diabetes Care 2000;23:S63-S64.
33. The Tobacco Use and Dependence Clinical Practice Guideline Panel, Staff and Consortium Representatives. A clinical practice guideline for treating tobacco use and dependence. A US Public Health Service report. JAMA 2000;283:3244-3254.
34. Jorenby DE, Leischow SJ, Nides MA et al. A controlled tiral of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med 1999;340:685-691.
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Temple University School of Pharmacy is approved by the American Council on Pharmaceutical Education (ACPE) as a provider of continuing pharmaceutical education. Its CE programs are developed in accordance with the “Criteria for Quality and Interpretive Guidelines” of
ACPE. This program is acceptable for 2.0 hours of Continuing Education Credits (0.2
CEU) through September 30, 2003. ACPE Pgm I.D. 057-999-00-080-H01.
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