Long-term Study of Nateglinide+Valsartan to Prevent or Delay Type II Diabetes Mellitus and Cardiovascular Complications

Conditions

Diabetes Mellitus, Type 2

Keywords

Prevention, Diabetes type 2, valsartan, nateglinide

Brief summary

This study is a test of the safety and effectiveness of two drugs, one for diabetes and one for hypertension, in keeping patients with high lab values of glucose from progressing to frank diabetes and developing cardiovascular complications. People in this study cannot have frank diabetes but are considered borderline based on blood tests. People in the study take none, one or both of the drugs and do not know which one(s) they are taking.

Robert M. Califf, John J.V. McMurray, Rury R. Holman, Steven M. Haffner, M. Angelyn Bethel et al. (54 authors)

UNC Libraries2021-07-038 citations

10.17615/ypnd-nk38

International Variation in Outcomes Among People with Cardiovascular Disease or Cardiovascular Risk Factors and Impaired Glucose Tolerance: Insights from the NAVIGATOR Trial

Marília Harumi Higuchi dos Santos, Abhinav Sharma, Jie‐Lena Sun, Karen S. Pieper, John J.V. McMurray et al. (7 authors)

Journal of the American Heart Association2017-01-1118 citations

10.1161/jaha.116.003892

Prospective relationships between body weight and physical activity: an observational analysis from the NAVIGATOR study

David Preiss, Laine Thomas, Daniel Wojdyla, Steven M. Haffner, Jason M. R. Gill et al. (11 authors)

BMJ Open2015-08-0115 citations

10.1136/bmjopen-2015-007901

How many unpublished studies? ClinicalTrials.gov (n = 2614 studies): diabetes | Closed Studies | Interventional Studies | Phase 3, 4 | Search Date: Oct 27, 2014

Ramirez Jorge H

Figshare2014-01-01

10.6084/m9.figshare.1249628.v1

Association between change in daily ambulatory activity and cardiovascular events in people with impaired glucose tolerance (NAVIGATOR trial): a cohort analysis.

Yates T, Haffner SM, Schulte PJ, Thomas L, Huffman KM, Bales CW, Califf RM, Holman RR, McMurray JJ, Bethel MA, Tuomilehto J, Davies MJ, Kraus WE.

2013-12-20169 citations

10.1016/s0140-6736(13)62061-9

Role of diuretics, blockers, and statins in increasing the risk of diabetes in patients with impaired glucose tolerance: reanalysis of data from the NAVIGATOR study

Long Shen, Bimal Shah, Eric Reyes, Laine Thomas, Daniel Wojdyla et al. (19 authors)

BMJ2013-12-09114 citations

10.1136/bmj.f6745

Effect of valsartan on the incidence of diabetes and cardiovascular events.

NAVIGATOR Study Group, McMurray JJ, Holman RR, Haffner SM, Bethel MA, Holzhauer B, Hua TA, Belenkov Y, Boolell M, Buse JB, Buckley BM, Chacra AR, Chiang FT, Charbonnel B, Chow CC, Davies MJ, Deedwania P, Diem P, Einhorn D, Fonseca V, Fulcher GR, Gaciong Z, Gaztambide S, Giles T, Horton E, Ilkova H, Jenssen T, Kahn SE, Krum H, Laakso M, Leiter LA, Levitt NS, Mareev V, Martinez F, Masson C, Mazzone T, Meaney E, Nesto R, Pan C, Prager R, Raptis SA, Rutten GE, Sandstroem H, Schaper F, Scheen A, Schmitz O, Sinay I, Soska V, Stender S, Tamás G, Tognoni G, Tuomilehto J, Villamil AS, Vozár J, Califf RM.

2010-03-14433 citations

10.1056/nejmoa1001121

Effect of nateglinide on the incidence of diabetes and cardiovascular events.

NAVIGATOR Study Group, Holman RR, Haffner SM, McMurray JJ, Bethel MA, Holzhauer B, Hua TA, Belenkov Y, Boolell M, Buse JB, Buckley BM, Chacra AR, Chiang FT, Charbonnel B, Chow CC, Davies MJ, Deedwania P, Diem P, Einhorn D, Fonseca V, Fulcher GR, Gaciong Z, Gaztambide S, Giles T, Horton E, Ilkova H, Jenssen T, Kahn SE, Krum H, Laakso M, Leiter LA, Levitt NS, Mareev V, Martinez F, Masson C, Mazzone T, Meaney E, Nesto R, Pan C, Prager R, Raptis SA, Rutten GE, Sandstroem H, Schaper F, Scheen A, Schmitz O, Sinay I, Soska V, Stender S, Tamás G, Tognoni G, Tuomilehto J, Villamil AS, Vozár J, Califf RM.

2010-03-14304 citations

10.1056/nejmoa1001122

Interventions

DRUGValsartan 160 mg + nateglinide 60 mg

The double-blinding of the randomized study medication was maintained by the use of identical placebo and active tablets and capsules for nateglinide and valsartan, respectively. Patients were instructed not to take the morning dose of either medication nor to eat breakfast on the day of a scheduled study visit, but to wait until after the visit was completed. Patients not tolerating the higher dose (Level 2) were down-titrated to receive Level 1. Patients not tolerating the lower dose (Level 1) had a treatment interruption. Starting at Week 2 and throughout the study, attempts were to be made to reach the highest dose level (Level 2), if medically acceptable. Following each change in dose level or re-initiation of treatment, tolerability was assessed after 2 weeks of exposure.

DRUGValsartan 160 mg + nateglinide placebo

The double-blinding of the randomized study medication was maintained by the use of identical placebo and active tablets and capsules for nateglinide and valsartan, respectively. Patients were instructed not to take the morning dose of either medication nor to eat breakfast on the day of a scheduled study visit, but to wait until after the visit was completed. Patients not tolerating the higher dose (Level 2) were down-titrated to receive Level 1. Patients not tolerating the lower dose (Level 1) had a treatment interruption. Starting at Week 2 and throughout the study, attempts were to be made to reach the highest dose level (Level 2), if medically acceptable. Following each change in dose level or re-initiation of treatment, tolerability was assessed after 2 weeks of exposure.

DRUGNateglinide 60 mg + valsartan placebo

The double-blinding of the randomized study medication was maintained by the use of identical placebo and active tablets and capsules for nateglinide and valsartan, respectively. Patients were instructed not to take the morning dose of either medication nor to eat breakfast on the day of a scheduled study visit, but to wait until after the visit was completed. Patients not tolerating the higher dose (Level 2) were down-titrated to receive Level 1. Patients not tolerating the lower dose (Level 1) had a treatment interruption. Starting at Week 2 and throughout the study, attempts were to be made to reach the highest dose level (Level 2), if medically acceptable. Following each change in dose level or re-initiation of treatment, tolerability was assessed after 2 weeks of exposure.

DRUGValsartan placebo + nateglinide placebo

The double-blinding of the randomized study medication was maintained by the use of identical placebo and active tablets and capsules for nateglinide and valsartan, respectively. Patients were instructed not to take the morning dose of either medication nor to eat breakfast on the day of a scheduled study visit, but to wait until after the visit was completed. Patients not tolerating the higher dose (Level 2) were down-titrated to receive Level 1. Patients not tolerating the lower dose (Level 1) had a treatment interruption. Starting at Week 2 and throughout the study, attempts were to be made to reach the highest dose level (Level 2), if medically acceptable. Following each change in dose level or re-initiation of treatment, tolerability was assessed after 2 weeks of exposure.

Study design

Allocation

RANDOMIZED

Intervention model

FACTORIAL

Primary purpose

PREVENTION

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

50 Years to 99 Years

Healthy volunteers

No

Inclusion criteria

* Adults * Impaired glucose tolerance * Age dependent risk factors

Exclusion criteria

* Frank diabetes For detailed information, call contact person.

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Patients Reaching the Endpoint: Progression to Diabetes - Valsartan Versus Non-valsartan	Mean patient duration of 4.2 years	Progression to diabetes was determined by (a) an algorithm based on central laboratory measurements of fasting plasma glucose and/or a 2 hour oral glucose tolerance test or (b) adjudication by the Diabetes Endpoint Adjudication Committee.
Percentage of Patients Reaching the Endpoint: Extended Morbidity and Mortality Event - Valsartan Versus Non-valsartan	Mean patient duration of 5.6 years	The extended cardiovascular endpoint was defined as a cardiovascular morbidity/mortality event including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, revascularization procedure, hospitalization for congestive heart failure, and hospitalization for unstable angina.
Percentage of Patients Reaching the Endpoint: Core Cardiovascular Morbidity and Mortality Event - Valsartan Versus Non-valsartan	Mean patient duration of 5.8 years	The core cardiovascular endpoint was defined as a cardiovascular morbidity/mortality event including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and hospitalization for congestive heart failure.
Percentage of Patients Reaching the Endpoint: Progression to Diabetes - Nateglinide Versus Non-nateglinide	Mean patient duration of 4.2 years	Progression to diabetes was determined by (a) an algorithm based on central laboratory measurements of fasting plasma glucose and/or a 2 hour oral glucose tolerance test or (b) adjudication by the Diabetes Endpoint Adjudication Committee.
Percentage of Patients Reaching the Endpoint: Extended Morbidity and Mortality Event - Nateglinide Versus Non-nateglinide	Mean patient duration of 5.6 years	The extended cardiovascular endpoint was defined as a cardiovascular morbidity/mortality event including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, revascularization procedure, hospitalization for congestive heart failure, and hospitalization for unstable angina.
Percentage of Patients Reaching the Endpoint: Core Cardiovascular Morbidity and Mortality Event - Nateglinide Versus Non-nateglinide	Mean patient duration of 5.8 years	The core cardiovascular endpoint was defined as a cardiovascular morbidity/mortality event including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and hospitalization for congestive heart failure.

Countries

Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, China, Colombia, Czechia, Denmark, Ecuador, Finland, France, Germany, Greece, Guatemala, Hong Kong, Hungary, Italy, Malaysia, Mexico, Netherlands, Norway, Peru, Poland, Russia, Singapore, Slovakia, South Africa, Spain, Sweden, Switzerland, Taiwan, Turkey (Türkiye), United Kingdom, United States, Uruguay

Participant flow

Recruitment details

Initially enrolled 9518, 212 excluded.

Participants by arm

Arm	Count
Valsartan 160 mg od + Nateglinide 60 mg ac For the first 2 weeks of treatment, patients took the combination of nateglinide 30 mg (3 times daily ante cibum \[ac, before meals\]) and valsartan 80 mg (once daily \[od\] in the morning). After 2 weeks, patients were uptitrated to nateglinide 60 mg ac and valsartan 160 mg od.	2,316
Valsartan 160 mg od + Placebo Nateglinide For the first 2 weeks of treatment, patients took valsartan 80 mg once daily (od) once in the morning. After 2 weeks, patients were uptitrated to 160 mg valsartan od. Patient also received placebo matching nateglinide tablets identical to the active nateglinide tablets (ac, before meals).	2,315
Nateglinide 60 mg ac + Placebo Valsartan For the first 2 weeks of treatment, patients took one 30 mg tablet of nateglinide with a glass of water 1-30 minutes before each main meal of the day, ie, 3 times daily ante cibum (ac, before meals). If a meal was missed, the patient was not to take a tablet. After 2 weeks, patients were uptitrated to 60 mg nateglinide ac. Patients also received placebo matching valsartan capsules identical to the active valsartan capsules.	2,329
Placebo Patients took 3 placebo tablets identical to nateglinide tablets 3 times daily ac and 1 placebo capsule identical to valsartan capsule once daily in the morning.	2,346
Total	9,306

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	lost to follow-up for all-cause death	296	292	313	310

Baseline characteristics

Characteristic	Valsartan 160 mg od + Nateglinide 60 mg ac	Valsartan 160 mg od + Placebo Nateglinide	Nateglinide 60 mg ac + Placebo Valsartan	Placebo	Total
Age, Continuous	63.7 years STANDARD_DEVIATION 6.75	63.7 years STANDARD_DEVIATION 6.91	63.8 years STANDARD_DEVIATION 6.82	63.9 years STANDARD_DEVIATION 6.88	63.8 years STANDARD_DEVIATION 6.84
Sex: Female, Male Female	1174 Participants	1140 Participants	1194 Participants	1203 Participants	4711 Participants
Sex: Female, Male Male	1142 Participants	1175 Participants	1135 Participants	1143 Participants	4595 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	1,970 / 2,297	1,932 / 2,283	1,951 / 2,305	1,934 / 2,316
serious Total, serious adverse events	1,031 / 2,297	1,040 / 2,283	1,035 / 2,305	1,049 / 2,316

Outcome results

Primary

Percentage of Patients Reaching the Endpoint: Core Cardiovascular Morbidity and Mortality Event - Nateglinide Versus Non-nateglinide

The core cardiovascular endpoint was defined as a cardiovascular morbidity/mortality event including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and hospitalization for congestive heart failure.

Time frame: Mean patient duration of 5.8 years