Ongoing Trials and Lifestyle Changes



Paul Thompson, MD: Let’s talk a bit about some of the long-term studies with GLP1 [glucagon-like peptide 1] inhibitors. You’ve already talked about some of the outcome studies in which they’re positive. Can you give us a brief summary of those?

Robert Busch, MD: Yes. The first positive study that came out was the LEADER trial with liraglutide, or Victoza. It lowered MI [myocardial infarction] risk. They took mainly cardiac patients. It lowered MI, stroke, and death 13% and was driven by lowering of death. Then the semaglutide study came out recently. The SUSTAIN trial, as it was called, used the subcutaneous weekly semaglutide. That lowered MI, stroke, and death by 26%. Stroke risk went down 39%. Both of those claim in the package insert to lower MACE [major adverse cardiovascular events]. The most recent trial that came out was the REWIND trial. That was from dulaglutide, or Trulicity. They studied primary prevention. Sixty-nine percent of patients had just diabetes with either hypertension, hyperlipidemia, or smoking. Thirty-one percent were the typical patients who had ASCVD [atherosclerotic cardiovascular disease]. In that study, they lowered MI, stroke, and death by 12% and lowered stroke by 24%. Those are the 3 that have it in the package insert.

Interestingly, the EXSCEL trial with Bydureon [exenatide], which looked at secondary prevention, trended to lower events. The disclaimer there is that it would have had benefit, but there was too much SGLT2 [sodium-glucose co-transporter 2] inhibitor drop-in in the placebo group. When you’re doing a double-blind study but you’re supposed to get the A1C [glycated hemoglobin] to goal in either group, if you’re on placebo, your A1C is higher, so you’re more tempted to add other medication. Unfortunately, with the design of the study, there were more patients on SGLT2s, which have cardiac benefit, in the placebo group. That impacted the study. It was similar to the FIELD trial with the statin therapy that ruined that trial. The Bydureon trial would have been positive, and most of us think it’s a class effect of GLP1. Unfortunately, it’s not in their label because the study missed the mark.

Paul Thompson, MD: You know what’s amazing to me? For so long, we were unable to show that controlling diabetes did much. Now we have all these drugs that have been shown conclusively to have beneficial health outcomes. That’s another reason that primary care doctors and cardiologists need to get on board with this. The data are unequivocal. We have multiple agents now that have actually been shown to save lives. Let’s talk a bit about lifestyle changes. We’d be remiss not to at least address them. What are your thoughts?

Robert Busch, MD: We’re very spoiled. Endocrinologists usually have a diabetes educator in the office. I’m sure you’re savvier with this because of being a lipidologist. We had 1 week of nutrition in medical school. Half the plate was green, a quarter was fish or chicken, a quarter was starch. For most people, 98% is starch and there’s nothing green on the plate. Diet and exercise obviously help a lot. You mentioned obesity worsening insulin resistance. Even small amounts of weight loss, perhaps 5%, is a big deal. If the patient is on insulin, they lower their insulin needs or they can get their A1C down, then you could taper down 1 of the drugs.

Paul Thompson, MD: I have a comment, but I’d like your reflection on it. I often go to drugs very quickly. The reason I go to drugs very quickly is that I want people to exercise more, lose weight, and follow good diets. Unfortunately, they don’t. What I often found in the past is that I waited and waited, and we got nowhere. I always say that waiting for most patients to have an exercise program and lose weight is like Waiting for Godot. It’s like Samuel Beckett’s classic play. The guy never shows up. I don’t want to overdo this, but the nice thing is that we have these drugs now like GLP1 agonists that can help people control their sugar, lose weight, and reduce their cardiovascular events.

I much more frequently will start people on some of these agents like metformin, SGLT2 inhibitors, or GLP1 inhibitors, rather than waiting forever. I’m concerned about the fact that sometimes, we don’t get around to doing something. I often say to my research trainees, ”I don’t care what you do. Just do something.” I feel the same way with a lot of patients. We sometimes wait too long. What are your thoughts on that?

Robert Busch, MD: I say the exact same as you do. In fact, it would be off-label use. As Ralph DeFronzo, MD, says, 6.5% A1C level is diabetes and 6.4% is prediabetes, but you didn’t get diabetes the minute you crossed over. So I treat my prediabetic patients with the heart-smart drugs, particularly if they lose weight on them. It’s a way to jumpstart someone’s diet. If they see success right in the beginning, it’s motivating. A lot of these people joined a health club when gyms were open. It motivated them. They finally lost weight when they couldn’t lose weight for years.

Paul Thompson, MD: Nothing breeds success like success. I’d like to pick on one of the other things that’s always bothered me. Those are the studies that said that you’re just as good with a hemoglobin A1C of 7% versus under 7%. Can you discuss those studies for us a bit? There are a lot of times when I push to get glucose hemoglobin A1Cs lower, as a cardiologist, I’ll get some pushback from their primary care doctors. I rarely get that from the endocrinologists, but a lot of primary care doctors say, “Paul, it’s not that important whether they’re at 6.4% or 6.1%. They do just as well as the group that’s slightly over 7%.” What are your thoughts?

Robert Busch, MD: The American College of Endocrinology guidelines state that A1C should be below 6.5%. If you’re using nonhypoglycemia drugs, you can’t get your A1C very good. I tell the patient, “You can’t win too much money in Powerball. If I get your A1C to 6.5% or 6.2%, and I’m using a GLP1 agonist or SGLT2 inhibitor, that’s great. You’re not going to bottom out your sugar. You don’t have to do finger sticks because you’re not on anything that will make your sugar low.” I’m not worried about getting their A1C too low, as long as I can’t get the patient hypoglycemic. You don’t get hypoglycemia on the new drugs.

Paul Thompson, MD: Correct me if I’m wrong, but I am more aggressive. With my patients who have hemoglobin A1Cs of 6% and such, it bothers me that they really should be 5.8% or below. I’m always concerned that they’re glycosylating other things. They’re glycosylating endothelial proteins, and as I said earlier, apolipoprotein B. I actually push lower. Am I too aggressive?

Robert Busch, MD: No. If my cardiologists were like you, I’d be unemployed here, so please don’t share this with all the Albany, New York, cardiologists. I agree with you very much. It’s in our literature that cardiologists are allergic to SGLT2 inhibitors, so I’m glad you’re not. We have to desensitize cardiologists and primary care doctors to SGLT2 inhibitors and GLP1 agonists.

Paul Thompson, MD: Do you have advice on diet for patients with these issues?

Robert Busch, MD: They’re on lower-carbohydrate diets. It’s an eat this, not that approach. They substitute certain things. When they’re on a GLP1 agonist, their appetite is down. They can satisfy the cravings they had before with a new lower-carbohydrate diet, or with foods that they like in smaller portions. My patients all see a nutritionist routinely for the first go-around.

A lot of them say after a while, “I’ve already seen the nutritionist before in the past.” For someone who is very motivated and seeing the new physician or getting some new drugs, a visit to the nutritionist would be very valuable.

Paul Thompson, MD: What about those of us, or those primary care doctors and cardiologists, who don’t have a nutritionist readily available? Do you have weight loss advice that you give people? I was very interested in that article in the December 2019 issue of The New England Journal of Medicine talking about intermittent starvation and intermittent fasting. Do you have any thoughts on that?

Robert Busch, MD: Yes, I have some patients doing that, but I’m not that adept at that. It’s a good idea, and I’m sure you’re more adept at those things in the counseling that you would give.

Paul Thompson, MD: I’ll give you what I’ve done with some patients. I encourage them not to eat breakfast and lunch, and only eat dinner. Let me give you the rationale. If you only eat dinner, by the time you go to bed, you actually start to generate ketosis overnight. Ketones suppress appetite, so then if you skip breakfast, you’re less hungry. You skip lunch, you’re less hungry, and eat dinner. I actually did it for myself. My wife told me at one point that she thought I looked 26 weeks pregnant, and I knew I wasn’t. I did it. I started in January. I went down 15 lb pretty easily. I’m on the see-food diet. If you see it, you eat it. With that, I actually found it quite useful.

I’ve done it with a bunch of patients without the benefit of having a nutritionist nearby. Some of them can do it quite well. Some of them can’t. The key issue is not getting that carbohydrate in the morning that turns on your hunger. I know there will be a lot of nutritionists out there tweeting me bad things, almost as if I were running for president. It’s important to address weight with these patients. The drugs are great. The new diabetes drugs we have are great at helping people lose weight, but for those who you’re not necessarily starting on them right away, that’s an important thing to do.

Transcript Edited for Clarity

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