Two diabetes drug classes can increase, maintain beta-cell function
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The thiazolidinedione pioglitazone and GLP-1 receptor agonists are the only two diabetes drugs proved to increase and maintain beta-cell function, and both should be first-line therapies for patients, according to a speaker.
Overt diabetes does not occur in the absence of progressive beta-cell failure, Ralph A. DeFronzo, MD, professor of medicine and chief of the diabetes division at the University of Texas Health Science Center at San Antonio, said during a presentation at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. Several sophisticated methods can measure beta-cell function; however, HbA1c can serve as a relatively simple measure for the clinician to assess for persistently elevated glucose concentrations and ultimately decide whether a person is on the right therapy regimen.
“If the HbA1c is rising, you have the patient on the wrong drug,” DeFronzo said. “Furthermore, it means you have the patient on drugs that are not preserving beta-cell function. There are not many options in terms of choosing drugs that preserve that function.”
‘Arbitrary cut points’ and beta-cell function
Data from the San Antonio metabolism study, published in Diabetologia in 2004, demonstrated a progressive decline in beta-cell function that begins even among patients with seemingly “normal” glucose tolerance, DeFronzo said. When insulin secretion is related to the underlying insulin resistance, beta-cell function in adults with obesity and normal glucose tolerance, impaired glucose tolerance and type 2 diabetes is superimposable on that of lean individuals with the same category of glucose tolerance, he said.
“Clearly, this disease starts much earlier, and we use these arbitrary cut points that are based on glucose or HbA1c, but we have forgotten about pathophysiology,” DeFronzo said.
Early in the natural history of type 2 diabetes, tissues become resistant to insulin and beta cells can “read” the severity of insulin resistance and appropriately adjust their secretion of insulin, DeFronzo said. If beta cells maintain this high insulin secretory response, a person will maintain normal glucose tolerance.
“But eventually, as your beta cells start to fail, you are going to see the onset of diabetes,” DeFronzo said. “If we had a way of preserving beta-cell function, we would keep the HbA1c and glycemic control within the normal range.”
Choosing the right agents
The landmark U.K. Prospective Diabetes Study clearly demonstrated that sulfonylureas and metformin “do not work” for most people with type 2 diabetes in the long term, primarily because neither drug has a major affect on the beta cell, DeFronzo said. Similarly, data from the GRADE study, a head-to-head comparison of four classes of glucose-lowering drugs presented at the American Diabetes Association Scientific Sessions in June, showed the GLP-1 receptor agonist liraglutide (Victoza, Novo Nordisk) and insulin glargine (Lantus, Sanofi) were more effective for maintaining HbA1c below 7% than a sulfonylurea or DPP-IV inhibitor.
Insulin clamp data have also demonstrated TZDs lead to improved beta-cell function, which correlates strongly with improved glycemic control, whereas GLP-1 receptor agonists effectively lower HbA1c, preserve beta-cell function and inhibit glucagon secretion.
“There are only two drugs that will increase beta-cell function and preserve the increase on a long-term basis,” DeFronzo said. “They are pioglitazone and the GLP-1 receptor agonist. I know people are reluctant to use pioglitazone. I have used it since the 1990s; it is a fantastic drug. Even with advanced disease, these two drugs will work.”
Reference:
Gastaldelli A, et al. Diabetologia. 2004;doi:10.1007/s00125-003-1263-9.
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DeFronzo DA. Antidiabetic agents and prevention of beta-cell failure: Fact and fiction. Presented at: World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease; Dec. 2-4, 2021; Los Angeles (hybrid meeting).
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