Autonomic neuropathy predisposes to rosiglitazone-induced vascular leakage in insulin-treated patients with type 2 diabetes: a randomised, controlled trial on thiazolidinedione-induced vascular leakage

Abstract

Aims/hypothesis: The mechanism of fluid-related complications caused by thiazolidinedione derivatives is unclear. One potential mechanism is thiazolidinedione-induced arterial vasodilatation, which results in vascular leakage and a fall in blood pressure, normally counterbalanced by sympathetic activation and subsequent renal fluid retention. We hypothesised that thiazolidinedione-induced vascular leakage will be particularly prominent in patients with autonomic neuropathy.

Methods: We conducted a randomised, double-blind, placebo-controlled, parallel study in 40 patients with type 2 diabetes on insulin treatment recruited from a university medical centre. The randomisation was performed by a central office using a randomisation schedule. Both treatment groups, placebo (n = 21) and rosiglitazone (n = 19), were stratified for sex and level of autonomic neuropathy as assessed by Ewing score (<2.5 or >or=2.5). We investigated the effects of 16 weeks of treatment with rosiglitazone 4 mg twice daily on vascular leakage (transcapillary escape rate of albumin, TERalb), body weight, extracellular volume and plasma volume.

Results: Thirty-nine patients were included in the analysis. In patients with high Ewing scores (n = 16), rosiglitazone increased TERalb significantly (DeltaTERalb: rosiglitazone +2.43 +/- 0.45%/h, placebo -0.11 +/- 0.15%/h, p = 0.002), while rosiglitazone had no effect in the patients with low Ewing scores (n = 23). Rosiglitazone-induced increases in TERalb and Ewing score at baseline were correlated (r = 0.65, p = 0.02). There was no correlation between Ewing score and rosiglitazone-induced changes in fluid variables. One subject was withdrawn from the study because of atrial fibrillation.

Conclusions/interpretation: Rosiglitazone may increase vascular leakage in insulin-treated patients with type 2 diabetes with autonomic neuropathy. Autonomic neuropathy did not exaggerate rosiglitazone-induced fluid retention. Therefore, autonomic neuropathy should be considered as a risk factor for thiazolidinedione-induced oedema, not for thiazolidinedione-induced fluid retention.

Trial registration: ClinicalTrials.gov NCT00422955.

Funding: GlaxoSmithKline.

Figures

Fig. 1

Schematic representation of the hypothesis. The local consequence of rosiglitazone-induced vasodilatation will be increased hydrostatic pressure leading to an elevation in capillary filtration (vascular leakage), which predisposes to oedema formation (top). An intact sympathetic nervous system counteracts the vasodilator effect, which will prevent increased vascular leakage. The systemic consequence of vasodilatation is reduction of blood pressure (bottom), leading to renin production and sodium retention. On the one hand, an intact sympathetic nervous system prevents reduction in blood pressure immediately; on the other hand, sympathetic activation directly stimulates renin production; the result is diminished and elevated sodium retention respectively. RAAS, renin–angiotensin–aldosterone system

Fig. 2

Enrolment of study participants, distribution among subgroups and flow of participants through the study. aTo ensure reliable results, calculated transcapillary escape rates of albumin (TERalb) with correlation coefficients below 80% between the extinction curve and the actual measured time points were excluded from this analysis. FPG, fasting plasma glucose

Fig. 3

Rosiglitazone induced vascular leakage in the autonomic neuropathy subgroups. a Mean model-adjusted change in transcapillary escape rate of albumin (TERalb) during treatment with either rosiglitazone or placebo within the subgroup of participants with a high Ewing score (left) and with a low Ewing score (right) (dichotomous). Values are means with SE. The data in this figure are model-adjusted for the comparison between rosiglitazone and placebo within a Ewing score subgroup. Therefore, we cannot derive from this figure the exact model-adjusted difference in TERalb change (+1.96%/h) due to treatment with rosiglitazone between participants with high and low Ewing score (see Methods). Black bars, rosiglitazone; white bars, placebo. ap = 0.002; bp = 0.03; cNS. b Correlation (r = 0.65, p = 0.02) between baseline Ewing score (continuous) and change in TERalb (individual raw data, therefore not model-adjusted) during treatment with rosiglitazone

Fig. 4

Relationships of vascular leakage with diastolic blood pressure and total body water. a Inverse correlation (r = −0.96, p = 0.002) between rosiglitazone-induced changes in diastolic blood pressure (DBP) and transcapillary escape rate of albumin (TERalb) in participants on rosiglitazone with established autonomic neuropathy (n = 7; two participants had almost exactly the same readings for change in DBP and change in TERalb). b Inverse relationship (r = −0.76, p = 0.004) between rosiglitazone-induced changes in TERalb and changes in total body water (TBW) in all participants treated with rosiglitazone with reliable TERalb measurements (n = 13)