Randomized Olmesartan and Diabetes Microalbuminuria Prevention - ROADMAP

Description:

In patients with type 2 diabetes mellitus and hypertension, but normoalbuminuria and normal renal function, studies have demonstrated that early treatment with angiotensin-converting enzyme (ACE) inhibitors delays the onset of microalbuminuria. It is unclear if this is true for angiotensin-receptor blockers (ARBs) as well.

Accordingly, the ROADMAP trial sought to evaluate the safety and efficacy of olmesartan compared with placebo in delaying the development of microalbuminuria in patients with type 2 diabetes, normoalbuminuria, and at least one cardiovascular (CV) risk factor.

Hypothesis:

Olmesartan medoxomil would be superior to placebo in delaying the development of microalbuminuria in patients with type 2 diabetes, normoalbuminuria, and at least one CV risk factor.

Study Design

  • Blinded
  • Parallel
  • Randomized
  • Placebo Controlled

Patient Populations:

  • Type 2 diabetes mellitus with glycated hemoglobin ≥6.5% or receiving treatment for diabetes
  • At least one CV risk factor
  • Age 18-75 years
  • Normoalbuminuria (≤35 mg albumin/g urine creatinine for women and ≤25 mg albumin/g urine creatinine for men)

    Number of enrollees: 4,447
    Duration of follow-up: 4 years
    Mean patient age: 57.7 years
    Percentage female: 54%

Exclusions:

  • Documented renal and/or renal-vascular disease (including malignant or severe renal disease)
  • History of nephrectomy and/or renal transplantation
  • Need for dialysis
  • Recent history (within 6 months of starting the study) of myocardial infarction, stroke, transient ischemic attack, myocardial revascularization, or reperfusion
  • Recent use (within 6 months of starting the study) of ARBs or ACE inhibitors
  • Severe hypertension, defined as systolic BP >200 mm Hg and/or diastolic BP >110 mm Hg
  • Severe uncontrolled hyperlipidemia
  • Severe heart failure
  • Bradycardia
  • Significant narrowing of the aortic bicuspid valve
  • Severe obstruction of cardiac outflow (hypertrophic cardiomyopathy, New York Association class III-IV)

Primary Endpoints:

  • Time to development of microalbuminuria

Secondary Endpoints:

  • Renal events
  • Composite of CV complications and CV death

Drug/Procedures Used:

Patients were randomized to receive either 40 mg of olmesartan medoxomil once daily or placebo. Blood pressure (BP) control (<130/80 mm Hg) in both groups was achieved by adding, as needed, antihypertensive agents that did not block the renin–angiotensin system. If microalbuminuria was confirmed during follow-up, the patient was assigned to an open-label phase in which he or she received olmesartan at a dose of 40 mg daily.

Principal Findings:

A total of 4,447 patients were randomized, 2,232 to olmesartan and 2,215 to placebo. Baseline characteristics were fairly similar between the two arms, except for body mass index, which was higher in the olmesartan arm (31.1 vs. 30.9 kg/m2). The mean duration of diabetes was 6.1 years, with 93% having received prior treatment for diabetes. The mean glycated hemoglobin level was 7.7%. More than 97% of the patients had at least two cardiovascular risk factors in addition to type 2 diabetes, and 67.7% had at least four. The mean baseline BP) was 136/81 mm Hg. The mean baseline creatinine was 0.9 mg/dl, with a mean estimated glomerular filtration rate (eGFR) of 84.9 ml/min/1.73 m2; about 6% had an eGFR <60 ml/min/1.73 m2. The mean urinary albumin-to-creatinine ratio was 6.1, with a median of 4.

The mean BP during the follow-up period was 125.7/74.3 mm Hg in the olmesartan arm and 128.7/76.2 mm Hg in the placebo arm. Target BP of <130/80 mm Hg was attained in about 80% of the patients in the olmesartan arm and 71% of the patients in the placebo arm at month 48. Over the duration of follow-up, microalbuminuria developed in 8.2% of patients in the olmesartan arm, as compared with 9.8% in the placebo arm. The primary endpoint of time to onset of microalbuminuria was significantly reduced in the olmesartan arm compared with placebo (722 days vs. 576 days, hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.63-0.94, p = 0.01). Similar results were noted on per-protocol analysis, and after adjustment for differences in BP levels between the two arms. Mean eGFR declined to a slightly greater extent in the olmesartan arm compared with placebo, although end-stage renal disease did not develop in any patient, and the proportion of patients with a doubling of creatinine was similar between the two arms (~1%).

Clinical endpoints including all-cause mortality (1.2% vs. 0.7%, p = 0.1), all CV complications (3.6% vs. 4.1%, p = 0.37), and a composite of CV complications or CV death (4.3% vs. 4.2%, p = 0.99) were similar between the two arms. However, CV death was higher in the olmesartan arm (0.7% vs. 0.1%, HR 4.94, 95% CI 1.43-17.06, p = 0.01), mainly due to a higher rate of sudden cardiac death (0.3% vs. <0.1%) and death due to myocardial infarction (0.2% vs. 0). There seemed to be evidence of effect modification by the presence of coronary artery disease and systolic BP, with patients with pre-existing coronary artery disease, especially those in the lowest quartile of systolic BP, and the highest quartile of BP reduction demonstrating the highest risk of CV death.

At least one drug-related event was higher in the olmesartan arm compared with placebo (11.4% vs. 7.5%, p < 0.001), with about 23% of patients in both arms prematurely stopping the study medication. Serious events were similar (0.2% vs. <0.1%, p = 0.18). Patients in the olmesartan arm had a higher incidence of hypotension (2.6% vs. 0.3%, p < 0.001) and dizziness (4.6% vs. 2.8%, p = 0.001), but a lower incidence of headaches (4.5% vs. 6.9%, p < 0.001) and peripheral edema (2.7% vs. 3.9%, p = 0.03); the incidence of hyperkalemia was similar (0.5% vs. 0.4%, p = 0.5).

Interpretation:

The results of the ROADMAP trial indicate that olmesartan significantly retards the development of microalbuminuria in patients with type 2 diabetes, normoalbuminuria, and at least one CV risk factor, although the proportion of patients who developed microalbuminuria at the end of 4 years was comparable between the two arms. There was also a slightly greater decline in eGFR in the olmesartan arm over the duration of follow-up, with a slight increase in the incidence of CV death in the olmesartan arm, mainly in patients with pre-existing coronary artery disease.

The beneficial effect of olmesartan in delaying the development of microalbuminuria is similar to those noted with trandolapril in the BENEDICT trial in patients with type 2 diabetes. The increase in CV deaths noted in the olmesartan arm is concerning, and deserves further study. Whether this represents a drug-related effect, or represents the detrimental effect of overzealous BP reduction, especially in patients with pre-existing coronary artery disease, will need to be further examined.

References:

Haller H, Ito S, Izzo JL Jr, et al., on behalf of the ROADMAP Trial Investigators. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med 2011;364:907-17.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Prevention, Atherosclerotic Disease (CAD/PAD), SCD/Ventricular Arrhythmias, Statins, Hypertension

Keywords: Coronary Artery Disease, Follow-Up Studies, Diabetes Mellitus, Type 2, Hypotension, Renin-Angiotensin System, Hyperkalemia, Edema, Risk Factors, Creatinine, Headache, Hemoglobin A, Glycosylated, Imidazoles, Dizziness, Confidence Intervals, Hypertension, Death, Sudden, Cardiac, Angiotensin Receptor Antagonists, Myocardial Infarction, Kidney Failure, Chronic, Tetrazoles, Body Mass Index, Indoles, Glomerular Filtration Rate


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