The present study is the first to investigate the effect of rosiglitazone and ramipril on arterial stiffness in newly diagnosed never treated T2DM patients without any cardiovascular (CV) complication using strict inclusion and exclusion criteria. Although the treatments showed a significant change in preclinical vasculopathy from the baseline, but could not find any difference in comparison to placebo. The main reason why diabetic patients failed to show any changes may be due to shorter duration of intervention3
and/or lower dose of the drugs.14
The much-developed vasculopathy in established diabetes may need intervention for a longer period of time7
and/or the use of higher doses of rosiglitazone (8 mg)16
and ramipril (10 mg).7
The rationale of using standard dose of rosiglitazone 4 mg/day was found to be effective in controlling biochemical parameters of diabetes in most of the previous clinical trials.17
Thiazolidinediones are found to be most effective when used with the earliest form of diabetes and also in the drug naïve patients when insulin secretion is still substantial.19
Phillips et al17
recommend that once-daily dose (4 mg) may be sufficient as first-line therapy for patients with recent diagnoses, and 4 mg twice daily for patients with more advanced diabetes. Our study demonstrated a clear trend of decreasing PWV, AI and other hemodynamics variables throughout the study period (significant with baseline, ), though the changes were not significant in comparison to placebo. The reason of insignificant improvement may be that large arteries have a major component of fixed fibrotic tissue which probably needs more time for ‘tissue repair’ in much developed vasculopathy in patients with T2DM.3
Shargorodsky et al3
increased the dose from 4 mg/daily dose to 8 mg/daily after 3-month treatment in patients who had hemoglobin A1c
level > 9% and continued for further 3 months. However, they failed to show any changes in large artery stiffness in T2DM with increased dose. Pistrosch et al4
demonstrated that rosiglitazone (4 mg twice daily) had therapeutic effects on endothelial dysfunction in T2DM (n = 12) patients in a 12-week double blind cross-over study. From this evidence, it may be suggested that higher dose of rosiglitazone is needed for longer duration to reverse the preclinical macrovasculopathy.
The present study is the first to conduct a clinical trial with standard dose of ramipril (5 mg daily) to examine its effects on arterial stiffness. Previous studies used 1.25 mg/day,14
or 10 mg/day7
to study the cardioprotective effects in patients with T2DM. However, 1.25 mg/day and 2.5 mg/day failed to show any effect on CV outcomes. The SECURE study also showed a strong dose dependency of atherosclerosis progression, with highest benefit in the ramipril 10 mg/day study group than 2.5 mg/day group.7
Ramipril 10 mg/day was also the dose used in the HOPE trial, where it had very clear benefits on a range of clinical end points. The absence of CV protection with standard dose of ramipril in our study may suggest that a higher dose is required to reverse the macrovasculopathy in diabetes patients.
The present study is also the first to conduct a clinical trial with 1-year duration to examine the effects of ramipril on diabetic vasculopathy. Previous short-term studies (12 week to 6 months) on diabetes8
and hypertensive patients22
investigated effectiveness of ACE inhibitors on arterial stiffness could not definitively establish therapeutic efficacy. In a recent study, Kaiser et al8
compared the effects of a β-blocker (nebivolol) with an ACE inhibitor (enalapril) on parameters of insulin sensitivity, peripheral blood flow and arterial stiffness in T2DM patients assessing PWV and AI using SphygmoCor. No differences between nebivolol and enalapril were observed on any of above mentioned parameters. The authors suggested larger scale clinical trials with a longer treatment duration to investigate hard clinical endpoints in hypertensive T2DM patients. Another study24
examined the effect of angiotensin-converting enzyme (ACE) inhibitors (perindopril) on arterial stiffness for 7 months and suggested that high doses of ACE inhibitors, administered for a long period of time, are required in hypertensive T2DM patients to obtain a marked inhibition of the renin–angiotensin system and to reduce carotid stiffness.
In contrast, long-term studies7
established cardioprotective effects of ramipril in patients with T2DM. The SECURE, and MICRO-HOPE studies conducted for 4.5 years showed clear benefits of ramipril on CV end points. Bosch et al25
reported that prolonged use of ramipril prevents incidence of stroke in patients with vascular diseases and diabetes, followed for 4.5 years as part of the HOPE study. A study conducted by Hosomi et al9
demonstrated long-term treatment (2 years) with an ACE inhibitor (enalapril) and confirmed that ‘age-related’ and ‘diabetic-associated’ atherosclerosis was slowed down by chronic treatment for a period of 2 years. In their study systolic blood pressure (SBP) decreased on average by 4.8 mmHg during the first year and was maintained at the same level during the second year. The author speculated that decreased SBP during the first period may slightly constrict the common carotid artery and may transiently increase the apparent intima-media thickness (IMT), which may in turn decrease the wall tension and eventually slow the rate of IM thickening. It is suggested that a minimum 2-year treatment period is needed to evaluate therapeutic efficacy on IMT and to exclude possible early (up to 1 year) confounding of transient or apparent effects due to decreased SBP. Intra-group analysis in our study showed mean reduction of 6.64 mmHg in SBP in T2DM patients and this suggests long-term treatment (>2 years) with ramipril to demonstrate significant improvement in arterial stiffness.
Considering all this evidence, it can be emphasized that treatment with ramipril needs higher doses (10 mg or more) and longer treatment (>2 years) and this is confirmed by SECURE and DIABHYCAR studies. The SECURE study showed improvement of arterial stiffness with higher doses (10 mg/day, not with 2.5 mg/day) for a treatment of 4.5 years and on the other hand DIABHYCAR study failed to show any improvement with 1.25 mg/day for a period of 2.5 years.
As the studies with rosiglitazone and ramipril on arterial stiffness are very limited, further randomized controlled trials should be undertaken for a longer period of time, possibly with higher doses, to show whether rosiglitazone and ramipril can reverse pre-clinical macrovasculopathy in T2DM.