Use of FGF21 analogs for the treatment of metabolic disorders: a systematic review and meta-analysis

Carbonetti, Maria Paula; Almeida-Oliveira, Fernanda; Majerowicz, David

doi:10.20945/2359-4292-2022-0493

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Review • Arch. Endocrinol. Metab. 68 • 2024 • https://doi.org/10.20945/2359-4292-2022-0493 copy

Use of FGF21 analogs for the treatment of metabolic disorders: a systematic review and meta-analysis

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

FGF21 is a hormone produced primarily by the liver with several metabolic functions, such as induction of heat production, control of glucose homeostasis, and regulation of blood lipid levels. Due to these actions, several laboratories have developed FGF21 analogs to treat patients with metabolic disorders such as obesity and diabetes. Here, we performed a systematic review and meta-analysis of randomized controlled trials that used FGF21 analogs and analyzed metabolic outcomes. Our search yielded 236 articles, and we included eight randomized clinical trials in the meta-analysis. The use of FGF21 analogs exhibited no effect on fasting blood glucose, glycated hemoglobin, HOMA index, blood free fatty acids or systolic blood pressure. However, the treatment significantly reduced fasting insulinemia, body weight and total cholesterolemia. None of the included studies were at high risk of bias. The quality of the evidence ranged from moderate to very low, especially due to imprecision and indirection issues. These results indicate that FGF21 analogs can potentially treat metabolic syndrome. However, more clinical trials are needed to increase the quality of evidence and confirm the effects seen thus far.

Keywords
FGF21; blood glucose; metabolic syndrome; glycated hemoglobin A; fasting; blood pressure; obesity; lipids

Section and Topic	Item #	Checklist item	Location where item is reported
TITLE
Title	1	Identify the report as a systematic review.	Page 1
ABSTRACT
Abstract	2	See the PRISMA 2020 for Abstracts checklist.	Page 1
INTRODUCTION
Rationale	3	Describe the rationale for the review in the context of existing knowledge.	Pages 1 and 2
Objectives	4	Provide an explicit statement of the objective(s) or question(s) the review addresses.	Page 2
METHODS
Eligibility criteria	5	Specify the inclusion and exclusion criteria for the review and how studies were grouped for the syntheses.	Page 3
Information sources	6	Specify all databases, registers, websites, organizations, reference lists and other sources searched or consulted to identify studies. Specify the date when each source was last searched or consulted.	Page 3
Search strategy	7	Present the full search strategies for all databases, registers and websites, including any filters and limits used.	Page 3
Selection process	8	Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.	Page 3
Data collection process	9	Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.	Page 3
Data items	10a	List and define all outcomes for which data were sought. Specify whether all results that were compatible with each outcome domain in each study were sought (e.g., for all measures, time points, analyses), and if not, the methods used to decide which results to collect.	Page 3
Data items	10b	List and define all other variables for which data were sought (e.g., participant and intervention characteristics, funding sources). Describe any assumptions made about any missing or unclear information.	Page 3
Study risk of bias assessment	11	Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.	Page 3
Effect measures	12	Specify for each outcome the effect measure(s) (e.g., risk ratio, mean difference) used in the synthesis or presentation of results.	Page 3
Synthesis methods	13a	Describe the processes used to decide which studies were eligible for each synthesis (e.g., tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).	Page 3
	13b	Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics or data conversions.	Page 3
	13c	Describe any methods used to tabulate or visually display results of individual studies and syntheses.	Page 3
	13d	Describe any methods used to synthesize results and provide a rationale for the choice(s). If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.	Page 3
	13e	Describe any methods used to explore possible causes of heterogeneity among study results (e.g., subgroup analysis, meta-regression).	Page 3
	13f	Describe any sensitivity analyses conducted to assess robustness of the synthesized results.	Page 3
Reporting bias assessment	14	Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).	Page 3
Certainty assessment	15	Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome.	Page 3
RESULTS
Study selection	16a	Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.	Fig. S1
Study selection	16b	Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.	Page 3
Study characteristics	17	Cite each included study and present its characteristics.	Table S2
Risk of bias in studies	18	Present assessments of risk of bias for each included study.	Fig. S2
Results of individual studies	19	For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g., confidence/credible interval), ideally using structured tables or plots.	Pages 5 and 8
Results of syntheses	20a	For each synthesis, briefly summarize the characteristics and risk of bias among contributing studies.	Pages 5 and 8
	20b	Present results of all statistical syntheses conducted. If meta-analysis was performed, present for each the summary estimate and its precision (e.g., confidence/credible interval) and measures of statistical heterogeneity. If comparing groups, describe the direction of the effect.	Pages 5 and 8
	20c	Present results of all investigations of possible causes of heterogeneity among study results.	Pages 5 and 8
	20d	Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results.	Pages 5 and 8
Reporting biases	21	Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed.	Fig. S2
Certainty of evidence	22	Present assessments of certainty (or confidence) in the body of evidence for each outcome assessed.	Table 1
DISCUSSION
Discussion	23a	Provide a general interpretation of the results in the context of other evidence.	Pages 9, 10, and 12
	23b	Discuss any limitations of the evidence included in the review.	Page 12
	23c	Discuss any limitations of the review processes used.	Page 12
	23d	Discuss implications of the results for practice, policy, and future research.	Page 12
OTHER INFORMATION
Registration and protocol	24a	Provide registration information for the review, including register name and registration number, or state that the review was not registered.	Page 12
	24b	Indicate where the review protocol can be accessed, or state that a protocol was not prepared.	Page 12
	24c	Describe and explain any amendments to information provided at registration or in the protocol.	Page 12
Support	25	Describe sources of financial or nonfinancial support for the review, and the role of the funders or sponsors in the review.	Page 12
Competing interests	26	Declare any competing interests of review authors.	Page 12
Availability of data, code and other materials	27	Report which of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review.	Page 12

Study	Sample size	Age (years)	Male (%)	White (%)	BMI (kg/m²)	Fasting glucose (mg/dL)	HbA1c (%)	Total cholesterol (mg/dL)	Systolic blood pressure (mmHg)	Fasting FFA (μmol/L)	Status of participants	Intervention
Gaich and cols., 2013	46	57.7	26 (57)	96	32.1	171.9	7.96	NA	NA	NA	Obesity and T2DM	Subcutaneous dose of LY2405319 (3, 10 or 20 mg) daily for 28 days
Dong and cols., 2015	84	55.5	60 (71)	92	30.4	173.4	8.60	NA	NA	NA	Overweight or obesity and T2DM	Single intravenous dose of PF-05231023 (0.5, 1.5, 5, 15, 50, 100 or 200 mg)
Talukdar and cols., 2016	50	55.7	39 (78)	90	29.7	168.0	8.18	NA	NA	NA	Overweight or obesity and T2DM	Intravenous dose of PF-05231023 (5, 25, 100 or 140 mg) twice weekly for four weeks
Kim and cols., 2017	107	53.4	76 (71)	89	34.0	NA	NA	153.8	121.6	NA	Obesity and hypertriglyceridemia (with or without T2DM)	Intravenous dose of PF-05231023 (25, 50, 100 or 150 mg) once weekly for four weeks
Charles and cols., 2019	96	56.0	53 (55)	76	35.0	151.0	7.80	NA	NA	NA	Obesity and T2DM	Subcutaneous dose of pegbelfermin (1, 5 or 20 mg daily, or 20 mg weekly) for 12 weeks
Kaufman and cols., 2020	69	55.5	39 (57)	NA	32.0	183.7	7.90	196.5	123.9	544.2	Overweight or obesity and T2DM	Subcutaneous dose of AKR-001 (7, 21, 70 or 140 mg) once weekly or once every two weeks twice for four weeks
Rader and cols., 2022	61	45.5	30 (49)	80	36.1	100.9	5.5	214.1	124.5	NA	Obesity and hypertriglyceridemia (with or without T2DM)	Subcutaneous dose of LLF580 (300 mg) every four weeks for 12 weeks
Loomba and cols., 2023	81	51.9	31 (38)	92	34.6	132.1	6.7	NA	NA	430.3	Overweight or obesity and NASH (with or without T2DM)	Subcutaneous dose of pegbelfermin (3, 9, 18 or 27 mg once weekly, or 18 or 36 mg once every two weeks) for 12 weeks

Outcomes	Number of participants (studies)	Quality of the evidence (GRADE)	Size effect (95% CI)
Fasting glucose	434 (7 studies)	Moderate, due to indirectness	−0.11 (−0.34 to 0.11)
Glycated hemoglobin	252 (3 studies)	Very low, due to indirectness, imprecision, and publication bias	−0.02 (−0.31 to 0.26)
Fasting insulin	368 (6 studies)	Very low, due to indirectness, imprecision, and publication bias	−0.30 (−0.55 to −0.05)
HOMA	319 (4 studies)	Very low, due to indirectness, imprecision, and publication bias	−0.02 (−0.27 to 0.24)
Body weight	342 (5 studies)	Very low, due to indirectness, imprecision, and publication bias	−0.29 (−0.55 to −0.04)
Systolic blood pressure	124 (2 studies)	Very low, due to indirectness, imprecision, and publication bias	0.36 (−0.02 to 0.74)
Total cholesterol	228 (4 studies)	Moderate, due to indirectness, imprecision, and size effect	−0.55 (−0.87 to −0.22)
Free fatty acids	60 (1 study)	Low, due to imprecision and publication bias	0.21 (−0.37 to 0.78)

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[1] Correspondence to: David Majerowicz majerowicz@pharma.ufrj.br