Pioglitazone Improved Metabolic Syndrome
"........We found that the administration of pioglitazone, but not fenofibrate, improved insulin resistance, blood pressure, and lipid profile over a 12-month period... We did not find any significant changes in the lipid profile, insulin resistance, or blood pressure in HIV-positive subjects after 12 months of fenofibrate treatment...pioglitazone during a 1-year period increases serum adiponectin levels and is as efficacious as treatment with rosiglitazone in improving insulin resistance in patients with HAART-induced metabolic syndrome. It also appears to have more-favorable effects on the blood pressure and lipid profile of such patients than does rosiglitazone. The effect of pioglitazone on insulin resistance may be mediated, at least in part, by the increase in adiponectin levels...
... In contrast to the previous open-label study to evaluate pioglitazone therapy among 11 HIV-positive patients receiving HAART, we found that, consistent with the effects seen in non--HIV-infected subjects with diabetes, pioglitazone improves insulin resistance and favorably affects the lipid profile by decreasing triglyceride levels and increasing HDL cholesterol levels. In addition, although LDL cholesterol levels tended to increase, the LDL particle size tended to increase, too, which resulted in lower levels of atherogenic LDL cholesterol. In contrast, rosiglitazone increased cholesterol and triglyceride levels. However, conflicting, yet limited, data exist on the effect of these 2 medications on the body composition of patients who are receiving antiretroviral therapy [3--6]. We also report, for the first time, that, in agreement with data from rodent studies, pioglitazone treatment improved blood pressure in subjects with HAART-induced metabolic syndrome." Full text of this study is reported after the links below.
1. Rosiglitazone & Pioglitazone Treatment for Lipodystrophy, diabetes, effects on lipids
URL: http://www.natap.org/2005/HIV/011005_07.htm - 10 Jan 2005
2. Pioglitazone Improves Liver, Body Fat, Glucose
URL: http://www.natap.org/2004/jan/010804_04.htm - 18 May 2004
3. Pioglitazone in Lipodystrophy
URL: http://www.natap.org/2003/sept/091003_4.htm - 12 Mar 2004
4. Pilot Study of Pioglitazone In Nonalcoholic Steatohepatitis (fatty liver)
URL: http://www.natap.org/2003/DDW/day16.htm -12 Mar 2004
Improvement in Highly Active Antiretroviral Therapy--Induced Metabolic Syndrome by Treatment with Pioglitazone but Not with Fenofibrate: A 2 × 2 Factorial, Randomized, Double-Blinded, Placebo-Controlled Trial
Clinical Infectious Diseases March 21, 2005;40:745-749
Alina Gavrila,1 William Hsu,1,4 Sotirios Tsiodras,2 John Doweiko,2 Shiva Gautam,3 Lizabeth Martin,1 Alan C. Moses,1,4 Adolf W. Karchmer,2 and Christos S. Mantzoros1
Divisions of 1Endocrinology and Metabolism, 2Infectious Diseases, and 3Translational Research, Department of Medicine, Beth Israel Deaconess Medical Center, and 4Joslin Diabetes Center, Boston, Massachusetts
We designed a 2 × 2 factorial, randomized, double-blinded, placebo-controlled trial to evaluate the effects of treatment with pioglitazone and/or fenofibrate in patients with highly active antiretroviral therapy (HAART)--induced metabolic syndrome. We found that the administration of pioglitazone, but not fenofibrate, improved insulin resistance, blood pressure, and lipid profile over a 12-month period.
HAART leads to profound and sustained suppression of HIV-1 replication, but it also results in the development of a metabolic syndrome, which confers an increased risk for developing premature atherosclerotic cardiovascular disease . Pioglitazone, 1 of the 2 thiazolidinediones that are currently available, improves insulin resistance and has a more favorable effect on lipid profile than does rosiglitazone in non--HIV-infected patients with diabetes . Although a few studies on the role of rosiglitazone in HAART-induced metabolic syndrome have been published [3--6], no randomized, placebo-controlled studies of the use of pioglitazone have been published. In addition, although open-label, uncontrolled studies have reported that fenofibrate, a fibric acid derivative, improves dyslipidemia and hyperglycemia in patients with HAART-induced metabolic syndrome [7--10], no randomized trials have been published to date.
Study design. We designed a 2 × 2 factorial, randomized, double-blinded, placebo-controlled study to evaluate the effect of pioglitazone and fenofibrate administration for 1 year in patients who developed metabolic abnormalities after starting HAART. Patients were >8 years old, had at least 6 months of cumulative exposure to any antiretroviral regimen, and had developed either (1) insulin resistance (fasting serum insulin level, >20 μU/mL) or impaired glucose tolerance or type 2 diabetes and (2) dyslipidemia (fasting triglyceride level, >300 mg/dL, and/or low-density lipoprotein [LDL] cholesterol level, >130 mg/dL) after starting HAART. Receipt of antihyperglycemic or hypolipidemic medications was stopped, and subjects were instructed to follow the American Heart Association Step II diet and to keep their exercise patterns stable throughout the study. All subjects received placebo therapy during the 1-month run-in phase, and treatment-compliant subjects were then randomized, using a 2 × 2 factorial design, to 1 of the 4 treatment groups. If hyperglycemia persisted after at least 1 month of receipt of the study medications, the dosage of pioglitazone (or its corresponding placebo) was increased from 30 mg/day—the dosage at baseline—to a maximum of 45 mg/day (in 2 subjects); the fenofibrate dosage remained 200 mg/day throughout the study. During the 12-month interventional phase, subjects were evaluated monthly for their compliance with the regimens and for the safety of the regimens. Efficacy assessment visits were completed at baseline and then 3 months and 12 months after randomization. A formal pill count was performed every 3 months.
We evaluated the effect of each study medication separately by comparing the patients who were taking active pioglitazone with patients who were taking the corresponding placebo and by comparing patients who were taking active fenofibrate with patients who were taking the corresponding placebo. We used the Wilcoxon signed rank test (with SPSS software, version 11.0; SPSS) to compare selected metabolic and lipid values at baseline with the levels that were obtained at months 3 and 12. All tests were 2-tailed, and the statistical significance was set at the P < .05 level. We report only the results of intention-to-treat analysis; on-treatment analysis provided similar results.
According to the 2 × 2 factorial design, of the 14 subjects who were randomized to receive treatment, 7 subjects received active pioglitazone and 7 received the corresponding placebo, whereas 6 subjects received active fenofibrate and 8 received the corresponding placebo (figure 1). The study group included 13 men and 1 woman, with a mean age (±SD) of 48 ± 8.6 years. Five subjects had mixed-fat redistribution, 5 subjects had fat accumulation, 3 subjects had fat wasting, and 1 subject did not have any fat redistribution; there was no significant difference in the number of subjects with the different types of fat redistribution among the treatment groups. Six subjects received a diagnosis of diabetes, 1 had impaired fasting glucose levels, and 7 had insulin resistance at baseline; there was no significant difference in the distribution of subjects with these characteristics among the treatment groups.
The mean duration of HIV infection (±SD) was 10.1 ± 3.2 years. At baseline, all subjects were taking nucleoside reverse-transcriptase inhibitors (NRTIs), 50% were taking protease inhibitors (PIs), and 43% were taking nonnucleoside reverse-transcriptase inhibitors (NNRTIs). There was no significant difference in the number of PIs, NRTIs, or NNRTIs that were being received, as well as viral load and CD4 count, between the groups at baseline. The mean CD4 count (±SD) decreased significantly during the study (575.3 ± 394.2 cells/μL at month 0 vs. 503.8 ± 359.6 cells/μL at month 12; P = .04), but mean viral loads did not change. No new opportunistic infections were diagnosed during the study.
Pioglitazone treatment versus placebo treatment. The characteristics at baseline did not differ between the subjects taking pioglitazone and the subjects taking the corresponding placebo. Mean insulin resistance index values (homeostasis model assessment [HOMA-IR] and quantitative insulin sensitivity check index [QUICKI]) and fasting insulin levels improved significantly during the 12-month study period in the pioglitazone group but not in the placebo group. Pioglitazone treatment also tended to decrease fasting glucose levels. In accordance with these findings, mean adiponectin levels increased significantly after the administration of pioglitazone (table 1). The mean systolic blood pressure decreased by 〜10% (P = .03), and diastolic blood pressure also tended to decrease (P = .06) after 12 months of pioglitazone therapy (table 1).
The mean fasting triglyceride levels decreased by 27.5% during the 12-month study period in the pioglitazone group but not in the placebo group (table 1). We found an increase that was of borderline significance in the mean high-density lipoprotein (HDL) cholesterol level after 12 months of pioglitazone therapy (P = .06), although the mean HDL cholesterol level decreased with placebo treatment (P = .05). Therefore, after we adjusted for the decrease in the mean HDL cholesterol level in the placebo group, the increase in the mean HDL cholesterol level with pioglitazone treatment became statistically significant and was 27% at month 3 (P = .03) and 40.5% at month 12 (P = .01). The increase in the mean LDL cholesterol level with pioglitazone treatment was of borderline significance at month 12 (P = .07), but there was no significant change noted in the mean LDL cholesterol level in the placebo group. We found no changes in the mean total cholesterol, apolipoprotein A, apolipoprotein B, or fasting free fatty acid levels in either the active pioglitazone or placebo groups. Nuclear magnetic resonance lipid analysis showed that the mean LDL particle size (±SEM) tended to increase after pioglitazone treatment (19.9 ± 0.4 nm at baseline vs. 20.5 ± 0.4 nm at month 3; P = .06 for month 3 vs. baseline; and 20.6 ± 0.3 nm at month 12; P = .06 for month 12 vs. baseline). Weight, body mass index, total fat mass, and trunk fat mass tended to increase, and the mean waist circumference and abdominal skin-fold thickness increased significantly during 12 months in the pioglitazone group.
Fenofibrate treatment versus placebo treatment. There were no significant changes in glucose metabolism and insulin resistance at months 3 or 12 in the fenofibrate group (mean values ± SEM: fasting glucose level, 128.5 ± 22.5 mg/dL at baseline, 102.7 ± 7.5 mg/dL at month 3, and 111.5 ± 6.4 mg/dL at month 12; fasting insulin level, 15.5 ± 4.6 μIU/mL at baseline, 11.0 ± 3.5 μIU/mL at month 3, and 12.1 ± 3.3 μIU/mL at month 12; and HOMA-IR values, 5.4 ± 2.2 at baseline, 3.1 ± 1.2 at month 3, and 3.5 ± 1.2, at month 12; all P values, >.10) or in the corresponding placebo group.
Fasting triglyceride levels did not change significantly in the fenofibrate group (mean ± SEM, 321.7 ± 72.0 mg/dL at baseline, 275.5 ± 100.6 mg/dL at month 3, and 255.5 ± 104.3 mg/dL at month 12; all P values, >.10) or the corresponding placebo group. In addition, no improvement in mean total, LDL, and HDL cholesterol levels, apolipoprotein A and B levels, or fasting free fatty acid levels were observed. Neither fenofibrate nor placebo treatment changed blood pressure significantly.
The mean rates of treatment compliance (±SD) were 91.6% ± 10.3% of prescribed pills among patients in the pioglitazone/corresponding placebo group and 89.2% ± 10.7% of prescribed pills among patients in the fenofibrate/corresponding placebo group. We found no significant difference in compliance rates between the groups receiving active medications and the groups receiving a corresponding placebo or between subjects who completed therapy and subjects who did not. One subject who received the corresponding placebo for both of the study medications stopped participation in the study before the first outcome-assessment visit (month 3); 1 patient in each of the 4 treatment groups stopped participation in the study after the visit at month 3. Importantly, the data from month 3 (when only 1 subject who was receiving placebo stopped participation) are almost identical to the data from month 12 , indicating that the dropout rate had no significant effect on the study outcomes, as is formally shown in the intention-to-treat and on-treatment analyses.
Discussion. On the basis of our randomized, placebo-controlled study, we report, for the first time, that treatment with pioglitazone during a 1-year period increases serum adiponectin levels and is as efficacious as treatment with rosiglitazone in improving insulin resistance in patients with HAART-induced metabolic syndrome. It also appears to have more-favorable effects on the blood pressure and lipid profile of such patients than does rosiglitazone. The effect of pioglitazone on insulin resistance may be mediated, at least in part, by the increase in adiponectin levels.
In contrast to the previous open-label study to evaluate pioglitazone therapy among 11 HIV-positive patients receiving HAART , we found that, consistent with the effects seen in non--HIV-infected subjects with diabetes, pioglitazone improves insulin resistance and favorably affects the lipid profile by decreasing triglyceride levels and increasing HDL cholesterol levels. In addition, although LDL cholesterol levels tended to increase, the LDL particle size tended to increase, too, which resulted in lower levels of atherogenic LDL cholesterol. In contrast, rosiglitazone increased cholesterol and triglyceride levels. However, conflicting, yet limited, data exist on the effect of these 2 medications on the body composition of patients who are receiving antiretroviral therapy [3--6]. We also report, for the first time, that, in agreement with data from rodent studies , pioglitazone treatment improved blood pressure in subjects with HAART-induced metabolic syndrome.
We did not find any significant changes in the lipid profile, insulin resistance, or blood pressure in HIV-positive subjects after 12 months of fenofibrate treatment. Although previous open-label trials of HIV-positive patients who received fenofibrate showed significant reductions in serum triglyceride levels, the uncontrolled design of those studies could not exclude potential bias by changes in factors such as diet, exercise, or immune status. On the basis of our data, 600 subjects would be needed for a clinical trial to have 80% power to detect a significant difference in triglyceride levels, and >80 subjects would be needed to detect a significant difference in HOMA-IR values after the administration of fenofibrate.
In conclusion, pioglitazone is efficacious and well tolerated in the treatment of HAART-induced metabolic syndrome. Because pioglitazone has effects similar to those of rosiglitazone on insulin resistance and glucose metabolism, comparative studies of rosiglitazone are warranted to demonstrate whether pioglitazone has more beneficial effects on the lipid profile and hypertension. This would justify the preferential use of pioglitazone for HIV-positive subjects who develop HAART-induced metabolic syndrome. Additional, larger studies to investigate the effect of fenofibrate in patients with higher triglyceride levels—possibly for each lipodystrophy subgroup separately—are also warranted, as are larger studies to investigate the role of treatment with pioglitazone in combination with fenofibrate.
Financial support. This study was supported, in part, by grants from the National Institutes of Health (grant M01-RR 01032, to the Beth Israel Deaconess Medical Center General Clinical Research Center, and grant K30 HL04095, to A.G.), and by a Takeda grant and an American Diabetes Association Clinical Research Grant (to C.S.M.).
1. Leow MK, Addy CL, Mantzoros CS. Clinical review 159: Human immunodeficiency virus/highly active antiretroviral therapy--associated metabolic syndrome: clinical presentation, pathophysiology, and therapeutic strategies. J Clin Endocrinol Metab 2003; 88:1961--76. First citation in article | PubMed | CrossRef
2. van Wijk JP, de Koning EJ, Martens EP, Rabelink TJ. Thiazolidinediones and blood lipids in type 2 diabetes. Arterioscler Thromb Vasc Biol 2003; 23:1744--9. First citation in article | PubMed | CrossRef
3. Hadigan C, Yawetz S, Thomas A, Havers F, Sax PE, Grinspoon S. Metabolic effects of rosiglitazone in HIV lipodystrophy: a randomized, controlled trial. Ann Intern Med 2004; 140:786--94. First citation in article | PubMed
4. Carr A, Workman C, Carey D, et al. No effect of rosiglitazone for treatment of HIV-1 lipoatrophy: randomised, double-blind, placebo-controlled trial. Lancet 2004; 363:429--38. First citation in article | PubMed | CrossRef
5. Sutinen J, Hakkinen AM, Westerbacka J, et al. Rosiglitazone in the treatment of HAART-associated lipodystrophy—a randomized double-blind placebo-controlled study. Antivir Ther 2003; 8:199--207. First citation in article | PubMed
6. Gelato MC, Mynarcik DC, Quick JL, et al. Improved insulin sensitivity and body fat distribution in HIV-infected patients treated with rosiglitazone: a pilot study. J Acquir Immune Defic Syndr 2002; 31:163--70. First citation in article | PubMed
7. Palacios R, Santos J, Gonzalez M, et al. Efficacy and safety of fenofibrate for the treatment of hypertriglyceridemia associated with antiretroviral therapy. J Acquir Immune Defic Syndr 2002; 31:251--3. First citation in article | PubMed
8. de Luis DA, Bachiller P, Aller R. Fenofibrate in hyperlipidaemia secondary to HIV protease inhibitors: fenofibrate and HIV protease inhibitor. Nutrition 2001; 17:414--5. First citation in article | PubMed | CrossRef
9. Calza L, Manfredi R, Chiodo F. Statins and fibrates for the treatment of hyperlipidaemia in HIV-infected patients receiving HAART. AIDS 2003; 17:851--9. First citation in article | PubMed | CrossRef
10. Caramelli B, de Bernoche CY, Sartori AM, et al. Hyperlipidemia related to the use of HIV-protease inhibitors: natural history and results of treatment with fenofibrate. Braz J Infect Dis 2001; 5:332--8. First citation in article | PubMed
11. Calmy A, Hirschel B, Hans D, Karsegard VL, Meier CA. Glitazones in lipodystrophy syndrome induced by highly active antiretroviral therapy. AIDS 2003; 17:770--2. First citation in article | PubMed | CrossRef
12. Dobrian AD, Schriver SD, Khraibi AA, Prewitt RL. Pioglitazone prevents hypertension and reduces oxidative stress in diet-induced obesity. Hypertension 2004; 43:48--56. First citation in article | PubMed | CrossRef