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Effect of Pioglitazone on Metabolic Syndrome Risk Factors: Results of Double-Blind, Multicenter, Randomized Clinical Trials*

Posted on: Thursday, 17 March 2005, 03:00 CST

Key words: Diabetes mellitus - Lipids - Metabolic syndrome - Obesity - Pioglitazone - Syndrome X - Thiazolidinediones

ABSTRACT

Objective: To evaluate the effect of pioglitazone, metformin, and/ or sulfonylurea on metabolic syndrome and its component parameters after a year of treatment.

Methods: Adult patients with poorly controlled type 2 diabetes were enrolled in 4 multicenter, double-blind studies and received pioglitazone, sulfonylurea, metformin, or a combination of any 2 agents. Post hoc analyses were performed on data from patients with evaluations at baseline and week 52, and treatment groups were compared to determine change from baseline in metabolic syndrome status and its component variables by using the McNemar test and analysis of covariance, respectively.

Results: Most patients (72.1%) had metabolic syndrome at baseline. Change in the proportion of patients with metabolic syndrome status was significant in each monotherapy and the pioglitazone plus metformin combination groups. Pioglitazone alone or in combination with metformin resulted in a significantly greater percent decrease from baseline in triglycrides (pioglitazone vs. metformin, 10.3%; pioglitazone vs. sulfonylurea, 6.5%; pioglitazone plus metformin vs. sulfonylurea plus metformin, 13.4%; P< 0.05) and a greater percent increase from baseline in high-density lipoprotein (HDL) cholesterol (pioglitazone vs. metformin, 9.1%; pioglitazone vs. sulfonylurea, 12.6%; pioglitazone plus metformin vs. sulfonylurea plus metformin, 17.8%; P < 0.001) at week 52 than did the respective comparison groups. A significant decrease from baseline in the ratio of urinary albumin to creatinine was found only with pioglitazone monotherapy (-1.764 mg/ mmol; P < 0.001), which was significantly greater than the change in the metformin monotherapy group (2.1%; P < 0.05). Significant decrease in blood pressure was observed in the pioglitazone monotherapy and pioglitazone plus sulfonylurea groups, with no significant treatment group differences.

Conclusions: Treatment with pioglitazone as monotherapy or combination therapy led to sustained, positive effects on important components of metabolic syndrome in patients with type 2 diabetes, independent of effects on blood glucose control and, as such, could be translated to potential for reducing the risk of cardiovascular disease.

Introduction

Metabolic syndrome, also called insulin resistance syndrome or syndrome X, is a cluster of risk factors responsible for much of the excessive cardiovascular comorbidity among patients with type 2 diabetes mellitus1-7. Various definitions of metabolic syndrome are provided by different organizations. The World Health Organization (WHO) has defined the syndrome to include a combination of impaired glucose tolerance, diabetes, or insulin resistance; central obesity and/or body mass index (BMI) > 30kg/m^sup 2^; elevated blood pressure; microalbuminuria; and lipid abnormalities (i.e., elevated levels of triglycerides and low levels of high-density lipoprotein [HDL] cholesterol) (Table 1)8. Isomaa et al. reported that 42% to 64% of patients with impaired glucose tolerance and as many as 84% of patients with type 2 diabetes meet the WHO criteria for metabolic syndrome9. Metabolic syndrome affects approximately one quarter of adults in North America10.

Given the name syndrome X in 1988(2), the syndrome and its individual components have been associated with an increased risk of cardiovascular disease3-6. In a recent study by Bonora et al., patients with metabolic syndrome were at increased risk for both carotid atherosclerosis and coronary heart disease4. Similarly, in a study by Lakka et al., the risk of coronary artery disease and mortality was approximately 3-fold higher in patients with metabolic syndrome than in those without7.

Insulin resistance may be the common cause of the individual components of metabolic syndrome11. Increased fasting glucose (110- 125mg/dL [6.16.9mmol/L]), an indicator of insulin resistance, is frequently accompanied by other metabolic risk factors12-13. A portion of the population with increased fasting glucose eventually develops type 2 diabetes13,14.

The management of diabetes in patients with metabolic syndrome thus should not only focus on blood glucose control but also include strategies for reduction of the metabolic risk factors15. The metabolic risk factors both define metabolic syndrome and represent potential targets for therapeutic intervention16. Early management of metabolic syndrome and its components may have a significant effect on cardiovascular disease17-19.

Table 1. World Health Organization metabolic syndrome definition[dagger]

The therapeutic armamentarium for diabetes expanded with the approval of the thiazolidinediones, a novel antihyperglycemic class of drugs currently represented by 2 agents, one of which is pioglitazone (Actos*). Through activation of peroxisome proliferatoractivated receptor γ (PPAR-γ), thiazolidinediones decrease insulin resistance, resulting in glycemic improvements in patients with type 2 diabetes20. In trials conducted for periods as long as 26 weeks, pioglitazone effectively treated insulin resistancerelated hyperglycemia, decreased triglycerides, and increased HDL cholesterol21-23. Pioglitazone has also been observed to decrease urinary albumin excretion, a known marker of cardiovascular risk in patients with type 2 diabetes24,25. Of interest is whether these favorable effects of pioglitazone on components of metabolic syndrome are sustained over a longer treatment period.

In this paper, we report results of post hoc analyses performed on data from 4 randomized prospective clinical studies to evaluate the effect of pioglitazone, metformin, and/or sulfonylurea regimens on metabolic syndrome and its component parameters after 1 year of therapy.

Methods

Patients between the ages of 35 and 75 years with type 2 diabetes mellitus (hemoglobin A^sub lc^ [AlC] of 7.5% to 11 % at screening) poorly controlled with diet alone (monotherapy studies) or a stable dose of metformin or sulfonylurea (combination therapy studies) for at least 3 months were eligible for enrollment in the 4 clinical studies. The 4 studies had the same inclusion and exclusion criteria26-28. Among the exclusion criteria for the trials were type 1 diabetes, cardiac or cerebrovascular conditions (e.g., myocardial infarction, transient ischemic attacks, or cerebrovascular accident) within the 6 months before screening, or symptomatic heart failure. Patients were permitted to take lipidlowering agents (i.e., β- hydroxy-β-methylglutarylCoA [HMG CoA] reductase inhibitor or fibrate) and antihypertensive agents (i.e., angiotensin-converting enzyme [ACE] inhibitor, angiotensin receptor blocker [ARB], or calcium channel blocker), as necessary, during study participation, and the proportions of patients using these agents were similar across comparison groups. The patients were instructed to adhere to a disease- and body weight-oriented diet for the whole course of the study, with the target of body weight normalization and supply of individually appropriate calories and nutrients. Patients were offered dietary advice or counseling, if needed, throughout the 52 weeks.

The 4 studies were prospective, double-blind, randomized, multicenter, multinational (29 countries) 52-week trials26-28. (Two of these trials have been published as an abstract, and data are on file.) Trials consisted of a 12-week (metformin dose titrated up) or 16-week (sulfonylurea dose titrated up) titration period during which the drug dose in each treatment was increased to the maximum tolerated dose followed by a maintenance period of at least 36 weeks. In each of these trials, the local ethics committees at participating sites approved the protocol, and patients or legally authorized representatives provided written, informed consent before patient enrollment.

In the 2 monotherapy studies27, patients were randomized to receive pioglitazone 30mg, metformin 850mg, or sulfonylurea (gliclazide) 80mg once daily; the dose of the study drug was increased every 4 weeks during the titration period, on the basis of tolerability, to 45 mg once daily, 850 mg 3 times daily, and 160mg twice daily, respectively. In the 2 combination therapy studies26'28, patients who had failed to improve with a sulfonylurea or metformin regimen (each taken before study enrollment at > 50% of the maximum recommended dose or at the maximum tolerated dose for > 3 months) were randomized to receive pioglitazone, metformin (in those failing with sulfonylurea), or sulfonylurea (in those failing with metformin). In the 2 combination therapy studies, patients continued taking the same antihyperglycemic agent (metformin or sulfonylurea) at the same dose as that taken before study enrollment. The 2 combination studies involved 2 separate sets of patients receiving sulfonylurea plus metformin to compare with the pioglitazone plus metformin and pioglitazone plus sulfonylurea combination groups.

Glycemic control in study participants was evaluated by measuring AlC and fasting plasma glucose. Serum lipid profiles, including triglycerides and total, lowdensity lipoprotein (LDL), and HDL cholesterol, were evaluated at baseline and week 52. Both lipids and gluco\se were measured while the patient was fasting. Systolic and diastolic blood pressures were also measured at predetermined times. The BMI and ratio of urinary albumin to creatinine (spot collected) were calculated at baseline and week 52.

A subset of patients with required data for metabolic syndrome evaluation at both baseline and 52 weeks from the intent-to-treat population was included in this post hoc analysis. No data on subjects who switched to other medications were available because they were excluded from the original study. The status of metabolic syndrome and its component parameters was determined at baseline and week 52 for each patient by using the WHO definition8 for metabolic syndrome (Table 1). Type 2 diabetes patients in this study were classified as having metabolic syndrome if they satisfied 2 or more of the metabolic syndrome criteria in addition to having diabetes. Statistical analyses were conducted by using a population of patients who had data recorded at baseline and week 52 for metabolic syndrome components. Results in the pioglitazone monotherapy group were compared with those in the metformin group and the sulfonylurea group. Results were compared between each pioglitazone combination therapy group and the corresponding sulfonylurea plus metformin combination therapy group.

The status (present versus absent) of metabolic syndrome at baseline and week 52 for each treatment group was the primary outcome and was compared by using the McNemar test. For the subset of patients having metabolic syndrome at baseline, change from baseline in each of the 5 component variables (triglycerides, HDL cholesterol, blood pressure, BMI, and ratio of urinary albumin to creatinine) was assessed for each treatment group. Statistical significance of the change from baseline within each treatment group was assessed by using a paired t test. The results of the paired t test are discussed in the text only within the Results section and are not presented in the tables.

Change from baseline in each parameter was compared between treatment groups by using analysis of covariance, with treatment group as the factor and baseline value of the respective parameter as the covariate. Estimated differences were obtained from differences between treatment groups in mean change from baseline and were part of the analysis of covariance performed on each parameter. Pioglitazone monotherapy was compared to the metformin and sulfonylurea monotherapy groups. Pioglitazone in combination therapy with metformin or sulfonylurea was compared with the respective sulfonylurea plus metformin groups.

Results

A total of 3713 patients were randomized and took at least 1 dose of study drug. There were 1221 patients in the pioglitazone monotherapy group, 597 in the metformin monotherapy group, 626 in the sulfonylurea monotherapy group, 317 in the pioglitazone plus metformin group, 313 in the sulfonylurea plus metformin group (comparison group for pioglitazone plus metformin), 319 in the pioglitazone plus sulfonylurea group, and 320 in the metformin plus sulfonylurea group (comparison group for pioglitazone plus sulfonylurea).

Overall, the treatment groups compared had similar baseline demographic characteristics and glycemic parameters (Table 2). Mean baseline AlC across the treatment groups was 8.7%. Patients receiving monotherapy had an average duration of diabetes of 3 years, as compared with a 2-fold longer average of 6 to 7 years in patients receiving combination therapy (Table 2). Across treatment groups, more patients were male (57%) and younger than 65 years (77%).

A total of 82.8% (3076 of 3713) of patients from the total study population had baseline and week 52 visits. According to the WHO criteria, 72.1% of patients had metabolic syndrome at baseline. Of the total number of patients in each monotherapy group, the proportion of patients with metabolic syndrome decreased 9.2% (95% confidence interval [CI] 6.5% to 12%) in the pioglitazone group, 7.7% (95% CI 3.5% to 11.9%) in the metformin group, and 4.3% (95% CI 0.4% to 8.3%) in the sulfonylurea group. In the combination therapy groups, the proportion of patients with metabolic syndrome decreased 10% (95% CI 4.4% to 15.6%) in the pioglitazone plus metformin group, 2.4% (95% CI -3.9% to 8.7%) in the pioglitazone plus sulfonylurea group, and 3.9% (95% CI -2.6% to 10.3%) in the metformin plus sulfonylurea group (from the pioglitazone plus sulfonylurea study). In the sulfonylurea plus metformin group (from the pioglitazone plus metformin study), the proportion of patients with metabolic syndrome increased by 1.1% (95% CI -6.0% to 3.7%) (Table 3).

Table 2. Baseline demographic and clinical characteristics

In analyses of the component parameters for metabolic syndrome, a significant increase from baseline in HDL cholesterol (P < 0.001) was seen in all treatment groups, with the exception of the metformin plus sulfonylurea groups. Pioglitazone, as monotherapy and in combination with metformin or sulfonylurea, demonstrated significantly greater increase from baseline in HDL cholesterol than did the respective comparison groups (Table 4).

Of the patients who met the HDL cholesterol criteria for metabolic syndrome at baseline, 67% in the pioglitazone and pioglitazone plus metformin groups and 63% in the pioglitazone plus sulfonylurea group no longer met the HDL cholesterol criteria for metabolic syndrome at week 52. Similarly, a large number of patients in the metformin (42%), sulfonylurea (38%), and the 2 metformin plus sulfonylurea groups (30% in the pioglitazone plus metformin comparator group and 45% in the pioglitazone plus sulfonylurea treatment group) had HDL cholesterol values of 0.91 or 1.04mmol/L or greater at week 52 and no longer met the metabolic syndrome criteria for HDL cholesterol (Table 5).

A significant decrease from baseline in triglycerides (P < 0.05) was seen in all treatment groups. A significantly greater decrease from baseline in triglycerides was found with pioglitazone as monotherapy and in combination with metformin than in the comparison groups (Table 4). Of the patients who met the triglyceride criterion for metabolic syndrome at baseline (≥ 1.69mmol/L [≥ 150mg/dL]), 34% of patients in the pioglitazone, 28% of patients in the pioglitazone plus sulfonylurea, and 24% of patients in the pioglitazone plus metformin groups had triglyceride values less than 1.69 mmol/L at week 52 and no longer met the metabolic syndrome criterion for triglycerides (Table 5).

Table 3. Presence of metabolic syndrome for treatment groups*

The urinary albumin to creatinine ratio decreased significantly in the pioglitazone monotherapy group (P < 0.001), with the decrease significantly greater than in the metformin monotherapy group (P = 0.007), in which the ratio increased. Of the patients who met the urinary albumin to creatinine ratio criterion for metabolic syndrome at baseline (> 3.39mg/mmol), 43% of patients in the pioglitazone, 45% of patients in the pioglitazone plus sulfonylurea, and 38% of patients in the pioglitazone plus metformin groups had urinary albumin to creatinine ratios less than 3.39mg/mmol at week 52 and no longer met the metabolic syndrome criterion (Table 5).

There was a small but statistically significant increase from baseline in BMI in each of the pioglitazone groups and in the sulfonylurea monotherapy group (P < 0.001), with the difference between groups significant for each comparison except that between the pioglitazone plus metformin and sulfonylurea plus metformin combination therapy groups (Table 4).

A significant decrease from baseline in diastolic blood pressure was found in all groups (all P < 0.05), except for the pioglitazone plus metformin group (P = 0.35) and the sulfonylurea plus metformin group (P = 0.90) of the same study. For systolic blood pressure, a significant decrease from baseline was observed in the pioglitazone (P < 0.001) and pioglitazone plus sulfonylurea (P = 0.016) groups. The change from baseline in systolic blood pressure was not statistically significant in the other treatment groups. There were no statistically significant differences between treatment groups for change from baseline in systolic or diastolic blood pressure (Table 4).

Discussion

Post hoc analyses from 4 randomized prospective clinical studies with similar protocols showed that pioglitazone had a significant effect on metabolic syndrome and its component parameters. The 4 studies included a large population of adults with type 2 diabetes (mean duration, 3 to 7 years) poorly controlled with diet (monotherapy) or metformin/sulfonylurea (combination therapy).

Table 4. Analysis of covariance: change from baseline to week 52 in metabolic syndrome risk factors

Table 5. Patients not meeting metabolic syndrome criteria from baseline to week 52

Of the patients with metabolic syndrome at baseline, 10% in one of the sulfonylurea plus metformin groups (pioglitazone plus metformin comparator) and 19% to 23% in each of the other treatment groups did not meet the criteria for metabolic syndrome at week 52, most often because of an increase in HDL cholesterol and a decrease in triglycerides. Our results are consistent with those from a trial of shorter duration in which significant increase from baseline in HDL cholesterol and significant decrease from baseline in triglyceride levels were observed after 16 weeks of 30 mg of pioglitazone combined with metformin22. Derosa et al. reported a significant increase in HDL cholesterol after 12 months of treatment with pioglitazone plus sulfonylurea combination therapy29.

The significant changes from baseline in HDL cholesterol levels (+0.20mmol/L with pioglitazone monotherapy and +0.17 to +0.19 mmol/ L with pioglitazone combination therapy) are encouraging in light of the results of the recent Veterans Affairs High-Density Lipoprotein Intervention Trial, in which coronary heart diseas\e events were reduced by 11% for every 0.13 mmol/ L increase in HDL cholesterol (P = 0.02) with fibrate therapy30. Given the high risk of coronary artery disease in patients with metabolic syndrome, target levels have been established for the lipid parameters6,31.

Microalbuminuria, a component of metabolic syndrome8, is an important risk factor for cardiovascular disease in patients with diabetes25,32. Among the patients who had metabolic syndrome in our study, pioglitazone significantly decreased the urinary albumin to creatinine ratio by a third, with a significantly greater decrease as compared with findings with metformin monotherapy. Nakamura et al. documented a similar decrease in urinary albumin excretion in patients with diabetes and microalbuminuria treated with pioglitazone24. The effect of the reduction in urinary albumin excretion by pioglitazone on cardiovascular risk or future risk of progression to advanced nephropathy is not known.

The increase from baseline in BMI was statistically significant in each of the pioglitazone-containing groups and in the sulfonylurea monotherapy group. The increase in BMI was paradoxically associated with improvement in markers of insulin resistance (e.g., HDL, triglycerides, and glucose)26-28. A statistically significant decrease in BMI was found in the metformin monotherapy group. That patients treated with pioglitazone in these 4 studies had a decrease in insulin resistance and glucose levels26- 28 despite an increase in BMI may be explained by a redistribution of fat from visceral (most conducive for interference with insulin action) to subcutaneous deposits33. This shift in fat distribution with use of pioglitazone merits consideration, since visceral obesity is a strong risk factor for cardiovascular disease and diabetes32.

In our study, statistically significant decreases from baseline were noted for diastolic and systolic blood pressures in the pioglitazone and pioglitazone plus sulfonylurea groups. Hypertension not only increases the risk of cardiovascular disease in patients with diabetes34,35 but also is a risk factor for microalbuminuria36. In clinical trials involving diabetic patients, blood pressure control was associated with significant risk reductions for cardiovascular events and death37,38. On the basis of these observations, the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recently updated their recommendations for treatment of hypertension, including a blood pressure goal of lower than 130/80 mmHg in patients with hypertension and diabetes39. Because most patients with hypertension require 2 or more drugs to achieve their blood pressure goal40, blood pressure lowering with antihyperglycemic therapy may facilitate achievement of target blood pressure in patients with diabetes and/or reduce the number of antihypertensive agents necessary to do so.

The results of our study support the effect of pioglitazone therapy to extend beyond control of blood sugar levels and include components of metabolic syndrome such as modification of dyslipidemia. Taken together, these findings from post hoc analyses raise the prospect of reducing cardiovascular risk with use of pioglitazone. A study evaluating clinical end points (e.g., myocardial infarction, stroke) is necessary to confirm that reduction of composite risk factors of metabolic syndrome by using pioglitazone will result in a decreased risk of macrovascular complications of diabetes. Such a study is currently under way (the Prospective Pioglitazone Clinical Trial in Macrovascular Events or PROactive trial)41.

As with every study, there are limitations. The study was a post hoc analysis and was conducted in patients having data at baseline and at week 52. Data on noncompliant patients could have been lost because of early termination, thus limiting generalizability of study results.

Conclusion

In conclusion, treatment with pioglitazone as monotherapy or combination therapy and sulfonylurea or metformin as monotherapy or in combination led to sustained, positive effects on important components of metabolic syndrome in patients with type 2 diabetes, independent of effects on blood glucose level. Pioglitazone in monotherapy or combination therapy showed a significantly greater effect on lipid parameters compared to findings with metformin or sulfonylurea, which could be translated to potential for reducing the risk of cardiovascular disease.

Acknowledgements

The studies described in this paper were sponsored by Takeda Europe Research and Development Centre, Etd, London, UK.

We would like to acknowledge Jeannie Xie, MS, and Eixian Peng, MS, for their diligent data analysis and programming efforts and Yaping Xu, MPH, MBA, for statistical support.

* These data were presented at the 2004 Annual Meeting of the American Diabetes Association, Orlando, FL, June 4-8, 2004

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2864_5, Accepted for publication: 15 December 2004

Published Online: 14 January 2005

doi: 10.1185/030079904X20295

Rukmini Rajagopalan, Shrividya Iyer and Mehmood Khan

Takeda Pharmaceuticals North America, Inc., Lincolnshire, IL, USA

Address for correspondence: Dr Rukmini Rajagopalan, Takeda Pharmaceuticals North America, Inc., 475 Half Day Road, Lincolnshire, IL 60069, USA. Tel.: +1-847-383-3619; Fax: +1-847-383- 3056; email: rrajagopalan@tpna.com

Copyright Librapharm Jan 2005

Source: Current Medical Research and Opinion

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