Implications of Rosiglitazone and Pioglitazone on Cardiovascular Risk in Patients With Type 2 Diabetes Mellitus

Brian K. Irons, PharmD; Ronald Shane Greene, PharmD; Timothy A. Mazzolini, PharmD; Krystal L. Edwards, PharmD; Rebecca B. Sleeper, PharmD

Pharmacotherapy. 2006;26(2):168-181. 

Abstract and Introduction

Abstract

Clinical data suggest that thiazolidinediones-specifically, rosiglitazone and pioglitazone-may improve cardiovascular risk factors through multiple mechanisms. Low insulin sensitivity has been described as an independent risk factor for coronary artery disease and cerebrovascular disease. Patients with insulin resistance often have several known risk factors, such as obesity, dyslipidemia, and hypertension. Other emerging risk factors may be prevalent in patients with insulin resistance, such as hyperinsulinemia, elevated C-reactive protein, elevated plasminogen activator inhibitor levels, and small, dense, low-density lipoproteins. The only available drug class that primarily targets insulin resistance is the thiazolidinediones. These drugs have shown efficacy in affecting surrogate markers of cardiovascular risk in patients with diabetes mellitus. Alterations in these risk factors are likely due to their effects on improving insulin sensitivity and/or glycemic control. Trials to assess whether thiazolidinediones actually reduce cardiovascular outcomes are continuing.

Introduction

Patients with type 2 diabetes mellitus have a significantly higher risk for cardiovascular disease than those without diabetes. The risk of a cardiovascular event or death in a patient with diabetes is similar to that in a patient with existing heart disease and no diabetes.[1] Type 2 diabetes is considered the sixth leading cause of death in the United States, with most of these deaths attributed to cardiovascular disease.[2,3] With respect to treatment costs, more of the direct costs are for treating the cardiovascular complications of diabetes than for any other complication.[4] With a 2–4-fold higher risk of heart disease or cerebrovascular disease and the increasing prevalence of diabetes in the United States, the toll of diabetes-related heart disease in the decades to come is nothing less than alarming.[3,5]

Increasing clinical data suggest that thiazolidinediones may reduce cardiovascular risk factors through multiple mechanisms.[6–10] Much of the literature supporting this potential new role of thiazolidinediones is centered around troglitazone, which was taken off the U.S. market several years ago secondary to the risk of hepatotoxicity. Thus, this review focuses specifically on the human data connecting cardiovascular risk reduction and the currently available thiazolidinediones in the United States, rosiglitazone and pioglitazone.

Thiazolidinediones and Insulin Resistance

The causes of cardiovascular complications related to diabetes are multifactorial. Alterations in lipids, platelet activity, hypercoagulability, abnormal blood flow, and endothelial dysfunction have been implicated in perpetuating cardiovascular disease risk in patients with diabetes.[3,5,11] How these alterations come about as a result of diabetes is still a point of significant research, but insulin resistance may be one of the primary underlying causes. Diabetes often starts with underlying insulin resistance, which leads to a compensatory increase in pancreatic insulin output to maintain euglycemia.[12] Eventually, the body's insulin output can no longer overcome these alterations in insulin sensitivity, which leads to the characteristic hyperglycemia associated with diabetes.

Low insulin sensitivity has been described as an independent risk factor for coronary artery and cerebrovascular disease.[13-15] Patients with insulin resistance often have several known cardiovascular disease risk factors, such as obesity, dyslipidemia, and hypertension, which are now more commonly referred to as the metabolic syndrome.[16-19] Other emerging cardiovascular disease risk factors may be prevalent in patients with this syndrome, such as hyperinsulinemia, elevated C-reactive protein (CRP) and plasminogen activator inhibitor type 1 (PAI-1) levels, and small, dense, low-density lipoprotein cholesterol (LDL) particles.[17,18]

Treatment strategies to reduce cardiovascular disease in patients with diabetes are aggressive hypertension and lipid control, and antiplatelet therapy.[11,20] Intuitively, improving glycemic control might reduce cardiovascular outcomes; in addition, some epidemiologic evidence has shown a reduction in cardiovascular risk with improved glycemic control.[21-23] However, large-scale prospective interventions to improve glycemic control have demonstrated improvements in the microvascular complications of diabetes but have not shown significantly reduced cardiovascular outcomes.[21] Limited data suggest metformin for patients with diabetes who are overweight[24] or acarbose to reduce cardiovascular events.[25] Continuing prospective studies designed primarily to assess glycemic control on cardiovascular outcomes are pending.[26]

The only class of drugs available that primarily targets insulin resistance is the thiazolidinediones. These drugs act as potent agonists of peroxisome proliferator-activated receptor β (PPAR-γ), which is expressed primarily in adipose tissue but can be found in the muscle, liver, pancreas, and vasculature.[6] Thiazolidinediones exert their hypoglycemic effect by binding to PPAR-γ receptors, which then alter the expression of proteins implicated in the metabolism of lipids and glucose. This leads to more insulin-sensitive cells and hence reduced insulin resistance.[7,27]

How thiazolidinediones work in the body to reduce insulin resistance is multifactorial, complex, and beyond the scope of this review. The effects of thiazolidinediones in altering insulin resistance lead to their utility in reducing hyperglycemia in patients with diabetes. Given the relationship between insulin resistance and cardiovascular risk of diabetes, drugs that specifically improve insulin resistance may offer new hope in reducing cardiovascular risk in addition to improving glycemic control.

Cardiovascular Risk Factors

Dyslipidemia

Dyslipidemia is a well-known risk factor for cardiovascular disease. Patients with diabetes have an increased prevalence of dyslipidemia, which increases their overall rate of developing cardiovascular disease.[20] This increased risk is recognized by the third report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.[16] The panel designated diabetes as a coronary heart disease risk equivalent, placing diabetic patients' lipid panel goals at the same level as those for patients with existing cardiovascular disease.

The lipid profile abnormalities associated with diabetes—more specifically, insulin resistance— include elevated triglyceride levels, decreased high-density lipoprotein cholesterol (HDL) levels, and a qualitative change to small, dense LDL particles. Collectively, this lipid profile lends itself to a greater risk of atherosclerosis. The pathophysiology and association with increased atherosclerosis risk of the diabetic dyslipidemia profile has been reviewed elsewhere.[28-31] Briefly, in patients with hyperglycemia and insulin resistance, production and retention of triglyceride-rich very low-density lipoprotein cholesterol (VLDL) particles are increased. These VLDL particles, through cholesteryl ester transfer protein, exchange triglyceride components for cholesteryl esters (core lipids) in both LDL and HDL particles. While in the liver, the triglyceride-rich LDL and HDL particles may undergo hydrolysis by hepatic lipase or lipoprotein lipase. This hydrolysis, coupled with the net loss in cholesteryl esters, leads to smaller, denser LDL and HDL particles. According to one theory, the increase in atherosclerotic risk associated with small, dense LDL particles may be related to greater susceptibility of the particles to oxidation, longer resident time in the body due to diminished affinity for LDL receptors, and increased permeability through cell membranes due to the smaller particle size.[31]

In addition to their ability to decrease insulin resistance and ultimately improve hyperglycemia, the thiazolidinediones increase lipid uptake and storage within the adipocytes by means of the PPAR-γ receptor.[32] As such, this class of agents would logically be a target for improving the atherogenic diabetic dyslipidemia profile. Two large meta-analyses evaluated the effect of rosiglitazone and pioglitazone therapy on diabetic dyslipidemia.[10,33] The earlier one assessed randomized, double-blind, placebo-controlled studies in which either rosiglitazone 4 or 8 mg/day or pioglitazone 15, 30, or 45 mg/day was administered as monotherapy or in combination with other antidiabetic agents in patients with diabetes for at least 8 weeks.[33] Nineteen trials evaluating 3236 rosiglitazone-treated and 2068 pioglitazone-treated patients met the criteria for inclusion in this metaanalysis.

Rosiglitazone monotherapy, compared with pioglitazone monotherapy, significantly increased LDL (16.6 vs 2.7 mg/dl, p < 0.05) and total cholesterol (26.3 vs 1.92 mg/dl, p < 0.05) levels. Pioglitazone monotherapy also significantly lowered fasting triglyceride levels, whereas rosiglitazone monotherapy mildly increased these levels (-19.7 vs 8.1 mg/dl, p < 0.05). The same statistically significant differences persisted when rosiglitazone combination therapy was compared with pioglitazone combination therapy.

The second meta-analysis evaluated randomized controlled trials that involved at least 30 patients with diabetes receiving either rosiglitazone 4 or 8 mg/day or pioglitazone 30 or 45 mg/day as either monotherapy or in combination with other antidiabetic agents for at least 12 weeks.[10] Twenty-three trials enrolling over 3000 patients receiving pioglitazone and over 5000 receiving rosiglitazone met the inclusion criteria (12 of these trials were also included in the earlier meta-analysis[33]).

Rosiglitazone significantly increased LDL (15.3 mg/dl, 95% confidence interval [CI] 13.0–17.5) and total cholesterol (21.3 mg/dl, 95% CI 17.7–24.9) levels. By comparison, pioglitazone had neutral effects on LDL (-0.4 mg/dl, 95% CI -4.7–3.9) and total cholesterol (-0.1 mg/dl, 95% CI -5.3–5.1) levels. In addition, pioglitazone reduced fasting triglyceride levels (39.7 mg/dl, 95% CI -53.1 to -26.4) compared with rosiglitazone (-1.1 mg/dl, 95% CI -14.5–12.3). Both rosiglitazone and pioglitazone significantly improved HDL (2.71 and 4.55 mg/dl, respectively).

In the first multicenter, prospective, randomized, double-blind, placebo-controlled trial conducted, pioglitazone was directly compared with rosiglitazone in patients with diabetes and mild dyslipidemia (mean baseline LDL level 108 mg/dl).[34] Patients taking cholesterol-lowering drugs at the time were excluded. Pioglitazone 30 mg/day, titrated to 45 mg/day, was administered to 369 patients, and rosiglitazone 4 mg/day, titrated to 8 mg/day, to 366 patients.

Over a 24-week period, pioglitazone therapy, compared with rosiglitazone therapy, significantly decreased triglyceride levels (-51.9 vs 13.1 mg/dl, p < 0.001) and increased HDL levels (5.2 vs 2.4 mg/dl, p < 0.001). Both agents increased LDL, but pioglitazone did so with a significantly lesser amount than did rosiglitazone (12.3 vs 21.3 mg/dl, p < 0.001). Compared with rosiglitazone, pioglitazone also increased overall LDL particle size (p = 0.005) and reduced LDL particle concentration (p < 0.001). These data correlate with and support the findings from the metaanalyses discussed above.[10,33]

In a year-long, prospective comparison in patients with diabetes, pioglitazone 45 mg/day affected HDL levels more favorably than did the sulfonylurea glicazide 160 mg twice/day, with an increase of 8.5 and 2.3 mg/dl, respectively (p < 0.001).[35] No statistically significant differences were noted between the two drugs with respect to triglycerides. The LDL levels were increased with pioglitazone but reduced with glicazide (4.6 vs -6.6 mg/dl, p < 0.001). Use of statins in the two treatment groups was not discussed.

Metformin also has altered diabetic dyslipidemia. A meta-analysis of metformin found that this agent significantly yet modestly, lowered triglyceride (5.0 mg/dl), LDL (8.5 mg/dl), and total cholesterol (10.0 mg/dl) levels with minimal effects on HDL levels.[36] The authors concluded that the effect on triglyceride levels was associated with the glycemic-lowering properties of metformin, whereas the effect on LDL and total cholesterol levels was independent of the glycemic improvements.

The thiazolidinediones may not be equal in their effects on lipid parameters. The trials discussed above suggest that pioglitazone may have advantages over rosiglitazone in terms of improving triglyceride and HDL levels. Both agents may negatively affect LDL levels. Some authors believe that the increase in LDL level may actually be related to alterations in LDL character to lighter, less dense LDL particles.[33] The clinical implications of these findings have yet to be determined. Also, the thiazolidinediones are not the only class of oral antidiabetic drugs that alter lipids.

Hypertension

Hypertension significantly increases the risk for both the macrovascular and microvascular complications of diabetes and is a well-established cardiovascular disease risk factor. Because of the increased complication risk, the goal blood pressure in patients with diabetes is less than 130/80 mm Hg.[20] In the United Kingdom Prospective Diabetes Study, each decrease of 10 mm Hg in mean systolic blood pressure was associated with a decreased risk of 11% for myocardial infarction and of 13% for microvascular complications.[37] Also, one study showed that insulin resistance and hyperinsulinemia contributed to increased blood pressure, and that hypertension and insulin resistance frequently coexist and may be part of the cause of cardiovascular disease.[38]

Several trials have demonstrated rosiglitazone's blood pressure–lowering effects. In a small, open-label study, 24 patients with hypertension but no diabetes were given rosiglitazone 8 mg/day along with their usual antihypertensive treatment, excluding angiotensin-converting enzyme (ACE) inhibitors.[39] After 16 weeks of treatment, statistically significant reductions were noted in mean 24-hour ambulatory blood pressure: systolic from 131 ± 3 to 126 ± 3 mm Hg (p < 0.02) and diastolic from 80 ± 2 to 73 ± 2 mm Hg (p < 0.0001). The decrease in mean systolic blood pressure was correlated with improved insulin sensitivity (r = 0.59, p < 0.005). Patients' antihypertensive therapy was kept constant during the study.

In a 6-month, open-label study, 52 patients with diabetes (30 of whom had hypertension) were treated with rosiglitazone 4–8 mg/day (antihypertensive drug treatment remained unchanged throughout the study).[40] Systolic blood pressure decreased from 143.8 ± 2.7 to 123.7 ± 2.2 mm Hg (p < 0.001) and diastolic from 79.7 ± 1.5 to 62.5 ± 1.5 mm Hg (p < 0.001). This study demonstrated a continuous decrease in both systolic and diastolic blood pressure over the 6-month period; no plateau was reached.

A study involving 18 patients with impaired glucose tolerance (hypertension status unknown) compared rosiglitazone 8 mg/day with placebo and found significantly lower mean 24-hour ambulatory systolic blood pressure in the rosiglitazone-treated patients (-10 mm Hg, p = 0066).[41] Diastolic blood pressure was lower in the rosiglitazone group, but the difference was not statistically significant (-8 mm Hg, p = 0.0126). Patients' antihypertensive therapy was kept constant during the study.

The results of these trials demonstrate the blood pressure–lowering effects of rosiglitazone in patients with or without diabetes when compared with placebo.

Rosiglitazone has been compared with other oral antidiabetic drugs in relation to blood pressure–lowering effects. In a 52-week, open-label, randomized study of patients with diabetes (only 7% with hypertension), rosiglitazone 8 mg/day in 104 patients lowered blood pressure compared with glyburide 10.5 mg/day (mean daily dose) in 99 patients.[42] Benefits were noted in both systolic (mean difference -3.5 mm Hg, p = 0.0219) and diastolic (mean difference -2.7 mm Hg, p = 0.046) blood pressure. In this study, diuretics could be administered and were maintained at a constant dose during the trial.

In a 16-week, randomized, double-blind trial involving patients with diabetes with and without hypertension, rosiglitazone 8 mg/day in 24 patients lowered diastolic blood pressure more than metformin 1500 mg/day in 28 patients or placebo in 22.[43] The overall mean difference was -4 mm Hg (range -7 to -1 mm Hg, p < 0.005) versus placebo, and -2 mm Hg (range -5–1, p = NS) versus metformin.

The antihypertensive effects of pioglitazone have not been as conclusive. Pioglitazone has decreased arterial pressure in rat models and prevented development of hypertension.[44] In a small, open-label study involving 10 patients with diabetes, pioglitazone 30 mg/day lowered mean blood pressure from 109 ± 14 to 101 ± 10 mm Hg over 3 months (p < 0.01).[45] Systolic blood pressure was decreased by 7.0 ± 4.9 mm Hg (p < 0.01), diastolic by 6.3 ± 6.9 mm Hg (p < 0.05). The authors did not mention antihypertensive drugs taken at baseline or during the study.

In an open-label study of patients with diabetes receiving maximum doses of metformin and insulin secretagogues, 28 patients were randomized to isophane (NPH) insulin at bedtime to maintain euglycemia, and 30 patients to pioglitazone 30–45 mg/day for 16 weeks.[46] During the study, patients were allowed to take antihypertensive drugs, including ACE inhibitors, at stable doses. The blood pressure effects in patients receiving pioglitazone compared with those receiving insulin treatment were nonsignificant, with mean decreases in systolic blood pressure of 2 ± 22 mm Hg (range -14–10, p = 0.72) and in diastolic blood pressure of 4 ± 10 mm Hg (range -9–1, p = 0.14).

Available data suggest that the thiazolidinediones may have modest effects in terms of lowering blood pressure in patients with diabetes, but the clinical implications of these small decreases have yet to be determined. Comparative blood pressure data regarding other antidiabetic drugs are conflicting.

Microalbuminuria

Studies have shown that microalbuminuria is linked to cardiovascular morbidity and mortality and is an early marker of metabolic syndrome.[38,47-49] Specifically, microalbuminuria is linked as an independent predictor of strokes, death, myocardial infarction, and possibly chronic heart failure.[49] The Insulin Resistance in Atherosclerosis Study found a correlation between increasing degree of insulin sensitivity and decreasing prevalence of microalbuminuria in patients without diabetes.[50] The relationship was still significant after adjusting for sex, age, body mass index, blood pressure, blood glucose, and ethnicity. In a post hoc analysis of the Heart Outcomes Prevention Evaluation (HOPE) trial, patients with microalbuminuria, with and without diabetes (1140 and 823 patients, respectively), had an increased adjusted relative risk (RR) of major cardiovascular events (RR 1.83, 95% CI 1.64–2.05), all-cause death (RR 2.09, 95% CI 1.84–2.38), and hospitalization for chronic heart failure (RR 3.23, 95% CI 2.54–4.10).[49] Interventions that improve insulin sensitivity, lower blood pressure, and enhance glucose control have reduced microalbumin levels.[38]

Pioglitazone's effects on urinary albumin excretion in normotensive patients with diabetes and microalbuminuria were compared with the sulfonylurea glibenclamide 5 mg/day and the α-glucosidase inhibitor voglibose 0.6 mg/day in a 3-month, randomized controlled trial.[51] There were 15 patients in each of the three groups. Patients were not permitted to take any antihypertensive agents, including ACE inhibitors, during the study. Pioglitazone 30 mg/day significantly lowered urinary albumin excretion from baseline (from 142.8 ± 42.2 to 48.4 ± 18.2 µg/min, p < 0.01). No significant changes from baseline were noted in the glibenclamide or voglibose groups.

In a 16-week trial, 30 metformin-treated patients with diabetes were given pioglitazone 30–45 mg/day, and 28 were given NPH insulin titrated to maintain euglycemia.[46] The pioglitazone and NPH insulin resulted in similar improvements in the microalbumin: creatinine ratio. The patients were allowed antihypertensive treatment, including ACE inhibitors or angiotensin receptor antagonists, but no changes in these therapies were allowed during the study. The results demonstrated a mean change of -25.6 ± 63.6 mg/g in the microalbumin:creatinine ratio in the pioglitazone group and of -58.3 ± 91.9 mg/g in the insulin group (p = 0.13 between groups).

A 12-week, randomized study comparing gliclazide (21 patients) with pioglitazone (19) found significant reductions from baseline in the urinary albumin:creatinine ratio in both groups (p < 0.001).[52] However, no difference between treatment groups was found. Patients in both groups were allowed to continue taking antihypertensive drugs. A similar number of patients in each group received ACE inhibitors or dihydropyridine calcium channel blockers.

A 52-week, randomized, open-label study compared treatment with rosiglitazone versus glyburide in patients with diabetes.[53] Patients taking ACE inhibitors, angiotensin receptor antagonists, or calcium channel blockers within the past 12 months were excluded from the study. However, patients could be taking other classes of antihypertensives. Rosiglitazone 8 mg/day (57 patients) reduced microalbuminuria to a greater extent than glyburide 10 mg/day (64 patients). In the rosiglitazone group, 43% of patients who had microalbuminuria at baseline achieved normal urinary albumin levels compared with only 6% in the glyburide group (p = NS). Fewer patients in the rosiglitazone group without microalbuminuria at baseline developed microalbuminuria during the study, but the difference was not statistically significant.

A 26-week, randomized study involved 493 patients with diabetes, approximately 25% of whom had microalbuminuria at baseline.[54] Results showed that patients treated with rosiglitazone 4–8 mg/day had a ratio of urinary albumin:creatinine 22% lower than at baseline (p < 0.001), compared with patients receiving placebo, who had a nonsignificant 4% increase. The thiazolidinediones may have a role in improving urinary albumin excretion. However, they likely do not have a niche in this area compared with other available antidiabetic drugs.

Adiponectin

Adiponectin, an adipocytokine secreted by fat cells, has been linked to cardiovascular disease. Several studies have demonstrated a significant association between low levels of adiponectin and increased risk of cardiovascular disease, leading to the conclusion that adiponectin may have antiatherogenic effects.[55-8] These effects are thought to occur through several different mechanisms.[59-62] Adiponectin has prevented monocyte adhesion to endothelial cells and inhibited foam cell formation by macrophages (which are associated with formation of atherosclerotic plaques). It is thought to be involved in suppressing the proliferation and migration of vascular smooth muscle by decreasing the effects of various growth factors. Adiponectin levels in patients with diabetes and existing coronary artery disease are significantly lower than in patients without coronary artery disease.[63] Adiponectin has been related to insulin resistance, with levels significantly lower in patients with than without diabetes. It also has increased insulin sensitivity and suppressed hepatic glucose production.[61]

Several small, short-term studies have investigated the effects of rosiglitazone and pioglitazone on adiponectin levels in patients with diabetes.[64-70] The largest of these studies was a randomized, double-blind trial involving 64 patients with diabetes; 30 were treated with rosiglitazone 2 mg twice/day, the remaining 34 with placebo.[64] The investigators found that adiponectin concentrations were increased 2-fold from baseline after 3 months of rosiglitazone therapy (p < 0.0005), but no significant changes were observed in those given placebo.

Similarly, in a small, 16-week, open-label study investigating the effects of pioglitazone 45 mg/day in 11 patients with diabetes, adiponectin levels increased 3-fold (p < 0.0001).[65] (No control group was included.) Because hypoadiponectinemia has been associated with an increased risk of cardiovascular disease, one can surmise that a drug such as rosiglitazone or pioglitazone that significantly increases this protein could result in reduced cardiovascular disease risk. No published studies have investigated the effects of other hypoglycemic agents on adiponectin levels.

C-Reactive Protein

C-reactive protein is a well-established clinical marker of inflammation that has been linked with cardiovascular disease. Several studies have demonstrated that increased CRP levels were directly associated with cardiovascular disease independent of other known risk factors in patients with and without diabetes.[71-74] Reduction of CRP levels with statin therapy has been associated with a significant decrease in cardiovascular events independent of lipid-lowering effects, further signifying the potential role of CRP and the progression of atherosclerotic disease.[75]

A chronic subclinical inflammatory process is thought to be associated with development of insulin resistance and the metabolic syndrome. This hypothesis has been proven in several studies that demonstrated an inverse relationship between plasma CRP levels and insulin resistance.[76-78] Unfortunately, the literature does not provide enough evidence for evaluating the specific cause-effect relationship that exists between CRP and insulin resistance but suggests that the thiazolidinediones may have a role.

One study evaluated the effect of 26 weeks of therapy with rosiglitazone 4 mg/day, 8 mg/day, or placebo on CRP levels in 357 patients with diabetes.[79] This double-blind, randomized study found that compared with placebo, rosiglitazone significantly reduced CRP levels by 22–27% after the treatment period (p < 0.05). Percent reduction was not related to rosiglitazone dose, and treatment with statins was not discussed.

Another study found that 70 patients with diabetes randomized to pioglitazone 30 mg/day for 3 months experienced a reduction in CRP levels from baseline of more than 25% (p < 0.01).[80] No significant differences were noted in a control group of 66 patients. In this study, statins could be taken, but no mention was made of baseline statin therapy or changes in therapy during the trial.

A larger, 6-month, prospective, open-label trial compared pioglitazone 45 mg/day with glimepiride 1–6 mg/day in 192 patients with diabetes.[81] Results showed a significant reduction of 28% in CRP levels in patients receiving pioglitazone, compared with a 4% reduction in those receiving glimepiride (p < 0.05 between groups). No difference in statin therapy was noted at baseline. In the study comparing pioglitazone and rosiglitazone on lipid parameters discussed earlier,[34] both agents reduced CRP levels, but no differences between the two drugs were found (p = 0.288).

Metformin therapy has also reduced CRP levels, but to only half the reduction seen with troglitazone therapy.[82] Sulfonylurea therapy has not been associated with significant decreases in CRP levels.[83] The relationship and long-term outcomes among thiazolidinediones, CRP, and cardiovascular disease risk require further investigation. However, the studies discussed suggest that rosiglitazone and pioglitazone could decrease cardiovascular disease risk in patients with diabetes by significantly lowering CRP levels.

Visceral Fat

Obesity, abdominal fat distribution, insulin resistance, and the metabolic syndrome have been closely related to each other, and all are known risk factors for cardiovascular disease.[84-87] Visceral fat has a major effect on insulin resistance because the adipocytes in this fat, as opposed to other areas, such as subcutaneous fat, are more active and secrete larger amounts of fat products.[88] One of the more significant of the products secreted is the free fatty acids. Elevated levels of free fatty acids have induced insulin resistance as well as further β-cell destruction.[89-91] The free fatty acids are stored as triglycerides in adipocytes which, through lipolysis, can be converted back into free fatty acids to be used as an energy source by the body, typically in a fasting state.[92]

Normally, elevated free fatty acid levels stimulate pancreatic β-cells to secrete insulin, which then inhibits lipolysis because the adipocytes prevent further production of free fatty acids.[93] However, if these adipocytes become resistant to the inhibitory effects of insulin, overproduction of free fatty acids occurs. As the free fatty acids accumulate, the pancreatic β-cells attempt to dispose of them by nonoxidative metabolism, which can ultimately lead to an increase in β-cell apoptosis. In addition to this affect, free fatty acids will continue to accumulate in visceral areas, leading to an increase in abdominal fat, further contributing to the insulin resistance syndrome and increasing the risk of cardiovascular disease.

In a small, open-label study involving nine patients with diabetes, rosiglitazone 4 mg twice/day for 3 months resulted in a significant decrease (-39%) in plasma fatty acid concentrations, improvements in peripheral adipocyte insulin responsiveness (+52%), and redistribution of intracellular lipid from visceral to peripheral adipocytes.[94] In a prospective, open-label study, pioglitazone 45 mg/day administered for 16 weeks in 13 patients with diabetes demonstrated a 14% increase in subcutaneous fat (p < 0.01), a 9% decrease in visceral fat (p < 0.05), and a subsequent 25% decrease in visceral:subcutaneous fat distribution (p < 0.01).[95] The improved insulin sensitivity achieved with thiazolidinediones may lead to a decrease in free fatty acids that will consequently lead to reductions in visceral fat accumulation, positively affecting other cardiovascular risk factors.

Plasminogen Activator Inhibitor Type 1

Atherosclerosis can result from a number of endogenous mechanisms, including abnormalities within the fibrinolytic system; PAI-1 is the main inhibitor of fibrinolysis within this system. Produced in vascular endothelial cells, PAI-1 levels have been elevated in patients with hyperinsulinemic conditions such as diabetes, metabolic syndrome, and polycystic ovarian syndrome.[8,96] This elevated PAI-1 level has been linked to a heightened risk of atherosclerosis and, subsequently, cardiovascular disease.

In vitro data suggest that the thiazolidinediones, including rosiglitazone and pioglitazone, decrease PAI-1 production and PAI-1 mRNA. This decrease appears to be mediated by the activation of PPAR-γ, signaling transcriptional repression.[97-100] In contrast, one study found that metformin, but not the thiazolidinediones, significantly decreased PAI-1 production and mRNA.[101] Pioglitazone was the only U.S.-marketed thiazolidinedione included in the trial.

In a small, 6-month, randomized, double-blind study involving 16 patients with diabetes, neither those receiving rosiglitazone 8 mg/day nor those receiving placebo showed improvements in plasma PAI-1 levels.[102] However, a much larger, 26-week, randomized, double-blind, parallel-group study (published in abstract form only) evaluated rosiglitazone's effects on PAI-1.[103] The authors compared the sulfonylurea glibenclamide 10 mg/day as monotherapy (49 patients), with the combination of glibenclamide 10 mg/day and rosiglitazone 4 mg/day (46 patients). Results indicated that the glibenclamide-rosiglitazone combination significantly lowered PAI-1 activity (21.8% relative reduction) and PAI-1 antigen (33.8%) compared with glibenclamide alone. When pioglitazone and rosiglitazone were prospectively compared in patients with diabetes and mildly elevated LDL levels, both drugs reduced PAI-1 levels.[34] However, no significant differences were noted between the two agents (p = 0.623).

The findings of several clinical trials have supported the reduction in PAI-1 mRNA and/or activity with metformin,[104-106] sulfonylureas,[107-109] insulin,[107] and repaglinide,[108] with only one trial reporting increased PAI-1 activity in sulfonylureas and insulin.[110] Therefore, limited data seem to suggest that thiazolidinediones may decrease PAI-1 activity and levels, which may theoretically reduce the cardiovascular risk associated with abnormal fibrinolysis. However, this decrease in PAI-1 activity or levels does not appear to be unique to the thiazolidinediones alone.

Matrix Metalloproteinases

Rupture of unstable atherosclerotic plaques located within the coronary arteries instigates acute coronary events such as myocardial infarction and angina. These atherosclerotic plaques are dynamic structures that are continuously being remodeled and reshaped.[111,112] This extracellular matrix remodeling is controlled primarily by the matrix metalloproteinases (MMPs). Numerous MMPs have been identified and are presumed to degrade and reabsorb any extracellular protein matrix.[113] However, MMP-9 has the largest body of research with regard to atherosclerotic plaque instability.

One study identified MMP-9 in 83% of coronary atherectomy specimens from patients with unstable angina, 75% of the patients with stable angina.[112] The authors determined that the source of MMP-9 appeared to be from macrophages and smooth muscle cells. Another study found the expression of PPAR-γ receptors on macrophages in human atherosclerotic lesions.[114] One group of authors evaluated the circulating plasma levels of MMP-9 in patients with diabetes and treated hypertension compared with healthy individuals.[115] They found a significantly higher plasma level of MMP-9 in the diabetes group than in the healthy patients (p = 0.028). This suggests an increased atherosclerotic risk in the patients with diabetes. These and other data have laid the groundwork for evaluating the effects of thiazolidinediones on regulatory control of MMPs, specifically MMP-9.

A double-blind, randomized study evaluated serum MMP-9 levels in patients with diabetes treated with rosiglitazone 4 mg/day (126 patients) and 8 mg/day (136).[79] Results in these patients were evaluated and compared with those in 95 patients treated with placebo for 26 weeks. Compared with the placebo group, a significant decline in total serum MMP-9 levels was found for both rosiglitazone groups (-12.4%, 95% CI -22.3% to -1.0% with 4 mg/day and -23.4%, 95% CI -31.3% to -13.9% with 8 mg/day).

A 12-week, randomized, placebo-controlled, single-blind study evaluated the effects of rosiglitazone 8 mg/day on MMP-9 serum levels in patients with diabetes and documented coronary artery disease.[116] A significant decrease in MMP-9 serum levels was noted as early as 2 weeks after the start of treatment (-19.6%, p < 0.05) and persisted until the end of the trial (-24.1%, p < 0.05). A prospective, open-label trial compared pioglitazone 45 mg/day with glimepiride 1–6 mg/day for 6 months in 192 patients with diabetes.[81] Pioglitazone reduced MMP-9 levels by 14% (p < 0.005 compared with baseline), whereas glimepiride showed a statistically nonsignificant 4% increase (p < 0.05 between groups). Other antidiabetic agents have not been studied with regard to MMP-9 level reduction in patients with diabetes.

The data discussed suggest that treatment with thiazolidinediones may decrease serum MMP-9 levels through what appears to be an alteration in MMP-9 gene transcription. This suggests that the thiazolidinediones may decrease overall atherosclerotic risk by decreasing the amount of circulating MMP-9. However, the direct correlation between serum MMP-9 concentrations and arterial cell wall MMP-9 concentrations, and ultimately a decrease in cardiovascular risk, cannot be concluded based on these studies alone.

Carotid Intima-Media Thickness

Intima-media thickness in the internal or common carotid artery has been used to detect subclinical atherosclerosis and is thought to possibly reflect systemic atherosclerosis.[14] A large intima-media thickness, or increased changes over time in intima-media thickness depth, suggests a higher potential for atherosclerosis. Studies have shown a negative association with insulin sensitivity and intima-media thickness in patients with and without diabetes even after controlling for traditional cardiovascular risk factors.[14,15] Compared with patients without diabetes, intima-media thickness may be increased in both newly diagnosed patients and those with established disease.[117]

In a double-blind, randomized study of 92 patients with established coronary heart disease but no diabetes, rosiglitazone 8 mg/day for 48 weeks was associated with a significant reduction in intima-media thickness changes compared with placebo.[118] In another study, in 53 patients with diabetes, 6 months of treatment with pioglitazone 30 mg/day showed reductions in intima-media thickness (-0.084 mm).[119] The 53 patients receiving sulfonylureas experienced an increased intima-media thickness (+0.022 mm, p < 0.001). No significant differences in statin therapy were noted between the treatment groups.

A 6-month, randomized, open-label study compared pioglitazone 45 mg/day with glimepiride 1–6 mg/day.[81] Pioglitazone reduced intima-media thickness by 0.056 mm (p < 0.001), whereas glimepiride demonstrated a nonsignificant reduction of 0.013 mm (p < 0.001 between groups).

These studies suggest that thiazolidinediones may have an inhibitory effect on early atherosclerosis in patients with and without diabetes. Acarbose, compared with placebo, has also had effects on intima-media thickness in patients with impaired glucose tolerance.[120] No studies assessing metformin's effect on intima-media thickness were found in the literature. The thiazolidinediones may have a more beneficial effect than sulfonylureas in modifying the potential cardiovascular disease risk factor, but data are limited. However, we do not know whether they offer more benefit than other antidiabetic drugs in this area.

Coronary Stent Restenosis

Revascularization procedures such as coronary artery angioplasty and stent placement are common in patients with established heart disease. Patients with diabetes are at increased risk of restenosis after coronary stent placement compared with those without diabetes.[121] In patients with impaired glucose tolerance, a surrogate marker of insulin resistance, neointimal tissue proliferation after stent placement is higher than in those with normal glucose tolerance.[122] In addition, insulin resistance has been linked with higher restenosis rates in patients with and without diabetes.[123,124]

A prospective, case-controlled study assessed the effects of rosiglitazone on restenosis rates in patients with diabetes who recently underwent coronary stent placement.[125] The day before stent placement, 38 patients were randomly assigned to rosiglitazone 4 mg/day, and 45 to conventional diabetes therapy with other oral antidiabetic drugs (primarily metformin or sulfonylureas) or insulin. Angiographic end points of the study were restenosis (defined as > 50% follow-up stenosis), percent stenosis, and instent minimal lumen diameter. After 6 months of treatment, no differences were noted in glycemic control between the two groups. However, the rosiglitazone group had a much lower rate of restenosis than the control group (18% and 38%, respectively, p = 0.03). The overall diameter of stenosis in the rosiglitazone group was also significantly reduced compared with the control group (23% vs 41%, p = 0.004) as was the minimal lumen diameter (p = 0.009).

The results of this study conflicts with those from earlier studies, which showed no benefit with rosiglitazone or pioglitazone in reducing stent restenosis.[102,126] These earlier studies involved fewer patients and used different techniques in stenosis assessment, which may explain some of the conflicting results.

Rosiglitazone may help reduce restenosis rates after coronary stent placement in patients with diabetes, and this effect may be independent of glycemic control. The effect with rosiglitazone may be better than that with metformin or sulfonylureas. Regarding glucosidase inhibitors and any beneficial effects of pioglitazone, information in this area is lacking.

Heart Failure and Thiazolidinedione Use

Despite the potential reduction in risk of cardiovascular disease, case studies and retrospective, observational studies have reported an increased risk for development of heart failure with administration of thiazolidinediones.[127-129] Whether these agents actually cause heart failure or merely exacerbate undiagnosed, subclinical heart failure through fluid retention is unknown, but evidence lends itself to the latter.[130] No specific human data suggest that drugs in this class have a direct negative effect on cardiac function. In fact, evidence suggests that no alterations in left ventricular mass index or ejection fraction occur with thiazolidinedione therapy.[131]

Despite warnings from the thiazolidinedione manufacturers not to prescribe these agents for patients with existing heart failure, this occurs. In the Medicare population, treatment with thiazolidinediones increased after the release of the two available agents in the United States.[132] According to the American Diabetes Association and the American Heart Association, thiazolidinediones should not be prescribed for patients with both diabetes and New York Heart Association (NYHA) class III or IV heart failure.[133] They should be cautiously prescribed for only those with NYHA class I or II disease. If peripheral edema, fluid retention, or signs and symptoms of heart failure occur with thiazolidinedione, the therapy should be discontinued.

Use of Thiazolidinediones for Reduction of Cardiovascular Disease Outcomes

The only trial to date to specifically assess whether a thiazolidinedione affects cardiovascular outcomes is the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive).[134] This randomized, secondary prevention trial prospectively studied patients with both type 2 diabetes and a history of cardiovascular disease. Compared with placebo (2633 patients), treatment with pioglitazone 45 mg/day (2605 patients) for an average of 34.5 months did not show a significant difference (hazard ratio 0.90, 95% CI 0.80–1.02) in the primary outcome (combined cardiovascular morbidity and all-cause mortality). The study did find a significant difference in the secondary combined outcome of all-cause mortality, nonfatal myocardial infarction, and stroke (hazard ratio 0.84, 95% CI 0.72–0.98).

The Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) study is an ongoing trial involving nearly 4000 patients with type 2 diabetes.[135] The study is assessing rosiglitazone's ability to reduce cardiovascular events in combination with either metformin or a sulfonylurea. Completion of the study is expected in 2009.

We do not endorse specifically the administration of thiazolidinediones to lower cardiovascular risk in patients with diabetes. The data merely support the theory that the thiazolidinediones may have a future role in treating both the hyperglycemia and the cardiovascular disease associated with diabetes. Medical history has shown us that reducing cardiovascular risk factors does not necessarily equate with reducing cardiovascular events. Not so long ago, hormone replacement therapy was widely prescribed for postmenopausal women and was thought to potentially reduce cardiovascular risk through mechanisms such as improvements in dyslipidemia. However, clinical outcome data specifically designed to assess the role of hormone replacement therapy in reducing cardiovascular events in this population showed no benefit with respect to heart disease.[136] The data actually demonstrated a small increased risk for other conditions. Thus, until the thiazolidinediones demonstrate proven effects in reducing cardiovascular outcomes rather than risk, their use should be limited to treating hyperglycemia in patients with diabetes.

Conclusion

Thiazolidinediones have shown encouraging results, primarily in affecting surrogate markers of cardiovascular risk in patients with diabetes. The alterations in these risk factors are likely due to the drugs' effects in improving insulin sensitivity and/or glycemic control. Based on available information, differences may exist between pioglitazone and rosiglitazone in their effects on these risk factors, and both have not necessarily been studied with regard to each risk factor described. In some cases, the thiazolidinediones may not have any advantage over other existing antidiabetic drugs. In addition, not all antidiabetic drugs have been fully evaluated as to their effects on these cardiovascular risk factors. The data supporting administration of thiazolidinediones for altering or reducing known or emerging cardiovascular risk factors is intriguing. However, caution must be used in interpreting the data for use in clinical practice.

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