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Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication



Background

The prevalence of type 2 diabetes mellitus (T2DM) is increasing rapidly with 221 million cases predicted world-wide by the year 2010. As well as increasing the risk of cardiovascular disease (CVD) two to four fold, T2DM is the leading cause of blindness in working age adults, end-stage renal disease and non-traumatic lower extremity amputations. People with dysglycaemia, especially those with impaired glucose tolerance (IGT), are at increased risk of developing both CVD and T2DM. Recent studies, inclduing the DPP, STOP-NIDDM and Finnish DPS, have shown that treating IGT subjects with lifestyle measures, acarbose or metformin can reduce their risk of developing T2DM.

Rationale

The DREAM study is investigating whether treatment with an ACE inhibitor (ramipril) and/or a thiazolidinedione (rosiglitazone) can delay or prevent the development of T2DM. These two agents are of particular interest as a post hoc analysis of the HOPE study has suggested that ramipril may delay the onset of diabetes whilst the TRIPOD study showed that a reduced rate of progression to diabetes in women given the thiazolidinedione troglitazone subsequent to a diagnosis of gestational diabetes mellitus. Ramipril, which has direct effects on the renin-angiotensin-kallikrein system, may prevent diabetes through effects on the beta cell and by vascular and metabolic effects on muscle (partially mediated by nitric oxide) that may amplify the effects of insulin. Rosiglitazone improves insulin sensitivity and may have a beta cell cytoprotective effect but does not appear to directly affect the renin-angiotensin-kallikrein system. As the mechanisms by which either drug may prevent diabetes differ, they are unlikely to interact during a clinical trial and indeed may be complementary.

Subjects

A two year recruitment period aims to randomise 4000 individuals at high risk for T2DM. To be included, subjects must be aged 30 or older and have IGT (i.e. a 2 hour plasma glucose post 75  g glucose challenge of 7.8 to 11.0 mmol/L (140 to 199 mg/dl)) or IFG (i.e. a fasting plasma glucose >= 6.1 mmol/L (110 mg/dl)) and no diabetes (i.e. a fasting plasma glucose < 7.0 mmol/L (126 mg/dl)).

Key exclusion criteria include:

Randomisation

Eligible subjects will be randomised in a 2x2 factorial manner to double-blind study medication with:

and, simultaneously, to:

Ramipril
Arm

Rosiglitazone
Arm
1,000
ramipril
rosiglitazone
1,000
placebo
rosiglitazone
2,000
rosiglitazone
1,000
ramipril
placebo
1,000
placebo
placebo
2,000
placebo

2,000
ramipril
2,000
placebo
4,000
subjects
in total

Three Year Follow-Up

All subjects will be followed up for at least 3 years including any who discontinue study medication. Measurements taken at specified visits will include FPG, OGTT, ALT, potassium, creatinine, HbA1c, urinary albumin/creatinine ratio, heart rate, blood pressure, ankle pressure and ECG. Reports of any hospitalisation, death, surgery, or serious adverse events will be collected at every visit.

Study Management and Funding

The DREAM study is an international trial co-ordinated by the Canadian Cardiovascular Collaboration (CCC) at McMaster University, Hamilton, Canada. European sites are managed by the EuroDREAM project office at the Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism. The study is funded jointly by the Canadian Institutes of Health Research, Aventis Pharma, King Pharmaceuticals and GlaxoSmithKline.