Fixed-Dose Combinations in Diabetes Care

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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: If I was listening to you carefully enough, I think I counted at least four drugs that you really liked that were in your toolbox at this point, which brings up the whole question of fixed-dose combination agents for diabetes. What are some of the pros and cons of using it?

Robert Busch, MD: Well, the pro is one, copay often covered, and the other pro is pill burden. And, if the patient could take their pills once a day in the morning, we talked about the cognitive patient. One pill a day, and if they’re on a GLP, there is some weekly GLPs. So, they could be on a pill a day and the caregiver—the daughter, or son, or spouse, or significant other—could give their shot once a week.

Peter L. Salgo, MD: And what do we know about the efficacy data with these combinations?

Robert Busch, MD: The combos haven’t been tested per se that way, but I think the FDA allows it because of bioequivalence. So, the combo data, we have SGLT2s and metformin, and we have SGLT2s and DPP4 with one company—another will come out with that, and a third will come out with that later on when Merck has their combo. We don’t have the DeFronzo triple pill that he’s tried for years—he tried to get Takada to do a triple pill. Now where you have the glitazones making a return, maybe we’ll have SGLT2/metformin/TZD.

Peter L. Salgo, MD: Well, keep us in the present. What do we know about blood pressure?

Robert Busch, MD: Because you have the SGLT2, the blood pressure and the weight will still go down on the combos—whatever it’s combined with, whether it’s a DPP4 or metformin.

Ralph DeFronzo, MD: Also, GLP-1 receptor agonists reduce the blood pressure, as do the thiazolidinediones. So, there are other drugs which also reduce the blood pressure, but independent of it, hypertension needs to be treated with hypertension drugs. It’s great if your diabetes drug normalizes the blood pressure, but if it doesn’t—and more than often it won’t—you need to make sure that the blood pressure is at the level you want. Now, what blood pressure level you’re going to choose has become very controversial, but at least you choose the level that you think is best. We used to think 130/80 was optimal. But then ACCORD came out, and we said maybe less than 140/90 is better. And now we have SPRINT done in non-diabetics that says your blood pressure should be 120/80 to 130/80. So, there is some controversy, and I would say it’s an unresolved issue. But whichever number you like, whether it’s 140/90, 130/80, you need to get to that goal.

Peter L. Salgo, MD: All-comers, all your patients—not just for the endocrinologist, but you see a much broader base—what do you look for in a patient that would say to you fixed-dose combination pill is better than mixing and matching, and doing a little tap dance here?

Pamela Kushner, MD: An A1C more than 7.5, it’s a nice place to start.

Peter L. Salgo, MD: What does that mean though?

Pamela Kushner, MD: It means that, that would be a patient that I know is going to need multiple medications to get there. So, starting on a fixed-dose combination is going to be a better chance that I’m going to get to success, and be able to maintain that success longer.

Ralph DeFronzo, MD: I’ll make a couple of points with regards to fixed-dose combinations. We haven’t gone through each of the individual eight members of the ominous octet, but there are eight major pathophysiologic disturbances. One drug is not going to correct all of those, you need to use them in combination. Moreover, they feed back on each other. So, I’m just going to take two of the problems: insulin resistance and beta cell failure. You can have drugs that work on the beta cell, you can have drugs that improve insulin resistance. It’s unlikely, other than pioglitazone, you’ll find one that corrects both. More importantly, when you’re insulin resistant, that puts a big stress on the beta cell, and so that’s going to exacerbate the beta cell dysfunction. So, it’s good to have drugs that primarily work on the beta cell, but it’s also good to have drugs that work on the insulin resistance because this is interaction. And, also, if you put the drugs together, that if you’re using lower doses, you’re less likely to get the side effects.

Jeffrey Miller, MD: Synergistic is the word you’re looking for.

Ralph DeFronzo, MD: Yes, absolutely. You get more than additive effect sometimes.

Pamela Kushner, MD: Although you don’t get an additive effect usually. When we’re talking about synergism, we’re talking about you’re adding up the reduction you get from the metformin and the reduction you’re getting, let’s say, from the DPP4 or SGLT2. And then you’re going to have much more of an effect than you would get from one. I don’t think that we usually see that. We don’t see that.

Jeffrey Miller, MD: Mechanism of action is synergistic.

Robert Busch, MD: Complementary.

Pamela Kushner, MD: Correct, mechanism of action.