Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Mapping the effectiveness and risks of GLP-1 receptor agonists

An Author Correction to this article was published on 31 January 2025

This article has been updated

Abstract

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are increasingly being used to treat diabetes and obesity. However, their effectiveness and risks have not yet been systematically evaluated in a comprehensive set of possible health outcomes. Here, we used the US Department of Veterans Affairs databases to build a cohort of people with diabetes who initiated GLP-1RA (n = 215,970) and compared them to those who initiated sulfonylureas (n = 159,465), dipeptidyl peptidase 4 (DPP4) inhibitors (n = 117,989) or sodium−glucose cotransporter-2 (SGLT2) inhibitors (n = 258,614), a control group composed of an equal proportion of individuals initiating sulfonylureas, DPP4 inhibitors and SGLT2 inhibitors (n = 536,068), and a control group of 1,203,097 individuals who continued use of non-GLP-1RA antihyperglycemics (usual care). We used a discovery approach to systematically map an atlas of the associations of GLP-1RA use versus each comparator with 175 health outcomes. Compared to usual care, GLP-1RA use was associated with a reduced risk of substance use and psychotic disorders, seizures, neurocognitive disorders (including Alzheimer’s disease and dementia), coagulation disorders, cardiometabolic disorders, infectious illnesses and several respiratory conditions. There was an increased risk of gastrointestinal disorders, hypotension, syncope, arthritic disorders, nephrolithiasis, interstitial nephritis and drug-induced pancreatitis associated with GLP-1RA use compared to usual care. The results provide insights into the benefits and risks of GLP-1RAs and may be useful for informing clinical care and guiding research agendas.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Cohort construction flow chart.
Fig. 2: Systematic evaluation of the effectiveness and risks of incident use of GLP-1RAs compared to incident use of sulfonylureas, DPP4 inhibitors SGLT2 inhibitors and a control group composed of equal proportions of sulfonylureas, DPP4 inhibitors and SGLT2 inhibitors.
Fig. 3: Manhattan plot for systematic evaluation of the effectiveness and risks of incident GLP-1RA use.
Fig. 4: Systematic evaluation of the effectiveness and risks of incident GLP-1RA use compared to usual care.
Fig. 5: Forest plots for systematic evaluation of the effectiveness and risks of incident GLP-1RA use compared to usual care.
Fig. 6: Outcomes with reduced or increased risks with incident GLP-1RA use compared to usual care.

Similar content being viewed by others

Data availability

The data that support the findings of this study are available from the US Department of Veterans Affairs. VA data are made freely available to researchers behind the VA firewall with an approved VA study protocol. For more information, please visit https://www.virec.research.va.gov or contact the VA Information Resource Center (VIReC) at VIReC@va.gov.

Code availability

The analytic code is available at https://github.com/yxie618/GLP1.

Change history

References

  1. Pfeffer, M. A. et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N. Engl. J. Med. 373, 2247–2257 (2015).

    CAS  PubMed  Google Scholar 

  2. Marso, S. P. et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 375, 311–322 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Marso, S. P. et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 375, 1834–1844 (2016).

    CAS  PubMed  Google Scholar 

  4. Husain, M. et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 381, 841–851 (2019).

    CAS  PubMed  Google Scholar 

  5. Holman, R. R. et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 377, 1228–1239 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Hernandez, A. F. et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet 392, 1519–1529 (2018).

    CAS  PubMed  Google Scholar 

  7. Gerstein, H. C. et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 394, 121–130 (2019).

    CAS  PubMed  Google Scholar 

  8. Gerstein, H. C. et al. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes. N. Engl. J. Med. 385, 896–907 (2021).

    CAS  PubMed  Google Scholar 

  9. Perkovic, V. et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N. Engl. J. Med. 391, 109–121 (2024).

    Google Scholar 

  10. Kosiborod, M. N. et al. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. N. Engl. J. Med. 389, 1069–1084 (2023).

    CAS  PubMed  Google Scholar 

  11. Gerstein, H. C. et al. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet 394, 131–138 (2019).

    CAS  PubMed  Google Scholar 

  12. Mann, J. F. E. et al. Liraglutide and renal outcomes in type 2 diabetes. N. Engl. J. Med. 377, 839–848 (2017).

    CAS  PubMed  Google Scholar 

  13. Muskiet, M. H. A. et al. Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 6, 859–869 (2018).

    CAS  PubMed  Google Scholar 

  14. Tuttle, K. R. et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol. 6, 605–617 (2018).

    CAS  PubMed  Google Scholar 

  15. Wilding, J. P. H. et al. Once-weekly semaglutide in adults with overweight or obesity. N. Engl. J. Med. 384, 989–1002 (2021).

    CAS  PubMed  Google Scholar 

  16. Jastreboff, A. M. et al. Tirzepatide once weekly for the treatment of obesity. N. Engl. J. Med. 387, 205–216 (2022).

    CAS  PubMed  Google Scholar 

  17. Kelly, A. S. et al. A randomized, controlled trial of liraglutide for adolescents with obesity. N. Engl. J. Med. 382, 2117–2128 (2020).

    CAS  PubMed  Google Scholar 

  18. Wharton, S. et al. Daily oral GLP-1 receptor agonist orforglipron for adults with obesity. N. Engl. J. Med. 389, 877–888 (2023).

    CAS  PubMed  Google Scholar 

  19. Watanabe, J. H., Kwon, J., Nan, B. & Reikes, A. Trends in glucagon-like peptide 1 receptor agonist use, 2014 to 2022. J. Am. Pharm. Assoc. 64, 133–138 (2024).

    CAS  Google Scholar 

  20. Hegland, T.A., Fang, Z. & Bucher, K. GLP-1 medication use for type 2 diabetes has soared.JAMA 332, 952–953 (2024).

    PubMed  Google Scholar 

  21. Sodhi, M., Rezaeianzadeh, R., Kezouh, A. & Etminan, M. Risk of gastrointestinal adverse events associated with glucagon-like peptide-1 receptor agonists for weight loss. JAMA 330, 1795–1797 (2023).

    PubMed  PubMed Central  Google Scholar 

  22. Vidal, J., Flores, L., Jiménez, A., Pané, A. & de Hollanda, A. What is the evidence regarding the safety of new obesity pharmacotherapies. Int. J. Obes. https://doi.org/10.1038/s41366-024-01488-5 (2024).

  23. Wang, W. et al. Association of semaglutide with risk of suicidal ideation in a real-world cohort. Nat. Med. 30, 168–176 (2024).

    PubMed  PubMed Central  Google Scholar 

  24. Laurindo, L. F. et al. GLP-1a: going beyond traditional use. Int. J. Mol. Sci. 23, 739 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Rubin, R. Could GLP-1 receptor agonists like semaglutide treat addiction, Alzheimer disease, and other conditions? JAMA 331, 1519–1521 (2024).

    PubMed  Google Scholar 

  26. Wang, W. et al. Associations of semaglutide with incidence and recurrence of alcohol use disorder in real-world population. Nat. Commun. 15, 4548 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang, W. et al. Association of semaglutide with tobacco use disorder in patients with type 2 diabetes: target trial emulation using real-world data. Ann. Intern. Med. 177, 1016–1027 (2024).

    PubMed  Google Scholar 

  28. Drucker, D. J. The benefits of GLP-1 drugs beyond obesity. Science 385, 258–260 (2024).

    CAS  PubMed  Google Scholar 

  29. Lenharo, M. Why do obesity drugs seem to treat so many other ailments? Nature 633, 758–760 (2024).

    CAS  PubMed  Google Scholar 

  30. Al-Aly, Z., Xie, Y. & Bowe, B. High-dimensional characterization of post-acute sequelae of COVID-19. Nature 594, 259–264 (2021).

    CAS  PubMed  Google Scholar 

  31. Leggio, L. et al. GLP-1 receptor agonists are promising but unproven treatments for alcohol and substance use disorders. Nat. Med. 29, 2993–2995 (2023).

    CAS  PubMed  Google Scholar 

  32. Wium-Andersen, I. K. et al. Use of GLP-1 receptor agonists and subsequent risk of alcohol-related events. A nationwide register-based cohort and self-controlled case series study. Basic Clin. Pharmacol. Toxicol. 131, 372–379 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Klausen, M. K. et al. Exenatide once weekly for alcohol use disorder investigated in a randomized, placebo-controlled clinical trial. JCI Insight 7, e159863 (2022).

    PubMed  PubMed Central  Google Scholar 

  34. Yammine, L., Balderas, J. C., Weaver, M. F. & Schmitz, J. M. Feasibility of exenatide, a GLP-1R agonist, for treating cocaine use disorder: a case series study. J. Addict. Med. 17, 481–484 (2023).

    PubMed  Google Scholar 

  35. Angarita, G. A. et al. Testing the effects of the GLP-1 receptor agonist exenatide on cocaine self-administration and subjective responses in humans with cocaine use disorder. Drug Alcohol Depend. 221, 108614 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Dixit, T. S., Sharma, A. N., Lucot, J. B. & Elased, K. M. Antipsychotic-like effect of GLP-1 agonist liraglutide but not DPP-IV inhibitor sitagliptin in mouse model for psychosis. Physiol. Behav. 114−115, 38–41 (2013).

    Google Scholar 

  37. Gunturu, S. The potential role of GLP-1 agonists in psychiatric disorders: a paradigm shift in mental health treatment. Indian J. Psychol. Med. 46, 193–195 (2024).

    PubMed  PubMed Central  Google Scholar 

  38. López-Ojeda, W. & Hurley, R. A. Glucagon-like peptide 1: an introduction and possible implications for neuropsychiatry. J. Neuropsychiatry Clin. Neurosci. 36, A4–A86 (2024).

    PubMed  Google Scholar 

  39. Flintoff, J., Kesby, J. P., Siskind, D. & Burne, T. H. J. Treating cognitive impairment in schizophrenia with GLP-1RAs: an overview of their therapeutic potential. Expert Opin. Investig. Drugs 30, 877–891 (2021).

    CAS  PubMed  Google Scholar 

  40. European Medicines Agency. Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 8−11 April 2024. https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-8-11-april-2024 (12 April 2024).

  41. Du, H., Meng, X., Yao, Y. & Xu, J. The mechanism and efficacy of GLP-1 receptor agonists in the treatment of Alzheimer’s disease. Front. Endocrinol. 13, 1033479 (2022).

    Google Scholar 

  42. Mehan, S. et al. Potential roles of glucagon-like peptide-1 and its analogues in dementia targeting impaired insulin secretion and neurodegeneration. Degener. Neurol. Neuromuscul. Dis. 12, 31–59 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Colin, I. M., Szczepanski, L. W., Gérard, A. C. & Elosegi, J. A. Emerging evidence for the use of antidiabetic drugs, glucagon-like peptide 1 receptor agonists, for the treatment of Alzheimer’s disease. touchREV. Endocrinol. 19, 16–24 (2023).

    PubMed  PubMed Central  Google Scholar 

  44. Lenharo, M. Obesity drugs have another superpower: taming inflammation. Nature 626, 246 (2024).

    CAS  PubMed  Google Scholar 

  45. Nørgaard, C. H. et al. Treatment with glucagon-like peptide-1 receptor agonists and incidence of dementia: data from pooled double-blind randomized controlled trials and nationwide disease and prescription registers. Alzheimer’s Dement. 8, e12268 (2022).

    Google Scholar 

  46. De Giorgi, R. et al. 12-month neurological and psychiatric outcomes of semaglutide use for type 2 diabetes: a propensity-score matched cohort study. eClinicalMedicine 74, 102726 (2024).

    PubMed  PubMed Central  Google Scholar 

  47. Atri, A. et al. evoke and evoke+: design of two large-scale, double-blind, placebo-controlled, phase 3 studies evaluating the neuroprotective effects of semaglutide in early Alzheimer’s disease. Alzheimer’s Dement. 18, e062415 (2022).

    Google Scholar 

  48. Manavi, M. A. Neuroprotective effects of glucagon-like peptide-1 (GLP-1) analogues in epilepsy and associated comorbidities. Neuropeptides 94, 102250 (2022).

    CAS  PubMed  Google Scholar 

  49. Wang, L. et al. Semaglutide attenuates seizure severity and ameliorates cognitive dysfunction by blocking the NLR family pyrin domain containing 3 inflammasome in pentylenetetrazole‑kindled mice. Int. J. Mol. Med. 48, 219 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Hussein, A. M. et al. Effects of GLP-1 receptor activation on a pentylenetetrazole−kindling rat model. Brain Sci. 9, 108 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Liu, S. et al. The glucagon-like peptide-1 analogue liraglutide reduces seizures susceptibility, cognition dysfunction and neuronal apoptosis in a mouse model of Dravet syndrome. Front. Pharmacol. 11, 136 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Sattar, N. et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol. 9, 653–662 (2021).

    CAS  PubMed  Google Scholar 

  53. Jia, G., Aroor, A. R. & Sowers, J. R. Glucagon-like peptide 1 receptor activation and platelet function: beyond glycemic control. Diabetes 65, 1487–1489 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Drucker, D. J. The cardiovascular biology of glucagon-like peptide-1. Cell Metab. 24, 15–30 (2016).

    CAS  PubMed  Google Scholar 

  55. Sternkopf, M. et al. Native, intact glucagon-like peptide 1 is a natural suppressor of thrombus growth under physiological flow conditions. Arter. Thromb. Vasc. Biol. 40, e65–e77 (2020).

    CAS  Google Scholar 

  56. Steven, S. et al. Glucagon-like peptide-1 receptor signalling reduces microvascular thrombosis, nitro-oxidative stress and platelet activation in endotoxaemic mice. Br. J. Pharmacol. 174, 1620–1632 (2017).

    CAS  PubMed  Google Scholar 

  57. Cameron-Vendrig, A. et al. Glucagon-like peptide 1 receptor activation attenuates platelet aggregation and thrombosis. Diabetes 65, 1714–1723 (2016).

    CAS  PubMed  Google Scholar 

  58. Zhang, Y., Chen, R., Jia, Y., Chen, M. & Shuai, Z. Effects of exenatide on coagulation and platelet aggregation in patients with type 2 diabetes. Drug Des. Devel. Ther. 15, 3027–3040 (2021).

    PubMed  PubMed Central  Google Scholar 

  59. Horvei, L. D., Brækkan, S. K. & Hansen, J. B. Weight change and risk of venous thromboembolism: the Tromsø study. PLoS ONE 11, e0168878 (2016).

    PubMed  PubMed Central  Google Scholar 

  60. de Lemos, J. A. et al. Tirzepatide reduces 24-hour ambulatory blood pressure in adults with body mass index ≥27 kg/m2: SURMOUNT-1 Ambulatory Blood Pressure Monitoring Substudy. Hypertension 81, e41–e43 (2024).

    PubMed  Google Scholar 

  61. Goodwill, A. G. et al. Cardiovascular and hemodynamic effects of glucagon-like peptide-1. Rev. Endocr. Metab. Disord. 15, 209–217 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Ribeiro-Silva, J. C., Tavares, C. A. M. & Girardi, A. C. C. The blood pressure lowering effects of glucagon-like peptide-1 receptor agonists: a mini-review of the potential mechanisms. Curr. Opin. Pharmacol. 69, 102355 (2023).

    CAS  PubMed  Google Scholar 

  63. Goud, A., Zhong, J., Peters, M., Brook, R. D. & Rajagopalan, S. GLP-1 agonists and blood pressure: a review of the evidence. Curr. Hypertens. Rep. 18, 16 (2016).

    PubMed  Google Scholar 

  64. Yang, F. et al. GLP-1 receptor: a new target for sepsis. Front. Pharmacol. 12, 706908 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Helmstädter, J. et al. GLP-1 analog liraglutide improves vascular function in polymicrobial sepsis by reduction of oxidative stress and inflammation. Antioxidants 10, 1175 (2021).

    PubMed  PubMed Central  Google Scholar 

  66. Yi, H. et al. Activation of glucagon-like peptide-1 receptor in microglia exerts protective effects against sepsis-induced encephalopathy via attenuating endoplasmic reticulum stress-associated inflammation and apoptosis in a mouse model of sepsis. Exp. Neurol. 363, 114348 (2023).

    CAS  PubMed  Google Scholar 

  67. Scirica, B. et al. The effect of semaglutide on mortality and COVID-19–related deaths.JACC 84, 1632–1642 (2024).

    CAS  PubMed  Google Scholar 

  68. Wang, L., Xu, R., Kaelber, D. C. & Berger, N. A. Glucagon-like peptide 1 receptor agonists and 13 obesity-associated cancers in patients with type 2 diabetes. JAMA Netw. Open 7, e2421305 (2024).

    PubMed  PubMed Central  Google Scholar 

  69. Yu, M. et al. The relationship between the use of GLP-1 receptor agonists and the incidence of respiratory illness: a meta-analysis of randomized controlled trials. Diabetol. Metab. Syndr. 15, 164 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Altintas Dogan, A. D. et al. Respiratory effects of treatment with a glucagon-like peptide-1 receptor agonist in patients suffering from obesity and chronic obstructive pulmonary disease. Int. J. Chron. Obstruct. Pulmon. Dis. 17, 405–414 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Foer, D. et al. Association of GLP-1 receptor agonists with chronic obstructive pulmonary disease exacerbations among patients with type 2 diabetes. Am. J. Respir. Crit. Care Med. 208, 1088–1100 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Pradhan, R. et al. Novel antihyperglycaemic drugs and prevention of chronic obstructive pulmonary disease exacerbations among patients with type 2 diabetes: population based cohort study. BMJ 379, e071380 (2022).

    PubMed  PubMed Central  Google Scholar 

  73. Yeo, Y.H. et al. Increased risk of aspiration pneumonia associated with endoscopic procedures among patients with glucagon-like peptide 1 receptor agonist use.Gastroenterology 167, 402–404 (2024).

    CAS  PubMed  Google Scholar 

  74. Dixit, A. A., Bateman, B. T., Hawn, M. T., Odden, M. C. & Sun, E. C. Preoperative GLP-1 receptor agonist use and risk of postoperative respiratory complications. JAMA 331, 1672–1673 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Wang, W. et al. The role of glucagon-like peptide-1 receptor agonists in chronic obstructive pulmonary disease. Int. J. Chron. Obstruct. Pulmon. Dis. 18, 129–137 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Langenberg, C., Hingorani, A. D. & Whitty, C. J. M. Biological and functional multimorbidity—from mechanisms to management. Nat. Med. 29, 1649–1657 (2023).

    CAS  PubMed  Google Scholar 

  77. Xie, Y., Choi, T. & Al-Aly, Z. Postacute sequelae of SARS-CoV-2 infection in the pre-Delta, Delta, and Omicron eras. N. Engl. J. Med. 391, 515–525 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Cai, M., Xie, Y., Topol, E. J. & Al-Aly, Z. Three-year outcomes of post-acute sequelae of COVID-19. Nat. Med. 30, 1564–1573 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Bowe, B., Xie, Y. & Al-Aly, Z. Postacute sequelae of COVID-19 at 2 years. Nat. Med. 29, 2347–2357 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Xu, E., Xie, Y. & Al-Aly, Z. Long-term gastrointestinal outcomes of COVID-19. Nat. Commun. 14, 983 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Xu, E., Xie, Y. & Al-Aly, Z. Risks and burdens of incident dyslipidaemia in long COVID: a cohort study. Lancet Diabetes Endocrinol. 11, 120–128 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Xie, Y., Choi, T. & Al-Aly, Z. Long-term outcomes following hospital admission for COVID-19 versus seasonal influenza: a cohort study. Lancet Infect. Dis. 24, 239–255 (2024).

    PubMed  Google Scholar 

  83. Al-Aly, Z. & Topol, E. Solving the puzzle of long Covid. Science 383, 830–832 (2024).

    CAS  PubMed  Google Scholar 

  84. Al-Aly, Z. et al. Long COVID science, research and policy. Nat. Med. 30, 2148–2164 (2024).

    CAS  PubMed  Google Scholar 

  85. Xie, Y. et al. Proton pump inhibitors and risk of incident CKD and progression to ESRD. J. Am. Soc. Nephrol. 27, 3153–3163 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Xie, Y. et al. Risk of death among users of proton pump inhibitors: a longitudinal observational cohort study of United States veterans. BMJ Open 7, e015735 (2017).

    PubMed  PubMed Central  Google Scholar 

  87. Xie, Y. et al. Long-term kidney outcomes among users of proton pump inhibitors without intervening acute kidney injury. Kidney Int. 91, 1482–1494 (2017).

    CAS  PubMed  Google Scholar 

  88. Xie, Y. et al. Higher blood urea nitrogen is associated with increased risk of incident diabetes mellitus. Kidney Int. 93, 741–752 (2018).

    CAS  PubMed  Google Scholar 

  89. Maynard, C. Ascertaining veterans’ vital status: VA data sources for mortality ascertainment and cause of death. https://www.hsrd.research.va.gov/for_researchers/cyber_seminars/archives/3783-notes.pdf (2017).

  90. Cai, M. et al. Temporal trends in incidence rates of lower extremity amputation and associated risk factors among patients using Veterans Health Administration services from 2008 to 2018. JAMA Netw. Open 4, e2033953 (2021).

    PubMed  PubMed Central  Google Scholar 

  91. Xie, Y. et al. Comparative effectiveness of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, and sulfonylureas on risk of major adverse cardiovascular events: emulation of a randomised target trial using electronic health records. Lancet Diabetes Endocrinol. 11, 644–656 (2023).

    CAS  PubMed  Google Scholar 

  92. Xie, Y. et al. Clinical implications of estimated glomerular filtration rate dip following sodium−glucose cotransporter-2 inhibitor initiation on cardiovascular and kidney outcomes. J. Am. Heart Assoc. 10, e020237 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Xie, Y. et al. Comparative effectiveness of sodium−glucose cotransporter 2 inhibitors vs sulfonylureas in patients with type 2 diabetes. JAMA Intern. Med. 181, 1043–1053 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Xie, Y. et al. Comparative effectiveness of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, and sulfonylureas on risk of kidney outcomes: emulation of a target trial using health care databases. Diabetes Care 43, 2859–2869 (2020).

    PubMed  Google Scholar 

  95. Xie, Y. et al. Comparative effectiveness of the sodium−glucose cotransporter 2 inhibitor empagliflozin versus other antihyperglycemics on risk of major adverse kidney events. Diabetes Care 43, 2785–2795 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Xie, Y., Choi, T. & Al-Aly, Z. Nirmatrelvir and the risk of post-acute sequelae of COVID-19.JAMA Intern. Med. 183, 554–564 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Xie, Y., Bowe, B. & Al-Aly, Z. Nirmatrelvir and risk of hospital admission or death in adults with Covid-19: emulation of a randomized target trial using electronic health records. BMJ 381, e073312 (2023).

    PubMed  Google Scholar 

  98. Xie, Y., Bowe, B. & Al-Aly, Z. Molnupiravir and risk of hospital admission or death in adults with Covid-19: emulation of a randomized target trial using electronic health records. BMJ 380, e072705 (2023).

    PubMed  Google Scholar 

  99. Xie, Y., Choi, T. & Al-Aly, Z. Molnupiravir and risk of post-acute sequelae of Covid-19: cohort study. BMJ 381, e074572 (2023).

    PubMed  Google Scholar 

  100. van Buuren, S. Multiple imputation of discrete and continuous data by fully conditional specification. Stat. Methods Med. Res. 16, 219–242 (2007).

    PubMed  Google Scholar 

  101. Harrell, F. E. Regression Modeling Strategies: With Applications to Linear Models, Logistic and Ordinal Regression, and Survival Analysis (Springer, 2015).

  102. Schneeweiss, S. Automated data-adaptive analytics for electronic healthcare data to study causal treatment effects. Clin. Epidemiol. 10, 771–788 (2018).

    PubMed  PubMed Central  Google Scholar 

  103. Schneeweiss, S. et al. High-dimensional propensity score adjustment in studies of treatment effects using health care claims data. Epidemiology 20, 512–522 (2009).

    PubMed  PubMed Central  Google Scholar 

  104. Austin, P. C. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity‐score matched samples. Stat. Med. 28, 3083–3107 (2009).

    PubMed  PubMed Central  Google Scholar 

  105. Crump, R. K., Hotz, V. J., Imbens, G. W. & Mitnik, O. A. Dealing with limited overlap in estimation of average treatment effects. Biometrika 96, 187–199 (2009).

    Google Scholar 

  106. Hernan, M. A. & Robins, J. M. Causal Inference: What If (CRC Press, 2010).

  107. Uno, H. et al. Moving beyond the hazard ratio in quantifying the between-group difference in survival analysis. J. Clin. Oncol. 32, 2380–2385 (2014).

    PubMed  PubMed Central  Google Scholar 

  108. Andersen, P. K., Hansen, M. G. & Klein, J. P. Regression analysis of restricted mean survival time based on pseudo-observations. Lifetime Data Anal. 10, 335–350 (2004).

    PubMed  Google Scholar 

  109. Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. B 57, 289–300 (1995).

    Google Scholar 

Download references

Acknowledgements

Support for VA and Centers for Medicare and Medicaid Services data is provided by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development, VA Information Resource Center (Project Number/Data Use Agreement ID Al-Aly-01-A-1). This research was funded by the US Department of Veterans Affairs (to Z.A.A.). The funder of this study had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The contents do not represent the views of the US Department of Veterans Affairs or the US government.

Author information

Authors and Affiliations

Authors

Contributions

Research area and study design: Y.X., Z.A.A.; data acquisition: Y.X., T.Y., Z.A.A.; data analysis and interpretation: Y.X., T.Y., Z.A.A.; statistical analysis: Y.X., T.Y., Z.A.A.; drafting the manuscript Y.X., Z.A.A.; critical revision of the manuscript Y.X., T.Y., Z.A.A.; administrative, technical, or material support: Z.A.A.; supervision and mentorship: Z.A.A. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. Z.A.A. takes responsibility that this study has been reported honestly, accurately and transparently; that no important aspects of the study have been omitted, and that any discrepancies from the study as planned have been explained. Y.X. and Z.A.A. had full access to all data and Y.X. and Z.A.A. verified the accuracy of the underlying data.

Corresponding author

Correspondence to Ziyad Al-Aly.

Ethics declarations

Competing interests

Y.X. and Z.A.A. are uncompensated consultants for Pfizer. No other potential competing interests relevant to this article are reported.

Peer review

Peer review information

Nature Medicine thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: Ming Yang, in collaboration with the Nature Medicine team.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Standardized mean differences of covariates in incident GLP-1RA compared to sulfonylureas, DPP4i, SGLT2i, a control composited of equal proportion of incident sulfonylureas, DPP4i, SGLT2i use and a control of participants who received usual care before and after weighting.

X-axis: absolute standardized mean difference from 0 to 0.5 where a value larger than 0.5 was plotted as 0.5. A value of less than 0.1 indicates balance was achieved. eGFR, estimated glomerular filtration rate; HbA1c, hemoglobin A1c; ACE/ARB, angiotensin converting enzyme inhibitors/angiotensin-receptor blockers Postop, Postprocedural; GLP-1RA, glucagon-like peptide-1 receptor agonist; DPP4i, dipeptidyl peptidase-4 inhibitor; SGLT2i, sodium-glucose co-transporter-2 inhibitor.

Supplementary information

Reporting Summary

Supplementary Tables

Supplementary Tables 1−15.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xie, Y., Choi, T. & Al-Aly, Z. Mapping the effectiveness and risks of GLP-1 receptor agonists. Nat Med (2025). https://doi.org/10.1038/s41591-024-03412-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41591-024-03412-w

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research