Available Treatments for Type 2 Diabetes



Paul Thompson, MD: 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.

Robert Busch, MD:You say 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.

Paul Thompson, MD: 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.

Robert Busch, MD: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.

Paul Thompson, MD: 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.

Robert Busch, MD: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.

Paul Thompson, MD: Yes. I intentionally saved 1 of the best drug classes for last. Those are the GLP1 agonists.

Robert Busch, MD: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.

Paul Thompson, MD: 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?

Robert Busch, MD: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.

Paul Thompson, MD: Be careful with this pro-BNP stuff. I don’t want you invading cardiology.

Robert Busch, MD:OK.

Paul Thompson, MD: 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.

Transcript Edited for Clarity

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