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.)
Holman
Rury R
RR
Haffner
Steven M
SM
McMurray
John J
JJ
Bethel
M Angelyn
MA
Holzhauer
Björn
B
Hua
Tsushung A
TA
Belenkov
Yuri
Y
Boolell
Mitradev
M
Buse
John B
JB
Buckley
Brendan M
BM
Chacra
Antonio R
AR
Chiang
Fu-Tien
FT
Charbonnel
Bernard
B
Chow
Chun-Chung
CC
Davies
Melanie J
MJ
Deedwania
Prakash
P
Diem
Peter
P
Einhorn
Daniel
D
Fonseca
Vivian
V
Fulcher
Gregory R
GR
Gaciong
Zbigniew
Z
Gaztambide
Sonia
S
Giles
Thomas
T
Horton
Edward
E
Ilkova
Hasan
H
Jenssen
Trond
T
Kahn
Steven E
SE
Krum
Henry
H
Laakso
Markku
M
Leiter
Lawrence A
LA
Levitt
Naomi S
NS
Mareev
Viacheslav
V
Martinez
Felipe
F
Masson
Chantal
C
Mazzone
Theodore
T
Meaney
Eduardo
E
Nesto
Richard
R
Pan
Changyu
C
Prager
Rudolf
R
Raptis
Sotirios A
SA
Rutten
Guy E H M
GE
Sandstroem
Herbert
H
Schaper
Frank
F
Scheen
Andre
A
Schmitz
Ole
O
Sinay
Isaac
I
Soska
Vladimir
V
Stender
Steen
S
Tamás
Gyula
G
Tognoni
Gianni
G
Tuomilehto
Jaako
J
Villamil
Alberto S
AS
Vozár
Juraj
J
Califf
Robert M
RM
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