Medication Options for Type 2 Diabetes with Dr. Diana Isaacs


Diana Isaacs, PharmD, BCPS, BCACP, BC-ADM, CDCES, is a pharmacist with board certifications in pharmacotherapy, ambulatory care and advanced diabetes management. She was the recipient of the 2020 ADCES Educator of the Year award, and serves as the Continuous Glucose Monitoring and Remote Monitoring program coordinator at the Cleveland Clinic. Dr. Issacs recently spoke with Beyond Type 2 to discuss what a typical treatment path might look like for someone living with type 2 diabetes, and why.

For more information on how to talk to your provider about your treatment options, click here

The following transcript has been edited for length and clarity.

BT2: Thanks for speaking with us Dr. Isaacs. Can you start by telling us about metformin? Why is metformin the first line medication for people living with type 2 diabetes?

Diana Isaacs: According to all of our guidelines, for example from the American Diabetes Association, it is the first line of treatment and is a low-cost option. But also it’s been around years. It’s a medication that’s been tried and true and has demonstrated safety and effectiveness. That’s why generally we will start with it. Also through its mechanism of action, it actually decreases how much of the blood sugar the liver puts out. So, it doesn’t cause blood sugars to go too low and cause hypoglycemia. From that aspect, it’s a lot safer to use, too. 

It is common that people may stop taking it. The most common side effect is usually stomach upset or diarrhea. There are some strategies to be able to reduce that. A lot of times if people start with too high of a dose or they don’t take it with food, that will make these things worse. There’s also an extended-release formulation that really helps with that. Some people may just need a lower dose of it. So there are things we can do, but generally, we try to use that in every person with type 2 diabetes (T2D) if they can tolerate it.

If metformin isn’t helping someone achieve their glycemic targets or get their A1C closer to their goal, what is the next line of treatment?

It depends on other conditions. For example, if a person has kidney disease, heart failure, cardiovascular disease, or high-risk factors for cardiovascular disease, then we have specific medications, mainly the SGLT-2 inhibitors and then the GLP-1 receptor agonist class of medications. 

And then depending on other factors, for example, weight. If the goal is to lose weight or to not have weight gain, then again these two medication classes are recommended. The GLP-1 receptor agonists tend to have a little bit more loss than the SGLT-2 inhibitors. 

Cost is a big consideration and unfortunately, these two medication classes that I just mentioned are much more expensive. None of them have any generics available at this time. And so when the cost is a major issue, the guidelines say, well then you might consider using a sulfonylurea or GLP-1 medication, or the next option might be a DPP-4 inhibitor. 

SGLT-2 inhibitors—those are the ones that cause you to excrete some extra glucose through your urine?

That is correct. They lower that blood glucose threshold, and then more of it is excreted. You also lose more calories, blood pressure goes down, as well as weight. 

How do GLP-1 agonists work to lower blood sugar?

They have a four-part mechanism of action and are really amazing. They cause the pancreas to release more insulin and they also suppress glucagon. But the thing is they do so in a glucose-dependent way. Meaning if blood glucose is high, they’re going to cause more insulin to be secreted. But if a person doesn’t eat anything that won’t happen and that’s really important because that means they don’t cause hypoglycemia because they work that way.

Compared to sulfonylureas, which unfortunately do cause hypoglycemia. They also slow gastric emptying, so that means the food has longer to digest. Often that also helps to promote fullness. But also it means less of a spike of blood glucose after eating. Then they also seem to have some central effects on the brain as well, where they just cause more satiety, more fullness and the person tends to not be as hungry.

Weight loss is very common with those medications. In fact, there are two in that drug class that are actually approved specifically for weight loss. Just for weight loss and higher doses than the others, even for people without diabetes.

Are there different kinds of GLP-1s? How would a doctor decide which is most most appropriate for someone living with T2D?

There are weekly ones versus daily and then there’s one that’s twice a day. It’s good to know your options. If you don’t have to take twice a day medication and you could take once a week, many people would prefer to do that. And then there are differences in the device itself. Some are reusable pens, some are one-time use pens. I don’t know for some people that this may be important, but the needle size is actually a little bit different between devices. So it can be individualized based on what the person prefers.

For GLP-1s, most of them are injectable. There is now one in a pill form which has to be taken daily on an empty stomach, 30 minutes spread apart from any food or beverages. Only four ounces of water could be taken with it. So, it has special dosing requirements, but at least it offers people options, injectable versus daily.

For SGLT-2s, those are available as pills, correct? They also don’t cause low blood sugar by themselves, but if you’re taking insulin with it, you may not need as much insulin and may need to work with your healthcare team to lower your doses. 

Exactly. Anytime you add really any drug, whether it’s metformin, it’s the SGLT-2 inhibitor or the GLP-1 agonist to insulin, you need to monitor blood sugars. It’s very common that we may need to decrease insulin doses. By themselves none of the drugs we’ve talked about cause hypoglycemia. But whenever you combine with insulin or with a sulfonylurea, then that can happen.

How do sulfonylureas work?

They’re probably our oldest drug class and have been around forever. They work directly on the pancreas, the beta cells to cause them to secrete more insulin. So they are really effective, especially at first when someone has been newly diagnosed with type 2 diabetes. But there is some concern over time that they become less effective because the pancreas may not be as good at being able to put out all that extra insulin.

They also don’t care if you’ve eaten or not. So if a person does take it and skips a meal or eats less than usual or is more active, then they do have that risk of going too low.

But many times we see these drugs are prescribed because the cost is very, very low. And so for someone that doesn’t have health insurance or has a high deductible plan or whatever we see that these are being used.

Let’s talk about TZDs, would you say they’re less commonly prescribed? 

Yeah, so the TZDs are thiazolidinediones for the long name. They actually have a really unique mechanism of action in that they cause the muscles and the cells to be more sensitive to insulin. I’ve heard it described as an exercise in a pill. Because that’s also what exercise does, it makes the muscles more sensitive and thus takes up more glucose into the cells. There are just some concerns about some of the side-effects of this class. Unfortunately they typically cause weight gain instead of weight loss, and that’s not ideal. Sulfonylureas actually also can cause a little bit of weight gain, too. They also can cause some fluid retention. We have to be really careful using TZDs in people with heart failure. Then also there’s some concern about bone loss over time. They are not without side-effects, but they are very effective and they’ve actually been shown to be really good for people with fatty liver disease. So it is an option and it is a low-cost option. Pioglitazone is generic so that’s definitely lower cost.

You’ve just described four other treatment options other than metformin. It seems like it’s really important for patients to sit down with their doctor and learn about all their options, and why they’re being prescribed what they are.  

Exactly. There are also the DPP-4 inhibitors, which have fallen out of favor because they work very similarly to the GLP-1 agonists. They’re actually inhibiting the breakdown of GLP-1 that your own body can make. So they’re less effective than GLP-1 agonists because it’s reliant on how much GLP-1 your body can make. People with type 2 diabetes typically just don’t make enough, so it’s still a problem. So they’re less effective, but they’re very neutral in those side effects and are very well tolerated. People don’t gain weight from them or anything. But the reason they’ve really fallen out of favor is that when you compare that class to the GLP-1 agonists and the SGLT-2 inhibitors, they’re very neutral on all outcomes. Like effects on heart failure, effects on kidneys, effects on cardiovascular disease. Which is fine, we’re glad they’re not harmful. But now we have these two great classes of medications that seem to help all of these conditions.

We know people with type 2 diabetes are at a higher risk of all of these things happening. So to have a drug that can protect you long-term is really, really exciting. It seems like they do this even irrespective of how much blood sugar is lowered. So that’s really amazing. That’s why we want people to know about these classes and to ask their doctor. Ask their healthcare team if they could be a candidate for these agents.

That was a helpful dive into the treatment options for type 2 diabetes. Do you think it’s important for people with T2D to be proactive about bringing up these options with their providers?

Yes! Many doctors’ visits are only 20 minutes, so you want to come in prepared. Do your research and bring it up and come in prepared to discuss because your doctor may not have had time to research all the options before your appointment.

Thank you for your insights and expertise!

Another important medication for people with type 2 diabetes, who may need it, is insulin. Learn more about insulin and how it can help you improve your life with T2D by visiting our resources here.

Educational content related to Type 2 diabetes is made possible with support from Lilly Diabetes. Beyond Type 2 maintains full editorial control of all content published on our platforms.

WRITTEN BY Ginger Vieira, POSTED 11/15/21, UPDATED 12/13/22

Ginger Vieira is an author and writer living with type 1 diabetes, celiac disease, fibromyalgia and hypothyroidism. She’s authored a variety of books, including “When I Go Low” (for kids), “Pregnancy with Type 1 Diabetes,” and “Dealing with Diabetes Burnout.” Before joining Beyond Type 1 as digital content manager, Ginger wrote for Diabetes Mine, Healthline, T1D Exchange, Diabetes Strong and more! In her free time, she is jumping rope, scootering with her daughters, or walking with her handsome fella and their dog.