The DOI matches its Crossref record; 80 of the 82 references it cites were found in a registry or an index.
AKR-001, an Fc-FGF21 Analog, Showed Sustained Pharmacodynamic Effects on Insulin Sensitivity and Lipid Metabolism in Type 2 Diabetes Patients
Open accessAbstract
Experimental fibroblast growth factor 21 (FGF21) analogs can improve lipid profiles in patients with metabolic diseases. However, their effects on markers of insulin sensitivity appear to be minimal, potentially because of insufficient exposure. Systemic drug levels vary from sub-pharmacological to demonstrating pharmacodynamic effects but with dose-limiting adverse events. Here we report results from a phase 1 multiple ascending dose study of AKR-001, an Fc-FGF21 fusion protein engineered for sustained systemic pharmacologic exposure, in individuals with type 2 diabetes. With a half-life of 3-3.5 days, the peak-to-trough ratio under steady-state conditions is approximately 2 following QW dosing. AKR-001 appears to demonstrate pharmacodynamic effects on serum markers of insulin sensitivity and acceptable tolerability up to and including 70 mg QW. Positive trends in lipoprotein profile, including triglycerides, non-high-density lipoprotein (non-HDL) cholesterol, HDL-C, and apolipoproteins B and C3 are consistent with other FGF21 analogs. AKR-001's clinical profile supports further evaluation as a treatment for metabolic diseases.
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“Administration of the FGF21 analogues AKR-001 (ref. 88) and pegbelfermin89 in humans with NASH results in marked absolute decreases in liver fat (up to 70%) and significant amelioration of liver fibrosis88,89.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [88]
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“two other FGF21 analogues, AKR-001 (also known as efruxifermin)88 and pegbelfermin89,90, have not been found to significantly decrease body weight in people with obesity or type 2 diabetes.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [88]
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“most adverse effects associated with FGF21-analogue administration are gastrointestinal81,87,88.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [88]
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In the citing paper
“PF-05231023 has been found to increase markers of bone turnover in humans81, whereas AKR-001 (ref. 88) and pegbelfermin89 have not.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [88]
Experimental — accuracy not yet measuredIn the citing paper
“all analogues consistently have a pronounced ability to decrease plasma triglyceride levels, in many cases by as much as ~70% (refs. 81,87–91).”
From Metabolic messengers: FGF21 (2021) · cites this paper as [88]
In the citing paper
“some compounds do not significantly affect insulin sensitivity81, while others significantly increase insulin sensitivity in people with type 2 diabetes87,88.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [88]
In the citing paper
“the magnitude of the glucose-lowering effects of FGF21 analogues is clearly lower in humans than rodents81,87–91, perhaps because of differences in brown adipose tissue metabolism between species65.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [88]
In the citing paper
“Pharmacological administration of FGF21 or FGF21 analogues exerts lipid-lowering effects through accelerated lipoprotein catabolism108, suppression of postprandial lipolysis in adipose tissues88, decreased hepatic endoplasmic reticulum and oxidative stress109,110, and increased beta-oxidation of lipids in the liver62”
From Metabolic messengers: FGF21 (2021) · cites this paper as [88]
In the citing paper
“clinical studies in patients with obesity and type 2 diabetes have found that FGF21-analogue administration markedly induces plasma adiponectin levels81,87–89”
From Metabolic messengers: FGF21 (2021) · cites this paper as [88]
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Cites
Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes
Marso, S. P., Daniels, G. H., Brown-Frandsen, K., Kristensen, P., Mann, J. F. E., Nauck, M. A., Nissen, S. E., Pocock, S., Poulter, N. R., Ravn, L. S., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1603827 · Cited by 7,629
Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention
Younossi, Z., Anstee, Q. M., Marietti, M., Hardy, T., Henry, L., Eslam, M., George, J., & Bugianesi, E. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2017.109 · Cited by 5,249
Donnelly, K. L., Smith, C. I., Schwarzenberg, S. J., Jessurun, J., Boldt, M. D., & Parks, E. J. (2005) · Journal of Clinical Investigation · doi:10.1172/jci23621 · Cited by 3,604
AIC model selection using Akaike weights
Wagenmakers, E.-J., & Farrell, S. (2004) · Psychonomic Bulletin & Review · doi:10.3758/bf03206482 · Cited by 2,684
Neuschwander-Tetri, B. A., Loomba, R., Sanyal, A. J., Lavine, J. E., Van Natta, M. L., Abdelmalek, M. F., Chalasani, N., Dasarathy, S., Diehl, A. M., Hameed, B., et al. (2015) · The Lancet · doi:10.1016/s0140-6736(14)61933-4 · Cited by 2,237
Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease
Ipsen, D. H., Lykkesfeldt, J., & Tveden-Nyborg, P. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2860-6 · Cited by 1,471
Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis
Diehl, A. M., & Day, C. (2017) · New England Journal of Medicine · doi:10.1056/nejmra1503519 · Cited by 1,283
Adiponectin, a Therapeutic Target for Obesity, Diabetes, and Endothelial Dysfunction
Elumalai, A., & Jain, S. K. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18061321 · Cited by 1,206
Xu, J., Lloyd, D. J., Hale, C., Stanislaus, S., Chen, M., Sivits, G., Vonderfecht, S., Hecht, R., Li, Y.-S., Lindberg, R. A., et al. (2009) · Diabetes · doi:10.2337/db08-0392 · Cited by 1,151
Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease
The TG and HDL Working Group of the Exome Sequencing Project, N. H. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1307095 · Cited by 1,071
Research works printed but not linked: 1
- Charles, 2016, A phase 1 study of BMS-986036 (pegylated FGF21) in healthy obese subjects, Hepatology, 64, 546A
Cited by
Sorted by citations
Harrison, S. A., Ruane, P. J., Freilich, B. L., Neff, G., Patil, R., Behling, C. A., Hu, C., Fong, E., de Temple, B., Tillman, E. J., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01425-3 · Cited by 368
Self-citationFlippo, K. H., & Potthoff, M. J. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00354-2 · Cited by 311
Treatment of type 2 diabetes: challenges, hopes, and anticipated successes
Nauck, M. A., Wefers, J., & Meier, J. J. (2021) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(21)00113-3 · Cited by 315
Harrison, S. A., Frias, J. P., Neff, G., Abrams, G. A., Lucas, K. J., Sanchez, W., Gogia, S., Sheikh, M. Y., Behling, C., Bedossa, P., et al. (2023) · The Lancet Gastroenterology & Hepatology · doi:10.1016/s2468-1253(23)00272-8 · Cited by 276
Self-citationAn adipocentric perspective on the development and progression of non-alcoholic fatty liver disease
Lee, E., Korf, H., & Vidal‐Puig, A. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2023.01.024 · Cited by 235
Metadata
- Authors
- Kaufman, A., Abuqayyas, L., Denney, W. S., Tillman, E. J., & Rolph, T.
- Affiliations
- Amgen (United States) (US)
- Corresponding author
- Rolph, Tim
- Venue
- Cell Reports Medicine
- Publisher
- Elsevier BV
- Published
- 2020-07
- Volume
- 1
- Issue
- 4
- Pages
- 100057
- ISSN
- 2666-3791 (ISSN-L)
- PMC
- PMC7659583
- OpenAlex
- W3044370932
- Cited by
- 131
- References
- 82
- Citations by year
- 2026: 12 · 2025: 24 · 2024: 25 · 2023: 21 · 2022: 26 · 2021: 19 · 2020: 4
- FWCI
- 5.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports Medicine (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Pfizer
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- FGF21 analogs, type 2 diabetes, insulin sensitivity, lipid metabolism, pharmacodynamics, pharmacokinetics, lipoprotein profile, triglycerides, non-HDL cholesterol, apolipoprotein B, apolipoprotein C-III, tolerability
- MeSH terms
- Adult, Blood Glucose, Body Weight, Diabetes Mellitus, Type 2, Double-Blind Method, Female, Fibroblast Growth Factors, Humans, Insulin, Insulin Resistance, Lipids, Male, Middle Aged, Obesity, Recombinant Fusion Proteins, Triglycerides, United States, Placebo Effect, Lipid Metabolism
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