186
Views
10
CrossRef citations to date
0
Altmetric
Original

Rosiglitazone reduces office and diastolic ambulatory blood pressure following 1‐year treatment in non‐diabetic subjects with insulin resistance

, , &
Pages 95-100 | Received 10 Nov 2006, Accepted 10 Apr 2007, Published online: 08 Jul 2009

Abstract

Objective. Rosiglitazone (RSG) has been reported to reduce blood pressure (BP) in patients with type‐2 diabetes, but similar effects in non‐diabetic people with insulin resistance is less clear. Our aim was to test the long‐term BP‐lowering effects of RSG compared with placebo. Methods. We recruited participants for BP evaluation of RSG treatment from a larger intervention trial. Office BP was recorded in 355 non‐diabetic subjects with insulin resistance randomized to receive either RSG or placebo for 52 weeks. Ambulatory BP monitoring (ABPM; Spacelab 90207) was performed in a subgroup of 24 subjects (RSG: n = 11; placebo n = 13). Results. After 1 year, the office BP decreased by −3.1 mmHg systolic (p<0.05) and −3.8 mmHg diastolic (p<0.001) in the RSG group versus placebo. In patients treated with RSG, at 1 year there was a trend for a reduction from baseline for mean 24‐h diastolic BP (DBP), daytime DBP and night‐time DBP (−4.39, −5.26 and −2.93 mmHg, respectively). However, only daytime DBP was significantly lower in the RSG group compared with control (adjusted mean difference: −4.41 mmHg, p = 0.007). There was also a non‐significant trend for a reduction in mean 24‐h systolic BP (SBP), daytime SBP and night‐time SBP (−2.70, −2.51 and −3.35 mmHg, respectively). Conclusions. RSG treatment for 1 year was associated with a small but significant decrease in diastolic 24‐h ambulatory diastolic BP, and both systolic and diastolic office BPs in non‐diabetic people with insulin resistance.

Introduction

Blood pressure (BP) regulation is a complex physiological process with many determinants that include a putative role for insulin resistance and hyperinsulinaemia Citation[1], Citation[2]. Previous observational studies have shown that the strongest associations between BP and hyperinsulinaemia exist when precise measurements have been applied, e.g. by use of data from ambulatory BP monitoring (ABPM) and measures of insulin sensitivity, as compared with simple office BP and fasting insulin Citation[3]. By modifying insulin resistance, BP has been reduced through lifestyle improvement such as increased physical activity and pursuing a healthy diet Citation[4], Citation[5]. Furthermore, some antihypertensive drugs with improving effects on insulin sensitivity have well described beneficial effects on haemodynamic and metabolic function Citation[6]. Agents that block the renin–angiotensin system may be particularly useful in this respect, as these agents may also retard the onset of type‐2 diabetes in patients with hypertension Citation[7].

Recently, the thiazolidinediones (glitazones) or PPAR‐gamma agonists have been shown to improve insulin sensitivity and to lower BP, according to a recent meta‐analysis based on 37 studies Citation[8]. Most of the studies on BP effects by glitazone therapy have, however, included few patients or have been of short duration Citation[8–15]. Only four previous studies were of 1‐year duration and they all included patients with established type‐2 diabetes Citation[8], Citation[15]. There is therefore a need for intervention studies of longer duration also in pre‐diabetic subjects with insulin resistance, in order to establish whether the BP‐lowering effect of glitazones could eventually be counteracted by the time‐dependent weight increase induced by these drugs Citation[13].

We used data from the Rosiglitazone Atherosclerosis Study (RAS) Citation[16] to analyse the effects of rosiglitazone (RSG) treatment after 1 year in subjects with insulin resistance in a placebo‐controlled study. The aim of the study was to study BP changes from both office‐based measurements in all, as well as from ABPM in a subset of subjects.

Subjects and Methods

RAS was a randomized, double blind, placebo‐controlled, single‐centre clinical trial, carried out at the University Hospital in Malmö, Sweden. The main objective was to compare effects on carotid intima media thickness by treatment with RSG 4–8 mg versus placebo for 1 year Citation[16]. Recruitment and screening of participants into the trial was done from the cardiovascular program of the “Malmö Diet and Cancer” (MDC) cohort Citation[17], Citation[18]. As part of this screening study (n = 5540), each subject's level of estimated insulin resistance was assessed using the homeostasis model assessment (HOMA‐IR) Citation[19]. Non‐diabetic subjects (n = 4748) whose values exceeded the gender‐specific 75th percentile (i.e. 1.80 for women and 2.12 for men) were considered to have insulin resistance (n = 1189). Inclusion criteria at the RAS screening visit were subjects with insulin resistance syndrome (IRS) as defined by the European Group for the Study of Insulin Resistance (EGIR) criteria Citation[20], i.e. with HOMA‐IR value >1.80 for females or >2.12 for males in combination, with at least two of the following conditions, hyperglycaemia (plasma glucose ⩾6.1 mmol/l), hypertension (BP ⩾140/90 mmHg or current use of BP‐lowering medication), dyslipidaemia (triglycerides >2.0 mmol/l or HDL‐cholesterol <0.9 mmol/l for men, and <1.0 mmol/l for women), or central obesity (waist circumference ⩾94 cm for men and ⩾80 cm for women). Three hundred and fifty‐seven of the screened IRS subjects without diabetes consented to participation, but two subjects were excluded because of a protocol violation. Neither of these two subjects had started any study treatment. All 355 IRS participants provided written informed consent. The main RAS trial Citation[16] also included a sub‐group of type‐2 diabetes patients (n = 199), which will not be discussed further in this paper. The Ethics Committee of Lund University approved the study.

Patients with any of the following criteria were excluded: if they had antihypertensive therapy initiated within 6 months prior to study start or if they had increased the dose of anti‐hypertensive therapies within the 3 months prior to study start, previous exposure to a glitazones or other PPAR‐gamma agonist, patients whose BP was above 170 mmHg systolic or 100 mmHg diastolic, or a history of severe cardiac, hepatic or renal disease Citation[16].

After a 4‐week run‐in period, participants were randomized in a double‐blind manner to receive either placebo or RSG for 52 weeks. They received single‐dose placebo and RSG 4 mg once daily for the initial 8 weeks and. RSG and matching placebo tablets were supplied by GlaxoSmith Kline (UK). In addition, a subset of patients was included in a sub‐study of patients in order to assess ABPM.

The first participant was randomized in March 2002, and the 52 weeks treatment period was completed for all participants by November 2004. Weight (in kg) and waist and hip circumference (in cm) were measured every 6 months.

Office BP was measured in all subjects (n = 355, but complete information available in 330 subjects) as a mean (mmHg) of two readings (Korotkoff I and V) in the supine position at baseline and follow‐up. Ambulatory BP and heart rate was measured in a sub‐sample (n = 77) at baseline and follow‐up by use of a Spacelab 90207 device for 25 h, but data from the first hour was excluded from the analyses. BP was recorded three times an hour during the day‐time (06:00–22:00 h) and twice an hour during the night‐time (22:00–06:00 h). Only successful recordings (⩾75% of planned ABPM episodes) were accepted for further evaluation. Minimal editing was carried out, by deleting data for systolic BP (SBP) >300 mmHg or less than 50 mmHg, or diastolic BP (DBP) >200 mmHg. After 1 year, 43 subjects with ABPM were excluded due to withdrawal from RAS due to adverse effects or other reason (n = 10), protocol violations (n = 4), short observation time (less than 23 weeks) in the study (n = 10), or fewer than 75% successful ABPM recordings (n = 19). Therefore only 24 subjects (RSG 11, placebo 13) with ABPM had a complete dataset both at baseline and 1‐year follow‐up for day‐time, night‐time and 24‐hr recordings. Only subjects without any changes in drug medication affecting BP during the study were included.

All biochemical measurements were performed by Quest Diagnostics Clinical Trials, London, UK. Glycaemic parameters (fasting blood glucose and insulin and HbA1C) and fasting lipid profile [total cholesterol, low‐density lipoprotein‐cholesterol, high‐density lipoprotein (HDL)‐cholesterol and triglycerides] was determined, as previously described Citation[16]. Vital status was obtained for all subjects at termination of the study.

Statistical methods

Descriptive data at baseline are shown as means and standard (SD), or proportions (%). An analysis of covariance (ANCOVA) was used to calculate the significance of BP changes from baseline to follow‐up, adjusting for baseline value. The primary statistical analysis for clinic BP was performed using the intention‐to‐treat (ITT) population with the last observation carried forward (LOCF) for missing values. Statistical analysis was performed with SAS software, and the statistical team of the sponsor was involved in the final data analysis. A p‐value less than 0.05 were considered significant.

Results

Baseline characteristics

Subjects with IRS were well balanced at baseline in the RSG treatment group and the placebo group with mean office BPs of 143/84 mmHg and 144/84 mmHg, respectively (Table ).

Table I. Baseline clinical characteristics of subjects (n = 355) with insulin resistance (based on HOMA‐IR) and randomized to rosiglitazone or placebo.

Effects on body weight, HOMA‐IR and office BP

After 1 year of treatment, body weight increased by 1.01 (SE = 0.26) kg in the RSG group as compared with a decrease of −0.26 (0.25) kg in the placebo group (p<0.001). Similar changes for HOMA‐IR were −1.06 (0.16) units and 0.02 (0.15) units in the two groups, respectively (p<0.001). The mean office BP decreased by −3.1 mmHg systolic (p<0.05) and −3.8 mmHg diastolic (p<0.001) in the RSG treated group versus placebo (Table ).

Table II. Effects on office and ambulatory blood pressure (BP) levels (mmHg) as well as heart rate (HR) after 1 year of treatment with rosiglitazone versus placebo in the Rosiglitazone Atherosclerosis Study (RAS) trial.

Effects on ambulatory BP and heart rate

Ambulatory BP, conducted in a subset of the IRS cohort (n = 13), showed a decrease from baseline to 1 year in the RSG group in 24‐h DBP (mean±SE = 4.41±1.39 mmHg), daytime DBP (mean±SE = 5.26±1.09 mmHg) and night‐time DBP (mean±SE = 2.93±1.45 mmHg), which was significantly lower compared with placebo for daytime DBP only (adjusted mean difference: −4.39 mmHg [95% CI −7.45 to −1.33], p = 0.007).

Correspondingly, ambulatory 24‐h SBP did not differ between groups (Table ).

For heart rate (HR), 24‐h, daytime and night‐time HR measurements were similar at 1 year compared with baseline in both treatment groups.

Discussion

This 1‐year, randomized intervention trial demonstrated that treatment with RSG reduced both office BP (SBP and DBP), and diastolic daytime ambulatory BP in subjects with insulin resistance as evaluated by the HOMA‐IR index. Even if this lowering of BP was rather modest, a 3–4‐mmHg reduction compared with placebo, evidence from one meta‐analysis of hypertension trials, has shown that even a modest BP reduction could be associated with clinical benefits Citation[21]. The prognostic benefit of day‐time as compared with night‐time BP for the assessment of future cardiovascular events is still unknown Citation[22], although cardiovascular risk has been shown to be directly and independently associated with the observed ambulatory SBP and DBP, and inversely associated with the degree of ambulatory BP reduction from day to night Citation[23].

According to a recent meta‐analysis Citation[8], when compared with baseline, glitazone therapy on average lowered SBP by 4.70 mmHg (95% CI 6.13 to 3.27), and DBP by 3.79 mmHg (95% CI 5.82 to 1.77). When compared with placebo, glitazones on average lowered SBP by 3.47 mmHg (95% CI 4.91 to 2.02) and DBP by 1.84 mmHg (95% CI −3.43 to −0.25). These changes are compatible with the effects seen in our trial, and further supported by a recent systematic review Citation[15]. In the DREAM trial, a small but significant effect on office BP reduction was noticed Citation[24]. This was also the case in the placebo‐controlled PROspective pioglitAzone Clinical Trial In macroVascular Events (PROActive) trial for secondary prevention in patients with type‐2 diabetes Citation[25], where it was reported a slight BP‐lowering effect of pioglitazone versus placebo, which may have contributed to the positive secondary endpoint effect even if the primary endpoint of the trial did not differ between the treatment groups. Recently it was also shown that RSG added to background therapy with metformin in patients with type‐2 diabetes provided greater reductions in microalbuminuria and BP as compared with glyburide treatment alone Citation[26].

Reductions in BP associated with RSG may be associated with improvements in sympathetic activity Citation[27] and endothelial function. Pistrosch et al. Citation[28] performed a study in patients with T2DM using RSG and nateglinide, and showed that despite similar improvements in glycaemic control, forearm blood flow in response to acetylcholine was significantly greater in the RSG group. Changes in the concentration of important inhibitors of the nitric oxide pathway also need to be considered. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthetase and is an important contributor to the development of endothelial dysfunction Citation[29], Citation[30]. Stuhlinger et al. Citation[31] demonstrated that in non‐diabetic individuals, the use of RSG was associated not only with improvements in insulin resistance but also with a reduction in the circulating concentrations of ADMA. Such RSG associated changes may also contribute to reported improvements in arterial function and elasticity that in some subjects may result in much larger reductions in BP Citation[32]. Some of the previous trials in non‐diabetic populations have shown similar benefits of RSG treatment on BP control despite a mean increase in weight Citation[33], Citation[34], but our trial was of considerably longer duration. This is important, as despite the increase in weight observed, there was a consistent reduction in BP

It is necessary to point out some important limitations of the study. Firstly, even if the number of subjects with office BP data was substantial compared with most other trials, the number of IRS subject who underwent ABPM was rather small. Several of the subjects and their ABPM information had to be excluded for quality control reasons, e.g. a low success rate of ambulatory recording, or a long time interval between drug intake and performing the ABPM. Secondly, the estimation of insulin resistance was based on an indirect method, the HOMA‐IR index, and not on the golden standard method, the hyperinsulinaemic, euglycaemic clamp that was used in a previous pilot study with glitazone and ABPM Citation[14]. Thirdly, we lack cardiovascular endpoint data to support the hypothesis that the small BP reduction of 3–4 mmHg associated with RSG treatment is associated with clinical benefits.

In conclusion, treatment with RSG for 1 year was associated with a small but significant decrease in diastolic ambulatory BP and in systolic and diastolic office BP in people with insulin resistance based on HOMA‐IR assessment.

Acknowledgements

The RAS study group recognizes that without the time and dedicated effort of all patients and the supporting staff at the Clinical Research Unit, this study would never have been accomplished. The study was financially sponsored by the Glaxo‐Smith Kline Ltd., UK. All study‐related clinical work was independently carried out at the University Hospital, Malmö, Sweden.

References

  • Ferrannini E., Buzzigoli G., Bonadonna R., Giorico M. A., Oleggini M., Graziadei L., et al. Insulin resistance in essential hypertension. N Engl J Med 1987; 317: 350–357
  • Pollare T., Lithell H., Berne C. Insulin resistance is a characteristic feature of primary hypertension independent of obesity. Metabolism 1990; 39: 167–174
  • Nilsson P., Lind L., Andersson P‐E., Hänni A., Berne C., Baron J., et al. On the use of ambulatory blood pressure recordings and insulin sensitivity in support of the insulin‐hypertension hypothesis. J Hypertens 1994; 12: 965–969
  • Nilsson P., Lindholm L., Scherstén B. Lifestyle changes improves insulin resistance in hyperinsulinemic subjects. A one‐year intervention study of hypertensives and normotensives in Dalby. J Hypertens 1992; 10: 1071–1078
  • Dengel D. R., Hagberg J. M., Pratley R. E., Rogus E. M., Goldberg A. P. Improvements in blood pressure, glucose metabolism, and lipoprotein lipids after aerobic exercise plus weight loss in obese, hypertensive middle‐aged men. Metabolism 1998; 47: 1075–1082
  • Lithell H. O. Effect of antihypertensive drugs on insulin, glucose, and lipid metabolism. Diabetes Care 1991; 14: 203–209
  • Mancia G., Grassi G., Zanchetti A. New‐onset diabetes and antihypertensive drugs. J Hypertens 2006; 24: 3–10
  • Qayyum R., Adomaityte J. A meta‐analysis of the effect of thiazolidinediones on blood pressure. J Clin Hypertens (Greenwich) 2006; 8: 19–28
  • St John Sutton M., Rendell M., Dandona P., Dole J. F., Murphy K., Patwardhan R., et al. A comparison of the effects of rosiglitazone and glyburide on cardiovascular function and glycemic control in patients with type 2 diabetes. Diabetes Care 2002; 25: 2058–2064
  • Tan M. H., Johns D., Strand J., Halse J., Madsbad S., Eriksson J. W., et al. GLAC Study Group. Sustained effects of pioglitazone vs. glibenclamide on insulin sensitivity, glycaemic control, and lipid profiles in patients with Type 2 diabetes. Diabet Med 2004; 21: 859–866
  • Negro R., Mangieri T., Dazzi D., Pezzarossa A., Hassan H. Rosiglitazone effects on blood pressure and metabolic parameters in nondipper diabetic patients. Diabetes Res Clin Pract 2005; 70: 20–25
  • Rajagopalan R., Iyer S., Khan M. Effect of pioglitazone on metabolic syndrome risk factors: Results of double‐blind, multicenter, randomized clinical trials. Curr Med Res Opin 2005; 21: 163–172
  • Yki‐Järvinen H. Thiazolidinediones. N Engl J Med 2004; 351: 1106–1118
  • Sarafidis P. A., Lasaridis A. N., Nilsson P. M., Hitoglou‐Makedou A. D., Pliakos C. I., Kiriakos A., et al. Ambulatory blood pressure reduction after rosiglitazone treatment in patients with type 2 diabetes and hypertension correlates with insulin sensitivity increase. J Hypertens 2004; 22: 1769–1777
  • Sarafidis P., Nilsson P. M. The effects of thiazolidinedione compounds on blood pressure levels – A systematic review. Blood Press 2006; 15: 135–150
  • Hedblad B., Nilsson P. M., Zambanini A., Berglund G. Rosiglitazone reduces carotid intima‐media thickness progression over 1 year in patients with type 2 diabetes but not in non‐diabetic people who have insulin resistance alone. J Internal Med 2007; 261: 293–305
  • Hedblad B., Nilsson P., Janzon L., Berglund G. Relation between insulin resistance and carotid intima‐media thickness and stenosis in non‐diabetic subjects. Results from a cross‐sectional study in Malmö, Sweden. Diabetic Med 2000; 17: 299–307
  • Hedblad B., Wikstrand J., Janzon L., Wedel H., Berglund G. Low dose metoprolol CR/XL and fluvastatin slow progression of carotid intima‐media thickness. Main results from the Beta‐blocker Cholesterol‐lowering Asymptomatic Plaque Study (BCAPS). Circulation 2001; 103: 1721–1726
  • Matthews D. R., Hosker J. P., Rudenski A. S., Naylor B. A., Treacher D. F., Turner R. C. Homeostasis model assessment: Insulin resistance and beta‐cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–419
  • Balkau B., Charles M. A., for the European Group for the Study of Insulin Resistance (EGIR). Comment on the provisional report from the WHO consultation. Diabet Med 1999; 16: 442–443
  • Turnbull F., Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of different blood‐pressure‐lowering regimens on major cardiovascular events: Results of prospectively‐designed overviews of randomised trials. Lancet 2003; 362: 1527–1535
  • Mancia G., Parati G. The role of blood pressure variability in end‐organ damage. J Hypertens 2003; 21 Suppl 6: S17–S23
  • Verdecchia P. Prognostic value of ambulatory blood pressure. Current evidence and clinical implications. Hypertension 2000; 35: 844–851
  • DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators; Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: A randomised controlled trial. Lancet 2006; 368: 1096–1105
  • Dormandy J. A., Charbonnel B., Eckland D. J. A., Erdmann E., Massi‐Benedetti M., Moules I. K., , on behalf of the PROactive investigators, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): A randomised controlled trial. Lancet 2005; 366: 1279–1289
  • Bakris G. L., Ruilope L. M., McMorn S. O., Weston W. M., Heise M. A., Freed M. I., et al. Rosiglitazone reduces microalbuminuria and blood pressure independently of glycemia in type 2 diabetes patients with microalbuminuria. J Hypertens 2006; 24: 2047–2055
  • Yosefy C., Magen E., Kiselevich A., Priluk R., London D., Volchek L., et al. Rosiglitazone improves, while glibenclamide worsens blood pressure control in treated hypertensive diabetic and dyslipidemic subjects via modulation of insulin resistance and sympathetic activity. J Cardiovasc Pharmacol 2004; 44: 215–222
  • Pistrosch F., Passauer J., Fischer S., Fuecker K., Hanefeld M., Gross P. In type 2 diabetes, rosiglitazone therapy for insulin resistance ameliorates endothelial dysfunction independent of glucose control. Diabetes Care 2004; 27: 484–90
  • Vallance P., Leone A., Calver A., Collier J., Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 1992; 339: 572–575
  • Boger R. H., Bode‐Boger S. M., Szuba A., Tsao P. S., Chan J. R., Tangphao O., et al. Asymmetric dimethylarginine (ADMA): A novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation 1998; 98: 1842–1847
  • Stuhlinger M. C., Abbasi F., Chu J. W., Lamendola C., McLaughlin T. L., Cooke J. P., et al. Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. JAMA 2002; 287: 1420–1426
  • Shargorodsky M., Wainstein J., Gavish D., Leibovitz E., Matas Z., Zimlichman R. Treatment with rosiglitazone reduces hyperinsulinemia and improves arterial elasticity in subjects with type 2 diabetes mellitus. Am J Hypertens 2003;16:617–622. Erratum in: Am J Hypertens 2003; 16: 84
  • Bennett S. M., Agrawal A., Elasha H., Heise M., Jones N. P., Walker M., et al. Rosiglitazone improves insulin sensitivity, glucose tolerance and ambulatory blood pressure in subjects with impaired glucose tolerance. Diabet Med 2004; 21: 415–422
  • Natali A., Baldeweg S., Toschi E., Capaldo B., Barbaro D., Gastaldelli A., et al. Vascular effects of improving metabolic control with metformin or rosiglitazone in type 2 diabetes. Diabetes Care 2004; 27: 1349–1357

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.