The importance of short-term off-target effects in estimating the long-term renal and cardiovascular protection of angiotensin receptor blockers.
Angiotensin receptor blockers (ARBs) have multiple effects that may contribute to their efficacy on renal/cardiovascular outcomes. We developed and validated a risk score that incorporated short-term changes in multiple risk markers to predict the ARB effect on renal/cardiovascular outcomes. The score was used to predict renal/cardiovascular risk at baseline and at month 6 in the ARB treatment arm of the Reduction of Endpoints in NIDDM (noninsulin-dependent diabetes mellitus) with the Angiotensin II Antagonist Losartan (RENAAL) trial. The net risk difference at these time points indicated the estimated long-term renal/cardiovascular treatment effect. Predicted relative risk reductions (RRRs) based on multiple markers were close to observed RRRs for renal (RRR(predicted): 30.1% vs. RRR(observed): 21.8%; P = 0.44) and cardiovascular outcomes (RRR(predicted): 9.4% vs. RRR(observed): 9.2%; P = 0.98), in addition to being markedly more accurate than predicted RRRs based on changes in single markers. The score was validated in an independent ARB trial. Predictions of long-term renal/cardiovascular ARB effects are more accurate when considering short-term changes in multiple risk markers, challenging the use of single markers to establish drug efficacy.
Department of Clinical Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
P A
PA
Smink
Department of Clinical Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Y
Y
Miao
Julius Center for Health Science and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
M J C
MJ
Eijkemans
Department of Clinical Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
S J L
SJ
Bakker
Diabetes Unit, Hadassah Hebrew University Hospital, Jerusalem, Israel.
I
I
Raz
1] Department of Medical Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark [2] Faculty of Health Sciences, Aarhus University, Aarhus, Denmark.
H-H
HH
Parving
Department of Clinical Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
J
J
Hoekman
Julius Center for Health Science and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
D E
DE
Grobbee
Department of Clinical Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
D
D
de Zeeuw
Department of Clinical Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
H J
HJ
Lambers Heerspink
D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use*; D000959:Antihypertensive Agents / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000517:prevention & control*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D006801:Humans; D007674:Kidney Diseases / Q000517:prevention & control*; D019808:Losartan / Q000627:therapeutic use; D040242:Risk Reduction Behavior; D013997:Time Factors; D016896:Treatment Outcome
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D019808:Losartan