Paul Thompson, MD: Hi, everyone. I’m Dr Paul Thompson. I’m the former chief of cardiology at Hartford Hospital in Hartford, Connecticut. Welcome to HCPLive® Peers & Perspectives®, which is a presentation titled “Evaluating the Diabetes-Cardiology Interface.” I’m lucky enough to be joined today by Dr Robert Busch, who is an internationally known diabetologist and endocrinologist from Albany Medical Center in Albany, New York. We’re going to be talking about that interface between cardiology, endocrinology, primary care, and the very important risk factor for heart disease: insulin resistance and diabetes.

Our goals today are to talk about cardiovascular disease with respect to insulin, glucose, metabolic syndrome, and diabetes management. We’ll discuss the importance of why cardiologists, endocrinologists, and primary care doctors need to know a lot about diabetes. I’m going to give you an example of why that’s important.

There’s something called the Early Acute Coronary Syndrome trial, in which they looked at about 9000 patients in 2013. Of those patients, about 30% had known diabetes. About 10% had diabetes that was easily diagnosable but wasn’t known. An additional 10% had prediabetes.

Bob, can you give us the basic background and the pathophysiology of type 2 diabetes?

Robert Busch, MD: Years before the diabetes starts, the patient is insulin resistant. If you’re insulin resistant, the blood sugar might go up an iota. If blood sugar goes up a bit, the pancreas will sense that and pour out more insulin. You’re insulin resistant to start with, and then you get compensatory insulin secretion. Eventually, the beta cell loses function, either for genetic or other reasons, and starts going bald. It’s not an on-off process as in type 1 diabetes, but the beta cell fades out over time. When that happens, the postmeal sugar goes up, and then the fasting sugar goes up. Until the fasting sugar goes up, some people don’t receive a diagnosis of diabetes. They have already had 10 years of insulin resistance with additional high triglycerides, low HDL [high-density lipoprotein], prehypertension or hypertension, and abdominal obesity. All those other inflammatory conditions are existing, and the patient is going on without knowing they have diabetes. They finally get the diagnosis, and they already have underlying heart disease because of all those other issues that have inflamed the endothelium.

Paul Thompson, MD: Bob, that’s a great point. I see it a lot. I run a lipid clinic, and I see it a lot because I see people who present with triglyceride elevations. What’s unknown is that a lot of those people who present with triglyceride elevations have early diabetes. It’s not known. Their hemoglobin A1C [glycated hemoglobin] can be borderline or normal, yet when you do an oral glucose challenge test, you note that they’re diabetic. One of the themes we need to get across to people today is to go hunting for those prediabetic patients. Why? If you start overglycosylating hemoglobin, you’re also glycosylating a lot of other proteins, including LDL [low-density lipoprotein] cholesterol and apolipoprotein B. Apolipoprotein B is part of LDL cholesterol. Before you present with frank diabetes, you’re already doing a lot of things wrong.

Dr Ralph DeFronzo, who is 1 of the greats in endocrinology and diabetes, always pointed out that when you have prediabetes, that is actually a misnomer because you’ve already lost about 50% of your islet cell insulin-secreting capacity. You’re already well down the pike toward being frankly diabetic. Do you have any comments about that?

Robert Busch, MD: Right, you have to lack beta cell secretion of insulin to get diabetes. If you have a 400-lb patient who is insulin resistant but their beta cells work, they will not get diabetes. Even though insulin resistance is the core defect, you have to lack the beta cell to get diabetes. You’re exactly right. Our cardiologists don’t know as much as you do, so thank you for bringing that up. You’ve lost a lot of beta cell function by the time diabetes is diagnosed.

Paul Thompson, MD: Right. The issue is that it leads to coronary disease. At 1 point, I tried to get the endocrinologists to become part of the cardiology division, because diabetes is a vascular disease. Bob, you belong in cardiology. You should be a cardiologist.

We all know the primary pathophysiology of insulin resistance, but can you just discuss that with us so we’re all at the same starting point? What are the biggest causes of diabetes?

Robert Busch, MD: A big cause is obesity. Genetics cause it. Obesity causes it. There is more insulin resistance in the obese patient, and that is exacerbated by their genetic problems. There are certain drugs that can cause it. One example is steroid therapy. We can have a patient perfectly well controlled, without diabetes or prediabetes. Someone can give them a steroid shot, and all of the sudden, their sugar sails up. It’s typical to get calls at night from patients saying, “My sugar is 400 mg/dL.” The first thing I ask is, “Did anything else change? Did you see the orthopedist today?” Patients say, “Yes, how did you know that?” They got a shot of steroids. Steroids, obesity, and genetic factors are some of the key contributors. There are some other drugs that do that too. Some of the HIV drug treatments can also set off diabetes.

Paul Thompson, MD: I agree with you. The key factor is obesity. I always tell patients that fat fights insulin. If you’re overweight, it doesn’t matter where it is. Abdominal obesity is clearly the worst, but fat fights insulin.

Pathophysiology of T2DM and Cardiovascular Disease

Paul Thompson, MD: Let’s talk a bit about the socioeconomic disparities, prevalence, and outcomes of diabetes. Certain ethnic groups are more vulnerable than others. Do you want to address that for us, Bob?

Robert Busch, MD: Almost all ethnic groups besides Caucasians are more vulnerable to diabetes. Asian Indians come to the United States and eat a Western diet, and they come prepackaged with insulin resistance, but they’re not obese. Their BMI [body mass index] doesn’t have to be 30 kg/m2 or 35 kg/m2 to get diabetes. They can be at 25 kg/m2 or 27 kg/m2 and have diabetes. As you know, they are at particularly high risk for coronary artery disease, even though they don’t have the look of a typical metabolic syndrome patient.

Paul Thompson, MD: That is a great point, and there are a lot of doctors out there who are of Indian origin. Remember that in your Indian patients. They can present with diabetes or prediabetes, and they don’t look like the typical Caucasian person with diabetes. They’re typically not obese, but they have prediabetes. That’s a great point. Talk to me a bit about when you think folks should be sent to an endocrinologist. I’m going to give you my bias. My bias is that all of us should be good enough to take care of most diabetes until it gets quite advanced. But you’re an endocrinologist, and I know you have to get the kids through college, so tell me when you think people should be referred to an endocrinologist.

Robert Busch, MD: I agree 100% with you. When I give any talk, I say, “This is diabetes. Do it yourself. No endocrinologist included. You don’t need us.” They have the same standard of care and the same drugs, and it usually takes 3 months to get into the local endocrinologist. As an endocrinologist, I’d rather be seeing thyroid disease and pheochromocytomas. My chief used to call it wax museum endocrinology. You go in the waiting room and say, “You’re hyperthyroid. You’re hypothyroid. You’re acromegalic. You’re cushingoid.” Diabetes pays the rent, and that’s what we end up doing.

Most endocrinologists didn’t go into endocrinology years ago because of diabetes. We had no drugs. Now we have a tantalizing array of drugs, and it’s fun to juggle them the right way. We play cardiologists. Just as you’re a cardiologist using diabetes drugs, we treat lipid disorders. We use PCSK9 inhibitors. We use Vascepa [icosapent ethyl]. We use the other drugs beyond statin therapy. We have statins in the drinking water, so our fields overlap. It’s not that I do the sugar and you do the lipids and blood pressure. We do both.

Paul Thompson, MD: You hit on some important points. One of the most important points you made is that it’s hard to get in to see the endocrinologist. One of my friends pointed out that only about 80 to 90 endocrinologists graduate out of training programs per year, so there is a shortage. Primary care doctors and cardiologists need to be able to manage diabetes. That’s why it’s important to listen.

The other thing is that the drugs we now have made it simple. They’ve made it easier to treat. 

We talked a bit about when primary care physicians and cardiologists should refer. It seems you’re saying that primary care doctors and primary care cardiologists need to be at least running through this gamut of potential drugs before sending patients to an endocrinologist. What’s your take-home message about going to an endocrinologist?

Robert Busch, MD: You’re definitely right. Also, if you’re treating a patient with diabetes and they have any kind of ASCVD [atherosclerotic cardiovascular disease] background, stop. You must give a drug that has cardiac benefit—either an SGLT2 inhibitor, a GLP1 receptor agonist, or both. Because you mentioned the weight loss, they have weight loss by different mechanisms. With the GLP1 agonists, you eat less. With the others, you’re urinating out calories, so the weight loss is additive. They also have combined efficacy for A1C [glycated hemoglobin], but additive efficacy for weight loss. These are the drugs that our cardiology and primary care colleagues use all the time. If they refer to an endocrinologist, the patient is going to come back with a GLP1 receptor agonist—probably a weekly GLP1 agonist—an SGLT2 inhibitor, and metformin tapered down. Goodbye, insulin. Goodbye, sulfonylurea. Goodbye, DPP4 inhibitors. That’s how they’ll come back to you, even if they come in on metformin, sulfonylurea, DPP4, and basal insulin.

T2DM Management: Endocrinologist or Local Physician? 

Give us an overview of the drugs. Let’s start with a group of drugs I like to pick on all the time: sulfonylureas. Give me your thoughts about sulfonylureas.

 like Dr Ralph DeFronzo, so I’m sure he influenced even the way you say it. Sulfonylureas work at the beta cell. They’re inexpensive, but they have no cardiac benefit, they increase hypoglycemia risk, and you’ll gain weight from them. But they’re inexpensive. They usually fill the doughnut hole when the patient can’t afford anything else at the end of the year and you have no samples of anything. Personally, I’m very spoiled. I work in a state capital. Our patients have great health coverage because they work for the state, and I almost never have to use a sulfonylurea. We don’t use them. They were great when I was a fellow in the early 1980s, but they’re not as great anymore because we have other drugs with more benefits. Other drugs have the benefits of weight loss, lack of hypoglycemia risk, and cardiovascular benefit.

I’m going to answer because I’m really down on sulfonylureas. One of the reasons I’m down on them is that they tend to, as you said, stimulate insulin secretion. That insulin secretion leads to increased body weight. Over time, at least in my clinical experience—and I don’t know the studies on this, but you would—they tend to make people heavier. When patients are heavier, it’s leading to a need for insulin. Fat fights insulin, so the bigger you get, the more likely you are to need insulin subsequently. It’s a good thing to avoid sulfonylureas. Give us your take on metformin.

Metformin works at the liver. It prevents the liver from secreting too much sugar. The package insert has changed over the past couple of years, and now metformin can be used down to a GFR [glomerular filtration rate] of 30 mL/min. It used to be recommended for those with a GFR of 60 mL/min or higher with a warning of lactic acidosis. Most of my colleagues have never seen lactic acidosis with it, so it’s widely used. It’s the beginning of all standards of care from the American Diabetes Association and American College of Endocrinology. It had cardiac benefit in 1 study, but that was a very small study, so it would never get the label for cardiac benefit. Now we have a lot of better drugs, but they are inexpensive, don’t cause hypoglycemia, and facilitate some weight loss. One thing our primary care colleagues know is that you can get vitamin B12 deficiency from metformin because it can block B12 absorption in the gut.

That’s a very interesting point. The other great point that is that you can use it with those higher-creatinine patients, which people have avoided, but simply at lower doses. It remains a good drug. Give us your intake on SGLT2 inhibitors.

I’m sure you’ll get to GLP1s. It’s just like you love your son and your daughter; they’re both our favorites. SGLT2 inhibitors block the absorption of glucose at the proximal tubule, so you release sugar, salt, and water in the urine. The sugar doesn’t come out as Domino sugar crystals—it’s pulling salt and water. You have lower blood pressure, lower weight, and lower fasting postprandial glucose and A1C. They don’t cause hypoglycemia. That alone would be enough—a drug that doesn’t cause hypoglycemia and lowers weight and blood pressure. But there’s more, as you well know. These drugs have a variety of other great benefits. They lower MI [myocardial infarction], stroke, and death risk. In the EMPA-REG OUTCOME study, they lowered risk of cardiac death. Some prevent heart failure. They treat heart failure with reduced ejection fraction. They are our be-all-and-end-all oral agent. We love them, except that there are some potential adverse effects and counseling that the patient has to have with them.

Yes. I intentionally saved 1 of the best drug classes for last. Those are the GLP1 agonists.

The GLP1 agonists are drugs that have multiple benefits. They lower appetite. They delay stomach emptying. They lower sugar production in the liver by lowering glucagon, and they increase insulin if the glucose is elevated. They’re smart secretagogues. They put out insulin when you need it like a thermostat. Even if the beta cell doesn’t work well, they still lower appearance of sugar. They still lower appetite, so that means fewer calories in by mouth, fewer calories in by stomach, and fewer calories in by liver. You can use them late in the course of diabetes or early in the course of diabetes. Most of them are injectable, either twice a day, once a day, or once a week. There is a relatively new oral GLP1 inhibitor that’s taken in a specific way daily, first thing in the morning. The other big benefit of these drugs is that they lower MI, stroke, and death risk. Several of them have very positive cardiac outcome studies.

One of the most attractive things that you pointed out is the fact that they are associated with weight loss, so it actually helps control the underlying cause.

We never hit on the glitazones. We never said anything about pioglitazone. That’s not a frequently used drug. It’s not loved by cardiologists because people get fluid retention and can go into heart failure. Do you have a passing thought on pioglitazone?

Yes, as a lipidologist, you know that pioglitazone lowers triglycerides. It had good outcome studies. The PROactive study would have been positive, except that they included vascular events as part of the MI, stroke, and death outcomes. They added revascularization, and that killed the study. If you looked at 3-point MACE [major adverse cardiovascular events] in their outcome study, they lowered that, and specifically lowered stroke. In Connecticut, Dr Silvio Inzucchi et al. did the IRIS trial in patients who had MI or stroke in the past but did not have diabetes. When they gave patients pioglitazone, it lowered risk of stroke and MI by 25%. We do like that as a heart-smart drug, as long as the patient hasn’t had bladder cancer or history of heart failure. They got a bad rap because of the heart failure, but we can listen to the patients’ lungs. Sometimes, I do a BNP [brain natriuretic peptide] level on some of my patients if I’m worried about heart failure. I follow that to make sure, and I use lower doses than I once did. I use 15 mg or 30 mg. I don’t go to 45 mg.

Be careful with this pro-BNP stuff. I don’t want you invading cardiology.

That’s very smart. In most cases, we have other drugs, so I don’t use them a lot. I don’t use pioglitazone a lot, but I wanted your input on that.

Available Treatments for Type 2 Diabetes

I want to hit on 1 of the other issues that I’m always trying to talk about, and that is how you can be fooled into not seeing diabetes in borderline patients who have a normal hemoglobin A1C [glycated hemoglobin]. You can be tricked into thinking that there’s nothing going on. Their glucose is a little high. Their hemoglobin A1C is not bad, and you overlook the possibility that they actually have diabetes or prediabetes.

Hemoglobin A1C is a 3-month average, but the red cells don’t last 3 months if you have hemolytic anemia, certain hemoglobinopathies, and renal disease. In that case, the A1C might not reflect the overall 3-month average glycemic control. There’s a 1-month average we use called a fructosamine. We do that in pregnant diabetics or patients who have turned over a new leaf if they come back to you in a month and you want to show that their average sugar has improved. Those are patients in whom we do a 1-month average. But there are certain patients in whom, if you’re really suspicious that they have diabetes, you do a glucose tolerance test, much like in the old days. The A1C is a nice shortcut, but it doesn’t always reflect whether the patient has diabetes.

Bob, is it also possible that the hemoglobin A1C is normal, yet the person has big spikes postprandially that are deleterious? Or does that not happen often?

Usually, the A1C is pretty sensitive, unless they have some kind of hemoglobinopathy or red cell turnover. If someone had a gastrointestinal bleed or is constantly replenishing with new red cells, that red cell hasn’t been exposed to glucose yet. Your A1C could be better than your glucose levels.

Ensuring an Accurate Diagnosis of T2DM

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?

: 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.

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?

: 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.

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 

 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?

: 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.

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?

: 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.

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?

: 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.

Do you have advice on diet for patients with these issues?

: 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.

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 

 talking about intermittent starvation and intermittent fasting. Do you have any thoughts on that?

: 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.

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.

Ongoing Trials and Lifestyle Changes 

What about the collaboration between cardiologists, endocrinologists, primary care doctors, and nutritionists? How do you manage that? For example, you’re an endocrinologist. You can clearly change the drugs, and the primary care doctor is not going to be upset. What are your thoughts about cardiologists doing that? Do you have an opinion about it?

: The fear that some cardiologists have is that they’re going to cause hypoglycemia. First of all, if they’re not on insulin or sulfonylurea, they’re not going to have hypoglycemia, so that’s a nonissue. You can’t get the sugar very good, as you were mentioning before, if they’re not on insulin or sulfonylurea.

I would welcome my cardiologists doing that, but in my area, and we have a lot of cardiologists here, I have never seen a patient come to me on an SGLT2 [sodium-glucose co-transporter 2] inhibitor or GLP1 [glucagon-like peptide 1] agonist. More importantly, I don’t even see it suggested in the note. You are very well versed on treatment of heart failure with reduced ejection fraction and prevention of heart failure in the DECLARE trial with dapagliflozin. I don’t know why they don’t use it a lot more. These drugs are very safe. It may be because they don’t know the dose of Diflucan [fluconazole] to treat the yeast infection. With SGLT2 inhibitors, you have to talk to the patient about how they’re going to urinate a lot the next week. You ask what they like to drink. You want them to drink something without calories. Do they have yeast infections? Is the man uncircumcised, so he can get a yeast infection? It takes a little time to discuss that with the patient. Once you’re comfortable with it, these are your drugs, as well as mine. It’s like saying, “I’m not going to use a statin because you can get muscle aches, and I might have to look at your liver test once in a while.”

That’s a very important point, though, to make sure patients understand. Some patients will not want to use SGLT2 inhibitors because of the risk of genital yeast infections. As for the point about being circumcised or uncircumcised, I remember how upset my nurse was the first time I started asking patients about that, but it’s a very important point to make sure that people keep themselves very clean in that area. That’s the biggest drawback.

It’s a big concern to many of us. Your point is extremely well taken. These drugs can be used without a great deal of worry, as long as patients are not on sulfonylurea or insulin. These are smart drugs. GLP1 agonists are smart drugs. They’re not going to go beyond what you want that sugar to be. I try to seek hemoglobin A1C levels under 6%, frankly. You can get them without causing trouble. People lose weight and they feel better.

The Collaborative Management of T2DM

What advice do you give cardiologists, or do you not even talk to us? What important advice do you give us, in terms of managing diabetes?

: If your patient with diabetes comes to you and they’re not on one of these heart-smart drugs, a GLP1 [glucagon-like peptide 1] agonist or SGLT2 [sodium-glucose co-transporter 2] inhibitor, at least put it in the note. If you’re comfortable doing it, it becomes part of your routine once you’ve done it a couple times, just as a statin or RAS [renin-angiotensin system] blocker is. It should be part of your routine, as treating lipids are part of my routine. It’s not, “OK, I do your diabetes. I’m not doing your blood pressure or your lipids.” I’m doing all 3. As a cardiologist, you should address diabetes when you have heart-smart drugs, and do it in collaboration with whoever else is managing the diabetes. Put it in the note.

Even if the patient is on insulin or sulfonylurea and they’re not on the heart-smart drug, you might want to put it in the note. You can also initiate it, but tell the patient, “Your primary care doctor is managing your diabetes. These drugs will make your other drugs more effective. Call the other doctor to let them know.” It’s just as a good orthopedist would say, “I’m giving you a shot of steroids. Call your doctor who manages your diabetes, because your sugar might go up, even though I don’t expect them to titrate the insulin.”

Yes. I’ll put in my 2 cents. Cardiologists always ask me, “Don’t you get in trouble with the primary care doctor when you, as a cardiologist, change things?” I never have. I do that by making sure that I let them know with the note I send them, and also give a good explanation as to why I’m doing it. I give the outcome data on various drugs to show that they work, and discuss the frequency of prediabetes leading to coronary disease before it becomes frank diabetes. The fact that, by using some of these drugs, we can actually prevent people from going from prediabetes to frank diabetes is very important.

One of the things I push really hard is that you can actually spare the patient from needing an endocrinologist if you start these drugs early, when they’re prediabetic, and you stop them from progressing to the point where they need insulin. My usual method is that when I begin to think I need to start them on insulin, that’s when I send them to an endocrinologist. That’s beyond my ability to handle easily.

: Our first injectable is a GLP1 agonist. If they were on an SGLT2 inhibitor, you and I both could feel comfortable adding the GLP1 agonist. That’s the first injectable we give, and it’s recommended by the American College of Endocrinology and the American Diabetes Association. If you have other oral treatments, an SGLT2 inhibitor, and a GLP1 agonist, that combination has a very powerful glucose lowering event without hypoglycemia. Many of your patients will not have to see an endocrinologist and may not even get the diabetes, if they’re prediabetic.

I totally agree with that. We use PCSK9 inhibitors and others, but it took me a little time to get started with the injectable. Once I did a few patients, it wasn’t very hard at all. The amazing thing is, I remember seeing this patient in the waiting room. I looked at him and said, “My gosh, that guy looks great.” I forgot that I had started him on a GLP1 agonist, and when I got into the room, I said, “Oh, that’s why he’s lost the weight. That’s why he looks so much better.” It’s a testament to the fact that these agents work so well. Are there any other things you think we should discuss, Bob?

: As you said, primary care physicians should do this, as well. I tell my primary care pals, “Why do you want us to get the hugs from your patient?” That was back when we could hug each other. When these patients lose weight, their numbers are getting better, and they don’t have to do finger sticks, even when they’re not on insulin or sulfonylureas, they’re very happy patients. I always feel that if primary care doctors did it themselves, they would be the heroes. Why are we the heroes to get a patient off insulin and get them to lose weight, when it’s their patient? It’s almost unfair. We thank them for the referral, but they could do it themselves and not need the endocrinologist.

Yes, it is quite amazing how much we can do. Again, I’m not trained as an endocrinologist, but it’s amazing how much I feel I can do as a cardiologist in this day and age. There is one thing I’d like to emphasize. We mentioned it, but probably in passing. As a cardiologist who is interested in lipids, I am referred a lot of patients with hypertriglyceridemia. I have noticed over the years that I would see these patients with triglycerides in the 300s, 400s, and 500s [mg/dL]. I would treat them, and then 4 or 5 years later, they would present with diabetes. A lot of doctors forget that high triglycerides are an early sign of diabetes. They are prediabetic.

I’m not sure this is true, so I’m asking you. I’ve always said it takes more insulin to regulate fat metabolism than it does glucose metabolism. I don’t know if that’s true, but in my mind, it is. I’ve seen these people and followed them over time. I know you know this, but I want the primary care doctors and cardiologists out there to remember, insulin pushes free fatty acids into the fat cell. If you don’t have enough insulin, the free fatty acids come out and they go into the blood. The liver makes triglycerides in proportion to the amount of free fatty acids in the blood. If the free fatty acids are high because of low insulin levels, you’re going to have high triglycerides. That’s an early sign.

I say the following: every hypertriglyceridemic is a diabetic wannabe. They don’t want to be, but they could be.

: Excellent. Can I take time to write down your pearls of wisdom during this discussion? That’s great, and I agree with you. As you know, part of metabolic syndrome is high triglycerides and low HDL [high-density lipoprotein]. These patients often have high triglycerides. The high triglyceride, low HDL, and other components of metabolic syndrome are frying the endothelium before the patient gets the diabetes diagnosis and you say, “Now, I’ll be aggressive with you.”

Yes, but you also said something else earlier that I let pass and I should have mentioned. You brought up diastolic dysfunction. There is increasing evidence that diastolic dysfunction—stiff hearts, heart failure with preserved ejection fraction, or hearts that squeeze well, but don’t relax well—may be related to the metabolic syndrome. It may actually be things like fat infiltration, just as fat can infiltrate skeletal muscle. Maybe there’s fat infiltration in the ventricle leading to some of that diastolic dysfunction or some of the cytokines associated with glucose intolerance.

I’ll tell you, this cardiology/endocrinology diabetes work is getting much closer together. You’re even ordering BNP [B-type natriuretic peptide] levels.

: And PCSK9 inhibitors, Vascepa [icosapent ethyl], and all the other stuff that cardiologists do.

Let’s pretend that you’re coaching me as a cardiologist to start someone on a GLP1 agonist, such as exenatide. Tell me what I should do. Let’s take 1 drug and you decide. Who is the patient I decide to do it on? What medicine should they be on already, and what do I do? Suppose the person comes in on metformin, and I want to get them to lose some weight. I don’t want to take the risk of hypoglycemia. I want to use a GLP1 agonist. Tell me what to do.

: What I would do is a once-weekly injectable, but weight loss sells the drug to the patient. Tell the patient they’re getting a once-a-week medication. They may say, “I don’t want to be on the needle.” Once I tell them they’ll lose weight on it, they’ll put the needle in their eyeball. They want to lose weight. Getting over that obstacle is important. No one complains about the second dose of the weekly injectable because the first dose is so easy. I do it right there in the office. These weekly drugs are not tied to food, so you can give them in the office. They leave with it in them already. You warn them that one person’s early satiety is another person’s nausea. Some people just eat less, but other people get nauseous on them. You have to have strategies to avoid the nausea.

What are those strategies? I recommend smaller meals, less fatty food, and less alcohol. You don’t want to do something that’s going to delay the stomach emptying more. You don’t want to start it the Wednesday before Thanksgiving, so they gorge themselves and get so sick they’ll never take it again. Nausea, to some people, is transient. And don’t increase the dose while they’re nauseous. Exenatide weekly is one-size-fits-all dosing, but some of the others have different doses. Don’t increase liraglutide from 0.6 to 1.2 to 1.8 mg if they’re still nauseous on the lower dose. Wait until the nausea goes away. Use the strategies to relieve nausea, and then increase the dose later, if needed.

Is that a positive for exenatide? In other words, you don’t have to titrate up.

: Yes, exenatide requires no titration. Because the GLP1 agonist is in microspheres, it slowly self-titrates, so the nausea rates tend to be much lower with exenatide than some of the other ones.

The whole thing about fatty foods is that fat impedes gastric emptying. Is that right?

: In terms of the SGLT2 inhibitors, the counseling there is, “You’re going to be urinating a lot in the next week. What do you like to drink?” Don’t get the patient dehydrated. Also address the genitourinary hygiene that you talked about before. Discuss stopping it if you can’t eat or drink, because you can set off ketoacidosis in rare cases. Interestingly, one of the theories with some of the SGLT2 inhibitors having heart benefit is that they increase ketones. This is a theory of Ralph DeFronzo, MD. Ketones are a preferred fuel for an ischemic heart. If they’re insulin resistant and can’t use carbs as a fuel, ketones can still get into the heart and nourish the heart. The slight increase in ketones might be the cardiac beneficial effects that these drugs have. They work so quickly to provide benefit. It’s too quick to be antiatherosclerotic. Something else is going on that has the benefit.

That’s very interesting. In that review article I mentioned in 

, one of the things they talked about were some animal studies showing increased exercise performance on a ketogenic diet. What is the dose I would prescribe when I start someone on a GLP1 inhibitor, like exenatide?

: Exenatide is a 2-mg, once-weekly dose. If you’re starting liraglutide, begin with 0.6 mg daily. For semaglutide starting dose is 0.25 mg weekly for 4 weeks. Dulaglutide is 0.75 mg weekly for 4 weeks. Then you can up-titrate after.

That’s useful, because primary care doctors are so busy that sometimes, knowing everything you need to know so you can get started is helpful. I found that after I did it a few times, it was quite easy and no big problem.

Advice for Cardiologists Managing T2DM

: Coming attractions in our field include what’s called a GLP1/GIP [glucagon-like peptide 1/glucose-dependent insulinotropic polypeptide]. Eli Lilly and Co has 1, and the other companies are developing them. They have more weight loss benefit than the current GLP1 agonists, and they’re doing cardiovascular trials. There will be higher doses of some of the drugs that will facilitate more weight loss. It will be more than the usual 5% to 10%. Maybe you’ll have 15% to 20% weight loss with a once-weekly injection. That will be coming out down the line. Since you mentioned heart failure with preserved ejection fraction, the data for SGLT2 [sodium-glucose co-transporter 2] inhibitors in patients with preserved ejection fraction will be out. We already have them for reduced ejection fraction. That’s when cardiologists will take over our field, because they’re not going to let that pass. They might let HFrEF [heart failure with reduced injection fraction] pass, but we don’t have a lot of treatments for HFpEF [heart failure with preserved injection fraction], from what I’ve understood. Is that correct? I don’t know, what are the other treatments for heart failure with preserved ejection fraction?

We treat them like they have heart failure. That’s it. We just want to make them asymptomatic as best we can, but we don’t have a strategy to treat those patients.

: One thing you mentioned before about preventing diabetes in the prediabetic was shown in the heart failure with reduced ejection fraction study with dapagliflozin, an SGLT2 inhibitor. When they treated nondiabetics, they had benefit, as well. Silvio Inzucchi, MD, showed that those patients were less likely to progress to diabetes. He used it in the prediabetic. It’s not in the drug’s label, but you and I as clinicians can do what is appropriate for the patient. I’ve used SGLT2 inhibitors in prediabetics, particularly if they have heart failure, to treat the heart failure. By the way, I’m probably preventing your diabetes.

If I told my chief of endocrinology 30 years ago that I’d have a pill that could lower weight, blood pressure, A1C [glycated hemoglobin], prevent heart failure, treat heart failure, and prevent kidney disease with no hypoglycemia, they would fire me for fantasizing. SGLT2 inhibitors do all of that in a pill. GLP1 agonists complement that with their cardiac benefit and weight loss. We have extraordinary drugs. They should be used by all of our medical colleagues, not just by the endocrinologists.

Do you think metformin is on its way out, or will it still have a strong role?

: Last week, metformin wasn’t doing well with the generic that was carcinogenic. Because it’s inexpensive with a little weight loss and no hypoglycemia, it is the no. 1 drug we prescribe. That would be like you being told that atorvastatin has a carcinogen in it. That’s not every metformin, but with the other drugs having heart benefits, more weight loss, and more outcome data, metformin won’t end up being in the front line down the line.

The big seller is the amount of weight loss that patients get. People who come in with type 2 diabetes tend to be obese. They’ve been trying to lose weight. It’s hard to do it when you have insulin resistance, and then you’re putting them on a drug in which they can lose weight.

We covered the gamut. You’re a great speaker. I want to thank everyone for joining us on this 

 presentation discussing the interface between cardiology and endocrinology with respect to insulin resistance and diabetes. I want to thank Dr Busch for a very insightful discussion, and I want to thank the audience for joining us. I hope you found it useful and informative.

Evaluating the Diabetes-Cardiology Interface

EP 1: Pathophysiology of T2DM and Cardiovascular Disease

EP 2: T2DM Management: Endocrinologist or Local Physician?

EP 3: Available Treatments for Type 2 Diabetes

EP 4: Ensuring an Accurate Diagnosis of T2DM

EP 5: Ongoing Trials and Lifestyle Changes

EP 6: The Collaborative Management of T2DM

EP 7: Advice for Cardiologists Managing T2DM

EP 8: The Future of T2DM Management