Treatment effect heterogeneity following type 2 diabetes treatment with GLP1-receptor agonists and SGLT2-inhibitors: a systematic review

Katherine G. Young; Eram  Haider McInnes; Robert J. Massey; Anna R. Kahkoska; Scott J. Pilla; Sridharan Raghavan; Maggie A. Stanislawski; Deirdre K. Tobias; Andrew P. McGovern; Adem Y. Dawed; Angus G. Jones; Ewan R. Pearson; John M. Dennis

doi:10.1038/s43856-023-00359-w

Treatment effect heterogeneity following type 2 diabetes treatment with GLP1-receptor agonists and SGLT2-inhibitors: a systematic review

Katherine G. Young, Eram Haider McInnes, Robert J. Massey, Anna R. Kahkoska, Scott J. Pilla, Sridharan Raghavan, Maggie A. Stanislawski, Deirdre K. Tobias, Andrew P. McGovern, Adem Y. Dawed, Angus G. Jones, Ewan R. Pearson (Lead / Corresponding author), John M. Dennis (Lead / Corresponding author),

Population Health and Genomics

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Abstract

Background: A precision medicine approach in type 2 diabetes requires the identification of clinical and biological features that are reproducibly associated with differences in clinical outcomes with specific anti-hyperglycaemic therapies. Robust evidence of such treatment effect heterogeneity could support more individualized clinical decisions on optimal type 2 diabetes therapy.

Methods: We performed a pre-registered systematic review of meta-analysis studies, randomized control trials, and observational studies evaluating clinical and biological features associated with heterogenous treatment effects for SGLT2-inhibitor and GLP1-receptor agonist therapies, considering glycaemic, cardiovascular, and renal outcomes. After screening 5,686 studies, we included 101 studies of SGLT2-inhibitors and 75 studies of GLP1-receptor agonists in the final systematic review.

Results: Here we show that the majority of included papers have methodological limitations precluding robust assessment of treatment effect heterogeneity. For SGLT2-inhibitors, multiple observational studies suggest lower renal function as a predictor of lesser glycaemic response, while markers of reduced insulin secretion predict lesser glycaemic response with GLP1-receptor agonists. For both therapies, multiple post-hoc analyses of randomized control trials (including trial meta-analysis) identify minimal clinically relevant treatment effect heterogeneity for cardiovascular and renal outcomes.

Conclusions: Current evidence on treatment effect heterogeneity for SGLT2-inhibitor and GLP1-receptor agonist therapies is limited, likely reflecting the methodological limitations of published studies. Robust and appropriately powered studies are required to understand type 2 diabetes treatment effect heterogeneity and evaluate the potential for precision medicine to inform future clinical care.

Original language	English
Article number	131
Number of pages	20
Journal	Communications Medicine
Volume	3
Early online date	5 Oct 2023
DOIs	https://doi.org/10.1038/s43856-023-00359-w
Publication status	E-pub ahead of print - 5 Oct 2023

Keywords

Drug therapy
Predictive markers
Type 2 diabetes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Final published versionFinal published version, 1.02 MBLicence: CC BY

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Young, K. G., Haider McInnes, E., Massey, R. J., Kahkoska, A. R., Pilla, S. J., Raghavan, S., Stanislawski, M. A., Tobias, D. K., McGovern, A. P., Dawed, A. Y., Jones, A. G., Pearson, E. R., Dennis, J. M. (2023). Treatment effect heterogeneity following type 2 diabetes treatment with GLP1-receptor agonists and SGLT2-inhibitors: a systematic review. Communications Medicine, 3, Article 131. Advance online publication. https://doi.org/10.1038/s43856-023-00359-w

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title = "Treatment effect heterogeneity following type 2 diabetes treatment with GLP1-receptor agonists and SGLT2-inhibitors: a systematic review",

abstract = "Background: A precision medicine approach in type 2 diabetes requires the identification of clinical and biological features that are reproducibly associated with differences in clinical outcomes with specific anti-hyperglycaemic therapies. Robust evidence of such treatment effect heterogeneity could support more individualized clinical decisions on optimal type 2 diabetes therapy.Methods: We performed a pre-registered systematic review of meta-analysis studies, randomized control trials, and observational studies evaluating clinical and biological features associated with heterogenous treatment effects for SGLT2-inhibitor and GLP1-receptor agonist therapies, considering glycaemic, cardiovascular, and renal outcomes. After screening 5,686 studies, we included 101 studies of SGLT2-inhibitors and 75 studies of GLP1-receptor agonists in the final systematic review.Results: Here we show that the majority of included papers have methodological limitations precluding robust assessment of treatment effect heterogeneity. For SGLT2-inhibitors, multiple observational studies suggest lower renal function as a predictor of lesser glycaemic response, while markers of reduced insulin secretion predict lesser glycaemic response with GLP1-receptor agonists. For both therapies, multiple post-hoc analyses of randomized control trials (including trial meta-analysis) identify minimal clinically relevant treatment effect heterogeneity for cardiovascular and renal outcomes.Conclusions: Current evidence on treatment effect heterogeneity for SGLT2-inhibitor and GLP1-receptor agonist therapies is limited, likely reflecting the methodological limitations of published studies. Robust and appropriately powered studies are required to understand type 2 diabetes treatment effect heterogeneity and evaluate the potential for precision medicine to inform future clinical care.",

keywords = "Drug therapy, Predictive markers, Type 2 diabetes",

author = "Young, {Katherine G.} and {Haider McInnes}, Eram and Massey, {Robert J.} and Kahkoska, {Anna R.} and Pilla, {Scott J.} and Sridharan Raghavan and Stanislawski, {Maggie A.} and Tobias, {Deirdre K.} and McGovern, {Andrew P.} and Dawed, {Adem Y.} and Jones, {Angus G.} and Pearson, {Ewan R.} and Dennis, {John M.}",

note = "Funding Information: This study was supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. K.G.Y. and J.M.D. are supported by Research England{\textquoteright}s Expanding Excellence in England (E3) fund. A.R.K. is supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant KL2TR002490. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. S.R. is funded by a US Department of Veterans Affairs Award IK2-CX001907, and a Webb-Waring Biomedical Research Award from the Boettcher Foundation. J.M.D. is funded by the EFSD Rising Star Fellowship Programme, the UK Medical Research Council (MR/N00633X/1), and a BHF-Turing Cardiovascular Data Science Award (SP/19/6/34809). M.S. is funded by the National Institutes of Health, K01HL157658. Copyright: {\textcopyright} 2023. Springer Nature Limited.",

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Young, KG, Haider McInnes, E , Massey, RJ, Kahkoska, AR, Pilla, SJ, Raghavan, S, Stanislawski, MA, Tobias, DK, McGovern, AP, Dawed, AY, Jones, AG, Pearson, ER, Dennis, JM 2023, 'Treatment effect heterogeneity following type 2 diabetes treatment with GLP1-receptor agonists and SGLT2-inhibitors: a systematic review', Communications Medicine, vol. 3, 131. https://doi.org/10.1038/s43856-023-00359-w

TY - JOUR

T1 - Treatment effect heterogeneity following type 2 diabetes treatment with GLP1-receptor agonists and SGLT2-inhibitors

T2 - a systematic review

AU - Young, Katherine G.

AU - Haider McInnes, Eram

AU - Massey, Robert J.

AU - Kahkoska, Anna R.

AU - Pilla, Scott J.

AU - Raghavan, Sridharan

AU - Stanislawski, Maggie A.

AU - Tobias, Deirdre K.

AU - McGovern, Andrew P.

AU - Dawed, Adem Y.

AU - Jones, Angus G.

AU - Pearson, Ewan R.

AU - Dennis, John M.

N1 - Funding Information: This study was supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. K.G.Y. and J.M.D. are supported by Research England’s Expanding Excellence in England (E3) fund. A.R.K. is supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant KL2TR002490. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. S.R. is funded by a US Department of Veterans Affairs Award IK2-CX001907, and a Webb-Waring Biomedical Research Award from the Boettcher Foundation. J.M.D. is funded by the EFSD Rising Star Fellowship Programme, the UK Medical Research Council (MR/N00633X/1), and a BHF-Turing Cardiovascular Data Science Award (SP/19/6/34809). M.S. is funded by the National Institutes of Health, K01HL157658. Copyright: © 2023. Springer Nature Limited.

PY - 2023/10/5

Y1 - 2023/10/5

N2 - Background: A precision medicine approach in type 2 diabetes requires the identification of clinical and biological features that are reproducibly associated with differences in clinical outcomes with specific anti-hyperglycaemic therapies. Robust evidence of such treatment effect heterogeneity could support more individualized clinical decisions on optimal type 2 diabetes therapy.Methods: We performed a pre-registered systematic review of meta-analysis studies, randomized control trials, and observational studies evaluating clinical and biological features associated with heterogenous treatment effects for SGLT2-inhibitor and GLP1-receptor agonist therapies, considering glycaemic, cardiovascular, and renal outcomes. After screening 5,686 studies, we included 101 studies of SGLT2-inhibitors and 75 studies of GLP1-receptor agonists in the final systematic review.Results: Here we show that the majority of included papers have methodological limitations precluding robust assessment of treatment effect heterogeneity. For SGLT2-inhibitors, multiple observational studies suggest lower renal function as a predictor of lesser glycaemic response, while markers of reduced insulin secretion predict lesser glycaemic response with GLP1-receptor agonists. For both therapies, multiple post-hoc analyses of randomized control trials (including trial meta-analysis) identify minimal clinically relevant treatment effect heterogeneity for cardiovascular and renal outcomes.Conclusions: Current evidence on treatment effect heterogeneity for SGLT2-inhibitor and GLP1-receptor agonist therapies is limited, likely reflecting the methodological limitations of published studies. Robust and appropriately powered studies are required to understand type 2 diabetes treatment effect heterogeneity and evaluate the potential for precision medicine to inform future clinical care.

AB - Background: A precision medicine approach in type 2 diabetes requires the identification of clinical and biological features that are reproducibly associated with differences in clinical outcomes with specific anti-hyperglycaemic therapies. Robust evidence of such treatment effect heterogeneity could support more individualized clinical decisions on optimal type 2 diabetes therapy.Methods: We performed a pre-registered systematic review of meta-analysis studies, randomized control trials, and observational studies evaluating clinical and biological features associated with heterogenous treatment effects for SGLT2-inhibitor and GLP1-receptor agonist therapies, considering glycaemic, cardiovascular, and renal outcomes. After screening 5,686 studies, we included 101 studies of SGLT2-inhibitors and 75 studies of GLP1-receptor agonists in the final systematic review.Results: Here we show that the majority of included papers have methodological limitations precluding robust assessment of treatment effect heterogeneity. For SGLT2-inhibitors, multiple observational studies suggest lower renal function as a predictor of lesser glycaemic response, while markers of reduced insulin secretion predict lesser glycaemic response with GLP1-receptor agonists. For both therapies, multiple post-hoc analyses of randomized control trials (including trial meta-analysis) identify minimal clinically relevant treatment effect heterogeneity for cardiovascular and renal outcomes.Conclusions: Current evidence on treatment effect heterogeneity for SGLT2-inhibitor and GLP1-receptor agonist therapies is limited, likely reflecting the methodological limitations of published studies. Robust and appropriately powered studies are required to understand type 2 diabetes treatment effect heterogeneity and evaluate the potential for precision medicine to inform future clinical care.

KW - Drug therapy

KW - Predictive markers

KW - Type 2 diabetes

U2 - 10.1038/s43856-023-00359-w

DO - 10.1038/s43856-023-00359-w

M3 - Article

C2 - 37794166

SN - 2730-664X

VL - 3

JO - Communications Medicine

JF - Communications Medicine

M1 - 131

ER -

Treatment effect heterogeneity following type 2 diabetes treatment with GLP1-receptor agonists and SGLT2-inhibitors: a systematic review

Abstract

Keywords

UN SDGs

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