Rationale for a Combination Approach in Diabetes

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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: Let’s look at combination antidiabetic regimens. You alluded to this; it’s such a pleasure now that we have all of these drugs. I’m getting a sense that everybody wants to mix and match a little bit, and get the benefits from each of these drugs in some ways. So, what is the rationale? Perhaps you can help me out on the rationale for using a combination approach as opposed to a single drug.

Pamela Kushner, MD: Well, because we said that we doubt that one medication is going to get your patient to the goal if their A1C is above 7.5…

Peter L. Salgo, MD: Especially if that medication isn’t working at all.

Pamela Kushner, MD: Especially if that medicine is not working. So, I feel like you’re going to have better tolerability, and that way you’re adding on, you’re getting your patient to their goal quicker. One of the reasons why I think, Jeff, that bromocriptine didn’t hit off so well is you’re getting a little. The DPP4/metformin combination is more popular. It’s been out there longer, and you’re getting a higher A1C reduction, not dramatic but you’re getting .6, .7. You’re getting less effects. It’s a pretty easy drug to start people on.

Jeffrey Miller, MD: I think one of the big issues with bromocriptine is marketing. If Big Pharma had bromocriptine, maybe it would be a blockbuster billion dollar drug, who knows.

Pamela Kushner, MD: But side effects are very important.

Jeffrey Miller, MD: Yes, right.

Pamela Kushner, MD: And, we know that DPP4s have so few side effects with them, and that’s one of the reasons why they’re a very popular combination. So, I think that you’re helping your patient get used to the idea of multiple medications, which we know is part of treating diabetes. And what we need to do is help clinicians get comfortable with the fact that very few clinicians nowadays expect one blood pressure medicine to do everything for their patient. They don’t just keep going up, and up, and up.

Peter L. Salgo, MD: They don’t? Not based on the patients I’ve seen.

Robert Busch, MD: And we use combinations all the time. Where’s the diabetes combinations? We may use the combos, but a lot of our colleagues still do independently.

Peter L. Salgo, MD: Let me understand what you’re saying. Are you implying—and I don’t mean this to be disparaging to any group—that it’s more likely for an endocrinologist to use a combination drug than for a primary care physician to use a combination?

Robert Busch, MD: Well, everyone uses combinations for blood pressure, one pill—2 drugs or 3 drugs in the same pill. But for diabetes drugs, we certainly have the option. You’re gun-shy and say, ‘Well, I won’t know what side effect the patient had.’ If you’re on SGLT2/metformin, you have diarrhea, that’s the metformin. If you have a yeast infection…So, you can figure out the side effect. If you’re on DPP4/metformin, the diarrhea is from the metformin.

Pamela Kushner, MD: Very well said, Bob.

Jeffrey Miller, MD: Coming back to Dr. Kushner’s original question about monotherapy versus combination therapy. In the UKPDS (United Kingdom Prospective Diabetes Study), the famous Nike hockey stick swish, you talk about durability. It may work in the short-term, but then over here, you go out of control.

Peter L. Salgo, MD: So, if you’re going to use combinations here, and I’ll let you weigh in on this first anyway, what do we know about the effects of combining different non-insulin antidiabetic agents? There’s metformin plus a whole bunch, right? There’s metformin plus DPP4s. How do you go about making these cocktails?

Ralph DeFronzo, MD: There are lots of good combinations but there are few that have been tested. So, in the EDIC study—this is from a grant supported by the ADA (American Diabetes Association). It’s now been extended for another 3 years, and also funded by the NIH (National Institutes of Health)—we decided to test the ADA algorithm, which was we put you on metformin and when you fail, and you will, I’ll add a sulfonylurea. And when you fail, and you will, we add basal insulin. This is the treat to fail, this is what most people do. We chose a triple therapy algorithm—which was a GLP-1 receptor agonist—which we knew would promote weight loss, and had a big effect on the beta cell low-dose pioglitazone, 30 mg. Most people don’t realize pioglitazone—in addition to being a great insulin sensitizer—has a huge effect on the beta cell, and then metformin. They started with an A1C of about 8.8. A1C came down in both groups to about 6.3. Now, with the ADA algorithm, at the end of 3 years, they’re up to about 6.7. With the triple therapy algorithm, they’re at 5.9. The incidence of hypoglycemia was seven-and-a-half fold greater with the ADA algorithm, but our A1C is 5.9, they’re at 6.7. We measured beta cell function. At the end of 3 years, you have perfectly normal beta cell function with the triple therapy algorithm. With the ADA algorithm, you’ve lost about 90% of your beta cell function. With the triple therapy algorithm, there’s a 60% improvement in insulin sensitivity, absolutely no improvement in the insulin resistance with the ADA algorithm. Weight gain with the ADA algorithm at 3 years, 3.7 kg. Weight loss with the triple therapy algorithm, 3 kg. This is total destruction of the ADA algorithm, if you understand what these things are. Now, is this the best triple therapy? I think that, quite frankly, if I were to do the study again, I would not use metformin. I would use the SGLT2 inhibitor. Is this practical? Are people going to put people on a SGLT2 inhibitor, GLP-1, and pioglitazone? Probably not. What is the best? I’m not sure. I can’t do every single study in the world. I have 4 NIH grants, but even that won’t support all of this. I think that other people need to. Every endocrinologist has their own favorite drugs. In fact, I think amongst the table here, you’re seeing we like a particular group of these 4 drugs, and endocrinologists will mix and match those. What's really important—and I do think you should start with combo because there are too many pathophysiologic problems—is to follow to see what happens to the patient. And, if you’re well controlled, you’re in good shape. If things are not working, then you have to change. And my guess is if you went around the table, you’d probably get a little bit different flavor of how people would mix and match drugs.

Pamela Kushner, MD: But Peter, I have to ask him because he’s messing with motherhood and apple pie here. When you said if you did the study again you wouldn’t use metformin.

Ralph DeFronzo, MD: Yes.

Pamela Kushner, MD: And the reason is?

Ralph DeFronzo, MD: Because I think that the SGLT2 inhibitors are a better class of drugs than metformin. Can I absolutely prove that? The answer is no, but from the pathophysiologic standpoint, there’s this huge defect at the level of the kidney that none of the other drugs are going to correct. I also know that if I lower the glucose, I get rid of the gluco-toxicity, I improve beta cell function, I improve insulin sensitivity, and I also have to say that I’m maybe a little bit swayed by the results of the EMPA-REG OUTCOME study. Now, can I definitively say that SGLT2 would be better than metformin? No, but we don’t have evidence to support every single thing that we say. And some of it’s based on the science.

Pamela Kushner, MD: It sounds like the understatement of the year.

Ralph DeFronzo, MD: See, I’m a strong believer that if you correct the underlying pathophysiology, you would be successful. And the drugs that I’m proposing are the drugs that attack the underlying pathophysiology, and they’re more likely to give you a durable response in a long-term basis.