Combination Approaches in Type 2 Diabetes Management

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The MD Magazine Peer Exchange "Improving Management of Type 2 Diabetes Mellitus" features a panel of physician experts discussing current best practices to treating and managing patients with T2DM that generally includes lifestyle modifications as well as medication. The mechanisms of action, patient selection criteria, and side effects for various oral medication classes are included in the discussion.

This Peer Exchange is moderated by Peter Salgo, MD, professor of medicine and anesthesiology at Columbia University College of Physicians and Surgeons, and an associate director of Surgical Intensive Care at New York-Presbyterian Hospital.

The panelists are:

• Robert Busch, MD, director of clinical research in the Community Endocrine Group at Albany Medical Faculty Practice in Albany, NY
• Ralph DeFronzo, MD, professor of medicine and chief of the diabetes division at the University of Texas Health Science Center in San Antonio, TX
• Pamela Kushner, MD, clinical professor at UC Irvine Medical Center and director of Kushner Wellness at UC Irvine Medical Center in Los Alamitos, CA
• Jeffrey Miller, MD, professor of medicine and clinical director of the Division of Endocrinology and Diabetes at Jefferson Medical School in Philadelphia, PA

Peter L. Salgo, MD: We have all of these rationales for at least using combination therapy. Now let’s get down to the nitty gritty; which combinations to use. We’ve heard your questions and your answers. Pam, what combinations do you want to use?

Pamela Kushner, MD: Well, I like the combination of an SGLT2 with metformin. I like the combination of a DPP4 with metformin. It’s a nice starting combination. This is using a combined drug, but that doesn’t stop me using a GLP-1 with a combination therapy. Of course, I would not use a GLP-1 with a DPP4. So, we’ll remind our audience that that would be the same mechanism of action. But those are my favorite combinations. Can I promise you that I have no sulfonylureas (SU) that are being prescribed? I can’t promise you that because I’m in an indigent clinic practice, and sometimes we have to do prior authorizations for TZDs (thiazolidinediones). This is the reality of where I live, but I don’t use any combinations with metformin and a sulfonylurea. I don’t know if they make them anymore.

Peter L. Salgo, MD: Does that make sense to you?

Robert Busch, MD: The same four. So, I use GLP-1, metformin with an SGLT2, and pioglitazone. Those four cover full ominous octet and the cardiac benefit of the SGLT2, the benefit of the TZD, maybe metformin’s benefit, and the GLP-1 benefit. They all do the right thing.

Peter L. Salgo, MD: And where are you on this?

Jeffrey Miller, MD: I’m the same. I regret to whisper to Dr. DeFronzo that I do use SUs in people whose insurance plans or pockets does not afford expensive brand medications. I figured that metformin and SU is better than nothing, and that’s for a very small group of patients but there are patients. In the rest of the world, Third World countries, we still have to use the generics in full stop. I used metformin. I think one thing I’ve done longer than Dr. DeFronzo is metformin, I’ve used it since the 70s. But I have a question for Dr. DeFronzo, as a research and on ready clinician. When I did my training back in the 70s, in the early era we really didn’t have computers, I think there was a first generation Wang computer then. We always said that statistically, a P-value of less than 0.02 really was statistically significant, and a 0.4 and a 0.5 was questionable. This is EMPA-REG, right? It’s 0.04.

Ralph DeFronzo, MD: Yes.

Jeffrey Miller, MD: It’s statistically significant. You’d hang your hat on that, or it may be by chance?

Ralph DeFronzo, MD: Well, it is what it is. Whatever—0.04 or 0.5—it means, you have either a 4% or 5% chance of being wrong. So, do you like those statistics? I have to say that the MACE endpoint, which is the composite of cardiovascular mortality, non-fatal MI, non-fatal stroke really was totally driven by the mortality part.

Jeffrey Miller, MD: Mortality and CHF (congestive heart failure).

Ralph DeFronzo, MD: Yes. So, if you look at the mortality part, of course, the P-value is much greater. But, if you look at the composite endpoint, it’s not. I’ve always thought that it’s good to be alive rather than dead, so I like the fact that there is this high-risk group who will benefit from the SGLT2 inhibitor. The problem is it’s difficult to know exactly which of the patients are the ones that are going to benefit, and I think we’re going to see a lot more research trying to sort this out. The other big thing that’s very impressive is heart failure. Heart failure is a problem for our patients. It’s a very expensive problem, and also we saw a dramatic reduction, 45% or so.

Pamela Kushner, MD: In heart failure hospitalization?

Ralph DeFronzo, MD: In heart-failure hospitalization, yes. So, this is another very important part of the study. Now, I might say I totally agree with you that in many countries and in many places, SUs are the only drugs. Of course, we know from UKPDS that there was some benefit. Now, I have a great luxury in that I can decide which drugs are going to be in the Texas Diabetes Institute. In the real world, you don’t have that luxury, so I understand that many people—just because of the expense and having to deal with HMOs (Health Maintenance Organizations) and insurance companies—are going to have to be on SUs. So, that’s the practicality of it. But you’re asking me in the ideal world, if expense was not a problem—and expense is a huge problem—what would I do?

Jeffrey Miller, MD: It’s interesting. You raise the point that being alive is better than being dead, for most of us. But my late father who was an OBGYN primary care doctor tells a beautiful story of a patient who was doing a life insurance examination, and obviously one of the questions is family history. And he said, well, how’s your father? No, he died. How old was he? He was 85. What did he die of? Nothing serious.