Multiple Systems in T2D
T2D is driven by several pathophysiological defects, many of which can now be addressed with available therapies that enable individualizing treatment3,5
Multisystem Contributors Are Associated With Hyperglycemia and the Progression of T2D3,5
The graphic shows which processes in different organ systems can contribute to the development of hyperglycemia. In the kidney: Increased reabsorption of glucose. In the stomach/small intestine: Increased glucose uptake. At the level of the immune system: Dysregulation or inflammation. In the colon/microbiome: Abnormal microbiota, possibly reduced secretion of GLP-1. Dysfunction of neurotransmitters: Increased appetite and food intake. In the liver: Increased glucose production and hepatic insulin resistance. In the muscle: Reduced uptake of glucose into the peripheral muscle due to insulin resistance. In adipose tissue: Increased lipolysis. In the α-cells of the pancreas: Increased glucagon production. In the β-cells of the pancreas: Reduction in insulin production, reduction in the incretin effect and loss of cell mass of the β-cells.
Many different systems contribute to hyperglycemia directly and indirectly. Excess adipose is an important contributor. It is important to consider that many of these changes may begin years before a person is diagnosed and continue to worsen in the absence of specific medical interventions.6-12
Medications have unique roles in treating the metabolic mechanisms that drive T2D progression5,13,14
Medications treat core defects of T2D differently across classes, with some medications treating more core defects than others3,5,13,14
| Class | Direct Primary Physiological Action(s) | Pathophysiology |
|---|---|---|
| Biguanide (metformin) | Reduces hepatic glucose production | Liver |
| Sulfonylurea (SU) | Increases insulin secretion | Pancreatic β-cell |
| Thiazolidinedione (TZD) | Increases insulin sensitivity | Whole body |
| Dipeptidyl peptidase-4 (DPP-4) inhibitor |
|
|
| Sodium-glucose contransporter-2 (SGLT2) inhibitor | Blocks glucose reabsorption by the kidney, increasing glucosuria | Kidney |
| Glucagon-like peptide-1 receptor agonist (GLP-1 RA) |
|
|
| Glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist (GIP/GLP-1 RA) |
|
|
The schematic is intended to provide an overview of T2D drugs and is not specific to only 1 product within each class listed. It is not limited to making any expressed or implied comparison among products. The classes shown are from the ADA Standards of Care and do not represent all T2D classes available to treat hyperglycemia.
Which class would you choose for a patient like Ahmed?
Ahmed is showing signs of multiple core defects of T2D, including insulin resistance and excess adiposity, based on his elevated HbA1c and waist-to-hip ratio. Most urgently, these defects tend to be progressive and indicate that Ahmed is likely experiencing an ongoing decline in his β-cell function.3,5
Medications with the ability to address multiple defects, including excess adiposity, enable more comprehensive and effective T2D management.3
- Davies MJ, Aroda VR, Collins BS, et al. Management of hyperglycemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2022;45(11):2753-2786. doi:10.2337/dci22-0034
- Kendall DM, Cuddihy RM, Bergenstal RM. Clinical application of incretin-based therapy: therapeutic potential, patient selection and clinical use. Am J Med. 2009;122(6 suppl): 41 S37-S50. doi:10.1016/j.amjmed.2009.03.015
- Schwartz SS, Epstein S, Corkey BE, et al. The time is right for a new classification system for diabetes: rationale and implications of the β-cell-centric classification schema. Diabetes Care. 2016;39(2):179-186. doi:10.2337/dc15-1585
- UK Prospective Diabetes Study Group. Intensive blood-glucose control withsulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837-853. doi:10.1016/S0140-6736(98)07019-6
- DeFronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773-795. doi:10.2337/db09-9028
- Chait A, den Hartigh LJ. Adipose tissue distribution, inflammation and its metabolic consequences, including diabetes and cardiovascular disease. Front Cardiovasc Med. 2020;7:22. doi:10.3389/fcvm.2020.00022
- de Luca C, Olefsky JM. Inflammation and insulin resistance. FEBS Lett. 2008;582(1):97-105. doi:10.1016/j.febslet.2007.11.057
- Xu H, Barnes GT, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112(12):1821-1830. doi:10.1172/JCI19451
- Trouwborst I, Bowser SM, Goossens GH, Blaak EE. Ectopic fat accumulation in distinct insulin resistant phenotypes; targets for personalized nutritional interventions. Front Nutr. 2018;5:77. doi:10.3389/fnut.2018.00077
- Raji A, Seely EW, Arky RA, Simonson DC. Body fat distribution and insulin resistance in healthy Asian Indians and Caucasians. J Clin Endocrinol Metab. 2001;86(11):5366-5371. doi:10.1210/jcem.86.11.7992
- Kozawa J, Shimomura I. Ectopic fat accumulation in pancreas and heart. J Clin Med. 2021;10(6):1326. doi:10.3390/jcm10061326
- Ye R, Onodera T, Scherer PE. Lipotoxicity and β cell maintenance in obesity and type 2 diabetes. J Endocr Soc. 2019;3(3):617-631. doi:10.1210/js.2018-00372
- Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140-149. doi:10.2337/dc14-2441
- Mounjaro (tirzepatide once weekly) [Summary of Product Characteristics]. Houten, The Netherlands: Eli Lilly and Company.
- Campbell IW. Need for intensive, early glycemic control in patients with type 2 diabetes. J Brit Cardiol. 2000;7:625-631.
- Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577-1589. doi:10.1056/NEJMoa0806470
- Matthews D, Del Prato S, Mohan V, et al. Insights from VERIFY: early combination therapy provides better glycaemic durability than a stepwise approach in newly diagnosed type 2 diabetes. Diabetes Ther. 2020;11(11):2465-2476. doi:10.1007/s13300-020-00926-742
- Del Prato S, Foley JE, Kothny W, et al. Study to determine the durability of glycaemic control with early treatment with a vildagliptin-metformin combination regimen vs. standard-of-care metformin monotherapy—the VERIFY trial: a randomized double-blind trial. Diabet Med. 2014;31(10):1178-1184. doi:10.1111/dme.12508
- American Diabetes Association Professional Practice Committee. 6. Glycemic targets: Standards of Medical Care in Diabetes—2022. Diabetes Care. 2022;45(suppl 1):S83-S96.
- Gomes MB, Rathmann W, Charbonnel B, et al. Treatment of type 2 diabetes mellitus worldwide: baseline patient characteristics in the global DISCOVER study. Diabetes Res Clin Pract. 2019;151:20-32. doi:10.1016/j.diabres.2019.03.024
- Lind M, Imberg H, Coleman RL, et al. Historical HbA1c values may explain the type 2 diabetes legacy effect: UKPDS 88. Diabetes Care. 2021;44(10):2231-2237. doi:10.2337/dc20-2439
- Laiteerapong N, Ham SA, Gao Y, et al. The legacy effect in type 2 diabetes: impact of early glycemic control on future complications (The Diabetes & Aging Study). Diabetes Care. 2019;42(3):416-426. doi:10.2337/dc17-1144