Multiple Effects of Anti-Diabetic Medications

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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: You did mention in your dissertation the SGLT2 inhibitors, and you mentioned DPP4 inhibitors and other medications, as well. Dr. Miller, if you would, walk us through a little bit about the mechanism of action for the SGLT2s, the DPP4s, and the effect of each of these drugs on some of these big, big issues: blood pressure, cholesterol, and weight.

Jeffrey Miller, MD: If we’re talking specifically DPP4s and we’re talking specifically SGLT2 inhibitors—Dr. DeFronzo will tell you all about the incretin effect—the DPP4s basically cause glucose-dependent insulin secretion from the beta cell and minimize excessive amounts of glucagon secretion from the alpha cell. The disadvantage is they don’t do a whole lot to blood glucose or A1C. The advantage is, because they don’t do a lot to glucose or A1C, they don’t have many side effects. And because they work to inhibit insulin secretion from the glucose-dependent beta cell, it minimizes the risk of hypoglycemia. The SGLT2 inhibitors, on the contrary, work on the proximal renal tubule to promote glucosuria/glycosuria, they’re glucuretic agents. Because they work outside of the beta cell, they also have a minimum risk of hypoglycemia. For a whole variety of reasons, including that they are glucuretic, we therefore waste calories and they’re associated with a 10- to 12-pound weight loss. DPP4 inhibitors tend to be weight-neutral. In terms of blood pressure, DPP4 inhibitors are blood-pressure neutral. SGLT2 inhibitors will reduce systolic pressure by about 4 to 6 mm Hg.

Peter L. Salgo, MD: When I first heard about the weight loss associated with these drugs, the first thought was it’s purely volume because there’s a glucose-induced osmotic diuresis. The first time I heard about this I wasn’t impressed. Fluid is fluid, but it’s more than that.

Jeffrey Miller, MD: It definitely is. Dr. DeFronzo could give you a beautiful dissertation.

Ralph DeFronzo, MD: Initially, when you start on the SGLT2 inhibitor, you do go into a little bit of negative salt and water balance. And, as Dr. Miller’s pointed out, it’s probably important in lowering the blood pressure, so that’s an advantage. But, after the first 2 or 3 days, you come back into a normal salt and water balance, and then the weight loss after that—again as Dr. Miller pointed out—is really fat weight loss. And there’s also a significant amount of visceral weight loss that goes with it. On a long-term basis, as you drop the glucose and maybe as you drop some weight, you actually do see an improvement in beta cell function in the insulin sensitivity studies that we’ve carried out. Short-term, that’s reversal of glucose toxicity. Long-term, I think the weight loss also starts to kick in. So, there are lots of important reasons that these drugs are pretty good agents for our type 2 diabetic patients.

Peter L. Salgo, MD: So, it occurs to me, that’s the opposite of a double-whammy. Not only do you get better beta cell function, better glucose control, but your cardiovascular risk improves, if you will. It goes down, the risk goes down because the weight loss is in that.

Ralph DeFronzo, MD: Well, we have a recent study called the EMPA-REG OUTCOME study, a very well-controlled study with a large number of people at extremely high risk. They’d either had MI, stroke, or something bad to get into the study. There was a significant increase in the MACE endpoint—major adverse cardiovascular events—and a large decrease, 40% to 45%, in mortality and cardiovascular mortality, and also a 40% to 45% decrease in hospitalization for heart failure. Now, whether we’ll see this with all of the other SGLT2 inhibitors, personally, I think that this is going to be a class effect. But we’ll have to wait till the newer studies with CANVAS and DECLARE come out. And whether this is generalizable to all diabetics, we’ll have to see. Earlier in the natural history of the disease, the less sick population remains to be established, and whether or not we’ll see the same cardiovascular management.

Jeffrey Miller, MD: But there was no change in non-fatal CV, AMI, or stroke.

Ralph DeFronzo, MD: This is a good point, and this is a kind of funny surprising result. So, the hazard ratio for non-fatal MI went down a little bit to 0.87, but it was not significant. For stroke, it went up: the hazard ratio is 1.13, I believe, but not significant. It’s all about decrease in cardiovascular mortality, and that makes it sort of an interesting phenomena in terms of what’s responsible for this. Personally, I think it’s a combination of simultaneously afterload reduction, dropping the blood pressure, and preload reduction in a group of people who are highly susceptible. Now, there are lots of other reasons. Is there a change in arrhythmias? Is it the switch from glucose to ketone metabolism? Is it related to the increase in glucagon, the decrease in uric acid? We don’t know the answer, but at least you’re alive. That’s a good point.

Peter L. Salgo, MD: Where there’s life, there’s medication.

Pamela Kushner, MD: I do want to mention two points that I think are very valuable.

Peter L. Salgo, MD: Yes, go ahead.

Pamela Kushner, MD: First of all, what impressed me about the EMPA-REG data is that these are patients that I see every day. These are common patients that we see in our practice, so that’s the impressive thing about it. And the second point that hasn’t been raised yet is we talk about the benefits of GLP-1s, DPP4s, SGLT2s—and that is a huge benefit—but avoiding the hypoglycemia. And so I have a question for you, Dr. DeFronzo. How long would you say it takes to recover from a hypoglycemic event in patients who are getting the sulfonylureas and insulin? Because that’s a question I really don’t know the answer to.

Ralph DeFronzo, MD: Well, come back to EMPA-REG, and then I’ll lead on to your question. The side effect profile was incredibly good. There were virtually no side effects and a minimum amount of hypoglycemia. Now, sulfonylureas, that’s the common…

Peter L. Salgo, MD: By the way, you’re talking about the SGLT2s and DPP4s.

Ralph DeFronzo, MD: I was talking about, particularly, empagliflozin in the EMPA-REG OUTCOME study. But now to switch to the sulfonylureas and insulin: of course, the hypoglycemia can be quite profound and quite long. And, in fact, you may not come out of it. There are people who die from hypoglycemia that’s induced by sulfonylureas and insulin. So, there’s no real answer to your question. It depends upon how severe is the hypoglycemia. What’s your regulatory response like? There are lots of issues that come into play here, and for people listening in, sulfonylureas are the most common cause of hospitalization for hypoglycemia. Now, I can tell you the last time I used a sulfonylurea in one of my patients; I can tell you the patient’s name, the date, 1998. None of my patients are going to end up on sulfonylurea drugs.

Robert Busch, MD: And despite that, it’s the second most common prescribed drug after metformin, despite everything you’ve been teaching—and we’ve all been teaching for years.