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Exploring Glycemic Challenges With Experts in T2DM

Addressing the Physiologic Complexities of Type 2 Diabetes

Dr. Lawrence Blonde delves into eight physiologic abnormalities, known as the Ominous Octet, involved in type 2 diabetes and how you can use different therapeutic classes to target them in your patients.

Title: Addressing the Physiologic Complexities of Type 2 Diabetes

One of the key ideas in this video series is our need for greater awareness of the complex physiology of type 2 diabetes as we manage the disease.

This starts with the acknowledgment of the core physiologic defects. These are insulin resistance in muscle and the liver, along with decreased β-cell function.

Decreased β-cell function reduces insulin secretion, while insulin resistance in muscle and the liver reduces glucose uptake from blood. Together, these defects elevate the blood glucose levels of patients with type 2 diabetes.

There are, however, at least 5 other physiologic abnormalities contributing to glucose intolerance.

These are:

  • Decreased incretin effect in the GI tract
  • Increased insulin resistance in adipose cells
  • Increased glucose reabsorption by the kidneys
  • Neurotransmitter dysfunction in the brain and central nervous system
  • And increased glucagon secretion by pancreatic α-cells

Taken together, these 8 physiologic abnormalities are often referred to as the “Ominous Octet.”

The presence of multiple physiologic abnormalities could have important implications.

First, multiple therapies may be needed in combination to manage the multiple abnormalities that are associated with hyperglycemia.

Second, drug actions that target and help address these known physiologic abnormalities should be considered.

Third, to slow progressive loss of β-cell function, treatment should be started early.

By now, it’s common practice to treat patients with multiple therapies. In our clinical practices, we try various therapies and combine therapies as patient A1c levels exceed targets. In fact, treatment algorithms from the ADA and AACE recommend the use of combinations of oral therapies and combinations of injectable therapies.

As multiple physiologic abnormalities contribute to hyperglycemia, multiple drug classes are available to help address them. In fact, each of the 8 abnormalities that comprise the “Ominous Octet” can be targeted by one or more classes of antihyperglycemic therapies, as you can see here. Some of the abnormalities can be targeted with several treatments, while some of the treatments can target multiple abnormalities.

One of the founding principles of the AACE guidelines acknowledges the need for multiple-drug regimens, and recommends combinations using therapies with complementary mechanisms of action.

In appropriate patients, an approach that addresses the physiologic abnormalities of type 2 diabetes may include combining therapies that target different pathways.

References: 1. DeFronzo RA. From the triumvirate to the ominous octect: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773-795. doi:10.2337/db09-9028. 2. Aronoff SL, Berkowitz K, Shreiner B, Want L. Glucose metabolism and regulation: beyond insulin and glucagon. Diabetes Spectrum. 2004;17(3):183-190. doi:org/10.2337/diaspect.17.3.183. 3. Ferrannini E, DeFronzo RA. Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes. Eur Heart J. 2015;36(34):2288-2296. doi:10.1093/eurheartj/ehv239. 4. DeFronzo RA, Eldor R, Abdul-Ghani M. Pathophysiologic approach to therapy in patients with newly diagnosed type 2 diabetes. Diabetes Care. 2013;36(Suppl 2):S127-S138. doi:10.2337/dcS13-2013. 5. ADA standards of medical care in diabetes—2016. Diabetes Care. 2016;39(Suppl 1):S1-S112. 6. Garber AJ, Barzilay JI, Bloomgarden ZT, et al; American Association of Clinical Endocrinologists; American College of Endocrinology. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2016 executive summary. Endocr Pract. 2016;22(1):84-113. doi:10.4158/EP151126.CS. 7. Balena R, Hensley IE, Miller S, et al. Combination therapy with GLP-1 receptor agonists and basal insulin: a systematic review of the literature. Diabetes Obes Metab. 2013;15(6):485-502. doi:10.1111/dom.12025. 8. Bethel MA, Feinglos MN. Basal insulin therapy in type 2 diabetes. J Am Board Fam Pract. 2005;18(3):199-204.