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1.  Effect of rosiglitazone on progression of atherosclerosis: insights using 3D carotid cardiovascular magnetic resonance 
Background
There is recent evidence suggesting that rosiglitazone increases death from cardiovascular causes. We investigated the direct effect of this drug on atheroma using 3D carotid cardiovascular magnetic resonance.
Results
A randomized, placebo-controlled, double-blind study was performed to evaluate the effect of rosiglitazone treatment on carotid atherosclerosis in subjects with type 2 diabetes and coexisting vascular disease or hypertension. The primary endpoint of the study was the change from baseline to 52 weeks of carotid arterial wall volume, reflecting plaque burden, as measured by carotid cardiovascular magnetic resonance. Rosiglitazone or placebo was allocated to 28 and 29 patients respectively. Patients were managed to have equivalent glycemic control over the study period, but in fact the rosiglitazone group lowered their HbA1c by 0.88% relative to placebo (P < 0.001). Most patients received a statin or fibrate as lipid control medication (rosiglitazone 78%, controls 83%). Data are presented as mean ± SD. At baseline, the carotid arterial wall volume in the placebo group was 1146 ± 550 mm3 and in the rosiglitazone group was 1354 ± 532 mm3. After 52 weeks, the respective volumes were 1134 ± 523 mm3 and 1348 ± 531 mm3. These changes (-12.1 mm3 and -5.7 mm3 in the placebo and rosiglitazone groups, respectively) were not statistically significant between groups (P = 0.57).
Conclusion
Treatment with rosiglitazone over 1 year had no effect on progression of carotid atheroma in patients with type 2 diabetes mellitus compared to placebo.
doi:10.1186/1532-429X-11-24
PMCID: PMC2726137  PMID: 19635160
2.  Effects of oral fixed-dose combinations of telmisartan plus ramipril and losartan plus ramipril in hypertension: A multicenter, prospective, randomized, double-blind, phase iii trial in adult indian patients 
Background:
A new oral fixed-dose combination (FDC) of telmisartan plus ramipril is being introduced in India for the treatment of patients with stage 2 hypertension.
Objective:
The aim of this study was to compare the effectiveness and tolerability of an oral FDC of telmisartan plus ramipril with those of an oral FDC of losartan plus ramipril in adult Indian patients with stage 2 hypertension.
Methods:
This multicenter, prospective, randomized, double-blind, Phase III study was conducted at 5 centers in India. Indian patients aged 18 to 65 years with uncomplicated stage 2 essential hypertension (systolic/diastolic blood pressure [SBP/DBP], >160/>100 mm Hg) were enrolled. After a 2-week placebo run-in period, patients were randomly assigned to receive telmisartan 40 mg plus ramipril 5 mg (T + R) or losartan 50 mg plus ramipril 5 mg (L + R), PO (tablet) QD (before the morning meal) for 8 weeks. Supine blood pressure (BP) was measured at 0 (baseline) and 8 weeks of treatment. The primary end point was the mean reduction from baseline in BP. Responders were classified as patients who had a DBP <90 mm Hg at the end of 8 weeks of therapy. Tolerability was assessed using spontaneous reports of adverse events (AEs) during the follow-up visits and laboratory analyses performed at week 8.
Results:
A total of 289 patients were enrolled (155 men, 134 women; mean age, 50.74 years). Of these, 8 patients in the T + R group and 7 in the L + R group were lost to follow-up and considered withdrawals. At the end of week 8, the mean percentage reduction in SBP was significantly greater in the T + R group compared with that in the L + R group (24.1% vs 19.4%; P < 0.05). The mean percentage reduction in DBP was also significantly greater in the T + R group compared with that in the L + R group (17.3% vs 12.5%; P < 0.05). The response rates in the T + R and L + R groups were statistically similar (79.1% vs 68.7%). The most common AEs in the T + R and L + R groups were cough (9 [6.1%] and 11 [7.8%] patients, respectively) and headache (7 [4.7%] and 8 [5.7%] patients, respectively).
Conclusions:
The results in this study in Indian patients with stage 2 essential hypertension suggest that the FDC of T + R controlled BP more effectively compared with the FDC of L + R over 8 weeks. The response rates were similar between the 2 groups. Both treatments were well tolerated.
doi:10.1016/j.curtheres.2005.12.007
PMCID: PMC3966013
telmisartan; ramipril; losartan; stage 2 hypertension
3.  Change in cough reflex after treatment with enalapril and ramipril. 
BMJ : British Medical Journal  1989;299(6690):13-16.
OBJECTIVE--To find out whether enalapril or ramipril causes the sensitivity of the cough reflex to change or symptomatic cough to develop in patients with hypertension. DESIGN--Prospective, placebo controlled, double blind, randomised crossover study. SETTING--Academic units of clinical pharmacology and medicine. PATIENTS--20 Patients (nine men and 11 women) who needed to take angiotensin converting enzyme inhibitors to control hypertension. INTERVENTIONS--All patients received enalapril 10 mg daily, ramipril 10 mg daily, or placebo daily for one week in random order, with a washout period of at least one week between treatments. For assessment of sensitivity of the cough reflex the patients inhaled various concentrations of capsaicin solution in random order. MAIN OUTCOME MEASURES--Measurement of the doses of capsaicin required to cause two or more and five or more coughs or the development of a symptomatic cough. RESULTS--Blood pressure, symptoms of cough, and the sensitivity of the cough reflex to inhaled capsaicin were recorded at the start of the study and before and at the end of each treatment period. Plasma urea and creatinine concentrations and angiotensin converting enzyme activity were measured at the start of the study and the end of each treatment period. Data were analysed by two way analysis of variance. Mean blood pressure was 159/97 mm Hg at the start of the study and 152/92, 143/88, and 147/86 mm Hg after treatment with placebo, enalapril, and ramipril respectively. Mean (SE) plasma angiotensin converting enzyme activity was 2.2 (0.2) mmol/l/h after treatment with placebo and fell significantly to 1.3 (0.1) mmol/l/h and to 0.4 (0.1) mmol/l/h after treatment with enalapril and ramipril respectively. No patient complained of cough while taking placebo but three women complained of cough when taking both enalapril and ramipril. The mean (95% confidence interval) lowest dose of capsaicin causing two or more coughs was 2.4 (1.5 to 4.0), 1.8 (1.12 to 2.82), and 2.2 (1.7 to 3.0) nmol after treatment with placebo, enalapril, and ramipril respectively; none of these changes were significant. The lowest dose of capsaicin causing five or more coughs was 18.9 (13.9 to 25.8), 14.4 (8.4 to 24.5), and 15.3 (10.8 to 21.2) nmol respectively; none of these changes were significant. The three patients who complained of cough had normal sensitivity to capsaicin after treatment with placebo but had a considerably increased sensitivity after treatment with enalapril and ramipril. CONCLUSIONS--Both enalapril and ramipril increase the sensitivity of the cough reflex appreciably in patients who complain of cough during treatment, but they do not change the se
PMCID: PMC1836998  PMID: 2547470
4.  Pharmacological Treatment of the Pathogenetic Defects in Type 2 Diabetes 
Diabetes Care  2010;34(1):27-33.
OBJECTIVE
To determine the effect of treatment with insulin aspart compared with NPH insulin, together with metformin/placebo and rosiglitazone/placebo. The hypothesis was that combined correction of major pathogenetic defects in type 2 diabetes would result in optimal glycemic control.
RESEARCH DESIGN AND METHODS
This study was a 2-year investigator-driven randomized partly placebo-controlled multicenter trial in 371 patients with type 2 diabetes on at least oral antiglycemic treatment. Patients were assigned to one of eight treatment groups in a factorial design with insulin aspart at mealtimes versus NPH insulin once daily at bedtime, metformin twice daily versus placebo, and rosiglitazone twice daily versus placebo. The main outcome measurement was change in A1C.
RESULTS
A1C decreased more in patients treated with insulin aspart compared with NPH (−0.41 ± 0.10%, P < 0.001). Metformin decreased A1C compared with placebo (−0.60 ± 0.10%, P < 0.001), as did rosiglitazone (−0.55 ± 0.10%, P < 0.001). Triple therapy (rosiglitazone, metformin, and any insulin) resulted in a greater reduction in A1C than rosiglitazone plus insulin (−0.50 ± 0.14%, P < 0.001) and metformin plus insulin (−0.45 ± 0.14%, P < 0.001). Aspart was associated with a higher increase in body weight (1.6 ± 0.6 kg, P < 0.01) and higher incidence of mild daytime hypoglycemia (4.9 ± 7.5 vs. 1.7 ± 5.4 number/person/year, P < 0.001) compared with NPH.
CONCLUSIONS
Insulin treatment of postprandial hyperglycemia results in lower A1C than treatment of fasting hyperglycemia, at the expense of higher body weight and hypoglycemic episodes. However, insulin therapy has to be combined with treatment of both peripheral and liver insulin resistance to normalize blood glucose, and in this case, the insulin regimen is less important.
doi:10.2337/dc10-0531
PMCID: PMC3005476  PMID: 20929990
5.  Incidence of Diabetes Following Ramipril or Rosiglitazone Withdrawal 
Diabetes Care  2011;34(6):1265-1269.
OBJECTIVE
To examine the impact of withdrawing rosiglitazone and ramipril medication on diabetes incidence after closeout of the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial.
RESEARCH DESIGN AND METHODS
The 3,366 DREAM subjects at trial end who had not developed diabetes while taking double-blind study medication were transferred to single-blind placebo for 2 to 3 months before undergoing an oral glucose tolerance test. Glycemic status was analyzed for the trial plus washout period and for the washout period alone.
RESULTS
Following median (interquartile range) 71 (63–86) days drug withdrawal, overall glycemic status remained modestly improved in those allocated ramipril during the trial with an 11% increase in regression to normoglycemia, compared with placebo. In those previously allocated rosiglitazone, glycemic status remained substantially improved with a 49% reduction of new-onset diabetes or death and a 22% increase in regression to normoglycemia, compared with placebo. However, during the washout phase alone the incidence of diabetes or death was identical for those allocated previously to ramipril or placebo, or to rosiglitazone or placebo.
CONCLUSIONS
In people allocated to ramipril compared with those not allocated ramipril during the trial, the postwashout normoglycemia incidence was higher. In people allocated to rosiglitazone compared with those not allocated rosiglitazone during the trial, the postwashout incidence of diabetes was significantly lower and the incidence of normoglycemia was higher. During the washout period, diabetes incidence was the same for ramipril versus placebo and for rosiglitazone versus placebo. Rosiglitazone delays disease progression during treatment but the process resumes at the placebo rate when the drug is stopped.
doi:10.2337/dc10-1567
PMCID: PMC3114353  PMID: 21515846
6.  In a Subgroup of High-Risk Asians, Telmisartan Was Non-Inferior to Ramipril and Better Tolerated in the Prevention of Cardiovascular Events 
PLoS ONE  2010;5(12):e13694.
Background and Objectives
Results of the recently published ONTARGET study (The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) showed that telmisartan (80 mg/day) was non-inferior to ramipril (10 mg/day) in reducing cardiovascular events. Clinicians in Asia doubt tolerability of these doses for their patients. We therefore analyzed data from this study and a parallel study TRANSCEND (Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease). Our objectives were to compare Asians and non-Asians with respect to the following:
1) Effectiveness of telmisartan vs. ramipril in reducing cardiovascular events;
2) Proportions who reached the full dose of telmisartan, ramipril or placebo; and
3) Proportions of overall discontinuations, and discontinuations due to adverse effects.
Method
The ONTARGET study randomized 25,620 patients at risk of cardiovascular events to ramipril, telmisartan, or their combination. The primary composite endpoint was death caused by cardiovascular disease, acute MI, stroke, and hospitalization because of congestive heart failure. TRANSCEND randomized 5926 high-risk patients with a history of intolerance to ACE-inhibitors to telmisartan or placebo. The primary outcome was the same. In this substudy, we compared Asians and non-Asians as to how well they tolerated telmisartan (given in both studies) and ramipril (given in ONTARGET).
Results
1) Telmisartan was non-inferior to ramipril in lowering the primary endpoint among Asians (RR = 0.92; 95% CI: 0.74, 1.13); 2) more Asians achieved the full dose of either drug; 3) less withdrew (overall); and 4) less withdrew for adverse effects. Furthermore, telmisartan was better tolerated than ramipril. This advantage was greater among Asians.
Conclusion and Significance
Although Asians had lower BMI than non-Asians, Asians tolerated both drugs better. Regulatory agencies require reporting of safety and effectiveness data by ethnicity, but few comply with this requirement. This study shows that safety data in ethnic subgroups can help assess applicability of results to specific populations.
Trial Registration
ClinicalTrials.gov NCT00153101
doi:10.1371/journal.pone.0013694
PMCID: PMC3006195  PMID: 21200437
7.  Effect of Rosiglitazone and Ramipril on β-Cell Function in People With Impaired Glucose Tolerance or Impaired Fasting Glucose 
Diabetes Care  2009;33(3):608-613.
OBJECTIVE
The objective of this study was to determine the degree to which ramipril and/or rosiglitazone changed β-cell function over time among individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) who participated in the Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication (DREAM) Trial, which evaluated whether ramipril and/or rosiglitazone could prevent or delay type 2 diabetes in high-risk individuals.
RESEARCH DESIGN AND METHODS
The present analysis included subjects (n = 982) from DREAM trial centers in Canada who had oral glucose tolerance tests at baseline, after 2 years, and at the end of the study. β-Cell function was assessed using the fasting proinsulin–to–C-peptide ratio (PI/C) and the insulinogenic index (defined as 30–0 min insulin/30–0 min glucose) divided by homeostasis model assessment of insulin resistance (insulinogenic index [IGI]/insulin resistance [IR]).
RESULTS
Subjects receiving rosiglitazone had a significant increase in IGI/IR between baseline and end of study compared with the placebo group (25.59 vs. 1.94, P < 0.0001) and a significant decrease in PI/C (−0.010 vs. −0.006, P < 0.0001). In contrast, there were no significant changes in IGI/IR or PI/C in subjects receiving ramipril compared with placebo (11.71 vs. 18.15, P = 0.89, and −0.007 vs. −0.008, P = 0.64, respectively). The impact of rosiglitazone on IGI/IR and PI/C was similar within subgroups of isolated IGT and IFG + IGT (all P < 0.001). Effects were more modest in those with isolated IFG (IGI/IR: 8.95 vs. 2.13, P = 0.03; PI/C: −0.003 vs. −0.001, P = 0.07).
CONCLUSIONS
Treatment with rosiglitazone, but not ramipril, resulted in significant improvements in measures of β-cell function over time in pre-diabetic subjects. Although the long-term sustainability of these improvements cannot be determined from the present study, these findings demonstrate that the diabetes preventive effect of rosiglitazone was in part a consequence of improved β-cell function.
doi:10.2337/dc09-1579
PMCID: PMC2827518  PMID: 20009095
8.  Antihypertensive and cardiovascular effects of combined blockade of renin-angiotensin system with ACE inhibitor and angiotensin II type 1 receptor blocker in hypertensive patients: A 24-week randomized controlled double-dummy trial 
Heart International  2006;2(1):39.
Background.
In this study the effects of 24 weeks losartan and ramipril treatment, both alone and in combination, on blood pressure and left ventricular mass (LVM) and function, have been evaluated in hypertensives.
Methods.
57 hypertensives with stage 1 and 2 essential hypertension were included. After 4 weeks run in, a randomized double-blind, 3 arm, double dummy, independent trial was used. All patients were randomly allocated to 3 treatment arms consisting of losartan (50 mg/daily), ramipril (5 mg/daily), and combined (losartan 50 mg/ramipril 5 mg/daily) for 24 weeks. LVM, LVM/h2.7 and other echocardiographic measurements, BUN, creatinine and clearance and potassium were determined after run in and 24 weeks.
Results.
All groups were comparable for gender, age, BMI, BP and LVM. The prevalence of baseline left ventricular hypertrophy (LVH) was not significantly different among 3 groups. At the end of treatment, a significant (p<0.05) reduction in SBP, DBP, MBP, LVM and LVM/h2.7 were observed in all groups. The absolute and percent reduction in LVM/h2.7 were significantly higher in combined than losartan or ramipril groups and also in hypertensives with LVH. No significant change in absolute and percent reduction of SBP, DBP and MBP were found.
Conclusions.
These data indicate an additional cardioprotective effect of dual blockade of RAS in hypertensive patients with and without left ventricular hypertrophy.
doi:10.4081/hi.2006.39
PMCID: PMC3184655  PMID: 21977250
Ace-inhibitors; Angiotensin II receptor blockers; Left ventricular geometry and function
9.  Rosiglitazone for Active Ulcerative Colitis 
Gastroenterology  2007;134(3):688-695.
Background
Thiazolidinedione ligands for the gamma subtype of peroxisome proliferator-activated receptors (PPARγ), widely used to treat type 2 diabetes mellitus, have been proposed as novel therapies for ulcerative colitis.
Methods
This multicenter randomized, double blind, placebo-controlled clinical trial compared the efficacy of rosiglitazone (Avandia™) 4 mg orally twice daily versus placebo twice daily for 12 weeks in 105 patients with mild to moderately active UC. Disease activity was measured with the Mayo Score. The primary endpoint was clinical response (≥ 2 point reduction) at week 12. Clinical remission (Mayo Score ≤2), endoscopic remission, and quality of life were secondary outcomes.
Results
After 12 weeks of therapy, 23 patients (44%) treated with rosiglitazone and 12 patients (23%) treated with placebo achieved clinical response (p=0.04). Remission was achieved in 9 patients (17%) treated with rosiglitazone and 1 patient (2%) treated with placebo (p=0.01). Endoscopic remission was uncommon in either treatment arm (8% rosiglitazone vs. 2% placebo, p=0.34). Clinical improvement was evident as early as 4 weeks (p=0.049). Quality of life was significantly improved at week 8 (p=0.01) but not at week 4 (p=0.48) or 12 (p=0.14). Serious adverse events were rare.
Conclusions
Rosiglitazone was efficacious in the treatment of mild to moderately active ulcerative colitis.
doi:10.1053/j.gastro.2007.12.012
PMCID: PMC2276587  PMID: 18325386
10.  Short-Term Therapy with Rosiglitazone, a PPAR-γ Agonist, Improves Metabolic Profile and Vascular Function in Nonobese Lean Wistar Rats 
ISRN Pharmacology  2012;2012:130347.
A number of preclinical and clinical studies have reported blood-pressure-lowering benefits of thiazolidinediones in diabetic subjects and animal models of diabetes. This study was designed to further elucidate vascular effects of rosiglitazone, on healthy nonobese, lean animals. Adult male Wistar rats were randomized and assigned to control and rosiglitazone-treated groups and were dosed daily with either vehicle or rosiglitazone (10 mg kg−1 day−1) by oral gavage for 5 days. Compared with control group, rosiglitazone treatment significantly reduced plasma levels of triglycerides (>240%) and nonesterified free fatty acids (>268%) (both, P < 0.001). There were no changes in vascular contractility to KCl or noradrenaline between two groups. However, rosiglitazone therapy improved carbamylcholine-induced vasorelaxation (93 ± 3 % versus control 78 ± 2, P < 0.01) an effect which was abolished by L-NAME. There was no difference in sodium nitroprusside-induced vasorelaxation between the control and rosiglitazone-treated animals. These results indicate that short-term rosiglitazone therapy improves both metabolic profile and vascular function in lean rats. The vascular effect of rosiglitazone appears to be mediated by alteration in NO production possibly by activation of endothelial PPARγ. This increased NO production together with improved lipid profile may explain mechanism(s) of blood-pressure-lowering effects of thiazolidinediones on both human and experimental animals.
doi:10.5402/2012/130347
PMCID: PMC3432376  PMID: 22957269
11.  Ramipril-based versus diuretic-based antihypertensive primary treatment in patients with pre-diabetes (ADaPT) study 
Background
Previous randomized controlled trials demonstrated a protective effect of renin angiotensin system blocking agents for the development of type-2 diabetes in patients with pre-diabetes. However, there are no real-world data available to illustrate the relevance for clinical practice.
Methods
Open, prospective, parallel group study comparing patients with an ACE inhibitor versus a diuretic based treatment. The principal aim was to document the first manifestation of type-2 diabetes in either group.
Results
A total of 2,011 patients were enrolled (mean age 69.1 ± 10.3 years; 51.6% female). 1,507 patients were available for the per-protocol analysis (1,029 ramipril, 478 diuretic group). New-onset diabetes was less frequent in the ramipril than in the diuretic group over 4 years. Differences were statistically different at a median duration of 3 years (24.4% vs 29.5%; p < 0.05). Both treatments were equally effective in reducing BP (14.7 ± 18.0/8.5 ± 8.2 mmHg and 12.7 ± 18.1/7.0 ± 8.3 mmHg) at the 4 year follow-up (p < 0.001 vs. baseline; p = n.s. between groups). In 38.6% and 39.7% of patients BP was below 130/80 mmHg (median time-to-target 3 months). There was a significant reduction of cardiovascular morbidity and mortality in favour of ramipril (p = 0.033). No significant differences were found for a change in HbA1c as well as for fasting blood glucose levels during follow-up. The rate of adverse events was higher in diuretic treated patients (SAE 15.4 vs. 12.4%; p < 0.05; AE 26.6 vs. 25.6%; p = n.s).
Conclusions
Ramipril treatment is preferable over diuretic based treatment regimens for the treatment of hypertension in pre-diabetic patients, because new-onset diabetes is delayed.
doi:10.1186/1475-2840-11-1
PMCID: PMC3313888  PMID: 22230104
12.  Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin: randomised, double blind, placebo controlled trial (the DIABHYCAR study) 
BMJ : British Medical Journal  2004;328(7438):495.
Objective To investigate whether a low dose of the angiotensin converting enzyme (ACE) inhibitor ramipril lowers cardiovascular and renal events in patients with type 2 diabetes who have microalbuminuria or proteinuria.
Design Randomised, double blind, parallel group trial comparing ramipril (1.25 mg/day) with placebo (on top of usual treatment) for cardiovascular and renal outcomes for at least three years.
Setting Multicentre, primary care study conducted mostly by general practitioners in 16 European and north African countries.
Participants 4912 patients with type 2 diabetes aged >50 years who use oral antidiabetic drugs and have persistent microalbuminuria or proteinuria (urinary albumin excretion ≥ 20 mg/l in two consecutive samples), and serum creatinine ≤ 150 μmol/l.
Main outcome measures The primary outcome measure was the combined incidence of cardiovascular death, non-fatal myocardial infarction, stroke, heart failure leading to hospital admission, and end stage renal failure.
Results Participants were followed for 3 to 6 (median 4) years. There were 362 primary events among the 2443 participants taking ramipril (37.8 per 1000 patient years) and 377 events among the 2469 participants taking placebo (38.8 per 1000 patient years; hazard ratio 1.03 (95% confidence interval 0.89 to 1.20, P = 0.65)). None of the components of the primary outcome was reduced. Ramipril lowered systolic and diastolic blood pressures (by 2.43 and 1.06 mm Hg respectively after two years) and favoured regression from microalbuminuria (20-200 mg/l) or proteinuria (> 200mg/l) to normal level (< 20 mg/l) or microalbuminuria (P < 0.07) in 1868 participants who completed the study.
Conclusions Low dose (1.25 mg) ramipril once daily has no effect on cardiovascular and renal outcomes of patients with type 2 diabetes and albuminuria, despite a slight decrease in blood pressure and urinary albumin. The cardiovascular benefits of a daily higher dose (10 mg) ramipril observed elsewhere are not found with an eightfold lower daily dose.
doi:10.1136/bmj.37970.629537.0D
PMCID: PMC351842  PMID: 14960504
13.  Phosphodiesterase 5 Inhibition Improves β-Cell Function in Metabolic Syndrome 
Diabetes Care  2009;32(5):857-859.
OBJECTIVE
This study tested the hypothesis that phosphodiesterase 5 inhibition alone or in combination with ACE inhibition improves glucose homeostasis and fibrinolysis in individuals with metabolic syndrome.
RESEARCH DESIGN AND METHODS
Insulin sensitivity, β-cell function, and fibrinolytic parameters were measured in 18 adults with metabolic syndrome on 4 separate days after a randomized, crossover, double-blind, 3-week treatment with placebo, ramipril (10 mg/day), tadalafil (10 mg o.d.), and ramipril plus tadalafil.
RESULTS
Ramipril decreased systolic and diastolic blood pressure, ACE activity, and angiotensin II and increased plasma renin activity. Ramipril did not affect insulin sensitivity or β-cell function. In contrast, tadalafil improved β-cell function (P = 0.01). This effect was observed in women (331.9 ± 209.3 vs. 154.4 ± 48.0 32 μ · mmol−1 · l−1, respectively, for tadalafil treatment vs. placebo; P = 0.01) but not in men. There was no effect of any treatment on fibrinolysis.
CONCLUSIONS
Phosphodiesterase 5 inhibition may represent a novel strategy for improving β-cell function in metabolic syndrome.
doi:10.2337/dc08-1862
PMCID: PMC2671107  PMID: 19196886
14.  Diabetic retinopathy is associated with pulse wave velocity, not with the augmentation index of pulse waveform 
Background
To investigate the clinical differences between pulse wave velocity and augmentation index in diabetic retinopathy.
Methods
The subjects were 201 patients with type 2 diabetes. These subjects were measured for both augmentation index (AI) and brachial-ankle pulse wave velocity (baPWV) by a pulse wave analyzer. The relationships between AI, baPWV, and diabetic retinopathy were examined.
Results
BaPWV was significantly higher in patients with diabetic retinopathy than in individuals without the disease. (20.13 ± 3.66 vs.17.14 ± 3.60 m/s p < 0.001) AI was higher in patients with diabetic retinopathy, but not significantly. (19.5 ± 15.2 vs. 14.8 ± 20.5% p = 0.14) The association between baPWV and diabetic retinopathy remained statistically significant after adjustment. (Odds ratio: 1.21 Per m/s, 95% confidence interval: 1.07–1.37) On the other hand, the association between AI and diabetic retinopathy was not statistically significant. (Odds ratio: 1.01 Per %, 95% confidence interval: 0.98–1.03)
Conclusion
BaPWV is associated with diabetic retinopathy, but AI is not. The clinical significance appears to be different between PWV and AI in patients with diabetes.
doi:10.1186/1475-2840-7-11
PMCID: PMC2377239  PMID: 18439284
15.  Effect of cilostazol on arterial stiffness and vascular adhesion molecules in type 2 diabetic patients with metabolic syndrome: a randomised, double-blind, placebo-controlled, crossover trial 
Background
The phosphodiesterase inhibitor cilostazol has beneficial effects on atherosclerosis by virtue of vasodilatory and antiplatelet effects. However, less is known about the effect of cilostazol on arterial stiffness and biochemical markers related to vascular inflammation and endothelial dysfunction in type 2 diabetic patients with metabolic syndrome.
Methods
In this randomized, double-blind, crossover trial, 45 diabetic patients with metabolic syndrome were randomly assigned to either the cilostazol group (50 mg for 2 weeks, 100 mg for 6 weeks) or placebo group for an 8-week treatment phase, and then crossed over. Brachial-ankle pulse wave velocity (baPWV) and serum levels of inflammatory cytokines and vascular cellular adhesion molecules were measured before and after each treatment phase.
Results
Compared with the placebo group, the mean baPWV did not improve in the cilostazol group (mean difference 31.42 cm/sec, 95% CI −55.67 to 118.5). Cilostazol treatment significantly reduced soluble vascular cellular adhesion molecule-1 (sVCAM-1) level (from 1288.7 ± 285.6 to 1168.2 ± 252.3 ng/dL, P = 0.0003), and there was also significant mean difference between groups (mean difference 105.18 ng/dL, 95% CI 10.65 to 199.71). However, other biochemical markers including lipid profiles, high sensitivity C-reactive protein, adiponectin, interleukin-6, tumor necrosis factor-alpha, monocyte chemotactic protein-1, and soluble intercellular adhesion molecule-1 did not improve with cilostazol treatment.
Conclusion
Cilostazol treatment significantly reduced serum sVCAM-1 level, but this short term treatment was not associated with beneficial effect on arterial stiffness and other inflammatory markers.
Trial registration
(Clinical trial reg. no. NCT00573950, clinicaltrials.gov.)
doi:10.1186/1758-5996-5-41
PMCID: PMC3733748  PMID: 23886346
Cilostazol; Phosphodiesterase inhibitor; Arterial stiffness; Vascular adhesion molecules; Type 2 diabetes; Metabolic syndrome
16.  A double-blind randomized study comparing the effects of continuing or not continuing rosiglitazone + metformin therapy when starting insulin therapy in people with Type 2 diabetes1 
Diabetic Medicine   2007;24(6):618-625.
Aims
To compare the efficacy and safety of either continuing or discontinuing rosiglitazone + metformin fixed-dose combination when starting insulin therapy in people with Type 2 diabetes inadequately controlled on oral therapy.
Methods
In this 24-week double-blind study, 324 individuals with Type 2 diabetes inadequately controlled on maximum dose rosiglitazone + metformin therapy were randomly assigned to twice-daily premix insulin therapy (target pre-breakfast and pre-evening meal glucose ≤ 6.5 mmol/l) in addition to either rosiglitazone + metformin (8/2000 mg) or placebo.
Results
Insulin dose at week 24 was significantly lower with rosiglitazone + metformin (33.5 ± 1.5 U/day, mean ± se) compared with placebo [59.0 ± 3.0 U/day; model-adjusted difference −26.6 (95% CI −37.7, −15,5) U/day, P < 0.001]. Despite this, there was greater improvement in glycaemic control [HbA1c rosiglitazone + metformin vs. placebo 6.8 ± 0.1 vs. 7.5 ± 0.1%; difference −0.7 (−0.8, −0.5)%, P < 0.001] and more individuals achieved glycaemic targets (HbA1c < 7.0% 70 vs. 34%, P < 0.001). The proportion of individuals reporting at least one hypoglycaemic event during the last 12 weeks of treatment was similar in the two groups (rosiglitazone + metformin vs. placebo 25 vs. 27%). People receiving rosiglitazone + metformin in addition to insulin reported greater treatment satisfaction than those receiving insulin alone. Both treatment regimens were well tolerated but more participants had oedema [12 (7%) vs. 4 (3%)] and there was more weight gain [3.7 vs. 2.6 kg; difference 1.1 (0.2, 2.1) kg, P = 0.02] with rosiglitazone + metformin.
Conclusions
Addition of insulin to rosiglitazone + metformin enabled more people to reach glycaemic targets with less insulin, and was generally well tolerated.
doi:10.1111/j.1464-5491.2007.02141.x
PMCID: PMC1974817  PMID: 17403121
insulin; metformin; randomized controlled trial; thiazolidinediones; Type 2 diabetes mellitus
17.  Reappraisal of role of angiotensin receptor blockers in cardiovascular protection 
Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have shown cardioprotective and renoprotective properties. These agents are recommended as first-line therapy for the treatment of hypertension and the reduction of cardiovascular risk. Early studies pointed to the cardioprotective and renoprotective effects of ARBs in high-risk patients. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) established the clinical equivalence of the cardioprotective and renoprotective effects of telmisartan and ramipril, but did not find an added benefit of the combination over ramipril alone. Similar findings were observed in the Telmisartan Randomized AssessmeNt Study in aCE INtolerant subjects with cardiovascular Disease (TRANSCEND) trial conducted in ACEI-intolerant patients. In ONTARGET, telmisartan had a better tolerability profile with similar renoprotective properties compared with ramipril, suggesting a potential clinical benefit over ramipril. The recently completed Olmesartan Reducing Incidence of Endstage Renal Disease in Diabetic Nephropathy Trial (ORIENT) and Olmesartan and Calcium Antagonists Randomized (OSCAR) studies will further define the role of ARBs in cardioprotection and renoprotection for high-risk patients.
doi:10.2147/VHRM.S15787
PMCID: PMC3104608  PMID: 21633521
angiotensin receptor blockers; hypertension; outcomes; clinical trials
18.  Safety and Efficacy of the ACE-Inhibitor Ramipril in Alport Syndrome: The Double-Blind, Randomized, Placebo-Controlled, Multicenter Phase III EARLY PRO-TECT Alport Trial in Pediatric Patients 
ISRN Pediatrics  2012;2012:436046.
Introduction. Retrospective observational data show that ACE-inhibitor therapy delays renal failure and improves life expectancy in Alport patients with proteinuria. The EARLY PRO-TECT Alport trial assesses the safety and efficacy of early therapy onset with ramipril in pediatric Alport patients. Methods and analysis. This double-blind, randomized, placebo-controlled, multicenter phase III trial (NCT01485978; EudraCT-number 2010-024300-10) includes 120 pediatric patients aged 24 months to 18 years with early stages of Alport syndrome (isolated hematuria or microalbuminuria). From March 2012, up to 80 patients will be randomized 1:1 to ramipril or placebo. In the event of disease progression during 3-year treatment, patients are unblinded and ramipril is initiated, if applicable. Approximately 40 patients receive open-label ramipril contributing to the safety database. Primary end-points are “time to progression to next disease level” and “incidence of adverse drug events before disease progression.” Treatment effect estimates from the randomized comparison and Alport registry data will be combined in supportive analyses to maximize evidence. Conclusion. Without this trial, ACE inhibitors may become standard off-label treatment in Alport syndrome without satisfactory evidence base. The results are expected to be of relevance for therapy of all pediatric patients with kidney disease, and the trial protocol might serve as a model for other rare pediatric glomerulopathies.
doi:10.5402/2012/436046
PMCID: PMC3395192  PMID: 22811928
19.  Association between One-Hour Post-Load Plasma Glucose Levels and Vascular Stiffness in Essential Hypertension 
PLoS ONE  2012;7(9):e44470.
Objectives
Pulse wave velocity (PWV) is a surrogate end-point for cardiovascular morbidity and mortality. A plasma glucose value ≥155 mg/dl for the 1-hour post-load plasma glucose during an oral glucose tolerance test (OGTT) is able to identify subjects with normal glucose tolerance (NGT) at high-risk for type-2 diabetes (T2D) and for subclinical organ damage. Thus, we addressed the question if 1-hour post-load plasma glucose levels, affects PWV and its central hemodynamic correlates, as augmentation pressure (AP) and augmentation index (AI).
Methods
We enrolled 584 newly diagnosed hypertensives. All patients underwent OGTT and measurements of PWV, AP and AI. Insulin sensitivity was assessed by Matsuda-index.
Results
Among participants, 424 were NGT and 160 had impaired glucose tolerance (IGT). Of 424 NGT, 278 had 1-h post-load plasma glucose <155 mg/dl (NGT<155) and 146 had 1-h post-load plasma glucose ≥155 mg/dl (NGT≥155). NGT≥155 had a worse insulin sensitivity and higher hs-CRP than NGT<155, similar to IGT subjects. In addition, NGT ≥155 in comparison with NGT<155 had higher central systolic blood pressure (134±12 vs 131±10 mmHg), as well as PWV (8.4±3.7 vs 6.7±1.7 m/s), AP (12.5±7.1 vs 9.8±5.7 mmHg) and AI (29.4±11.9 vs 25.1±12.4%), and similar to IGT. At multiple regression analysis, 1-h post-load plasma glucose resulted the major determinant of all indices of vascular stiffness.
Conclusion
Hypertensive NGT≥155 subjects, compared with NGT<155, have higher PWV and its hemodynamic correlates that increase their cardiovascular risk profile.
doi:10.1371/journal.pone.0044470
PMCID: PMC3441532  PMID: 23028545
20.  Distinct vascular and metabolic effects of different classes of anti-hypertensive drugs✩ 
Background
ASCOT-BPLA study demonstrates that in hypertensive subjects, atenolol+bendroflumethiazide therapy is associated with higher incidence of adverse cardiovascular outcomes and developing diabetes than an amlodipine+perindopril regimen. This is not explained by changes in blood pressure alone. We hypothesized that distinct vascular and metabolic effects of anti-hypertensive drugs may explain these differential effects.
Methods
Either placebo or one class of anti-hypertensive drug (atenolol 100 mg, amlodipine 10 mg, hydrochlorothiazide 50 mg, ramipril 10 mg, or candesartan 16 mg) was given daily during 8 weeks to 31 patients in each of 6 arms of a randomized, single-blind, placebo-controlled, parallel study.
Results
Atenolol, amlodipine, and candesartan therapies significantly reduced systolic blood pressure when compared with ramipril (P<0.05 by ANOVA). Atenolol and thiazide therapies increased triglycerides levels greater than ramipril or candesartan (P=0.005 by ANOVA). Amlodipine significantly increased HDL cholesterol levels greater than atenolol (P=0.011 by ANOVA). Ramipril and candesartan therapies improved FMD and increased adiponectin levels and insulin sensitivity to a greater extent than atenolol or thiazide therapies (P<0.001 and P<0.015 by ANOVA). Amlodipine therapy increased adiponectin levels greater than atenolol therapy (P<0.05 by ANOVA). Ramipril, candesartan, and amlodipine therapies significantly decreased leptin levels to a greater extent when compared with atenolol or thiazide therapies (P<0.001 by ANOVA). Amlodipine therapies significantly decreased resistin levels greater than ramipril or candesartan therapies (P=0.001 by ANOVA).
Conclusions
We observed differential effects of anti-hypertensive drugs on endothelial dysfunction and plasma adipocytokines.
doi:10.1016/j.ijcard.2008.11.017
PMCID: PMC2862263  PMID: 19059660
Anti-hypertensive drugs; Endothelial function; Adipocytokines; Hypertension; Insulin resistance
21.  Bone Effects of Rosiglitazone in HIV-Infected Patients With Lipoatrophy 
HIV clinical trials  2012;13(4):212-221.
Objectives
Thiazoledinediones increase limb fat in HIV+ patients with lipoatrophy. However, their use in the general population has been associated with bone loss and fracture. We sought to determine the effects of rosiglitazone on bone metabolism in HIV-infected patients.
Methods
HIV+ patients with lipoatrophy were randomized to rosiglitazone versus placebo for 48 weeks in a double-blind, placebo-controlled trial. Limb fat, bone mineral density (BMD), bone formation markers (procollagen type 1 amino-terminal propeptide [P1NP], osteocalcin [OC]) and bone resorption markers (C-terminal telopeptide of type I collagen [CTX]) were measured, along with receptor activator for nuclear factor kappa β ligand (RANKL), osteoprotegerin (OPG), and inflammatory cytokines.
Results
Seventy-one subjects were randomized to rosiglitazone or placebo: 17% female and 51% white. Total BMD did not change significantly in either group. In the rosiglitazone group, P1NP showed statistically significant decreases at 24 and 48 weeks; however, changes compared to placebo were only significant at 24 weeks. OC decreased significantly in the rosiglitazone group at 24 weeks, but there were no between-group differences. CTX, RANKL, or OPG did not change for either group. Multivariable regression within the rosiglitazone arm showed P1NP changes were inversely associated with limb fat changes, protease inhibitors, and tenofovir use.
Conclusion
Rosiglitazone use was associated with decreased bone formation, but it did not alter bone resorption or total BMD. The increase in limb fat that accompanies rosiglitazone use appears to be associated with decreased osteoblast activity. Further studies are needed to determine the effect of thiazoledinediones on bone health in HIV-infected persons.
doi:10.1310/hct1304-212
PMCID: PMC3895474  PMID: 22849962
bone mineral density; bone turnover markers; HIV; rosiglitazone; thiazoledinediones
22.  Antidiabetic Rosiglitazone Reduces Soluble Intercellular Adhesion Molecule-1 Level in Type 2 Diabetic Patients with Coronary Artery Disease 
PPAR Research  2008;2008:548178.
Background. We investigated the level of soluble adhesion molecules in diabetic patients and the effect of the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist rosiglitazone on plasma levels of adhesion molecules and an inflammation marker in type 2 diabetic patients with coronary artery disease (CAD) after percutaneous coronary intervention (PCI). Methods. A total of 116 diabetic patients with CAD who had undergone PCI were randomized to receive rosiglitazone (4 mg/d) or not for 6 months. Plasma levels of soluble intercellular adhesion molecules (sICAM-1) and P-selectin (sP-selectin) were measured on ELISA. Results. After 6-month rosiglitazone treatment, plasma levels of sICAM-1 were lower than baseline and control group levels (370.4 (332.4–421.9) pg/mL versus 423.5 (327.4–500.3) pg/mL and 404.6 (345.2–483.4) pg/mL, P < .001). In addition, plasma levels of C-reactive protein were significantly reduced from baseline levels. However, plasma level of sP-selectin was not significantly lowered with rosiglitazone treatment than with control treatment after 6-month follow-up. Conclusions. Rosiglitazone reduces chronic inflammatory responses and improves levels of markers of endothelial dysfunction in patients with diabetes and CAD. PPAR-γ agonist may have a beneficial effect on the vascular endothelium through its anti-inflammatory mechanism and may be useful as therapy in patients undergoing PCI.
doi:10.1155/2008/548178
PMCID: PMC2605848  PMID: 19107216
23.  Randomized comparison of the effects of rosiglitazone vs. placebo on peak integrated cardiovascular performance, cardiac structure, and function 
European Heart Journal  2010;31(18):2262-2270.
Aims
To assess the effect of rosiglitazone on cardiovascular performance and cardiac function.
Methods and results
One hundred and fifty type 2 diabetes patients with cardiovascular disease (CVD) or ≥1 other CVD risk factor were randomized to receive rosiglitazone vs. placebo for 6 months. The primary outcome was peak oxygen uptake indexed to fat-free mass (VO2peak–FFM) during maximum exercise. A subset of 102 subjects underwent cardiac magnetic resonance imaging (cMRI). On hundred and eight subjects completed the study, including 75 completing the cMRI substudy. No significant differences were observed in mean VO2peak–FFM between rosiglitazone and placebo (26.1 ± 7.0 vs. 27.6 ± 6.6 mL/kg-FFM/min; P = 0.26). Compared with placebo, the rosiglitazone group had lower hematocrit (38 vs. 41%; P < 0.001) and more peripheral oedema (53.7 vs. 33.3%; P = 0.03). In the cMRI substudy, compared with placebo, the rosiglitazone group had larger end-diastolic volume (128.1 vs. 112.0 mL; P = 0.01) and stroke volume (83.7 vs. 72.9 mL; P = 0.01), and a trend toward increased peak ventricular filling rate (79.4 vs. 60.5; P = 0.07).
Conclusion
Rosiglitazone increased peripheral oedema but had no pernicious effects on cardiovascular performance or cardiac function, with modest improvement in selected cMRI measures. Changes in indirect markers of plasma volume suggest expansion with rosiglitazone.
Trial registration: clinicaltrials.gov identifier: NCT00424762.
doi:10.1093/eurheartj/ehq228
PMCID: PMC2938467  PMID: 20601395
Diabetes mellitus; Drugs; Heart failure; Exercise
24.  The Effect of Direct Renin Inhibition Alone and in Combination With ACE Inhibition on Endothelial Function, Arterial Stiffness, and Renal Function in Type 1 Diabetes 
Diabetes Care  2012;35(11):2324-2330.
OBJECTIVE
Diabetes is associated with renin-angiotensin system (RAS) activation, leading to renal and systemic vascular dysfunction that contribute to end-organ injury and significant morbidity. RAS blockade with ACE inhibitors reduces, but does not abolish, RAS effects. Accordingly, our aim was to determine if direct renin inhibition alone, and in combination with an ACE inhibitor, corrects early hemodynamic abnormalities associated with type 1 diabetes.
RESEARCH DESIGN AND METHODS
Arterial stiffness (augmentation index), flow-mediated vasodilatation (FMD), and renal hemodynamic function (inulin and paraaminohippurate clearance) were measured at baseline under clamped euglycemic and hyperglycemic conditions (n = 21). Measures were repeated after 4 weeks of aliskiren therapy and again after aliskiren plus ramipril.
RESULTS
Blood pressure–lowering effects of aliskiren were similar during clamped euglycemia and hyperglycemia. Combination therapy augmented this effect under both glycemic conditions (P = 0.0005). Aliskiren reduced arterial stiffness under clamped euglycemic and hyperglycemic conditions, and the effects were augmented by dual RAS blockade (−3.4 ± 11.2 to −8.0 ± 11.5 to −14.3 ± 8.4%, respectively, during euglycemia, P = 0.0001). During clamped euglycemia, aliskiren increased FMD; dual therapy exaggerated this effect (5.1 ± 3.3 to 7.5 ± 3.0 to 10.8 ± 3.5%, repeated-measures ANOVA, P = 0.0001). Aliskiren monotherapy caused renal vasodilatation during clamped hyperglycemia only. In contrast, dual therapy augmented renal vasodilatory effects during clamped euglycemia and hyperglycemia.
CONCLUSIONS
In patients with uncomplicated type 1 diabetes, aliskiren-based dual RAS blockade is associated with greater arterial compliance, FMD, and renal vasodilatation.
doi:10.2337/dc12-0773
PMCID: PMC3476932  PMID: 22837362
25.  Angiotensin –Converting Enzyme Inhibition or Mineralocorticoid Receptor Blockade Do Not Affect Incidence of Atrial Fibrillation in Patients Undergoing Cardiac Surgery 
Critical care medicine  2012;40(10):2805-2812.
Objective
This study tested the hypothesis that interruption of the renin-angiotensin system with either an angiotensin-converting enzyme inhibitor or a mineralocorticoid receptor antagonist will decrease the incidence of atrial fibrillation after cardiac surgery.
Design
Randomized double-blind placebo-controlled study.
Setting
University affiliated hospitals.
Patients
Four-hundred and forty-five adult patients in normal sinus rhythm undergoing elective cardiac surgery.
Interventions
One week to four days prior to surgery, patients were randomized to treatment with placebo, ramipril (2.5 mg the first three days followed by 5mg/day, with the dose reduced to 2.5mg/d on the first postoperative day only), or spironolactone (25 mg/day).
Measurements
The primary endpoint was the occurrence of electrocardiographically confirmed postoperative atrial fibrillation. Secondary endpoints included acute renal failure, hyperkalemia, the incidence of hypotension, length of hospital stay, stroke, and death.
Main Results
The incidence of atrial fibrillation was 27.2% in the placebo group, 27.8% in the ramipril group, and 25.9% in the spironolactone group (P=0.95). Patients in the ramipril (0.7%) or spironolactone (0.7%) group were less likely to develop acute renal failure than those randomized to placebo (5.4%, P=0.006). Patients in the placebo group tended to be hospitalized longer than those in the ramipril or spironolactone group (6.8±8.2 days versus 5.7±3.2 and 5.8±3.4 days, respectively, P=0.08 for the comparison of placebo versus the active treatment groups using log-rank test). Compared to patients in the placebo group, patients in the spironolactone group were extubated sooner after surgery (576.4±761.5 minutes versus 1091.3±3067.3 minutes, P=0.04).
Conclusions
Neither angiotensin-converting enzyme inhibition nor mineralocorticoid receptor blockade decreased the primary outcome of postoperative atrial fibrillation. Treatment with an angiotensin-converting enzyme inhibitor or mineralocorticoid receptor antagonist was associated with decreased acute renal failure. Spironolactone use was also associated with a shorter duration of mechanical ventilation after surgery.
doi:10.1097/CCM.0b013e31825b8be2
PMCID: PMC3588582  PMID: 22824930
angiotensin-converting enzyme inhibitors; aldosterone; atrial fibrillation; renal insufficiency; cardiac surgery

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