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Cited by 132Diabetes Treatment and ManagementDiabetes, Cardiovascular Risks, and LipoproteinsMetabolism, Diabetes, and Cancer

Long-term effects of metformin on diabetes prevention: identification of subgroups that benefited most in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study

Open access
Diabetes Prevention Program Research Group, Nathan, David M., Knowler, William C., Edelstein, Sharon, Crandall, Jill P., Dabelea, Dana, Goldberg, Ronald B., Kahn, Steven E. +279 more·2019·Diabetes Care
DOI 10.2337/dc18-1970PMC PMC6429636
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Abstract

OBJECTIVE: We examined the effects of metformin on diabetes prevention and the subgroups that benefited most over 15 years in the Diabetes Prevention Program (DPP) and its follow-up, the Diabetes Prevention Program Outcomes Study (DPPOS). RESEARCH DESIGN AND METHODS: During the DPP (1996–2001), adults at high risk of developing diabetes were randomly assigned to masked placebo (n = 1,082) or metformin 850 mg twice daily (n = 1,073). Participants originally assigned to metformin continued to receive metformin, unmasked, in the DPPOS (2002–present). Ascertainment of diabetes development was based on fasting or 2-h glucose levels after an oral glucose tolerance test or on HbA1c. Reduction in diabetes incidence with metformin was compared with placebo in subgroups by hazard ratio (HR) and rate differences (RDs). RESULTS: During 15 years of postrandomization follow-up, metformin reduced the incidence (by HR) of diabetes compared to placebo by 17% or 36% based on glucose or HbA1c levels, respectively. Metformin’s effect on the development of glucose-defined diabetes was greater for women with a history of prior gestational diabetes mellitus (GDM) (HR 0.59, RD −4.57 cases/100 person-years) compared with parous women without GDM (HR 0.94, RD −0.38 cases/100 person-years [interaction P = 0.03 for HR, P = 0.01 for RD]). Metformin also had greater effects, by HR and RD, at higher baseline fasting glucose levels. With diabetes development based on HbA1c, metformin was more effective in subjects with higher baseline HbA1c by RD, with metformin RD −1.03 cases/100 person-years with baseline HbA1c <6.0% (42 mmol/mol) and −3.88 cases/100 person-years with 6.0–6.4% (P = 0.0001). CONCLUSIONS: Metformin reduces the development of diabetes over 15 years. The subsets that benefitted the most include subjects with higher baseline fasting glucose or HbA1c and women with a history of GDM.

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  • There is strong evidence that oral glucose-lowering medications approved for diabetes reduce progression from prediabetes to diabetes.

    “There is strong evidence that oral glucose-lowering medications approved for DM reduce the progression of prediabetes to DM.888–896”

    From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [892]

    The Abstract reports that metformin reduced diabetes incidence compared with placebo over 15 years in adults at high risk of diabetes, and the Conclusions say its preventive effect persisted in this cohort. The paper addresses metformin, not oral glucose-lowering medications as a class, so it supports the claim for one medication but not the broader plural claim. The supplied passages have section labels but no page numbers. (LLM, conf=0.88)

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  • Acarbose may be associated with reduced risk of diabetes and coronary heart disease as shown in the STOP-NIDDM trial.

    “Additionally, acarbose may be associated with reduced risk of DM891–894 as well as coronary heart disease as shown in the STOP-NIDDM trial.892”

    From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [892]

    The Results passage reports reduced diabetes incidence with metformin, not acarbose. Searches of our copy for acarbose, STOP-NIDDM, and coronary heart disease found no passage addressing the claimed effects of acarbose in that trial. (LLM, conf=0.76)

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  • In a large randomized controlled trial of Chinese participants with coronary heart disease and impaired glucose tolerance, acarbose did not reduce major adverse cardiovascular events but did reduce the incidence of diabetes.

    “However, in a large RCT1058 of Chinese participants with coronary heart disease and IGT, acarbose did not reduce the risk of MACE, but did reduce the incidence of DM.891,892”

    From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [892]

    The Participants and Procedures section describes a trial comparing metformin, placebo, and lifestyle intervention in people at high risk of diabetes. Searches for acarbose and the claimed Chinese coronary-heart-disease trial found no passage addressing its cardiovascular or diabetes outcomes. The cited paper therefore does not verify the attributed claim. (LLM, conf=0.77)

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Research works printed but not linked: 1

  1. [10]10. Lachin JM. Biostatistical Methods: The As- sessment of Relative Risks, 2nd Edition. New York, John Wiley, 2000, p. 83-87

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Authors
Diabetes Prevention Program Research Group, Nathan, D. M., Knowler, W. C., Edelstein, S., Crandall, J. P., Dabelea, D., Goldberg, R. B., Kahn, S. E., Mather, K. J., Trandafirescu, G., Walker, E. A., Temprosa, M., Bray, G. A., Gadde, K., Chatellier, A., Arceneaux, J., Dragg, A., Duncan, C., Greenway, F. L., Hsia, D., Levy, E., Lockett, M., Ryan, D. H., Ehrmann, D., Matulik, M. J., Czech, K., DeSandre, C., Goldstein, B. J., Furlong, K., Smith, K. A., Wildman, W., Pepe, C., Calles, J., Ojito, J., Castillo-Florez, S., Giannella, A., Lara, O., Veciana, B., Haffner, S. M., Hazuda, H. P., Montez, M. G., Hattaway, K., Lorenzo, C., Martinez, A., Walker, T., Hamman, R. F., Testaverde, L., Anderson, D., Bouffard, A., Jenkins, T., Lenz, D., Perreault, L., Price, D. W., Steinke, S. C., Horton, E. S., Poirier, C. S., Swift, K., Caballero, E., Fargnoli, B., Guidi, A., Guido, M., Jackson, S. D., Lambert, L., Lawton, K. E., Ledbury, S., Sansoucy, J., Spellman, J., Montgomery, B. K., Fujimoto, W., Knopp, R. H., Lipkin, E. W., Morgan-Taggart, I., Murillo, A., Taylor, L., Thomas, A., Tsai, E. C., Trence, D., Kitabchi, A. E., Dagogo-Jack, S., Murphy, M. E., Taylor, L., Dolgoff, J., Clark, D., Ibebuogu, U., Lambeth, H., Ricks, H., Rutledge, L. M. K., Soberman, J. E., Molitch, M. E., Metzger, B. E., Johnson, M. K., Giles, M. M., Larsen, D., Pen, S. C., Larkin, M., McKitrick, C., Turgeon, H., Anderson, E., Bissett, L., Bondi, K., Cagliero, E., D’Anna, K., Delahanty, L., Florez, J. C., Goldman, V., Lou, P., Poulos, A., Raymond, E., Stevens, C., Tsent, B., Barrett-Connor, E., Carrion-Petersen, M. L., Claravall, L. N., Dowden, J. M., Horne, J., Leos, D., Mudaliar, S., Smith, J., Szerdi Janisch, S., Vejvoda, K., Pi-Sunyer, F. X., Lee, J. E., Foo, S. T., Hagamen, S., Marrero, D. G., Kelly, S. M., Putenney, P., Jackson, M. A., McAtee, G., Ackermann, R. T., Cantrell, C. M., Fineberg, E. S., Hadden, A., Kirkman, M. S., O’Kelly Phillips, E., Roach, P. J., Ratner, R. E., Aroda, V., Shapiro, S., Bavido-Arrage, C., Gibbs, P., Uwaifo, G., Wiggins, R., Saad, M. F., Watson, K., Botrous, M., Jinagouda, S., Budget, M., Conzues, C., Magpuri, P., Ngo, K., Xapthalamous, K., White, N. H., Brown, A. L., Das, S., Khare-Ranade, P., Stich, T., Santiago, A., Wernimont, C., Saudek, C. D., Hill Golden, S., Whittington, T., Brancati, F. L., Clark, J. M., Greene, A., Jiggetts, D., Mosley, H., Reusing, J., Rubin, R. R., Stephens, S., Utsey, E., Shade, D. S., Adams, K. S., Hemphill, C., Hyde, P., Canady, J. L., Colleran, K., Gonzeles, Y., Hernandez-McGinnis, D. A., King, C., Crandall, J., Brown, J. O., Adorno, E., Duffy, H., Goldstein, A., Lukin, J., Martinez, H., Pompi, D., Shamoon, H., Scheindlin, J., Wylie-Rosett, J., Orchard, T., Kriska, A., Jeffries, S., Kramer, M. K., Smith, M., Benchoff, C., Guimond, S., Pettigrew, J., Rubinstein, D., Semler, L., Venditti, E., Weinzierl, V., Arakaki, R. F., Baker-Ladao, N. K., Isonaga, M. K., Bermudez, N. E., Mau, M. K., Melish, J. S., Yamamoto, R. E., Cooeyate, N., Enote, A., Hoskin, M. A., Natewa, C., Percy, C. A., Acton, K. J., Andre, V. L., Barber, R., Begay, S., Bucca, B. C., Cook, S., Curtis, J., Dodge, C., Doughty, M. S., Kurland, J., Glass, J., Glass, M., Hanson, R. L., Ingraham, L. E., Kobus, K. M., Krakoff, J., Manus, C., McCabe, C., Michaels, S., Morgan, T., Nelson, J. A., Piromalli, C., Roy, R. J., Sangster, S., Smart, M., Tonemah, D. P., Williams, R., Wilson, C., Fowler, S., Larsen, M., Brenneman, T., Sherif, H., Abebe, S., Bamdad, J., Barkalow, M., Bethepu, J., Bezebeh, T., Butler, N., Callaghan, J., Carter, C. E., Christophi, C., Dwyer, G. M., Foulkes, M., Gao, Y., Gooding, R., Gottlieb, A., Grover, N., Hoffman, H., Hogan, A. N., Jablonski, K., Katz, R., Kolinjivadi, P., Lachin, J. M., Ma, Y., Pan, Q., Reamer, S., Sapozhnikova, A., Venditti, E. M., Kriska, A. M., Semler, L., Weinzierl, V., Marcovina, S., Strylewicz, G., Albers, J., Fradkin, J., Garfield, S., Lee, C., Gregg, E., Zhang, P., Herman, W. H., Brändle, M., & Brown, M. B.
ORCID
Venue
Diabetes Care
Publisher
American Diabetes Association
Published
2019-03-11
Volume
42
Issue
4
Pages
601-608
ISSN
  • 0149-5992 (ISSN-L)
  • 1935-5548
DOI
10.2337/dc18-1970
PMC
PMC6429636
OpenAlex
W4251583039
Cited by
128
References
17
Citations by year
2026: 12 · 2025: 12 · 2024: 18 · 2023: 19 · 2022: 12 · 2021: 19 · 2020: 24 · 2019: 12
FWCI
13.60
Type
journal article
Language
en
Open access
Licence
www.diabetesjournals.org/content/license (vor, 9 d)
Locations
  • Diabetes Care (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (U01-DK-048489)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
metformin, type 2 diabetes prevention, gestational diabetes mellitus, subgroups, Diabetes Prevention Program, Diabetes Prevention Program Outcomes Study, fasting blood glucose, HbA1c, women, drug response variability, prediabetes, glucose tolerance test
MeSH terms
Adult, Diabetes Mellitus, Type 2, Fasting, Female, Glucose Tolerance Test, Humans, Hypoglycemic Agents, Metformin, Middle Aged, Pregnancy, Incidence, Diabetes, Gestational

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