Thiazolidinediones, Insulin Resistance And Obesity: Finding A Balance

J. Wilding

Int J Clin Pract. 2006;60(10):1272-1280. 

Summary and Introduction

The clinical efficacy of currently available thiazolidinediones (TZDs) in improving glycaemic control and ameliorating several risk factors for cardiovascular disease (linked to their insulin-sensitising actions as well as direct vascular effects) is well established. Treatment-associated weight gain, however, which has been identified as a class effect of the TZDs, is seen in a number of patients. The magnitude of weight gain correlates in part with improved metabolic control, i.e. better responders are more prone to increases in body weight. The cardiovascular risk associated with obesity appears to be depot specific; while peripheral obesity is associated with a low risk of cardiovascular complications, central obesity confers a greater degree of risk. Evidence is reviewed that increases in body weight associated with TZD treatment are associated with neutral effects (or even, decreases) in visceral fat, the adipose depot that is associated with central obesity.

The thiazolidinediones (TZDs; rosiglitazone and pioglitazone) are a class of oral antidiabetic agents that exert their glucose-lowering effects by reducing insulin resistance,[1] an important underlying factor in the development of type 2 diabetes.[2] The clinical efficacy of the TZDs in improving glycaemic control, either as monotherapy or in combination with other agents such as metformin, sulphonylureas or insulin, is well documented in patients with type 2 diabetes.[3-11] Furthermore, the impact of TZDs on insulin resistance and associated risk factors for cardiovascular disease (CVD) and data from the PROactive trial[12] suggest that these agents may improve some cardiovascular outcomes in patients with type 2 diabetes. Insulin resistance, which is recognised as being a risk factor for CVD in its own right,[13] is also closely associated with a cluster of cardiovascular risk factors, including abdominal obesity, that are collectively labelled the metabolic syndrome.[14] Through their effects in reducing insulin resistance, the TZDs may favourably impact on other risk factors for CVD, including hypertension, dyslipidaemia and microalbuminuria, as well as non-traditional cardiovascular risk factors, such as markers of hypofibrinolysis (plasminogen activator inhibitor-1) and systemic inflammation (C-reactive protein).[15-19] In addition, the TZDs have direct actions at the level of the vessel wall.[20,21]

While the potential of the TZDs to improve the cardiovascular risk profile is apparent, data from clinical trials and post-marketing experience indicate that TZD therapy is associated with weight gain in some patients; although fluid retention may contribute, it is partly attributable to increase in fat mass.[22] At first, this appears to present a paradox, as obesity is closely related to insulin resistance[23] and is a significant risk factor for CVD.[24] However, it is now recognised that fat distribution is important in determining the risk of CVD.[25] In this article, evidence is reviewed that increases in body weight associated with TZD treatment are associated with neutral effects (or even, decreases) in visceral fat, which is widely regarded as being a risk factor for CVD. In addition, possible mechanisms to explain TZD-associated weight gain and the benefits of implementing concomitant lifestyle intervention measures are discussed.

The Thiazolidinediones: Mechanism of Action and Clinical Profile

The potent insulin-sensitising effect of the TZDs is mediated through activation of the peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor that regulates the production of proteins involved in glucose and lipid homeostasis.[26] The TZDs appear to improve insulin sensitivity via several mechanisms mediated by PPARγ, primarily in adipose tissue.[26] While the pre-dominant insulin-sensitising effects occur in skeletal muscle, these appear to be mediated indirectly via altered free fatty acid (FFA) supply.[27] For example, PPARγ acts as a central regulator of adipocyte differentiation.[26] First, stimulation of PPARγ by TZDs promotes fat cell differentiation, leading to the production of smaller, more insulin-sensitive adipocytes, which in turn promotes insulin-dependent glucose uptake into adipose tissue.[26] Second, PPARγ activation by TZDs affects the secretion of several substances from adipocytes that are involved in the regulation of insulin sensitivity and glucose metabolism, such as FFA and tumour necrosis factor alpha, which may lead to improvements in insulin signalling in insulin-sensitive tissues.[28] Importantly, the TZDs have been shown to increase levels of adiponectin,[19,29,30] a protein secreted by adipocytes that has anti-inflammatory properties,[31] is thought to enhance insulin sensitivity,[32] and is down-regulated in obesity and in type 2 diabetes.[33,34] All of these mechanisms decrease blood glucose levels.

The clinical efficacy of the TZDs has been demonstrated in numerous studies of patients with type 2 diabetes. Their effects in reducing insulin resistance are supported by clinical data from clamp studies and from estimates obtained using the homeostasis model assessment method, demonstrating clinically relevant improvements in insulin sensitivity.[5,35-38] Interestingly, one recent study has suggested that these effects extend to subjects with impaired glucose tolerance, in whom treatment with a TZD produced a significant increase in the insulin-sensitivity index of 24.3% over 12 weeks' treatment, compared with the decrease of 18.3% with placebo.[39] In terms of glycaemic control, TZDs (administered as monotherapy or in combination with other oral antidiabetic agents) significantly reduce HbA1c and fasting plasma glucose (FPG) to a similar degree, with greater reductions observed in patients with high-baseline glycaemic parameters.[3-11] In randomised monotherapy studies, TZD-mediated reductions in HbA1c in poorly controlled, drug-naïve patients are similar: 2.5% for rosiglitazone (8 mg/day)[40] and 2.6% for pioglitazone (45 mg/day)[7] compared with placebo. In a study of Mexican patients with type 2 diabetes who had inadequate glycaemic control on metformin therapy, the addition of rosiglitazone produced significant decreases in HbA1c and FPG.[11] Notably, the greatest reductions in glycaemic control were observed in rosiglitazone-treated patients with high baseline HbA1c (≥9.0%) or with body mass index (BMI) ≥ 27 kg/m2, although rosiglitazone has been found to be effective in lean as well as obese patients.[11,41] Data from long-term, open-label extension studies indicate that the effects of the TZDs on glycaemic control may be sustained over time.[8,42,43] Also, the TZDs may reduce the burden of CVD, as indicated by their effects on both traditional and non-traditional cardiovascular risk factors,[17,19,44,45] and reductions in myocardial infarction and stroke in the PROactive study.[12]

It is important to consider the benefit:risk profile when evaluating agents for long-term use. Troglitazone, the first commercially available TZD, was withdrawn from clinical practice because of the risk of drug-related hepatotoxicity. However, evidence from clinical trials and post-marketing experience indicate that hepatotoxicity is not a class effect.[46,47] Unlike other available oral antidiabetic agents, the TZDs do not increase the risk of hypoglycaemia or gastrointestinal side effects.[48] However, reports of oedema (usually mild-to-moderate in intensity) in 3-5% of TZD-treated patients in clinical trials have led to recommendations that these agents should be used with caution in patients with oedema or a history of heart failure.[49] This may be a particular problem in patients taking insulin, where rates of oedema in excess of 10% of patients have been reported. This limits the dose that can be prescribed with insulin in the USA to 4 mg of rosiglitazone, whereas in the European Union the combination is contraindicated.

Weight Gain: is it a Class Effect of the Thiazolidinediones?

Weight gain has been identified as a class effect of the TZDs, and previous reviews indicate an average weight gain of 3-4 kg over the first 6 months of TZD treatment, in line with treatments used in the United Kingdom Prospective Diabetes Study (UKPDS) (sulphonylureas and insulin).[20,22,48,50] Importantly, the rate of weight gain decreases after the first 6-12 months.[20,48,50] In placebo-controlled, double-blind clinical studies, dose-dependent increases in mean body weight have been observed with all TZDs, either as monotherapy or in combination with other antidiabetic agents.[4-11] Thus, weight gain appears to be a class effect of the TZDs, irrespective of the agent used. However, caution should be taken when comparing data from different studies, as changes in body weight may be affected by a number of factors, including baseline BMI, manipulations to pre-study antidiabetic medication, whether the methodology of last observation carried forward is applied to data from patients who withdraw and study regimen (e.g. the degree of diet and exercise reinforcement).

Weight gain associated with TZD treatment may vary greatly depending on the individual and on the treatment regimen employed. In particular, weight gain is more pronounced when TZDs are combined with sulphonylureas or insulin,[6,20] whereas, in combination with metformin, TZD-associated weight changes may be reduced, or even absent.[8,51] For example, in pooled data from observational studies involving 10,321 overweight patients treated with rosiglitazone 4-8 mg/day added to their existing metformin therapy, mean body weight decreased by 1.7 kg over 6 months.[52] Moreover, in three-quarters of patients, body weight was either constant or reduced (Figure 1).[52] In these pooled data, addition of rosiglitazone to metformin significantly improved glycaemic control compared with baseline.[52] Given the complementary mechanisms of the action of TZDs and metformin, coupled with neutral effects on weight gain at lower TZD doses, the combination of TZD and metformin therapy may be an appropriate choice for patients with inadequate glycaemic control. In addition, concomitant lifestyle intervention strategies, such as meal replacements and increased physical activity, may be of benefit in minimising TZD-related weight gain, as described in more detail below.[53] This may be of particular use in patients taking TZDs in combination with sulphonylurea or insulin therapy, who may be more prone to weight gain. For example, in a study of 172 type 2 diabetes patients randomised to rosiglitazone (4 or 8 mg/day) or placebo for 26 weeks, in addition to glimepiride (3 mg/day), mean weight increases of 0.9 kg (non-significant) and 1.7 kg (p = 0.006) were observed in patients taking 4 and 8 mg/day rosiglitazone, respectively.[54] Of note, HbA1c levels were significantly reduced in both TZD-treated groups compared with baseline and glimepiride plus placebo.[54]

Change in weight (%) by category in patients with type 2 diabetes treated with rosiglitazone plus metformin (n = 10,321). Reproduced from Rosak C et al.[52] Rosiglitazone plus metformin is effective and well tolerated in clinical practice: results from large observational studies in people with type 2 diabetes, International Journal of Clinical Practice, with permission from Blackwell Publishing

The weight gain reported in some TZD-treated patients may be caused by a combination of factors. First, in most of the TZD clinical studies, increases in body weight correlated with improvements in glycaemic control.[22] Of note, intensive glycaemic control strategies in the Diabetes Control and Complications Trial (DCCT) and UKPDS were associated with similar increases in weight compared with the TZDs. For example, after 5 years in the DCCT, patients receiving intensive therapy (insulin injections, administered at least three times daily) gained 4.6 kg on average compared with those on conventional therapy (insulin injections once or twice a day), in parallel with significant improvements in HbA1c.[55] Weight gain correlated statistically with the degree of glycaemic improvement, rather than with the insulin dose.[56] Similarly, over 10 years in the UKPDS, patients in the intensive blood glucose control group (sulphonylureas or insulin) gained a mean of 2.9 kg compared with patients taking conventional therapy (diet).[57] As before, increases in body weight in the UKPDS correlated with improvements in glycaemic control (Figure 2).[57] Less weight gain was reported in patients taking metformin therapy in the intensive arm of the UKPDS compared with sulphonylureas or insulin, with similar changes in weight compared with patients on conventional treatment.[58]

Mean change in weight in the United Kingdom Prospective Diabetes Study (overweight cohort). Reprinted from The Lancet, Vol. 352, UK Prospective Diabetes Study (UKPDS) Group, Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34), 854-865, 1998, with permission from Elsevier

Another factor contributing to TZD-related weight gain is increased adipocyte differentiation. As mentioned above, the antidiabetic effects of TZDs are mediated through PPARγ, a positive regulator of adipocyte differentiation.[26] Activation of PPARγ triggers the production of smaller, more insulin-sensitive adipocytes, pre-dominantly in the subcutaneous adipose compartment, and is likely to contribute to the TZD-mediated weight gain that has been observed in both animal and human studies.[20] In addition, TZD-associated weight gain is accompanied by increases in plasma volume. Because of this potential plasma volume expansion, TZDs are not recommended for patients with heart failure (New York Heart Association class III or IV).[49] Patients experiencing rapid increases in weight should be monitored for fluid accumulation and volume-related events such as oedema and congestive heart failure. Other factors that may influence body weight in patients taking TZDs include increased appetite and reductions in physical activity.[5,20] While the effect of TZDs on appetite in man is not clear, a study in animals suggests that any treatment-associated increase in appetite and body weight does not diminish the metabolic benefits of TZD treatment.[59] At present, the relative contributions of all of these factors are unknown, although studies are underway to further elucidate the mechanism(s) causing weight gain.

Effects of Thiazolidinediones on Regional Adiposity

Although weight gain is generally modest with TZD treatment, it has raised questions given the association between obesity and increased risk of type 2 diabetes and CVD.[60] For example, prospective data from the Framingham Heart Study indicates that individuals who are overweight (BMI 25.0-29.9) or obese (BMI ≥ 30) are at increased risk of hypertension and CVD.[24] However, it is important to recognise that not all fat depots are equivalent in terms of cardiovascular risk.[25] Peripheral obesity, defined as fat distributed subcutaneously on the buttocks, thighs and lower abdomen, is associated with no (or a low) risk of cardiovascular complications.[25] In contrast, individuals with central obesity (fat accumulation in the subcutaneous abdominal and visceral regions including increased hepatic fat) tend to be insulin resistant and are therefore more prone to cardiovascular complications.[25]

This susceptibility may be explained by the strong association between central obesity and insulin resistance, which is recognised as being an independent risk factor for CVD.[13,23] Indeed, central obesity is considered to be an important component of the metabolic syndrome.[61] Visceral obesity and insulin resistance are strongly associated with increased fat deposits in the liver, a condition known as non-alcoholic fatty liver disease (NAFLD); in some patients, this may progress to non-alcoholic steatohepatitis (NASH) and cirrhosis.[62] In individuals with increased visceral or intra-abdominal fat reserves, which are more lipolytically active compared with subcutaneous depots, excess FFA are released from triglyceride stores into the circulation.[28] Visceral fat drains into the hepatic portal vein, therefore delivering high concentrations of FFA to the liver and stimulating gluconeogenesis and other changes associated with hepatic insulin resistance.[28] Similarly, visceral fat and high plasma FFA concentrations are intimately linked with the development of skeletal muscle insulin resistance.[63] Evidently, it is not just absolute changes in weight, but where fat is deposited that is important in determining cardiovascular risk.

Importantly, despite the effects of TZDs on body weight, there is a mounting body of evidence indicating that these agents have depot-specific effects in adipose tissue. In a preclinical study, for example, while rosiglitazone stimulated adipocyte differentiation in human subcutaneous pre-adipocytes, cells from omental (visceral) tissue were not susceptible to the effects of rosiglitazone.[64] In animal models of diabetes, TZDs have reduced hepatic fat,[65,66] alongside marked improvements in insulin sensitivity.[66] Clinical studies support the ability of the TZDs to reduce hepatic fat.[35,67] In a 16-week, placebo-controlled study investigating the effects of rosiglitazone on insulin resistance, glycaemic control and body fat distribution in 33 type 2 diabetes patients, 95% of the increase in adiposity associated with rosiglitazone therapy occurred in peripheral or non-abdominal body regions (Figure 3).[35] The small increase in fat in the abdominal region occurred in subcutaneous rather than visceral tissue, leading to a significant reduction in the ratio of intra-abdominal to subcutaneous-abdominal fat area.[35] Furthermore, rosiglitazone was found to decrease hepatic fat levels by 45% relative to the placebo group, and these changes were accompanied by statistically significant improvements in insulin sensitivity and glycaemic control in rosiglitazone-treated patients vs. baseline and placebo.[35] Rosiglitazone has been shown to reduce liver fat when compared with metformin in patients with NAFLD[68] and to improve abnormal liver function tests in patients with NASH (Figure 4).[69] Finally, a recent report also suggested improvements in liver fibrosis in patients with NASH.[70] A recent study with pioglitazone further supports depot-specific effects. In 48 men and women treated for 24 weeks with 45 mg/day pioglitazone for 6 months, body fat increased by 3.9 kg, but there was no change in visceral fat.[71]

Effect of rosiglitazone 8 mg/day vs. placebo on intra-abdominal, subcutaneous and intrahepatic fat

The time course of changes in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) during treatment with rosiglitazone [Neuschwander-Tetri et al.[69]]. ALT and AST were measured at screening and again at treatment initiation (week 0), but there were no significant differences between these time points. *p < 0.01, Wilcoxon signed rank test compared to week 0; error bars indicate SD. Reprinted from Journal of Hepatology, Vol. 38, Neuschwander-Tetri BA et al. Interim results of a pilot study demonstrating the early effects of the PPAR-gamma ligand rosiglitazone on insulin sensitivity, aminotransferases, hepatic steatosis and body weight in patients with non-alcoholic steatohepatitis, 434-440, 2003, with permission from EASL

Several studies indicate, rather than a neutral effect, a significant reduction in visceral adipose tissue with TZD therapy.[72-75] In patients taking metformin, however, there is conflicting evidence, with some studies showing no significant change in visceral fat mass[73] and others showing significant decreases with metformin treatment (Figure 5).[74] Rosiglitazone (but not metformin) is also associated with decreases in hepatic fat, as shown by reductions in the liver:spleen attenuation ratio, and, while both agents reduced plasma FFA, the decrease was only statistically significant in the rosiglitazone group.[73] This may be a consequence of the ability of TZDs to reduce visceral fat, which is more lipolytic compared with the subcutaneous compartment. The different profiles of rosiglitazone and metformin in these studies reflect the potential benefits of TZDs and metformin in combination therapy.

Effect of rosiglitazone and metformin on subcutaneous abdominal adipose tissue (SCAAT) and visceral adipose tissue (VAT; Virtanen et al.). Asterisks (*) shown within columns are for the changes (p < 0.05) within the group. Copyright (c) 2003 American Diabetes Association. From Diabetes, Vol. 52, 2003; 283-290. Reprinted with permission from The American Diabetes Association

These findings are supported by data from other studies in which the TZDs either reduced or had neutral effects on the mean waist:hip ratio compared with baseline, despite increases in body weight, again indicating an increase in peripheral, rather than central, fat mass.[5,51,76] In another study, the addition of a TZD to individuals already taking sulphonylureas led to reductions in the level of gamma glutamyltransferase, a marker of visceral and hepatic fat.[77] In summary, all of these effects indicate that while TZDs may be associated with absolute increases in weight, their effects on fat distribution would, at least, be expected to have a neutral effect on cardiovascular risk. In fact, coupled with evidence that the TZDs ameliorate a number of cardiovascular risk factors, including insulin resistance, hypertension, dyslipidaemia, microalbuminuria and markers of hypofibrinolysis and inflammation, TZD-associated decreases in visceral fat may indicate an improvement in the cardiovascular risk profile.[15-19,78]

Managing Thiazolidinedione-Associated Weight Gain

It is important to consider how weight gain associated with TZD treatment can be managed in the clinical setting. One method involves the introduction of a lifestyle management plan in parallel with TZD treatment. In a study to evaluate the efficacy of a lifestyle intervention programme, 21 obese, insulin-treated patients with poorly controlled type 2 diabetes (mean baseline HbA1c = 9.0%, mean baseline BMI = 36.4) were randomised to either placebo or rosiglitazone 4 mg/day for 6 months, in addition to a lifestyle intervention programme (meal replacements, increased intake of fruit and vegetables and increased physical activity).[53] At the end of the study, modest weight loss was observed in both groups, with the greatest weight loss occurring over the first 12 weeks (8.6 kg for rosiglitazone, 5.4 kg for placebo), although weight loss continued over the duration of the study.[53] In addition, significant decreases in waist circumference (71 mm for placebo and 117 mm for rosiglitazone) and significant improvements in glycaemic control were observed in both groups after 6 months.[53] Greater reductions in weight and in waist circumference were observed with rosiglitazone vs. placebo, although the difference between the groups was not statistically significant.[53] Overall, this study highlighted the benefits of implementing lifestyle changes in type 2 diabetes patients with poor glycaemic control and demonstrated that TZD treatment does not necessarily impede weight loss, and may in fact enhance the effects of lifestyle intervention measures.[53] In addition, in a study in rats, food restriction potentiated the insulin-sensitising effect of a TZD, suggesting that diet control may bring additional benefits in treatment of type 2 diabetes.[79] A further route to managing weight gain associated with antidiabetic treatment may be provided by pharmacological weight-loss agents such as orlistat and sibutramine; these agents have been shown to bring benefits for weight control in combination with some antidiabetic therapies, but have not been studied in combination with TZDs.[80,81] Emerging treatments for diabetes that act via glucagon-like peptide 1 receptors such as exendin 9-39 (Exenatide) and liraglutide cause weight loss, and therefore may prove to be a logical combination therapy with TZDs in the management of type 2 diabetes, although clinical trials of these combinations have not yet been formally reported.

Recent basic research in mice has demonstrated that TZDs cause fluid retention via PPAR-γ-mediated increases in sodium absorption in the distal nephron, and that the diuretic amiloride can prevent TZD-induced fluid retention.[82] Whilst diuretics are commonly used in clinical practice to treat TZD-induced oedema, there is a theoretical basis for choosing either amiloride or spironolactone in preference to loop or thiazide diuretics in this situation, although this has not yet been reported in a clinical trial.

In conclusion, it is important to consider the benefit:risk ratio when evaluating an agent for long-term clinical use. The long-term efficacy of the TZDs has been confirmed, both in terms of their potent and sustained insulin-sensitising effects and their significant impact in improving glycaemic control, either as monotherapy or in combination therapy. In addition, there is preliminary evidence that this class of oral antidiabetic agents may have anti-atherogenic benefits, as indicated by their effects on a host of cardiovascular risk factors associated with insulin resistance. Clearly, further evidence from long-term outcome studies is required before this proposition can be confirmed.

However, while currently available TZDs generally have a favourable safety and tolerability profile, some concerns have been raised regarding the weight gain that may accompany treatment. Indeed, weight gain appears to be a class effect of the TZDs, although its magnitude is generally comparable with other conventional antidiabetic agents, such as the sulphonylureas and insulin.[47] Despite the well-known association between insulin resistance and obesity, TZD treatment is associated with reductions in insulin resistance, even in patients gaining weight. Importantly, weight gain appears to decrease after 6 months of TZD treatment, and tends to correlate with improvements in glycaemic control. Furthermore, increases in fat mass appear to be almost exclusively limited to subcutaneous, rather than central, fat depots, which has important implications in terms of cardiovascular risk. As central (including visceral) obesity is strongly associated with insulin resistance and an increased risk of cardiovascular complications, the reduction in visceral fat that is often observed with TZD therapy, despite increases in body weight, may indicate an additional benefit of the class. Finally, there is evidence that TZD-associated weight gain can be minimised by a number of methods, including concomitant use of a lifestyle intervention programme.

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