| | Thiazolidinediones for the treatment of type 2 diabetesReceived 8 May 2006; received in revised form 1 September 2006; accepted 19 September 2006. Abstract Thiazolidinediones (TZD), or glitazones, represent a new generation of antidiabetic drugs that have recently been introduced in Europe. They improve insulin resistance, one of the key anomalies involved in the pathogenesis of type 2 diabetes mellitus, by activating the nuclear peroxoxisome proliferator activated receptor-γ (PPAR-γ), leading to crucial metabolic alterations in adipose tissue. Rosiglitazone and pioglitazone have been shown to be active as monotherapy, in combination therapy with metformin or sulfonylureas, and even in triple therapy. They are generally well tolerated but can induce fluid retention. Cardiac failure is a contraindication for the use of TZDs, as is the concomitant administration of insulin. Aside from their effect on glycemic control, TZDs act on several cardiovascular risk factors and may protect pancreatic β cells from apoptosis. The cardiovascular protective effect of TZDs has recently been demonstrated with the results of the PROactive study, and long-term preservation of β-cell function is currently under further investigation. 1. Introduction  Insulin resistance plays a major role in the pathogenesis of type 2 diabetes [1], a disease leading to severe long-term cardiovascular complications. The glycemic deterioration observed over time in type 2 diabetes is attributable to a progressive decline in β-cell function [2]. Control of blood glucose levels is essential for the prevention of complications of the disease [3], [4]. Metformin, an insulin sensitizer acting predominantly on the liver by reducing hepatic glucose production, and sulfonylureas, which stimulate insulin release, rarely allow for long-term glycemic normalization, even when used in combination therapy, since they do not slow β-cell apoptosis. The recently introduced thiazolidinediones (TZDs), which act predominantly by enhancing peripheral insulin sensitivity, offer promising perspectives in terms of β-cell preservation [5], [6] and cardiovascular protection [7], [8]. 2. Pharmacological data 2.1. Rosiglitazone After oral administration of 2 mg rosiglitazone, the maximal concentration (Cmax) is achieved after 1.3 h, and the elimination half-life of the drug is 3.6 h. Food intake slightly slows the rate of absorption of the drug but not the amount of drug absorbed. The pharmacokinetics of rosiglitazone is not altered by age or mild to moderate renal impairment, but hepatic dysfunction significantly increases the area under the concentration curve. Rosiglitazone does not induce cytochrome P 450 3A4 metabolism. No drug interactions have been observed with ranitidine, metformin, or digoxin, but co-administration with acarbose slightly reduces the absorption of rosiglitazone [9]. 2.2. Pioglitazone The time to Cmax and the elimination half-life of pioglitazone are slightly longer than for rosiglitazone. The drug undergoes extensive hepatic metabolism via the CYP 2C8 and, more accessorily, the CYP 3A4, 2C9, and 1A1/2. Some metabolites (MII, III, IV) are active. Renal impairment leads to increased hepatic clearance by reduction of protein binding of the drug but does not alter the free plasma drug concentrations. No induction or inhibition of hepatic enzyme systems and no clinically significant drug interactions have been reported to date with pioglitazone [10]. 3. Mechanism of action of TZDs It was shown soon after their discovery that TZDs are agonists of the peroxysome proliferator activated receptors-γ (PPAR-γ) [11], [12]. Briefly, after the binding of a TZD to PPAR-γ, the macromolecular complex formed by PPAR-γ and the retinoic acid receptor is able to recruit an activator that allows the DNA transcription of peroxysome proliferator response elements (PPRE; Fig. 1). PPAR-γ is essentially expressed in adipose tissue and controls genes that are mostly involved in adipocyte differentiation and lipid metabolism. This cannot entirely explain the glucose-lowering effect of the drug since adipose tissue accounts for less than 5% of glucose utilization. The explanation of this paradox is that TZDs promote the differentiation of adipose tissue into small adipocytes, which are more insulin-sensitive than large adipocytes and, therefore, release into the bloodstream fewer free fatty acids (FFA), more adiponectin, and less TNF-α, resistin, and leptin. This leads to an improvement in peripheral glucose uptake in the skeletal muscle, a decrease in hepatic glucose production, and an increase in fat storage in adipose tissue [13]. 4. Metabolic effects of TZDs 4.1. Glucose metabolism In placebo-controlled studies, TZDs decrease fasting plasma glucose and HbA1c levels in a dose-dependent manner in monotherapy as well as in combination with metformin, sulfonylureas, or even in triple therapy [9], [10]. This glucose-lowering effect is related to an improvement in insulin sensitivity, as suggested by a decrease in plasma insulin levels during TZD treatment. In comparison to glibenclamide or gliclazide, the decrease in FPG and HbA1c is slower with TZDs and the maximal effect is reached only after 12 weeks, in accordance with the indirect mechanism of action of these drugs. By contrast, secondary deterioration of glycemic control is faster with sulfonylurea treatment than with TZD treatment [14]. The same is true to a lesser extent for comparative studies of TZDs with metformin [15]. 4.2. Lipid metabolism Both TZDs greatly decrease FFA levels and significantly increase HDL-C levels. Their effect on triglycerides and LDL-C levels is, however, different, perhaps because of a higher PPAR-γ selectivity of rosiglitazone. The differences observed in several placebo-controlled trials and switch studies from troglitazone to rosiglitazone or pioglitazone [16] have been confirmed recently in a head-to-head comparative study showing a decrease in fasting triglycerides and postprandial lipemia [17] and stability of LDL-C with pioglitazone, a non-significant variation of triglycerides, and an increase in LDL-C with rosiglitazone [18]. Both drugs reduce the proportion of small dense atherogenic LDL particles, but pioglitazone does so more efficiently than rosiglitazone. 5. Effects on other cardiovascular risk factors 5.1. Hypertension Most of the studies investigating the effects of TZDs on blood pressure have been performed with rosiglitazone and had a rather short duration. Also, the patient populations studied were different, i.e., hypertensive patients [19], patients with impaired glucose tolerance [20], and type 2 diabetes patients with [21] or without [22] hypertension. These studies were most often open-label and not always controlled and/or randomized. However, all studies showed positive effects on ambulatory systolic and diastolic pressure. The study with the longest duration was the open-label, active controlled study by Sutton et al. [22], who showed a significant decrease in diastolic blood pressure (− 2.3 mm Hg) after 52 weeks of 4 mg rosiglitazone (whereas in the glibenclamide group there was no difference). Systolic blood pressure did not change during rosiglitazone therapy, but it increased significantly in the glibenclamide patients (+3.8 mm Hg). There were no changes in left ventricular mass or ejection fraction in either group. 5.2. Microalbuminuria Microalbuminuria may be considered a risk indicator of vascular damage in type 2 diabetes. Therefore, a reduction in microalbuminuria – reflecting a decrease in vascular risk – may be beneficial. Bakris et al. [23] performed a 52-week, open-label, randomized study comparing the effects of rosiglitazone (4 mg) and glibenclamide (mean dose 10.5 mg) on microalbuminuria. After 28 weeks, a significant reduction in the albumin/creatinine ratio (ACR) was observed in both treatment groups, whereas after 52 weeks this was only true in the rosiglitazone group (normalization in 43% versus 6% in the glibenclamide group). Not unexpectedly, there was a strong correlation of the ACR reduction with changes in mean 24-hour systolic and diastolic blood pressure in the rosiglitazone group (not in the glibenclamide patients), but not with the glucose metabolism parameters. Similar observations have been found in an earlier double-blind, placebo-controlled study of rosiglitazone [24]. 5.3. Plasminogen activator inhibitor-1 (PAI-1) One of the components of the metabolic syndrome is increased PAI-1, which is associated with cardiovascular risk, probably because PAI-1 is associated with deficient fibrinolysis and intravascular thrombosis. Preliminary results of a double-blind, randomized, parallel-group study comparing single drug treatment with glibenclamide with the combination of glibenclamide (up to 10 mg/day) plus 4 mg rosiglitazone twice daily for 26 weeks were favorable [25]. PAI-1 activity, PAI-1 antigen, and tPA decreased significantly (33.8, 21.8, and 25.3%, respectively) in the group using rosiglitazone compared to the group only using glibenclamide. A significant decrease was also observed after 26 weeks of rosiglitazone plus glibenclamide with respect to baseline values, something that may contribute to the beneficial effect of rosiglitazone in endothelial dysfunction and to the decrease in cardiovascular complications [25]. 5.4. Adipocytokines Adipocytes (or fat cells) contain PPAR-γ in high concentration and also secrete many substances with metabolic activity, the so-called adipocytokines. These include substances with beneficial (e.g., leptin, adiponectin) as well as disadvantageous effects (e.g., free fatty acids (FFA), TNFα, IL-6, PAI-1, and resistin). In a double-blind, placebo-controlled study of 23 type 2 diabetes patients already treated with sulfonylurea drugs, Miyazaki et al. [26] investigated the effect of 45 mg pioglitazone (n=12) versus placebo (n=11) for 4 months on various adipocytokines. Apart from a decrease in HbA1c and fasting plasma glucose, pioglitazone showed significant decreases in circulating concentrations of FFA and TNFα and increments of adiponectin in comparison with baseline and placebo. Plasma leptin did not change significantly in either group. These direct effects of pioglitazone may very well contribute to the improved hepatic and peripheral insulin sensitivity and ameliorate glucose tolerance in type 2 diabetic patients. In a study on non-traditional risk factors for cardiovascular disease in type 2 diabetes patients, Haffner et al. [27] showed that rosiglitazone reduced levels of matrix metalloproteinase-9 (MMP-9) and C-reactive protein (CRP), but not of IL-6 and white blood cell count after 26 weeks of treatment. These data may explain in part the beneficial effects of rosiglitazone on cardiovascular risk. A summary of the effects of TZDs on cardiovascular risk factors is presented in Table 1. 5.5. Fat distribution The most prominent feature and probable cause of the metabolic syndrome and of (hepatic) insulin resistance is visceral fat accumulation. TZDs can cause a shift in fat distribution from visceral to subcutaneous depots [28], [29]. Although the total fat mass increases, HbA1c decreases due to improved hepatic and peripheral tissue insulin sensitivity. The concomitant decreased FFA plasma concentration points to a healthier fat cell, responding now to insulin stimulation of glucose uptake and suppression of lipolysis [29]. 5.6. Intima-media thickness Intima-media thickness (IMT), measured with the help of ultrasound, has been used as a surrogate marker of early atherosclerotic lesions, and IMT may be considered a surrogate endpoint of atherosclerotic disease. The effect of TZDs on IMT progression has been reported in studies with approximately 50–170 patients for a duration of 6–24 months [30], [31], [32], [33], [34]. The studies were mostly open; only one was randomized and double-blind [32]. Troglitazone [30], rosiglitazone (for non-diabetics with coronary artery disease) [32], and pioglitazone treatment [31], [33], [34] resulted in a significant decrease in IMT, pointing to a reduction in atherosclerosis in diabetic and non-diabetic patients. 5.7. Improvement in cardiovascular risk markers In a 6-month, prospective, open-label, controlled clinical study with 192 patients, Pfützner et al. [35] examined the effects of pioglitazone on inflammatory and atherogenic markers, both biochemical and clinical, as compared with glimepiride. Although HbA1c reduction was comparable in both groups, most parameters improved more effectively in the pioglitazone-treated patients. These parameters included insulin, LDL-C/HDL-C ratio, high-sensitivity CRP, MMP-9, MCP-1 (monocyte chemoattractant protein-1), and carotid IMT. No changes were seen in LDL-cholesterol, triglycerides, fibrinogen, von Willebrand factor, PAI-1, and a number of other markers of endothelial (dys)function. It may be concluded that pioglitazone has anti-inflammatory and antiatherogenic effects, independent of blood glucose control. 5.8. Re-stenosis after coronary stent implantation Coronary stent implantation leads to a high rate of re-stenosis, especially in diabetics, resulting in a poorer long-term prognosis than in non-diabetics. Antiplatelet drugs, anticoagulants, and statins have not been successful in reducing re-stenosis [36]. PPAR-γ agonists inhibit the growth of vascular smooth muscle cells (VSMC) and may prevent neo-intima formation and re-stenosis. Apart from one small study with negative results concerning 16 diabetes type 2 patients (8 on rosiglitazone and 8 on placebo) [37], there are now three randomized studies [38], [39] showing a decrease in re-stenosis after 6 months of treatment with either rosiglitazone [35], [38] or pioglitazone [38]. Choi et al. investigated 83 type 2 diabetes patients in a prospective, randomized, case-controlled trial and found a more than 50% reduction in the occurrence of re-stenosis and a lower degree of stenosis of the luminal diameter after rosiglitazone. High-sensitivity C-reactive protein (CRP) was reduced, but glucose and lipid parameters remained unchanged [36]. Wang et al. studied 71 randomly divided patients (rosiglitazone versus placebo) [39]. Plasma monocyte chemoattractant protein-1 (MCP-1) and CRP decreased, but fasting glucose, insulin, and HbA1c were significantly lowered in the rosiglitazone group. The occurrence of coronary events decreased, probably by not only improving metabolic parameters but also by reducing inflammatory responses [39]. Finally, Marx et al. performed a randomized, placebo-controlled, double-blind trial with pioglitazone in 50 non-diabetic CAD patients. Fibrinogen levels decreased significantly, but CRP, TNF-α, glucose parameters, and lipids did not. Neo-intima volume, total plaque volume, and mean stenosis of the luminal diameter decreased, suggesting a direct effect of TZD treatment on neo-intima volume after coronary stent implantation [38], independent of its metabolic actions. 6. Therapeutic perspectives 6.1. β-cell protection It has been well established in rats [40] and mice [41] that TZDs may prevent the progression from insulin resistance to overt diabetes by preserving β-cell mass and insulin secretion capacity. In type 2 diabetics, rosiglitazone, as compared to placebo or glibenclamide, significantly reduced the proinsulin/insulin ratio after 26 and 52 weeks, which is compatible with a reduction in β-cell dysfunction [42]. Moreover, pioglitazone significantly improved β-cell response by HOMA assessment when used either as monotherapy or in combination with metformin or sulfonylurea for a period of 16 or 26 weeks [24], [43], [44]. In a placebo-controlled, 26-week study of pioglitazone (30–45 mg), Miyazaki et al. [45] showed an increase in plasma insulin response during OGTT in diabetic patients. At the same time, plasma glucose levels decreased, pointing to an improvement in β-cell function. Juhl et al. [46] concluded from their study that 3 months of rosiglitazone treatment in type 2 diabetics did not influence insulin secretion per se, but that improved glucose-entrained, high-frequency insulin pulsatility suggested an increased ability of the β cell to sense and respond to glucose changes within the physiological range. TZDs may improve β-cell function through several mechanisms [47]. Improved insulin sensitivity may reduce glucotoxicity of the β cell, but lipotoxicity may decrease as well, as a result of the reduction in circulating FFA caused by increased insulin sensitivity of the cell and reduced levels of TNF [47]. In animals it has been shown that TZDs prevent deterioration of islet cell morphology, preserving pancreatic content and β-cell ultrastructure [40]. 6.2. Cardiovascular prevention (PROactive study) The results of the PROactive study have recently been reported [8]. This prospective, randomized, controlled study included 5238 type 2 diabetes patients with macrovascular complications who were followed for 3.45 years. Pioglitazone was given in addition to existing therapies. The expectations were high, but the results were not easy to interpret and have caused a lot of debate [48], [49], [50]. Some issues should be highlighted. The primary endpoint was a composite of disease endpoints (death, myocardial infarction, stroke, acute coronary syndrome), but also procedural endpoints (coronary and leg revasculations, leg amputations). Probably because of the inclusion of the procedural endpoints, any advantage that pioglitazone may have had over placebo could not be confirmed as far as the primary endpoint was concerned. The secondary endpoint consisted of the separate diseases of the primary endpoint, i.e., myocardial infarction, stroke, and (cardiovascular) death. Here, a significant decrease of 16% (p=0.027) was observed in the pioglitazone group [8]. Other problems included the rather fast recruitment and closure, possibly decreasing the power of the study. Also, one-third of the patients were using insulin, and it is not clear from the study whether these were the patients with the highest risk of heart failure/edema. There was a significant increase in edema not attributable to heart failure (221 events more in the pioglitazone group) as well as in heart failure (115 events more, p=<0.001), but no excess mortality. Although more hypoglycemias occurred during pioglitazone treatment, the hospital admission rate remained the same. There were more pneumonias in the pioglitazone group and a weight gain of 4 kg compared to the placebo group. A positive result was that insulin treatment could be reduced (or postponed) by 50% with pioglitazone [8]. Thus, pioglitazone reduced cardiovascular morbidity and mortality (but only measured with the secondary endpoint) in type 2 diabetics with a high risk of macrovascular complications. It reduced the need for insulin treatment, but caused weight gain, edema, and heart failure [8]. It is still not known which patients are at the greatest risk of heart failure after treatment with TZDs, what the prognosis of heart failure is, and whether it is safe to combine insulin and pioglitazone treatment [48]. In Table 2 an overview is given of proven and potential benefits and risks of TZDs.  | Benefits | | | Improved glycemic control | | | Lower insulin resistance/insulin levels | | | Fat redistribution/decreased visceral fat | | | Lower blood pressure | | | Improved pancreatic β-cell function | | | Improved endothelial function/decreased IMT | | | Reduced cardiovascular morbidity and mortality (PROactive) | | | Induction of ovulation in PCOS | | | Less bone turnover | | | Treatment for neoplasms | | | Decreased ALAT, suggesting decreased liver fat | | | Risks | | | Hepatotoxicity/potential for liver failure | | | Weight gain/increased total body fat (subcutaneous) | | | Edema/fluid retention | | | Pulmonary edema | | | Increased Lp(a) lipoprotein levels | | | | |
7. Adverse effects of TZDs TZDs do not induce hypoglycemias in monotherapy, but they do slightly increase the risk in combination with sulfonylureas. With pioglitazone and rosiglitazone, no cases of severe hepatotoxicity, such as those which led to the withdrawal of troglitazone from the market, have been observed [51], and in long-term cohort studies, like the PROactive study, TZDs decreased ALT levels by improving liver steatosis [8]. The main adverse effects of TZDs are related to fluid retention [52], which can result in pseudo-anemia, edema, and cardiac failure in patients with underlying heart disease. This has resulted in the restricted use of TZDs in Europe. However, TZDs do not induce cardiac hypertrophy or reduce the cardiac ejection fraction. The mechanism underlying the edema is unclear but probably involves both fluid retention and increased vascular permeability. In the majority of cases, edema is not related to cardiac insufficiency. Another frequent, and possibly limiting, adverse effect is weight gain, which is a consequence of the mechanism of action of TZDs. The average increase in body weight is about 2–3 kg, but it can be much more in some subjects. It generally occurs during the first year of treatment with no further increment. It has been shown to be related to the development of subcutaneous fat with no significant modification or even a trend to a decrease in abdominal fat and, as a consequence, no increase in insulin resistance or loss of therapeutic efficacy [53]. 8. TZDs in the treatment of type 2 diabetes The classical approach to the treatment of type 2 diabetes is stepwise, starting with diet and exercise, followed by the initiation of oral monotherapy, leading after a few years to combination therapy and, finally, to insulin therapy [54]. The change in therapy is generally dictated by the manifest failure of the treatment, with the mean glycemic control, i.e., HbA1c and glucose levels, over the years being above the recommended target goals. In many countries, sulfonylureas are frequently used as first-line drugs, and the dose is increased to the maximum recommended dose before starting combination therapy. In fact, in the majority of cases, an insulin sensitizer probably represents a better choice for the initial drug therapy. Metformin has been the recommended first-line drug ever since the UKPDS showed a benefit of this drug versus sulfonylureas or insulin in the prevention of cardiovascular events in overweight type 2 diabetic patients. In the case of a contraindication or intolerance to metformin, a TZD can be used alternatively with the goal of attaining a normal or near-normal HbA1c level, which can be targeted because insulin sensitizers do not induce severe hypoglycemia. The combination with a TZD represents a good therapeutic option if HbA1c exceeds 6.5% under a maximal, tolerated metformin regimen in obese or overweight patients. In lean subjects, the addition of a TZD to sulfonylurea monotherapy is allowed only if metformin is contraindicated or not tolerated. Finally, rosiglitazone can now be used in triple therapy with metformin and sulfonylurea. This strategy represents a valid alternative to basal insulin therapy combined with oral antidiabetic drugs, particularly in the 7–9% HbA1c range [55]. In more severely decompensated patients, insulin should be preferred and, in that case, the TZD treatment withdrawn. 9. Pharmaco-economic evaluation of TZDs The cost-effectiveness analyses performed to date have mainly been based on several combination therapy trials with an extrapolation of the event rates according to the UKPDS model with some local adaptations. It has been concluded that, in overweight type 2 diabetics, combined therapy with pioglitazone increases life expectancy at an acceptable cost for Germany [56]. In Sweden, the cost per life-year gained with a combination of pioglitazone and metformin or sulfonylurea is comparable with current treatments and can be considered as cost-effective in the national health care system [57]. The evaluation of pioglitazone in comparison to other strategies as first-line treatment in Canada also concluded that, for certain patient strata, this therapeutic alternative could be cost-effective [58]. In comparison to insulin, TZD treatment with rosiglitazone or pioglitazone reduced diabetes-related costs despite higher diabetes-related pharmacy costs in the US [59]. More precise pharmaco-economic evaluations will be available after the publication of long-term trials, like DREAM and RECORD. 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PII: S0953-6205(06)00257-3 doi:10.1016/j.ejim.2006.09.007 © 2006 European Federation of Internal Medicine. Published by Elsevier Inc. All rights reserved. | |
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