Off-target effects of RAAS-inhibition

This project shows that a pharmaceutical’s efficacy is both positively and negatively influenced by off-target changes in risk markers and that a multiple parameter risk response outcome score that integrates these effects is accurate in predicting drug efficacy on long-term disease outcomes. The test of a pharmaceutical’s efficacy is usually its ability to decrease long-term disease outcomes, or to induce effect in so-called on-target risk markers; like blood pressure and glucose levels for nephropathy. Recent studies however indicate that a pharmaceutical’s long-term effects are influenced by off-target risk markers, which should thus (also) be measured to predict long-term disease outcomes. For the case of nephropathy, this project demonstrates the many off-target effects Angiotensin Receptor Blockers exert and shows the relationship between these off-target effects and hard renal outcomes. A multiple parameter risk response score that integrates changes in these off-target risk markers with changes in on-target markers can be used to accurately predict these long-term outcomes. Both medicine developers and regulators can make use of this score to make timely estimates of pharmaceuticals’ efficacy.

Results

• Smink PA, Miao Y, De Zeeuw D, Lambers Heerspink HJ. Drug-induced changes in risk/biomarkers and their relationship with renal and cardiovascular long-term outcome in patients with diabetes. In: Clin Chem, 2011; 57(2): 186-95. (journal publication)
• Miao Y, Ottenbros SA, Laverman GD, Brenner BM, Cooper ME, Parving HH, et al. Effect of a reduction in uric acid on renal outcomes during losartan treatment: a post hoc analysis of the reduction of endpoints in non-insulin-dependent diabetes mellitus with the Angiotensin II Antagonist Losartan Trial. In: Hypertension, 2011; 58(1): 2-7. (journal publication)
• Miao Y, Dobre D, Heerspink HJ, Brenner BM, Cooper ME, Parving HH, et al. Increased serum potassium affects renal outcomes: a post hoc analysis of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial. In: Diabetologia, 2011; 54(1): 44-50. (journal publication)
• Off-target effects of RAAS-inhibition: importance on renal outcomes in patients with diabetes (thesis)