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Ralph DeFronzo, MD; Mark Harmel, MPH, CDCES
August 26, 2022

This transcript has been edited for clarity.
One of the major problems we have to deal with in terms of the treatment of type 2 diabetes is to recognize that it’s a very complicated disease with at least eight pathophysiologic disturbances, which I have referred to in my Banting Lecture as the “ominous octet.” It should be very obvious that if we have eight pathophysiologic defects, no one drug can correct eight pathophysiologic defects. We need to select drugs that actually reverse known etiologic problems, and we need to use them in combination.
We are fortunate today because we have many newer drugs that can be used in combination and are quite effective. In my opinion, we have four very good drugs. What are those four good drugs for treating our diabetic patients? At the top of the list, I would put the glucagon-like peptide 1 (GLP-1) receptor agonists, the sodium-glucose co-transporter 2 (SGLT2) inhibitors, and pioglitazone. Those are the three drugs that I use in combination to initiate therapy in all of my diabetic patients, irrespective of what the starting A1c is.
What’s number four on my good list? You may be surprised that it’s metformin. I brought metformin to the United States in 1995, and at that time we had insulin and sulfonylureas. It was a fantastic drug. We have much better drugs today.
Why do we have much better drugs? These drugs not only lower the A1c, but they keep the A1c down for a long period of time. Above and beyond that, they have other advantages. They are cardioprotective and they also are renoprotective.
What’s the big problem in our diabetic patients? What kills them? Cardiovascular disease. Now we have strong data with GLP-1 receptor agonists, SGLT2 inhibitors, and pioglitazone that they are cardioprotective. We really don’t have any data that tell us that metformin is cardioprotective.
From the standpoint of renal disease, we also now have very strong data with the SGLT2 inhibitors, emerging data from the GLP-1 receptor agonists, and a new class of drugs that don’t lower glucose, but finerenone, which is effective in providing protection against cardiovascular disease and renal disease.
Early treatment of type 2 diabetes is essential because we have an impairment in beta-cell function when you first see the diabetic patient, and what’s causing that progressive rise in A1c is progressive beta-cell failure. The other problem is with time we start to lose beta-cell mass. It is essential that we start early not only to improve beta-cell function but also to make sure that we prevent apoptosis, or death, of beta-cells.
We’ve also learned from the Diabetes Control and Complications Trial (DCCT) in patients with type 1 diabetes and from the United Kingdom Prospective Diabetes Study (UKPDS) in patients with type 2 diabetes that if you start early, on a long-term basis, you’re going to be in better shape in preventing both the micro- and macrovascular complications. There are nice articles that have looked at a long-term basis of both the DCCT and UKPDS published in Diabetes Care within the past 3-4 months.
What is the take-home message? Diabetes is complicated. Pathophysiology is complicated. We need multiple drugs. We need to use multiple drugs in combination to correct the underlying pathophysiologic disturbances and we need to start very early at the time of diagnosis.
As we look forward to the future, we need to start in the prediabetic state. I hate the term prediabetes. If your A1c is 6.4, you’re prediabetic. You think that’s any different from 6.5? We’ve shown in multiple studies that the exact same pathophysiologic disturbances are present in prediabetic and diabetic patients. I’m a strong believer that the earlier you start, the better off you are going to be in terms of getting patients controlled and preventing both the micro- and the macrovascular complications.
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Any views expressed above are the author’s own and do not necessarily reflect the views of WebMD or Medscape.

Cite this: Ralph A. DeFronzo, Mark Harmel. Earlier Is Better: Treat Patients Before Type 2 Diabetes Develops – Medscape – Aug 26, 2022.
Professor of Medicine, University of Texas Health San Antonio, San Antonio, Texas

Disclosure: Ralph DeFronzo, MD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AstraZeneca; Novo Nordisk; Boehringer Ingelheim; Intarcia
Serve(d) as a speaker or a member of a speakers bureau for: AstraZeneca
Received research grant from: Boehringer Ingelheim; AstraZeneca; Merck
Freelance videographer, Los Angeles, California
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