FUTURE CHALLENGES AND EMERGING SAFETY CONCERNS OF GLP-1 RECEPTOR AGONISTS, DUAL INCRETIN AGONISTS, AND SGLT2 INHIBITORS
Main Article Content
Keywords
.
Abstract
Three drug classes developed primarily to lower blood glucose, namely sodium–glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist tirzepatide, have been redefined by a sequence of large randomized controlled trials (RCTs) as cardiovascular, kidney and metabolic-protective therapies. With that efficacy now well established, attention is shifting to the questions that long-term, population-scale use raises: emerging safety signals, the durability of benefit, and the gaps that current randomized evidence has yet to close. This review takes the established RCT efficacy base as its starting point and then focuses on the future challenges and emerging safety concerns of these classes: class-specific adverse-event signals (gastrointestinal intolerance, euglycemic ketoacidosis, genital and necrotizing soft-tissue infection, lower-limb amputation, non-arteritic anterior ischemic optic neuropathy, lean-mass loss, and biliary events), cross-cutting issues (perioperative aspiration risk from delayed gastric emptying, and weight regain after discontinuation), the unmet evidence needs for combination therapy, emerging triple agonists, and hard-endpoint confirmation.
References
1. US Food and Drug Administration. Guidance for industry: diabetes mellitus, evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. 2008.
2. Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes (ACCORD). N Engl J Med. 2008;358:2545-2559.
3. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.
4. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes (VADT). N Engl J Med. 2009;360:129-139.
5. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes (EMPA-REG OUTCOME). N Engl J Med. 2015;373:2117-2128.
6. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes (CANVAS Program). N Engl J Med. 2017;377:644-657.
7. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes (DECLARE-TIMI 58). N Engl J Med. 2019;380:347-357.
8. Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes (VERTIS CV). N Engl J Med. 2020;383:1425-1435.
9. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction (DAPA-HF). N Engl J Med. 2019;381:1995-2008.
10. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure (EMPEROR-Reduced). N Engl J Med. 2020;383:1413-1424.
11. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction (EMPEROR-Preserved). N Engl J Med. 2021;385:1451-1461.
12. Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction (DELIVER). N Engl J Med. 2022;387:1089-1098.
13. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure (SOLOIST-WHF). N Engl J Med. 2021;384:117-128.
14. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy (CREDENCE). N Engl J Med. 2019;380:2295-2306.
15. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease (DAPA-CKD). N Engl J Med. 2020;383:1436-1446.
16. The EMPA-KIDNEY Collaborative Group. Empagliflozin in patients with chronic kidney disease (EMPA-KIDNEY). N Engl J Med. 2023;388:117-127.
17. Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in patients with diabetes and chronic kidney disease (SCORED). N Engl J Med. 2021;384:129-139.
18. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome (ELIXA). N Engl J Med. 2015;373:2247-2257.
19. Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes (EXSCEL). N Engl J Med. 2017;377:1228-1239.
20. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes (LEADER). N Engl J Med. 2016;375:311-322.
21. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes (SUSTAIN-6). N Engl J Med. 2016;375:1834-1844.
22. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND). Lancet. 2019;394:121-130.
23. Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (HARMONY Outcomes). Lancet. 2018;392:1519-1529.
24. Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes (PIONEER 6). N Engl J Med. 2019;381:841-851.
25. Gerstein HC, Sattar N, Rosenstock J, et al. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes (AMPLITUDE-O). N Engl J Med. 2021;385:896-907.
26. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes (SELECT). N Engl J Med. 2023;389:2221-2232. doi:10.1056/NEJMoa2307563.
27. Ryan DH, Lingvay I, Deanfield J, et al. Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial. Nat Med. 2024;30:2049-2057. doi:10.1038/s41591-024-02996-7.
28. Perkovic V, Tuttle KR, Rossing P, et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes (FLOW). N Engl J Med. 2024;391:109-121. doi:10.1056/NEJMoa2403347.
29. Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al. Semaglutide in patients with heart failure with preserved ejection fraction and obesity (STEP-HFpEF). N Engl J Med. 2023;389:1069-1084.
30. Kosiborod MN, Petrie MC, Borlaug BA, et al. Semaglutide in patients with obesity-related HFpEF and type 2 diabetes (STEP-HFpEF DM). N Engl J Med. 2024;390:1394-1407.
31. Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 trial of semaglutide in metabolic dysfunction–associated steatohepatitis (ESSENCE). N Engl J Med. 2025;392(21):2089-2099. doi:10.1056/NEJMoa2413258.
32. McGuire DK, Marx N, Mulvagh SL, et al. Oral semaglutide and cardiovascular outcomes in high-risk type 2 diabetes (SOUL). N Engl J Med. 2025;392(20). doi:10.1056/NEJMoa2501006. (verify volume/page)
33. McGuire DK, Marx N, Mulvagh SL, et al. Oral semaglutide and cardiovascular outcomes according to SGLT2 inhibitor use: prespecified analyses of the SOUL randomized trial. Circulation. 2025. doi:10.1161/CIRCULATIONAHA.125.074545.
34. Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes (SURPASS-2). N Engl J Med. 2021;385:503-515.
35. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). N Engl J Med. 2022;387:205-216.
36. Nicholls SJ, Pavo I, Bhatt DL, et al. Cardiovascular outcomes with tirzepatide versus dulaglutide in type 2 diabetes (SURPASS-CVOT). N Engl J Med. 2025;393:2409-2420. doi:10.1056/NEJMoa2505928.
37. Packer M, Zile MR, Kramer CM, et al. Tirzepatide for heart failure with preserved ejection fraction and obesity (SUMMIT). N Engl J Med. 2025;392(5):427-437. doi:10.1056/NEJMoa2410027.
38. Borlaug BA, Zile MR, Kramer CM, et al. Effects of tirzepatide on circulatory overload and end-organ damage in HFpEF and obesity: secondary analysis of SUMMIT. Nat Med. 2024;30(12):3434-3442. doi:10.1038/s41591-024-03374-z.
39. Kramer CM, Borlaug BA, Zile MR, et al. Tirzepatide reduces LV mass and paracardiac adipose tissue in obesity-related HFpEF: SUMMIT CMR substudy. J Am Coll Cardiol. 2025. doi:10.1016/j.jacc.2024.11.001.
40. Loomba R, Hartman ML, Lawitz EJ, et al. Tirzepatide for metabolic dysfunction–associated steatohepatitis with liver fibrosis (SYNERGY-NASH). N Engl J Med. 2024;391:299-310.
41. Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-hormone-receptor agonist retatrutide for obesity: a phase 2 trial. N Engl J Med. 2023;389:514-526.
42. Frías JP, Deenadayalan S, Erichsen L, et al. Cagrilintide plus semaglutide (CagriSema) in adults with overweight or obesity. Lancet. 2023;402:720-730. (verify citation)
43. Vallon V, Verma S. Effects of SGLT2 inhibitors on kidney and cardiovascular function. Annu Rev Physiol. 2021;83:503-528.
44. Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 2018;27:740-756.
45. Marx N, Husain M, Lehrke M, et al. GLP-1 receptor agonists for the reduction of atherosclerotic cardiovascular risk. Circulation. 2022;146:1882-1894.
46. Buse JB, Bain SC, Mann JFE, et al. Cardiovascular risk reduction with liraglutide and semaglutide: mediation analyses of the LEADER and SUSTAIN-6 trials. Diabetes Care. 2020;43:1546-1552. (verify citation)
47. Aroda VR, et al. Gastrointestinal adverse events with GLP-1 receptor agonists and dual GIP/GLP-1 agonists: incidence, mechanisms, and management. 2025. (narrative summary; verify primary sources).
48. Sodhi M, Rezaeianzadeh R, Kezouh A, Etminan M. Risk of gastrointestinal adverse events associated with GLP-1 receptor agonists for weight loss. JAMA. 2023;330:1795-1797.
49. He L, Wang J, Ping F, et al. Association of glucagon-like peptide-1 receptor agonist use with risk of gallbladder and biliary diseases: a systematic review and meta-analysis of randomized clinical trials. JAMA Intern Med. 2022;182:513-519. (cholelithiasis RR ~1.46).
50. Nauck MA, Friedrich N. Do GLP-1-based therapies increase cancer risk? Diabetes Care. 2013;36(Suppl 2):S245-S252. (pancreatitis/thyroid signal not confirmed in humans; verify).
51. Bezin J, Gouverneur A, Penichon M, et al. GLP-1 receptor agonists and the risk of thyroid cancer. Diabetes Care. 2023;46:384-390.
52. Hathaway JT, Shah MP, Hathaway DB, et al. Risk of nonarteritic anterior ischemic optic neuropathy in patients prescribed semaglutide. JAMA Ophthalmol. 2024;142:732-739. doi:10.1001/jamaophthalmol.2024.2296.
53. Simonsen E, Lund LC, Ernst MT, et al. Use of semaglutide and risk of non-arteritic anterior ischemic optic neuropathy: a Danish-Norwegian cohort study. Diabetes Obes Metab. 2025;27:1-10. doi:10.1111/dom.16316.
54. World Health Organization. The use of semaglutide medicines and risk of non-arteritic anterior ischemic optic neuropathy (NAION). WHO Pharmaceuticals Newsletter / safety alert, June 2025.
55. Neeland IJ, Linge J, Birkenfeld AL. Changes in lean body mass with GLP-1-based therapies and mitigation strategies. Diabetes Obes Metab. 2024;26(Suppl 4):16-27. doi:10.1111/dom.15728.
56. Heymsfield SB, Smith B, Wong M, et al. Total and regional appendicular skeletal muscle mass prediction from dual-energy X-ray absorptiometry body composition models. Sci Rep. 2023;13:5363. (DXA lean mass ~0.46 of total, ~0.70 of appendicular is skeletal muscle; whole-body MRI reference standard).
57. Buckinx F, Landi F, Cesari M, et al. Pitfalls in the measurement of muscle mass: a need for a reference standard. J Cachexia Sarcopenia Muscle. 2018;9:269-278.
58. Prado CM, Cawthon PM, Heymsfield SB, et al. Fundamental body-composition principles provide context for fat-free and skeletal-muscle loss with GLP-1 RA treatments. J Endocr Soc. 2024;8:bvae164. doi:10.1210/jendso/bvae164. (DXA cannot distinguish functional from fat-infiltrated muscle).
59. Tavoian D, Ampomah K, Amano S, et al. Changes in DXA-derived lean mass and MRI-derived cross-sectional area of the thigh are modestly associated. Sci Rep. 2019;9:10028. (DXA-MRI discordance in intervention trials; verify).
60. Cawthon PM, Orwoll ES, Peters KE, et al. Strong relation between muscle mass determined by D3-creatine dilution, physical performance, and incident falls and disability in older men (MrOS). J Gerontol A Biol Sci Med Sci. 2019;74:844-852.
61. Nuffer W, Trujillo JM. Lean mass loss and muscle-preserving co-therapies (bimagrumab, enobosarm, pemvidutide) with incretin-based weight loss: a review. 2025. (verify primary trials).
62. Qiu M, Ding LL, Zhan ZL, Liu SY. Sodium-glucose cotransporter 2 inhibitors and adverse events: meta-analysis (DKA RR ~2.57; genital infection; volume depletion RR 1.14; amputation RR 1.21; fracture). 2021.
63. Goldenberg RM, et al. Sodium-glucose cotransporter 2 inhibitors and diabetic ketoacidosis risk, including type 1 diabetes and sotagliflozin (FDA estimate ~1 case per 26 patient-years). 2021. (verify primary source).
64. Toyama T, Neuen BL, Jun M, et al. Genital infections and other safety outcomes with SGLT2 inhibitors: systematic review and meta-analysis. Diabetes Obes Metab. 2019;21:1237-1250. (genital infection RR ~2.86-3.75).
65. US Food and Drug Administration. FDA warns about rare occurrences of a serious infection of the genital area (Fournier's gangrene) with SGLT2 inhibitors. Drug Safety Communication, August 2018.
66. Lee SH, Kim JH. Time in range from continuous glucose monitoring: a novel metric for glycemic control. (review of HbA1c limitations: anemia, pregnancy, liver disease, hemoglobinopathy; glycemic variability). 2021. (verify).
67. Wright EE, et al. A view beyond HbA1c: role of continuous glucose monitoring. Diabetes Ther. (HbA1c unreliable in anemia, hemoglobinopathy, liver disease, iron deficiency; misses variability and hypoglycemia). (verify).
68. Toyama M, et al. Continuous glucose monitoring metrics in the assessment of glycemia in moderate-to-advanced CKD in diabetes. Kidney Int Rep. 2022. (GMI-HbA1c correlation attenuates with CKD stage: G3b r=0.68, G4 r=0.52, G5 r=0.22).
69. Inker LA, Heerspink HJL, Tighiouart H, et al. GFR slope as a surrogate endpoint for kidney disease progression in clinical trials: an individual participant-level meta-analysis (186,312 participants, 66 trials). (verify exact citation).
70. NKF-FDA-EMA workshop / Japan CKD Database analysis. eGFR slope as a surrogate endpoint for early CKD; acute eGFR dip with RAS inhibitors, finerenone, and SGLT2 inhibitors; 2-3 year slope; combining slope with albuminuria improves prediction. Clin Exp Nephrol. 2023-2024. (verify).
71. Herrington WG, et al. Effects of empagliflozin on conventional and exploratory acute and chronic kidney outcomes: an individual participant-level meta-analysis (EMPA-REG, EMPEROR-Reduced/Preserved, EMPA-KIDNEY). Lancet Diabetes Endocrinol. 2025. doi:10.1016/S2213-8587(25)00222-0.
72. Gaudino M, Hameed I, Khan FM, Braunwald E, Stone GW, et al. Trialists call for a rethink of MACE as a primary endpoint in cardiovascular trials. 2024. (heterogeneous components; varying definitions; obscures individual effects). (verify exact citation).
73. Kip KE, Hollabaugh K, Marroquin OC, Williams DO. The problem with composite end points in cardiovascular studies: the story of MACE and PCI. J Am Coll Cardiol. 2008;51:701-707. (no standard MACE definition; term MACE should not be used).
74. U.S. FDA Adverse Event Reporting System (FAERS) Essentials: a guide to understanding, applying, and interpreting adverse-event data; limitations of disproportionality analysis (no denominator, reporting/selection bias, confounding by indication). 2024. (verify).
75. Pharmacovigilance analysis of neurological adverse events associated with GLP-1 receptor agonists based on FAERS. Sci Rep. 2025;15. (disproportionality signal does not establish causality; selection bias tied to public awareness; cannot estimate incidence).
76. Wright JD, Chen L, Xu X, et al. GLP-1 receptor agonist use and the risk of pulmonary aspiration in patients undergoing surgery. Int J Surg. 2025. doi:10.1097/JS9.0000000000002425. (aspiration ~0.8%, no significant excess).
77. Ushakumari DS, Sladen RN; ASA, AGA, and 2025 ADS/ANZCA/GESA/NACOS multisociety guidance on peri-procedural management of GLP-1/GIP receptor agonists; FDA label update November 2024. (composite; verify individual sources).
78. Hashash JG, Thompson CC, Wang AY, et al. AGA rapid clinical practice update on the management of patients taking GLP-1 receptor agonists prior to endoscopy. Clin Gastroenterol Hepatol. 2024;22:705-707.
79. Aronne LJ, Sattar N, Horn DB, et al. Continued treatment with tirzepatide for maintenance of weight reduction (SURMOUNT-4). JAMA. 2024;331:38-48. doi:10.1001/jama.2023.24945.
80. Horn DB, Linetzky B, Davies MJ, et al. Cardiometabolic parameter change by weight regain on tirzepatide withdrawal: post hoc analysis of SURMOUNT-4. JAMA Intern Med. 2025. doi:10.1001/jamainternmed.2025.6112.
81. Jastreboff AM, et al. Tirzepatide for maintenance of bodyweight reduction in people with obesity (SURMOUNT-MAINTAIN). Lancet. 2026. doi:10.1016/S0140-6736(26)00656-2. (5 mg maintenance alternative to discontinuation).
82. Alawadhi AA, Alroudhan D, Alsaeed DJ, et al. LEAN mass Preservation with Resistance Exercise and Protein during semaglutide and tirzepatide therapy (LEAN-PREP study): a protocol for a randomised controlled trial. BMJ Open. 2026; 16(4): e116911.
83. Tinsley GM, Nadolsky S. Preservation of lean soft tissue during weight loss induced by GLP-1 and GLP-1/GIP receptor agonists: a case series. SAGE Open Med Case Rep. 2025;13:2050313X251388724.
84. Haines MS, et al. Older age, female sex, and lower protein intake are associated with greater muscle loss in adults with obesity prescribed semaglutide. Presented at: ENDO 2025 (Endocrine Society Annual Meeting); July 12–15, 2025; San Francisco, CA.
85. IQVIA / medRxiv preprint. How low could semaglutide prices fall? An analysis of production cost and implications for global access ahead of patent expiry. medRxiv. 2026. doi:10.64898/2026.03.04.26347508. (~10 countries, ~44% of population / ~48% obesity burden; generic injectable ~$28-140, oral ~$186-380 per person-year; 160 countries by end-2026 = 69% T2DM, 84% obesity).
86. Tatum M, et al. Are India and China ready for a surge of generic obesity drugs? / Indian biosimilar launches and Pharmarack market estimates. Lancet / trade reporting. 2026. (Dr Reddy's and other Indian manufacturers; 50+ brands anticipated in India). (verify).
87. GBD/Lancet obesity projection and International Diabetes Federation data on India's overweight/obesity (~440 million by 2050) and diabetes burden. (user-supplied context; verify primary source).
88. Basu S, Yudkin JS, Kehlenbrink S, et al. Expanding access to newer medicines for people with type 2 diabetes in low-income and middle-income countries: a cost-effectiveness and price-target analysis (HPACC). Lancet Diabetes Endocrinol. 2021;9:825-836. (SGLT2i target ~$214-224/person-year; GLP-1 RA ~$199-208/person-year).
89. Reduced insulin use and diabetes complications upon introduction of SGLT-2 inhibitors and GLP-1 receptor agonists in low- and middle-income countries: a microsimulation. PLoS Med. 2025;22:e1004559. doi:10.1371/journal.pmed.1004559.
2. Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes (ACCORD). N Engl J Med. 2008;358:2545-2559.
3. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.
4. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes (VADT). N Engl J Med. 2009;360:129-139.
5. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes (EMPA-REG OUTCOME). N Engl J Med. 2015;373:2117-2128.
6. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes (CANVAS Program). N Engl J Med. 2017;377:644-657.
7. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes (DECLARE-TIMI 58). N Engl J Med. 2019;380:347-357.
8. Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes (VERTIS CV). N Engl J Med. 2020;383:1425-1435.
9. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction (DAPA-HF). N Engl J Med. 2019;381:1995-2008.
10. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure (EMPEROR-Reduced). N Engl J Med. 2020;383:1413-1424.
11. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction (EMPEROR-Preserved). N Engl J Med. 2021;385:1451-1461.
12. Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction (DELIVER). N Engl J Med. 2022;387:1089-1098.
13. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure (SOLOIST-WHF). N Engl J Med. 2021;384:117-128.
14. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy (CREDENCE). N Engl J Med. 2019;380:2295-2306.
15. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease (DAPA-CKD). N Engl J Med. 2020;383:1436-1446.
16. The EMPA-KIDNEY Collaborative Group. Empagliflozin in patients with chronic kidney disease (EMPA-KIDNEY). N Engl J Med. 2023;388:117-127.
17. Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in patients with diabetes and chronic kidney disease (SCORED). N Engl J Med. 2021;384:129-139.
18. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome (ELIXA). N Engl J Med. 2015;373:2247-2257.
19. Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes (EXSCEL). N Engl J Med. 2017;377:1228-1239.
20. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes (LEADER). N Engl J Med. 2016;375:311-322.
21. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes (SUSTAIN-6). N Engl J Med. 2016;375:1834-1844.
22. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND). Lancet. 2019;394:121-130.
23. Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (HARMONY Outcomes). Lancet. 2018;392:1519-1529.
24. Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes (PIONEER 6). N Engl J Med. 2019;381:841-851.
25. Gerstein HC, Sattar N, Rosenstock J, et al. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes (AMPLITUDE-O). N Engl J Med. 2021;385:896-907.
26. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes (SELECT). N Engl J Med. 2023;389:2221-2232. doi:10.1056/NEJMoa2307563.
27. Ryan DH, Lingvay I, Deanfield J, et al. Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial. Nat Med. 2024;30:2049-2057. doi:10.1038/s41591-024-02996-7.
28. Perkovic V, Tuttle KR, Rossing P, et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes (FLOW). N Engl J Med. 2024;391:109-121. doi:10.1056/NEJMoa2403347.
29. Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al. Semaglutide in patients with heart failure with preserved ejection fraction and obesity (STEP-HFpEF). N Engl J Med. 2023;389:1069-1084.
30. Kosiborod MN, Petrie MC, Borlaug BA, et al. Semaglutide in patients with obesity-related HFpEF and type 2 diabetes (STEP-HFpEF DM). N Engl J Med. 2024;390:1394-1407.
31. Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 trial of semaglutide in metabolic dysfunction–associated steatohepatitis (ESSENCE). N Engl J Med. 2025;392(21):2089-2099. doi:10.1056/NEJMoa2413258.
32. McGuire DK, Marx N, Mulvagh SL, et al. Oral semaglutide and cardiovascular outcomes in high-risk type 2 diabetes (SOUL). N Engl J Med. 2025;392(20). doi:10.1056/NEJMoa2501006. (verify volume/page)
33. McGuire DK, Marx N, Mulvagh SL, et al. Oral semaglutide and cardiovascular outcomes according to SGLT2 inhibitor use: prespecified analyses of the SOUL randomized trial. Circulation. 2025. doi:10.1161/CIRCULATIONAHA.125.074545.
34. Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes (SURPASS-2). N Engl J Med. 2021;385:503-515.
35. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). N Engl J Med. 2022;387:205-216.
36. Nicholls SJ, Pavo I, Bhatt DL, et al. Cardiovascular outcomes with tirzepatide versus dulaglutide in type 2 diabetes (SURPASS-CVOT). N Engl J Med. 2025;393:2409-2420. doi:10.1056/NEJMoa2505928.
37. Packer M, Zile MR, Kramer CM, et al. Tirzepatide for heart failure with preserved ejection fraction and obesity (SUMMIT). N Engl J Med. 2025;392(5):427-437. doi:10.1056/NEJMoa2410027.
38. Borlaug BA, Zile MR, Kramer CM, et al. Effects of tirzepatide on circulatory overload and end-organ damage in HFpEF and obesity: secondary analysis of SUMMIT. Nat Med. 2024;30(12):3434-3442. doi:10.1038/s41591-024-03374-z.
39. Kramer CM, Borlaug BA, Zile MR, et al. Tirzepatide reduces LV mass and paracardiac adipose tissue in obesity-related HFpEF: SUMMIT CMR substudy. J Am Coll Cardiol. 2025. doi:10.1016/j.jacc.2024.11.001.
40. Loomba R, Hartman ML, Lawitz EJ, et al. Tirzepatide for metabolic dysfunction–associated steatohepatitis with liver fibrosis (SYNERGY-NASH). N Engl J Med. 2024;391:299-310.
41. Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-hormone-receptor agonist retatrutide for obesity: a phase 2 trial. N Engl J Med. 2023;389:514-526.
42. Frías JP, Deenadayalan S, Erichsen L, et al. Cagrilintide plus semaglutide (CagriSema) in adults with overweight or obesity. Lancet. 2023;402:720-730. (verify citation)
43. Vallon V, Verma S. Effects of SGLT2 inhibitors on kidney and cardiovascular function. Annu Rev Physiol. 2021;83:503-528.
44. Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 2018;27:740-756.
45. Marx N, Husain M, Lehrke M, et al. GLP-1 receptor agonists for the reduction of atherosclerotic cardiovascular risk. Circulation. 2022;146:1882-1894.
46. Buse JB, Bain SC, Mann JFE, et al. Cardiovascular risk reduction with liraglutide and semaglutide: mediation analyses of the LEADER and SUSTAIN-6 trials. Diabetes Care. 2020;43:1546-1552. (verify citation)
47. Aroda VR, et al. Gastrointestinal adverse events with GLP-1 receptor agonists and dual GIP/GLP-1 agonists: incidence, mechanisms, and management. 2025. (narrative summary; verify primary sources).
48. Sodhi M, Rezaeianzadeh R, Kezouh A, Etminan M. Risk of gastrointestinal adverse events associated with GLP-1 receptor agonists for weight loss. JAMA. 2023;330:1795-1797.
49. He L, Wang J, Ping F, et al. Association of glucagon-like peptide-1 receptor agonist use with risk of gallbladder and biliary diseases: a systematic review and meta-analysis of randomized clinical trials. JAMA Intern Med. 2022;182:513-519. (cholelithiasis RR ~1.46).
50. Nauck MA, Friedrich N. Do GLP-1-based therapies increase cancer risk? Diabetes Care. 2013;36(Suppl 2):S245-S252. (pancreatitis/thyroid signal not confirmed in humans; verify).
51. Bezin J, Gouverneur A, Penichon M, et al. GLP-1 receptor agonists and the risk of thyroid cancer. Diabetes Care. 2023;46:384-390.
52. Hathaway JT, Shah MP, Hathaway DB, et al. Risk of nonarteritic anterior ischemic optic neuropathy in patients prescribed semaglutide. JAMA Ophthalmol. 2024;142:732-739. doi:10.1001/jamaophthalmol.2024.2296.
53. Simonsen E, Lund LC, Ernst MT, et al. Use of semaglutide and risk of non-arteritic anterior ischemic optic neuropathy: a Danish-Norwegian cohort study. Diabetes Obes Metab. 2025;27:1-10. doi:10.1111/dom.16316.
54. World Health Organization. The use of semaglutide medicines and risk of non-arteritic anterior ischemic optic neuropathy (NAION). WHO Pharmaceuticals Newsletter / safety alert, June 2025.
55. Neeland IJ, Linge J, Birkenfeld AL. Changes in lean body mass with GLP-1-based therapies and mitigation strategies. Diabetes Obes Metab. 2024;26(Suppl 4):16-27. doi:10.1111/dom.15728.
56. Heymsfield SB, Smith B, Wong M, et al. Total and regional appendicular skeletal muscle mass prediction from dual-energy X-ray absorptiometry body composition models. Sci Rep. 2023;13:5363. (DXA lean mass ~0.46 of total, ~0.70 of appendicular is skeletal muscle; whole-body MRI reference standard).
57. Buckinx F, Landi F, Cesari M, et al. Pitfalls in the measurement of muscle mass: a need for a reference standard. J Cachexia Sarcopenia Muscle. 2018;9:269-278.
58. Prado CM, Cawthon PM, Heymsfield SB, et al. Fundamental body-composition principles provide context for fat-free and skeletal-muscle loss with GLP-1 RA treatments. J Endocr Soc. 2024;8:bvae164. doi:10.1210/jendso/bvae164. (DXA cannot distinguish functional from fat-infiltrated muscle).
59. Tavoian D, Ampomah K, Amano S, et al. Changes in DXA-derived lean mass and MRI-derived cross-sectional area of the thigh are modestly associated. Sci Rep. 2019;9:10028. (DXA-MRI discordance in intervention trials; verify).
60. Cawthon PM, Orwoll ES, Peters KE, et al. Strong relation between muscle mass determined by D3-creatine dilution, physical performance, and incident falls and disability in older men (MrOS). J Gerontol A Biol Sci Med Sci. 2019;74:844-852.
61. Nuffer W, Trujillo JM. Lean mass loss and muscle-preserving co-therapies (bimagrumab, enobosarm, pemvidutide) with incretin-based weight loss: a review. 2025. (verify primary trials).
62. Qiu M, Ding LL, Zhan ZL, Liu SY. Sodium-glucose cotransporter 2 inhibitors and adverse events: meta-analysis (DKA RR ~2.57; genital infection; volume depletion RR 1.14; amputation RR 1.21; fracture). 2021.
63. Goldenberg RM, et al. Sodium-glucose cotransporter 2 inhibitors and diabetic ketoacidosis risk, including type 1 diabetes and sotagliflozin (FDA estimate ~1 case per 26 patient-years). 2021. (verify primary source).
64. Toyama T, Neuen BL, Jun M, et al. Genital infections and other safety outcomes with SGLT2 inhibitors: systematic review and meta-analysis. Diabetes Obes Metab. 2019;21:1237-1250. (genital infection RR ~2.86-3.75).
65. US Food and Drug Administration. FDA warns about rare occurrences of a serious infection of the genital area (Fournier's gangrene) with SGLT2 inhibitors. Drug Safety Communication, August 2018.
66. Lee SH, Kim JH. Time in range from continuous glucose monitoring: a novel metric for glycemic control. (review of HbA1c limitations: anemia, pregnancy, liver disease, hemoglobinopathy; glycemic variability). 2021. (verify).
67. Wright EE, et al. A view beyond HbA1c: role of continuous glucose monitoring. Diabetes Ther. (HbA1c unreliable in anemia, hemoglobinopathy, liver disease, iron deficiency; misses variability and hypoglycemia). (verify).
68. Toyama M, et al. Continuous glucose monitoring metrics in the assessment of glycemia in moderate-to-advanced CKD in diabetes. Kidney Int Rep. 2022. (GMI-HbA1c correlation attenuates with CKD stage: G3b r=0.68, G4 r=0.52, G5 r=0.22).
69. Inker LA, Heerspink HJL, Tighiouart H, et al. GFR slope as a surrogate endpoint for kidney disease progression in clinical trials: an individual participant-level meta-analysis (186,312 participants, 66 trials). (verify exact citation).
70. NKF-FDA-EMA workshop / Japan CKD Database analysis. eGFR slope as a surrogate endpoint for early CKD; acute eGFR dip with RAS inhibitors, finerenone, and SGLT2 inhibitors; 2-3 year slope; combining slope with albuminuria improves prediction. Clin Exp Nephrol. 2023-2024. (verify).
71. Herrington WG, et al. Effects of empagliflozin on conventional and exploratory acute and chronic kidney outcomes: an individual participant-level meta-analysis (EMPA-REG, EMPEROR-Reduced/Preserved, EMPA-KIDNEY). Lancet Diabetes Endocrinol. 2025. doi:10.1016/S2213-8587(25)00222-0.
72. Gaudino M, Hameed I, Khan FM, Braunwald E, Stone GW, et al. Trialists call for a rethink of MACE as a primary endpoint in cardiovascular trials. 2024. (heterogeneous components; varying definitions; obscures individual effects). (verify exact citation).
73. Kip KE, Hollabaugh K, Marroquin OC, Williams DO. The problem with composite end points in cardiovascular studies: the story of MACE and PCI. J Am Coll Cardiol. 2008;51:701-707. (no standard MACE definition; term MACE should not be used).
74. U.S. FDA Adverse Event Reporting System (FAERS) Essentials: a guide to understanding, applying, and interpreting adverse-event data; limitations of disproportionality analysis (no denominator, reporting/selection bias, confounding by indication). 2024. (verify).
75. Pharmacovigilance analysis of neurological adverse events associated with GLP-1 receptor agonists based on FAERS. Sci Rep. 2025;15. (disproportionality signal does not establish causality; selection bias tied to public awareness; cannot estimate incidence).
76. Wright JD, Chen L, Xu X, et al. GLP-1 receptor agonist use and the risk of pulmonary aspiration in patients undergoing surgery. Int J Surg. 2025. doi:10.1097/JS9.0000000000002425. (aspiration ~0.8%, no significant excess).
77. Ushakumari DS, Sladen RN; ASA, AGA, and 2025 ADS/ANZCA/GESA/NACOS multisociety guidance on peri-procedural management of GLP-1/GIP receptor agonists; FDA label update November 2024. (composite; verify individual sources).
78. Hashash JG, Thompson CC, Wang AY, et al. AGA rapid clinical practice update on the management of patients taking GLP-1 receptor agonists prior to endoscopy. Clin Gastroenterol Hepatol. 2024;22:705-707.
79. Aronne LJ, Sattar N, Horn DB, et al. Continued treatment with tirzepatide for maintenance of weight reduction (SURMOUNT-4). JAMA. 2024;331:38-48. doi:10.1001/jama.2023.24945.
80. Horn DB, Linetzky B, Davies MJ, et al. Cardiometabolic parameter change by weight regain on tirzepatide withdrawal: post hoc analysis of SURMOUNT-4. JAMA Intern Med. 2025. doi:10.1001/jamainternmed.2025.6112.
81. Jastreboff AM, et al. Tirzepatide for maintenance of bodyweight reduction in people with obesity (SURMOUNT-MAINTAIN). Lancet. 2026. doi:10.1016/S0140-6736(26)00656-2. (5 mg maintenance alternative to discontinuation).
82. Alawadhi AA, Alroudhan D, Alsaeed DJ, et al. LEAN mass Preservation with Resistance Exercise and Protein during semaglutide and tirzepatide therapy (LEAN-PREP study): a protocol for a randomised controlled trial. BMJ Open. 2026; 16(4): e116911.
83. Tinsley GM, Nadolsky S. Preservation of lean soft tissue during weight loss induced by GLP-1 and GLP-1/GIP receptor agonists: a case series. SAGE Open Med Case Rep. 2025;13:2050313X251388724.
84. Haines MS, et al. Older age, female sex, and lower protein intake are associated with greater muscle loss in adults with obesity prescribed semaglutide. Presented at: ENDO 2025 (Endocrine Society Annual Meeting); July 12–15, 2025; San Francisco, CA.
85. IQVIA / medRxiv preprint. How low could semaglutide prices fall? An analysis of production cost and implications for global access ahead of patent expiry. medRxiv. 2026. doi:10.64898/2026.03.04.26347508. (~10 countries, ~44% of population / ~48% obesity burden; generic injectable ~$28-140, oral ~$186-380 per person-year; 160 countries by end-2026 = 69% T2DM, 84% obesity).
86. Tatum M, et al. Are India and China ready for a surge of generic obesity drugs? / Indian biosimilar launches and Pharmarack market estimates. Lancet / trade reporting. 2026. (Dr Reddy's and other Indian manufacturers; 50+ brands anticipated in India). (verify).
87. GBD/Lancet obesity projection and International Diabetes Federation data on India's overweight/obesity (~440 million by 2050) and diabetes burden. (user-supplied context; verify primary source).
88. Basu S, Yudkin JS, Kehlenbrink S, et al. Expanding access to newer medicines for people with type 2 diabetes in low-income and middle-income countries: a cost-effectiveness and price-target analysis (HPACC). Lancet Diabetes Endocrinol. 2021;9:825-836. (SGLT2i target ~$214-224/person-year; GLP-1 RA ~$199-208/person-year).
89. Reduced insulin use and diabetes complications upon introduction of SGLT-2 inhibitors and GLP-1 receptor agonists in low- and middle-income countries: a microsimulation. PLoS Med. 2025;22:e1004559. doi:10.1371/journal.pmed.1004559.
Article Sidebar
Published
Jun 16, 2026
Article Details
How to Cite
Kaustubh Bhardwaj, Himanshi Bhardwaj, Amit Tripathi, Latika Tolia, Snigdh Agarwal, Devashish Srivastava, & Swaraj Verma. (2026). FUTURE CHALLENGES AND EMERGING SAFETY CONCERNS OF GLP-1 RECEPTOR AGONISTS, DUAL INCRETIN AGONISTS, AND SGLT2 INHIBITORS. Journal of Population Therapeutics and Clinical Pharmacology, 33(2), 963-981. https://doi.org/10.69980/mng8r305
Section
Articles
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
All articles published in JPTCP are licensed under Copyright Creative Commons Attribution-NonCommercial 4.0 International License.
Author Biographies
Kaustubh Bhardwaj
Department of Pharmacology & Therapeutics, King George’s Medical University, Lucknow – 226003, Uttar Pradesh, India.
Himanshi Bhardwaj
Department of Pharmacology & Therapeutics, King George’s Medical University, Lucknow – 226003, Uttar Pradesh, India.
Amit Tripathi
Department of Pharmacology & Therapeutics, King George’s Medical University, Lucknow – 226003, Uttar Pradesh, India.
Latika Tolia
Department of Pharmacology & Therapeutics, King George’s Medical University, Lucknow – 226003, Uttar Pradesh, India.
Snigdh Agarwal
Department of Pharmacology & Therapeutics, King George’s Medical University, Lucknow – 226003, Uttar Pradesh, India.
Devashish Srivastava
Department of Pharmacology & Therapeutics, King George’s Medical University, Lucknow – 226003, Uttar Pradesh, India.
Swaraj Verma
Department of Pharmacology & Therapeutics, King George’s Medical University, Lucknow – 226003, Uttar Pradesh, India.
How to Cite
Kaustubh Bhardwaj, Himanshi Bhardwaj, Amit Tripathi, Latika Tolia, Snigdh Agarwal, Devashish Srivastava, & Swaraj Verma. (2026). FUTURE CHALLENGES AND EMERGING SAFETY CONCERNS OF GLP-1 RECEPTOR AGONISTS, DUAL INCRETIN AGONISTS, AND SGLT2 INHIBITORS. Journal of Population Therapeutics and Clinical Pharmacology, 33(2), 963-981. https://doi.org/10.69980/mng8r305
