Effect of nateglinide on the incidence of diabetes and cardiovascular events.
BACKGROUND
The ability of short-acting insulin secretagogues to reduce the risk of diabetes or cardiovascular events in people with impaired glucose tolerance is unknown.


METHODS
In a double-blind, randomized clinical trial, we assigned 9306 participants with impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors to receive nateglinide (up to 60 mg three times daily) or placebo, in a 2-by-2 factorial design with valsartan or placebo, in addition to participation in a lifestyle modification program. We followed the participants for a median of 5.0 years for incident diabetes (and a median of 6.5 years for vital status). We evaluated the effect of nateglinide on the occurrence of three coprimary outcomes: the development of diabetes; a core cardiovascular outcome that was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure; and an extended cardiovascular outcome that was a composite of the individual components of the core composite cardiovascular outcome, hospitalization for unstable angina, or arterial revascularization.


RESULTS
After adjustment for multiple testing, nateglinide, as compared with placebo, did not significantly reduce the cumulative incidence of diabetes (36% and 34%, respectively; hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15; P=0.05), the core composite cardiovascular outcome (7.9% and 8.3%, respectively; hazard ratio, 0.94, 95% CI, 0.82 to 1.09; P=0.43), or the extended composite cardiovascular outcome (14.2% and 15.2%, respectively; hazard ratio, 0.93, 95% CI, 0.83 to 1.03; P=0.16). Nateglinide did, however, increase the risk of hypoglycemia.


CONCLUSIONS
Among persons with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors, assignment to nateglinide for 5 years did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcomes. (ClinicalTrials.gov number, NCT00097786.)
Rury R
RR
Holman
Steven M
SM
Haffner
John J
JJ
McMurray
M Angelyn
MA
Bethel
Björn
B
Holzhauer
Tsushung A
TA
Hua
Yuri
Y
Belenkov
Mitradev
M
Boolell
John B
JB
Buse
Brendan M
BM
Buckley
Antonio R
AR
Chacra
Fu-Tien
FT
Chiang
Bernard
B
Charbonnel
Chun-Chung
CC
Chow
Melanie J
MJ
Davies
Prakash
P
Deedwania
Peter
P
Diem
Daniel
D
Einhorn
Vivian
V
Fonseca
Gregory R
GR
Fulcher
Zbigniew
Z
Gaciong
Sonia
S
Gaztambide
Thomas
T
Giles
Edward
E
Horton
Hasan
H
Ilkova
Trond
T
Jenssen
Steven E
SE
Kahn
Henry
H
Krum
Markku
M
Laakso
Lawrence A
LA
Leiter
Naomi S
NS
Levitt
Viacheslav
V
Mareev
Felipe
F
Martinez
Chantal
C
Masson
Theodore
T
Mazzone
Eduardo
E
Meaney
Richard
R
Nesto
Changyu
C
Pan
Rudolf
R
Prager
Sotirios A
SA
Raptis
Guy E H M
GE
Rutten
Herbert
H
Sandstroem
Frank
F
Schaper
Andre
A
Scheen
Ole
O
Schmitz
Isaac
I
Sinay
Vladimir
V
Soska
Steen
S
Stender
Gyula
G
Tamás
Gianni
G
Tognoni
Jaako
J
Tuomilehto
Alberto S
AS
Villamil
Juraj
J
Vozár
Robert M
RM
Califf
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D001786:Blood Glucose / Q000032:analysis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000401:mortality / Q000517:prevention & control*; D003510:Cyclohexanes / Q000009:adverse effects / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000517:prevention & control*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D015444:Exercise; D005260:Female; D005500:Follow-Up Studies; D018149:Glucose Intolerance / Q000178:diet therapy / Q000188:drug therapy* / Q000628:therapy; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D015994:Incidence; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D000077715:Nateglinide; D010649:Phenylalanine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016016:Proportional Hazards Models; D012307:Risk Factors; D013777:Tetrazoles / Q000627:therapeutic use; D017211:Treatment Failure; D014633:Valine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000068756:Valsartan
D047228:Angiotensin II Type 1 Receptor Blockers; D001786:Blood Glucose; D003510:Cyclohexanes; D007004:Hypoglycemic Agents; D013777:Tetrazoles; D000077715:Nateglinide; D010649:Phenylalanine; D000068756:Valsartan; D014633:Valine