Aggressive Management of Type 2 Diabetes to Prevent Macrovascular Complications

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Behavioral Objectives

After completing this continuing education article, the pharmacist should be able to:

1. Describe the basic pathophysiology of macrovascular disease in patients with type 2 diabetes.

2. Identify appropriate nonpharmacologic components of a type 2 diabetes treatment plan.

3. Describe the impact of hypertension, dyslipidemia, and hyperglycemia on macrovascular risk in a patient with type 2 diabetes.

4. Generate an evidence-based pharmaceutical care plan for the reduction of macrovascular risk for a patient with type 2 diabetes.

5. Define the adverse effects of common drugs used in the management of macrovascular risk in patients with type 2 diabetes.

Type 2 diabetes has become an epidemic in the United States. According to the Centers for Disease Control and Prevention, approximately 7% of the American population, or 20.8 million people, have diabetes; of these, 90% to 95% have type 2 diabetes. Another 41 million people have prediabetes. The prevalence is climbing?1.5 million new cases of diabetes were diagnosed in 2005.¹

The result of long-term, poorly controlled diabetes is vascular injury. Vascular complications are categorized as microvascular or macrovascular. Common microvascular complications include retinopathy, nephropathy, and neuropathy.^1-4 Common macrovascular complications of diabetes include coronary artery disease (CAD), cerebrovascular disease, and peripheral vascular disease (PVD). CAD accounts for approximately 50% to 80% of deaths in patients with diabetes.^5-7 Astoundingly, the risk of first myocardial infarction (MI) in a patient with diabetes is similar to the risk of recurrent MI in a patient without diabetes.⁸ The risk of stroke is 2 to 5 times higher in patients with diabetes as compared with the nondiabetic population.^1,5,6,9 The risk of peripheral arterial disease is also greater in patients with diabetes than in those without diabetes. It has been estimated that 20% of patients with diabetes who are over 40 years of age and 29% of those over 50 years of age have peripheral arterial disease.¹⁰

Health professionals of all disciplines have a responsibility to care for each patient in such a way that the risk of diabetic complications is minimized. Pharmacologic management is pivotal in the care of these patients. Management and prevention are complicated, however, by the existence of several targets of therapy, multiple pharmacologic agents from which to choose, and the considerable patient education required. Pharmacists are uniquely positioned as drug experts to promote optimal use of the best medications proven or likely to prevent diabetic complications.Weight loss, appropriate dietary habits, and smoking cessation are, of course, pivotal in the treatment of type 2 diabetes.³ This article will focus on macrovascular complications of diabetes and aggressive pharmacologic strategies to prevent them.

Mechanisms of Macrovascular Disease

The basic mechanisms of macrovascular disease in patients with diabetes are similar to patients without diabetes in that it is a result of atherosclerosis. Low-density lipoprotein cholesterol (LDL-C) particles penetrate the outer layer of the vessel wall (endothelial lining), become oxidized, and form foam cells when engulfed by macrophages.¹¹ Foam cells, free lipids, inflammatory cells, and immune cells accumulate to form an atheroma.¹² A variety of patient-specific characteristics facilitate the process, such as hypertension and smoking.

Macrovascular events most often occur when the atheroma becomes exposed to the systemic circulation.¹² This occurs when the barrier separating the atheroma from the vessel lumen (fibrous cap) erodes or ruptures, exposing the atheroma contents to platelet-activating agents. Primary hemostasis occurs, resulting in a platelet plug, followed by the coagulation process and thrombus formation. It appears diabetic patients are hypersensitive to stimulators of platelet aggregation.¹³ An ischemic event occurs at the site of injury, or the thrombus embolizes and occludes an artery at a different location. The clinical sequelae depend on the location of the occlusion and include ischemic stroke, MI, or PVD.

Patients with diabetes have a characteristic dyslipidemia profile (diabetic dyslipidemia) increasing their cardiovascular risk. They generally have elevated triglycerides and low high-density lipoprotein cholesterol (HDL-C).¹⁴ LDL-C is often not markedly elevated in patients with diabetes. The LDL-C particles, however, tend to be a subtype that is small and dense.¹⁵ Small, dense LDL-C particles more easily penetrate the endothelial lining, induce more endothelial dysfunction, and are oxidized more easily than larger, more buoyant LDL-C particles. A strong relationship is found between LDL-C particle size and risk of CAD.^16,17

Through a variety of complex pathways, insulin resistance, hyperglycemia, and excess free fatty acids place patients at increased risk for atherogenesis.¹⁸ For example, advanced glycation end products (AGEs) are a class of reactive species formed in hyperglycemic patients.¹⁹ The actions of the reactive species and AGEs are thought to include accelerated oxidation of LDL-C,²⁰ apoptosis of endothelial cells,¹⁹ decreased availability of vasodilatory nitric oxide,²¹ and peroxidation of phospholipid membranes.^21,23 Each of these pathways, when present, likely contributes to vascular dysfunction.

Antiplatelet Therapy

Aspirin is an effective agent for primary or secondary prevention of macrovascular events. It accomplishes the effects through inhibition of thromboxane. Thromboxane is a potent vasoconstrictor and stimulator of platelet aggregation, a key step in primary hemostasis preceding thrombus formation.¹³

The Anti-Platelet Trialists meta-analysis included 145 prospective trials of patients with a history of MI, stroke, transient ischemic attack, or vascular surgery. Patients taking aspirin received risk reductions for cardiovascular disease (CVD) events of approximately 25%. Patients with diabetes and those without diabetes received comparable benefits.²³ Aspirin is also effective in primary prevention, with reductions in macrovascular events of 15% to 44%.¹³

The American Diabetes Association (ADA) recommends aspirin for primary and secondary prevention strategy for vascular events (Table 1).³ The recommended dose is 75 to 162 mg daily. Caution is appropriate in patients at increased risk of hemorrhagic complications. For those individuals who cannot take aspirin, clopidogrel is a viable option.³ Clopidogrel has demonstrated a reduction in CVD events in diabetic patients and also has proven synergistic benefits with aspirin in diabetic patients with a history of atherothrombosis.^24,25

Hypertension

Hypertension and diabetes are common comorbidities: >40% of patients with diabetes are hypertensive.⁹ Hypertension is part of the constellation of metabolic abnormalities referred to as the metabolic syndrome.²⁶ It is independently associated with ischemic heart disease and stroke.²⁷ Patients with hypertension and diabetes are at greater risk for macrovascular disease than patients with one condition or the other.^3,9 When both diabetes and hypertension are present, stroke risk is dramatically increased. A 19-year prospective study by Hu and colleagues evaluated stroke rates in patients with and without diabetes and hypertension. Compared to patients with neither disease, hazard ratios of 1.35, 2.54, and 3.51 were found for patients with stage I hypertension (blood pressure 140- 159/90-94 mm Hg), diabetes, and both diseases, respectively.⁹

It has been established that lowering blood pressure to <140/<80 mm Hg reduces risk of macrovascular disease in patients with diabetes^3,28 and that blood pressures >115/75 mm Hg are associated with increased cardiovascular event rates and mortality.^3,29 Hypertension should be treated aggressively. A clinical challenge is choosing the best pharmacologic agents from a myriad of choices.

Many blood pressure-lowering agents have mechanisms that are advantageous for diseases other than hypertension. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends selecting drugs for hypertension that have been established as beneficial for a concurrent diagnosis in the individual patient (ie, drugs with a compelling indication).²⁷ JNC 7 identifies diuretics, ?-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and calcium channel blockers (CCBs) as drugs with a compelling indication for patients with diabetes.²⁷ Available evidence and accepted guidelines guide the clinician in making drug therapy choices and recommendations (Table 2).

ACE inhibitors and ARBs are commonly used first line in patients with diabetes due to their established benefits in the prevention and treatment of diabetic nephropathy.³⁰ ACE inhibitors and ARBs have also proven themselves effective at reducing macrovascular events. In a Heart Outcomes Prevention Evaluation (HOPE) trial substudy,³¹ ramipril 10 mg daily was compared with placebo in 3577 diabetic patients over 55 years of age with or without CVD. The study found a 25% reduction (P = 1.0004) in the primary composite end point including MI, stroke, or cardiovascular death. Evidence also suggests that ACE inhibitors are superior to dihydropyridine CCBs in reducing cardiovascular events.^32,33

In the Antihypertensive and Lipid- Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),³⁴ lisinopril and amlodipine were each compared to chlorthalidone, a thiazide diuretic, in 33,357 patients with hypertension and 1 other CVD risk factor, with a primary outcome measure of combined fatal CVD or nonfatal MI. No difference was noted in the primary end point over an average of 4.9 years in either comparison. For secondary analyses, chlorthalidone had small but significant benefits over lisinopril for new heart failure, stroke, and combined CVD.The results of these secondary analyses were not corroborated by a subsequent open-label study evaluating ACE inhibitors and thiazide diuretics.³⁵

Evidence regarding the use of ?-blockers in patients with diabetes is inconsistent. When compared with ACE inhibitors, similar benefits were found in a group of patients with diabetes.³⁶ When atenolol was compared with losartan in diabetic patients with left ventricular hypertrophy, a statistically significant benefit was found favoring losartan for a composite end point of cardiovascular morbidity and mortality.³⁷ For patients with a history of MI, ?-blockers provide a clear lifesaving benefit.³⁸ A common concern regarding ?-blocker therapy in patients with diabetes is the potential for worsening insulin sensitivity and masking hypoglycemic episodes. These issues are usually easily managed and are not contraindications to ?-blocker therapy in diabetic patients.²⁷

JNC 7 and the ADA agree, hypertension should be aggressively treated to a target blood pressure of <130/<80 mm Hg in patients with diabetes, which normally requires the use of more than 1 pharmacologic agent.^3,27 The ADA provides a grade A recommendation favoring the use of ACE inhibitors, ARBs, ?-blockers, diuretics, or CCBs as first line in patients with diabetes and hypertension.³ A grade E recommendation (expert consensus/clinical experience) is provided favoring ACE inhibitors or ARBs as first line and thiazide diuretics as second line in patients with diabetes and hypertension.

Lipid Management

Elevated levels of LDL-C and triglycerides are both independent risk factors for macrovascular disease.²⁶ Low HDL-C (under 40 mg/dL) is an independent predictor of macrovascular disease.²⁶ Table 2 lists dyslipidemia goals of therapy. Although lifestyle modifications should be part of every treatment plan, this section will focus on pharmacologic therapy.

Pharmacologic options for dyslipidemia are numerous. Discussion below is focused on 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), fibric acid derivatives, and niacin.

Statins are the most commonly used and the most thoroughly studied drugs in the treatment of dyslipidemia in diabetic patients. By inhibiting HMG-CoA reductase, statins inhibit the rate-limiting step of cholesterol synthesis.³⁹ Statins lower serum cholesterol directly through this inhibition. The primary mechanism of LDL-C lowering by statins, however, is up-regulation of hepatic and peripheral LDL-C receptors, which are responsible for the uptake and catabolism of LDL-C.³⁹ See Table 3 for estimates of the effects of individual statins on each component of the lipid profile. Statins have pleiotropic benefits beyond their actions in the cholesterol cycle. They have anti-inflammatory properties, promote atherosclerotic plaque stability, enhance endothelial function,³⁹ and may improve LDL-C particle size distribution. The clinical utility of these properties requires more study.

Adverse effects associated with statin drugs include liver function test (LFT) abnormalities and statin myopathy (any muscle complaints relating to statins). LFT elevations occur at rates of 0.5% to 2.0% and are generally mild, dosedependent, and reversible.^40,41 In clinical trials, approximately 1% to 5% of patients taking statins report myalgia⁴² (muscle complaints without elevation of serum creatinine kinase).⁴⁰

Atorvastatin, pravastatin, and simvastatin have been established to reduce mortality and significant cardiovascular events in a variety of patient populations, especially those patients with established vascular disease.^43-50 A class effect is unproven, yet likely. Risk reductions are likely most associated with degree of LDL-C lowering.⁵¹ Prevention of cardiovascular events in diabetic patients with statin drugs has been evaluated in substudies of large clinical studies and in stand-alone studies. Six studies have evaluated statin therapy in patients with LDL-C values near 100 mg/dL.

Three studies have found atorvastatin and simvastatin to reduce cardiovascular events in patients with diabetes.^43,47,50 Risk reductions in the primary cardiovascular end points were 22% to 37% compared with the controls?a statistically significant finding. Of the 3 studies, 1 involved primary prevention,⁴³ and 2 studied patients for both primary and secondary prevention.^47,50 Another 3 studies evaluated primary prevention of CVD in diabetic patients that only identified a nonsignificant trend in reducing macrovascular events.^52-54 These trials contained significant limitations, rendering their results difficult to interpret.

The best evidence regarding statin therapy favors aggressive statin treatment for primary prevention in patients with diabetes, even when baseline LDL-C values are 100 to 115 mg/dL.^43,47,50 A log-linear relationship has been identified between LDL-C lowering and risk reduction for CVD.⁵¹ For every 30 mg/dL LDL-C is reduced, the relative risk for CVD is reduced 30% at any given baseline level of LDL-C.

The American College of Physicians recommends statins for primary prevention of macrovascular complications in patients with diabetes with a cardiovascular risk factor, regardless of baseline LDL-C value.⁵⁵ Risk factors include age older than 55 years, hypertension, smoking, left ventricular hypertrophy, previous cerebrovascular disease, peripheral arterial disease, or a history of a cardiovascular event. The ADA recommends statin treatment for all diabetic patients over the age of 40 years to achieve an LDL-C reduction of 30% to 40%, regardless of baseline levels or prior disease.³

Available fibric acid derivatives (fibrates) include gemfibrozil and fenofibrate. Their mechanism of action includes the activation of peroxisome proliferator-activated receptor a(PPAR-a).³⁹ The result is increases in lipolysis and elimination of triglyceride-rich molecules by activating lipoprotein lipase and reducing synthesis of apolipoprotein C-III.⁵⁶

Fibrates are effective for lowering triglycerides and raising HDL-C.²⁶ Their effects on LDL-C levels vary depending on the type of dyslipidemia present, but they can decrease LDL-C in some patient populations and raise LDL-C levels in others (usually in patients with very high baseline triglyceride levels).^39,56 Fibrates shift LDL-C composition to larger, less dense particles that are less atherogenic.^56,57 Given the effects of fibrates on HDL-C, triglycerides, and LDL-C particle size, they target typical diabetic dyslipidemia.

Available data establish gemfibrozil as effective in prevention of cardiovascular events in a group of veteran men with CVD.⁵⁸ A 24% risk reduction in nonfatal MI or death from coronary heart disease was seen. A recent study evaluated long-term fenofibrate use in patients with type 2 diabetes, but it failed to establish a significant benefit for fenofibrate 200 mg daily versus placebo for CVD death or nonfatal MI (hazard ratio 0.89, P = .16).⁵⁹

Adverse effects of fibrates include gallstones, myopathy, and increased LFT abnormalities. When fibrates are used in combination with statins, caution should be used due to an increased risk of all levels of myopathy, particularly with gemfibrozil.^40,60 The package insert of every available statin includes recommendations regarding combination use with fibrates.^61-66 Recommendations include a reduction in the maximum statin dose or a recommendation against com- bined use with one or both available fibrates. Until new research provides more information on optimal use, caution should be applied in the combined use of statins and fibrates.

Niacin, also known as nicotinic acid and vitamin B³, is an effective agent in the treatment of dyslipidemia. Niacin is advantageous in patients with diabetes because it offers a broad benefit on all 3 components of the fasting lipid profile (Table 3), and it reduces the number of small dense LDL-C particles.^67,68 No recent studies of niacin monotherapy for reduction of macrovascular end points in patients with diabetes have been conducted, however.

Niacin use has been limited, especially in diabetic patients, by its adverse-effect profile, which includes flushing, hepatic dysfunction, hyperglycemia, and upper gastrointestinal distress.⁶⁹ Incidence of each adverse effect varies with the formulation. Extended-release (ER) products of niacin are less likely to cause flushing, but they are more likely to cause hepatotoxicity.^39,70 Potential for hyperglycemia is a concern in diabetic patients. In 2 recent studies, researchers found no or modest elevations in blood sugar with low-to-moderate doses of niacin compared with placebo in patients with diabetes.^71,72 In a randomized, placebo- controlled study, niacin ER 1000 mg daily resulted in no significant change in the hemoglobin A1C (Hgb A1C) when compared with placebo. Niacin ER 1500 mg daily resulted in a modest, but significant increase in the Hgb A1C of 0.3% (7.2%-7.5%, P = .048).⁷² Niacin may be used in diabetic patients, but monitoring for hyperglycemia is necessary.

Statins should be first-line treatment for most patients with diabetes, because of their established benefits. Aggressive treatment with atorvastatin and simvastatin has proven to reduce macrovascular events in diabetic patients, and the effect is likely transferable to other statins and correlated mostly to LDL-C reduction. Fibrates and niacin target the dyslipidemia profile often seen in diabetics, but lack direct evidence of a reduction in macrovascular end points. The remaining drugs targeting dyslipidemia, such as ezetimibe, should be considered when additional LDL-C reduction is needed or when other agents are contraindicated or not tolerated.

Antidiabetic Drugs

Antidiabetic drugs are efficacious in decreasing Hgb A1C and fingerstick blood glucose values associated with type 2 diabetes. Evidence evaluating their effects on cardiovascular end points is lacking. Since the early 1990s, several studies have indicated that poor glycemic control may significantly contribute to cardiovascular risk.⁷³ Although preliminary data have found a benefit for decreasing cardiovascular risk, the data are conflicting. More studies are needed to establish and quantify the potential benefits of antidiabetic drugs on reducing cardiovascular risk. Each class of antidiabetic medications and their effects on CVD have been evaluated in some way, but insulin secretagogues, metformin, and thiazolidinediones (TZDs) are the most prevalent in the literature and will be reviewed here.

Continued in Answer section below.

Preliminary data suggest that postprandial hyperglycemia is an important factor contributing to atherosclerosis.⁷⁴ Postprandial hyperglycemia can trigger a series of pathophysiologic events that may favor the development of microand macrovascular complications.⁷⁵ The effects of insulin secretagogues on postprandial hyperglycemia and CVD have been evaluated. Insulin secretagogues can be divided into 2 subclasses, the sulfonylureas and nonsulfonylureas. Sulfonylureas have been a mainstay of oral therapy of diabetes for years.⁷⁶ They bind to the sulfonylurea receptor on the surface of pancreatic ?-cells and thereby stimulate insulin release in the basal state and in response to glucose load.^77-79 By interacting with specific receptors in the pancreas, endogenous insulin secretion is stimulated without affecting insulin synthesis. Additionally, sulfonylureas may promote insulin sensitivity and insulin receptor binding.⁷⁸ Sulfonylureas decreased Hgb A1C concentrations by 1.0% to 1.5% when compared with placebo in clinical studies.⁸⁰

The most common side effects associated with sulfonylurea use are weight gain and hypoglycemia. The average incidence of hypoglycemia is 1% to 2% per year in patients treated with sulfonylureas.⁷⁷ Other side effects that may occur with first-generation agents include hyponatremia, skin rash, and alcoholinduced flushing.^77-79

Nateglinide and repaglinide are currently the nonsulfonylurea insulin secretagogues approved for treatment of type 2 diabetes. These medications work similarly to sulfonylureas but differ in pancreatic binding site and pharmacokinetics. Regarding pharmacokinetics, they have a quicker onset and shorter half-life.⁷⁷ Repaglinide has similar efficacy to sulfonylureas, but nateglinide lowers the Hgb A1C by only 0.5% to 1.0%.These drugs are well-suited pharmacokinetically to target postprandial hyperglycemia.^78,79 Similar to sulfonylureas, the primary adverse effect of repaglinide and nateglinide use is hypoglycemia, although this occurs less frequently. Weight gain seems to be lower with these agents when compared with sulfonylureas as well.^77-79

Health care providers are concerned that sulfonylurea therapy may increase the risk for CVD. The first study evaluating this relationship took place over 30 years ago and was conducted by the University Group Diabetes Program (UGDP). The study compared the effects of placebo, standard insulin dose, variable insulin dose, and a sulfonylurea, tolbutamide, on cardiovascular mortality. Incidence of CVD mortality among the groups was 4.9% (placebo), 6.2% (standard-dose insulin), 5.9% (variable-dose insulin), and 12.7% (tolbutamide). The findings of the UGDP study led the FDA to require a black-box warning in sulfonylurea packaging, indicating an increased risk of CVD mortality. The results have been questioned and the methods criticized, but the black-box warning still remains.⁷⁶

The United Kingdom Prospective Diabetes Study (UKPDS) evaluated 3867 patients with new-onset diabetes and the development of micro-and macrovascular complications. The study indicated that treatment with sulfonylureas is not harmful.⁸¹ The study demonstrated significant benefits in lowering the incidence of microvascular complications with sulfonylurea treatment, and a subsequent epidemiologic analysis showed that macrovascular complications were also reduced with improved glycemic control.⁸¹ A study conducted by Esposito and colleagues⁸⁰ compared treatment with repaglinide and glyburide and their effects on carotid intima-media thickness and markers of systemic vascular inflammation in patients with type 2 diabetes; these are surrogate markers of CVD. Reductions occurred in carotid intima- media thickness and inflammatory markers in both groups. Improvements were greater in the repaglinide group. The reduction in carotid intima-media thickness was associated with decreased postprandial hyperglycemia.⁸⁰

Data conflict regarding the use of sulfonylureas for treatment of type 2 diabetes and their effects on cardiovascular risk. Further studies are needed to define the association, if one exists. It has been suggested that sulfonylurea use be minimized in patients with CVD until more answers are found.⁷⁶

As previously discussed, insulin resistance may contribute considerably to the development of CVD in patients with metabolic syndrome and type 2 diabetes. Metformin is a biguanide antidiabetic medication that decreases hepatic glucose production, primarily by decreasing gluconeogenesis. It also may increase glucose uptake into skeletal muscles and decrease insulin resistance.^77-79 Metformin decreases Hgb A1C levels by 1.0% to 1.5% as demonstrated by several clinical trials.^78,79,82 Regarding the Hgb A1C decrease, metformin monotherapy is thought to be equivalent to sulfonylurea monotherapy, and when the 2 are used concurrently, the benefits are additive. In addition to its effects on glycemic control, metformin has been associated with neutral effects on weight gain or weight loss, improvements in lipid profile, and decreased levels of C-reactive protein.^78,79 Metformin is approved for monotherapy or in combination with other agents to treat type 2 diabetes.⁸³

Common adverse effects associated with metformin use are diarrhea, anorexia, bloating, and abdominal discomfort. These may occur in 10% to 15% of patients and are dose-dependent. These effects usually improve with time and are minimized by initiating metformin at a low dose and titrating slowly.^78,79

A rare but life-threatening adverse effect of metformin is lactic acidosis. The reported incidence of lactic acidosis is very small (0.03/1000 patient-years), but when it does occur, it is fatal in approximately 50% of patients. Reported cases of lactic acidosis have occurred primarily in patients with significant renal insufficiency. Contraindications to metformin therapy include renal disease or renal dysfunction (serum creatinine level >1.5 for men and >1.4 for women, or abnormal creatinine clearance), congestive heart failure requiring treatment, and acute or chronic metabolic acidosis. These conditions, particularly heart failure and renal impairment, are common comorbidities of diabetes, significantly reducing the number of patients whom metformin is an appropriate agent. Additionally, patients with hepatic dysfunction and excessive alcohol intake should generally not receive metformin therapy due to increased risk of lactic acidosis.⁸⁴

Beyond its effects on glycemic control, metformin may decrease LDL-C and triglyceride levels and may positively affect endothelial function.⁷⁷ Robinson and colleagues⁸⁵ conducted 2 crossover studies evaluating the effects of metformin on glycemic control and serum lipids. When the results of both studies were combined, there was a 0.6-mmol/L (23-mg/dL) decrease in total cholesterol and LDL-C levels; these results were statistically significant.⁸⁵ In another study,⁸⁶ metformin significantly decreased total cholesterol, LDL-C, and triglyceride levels when used as monotherapy or when added to sulfonylurea therapy. HDL-C levels increased 1 to 2 mg/dL in each group receiving metformin therapy.⁸⁶

The UKPDS⁸⁶ demonstrated the benefits of metformin in decreasing the risk of complications related to type 2 diabetes. In this study, overweight, newly diagnosed diabetic patients randomized to metformin experienced lower weight gain, hypoglycemia, and decreased cardiovascular risk compared with a conventional therapy cohort who were primarily treated with diet alone. Researchers found a 36% risk reduction in all-cause mortality, 39% relative risk reduction in MI, and 30% relative risk reduction in all end points of macrovascular complications for metformin when compared with the conventional group (mostly treated with lifestyle interventions only); all of these results were statistically significant.⁸⁶ Although metformin demonstrated significant cardiovascular benefits in this UKPDS substudy, it has been criticized for its design, and the effect of metformin on macrovascular events is not confirmed.^3,87

Metformin is an effective agent to treat type 2 diabetes and is considered by many as a first-line therapy due to its effects on Hgb A1C levels, weight-neutral properties, and modest benefit in the lipid profile. Metformin may decrease macrovascular complications, although further evidence is needed to confirm the benefit.

TZDs (pioglitazone and rosiglitazone) exert their action primarily by improving insulin sensitivity in various target tissues, including liver, skeletal muscle, and adipose tissue. They are agonists of PPARs; PPARs regulate glucose, lipid, and protein metabolism. They also play a role in some inflammatory diseases. Insulin sensitivity is improved via agonism of PPAR-?. Pioglitazone may also partially activate the PPAR-a, the same receptor fibrates work through.

Both TZDs are approved for monotherapy in type 2 diabetes or for use with oral agents or insulin for treatment of type 2 diabetes.⁸⁸ TZDs are effective in achieving goals of glycemic control; they may decrease Hgb A1C by 1% to 1.5%, which is comparable to sulfonylureas or metformin.^88,89

The common adverse effects associated with TZDs include weight gain, edema, anemia, and hepatotoxicity.^88,89 Weight gain averages 4 kg and usually plateaus after 6 months.⁸⁸ TZDs cause edema in 4% to 6% of patients undergoing treatment as compared with 1% to 2% on placebo or other hypoglycemic medications.⁸⁹ Liver toxicity of TZDs varies between agents, although clinically significant hepatotoxicity is rare for both agents.⁸⁹

In recent years, concern over using TZDs in patients with heart failure or those at risk due to the edema that may sometimes accompany their use has emerged. The studies evaluating this relationship show conflicting data.⁹⁰ There are warnings on the risk of heart failure associated with TZD use, especially in patients with significant heart disease, but the data also show that heart failure can sometimes occur in patients with diabetes who are at low risk for such events.⁹⁰ For these reasons, the ADA and the American Heart Association developed recommendations for the use of TZDs in patients at risk. They recommend that TZDs may be used in patients with New York Heart Association (NYHA) class I or II heart failure, with lower initiation and treatment doses and close monitoring. They recommend against the use of TZDs in patients with signs and symptoms of NYHA class III or heart failure, due to a potential increased risk of edema and/or heart failure.⁹⁰ When considering the use of TZDs in patients who are at risk or have heart failure, careful attention should be paid to these recommendations to ensure patient safety.

TZDs have shown favorable effects on dyslipidemia in several studies. LDL-C levels have remained unchanged in studies evaluating treatment with pioglitazone in combination with sulfonylurea, metformin, or insulin. In studies with rosiglitazone, LDL-C levels have increased 8% to 16%. HDL-C levels have increased up to 10% in studies with either drug. Decreases in triglyceride levels have been seen more often with pioglitazone treatment versus rosiglitazone.⁸⁹ An open-label trial of 127 patients compared pioglitazone with rosiglitazone and found that pioglitazone significantly reduced total cholesterol and LDL-C levels more than rosiglitazone.⁸⁸ The benefits of pioglitazone therapy on dyslipidemias are likely related to its partial PPAR-aactivity, similar to fibrates, whereas rosiglitazone seems to have only PPAR-?activity.^39,90 The effects of TZDs on the lipid profile provide a theoretical benefit in macrovascular risk and are important considerations in clinical decision-making in treating patients with type 2 diabetes.

The PROactive^91,92 clinical trial is among a series of studies evaluating the macrovascular effects of pioglitazone in patients with type 2 diabetes. This study evaluated the effects of pioglitazone on the progression of atherosclerosis and tested the hypothesis that pioglitazone decreases the incidence of macrovascular complications associated with type 2 diabetes in patients at high risk.⁹¹ A total of 5238 patients with type 2 diabetes and macrovascular disease were randomized to receive either pioglitazone (15 to 45 mg daily) or placebo. The primary end point was a composite of end points of allcause mortality, nonfatal MI (including silent infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle.⁹²

In the PROactive study,⁹² patients randomized to receive treatment with pioglitazone had a 10% reduction in the primary end point; this result was not statistically significant when compared with the placebo group. The results of this investigation indicated, however, that pioglitazone improved glucose, HDL-C, and triglyceride levels and, interestingly, blood pressure. Patients in the pioglitazonetreated group had a 16% reduction in the occurrence of the secondary end point (composite of all-cause mortality, nonfatal MI, and stroke), and this result was statistically significant. Safety and tolerability were similar between the treatment and placebo groups. The investigators concluded that pioglitazone reduces the risk of all-cause mortality, nonfatal MI, and stroke in patients with type 2 diabetes at high risk for macrovascular events.⁹² Given the significant differences found between secondary end points, however, further studies are needed to confirm the results.

The DREAM trial⁹³ is an international, multicenter randomized, double-blind, controlled trial that will evaluate whether treatment with ramipril and/or rosiglitazone prevents diabetes or reduces the number of new cases of diabetes. The study includes 5269 patients with impaired glucose tolerance (IGT) or impaired fasting glucose (IFG). The primary outcome of the study is newly diagnosed diabetes or death. The secondary outcomes are a composite of cardiac and renal events, and also the effects of either medication on fasting and postprandial glucose levels, regression to normal glucose levels, Hgb A1C levels, and insulin secretion. Of those randomized, 35% have IGT, 14% have IFG, and 51% have a combination of both.⁹³ Initial results of the DREAM trial have recently been released. Results from the ramipril arm of the trial showed no statistically significant difference in the primary outcome, but patients receiving ramipril treatment were more likely to show regression to normoglycemia; this result was statistically significant.⁹⁴ The participants treated with ramipril also had statistically significant decreases in systolic and diastolic blood pressure values.⁹⁴ The results of this study indicate that ramipril may favorably affect glucose metabolism, similar to the beneficial metabolic effects of ramipril demonstrated in the HOPE trial, which evaluated ramipril over a longer period of time.^94-95 Further research is needed to clarify the effects of ramipril on glucose metabolism, incidence of new-onset diabetes, and cardiovascular morbidity. ^94-95

The rosiglitazone arm of the DREAM⁹⁶ study showed promising results. Individuals receiving rosiglitazone had significantly less (11.6%) occurrence of the primary outcome than placebo (26%), and this result was statistically significant. Additionally, participants receiving rosiglitazone showed regression to normoglycmia (50.5%) more than the placebo group (30.3%), and this result was also statistically significant. There was no significant difference in cardiovascular event rates between the rosiglitazone and placebo groups.⁹⁶ The results of this arm of the DREAM study indicate that rosiglitazone may significantly reduce the incidence of type 2 diabetes and reduce glycemic levels to normal in those patients at risk.⁹⁶ Further studies in this area are needed to confirm these results and the potential benefits of rosiglitazone on cardiovascular morbidity and mortality.⁹⁶

The results of the PROactive study show some promising results regarding pioglitazone and potential cardiovascular benefits. The results of the DREAM trial and other upcoming study results investigating the effects of TZDs on cardiovascular risk should clarify the role of TZDs in patients at high risk or who already have CVD. Additional ongoing studies include the Study of Atherosclerosis with Ramipril and Rosiglitazone (STARR),⁹⁷ the Carotid intima-media tHICkness in Atherosclerosis using pioGlitazOne (CHICAGO),⁹⁸ and the Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation (PERISCOPE).⁹⁹ The STARR trial is evaluating the effects of ramipril and/or rosiglitazone on carotid intima-media thickness and is a substudy of the DREAM trial. Randomization began in July 2001 and the study end is projected for April 2007.⁹⁷ The CHICAGO study is an 18-month randomized study that has enrolled 439 patients with type 2 diabetes from the Chicago area. The study will compare the effects of pioglitazone and glimepiride on carotid intima-media thickness. The study will also assess for the occurrence of cardiovascular events and CVD risk among patients with type 2 diabetes.⁹⁸ The PERISCOPE study is comparing the effects of pioglitazone and glimepiride on the rate of progression of coronary artery atherosclerosis. Randomization began in August 2003 and the study end is projected for March 2008.⁹⁹

Summary

Macrovascular complications are a common source of morbidity and mortality in patients with type 2 diabetes. Pharmacologic treatment to maintain target blood pressure, reduction of LDL-C, and platelet antagonism are established methods to reduce the incidence of macrovascular complications and should be incorporated as soon as indicated. Improvement of glycemic control has not been established to reduce macrovascular complications. Evidence, albeit imperfect, does indicate that metformin and pioglitazone may reduce macrovascular complications. Definitive data are needed to confirm and quantify the benefit.

Pharmacists in many settings are uniquely positioned to advocate optimal drug use through patient education, physician education, and interventions on behalf of individual patients.

Todd R. Marcy, PharmD, BCPS, CDE, Assistant Professor, Department of Pharmacy; Stephanie Barud, PharmD, Clinical Assistant Professor, Department of Pharmacy; Clinical and Administrative Sciences, University of Oklahoma Health Sciences Center College of Pharmacy

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