. 2025 Mar;27(3):1444-1455.

doi: 10.1111/dom.16147. Epub 2024 Dec 26.

Assessing the benefit-risk profile of newer glucose-lowering drugs: A systematic review and network meta-analysis of randomized outcome trials

Huilin Tang¹, Bingyu Zhang^{2

3}, Yiwen Lu^{2

3}, William T Donahoo⁴, Naykky Singh Ospina⁴, Pareeta Kotecha¹, Ying Lu¹, Jiayi Tong^{2

5

6}, Steven M Smith^{1

7}, Eric I Rosenberg⁸, Stephen E Kimmel⁹, Jiang Bian¹⁰, Jingchuan Guo^{1

7}, Yong Chen^{2

3

6

11

12

13}

Affiliations

¹ Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, USA.
² The Center for Health AI and Synthesis of Evidence (CHASE), University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³ The Graduate Group in Applied Mathematics and Computational Science, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁴ Division of Endocrinology, Department of Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.
⁵ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
⁶ Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
⁷ Center for Drug Evaluation and Safety, University of Florida, Gainesville, Florida, USA.
⁸ Division of General Internal Medicine, Department of Medicine, University of Florida, Gainesville, Florida, USA.
⁹ Department of Epidemiology, College of Public Health and Health Professions and College of Medicine, University of Florida, Gainesville, Florida, USA.
¹⁰ Department of Health Outcomes and Biomedical Informatics, College of Medicine, University of Florida, Gainesville, Florida, USA.
¹¹ Leonard Davis Institute of Health Economics, Philadelphia, Pennsylvania, USA.
¹² Penn Medicine Center for Evidence-based Practice (CEP), Philadelphia, Pennsylvania, USA.
¹³ Penn Institute for Biomedical Informatics (IBI), Philadelphia, Pennsylvania, USA.

PMID: 39723481
PMCID: PMC12135018 (available on 2026-03-01)
DOI: 10.1111/dom.16147

Assessing the benefit-risk profile of newer glucose-lowering drugs: A systematic review and network meta-analysis of randomized outcome trials

Huilin Tang et al. Diabetes Obes Metab. 2025 Mar.

. 2025 Mar;27(3):1444-1455.

doi: 10.1111/dom.16147. Epub 2024 Dec 26.

Authors

Affiliations

¹ Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, USA.
² The Center for Health AI and Synthesis of Evidence (CHASE), University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³ The Graduate Group in Applied Mathematics and Computational Science, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁴ Division of Endocrinology, Department of Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.
⁵ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
⁶ Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
⁷ Center for Drug Evaluation and Safety, University of Florida, Gainesville, Florida, USA.
⁸ Division of General Internal Medicine, Department of Medicine, University of Florida, Gainesville, Florida, USA.
⁹ Department of Epidemiology, College of Public Health and Health Professions and College of Medicine, University of Florida, Gainesville, Florida, USA.
¹⁰ Department of Health Outcomes and Biomedical Informatics, College of Medicine, University of Florida, Gainesville, Florida, USA.
¹¹ Leonard Davis Institute of Health Economics, Philadelphia, Pennsylvania, USA.
¹² Penn Medicine Center for Evidence-based Practice (CEP), Philadelphia, Pennsylvania, USA.
¹³ Penn Institute for Biomedical Informatics (IBI), Philadelphia, Pennsylvania, USA.

PMID: 39723481
PMCID: PMC12135018 (available on 2026-03-01)
DOI: 10.1111/dom.16147

Abstract

Aim: To comprehensively evaluate the benefits and risks of glucagon-like peptide-1 receptor agonists (GLP-1RA), dipeptidyl peptidase 4 inhibitors (DPP4i), and sodium-glucose cotransporter 2 inhibitors (SGLT2i).

Materials and methods: A systematic search of PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to November 2023 to identify randomized cardiovascular and kidney outcome trials that enrolled adults with type 2 diabetes, heart failure, or chronic kidney disease and compared DPP4i, GLP-1RAs, or SGLT2i to placebo. Twenty-one outcomes (e.g., major adverse cardiovascular events [MACE], stroke, and hospitalization for heart failure [HHF]) were assessed. Data were pooled using population-averaged odds ratios (ORs) with 95% CIs.

Results: Twenty-six trials enrolling 198 177 participants were included. GLP-1RAs were most effective in lowering the risks of MACE (OR, 0.85, [95% CI, 0.79 to 0.92]) and stroke (0.84 [0.77, 0.91]), but increased the risk of thyroid cancer (1.58 [1.36, 2.50]). SGLT2i showed the greatest benefits in reducing the risk of HHF (0.68 [0.64, 0.73]) and improving composite renal outcomes (0.67 [0.58, 0.77]), but increased the risk of genital infections (3.11 [2.15, 4.50]). DPP4i were associated with a lower risk of certain psychiatric disorders, Parkinson's disease (0.54 [0.32, 0.92]), and amputation (0.70 [0.86, 0.93]), but an increased risk of neuropathy (1.10 [1.02, 1.18]) and pancreatitis (1.63 [1.40, 1.91]). The weighted origami plot suggested that GLP-1RAs were more suitable for reducing macrovascular and microvascular outcomes, while DPP4i might be better for neurodegenerative diseases and cancer concerns.

Conclusions: Given the distinct benefit-risk profiles, the selection of glucose-lowering drugs should be individualized based on patient characteristics and risk factors.

Keywords: DPP‐IV inhibitor; GLP‐1 analogue; SGLT2 inhibitor; meta‐analysis; type 2 diabetes.

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Conflict of interest statement

JG received consulting fees from Pfizer and received research funding from PhRMA foundation. NSO was supported by the National Cancer Institute of the National Institutes of Health under Award Number K08CA248972. The authors declare that there are no conflicts of interest relevant to this work.

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Assessing the benefit-risk profile of newer glucose-lowering drugs: A systematic review and network meta-analysis of randomized outcome trials

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Assessing the benefit-risk profile of newer glucose-lowering drugs: A systematic review and network meta-analysis of randomized outcome trials

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