The long‐term effects of rosiglitazone on serum lipid concentrations and body weight

Abstract

SummaryObjective Although rosiglitazone, an insulin sensitizer, is known to have beneficial effects on high density lipoprotein cholesterol (HDL-C) concentrations and low density lipoprotein (LDL) particle size, it has unwanted effects on total cholesterol (TC) and LDL cholesterol (LDL-C) concentrations and body weight in some short-term studies. The aim of this study was to evaluate the longterm effects of rosiglitazone on serum lipid levels and body weight. Design Open labelled clinical study. Patients and measurementsWe prospectively evaluated fasting serum glucose, haemoglobin A 1c (HbA 1c ), lipid profiles and body weight at baseline and every 3 months after the use of rosiglitazone (4 mg/day) for 18 months in 202 type 2 diabetic patients. Results TC levels increased maximally at 3 months and decreased thereafter. However, overall, TC levels remained significantly higher at 18 months than those at baseline. LDL-C levels from the 3-month to the 12-month timepoint were significantly higher than those at baseline. However, after 15 months, LDL-C concentrations were not significantly different from basal LDL-C concentrations. HDL-C levels increased after the first 3 months and these levels were maintained. The increment of change in HDL-C was more prominent in patients with low basal HDL-C concentrations than in patients with high basal HDL-C concentrations. Body weight increased after the first 3 months and these levels were maintained. Conclusions HDL-C and body weight increased and remained elevated for the duration of the study. There was an initial increase in LDL-C but this attenuated and by the end of the study was not significantly elevated above baseline levels.

Endocrine disrupting chemicals and disease susceptibility

“…Activating the PPARγ pathway drives mutipotent stromal stem cells to enter the adipogenic pathway whereas inhibition of PPARγ expression promotes an osteogenic fate [reviewed in 20, 21]. It is known that humans whose diabetes is being treated with rosiglitazone (a drug that activates PPARγ) develop more adipocytes and gain weight [22]. Therefore it is reasonable to hypothesize that chemicals capable of activating PPARγ might have the same effect [reviewed in 23].…”

Endocrine disrupting chemicals and the developmental programming of adipogenesis and obesity

“…The observation that obese individuals have more adipocytes leads naturally to the hypothesis that obesity is a consequence of more adipocytes. Although it is unclear at present whether such a causal connection exists between adipocyte number and obesity, it is known that mice with hyperplastic obesity become morbidly obese (Kim et al, 2007), and that humans whose diabetes is being treated with rosiglitazone (a drug that activates PPARγ) develop more adipocytes and gain weight (Shim et al, 2006). Obese subjects (in particular, those with early onset obesity (Salans et al, 1973)), are also predisposed to have more adipocytes.…”

A Nonthiazolidinedione Peroxisome Proliferator-Activated Receptor α/γ Dual Agonist CG301360 Alleviates Insulin Resistance and Lipid Dysregulation in db/db Mice

“…Through simultaneous activation of both PPAR␣ and PPAR␥, PPAR␣/␥ dual agonists have been expected to alleviate obesity and diabetes (Watkins and Whitcomb, 1998;Hirsch et al, 1999;Al-Salman et al, 2000;Tang et al, 2003;Shim et al, 2006). However, side effects of PPAR␣/␥ dual agonists still make them unsuitable for treatment of obesity and insulin resistance (Hellmold et al, 2007;Mittra et al, 2007;Tannehill-Gregg et al, 2007).…”

“…Without significant change in food intake (data not shown), increase in body weight and white adipose tissue (WAT) weight was observed in CG301360-treated db/db mice, albeit to a lesser extent than by rosiglitazone, a well known PPAR␥ agonist (Fig. 3, A and B) (Chaput et al, 2000;Shim et al, 2006).…”

“…Although TZDs potently sensitize insulin action in peripheral tissues to ameliorate insulin resistance, several negative concerns, such as weight gain, hepatotoxicity, edema, and heart failure, have been reported (Watkins and Whitcomb, 1998;Hirsch et al, 1999;Tang et al, 2003;Shim et al, 2006). Unlike TZD, PPAR␣ agonists mediate fatty acid oxidation to alleviate hypertriglyceridemia and also mildly reduce body adiposity (Guerre-Millo et al, 2000).…”