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Clinical Professor of Medicine
University of Washington
Rockwood Center for Diabetes and Endocrinology
Rockwood Clinic/MultiCare Health System
Carol Hatch Wysham, MD, has disclosed that she has received funds for research support from Abbot, Allergan, Lilly, and Novo Nordisk; consulting fees from Abbott, Janssen, Novo Nordisk, and Sanofi; and fees for non-CME/CE services from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Novo Nordisk, and Sanofi.
During the past 30 years, which certainly spans my career, the prevalence of diabetes has increased dramatically. Moreover, there has been improved understanding of the importance of addressing the extraglycemia manifestations of diabetes, including cardiovascular risk factors. I was taught in medical school that insulin resistance and insulin deficiency were the causative factors of type 2 diabetes. Even then, there was controversy about which came first, and that controversy continues today. But at that time, there was no discussion about the impact of glucagon, and we certainly didn’t know anything about gut hormones and the impact they have on insulin secretion. As a result, we were somewhat stuck in an impasse of treating hyperglycemia, either by stimulating insulin secretion or replacing insulin with injection.
Incretins: The Road to Discovery
When metformin was approved in the United States in 1995, we gained a new tool, which (in addition to other actions) decreases hepatic glucose production. Still, it was clear that we were not effectively treating diabetes. With further investigation, we discovered other issues related to the control of glucose, particularly in the postprandial state. Studies performed in the 1980s revealed that the amount of insulin made with oral delivery of glucose was significantly greater than that with IV glucose. In fact, it was estimated that in a person without diabetes, 70% or more of the postprandial insulin secretion was related to oral glucose delivery, suggesting that the intestine was involved. By contrast, persons with diabetes have a markedly blunted release of insulin after oral glucose delivery compared with IV, suggesting an impairment in either the amount or activity of this gut factor.
Many years later, we recognized that the gut is a hormone‑secreting organ. In particular, the incretins, or intestinal secretion of insulin hormones, are released by the small intestine in response to meals and are responsible for increasing insulin secretion and appropriately suppressing glucagon secretion. The first of these hormones to be characterized, GIP, did not result in increased insulin secretion in people with type 2 diabetes, whereas GLP-1 had therapeutic action. Hence, developing agents acting through GLP-1 receptors became the focus of many lines of research. The first commercially available GLP-1 receptor agonist, exenatide, was approved in 2005. At the same time, another class of medications, called DPP‑4 inhibitors, was developed to take advantage of the incretin pathway. These agents work by blocking the degradation of GIP and GLP‑1.
The advent of incretin-based therapies represented a revolution in diabetes treatment. We could not only improve glucose control, but we could control the postprandial glucose almost to normal, which is not possible even with rapid‑acting insulin. In addition, patients who received these medications lost weight. Although the nature of injectable therapies could pose a barrier to some patients, in my practice, if I told patients I could improve their glucose levels and help them lose weight, few turned that opportunity down. In my experience, the perceived barriers to injection that may prevent healthcare professionals from using these medicines are lower when you take time to explain the benefits.
State of Affairs in 2021
In 2021, we have numerous GLP‑1 receptor agonists available for once-daily, twice-daily, or weekly administration. Over time, we have developed agents that are associated with almost a 2% reduction in A1C and approximately 4‑ to 5-kg reductions in weight. Furthermore, these agents have been shown to be associated with improved cardiovascular outcomes when given to our patients with coexisting diabetes and cardiovascular disease. They now are incorporated in the American Diabetes Association standards for management of patients with diabetes such that they should be considered right after metformin in patients who have established cardiovascular disease.
As good as these agents are, we still have some limitations. First, we continue to encounter some perceived injection barrier that has resulted in slow uptake of these medications. In addition, significant proportions of patients still do not achieve good glycemic control. In clinical trials, at least 30% of participants fail to achieve A1C <7% and many do not reduce weight to the 5% threshold that we understand to be necessary for the metabolic benefits of weight loss in our patients. So, we are still working through other mechanisms and perhaps combination therapies that might help more patients meet the goals of improving glucose control, reducing weight, and regulating other complications of diabetes.
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