A Review of Cardiovascular Comorbidities of Diabetes

Learning ObjectivesAfter completing this continuing education article, the pharmacist or physician should be able to:

2. Explain the risk factors and pathophysiology of diabetes and its cardiovascular comorbidities.

4. Recommend lifestyle changes for diabetes, hypertension, and dyslipidemia to reduce the risk of CVD.

6. Discuss the role of diabetes self-management education programs.

B = Blood pressure

Insulin resistance is also a recognized component of a constellation of risk factors commonly referred as metabolic syndrome.⁷ Table 1 lists an updated definition of the diagnostic criteria of the metabolic syndrome by the American Heart Association and the National Heart, Lung, and Blood Institute.⁸ For a diagnosis of metabolic syndrome, 3 of the criteria listed in Table 1 are required. Identifying metabolic syndrome is important because of its link to cardiovascular morbidity and mortality⁹ and the development of diabetes. In fact, metabolic syndrome is associated with a 5- to 9-fold increase in risk for the development of type 2 diabetes.¹⁰

Diabetic DyslipidemiaAs a precursor to the onset of diabetes, lipid or cholesterol abnormalities begin occurring in what is known as an asymptomatic diabetic prodrome. During this time, very-low-density lipoprotein (VLDL) levels increase and the activity of insulin-dependent lipoprotein lipase, an enzyme that is normally responsible for removing triglycerides from food following consumption, slows. In a state of insulin deficiency, this enzyme is unable to work at maximum capacity, resulting in an increase in triglycerides in the bloodstream. Triglycerides enrich high-density lipoprotein (HDL) and low-density lipoprotein (LDL), resulting in the formation of small, dense LDL particles, which can be more easily oxidized. This leads to increased levels of potentially atherogenic particles and decreased HDL cholesterol levels. These triglycerideenriched lipoproteins, in patients with insulin resistance and type 2 diabetes, are able to enter vessel walls because of their smaller size, where they are oxidized. These particles bind to receptors on macrophages and are then phagocytized, subsequently leading to the formation of an atherosclerotic lesion.

This characteristic pattern–low HDL, elevated triglycerides, and small, dense LDL particles–is commonly referred to as diabetic dyslipidemia.^11,12 Currently, the National Cholesterol Education Program Adult Treatment Panel III (ATP III) and the American Diabetes Association (ADA) recommend the following goals: LDL <100 mg/dL, triglycerides <150 mg/dL, and HDL >40 mg/dL in men and >50 mg/dL in women (ADA only–ATP III classifies HDL levels). Currently, LDL remains the primary target of therapy because of its close association with CVD.^13,14 An optional LDL goal of <70 mg/dL has been proposed in patients with diabetes who also have evidence of CVD.15 Statins are commonly used to achieve the LDL goal and improve other cholesterol parameters. Combination therapy with a fibric acid derivative, cholesterol absorption inhibitor, nicotinic acid derivative, or bile acid resin may also be warranted to achieve target cholesterol goals. Similar to hypertension, lifestyle modifications such as dietary changes, weight reduction, and increased physical activity should be encouraged. Dietary modifications should include reductions in saturated fat intake (<7% of total calories) and cholesterol (<200 mg/day) and increases in plant stanols and sterols (2 g/day) as well as soluble fiber (10-25 g/day).¹³

Hypertension

Lifestyle recommendations are critical as an integral part of appropriate blood pressure management. Weight reduction of approximately 10 kg can result in a 5- to 20-mm Hg reduction in blood pressure. In addition, adopting the Dietary Approaches to Stop hypertension (DASH) diet that focuses on fruit and vegetable intake with low-fat dairy products and reduced saturated and total fats should also be encouraged. restricting dietary sodium intake to ≤2.4 g of sodium each day may lower blood pressure by 2 to 8 mm Hg. Performing ≥30 minutes of physical activity most days a week can help patients control blood pressure. Finally, restricting alcohol consumption to ≤2 drinks per day for men or 1 drink per day for women (where 1 drink is equivalent to 12 oz of beer, 5 oz of wine, or 1.5 oz of 80-proof liquor) is also beneficial to achieve target blood pressure goals.¹⁷

In the United States, smoking is the most preventable cause of mortality and is responsible for 1 of every 5 deaths. Smoking is associated with reduced fasting insulin levels and increased blood glucose levels.23 In the Nurses' Health Study, 114 247 women without diabetes, heart disease, or cancer were followed for 12 years. During this time, 2333 incident cases of type 2 diabetes were confirmed. After controlling for other risk factors, the relative risk of developing type 2 diabetes among women who smoked 25 or more cigarettes per day was 1.42 (95% CI, 1.18-1.72) compared with women who had never smoked.²⁴ Not only has smoking been implicated in the development of diabetes, it also increases the risk for microvascular complications. Thus, smoking cessation should be encouraged for all patients who smoke at every patient encounter.

Behavioral strategies and patient/ group counseling may also be a part of smoking cessation management. Pharmacologic options such as nicotine replacement therapy, bupropion, tricyclic antidepressants, and varenicline are effective in helping patients stop smoking. These therapies should be tailored to meet the needs of the individual patient.^23,25

5 Keys to Approaching Smoking Cessation

- Assess–interest in smoking cessation for current smokers

- Assist–in establishing a quit date, providing patient education, and helping in medication selection, if warranted

Reducing the Risk of CVD: Controlling Blood GlucoseAdequate glycemic control should also be implemented as an essential component for the management of diabetes to reduce microvascular and macrovascular complications. Earl diagnosis and treatment of diabetes is encouraged to reduce the complications associated with the disease. In fact, the classification of prediabetes (fasting blood glucose 100-125 mg/dL) by the ADA is used to target patients who are at risk for the development of diabetes and its complications. For patients with diabetes, a fasting preprandial blood glucose goal of 90 to 130 mg/dL and a postprandial blood glucose goal of <180 mg/dL are currently advised by the ADA. Also, hemoglobin A1C levels are targeted to <7% in the general population but may be targeted to <6% in individual patients.¹⁴

Metformin, a biguanide, is considered to be the gold standard of therapy for the treatment of type 2 diabetes.¹⁴ In addition to its ability to reduce fasting blood glucose and hemoglobin A1C levels via reducing hepatic gluconeogenesis, metformin has been shown to reduce cardiovascular events and deaths compared with other therapies.^26,27 Because many patients will require more than one medication to achieve glycemic control, the benefit of combination therapy for cardiometabolic risk reduction has been evaluated. Thiazolidinediones (TZDs), which include pioglitazone and rosiglitazone, are peroxisome proliferatoractivated receptor (PPAR)-gamma agonists that mediate glucose and lipid metabolism via activation of the nuclear transcription factor. PPARgamma activation results in triglyceride reduction and improvements in insulin sensitivity.¹⁰

In a 12-month, randomized, doubleblind, multicenter, parallel-group trial, glucose, coagulation, and fibrinolysis parameters in patients with a =6- month history of type 2 diabetes and metabolic syndrome who were experiencing either poor glycemic control or adverse effects on the maximum dose of metformin were assessed. A group of 96 patients continued to receive metformin but were randomized to receive either pioglitazone 15 mg once daily or rosiglitazone 4 mg once daily for 12 months. No changes in either group were noticed after 3 and 6 months of treatment. After 9 and 12 months of therapy, however, hemoglobin A1C levels, fasting plasma glucose, and postprandial blood glucose levels were significantly reduced in both groups. Total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels improved after 1 year of treatment in the pioglitazone group (P <.05 for comparison to baseline and to the rosiglitazone group). No significant improvements in total cholesterol, LDL cholesterol, or triglycerides were noted in the rosiglitazone group, however. Lipoprotein(a) levels, a risk marker for atherosclerosis, were significantly improved in the pioglitazone group compared with baseline (P <.05) and to the rosiglitazone group (P <.05). Both groups had significantly reduced homocysteine levels, another marker of atherosclerosis (P <.05 for both groups).²⁸

A similarly designed study using glimepiride, a second-generation sulfonylurea, was conducted. In this 12- month, double-blind, randomized, controlled, multicenter trial, 91 patients with a ≥6-month history of type 2 diabetes and metabolic syndrome with poor glycemic control or who were intolerant of diet, oral hypoglycemic agents, or metformin were included to assess various glycemic, coagulation, and fibrinolysis end points. All patients received glimepiride 4 mg/day divided into 2 doses. Patients were then randomized to receive pioglitazone 15 mg once daily or rosiglitazone 4 mg once daily. After 9 and 12 months of treatment, patients in both groups experienced significant improvements in glycemic control as determined by hemoglobin A1C, fasting plasma glucose, and postprandial blood glucose levels, compared with baseline. Comparisons to each treatment group were not significant. Patients in the pioglitazone group experienced improvements in all cholesterol parameters after 12 months of treatment when compared with baseline. Patients treated with rosiglitazone experienced improvements in cholesterol parameters, except for HDL when compared with baseline. These values were significantly different between the 2 treatment groups, however (Table 2).²⁹ The findings on lipid profiles are consistent with data from a meta-analysis that found that total cholesterol, LDL, and triglyceride levels were higher in patients treated with rosiglitazone compared with pioglitazone.³⁰

Although TZDs have demonstrated positive results in the previous studies, the same findings were not elucidated in a secondary prevention trial. The Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) trial was a randomized, prospective study of 5238 patients with type 2 diabetes and a history of macrovascular disease defined as an MI or stroke ≥6 months prior to study entry, acute coronary syndrome or coronary artery bypass surgery ≥3 months prior to study entry, or objective evidence of coronary artery disease or obstructive arterial disease in the leg. Patients were randomized to receive either pioglitazone 15 mg once daily titrated to 45 mg once daily or placebo, in addition to current diabetes medications. After an average of 34.5 months of therapy, 19.7% of patients in the pioglitazone group compared with 21.7% of patients in the placebo group experienced ³1 event of the primary composite end point: all-cause mortality, nonfatal MI, stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle (hazard ratio [HR], 0.90; 95% CI, 0.80-1.02; P = .095). In addition, patients treated with pioglitazone experienced improvements in most cholesterol parameters, although LDL levels slightly increased.^31,32

Late-breaking Safety Issues Recent attention has been placed on the safe use of rosiglitazone in patients with diabetes.³³ A meta-analysis of 42 trials comparing rosiglitazone with placebo and other comparators found an increased risk for MI (summary odds ratio for MI, 1.43 [95% CI, 1.03- 1.98; P = .03]) and death from cardiovascular causes (summary odds ratio for death from cardiovascular causes, 1.64 [95% CI, 0.98-2.74; P = .06]). Similar findings were noted when rosiglitazone was compared with other drugs as well as placebo, suggesting that other drugs were not necessarily protective of harmful effects. The authors discovered similar findings when looking at shorter-term trials (ie, 24-52 weeks), which may suggest that the risk for MI is a concern even following short-term treatment with the medication.

Debate over the question of how rosiglitazone increases the risk for MI is ongoing. Several theories have been posited, including the medication's adverse effect on the lipid profile; its ability to cause heart failure, which ultimately increases myocardial oxygen demand to cause ischemia; and its ability to induce a state of physiologic stress through hemoglobin A1C reduction to cause ischemia. Consideration has been given to differences in the pattern of gene activation and suppression via PPAR-gamma agonism.³³ At the time of publication, the US Food and Drug Administration (FDA) convened with an expert panel to discuss the increased cardiovascular risks associated with rosiglitazone based on the meta-analysis findings. The majority voted to keep rosiglitazone available on the market,³⁴ although the committee advised the immediate institution of warning labels and educational efforts. Questions about the data were raised, such as the consistency of the findings, especially in the trials that had comparator arms instead of placebo; in addition, the risk for ischemia appeared to be highest in patients receiving long-term nitrates and in those taking insulin. The chair of the FDA advisory committee published a report suggesting that future clinical trials involving medications for the treatment of type 2 diabetes should attempt to use clinical outcomes for end points, such as reductions in CVD, rather than surrogate markers alone such as hemoglobin A1C reduction.³⁵

Does This Hold True for Pioglitazone?

As with blood pressure and cholesterol, lifestyle modifications should be considered in patients with diabetes to lower blood glucose levels. Carbohydrate monitoring either by counting or exchanges should be encouraged to help patients achieve glycemic goals. Low-carbohydrate diets (<130 g/day) are not recommended, however, because the long-term effects of these diets are unknown. The ADA also advises ≥150 minutes each week of moderate-intensity physical activity or 90 minutes each week of vigorous aerobic exercise to reduce the risk of CVD.¹⁴

The ADA has developed recommendations for the use of aspirin in patients with diabetes. Aspirin reduces the risk for CVD by acting as an inhibitor of thromboxane synthesis to reduce vasoconstriction and platelet aggregation.³⁷ A great deal of evidence has demonstrated the benefit of aspirin in the primary and secondary prevention of heart disease in men and women with diabetes.^19,38-40 Table 3 lists specific recommendations on the use of aspirin in patients with diabetes. Doses of 75 to 162 mg/day are typically recommended and have been shown to be as effective as higher doses of aspirin. It is important to note that enteric-coated formulations do not appear to reduce the risk for gastrointestinal bleeding.³⁷

The Importance of the Patient's Own Effort

Harvey is a 47-year-old obese Native American man who comes into your clinic with the following primary complaint: “I have been peeing a lot more throughout the day and at night and seem to be thirsty all the time. It feels just like when they diagnosed me with diabetes a year ago.†As you look at his chart, you learn that he has a history significant for type 2 diabetes (1 year), hypertension (10 years), benign prostatic hyperplasia (1 year), and gout (“for as long as I can remember”). You also notice that he is taking metformin 1000 mg twice a day, rosiglitazone 4 mg daily, tamsulosin 0.4 mg

15 years. He also drinks 1 beer with dinner each night. His mother died at age 64 of breast cancer, and his father died at age 50 of an MI. He tells you that he measures

Patients like Harvey, who have diabetes, are at increased risk for microvascular and macrovascular complications. Thus, achieving glycemic, blood pressure, and cholesterol goals are vital to reduce the risk for these complications, especially CVD. Harvey also meets the criteria for the metabolic syndrome (ie, low HDL levels, hypertension, elevated fasting blood glucose, and elevated waist circumference), another strong CVD predictor. The importance of medication adherence should be emphasized to help Harvey achieve these goals. The recent controversy surrounding rosiglitazone has spurred patients to present with concerns about its safety. The FDA has voted to keep the product on the market unless further studies demonstrate the need to remove it. The highest risk for MI appears to be in older patients, those with existing coronary disease, and in patients taking insulin, none of which describe Harvey. His lipid panel is somewhat concerning, however. He is not at his LDL, HDL, or total cholesterol goals. Rosiglitazone has been noted to have an adverse effect on the lipid profile and thus may potentially push his cholesterol values further from goal. Therefore, if TZD therapy is to be continued, the patient should be educated about the risks versus the benefits of pioglitazone, which may have a more favorable effect on the lipid profile. TZD therapy has also been shown to improve lipoprotein(a) and homocysteine levels, both of which are markers of atherosclerosis. Combination therapy consisting of metformin and a TZD has shown efficacy in lowering the risk for heart disease. Educating Harvey on the signs and symptoms of an MI is also warranted. If noncompliance with TZD therapy is a concern because of his fear of adverse effects, suggesting a therapy switch to a sulfonylurea may be warranted. It is important that he take his medication daily to achieve his fasting blood glucose (90-130 mg/dL) and hemoglobin A1C (<7%, possibly <6%) target values. Harvey will also need therapy to attain his cholesterol goals: LDL goal, <100 mg/dL and HDL goal, >40 mg/dL. Statins are considered first-line agents to achieve the primary cholesterol target, LDL. Once the LDL goal has been achieved, secondary targets such as HDL and/or the metabolic syndrome may be considered. Although his blood pressure

CVD, and provide protection against the development of nephropathy. Ensuring that Harvey's potassium level and serum creatinine are within range is important for the safe use of ACE inhibitor therapy. With the exception of his cholesterol parameters, all other labs were within normal levels.

Smoking cessation should be encouraged in this patient. It is important to assess Harvey's stage in the cessation process and to assure him that help is available whenever he is ready to quit. Smoking cessation can help lower his blood pressure, reduce the risk for lung and heart disease, and improve his overall quality of life. If he is not ready to quit smoking today, smoking cessation should be assessed and encouraged at every patient encounter.

Because Harvey has type 2 diabetes and his age is >40 years, he is also a candidate for aspirin therapy for the primary prevention of CVD. He also has a family history of heart disease (father died from an MI at age 50) and currently smokes. Thus, initiation of aspirin 75-162 mg/day can help reduce thromboxane synthesis to prevent platelet aggregation. Encouraging physical activity, weight loss, and dietary modifications such as reductions in saturated fats, cholesterol, and sodium; increasing soluble fiber and plant stanols/sterols; and monitoring carbohydrate intake are also important lifestyle modifications to help achieve blood pressure, cholesterol, and glycemic goals. Finally, enrolling Harvey in a DSME program where he is at the center of the decision-making

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