Troglitazone has no effect on red cell mass or other erythropoietic parameters

Young, Melissa; Squassante, Lisa; Wemer, J.; Marle, Sjoerd P. van; Dogterom, Peter; Jonkman, J. H. G.

doi:10.1007/s002280050602

Cited by 32 publications

(27 citation statements)

References 7 publications

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“…An increased incidence of edema and decreases in mean Hb and hematocrit were also observed in patients treated with IϩRSG. These effects are consistent with expansion of plasma volume and hemodilution, which has been observed during treatment with all members of the TZD class (11,21). The incidence of edema was greater than that observed with monotherapy or in combination with metformin and sulfonylureas (11,22,23).…”

Section: Safety Parameterssupporting

confidence: 80%

“…RSG treatment was also associated with significantly greater increases in weight as compared with patients treated with IϩPBO. These increases may be attributable to several factors previously reported with TZDs, including improvement in glycemic control, fluid retention (11,21), adipocyte differentiation (11,26), and increased appetite (27). It is notable that despite weight increases observed with RSG treatment, no significant differences in WHR were observed between the IϩRSG and IϩPBO groups.…”

Section: Safety Parametersmentioning

confidence: 84%

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A Randomized Trial of Rosiglitazone Therapy in Patients With Inadequately Controlled Insulin-Treated Type 2 Diabetes

Raskin¹,

et al. 2001

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OBJECTIVE -To determine the efficacy and safety of rosiglitazone (RSG) when added to insulin in the treatment of type 2 diabetic patients who are inadequately controlled on insulin monotherapy. RESEARCH DESIGN AND METHODS-After 8 weeks of insulin standardization and placebo (PBO) run-in, 319 type 2 diabetic patients with mean baseline HbA 1c Ն7.5% (8.9 Ϯ 1.1 to 9.1 Ϯ 1.3) on twice-daily insulin therapy (total daily dose Ն30 U) were randomized to 26 weeks of additional treatment with RSG (4 or 8 mg daily) or PBO. Insulin dose could be downtitrated only for safety reasons. The primary end point was reduction of HbA 1c from baseline.RESULTS -RSG 4 and 8 mg daily significantly improved glycemic control, which was unchanged on PBO. By intent-to-treat analysis, treatment with RSG 8 mg plus insulin resulted in a mean reduction from baseline in HbA 1c of 1.2% (P Ͻ 0.0001), despite a 12% mean reduction of insulin dosage. Over 50% of subjects treated daily with RSG 8 mg plus insulin had a reduction of HbA 1c Ն1.0%. Neither total:HDL cholesterol nor LDL:HDL cholesterol ratios significantly changed with RSG treatment. Serious adverse events did not differ among groups.CONCLUSIONS -The addition of RSG to insulin treatment results in significant improvement in glycemic control and is generally well tolerated. Diabetes Care 24:1226 -1232, 2001T ype 2 diabetes is a common and serious disorder that accounts for Ͼ$100 billion in annual health care expenditures in the U.S. alone (1), mostly because of chronic complications associated with the condition. It is characterized by an impaired sensitivity of target tissues to insulin and impaired insulin secretion by pancreatic ␤-cells, which leads to hyperglycemia and, over time, to microvascular and macrovascular complications (2-6). Results of the U.K. Prospective Diabetes Study (UKPDS) have shown that improvement of glycemic control reduces these complications and that progressive ␤-cell failure usually leads to the need for combination therapy to maintain glycemic control (7-10). The UKPDS demonstrated that even insulin-treated patients were unable to sustain adequate glycemic control.The insulin-sensitizing effects of the thiazolidinedione (TZD) class of oral antidiabetic agents may alter the natural history of type 2 diabetes. By improving insulin sensitivity at the level of the target tissues, including adipose and muscle tissues, TZDs enhance the effectiveness of both endogenous and exogenous insulin (11), thereby improving glycemic control and perhaps slowing the decline of ␤-cell function. Rosiglitazone (RSG) is a potent TZD that binds to the peroxisome proliferator-activated receptor-␥ and improves insulin action in isolated tissues (11), ␤-cell function in animals (12,13) and humans (14), and glycemic control in patients with type 2 diabetes (15,16).This article reports the results of the efficacy and safety of RSG added to previously ineffective insulin monotherapy in patients with type 2 diabetes who participated in a multicenter randomized double-blind trial. The aim of ...

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Section: Safety Parameterssupporting

confidence: 80%

Section: Safety Parametersmentioning

confidence: 84%

A Randomized Trial of Rosiglitazone Therapy in Patients With Inadequately Controlled Insulin-Treated Type 2 Diabetes

Raskin¹,

et al. 2001

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“…Several studies have reported a decrease in hematocrit in response to TZD treatment, which has been interpreted as the result of an increase in plasma volume (40), but so far only one other study combined hematocrit with directly derived plasma volume measurements (41). Indeed, hematocrit decreased and plasma volume increased in our study, but, interestingly, we did not find a correlation between changes in hematocrit and changes in plasma volume.…”

Section: Characterization Of Subject With Tzd-induced Edemacontrasting

confidence: 63%

Fluid Retention and Vascular Effects of Rosiglitazone in Obese, Insulin-Resistant, Nondiabetic Subjects

et al. 2006

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OBJECTIVE -The use of thiazolidinedione (TZD) derivatives is associated with fluid retention, especially when combined with insulin. Because TZDs improve the metabolic effect of insulin, they may also reverse the blunted vascular response to insulin. We hypothesize that improvement of the action of insulin on vascular tone or permeability is the key mechanism of TZD-related fluid retention.RESEARCH DESIGN AND METHODS -In a randomized, double-blind, placebocontrolled, cross-over study in 18 obese, nondiabetic subjects with features of the metabolic syndrome, we investigated the effects of a 12-week treatment with 4 mg rosiglitazone twice a day on glucose disposal, hemodynamics (including forearm vasoconstrictor response to nitric oxide [NO]), synthase inhibition by N-monomethyl-L-arginine-acetate (L-NMMA), vascular permeability (transcapillary escape rate of albumin), and plasma volume during a hyperinsulinemiceuglycemic clamp (120 min, 120 mU/m 2 per min).RESULTS -As expected, rosiglitazone increased the glucose infusion rate during clamping. However, neither vascular permeability nor forearm blood flow response to hyperinsulinemia or L-NMMA was affected by rosiglitazone. Compared with placebo, rosiglitazone decreased diastolic blood pressure by 5 mmHg (95% CI 2.35-6.87, P ϭ 0.0005) and increased plasma volume by 255 ml/1.73 m 2 (80 -430, P ϭ 0.007). Interestingly, the positive effect of rosiglitazone on glucose disposal correlated with change in foot volume (R 2 ϭ 0.53, P ϭ 0.001).CONCLUSIONS -Rosiglitazone improved insulin sensitivity but had no effect on NOdependent vasodilatation in the forearm or vascular permeability in obese, insulin-resistant, nondiabetic subjects. As such, TZD-related fluid retention was not caused by improvement of the vascular actions of insulin. Nonetheless, rosiglitazone-induced improvement in insulin sensitivity appears to be correlated to edema formation. Diabetes Care 29:581-587, 2006T hiazolidinedione (TZD) derivatives improve insulin sensitivity and hence are valuable in the treatment of type 2 diabetes (1). Important adverse effects are fluid retention and peripheral edema formation. The precise mechanism(s) of these adverse effects are unclear and probably are multifactorial (2).Although multiple factors are involved, the existence of an initial trigger or main mechanism could be of clinical importance. In theory, the initial trigger of fluid retention may originate either from kidney, heart, or peripheral circulation. As TZD treatment is associated with a reduction in blood pressure (3-6), a primary renal mechanism seems unlikely. A primary cardiac origin also seems improbable, because long-term studies with rosiglitazone have not revealed any negative effect on myocardial structure or function (7).The combination of blood pressure reduction, fluid retention, and edema formation is compatible with changes in the peripheral circulation resulting in capillary leakage. This may be induced by certain actions of TZDs, such as improved insulin-mediated vasodilatation, direct vasoa...

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“…This decrease appears to be the consequence of an expansion of the extracellular compartment. Preliminary studies have shown no significant changes in red cell mass in treated patients (Young et al, 1999). The mechanism for expansion of the plasma volume has not been defined.…”

Section: Increase In Extracellular Volume and Edemamentioning

confidence: 97%

Insulin Resistance and Its Treatment by Thiazolidinediones

Lebovitz

Banerji²

2001

Recent Progress in Hormone Research

169

189

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Troglitazone has no effect on red cell mass or other erythropoietic parameters

Abstract: These data suggest that dilutional effects related to a modest increase in plasma volume may explain the haematological changes seen in other clinical trials with high doses of troglitazone, although this study has shown that the changes in plasma volume are not statistically significant.

Cited by 32 publications

References 7 publications

A Randomized Trial of Rosiglitazone Therapy in Patients With Inadequately Controlled Insulin-Treated Type 2 Diabetes

A Randomized Trial of Rosiglitazone Therapy in Patients With Inadequately Controlled Insulin-Treated Type 2 Diabetes

Fluid Retention and Vascular Effects of Rosiglitazone in Obese, Insulin-Resistant, Nondiabetic Subjects

Insulin Resistance and Its Treatment by Thiazolidinediones

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