Off-target effects of RAAS-inhibition: importance on renal outcomes in patients with diabetes

PhD ceremony: Ms. Y. Miao, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Off-target effects of RAAS-inhibition: importance on renal outcomes in patients with diabetes

Promotor(s): prof. D de Zeeuw, prof. D.E. Grobbee

Faculty: Medical Sciences

Drug development for patients with diabetes and nephropathy is based on effectiveness assessment of a single risk factor for renal and cardiovascular diseases (the so-called on-target risk factor). This effect is used to estimate the effect of the drug on clinically relevant endpoints. In addition, several parameters are evaluated to assess the safety of the drug. However, drugs exert effects on more risk factors than just the on-target risk factor. These so-called off-target effects ultimately affect the drug effectiveness on clinical endpoints, either positively or negatively.

In this thesis, the off-target effects of angiotensin II antagonists in patients with type 2 diabetes and nephropathy were studied. The ultimate aim is to develop a risk score that combines all the short-term on-target and off-target effects of a drug, and that produces a better estimate of the effectiveness of a drug on hard clinical endpoints. The results show that the effect of the AIIA losartan on uric acid after 6 months of therapy contributes to its ultimate renal protective effect. On the other hand, we demonstrated that the effect of losartan on serum potassium negatively influences the renal protective effect of losartan. When all the short-term off-target and on-target effects are combined in an algorithm, an accurate estimate of the final drug effect is obtained, in a much better way than when only the on-target effect is taken into consideration. This finding has important implications for drug development, registration, and individual patient care.