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Vaibhav Lasure,
Sakshi Shankhapal,
Pratiksha Sonawane,
Santosh Bansode,
Sachin Hodgar,
Vivekanand Kashid,
Pallavi Sonawane,
- Assistant Professor, Department of Pharmacology,Dr Kolpe Institute of Pharmacy,Ahmednagar, Maharashtra, Maharashtra, India
- Student, Department of Pharmacology,Dr Kolpe Institute of Pharmacy,Ahmednagar, Maharashtra, India
- Associate Professor, Department of Pharmacology,Dr Kolpe Institute of Pharmacy,Ahmednagar, Maharashtra, India
- Associate Professor, Department of Pharmacology,Dr Kolpe Institute of Pharmacy,Ahmednagar, Maharashtra, India
- Associate Professor, Department of Pharmacology,Dr Kolpe Institute of Pharmacy,Ahmednagar, Maharashtra, India
- Principal, MABD Institute of Pharmacy, aluka, Dist, Yeola, Maharashtra, India
- Student, Department of Pharmacology,Dr Kolpe Institute of Pharmacy,Ahmednagar, Maharashtra, India
Abstract
This review provides a comprehensive analysis of drugs approved by the U.S. Food and Drug Administration (USFDA) for managing diabetes mellitus (DM) from 2013 to 2022, including emerging treatments from phase 3 clinical trials during this period. Over the past decade, the treatment landscape for diabetes has evolved significantly, with new therapies not only improving blood sugar control but also targeting broader health outcomes like heart and kidney health. In this review, we looked closely at FDA-approved drugs and also explored promising treatments still in phase 3 clinical trials—those that have shown solid results and could soon change the way diabetes is managed.We gathered information from ClinicalTrials.gov, focusing only on trials that had clear, published outcomes, to ensure our analysis was grounded in reliable data. What we found was a wide range of innovative therapies under development, each working in different ways—from targeting hormones that affect insulin release to drugs that improve how the body handles glucose. Many of these new options aim to make treatment easier, with longer-lasting effects and fewer side effects. There’s also a growing trend toward combination therapies that tackle diabetes from multiple angles at once. Our study uncovers a wide range of innovative compounds in phase 3 trials, aiming at DM through diverse action mechanisms.
Keywords: Diabetes mellitus, clinical trials, novel drugs, approved diabetes drugs,USFDA.
[This article belongs to International Journal of Toxins and Toxics ]
Vaibhav Lasure, Sakshi Shankhapal, Pratiksha Sonawane, Santosh Bansode, Sachin Hodgar, Vivekanand Kashid, Pallavi Sonawane. Emerging Therapies for Diabetes Mellitus: Efficacy and Safety of USFDA-Approved Drugs and Late-Stage Clinical Trials. International Journal of Toxins and Toxics. 2025; 02(02):-.
Vaibhav Lasure, Sakshi Shankhapal, Pratiksha Sonawane, Santosh Bansode, Sachin Hodgar, Vivekanand Kashid, Pallavi Sonawane. Emerging Therapies for Diabetes Mellitus: Efficacy and Safety of USFDA-Approved Drugs and Late-Stage Clinical Trials. International Journal of Toxins and Toxics. 2025; 02(02):-. Available from: https://journals.stmjournals.com/ijtt/article=2025/view=208710
References
- Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007;316(5826):889-94.
- Hu FB, Manson JE, Stampfer MJ, Colditz G, Liu S, Solomon CG, et al. Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. N Engl J Med. 2001;345(11):790-7.
- Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet. 2014;383(9922):1068-83.
- Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet. 2014;383(9911):69-82.
- Dhankhar S, Chauhan S, Mehta DK, Nitika, Saini K, Saini M, et al. Novel targets for potential therapeutic use in Diabetes mellitus. Diabetol Metab Syndr. 2023;15(1):17.
- Chen J, Luo X, Qiu H, Mackey V, Sun L, Ouyang X. Drug discovery and drug marketing with the critical roles of modern administration. Am J Transl Res. 2018;10(12):4302-12.
- White WB, Pratley R, Fleck P, Munsaka M, Hisada M, Wilson C, et al. Cardiovascular safety of the dipetidyl peptidase-4 inhibitor alogliptin in type 2 diabetes mellitus. Diabetes Obes Metab. 2013;15(7):668-73.
- Jabbour SA, Hardy E, Sugg J, Parikh S. Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24-week, multicenter, randomized, double-blind, placebo-controlled study. Diabetes Care. 2014;37(3):740-50.
- Fala L. Invokamet (Canagliflozin plus Metformin HCl): First Fixed-Dose Combination with an SGLT2 Inhibitor Approved for the Treatment of Patients with Type 2 Diabetes. Am Health Drug Benefits. 2015;8(Spec Feature):70-4.
- Fala L. Tanzeum (Albiglutide): A Once-Weekly GLP-1 Receptor Agonist Subcutaneous Injection Approved for the Treatment of Patients with Type 2 Diabetes. Am Health Drug Benefits. 2015;8(Spec Feature):126-30.
- Raedler LA. Tresiba (Insulin Degludec Injection) and Ryzodeg 70/30 (Insulin Degludec and Insulin Aspart Injection): Two New Insulin Analogs for Glycemic Control in Diabetes Mellitus. Am Health Drug Benefits. 2016;9(Spec Feature):144-8.
- Raedler LA. Glyxambi (Empagliflozin/Linagliptin): A Dual-Acting Oral Medication Approved for the Treatment of Patients with Type 2 Diabetes. Am Health Drug Benefits. 2015;8(Spec Feature):171-5.
- Leon N, LaCoursiere R, Yarosh D, Patel RS. Lixisenatide (Adlyxin): A Once-Daily Incretin Mimetic Injection for Type-2 Diabetes. P T. 2017;42(11):676-711.
- Lingvay I, Pérez Manghi F, García-Hernández P, Norwood P, Lehmann L, Tarp-Johansen MJ, et al. Effect of Insulin Glargine Up-titration vs Insulin Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients With Uncontrolled Type 2 Diabetes: The DUAL V Randomized Clinical Trial. JAMA. 2016;315(9):898-907.
- Sorli C, Harashima SI, Tsoukas GM, Unger J, Karsbøl JD, Hansen T, et al. Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. Lancet Diabetes Endocrinol. 2017;5(4):251-60.
- Marrs JC, Anderson SL. Ertugliflozin in the treatment of type 2 diabetes mellitus. Drugs Context. 2020;9:1-12.
- Vilsbøll T, Ekholm E, Johnsson E, Dronamraju N, Jabbour S, Lind M. Dapagliflozin plus saxagliptin add-on therapy compared with insulin in patients with type 2 diabetes poorly controlled by metformin with or without sulfonylurea therapy: a randomized clinical trial. Diabetes Care. 2019;42(8):1464-72.
- Pieber TR, Aronson R, Hövelmann U, Willard J, Plum-Mörschel L, Knudsen KM, et al. Dasiglucagon—a next-generation glucagon analog for rapid and effective treatment of severe hypoglycemia: results of phase 3 randomized double-blind clinical trial. Diabetes Care. 2021;44(6):1361-7.
- Rosenstock J, Frías JP, Rodbard HW, Tofé S, Sears E, Huh R, et al. Tirzepatide vs insulin lispro added to basal insulin in type 2 diabetes: The SURPASS-6 randomized clinical trial. JAMA. 2023;330(17):1631-40.
- Matsuhisa M, Takita Y, Nasu R, Nagai Y, Ohwaki K, Nagashima H. Nasal glucagon as a viable alternative for treating insulin-induced hypoglycaemia in Japanese patients with type 1 or type 2 diabetes: a phase 3 randomized crossover study. Diabetes Obes Metab. 2020;22(7):1167-75.
- Sheu WH, Gantz I, Chen M, Suryawanshi S, Mirza A, Goldstein BJ, et al. Safety and efficacy of omarigliptin (MK-3102), a novel once-weekly DPP-4 inhibitor for the treatment of patients with type 2 diabetes. Diabetes Care. 2015;38(11):2106-14.
- Yamamoto F, Unno Y, Okamura T, Ikeda R, Ochiai K, Hayashi N. Long-term safety and effectiveness of linagliptin in Japanese patients with type 2 diabetes mellitus: a 3-year post-marketing surveillance study. Diabetes Ther. 2020;11(1):107-17.
- Kim SS, Kim IJ, Lee KJ, Park JH, Kim YI, Lee YS, et al. Efficacy and safety of sitagliptin/metformin fixed-dose combination compared with glimepiride in patients with type 2 diabetes: a multicenter randomized double-blind study. J Diabetes. 2017;9(4):412-22.
- Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(3):232-42.
- Lukashevich V, Del Prato S, Araga M, Kothny W. Efficacy and safety of vildagliptin in patients with type 2 diabetes mellitus inadequately controlled with dual combination of metformin and sulphonylurea. Diabetes Obes Metab. 2014;16(5):403-9.
- Gantz I, Sokolova L, Jain L, Iredale C, O’Neill EA, Wei Z, et al. Use of prohibited medication, a potentially overlooked confounder in clinical trials: omarigliptin (once-weekly DPP-4 inhibitor) monotherapy trial in 18- to 45-year-olds. Clin Ther. 2017;39(10):2024-37.
- Garg SK, Wernicke-Panten K, Wardecki M, Kramer D, Delalande F, Franek E, et al. Efficacy and safety of insulin aspart biosimilar SAR341402 versus originator insulin aspart in people with diabetes treated for 26 weeks with multiple daily injections in combination with insulin glargine: A randomized open-label trial (GEMELLI 1). Diabetes Technol Ther. 2020;22(2):85-95.
- Hsu L, Buckingham B, Basina M, Ekhlaspour L, von Eyben R, Wang J, et al. Fast-acting insulin aspart use with the MiniMed™ 670G system. Diabetes Technol Ther. 2021;23(1):1-7.
- Scheen AJ. Dulaglutide (LY-2189265) for the treatment of type 2 diabetes. Expert Rev Clin Pharmacol. 2016;9(3):385-99.
- Bode B, Stenlöf K, Sullivan D, Fung A, Usiskin K. Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hosp Pract (1995). 2013;41(2):72-80.
- Hollander P, Liu J, Hill J, Johnson J, Jiang ZW, Golm G, et al. Ertugliflozin compared with glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin: the VERTIS SU randomized study. Diabetes Ther. 2018;9(1):193-207.
- Kaku K, Kadowaki T, Seino Y, Okamoto T, Shirakawa M, Sato A, et al. Efficacy and safety of ipragliflozin in Japanese patients with type 2 diabetes and inadequate glycaemic control on sitagliptin. Diabetes Obes Metab. 2021;23(9):2099-108.
- Seman L, Macha S, Nehmiz G, Simons G, Ren B, Pinnetti S, et al. Empagliflozin (BI 10773), a potent and selective SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin Pharmacol Drug Dev. 2013;2(2):152-61.
- Pasqualotto E, Figueiredo Watanabe JM, Gewehr DM, da Silva Maintinguer R, van de Sande-Lee S, de Araujo GN, et al. Efficacy and safety of bexagliflozin in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Obes Metab. 2023;25(7):1794-802.
- Bhagavathula AS, Vidyasagar K, Tesfaye W. Efficacy and safety of tirzepatide in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized phase II/III trials. Pharmaceuticals (Basel). 2021;14(10):951.
- Ludvik B, Giorgino F, Jódar E, Frias JP, Fernández Landó L, Brown K, et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. Lancet. 2021;398(10300):583-96.
- Liu F, Liu Y, Liu M, Wu G, Zhang M, Zhang X, et al. Efficacy of once-daily glucagon-like peptide-1 receptor agonist lixisenatide as an add-on treatment to basal insulin in Asian and white adults with type 2 diabetes mellitus: an individual-level pooled analysis of phase III studies. J Diabetes Investig. 2021;12(8):1386-94.
- Lee SH, Gantz I, Round E, Latham M, O’Neill EA, Ceesay P, et al. A randomized, placebo-controlled clinical trial evaluating the safety and efficacy of the once-weekly DPP-4 inhibitor omarigliptin in patients with type 2 diabetes mellitus inadequately controlled by glimepiride and metformin. BMC Endocr Disord. 2017;17(1):70.
- Dagogo-Jack S, Liu J, Eldor R, Amorin G, Johnson J, Hille D, et al. Efficacy and safety of the addition of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sitagliptin: The VERTIS SITA2 placebo-controlled randomized study. Diabetes Obes Metab. 2018;20(3):530-40.
- Patel CA, Bailey RA, Vijapurkar U, Meininger G, Blonde L. A post-hoc analysis of the comparative efficacy of canagliflozin and glimepiride in the attainment of type 2 diabetes-related quality measures. BMC Health Serv Res. 2016;16:356.
- Kaku K, Enya K, Nakaya R, Ohira T, Matsuno R. Long-term safety and efficacy of fasiglifam (TAK-875), a G-protein-coupled receptor 40 agonist, as monotherapy and combination therapy in Japanese patients with type 2 diabetes: a 52-week open-label phase III study. Diabetes Obes Metab. 2016;18(9):925-9.
- Blonde L, Belousova L, Fainberg U, Garcia-Hernandez PA, Jain SM, Kaltoft MS, et al. Liraglutide as add-on to sodium-glucose co-transporter-2 inhibitors in patients with inadequately controlled type 2 diabetes: LIRA-ADD2SGLT2i, a 26-week, randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2020;22(6):929-37.
- Pratley RE, Eldor R, Raji A, Golm G, Huyck SB, Qiu Y, et al. Ertugliflozin plus sitagliptin versus either individual agent over 52 weeks in patients with type 2 diabetes mellitus inadequately controlled with metformin: The VERTIS FACTORIAL randomized trial. Diabetes Obes Metab. 2018;20(5):1111-20.
- Roussel R, Duran-García S, Zhang Y, Shah S, Darmiento C, Shankar RR, et al. Double-blind, randomized clinical trial comparing the efficacy and safety of continuing or discontinuing the dipeptidyl peptidase-4 inhibitor sitagliptin when initiating insulin glargine therapy in patients with type 2 diabetes: The CompoSIT-I Study. Diabetes Obes Metab. 2019;21(4):781-90.
- Del Prato S, Taskinen MR, Owens DR, von Eynatten M, Emser A, Gong Y, et al. Efficacy and safety of linagliptin in subjects with type 2 diabetes mellitus and poor glycemic control: pooled analysis of data from three placebo-controlled phase III trials. J Diabetes Complications. 2013;27(3):274-9.
- Frias JP, Zimmer Z, Lam RLH, Amorin G, Ntabadde C, Iredale C, et al. Double-blind, randomized clinical trial assessing the efficacy and safety of early initiation of sitagliptin during metformin uptitration in the treatment of patients with type 2 diabetes: The CompoSIT-M study. Diabetes Obes Metab. 2019;21(5):1128-35.
- Kadowaki T, Inagaki N, Kondo K, Nishimura K, Kaneko G, Maruyama N, et al. Efficacy and safety of canagliflozin as add-on therapy to teneligliptin in Japanese patients with type 2 diabetes mellitus: results of a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2017;19(6):874-82.
- Zhang L, Zhang M, Zhang Y, Tong N. Efficacy and safety of dulaglutide in patients with type 2 diabetes: a meta-analysis and systematic review. Sci Rep. 2016;6:18904.
- Aronow WS, Shamliyan TA. Comparative effectiveness and safety of empagliflozin on cardiovascular mortality and morbidity in adults with type 2 diabetes. Ann Transl Med. 2017;5(23):455.
- Bergenstal RM, Rosenstock J, Arakaki RF, Prince MJ, Qu Y, Sinha VP, et al. A randomized, controlled study of once-daily LY2605541, a novel long-acting basal insulin, versus insulin glargine in basal insulin-treated patients with type 2 diabetes. Diabetes Care. 2012;35(11):2140-7.
- Feng W, Chen W, Jiang S, Du L, Zhu D. Efficacy and safety of LY2963016 insulin glargine versus insulin glargine (Lantus) in Chinese adults with type 2 diabetes: a phase III, randomized, open-label, controlled trial. Diabetes Obes Metab. 2021;23(8):1786-94.
- Hollander PA, Carofano WL, Lam RLH, Golm GT, Eldor R, Crutchlow MF, et al. Efficacy and safety of MK-1293 insulin glargine compared with originator insulin glargine (Lantus) in type 2 diabetes: a randomized, open-label clinical trial. Diabetes Obes Metab. 2018;20(9):2229-37.
- Grunberger G, Bhargava A, Ly T, Zisser H, Ilag LL, Malone J, et al. Human regular U-500 insulin via continuous subcutaneous insulin infusion versus multiple daily injections in adults with type 2 diabetes: The VIVID study. Diabetes Obes Metab. 2020;22(3):434-41.
- Garg SK, Wernicke-Panten K, Rojeski M, Pierre S, Kirchhein Y, Jedynasty K. Efficacy and safety of biosimilar SAR342434 insulin lispro in adults with type 1 diabetes also using insulin glargine – SORELLA 1 Study. Diabetes Technol Ther. 2017;19(9):516-26.
- Frias JP, Bonora E, Nevarez Ruiz L, Li YG, Yu Z, Milicevic Z, et al. Efficacy and safety of dulaglutide 3.0 mg and 4.5 mg versus dulaglutide 1.5 mg in metformin-treated patients with type 2 diabetes in a randomized controlled trial (AWARD-11). Diabetes Care. 2021;44(3):765-73.
- Gantz I, Okamoto T, Ito Y, Sato A, Okuyama K, O’Neill EA, et al. A randomized, placebo-controlled trial evaluating the safety and efficacy of adding omarigliptin to antihyperglycemic therapies in Japanese patients with type 2 diabetes and inadequate glycemic control. Diabetes Ther. 2017;8(4):793-810.
- Miura J, Imori M, Nishiyama H, Imaoka T. Ultra-rapid lispro efficacy and safety compared to Humalog® in Japanese patients with type 1 diabetes: PRONTO-T1D subpopulation analysis. Diabetes Ther. 2020;11(9):2089-104.
- Burant CF, Viswanathan P, Marcinak J, Cao C, Vakilynejad M, Xie B, et al. TAK-875 versus placebo or glimepiride in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2012;379(9824):1403-11.
- Marcinak JF, Munsaka MS, Watkins PB, Ohira T, Smith N. Liver safety of fasiglifam (TAK-875) in patients with type 2 diabetes: review of the global clinical trial experience. Drug Saf. 2018;41(6):625-40.
- Chaudhury A, Duvoor C, Reddy Dendi VS, Kraleti S, Chada A, Ravilla R, et al. Clinical review of antidiabetic drugs: implications for type 2 diabetes mellitus management. Front Endocrinol (Lausanne). 2017;8:6.
- Dahlén AD, Dashi G, Maslov I, Attwood MM, Jonsson J, Trukhan V, et al. Trends in antidiabetic drug discovery: FDA approved drugs, new drugs in clinical trials and global sales. Front Pharmacol. 2021;12:807548.
- Benedetto Tiz D, Bagnoli L, Rosati O, Marini F, Santi C, Sancineto L. FDA-approved small molecules in 2022: clinical uses and their synthesis. Pharmaceutics. 2022;14(11):2362.
International Journal of Toxins and Toxics
Volume | 02 |
Issue | 02 |
Received | 21/02/2025 |
Accepted | 08/04/2025 |
Published | 12/04/2025 |
Publication Time | 50 Days |
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