Olmesartan for the Delay or Prev

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					Olmesartan for the Delay or
Prevention of Microalbuminuria
in Type 2 Diabetes
Hermann Haller, M.D., Sadayoshi Ito, M.D., Ph.D., Joseph L. Izzo, Jr., M.D., Andrzej Januszewicz, M.D., Shigehiro
Katayama, M.D., Ph.D., Jan Menne, M.D., Albert Mimran, M.D., Ton J. Rabelink, M.D., Ph.D., Eberhard Ritz, M.D., Luis
M. Ruilope, M.D., Lars C. Rump, M.D., and Giancarlo Viberti, M.D., for the ROADMAP Trial Investigators*

                                                                                     Ewa Badday, MD
• Microalbuminuria is an early predictor of
  diabetic nephropathy and premature
  cardiovascular disease.

• Diabetic nephropathy is increasingly common
  cause of end-stage renal disease.

• Development and rate of renal deterioration are
  most closely related to the patients blood
  pressure control
• Microalbuminuria :

    24-hour urine collection (between 30-300
 mg/24 hours)
    spot urine sample (30 to 300 mg/L).

Both must be measured on at least two of three
 measurements over a two to three month period.
• Prevalence of microalbuminuria in DM II 30-

• Incidence rate (3%/y) is usually found in
  persons who have had diabetes for 10-20 years,
  after which the rate progressively declines.
Treatment/prevention :
• Optimal blood glucose control (HbA1c <7%)
• Control of hypertension (BP <120/70 mmHg)
• ACE inhibitors use
• Avoidance of potentially nephrotoxic substances
  such as nonsteroidal anti-inflammatory
  medications and aminoglycosides
• Early detection and optimal management of
  diabetes, especially in the setting of family
  history of diabetes
Research question :
• P - Patients with DM II at least 6 years

• I - Olmesatrtan

• C – Placebo

• O - Olmesartan is associated with a delayed
  onset of microalbuminuria in patients with
  DM II.
Study design:
• Randomized, double blind, placebo-controlled,
  parallel-group, multicenter phase 3b study at
  262 collaboration centers in 19 European

• 4449 patients, age 18-75 yo with DM II

• Study conducted from 2006-2009
Inclusion :
1. Presence of DM type II
2. Normoalbuminuria
3. At least 1 additional cardiovascular risk factor
    elevated total cholesterol >5.2mmol/L or
   treatment for hyperlipidemia
    HDL- cholesterol less than 1.1mmol/L
    triglycerides >1.7mmol/L
    Hypertension SBP > 130 mmHg and/or
        DBP >80 mmHg
    obesity (BMI > 28kg/m2 )
    smoking > 5 cigarettes/ day
1. CrCl < 30 mL/min
2. Renal-vascular disease
3. Recent cardiovascular event in last 6 months
4. Severe hypertension ( SBP >200 mmHg or
   DPB> 110 mmHg)
5. Treatment with ARB or ACE-I within 6 months
   prior to screening.
Study Design :
• After screening phase each patient’s eligibility
  for the study was established during
  prerandomization phase (max 4weeks) during
  which normoalbuinuria was confirmed.
• During double blind treatment phase target
  blood pressure of less than 130/80mmHg was
  achieved using other antihypertensive agents
  than ACE-I or ARBs.
• During each visit urine sample and blood
  pressure was measured.

• BP less than 130/80mmHg at 48month:
     Olmesartan 80% vs Placebo 71%

• Mean blood pressure in the follow up period:
     Olmesartan 125.7/74.3 mmHg
     Placebo 128.7/76.2 mmHg
Primary end point:

• Time to the first onset of microalbuminuria (
  defined as urinary albumin-to-creatinine ratio
  [mg/gm] of more than 35 in women and more
  than 25 in men).
Microalbuminuria onset :
  - Olmesartan 8.2% vs. 9.8% in Placebo group

Median time to the onset :
   - Olmesartan 722 days vs. Placebo 576 days
Secondary end points:
    Mean estimated GFR declined
   85.0+/- 17.0ml/min/1.73m2  80.1+|-18.5ml/min/1.73m2
   Placebo :
   84.7+|- 17.3ml/min/1.73m2  83.7+|-18.3ml/min/1.73m2

   ESRD did not developed in any patient
Secondary end pints:
 Composite end point cardiovascular
 complications from cardiovascular causes were
 similar in both Olmesartan and Placebo groups:
 4.3% vs. 4.2%.

 Number of deaths from cardiovascular causes
 Olmesartan 15 vs. Placebo 3
Adverse effects:
   Olmasertan 15% vs. Placebo 15.2%

   Olmesartan 11.4% vs. Placebo 7.4%
• Olmesartan was associated with delayed onset of
  microalbuminuria with even though
  blood-pressure control in both groups was
  excellent according to current standards.
Study strengths:
- large randomized trial,
- double blinded,
- multicenter,
Study weaknesses:
- short duration
- short follow up period
- high premature withdrawals in both groups
- differences in blood pressure between treatment
  groups may have contributed to the primary
- Sponsor (Daiichi Sankyo Pharmaceuticals) had no
  role in design or conduction of the study but:
 - representatives in screening committee
 - analysis by employs of the sponsor
• ARB based therapy decreased onset of
  microabuminuria in patients with DM type II
• Favorable response to Olmesartan included:
  - higher systolic BP ( >135mmHg)
  - better controlled diabetes (HbA1c<7.3mg/dl)
  - lower lever of renal function
    ( est. GFR<84ml/min/1.73m2)
  - UACR ratio >4
• Excessive reduction of blood pressure in patient
  with preexisting CAD may confer a
  predisposition to an increased risk of death.
1. USRDS: the United States Renal Data System. Am J
   Kidney Dis 2003; 42 Suppl5:1-230
2. Bakris GL, Williams M, Dworkin L, et al. Preserving
   renal function in adults with hypertension and diabetes:
   a consensus approach. Am J Kidney Dis 2000;36:646-
3. Mogensen CE.Urinary albumin excretion in early and
   long-term juvenile diabetes.Scand Clin Lab Invest 1971;
   28: 183-93
4. Viberti GC, Hill RD, Jarret RJ, Argyropolos A, Mahmud
   U, Keen H. Microalbuminuria as a predictor of clinical
   nephropathy in insulin dependent diabetes mellitus.
   Lancet 1982;1:1430-2.

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