Effect of nateglinide on the incidence of diabetes and cardiovascular events
Open accessAbstract
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.)
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Thiazolidinediones increased the risk of heart failure hospitalization in several trials.
“Thiazolidinediones increased the risk of HF hospitalization in several trials and are not recommended in patients with diabetes and symptomatic HF. 165,[565][566][567]”
From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [565]
A multicentre multinational study found that nateglinide had no effect on the rate of diabetes or cardiovascular outcomes during 6.5 years of follow-up in over 9000 persons with IGT.
“A multicentre multinational study investigated the effect of nateglinide (a short-acting insulin secretagogue) in over 9000 persons with IGT and found no effect on the rate of diabetes or the cardiovascular outcomes during 6.5 years of follow-up.108”
From Prediabetes: a high-risk state for diabetes development (2012) · cites this paper as [108]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Regression Models and Life-Tables
Cox, D. R. (1972) · Journal of the Royal Statistical Society Series B: Statistical Methodology · doi:10.1111/j.2517-6161.1972.tb00899.x · Cited by 39,793 · see citing works
Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin
(2002) · New England Journal of Medicine · doi:10.1056/nejmoa012512 · Cited by 19,011 · see citing works
Tuomilehto, J., Lindström, J., Eriksson, J. G., Valle, T. T., Hämäläinen, H., Ilanne-Parikka, P., Keinänen-Kiukaanniemi, S., Laakso, M., Louheranta, A., Rastas, M., et al. (2001) · New England Journal of Medicine · doi:10.1056/nejm200105033441801 · Cited by 10,873 · see citing works
The metabolic syndrome—a new worldwide definition
Alberti, K. G. M., Zimmet, P., & Shaw, J. (2005) · The Lancet · doi:10.1016/s0140-6736(05)67402-8 · Cited by 9,352 · see citing works
Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus
The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (1997) · Diabetes Care · doi:10.2337/diacare.20.7.1183 · Cited by 6,220 · see citing works
Pan, X.-R., Li, G.-W., Hu, Y.-H., Wang, J.-X., Yang, W.-Y., An, Z.-X., Hu, Z.-X., Juan-Lin, Xiao, J.-Z., Cao, H.-B., et al. (1997) · Diabetes Care · doi:10.2337/diacare.20.4.537 · Cited by 4,320 · see citing works
Diabetes Prevention Program Research Group (2009) · The Lancet · doi:10.1016/s0140-6736(09)61457-4 · Cited by 3,020 · see citing works
Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial
Chiasson, J.-L., Josse, R. G., Gomis, R., Hanefeld, M., Karasik, A., & Laakso, M. (2002) · The Lancet · doi:10.1016/s0140-6736(02)08905-5 · Cited by 2,543 · see citing works
Discrete Sequential Boundaries for Clinical Trials
Lan, K. K. G., & DeMets, D. L. (1983) · Biometrika · doi:10.2307/2336502 · Cited by 2,310 · see citing works
Discrete sequential boundaries for clinical trials
GORDON LAN, K. K., & DEMETS, D. L. (1983) · Biometrika · doi:10.1093/biomet/70.3.659 · Cited by 2,310 · see citing works
Chiasson, J.-L., Josse, R. G., Gomis, R., Hanefeld, M., Karasik, A., Laakso, M., & for The STOP-NIDDM Trial Research Group (2003) · JAMA · doi:10.1001/jama.290.4.486 · Cited by 1,624 · see citing works
Impaired Fasting Glucose and Impaired Glucose Tolerance
Nathan, D. M., Davidson, M. B., DeFronzo, R. A., Heine, R. J., Henry, R. R., Pratley, R., & Zinman, B. (2007) · Diabetes Care · doi:10.2337/dc07-9920 · Cited by 1,396 · see citing works
(1999) · The Lancet · doi:10.1016/s0140-6736(98)12131-1 · Cited by 1,313 · see citing works
Intensive glucose control and macrovascular outcomes in type 2 diabetes
Turnbull, F. M., Abraira, C., Anderson, R. J., Byington, R. P., Chalmers, J. P., Duckworth, W. C., Evans, G. W., Gerstein, H. C., Holman, R. R., Moritz, T. E., et al. (2009) · Diabetologia · doi:10.1007/s00125-009-1470-0 · Cited by 1,189 · see citing works
Edelstein, S. L., Knowler, W. C., Bain, R. P., Andres, R., Barrett-Connor, E. L., Dowse, G. K., Haffher, S. M., Pettitt, D. J., Sorkin, J. D., Muller, D. C., et al. (1997) · Diabetes · doi:10.2337/diab.46.4.701 · Cited by 641 · see citing works
Edelstein, S. L., Knowler, W. C., Bain, R. P., Andres, R., Barrett-Connor, E. L., Dowse, G. K., Haffner, S. M., Pettitt, D. J., Sorkin, J. D., Muller, D. C., et al. (1997) · Diabetes · doi:10.2337/diabetes.46.4.701 · Cited by 641 · see citing works
Sartor, G., Scherstén, B., Carlström, S., Melander, A., Nordén, Å., & Persson, G. (1980) · Diabetes · doi:10.2337/diab.29.1.41 · Cited by 285 · see citing works
Murthy, K. K., Stevens, L. A., Stark, P. C., et al. (2005) · Kidney International · doi:10.1111/j.1523-1755.2005.00608.x · Cited by 144 · see citing works
Kahn, S. E., Montgomery, B. K., Howell, W., Ligueros‐Saylan, M., Hsu, C., Devineni, D., McLeod, J. F., Horowitz, A. D., & Foley, J. E. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.12.8105 · Cited by 105 · see citing works
Califf, R. M., Boolell, M., Haffner, S. M., Bethel, M. A., McMurray, J. J. V., Duggal, A., & Holman, R. R. (2008) · American Heart Journal · doi:10.1016/j.ahj.2008.05.017 · Cited by 99 · see citing works
Sartor, G., Scherstén, B., Carlström, S., et al. (1980) · Diabetes · doi:10.2337/diabetes.29.1.41 · Cited by 87 · see citing works
Determining the most appropriate components for a composite clinical trial outcome
Bethel, M. A., Holman, R. R., Haffner, S. M., Califf, R. M., Huntsman-Labed, A., Hua, T. A., & McMurray, J. J. V. (2008) · American Heart Journal · doi:10.1016/j.ahj.2008.05.018 · Cited by 39 · see citing works
Karunakara, S., Hammersley, M. S., Morris, R. J., Turner, R. C., & Holman, R. R. (1997) · Metabolism · doi:10.1016/s0026-0495(97)90319-x · Cited by 33 · see citing works
Saloranta, C., Guitard, C., Pecher, E., de Pablos-Velasco, P. L., Lahti, K., Brunel, P., & Groop, L. (2002) · Diabetes Care · doi:10.2337/diacare.25.12.2141 · Cited by 31 · see citing works
Califf, R. M., Boolell, M., & Sandström, H. (2008) · Cited by 20 · see citing works
Uto, Y., Teno, S., Iwamoto, Y., et al. (2002) · Metabolism · doi:10.1053/meta.2002.29008 · Cited by 13 · see citing works
Alberti (1998) · doi:10.1002/(sici)1096-9136(199807)15:7
Flagged first, then by citations
Research works printed but not linked: 1
- Uto Y, Teno S, Iwamoto Y, Omori Y, 26. Takizawa T. Improvement of glucose tol- erance by nateglinide occurs through en- hancement of early phase insulin secre- tion. Metabolism 2002;51:20-4. Guidance for industry: diabetes mel- 27. litus -evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Washington, DC: Department of Health and Human Services, December 2008. (Accessed March 9, 2010, at http:// www.fda.gov/downloads/Drugs/Guidance ComplianceRegulatoryInformation/ Guidances/ucm071627.pdf.)
Cited by
Sorted by citations
Prediabetes: a high-risk state for diabetes development
Tabák, A. G., Herder, C., Rathmann, W., Brunner, E. J., & Kivimäki, M. (2012) · The Lancet · doi:10.1016/s0140-6736(12)60283-9 · Cited by 2,958 · see citing works
Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future
Kahn, S. E., Cooper, M. E., & Del Prato, S. (2014) · The Lancet · doi:10.1016/s0140-6736(13)62154-6 · Cited by 1,743 · see citing works
2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes.
Marx, N., Federici, M., Schütt, K., Müller-Wieland, D., Ajjan, R. A., Antunes, M. J., Christodorescu, R. M., Crawford, C., Di Angelantonio, E., Eliasson, B., et al. (2023) · European Heart Journal · doi:10.1093/eurheartj/ehad192 · Cited by 1,642 · see citing works
Boussageon, R., Bejan-Angoulvant, T., Saadatian-Elahi, M., Lafont, S., Bergeonneau, C., Kassai, B., Erpeldinger, S., Wright, J. M., Gueyffier, F., & Cornu, C. (2011) · BMJ · doi:10.1136/bmj.d4169 · Cited by 803 · see citing works
Effect of valsartan on the incidence of diabetes and cardiovascular events
(2010) · New England Journal of Medicine · doi:10.1056/nejmoa1001121 · Cited by 660 · see citing works
Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus
Tahrani, A. A., Barnett, A. H., & Bailey, C. J. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.86 · Cited by 398 · see citing works
Siu, A. L., & on behalf of the U.S. Preventive Services Task Force* (2015) · Annals of Internal Medicine · doi:10.7326/m15-2345 · Cited by 319 · see citing works
Holman, R. R., Coleman, R. L., Chan, J. C. N., Chiasson, J.-L., Feng, H., Ge, J., Gerstein, H. C., Gray, R., Huo, Y., Lang, Z., et al. (2017) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(17)30309-1 · Cited by 323 · see citing works
Cavalot, F., Pagliarino, A., Valle, M., Di Martino, L., Bonomo, K., Massucco, P., Anfossi, G., & Trovati, M. (2011) · Diabetes Care · doi:10.2337/dc10-2414 · Cited by 322 · see citing works
Prediabetes and Cardiovascular Disease
Brannick, B., & Dagogo-Jack, S. (2018) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2017.10.001 · Cited by 293 · see citing works
Udell, J. A., Cavender, M. A., Bhatt, D. L., Chatterjee, S., Farkouh, M. E., & Scirica, B. M. (2015) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(15)00044-3 · Cited by 254 · see citing works
Yates, T., Haffner, S. M., Schulte, P. J., Thomas, L., Huffman, K. M., Bales, C. W., Califf, R. M., Holman, R. R., McMurray, J. J. V., Bethel, M. A., et al. (2014) · The Lancet · doi:10.1016/s0140-6736(13)62061-9 · Cited by 238 · see citing works
Bunck, M. C., Cornér, A., Eliasson, B., Heine, R. J., Shaginian, R. M., Taskinen, M.-R., Smith, U., Yki-Järvinen, H., & Diamant, M. (2011) · Diabetes Care · doi:10.2337/dc11-0291 · Cited by 240 · see citing works
Zinman, B., Harris, S. B., Neuman, J., Gerstein, H. C., Retnakaran, R. R., Raboud, J., Qi, Y., & Hanley, A. J. (2010) · The Lancet · doi:10.1016/s0140-6736(10)60746-5 · Cited by 235 · see citing works
Daily physical activity and type 2 diabetes: A review
Hamasaki, H. (2016) · World Journal of Diabetes · doi:10.4239/wjd.v7.i12.243 · Cited by 228 · see citing works
Phenotypes of prediabetes and stratification of cardiometabolic risk
Stefan, N., Fritsche, A., Schick, F., & Häring, H.-U. (2016) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(16)00082-6 · Cited by 208 · see citing works
Postprandial Hyperglycemia and Glycemic Variability
Standl, E., Schnell, O., & Ceriello, A. (2011) · Diabetes Care · doi:10.2337/dc11-s206 · Cited by 183 · see citing works
Sarwar, N., Aspelund, T., Eiriksdottir, G., Gobin, R., Seshasai, S. R. K., Forouhi, N. G., Sigurdsson, G., Danesh, J., & Gudnason, V. (2010) · PLoS Medicine · doi:10.1371/journal.pmed.1000278 · Cited by 175 · see citing works
Hopper, I., Billah, B., Skiba, M., & Krum, H. (2011) · European Journal of Cardiovascular Prevention & Rehabilitation · doi:10.1177/1741826711421687 · Cited by 149 · see citing works
Diagnosis and Treatment of Type 2 Diabetes in Adults
Kalyani, R. R., Neumiller, J. J., Maruthur, N. M., & Wexler, D. J. (2025) · JAMA · doi:10.1001/jama.2025.5956 · Cited by 145 · see citing works
Selph, S., Dana, T., Blazina, I., Bougatsos, C., Patel, H., & Chou, R. (2015) · Annals of Internal Medicine · doi:10.7326/m14-2221 · Cited by 134 · see citing works
Jonas, D. E., Crotty, K., Yun, J. D. Y., Middleton, J. C., Feltner, C., Taylor-Phillips, S., Barclay, C., Dotson, A., Baker, C., Balio, C. P., et al. (2021) · JAMA · doi:10.1001/jama.2021.10403 · Cited by 96 · see citing works
Emerging treatments for post-transplantation diabetes mellitus
Jenssen, T., & Hartmann, A. (2015) · Nature Reviews Nephrology · doi:10.1038/nrneph.2015.59 · Cited by 90 · see citing works
Does diabetes prevention translate into reduced long-term vascular complications of diabetes?
and the DPP Research Group, Nathan, D. M., Bennett, P. H., Crandall, J. P., Edelstein, S. L., Goldberg, R. B., Kahn, S. E., Knowler, W. C., Mather, K. J., Mudaliar, S., et al. (2019) · Diabetologia · doi:10.1007/s00125-019-4928-8 · Cited by 91 · see citing works
Ramirez, C. E., Nian, H., Yu, C., Gamboa, J. L., Luther, J. M., Brown, N. J., & Shibao, C. A. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-3415 · Cited by 76 · see citing works
Al-Salameh, A., Chanson, P., Bucher, S., Ringa, V., & Becquemont, L. (2019) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2018.08.007 · Cited by 77 · see citing works
Shi, W., Zhang, W., Zhang, D., Ren, G., Wang, P., Gao, L., Chen, H., & Ding, C. (2021) · Heart Rhythm · doi:10.1016/j.hrthm.2021.03.007 · Cited by 54 · see citing works
Kraus, W. E., Yates, T., Tuomilehto, J., Sun, J.-L., Thomas, L., McMurray, J. J. V., Bethel, M. A., & Holman, R. R. (2018) · BMJ Open Diabetes Research & Care · doi:10.1136/bmjdrc-2018-000523 · Cited by 59 · see citing works
Yandrapalli, S., Jolly, G., Horblitt, A., Sanaani, A., & Aronow, W. S. (2017) · Postgraduate Medicine · doi:10.1080/00325481.2017.1358064 · Cited by 50 · see citing works
Huffman, K. M., Sun, J.-L., Thomas, L., Bales, C. W., Califf, R. M., Yates, T., Davies, M. J., Holman, R. R., McMurray, J. J. V., Bethel, M. A., et al. (2014) · Metabolism · doi:10.1016/j.metabol.2014.01.002 · Cited by 45 · see citing works
The prevention of diabetes and cardiovascular disease in people with schizophrenia
Holt, R. I. G. (2015) · Acta Psychiatrica Scandinavica · doi:10.1111/acps.12443 · Cited by 37 · see citing works
Updated risk factors should be used to predict development of diabetes
Bethel, M. A., Hyland, K. A., Chacra, A. R., Deedwania, P., Fulcher, G. R., Holman, R. R., Jenssen, T., Levitt, N. S., McMurray, J. J. V., Boutati, E., et al. (2017) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2017.02.012 · Cited by 12 · see citing works
McManus, E. (2024) · PharmacoEconomics - Open · doi:10.1007/s41669-024-00487-6 · Cited by 10 · see citing works
- Authors
- The NAVIGATOR Study Group
- Affiliations
- University of Oxford (GB)
- Corresponding author
- The NAVIGATOR Study Group
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2010-04-22
- Volume
- 362
- Issue
- 16
- Pages
- 1463-1476
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W1855278889
- Cited by
- 477
- References
- 28
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 11 · 2023: 18 · 2022: 14 · 2021: 22 · 2020: 27 · 2019: 21 · 2018: 37 · 2017: 35 · 2016: 23 · 2015: 38 · 2014: 42 · 2013: 44 · 2012: 43
- FWCI
- 41.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- BORIS (University Library Bern) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Leicester Research Archive (University of Leicester) (submittedVersion)
- ORBi (University of Liège) (submittedVersion, other-oa)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- UNIFESP Institutional Repository (Universidade Federal de São Paulo) (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs
- Universitetet i Tromsø
- University of Washington
- Tulane University
- Joslin Diabetes Center
- University of Bern
- University College Cork
- Monash University
- Semmelweis Egyetem
- Gentofte Hospital
- Technische Universität Dresden
- University of Toronto
- Kuopion Yliopistollinen Sairaala
- Universidad de Buenos Aires
- Universidade de São Paulo
- National Taiwan University Hospital
- National Taiwan University
- University of Cape Town
- Lomonosov Moscow State University
- University of Illinois at Urbana-Champaign
- Duke Clinical Research Institute
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Keywords
- nateglinide, impaired glucose tolerance, insulin secretagogues, type 2 diabetes prevention, cardiovascular events, valsartan, hypoglycemia, lifestyle modification, cardiovascular risk factors, myocardial infarction, stroke, heart failure hospitalization
- MeSH terms
- Valsartan, Nateglinide, Blood Glucose, Body Weight, Cardiovascular Diseases, Cyclohexanes, Diabetes Mellitus, Type 2, Double-Blind Method, Drug Therapy, Combination, Female, Follow-Up Studies, Humans, Hypoglycemic Agents, Male, Middle Aged, Phenylalanine, Risk Factors, Tetrazoles, Valine, Exercise, Incidence, Proportional Hazards Models, Treatment Failure, Glucose Intolerance, Angiotensin II Type 1 Receptor Blockers, Kaplan-Meier Estimate
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
