Start early to treat risk factors in ‘pre-prediabetes,’ reduce complications
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PHILADELPHIA — Insulin resistance and beta-cell failure begin long before a diagnosis of prediabetes and aggressive treatment should begin as early as possible to reduce risk for a variety of complications, according to a speaker.
“Pre-prediabetes is a new term to emphasize that diabetes, as well as its complications including cardiovascular disease, starts long before the prediabetic stage defined by the American Diabetes Association of an HbA1c between 5.7% and 6.4%,” Ralph A. DeFronzo, MD, professor of medicine and chief of the diabetes division at the University of Texas Health Science Center at San Antonio, told Healio. “Treatment to prevent diabetes and its associated accelerated CVD needs to be initiated at the pre-prediabetic/prediabetic stage.”
Data now show that the beta-cell failure that is typically seen in overt type 2 diabetes actually occurs much earlier in the natural history of the disease and is more severe than previously appreciated, DeFronzo said during the Luminary in Cardiometabolic Medicine lecture at the Heart in Diabetes CME conference. Additionally, people with prediabetes have the same increased risk for acute MI as people with overt diabetes, indicating that coronary artery disease “must start” before the onset of prediabetes.
“Hyperglycemia cannot explain the increased risk for cardiovascular disease in prediabetic individuals,” DeFronzo said.
DeFronzo said that the underlying elements of metabolic syndrome, or what he calls “insulin resistance syndrome,” is where the real problem resides. These include obesity, hypertension, dyslipidemia, inflammation and hyperinsulinemia, which DeFronzo said have all showed similar insulin resistance rates compared with diabetes in insulin clamp studies.
“Most importantly, the molecular etiology of the insulin resistance directly promotes the atherosclerotic process,” DeFronzo told Healio.
Early intervention will be required to ameliorate insulin resistance, prevent beta-cell failure and loss of beta-cell mass, maintain normoglycemia and prevent microvascular complications, “which do not occur if the HbA1c is less than 6.5%,” DeFronzo said. This means that improved diagnostic tools will be required to identify high-risk individuals for the development of diabetes and CV events at the pre-prediabetic or prediabetic stage, he said.
“The person who has prediabetes has every metabolic abnormality as the person with full-blown type 2 diabetes,” DeFronzo said. “If we really want to stop the disease, we need to start when the disease really begins. We need to move back even further.”
DeFronzo said a holistic approach to the treatment of type 2 diabetes requires early combination therapy with drugs that correct multiple pathophysiologic abnormalities and provide CV and renal protection — namely, the thiazolidinedione pioglitazone, SGLT2 inhibitors and GLP-1 receptor agonists prescribed together.
“Anyone who thinks one drug is going to correct everything we have been talking about at this meeting does not understand the pathophysiology of type 2 diabetes, ASCVD and renal disease,” DeFronzo said during his presentation. “In hypertension, we use four drugs. In cancer, we use multiple drugs. In HIV/AIDS, we use multiple drugs.”
Several sophisticated methods can measure beta-cell function; however, HbA1c can serve as a relatively simple measure for the clinician to assess beta cell function. If the plasma glucose concentration is rising, this means that the beta cells are failing and the patient’s diabetic therapy needs to be reevaluated.
“We have an algorithm for treating these people — the DeFronzo algorithm,” he said. “Metformin is no. 4 on the list. I love metformin. It is a good drug, but it is not better than the other drugs. From my standpoint, we start all of our patients on triple therapy. Why? These are the drugs that will give you the CV, renal and microvascular protection.”
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DeFronzo RA. Session 14: Luminary in Cardiometabolic Medicine. Presented at: Heart in Diabetes; June 24-26, 2022; Philadelphia (hybrid meeting).
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