Type 2 Diabetes: DPP-4/SGLT-2 Inhibitor Combinations

Experts Javier Morales, MD, and Dhiren Patel, PharmD, CDE, BC-ADM, BCACP, provide their perspective on DPP-4/SGLT-2 inhibitor combinations and identify the clinical rationale behind this strategy for the management of type 2 diabetes.

Javier Morales, MD: Fortunately, in this day and age of pharmacotherapeutics, most of the agents that are currently available for the management of type 2 diabetes exist in coformulations. The sodium—glucose cotransporter 2 (SGLT-2) inhibitors do actually come in coformulation with a dipeptidyl peptidase-4 (DPP-4) inhibitor. Sometimes, this combination of therapy winds up being very effective because it’s important to target the core defects of type 2 diabetes that have been described as the ominous octet by Ralph DeFronzo. The more of these targets that you can address, the greater likelihood of achieving good glycemic control.

It winds up that the combination of an SGLT-2 inhibitor with a DPP-4 inhibitor offers superior efficacy over using either agent alone. In… patients who may not be at target with 1 agent or on no agent but still need to have a formidable glycated hemoglobin (A1C) reduction, initial combination therapy is often welcomed because it addresses the core defects of type 2 diabetes and the efficacy that’s offered. Sometimes, the combination of these agents could be used on the backbone of metformin in order to see an even better reduction in hemoglobin A1C altogether.

Dhiren Patel, PharmD, CDE, BC-ADM, BCACP: Some of the benefits of this combination therapy include that it works in a very complementary way because each drug has a unique mechanism of action. By allowing the combination, they hit different core defects and cover about 4% to 5% of the different core defects that affect a patient with type 2 diabetes.

The benefits include that, when taking this, …you’re combining a drug such as a DPP-4 inhibitor that’s typically weight neutral with one that has weight loss. You’re going to see weight loss in some of your patients. The other benefit is the pill burden. You have a patient who’s taking 1 medication now, and that could translate into 1 co-pay for that patient. You’re making sure that there’s durability in terms of the glycemic control because you’re getting to goal early. You have 2 drugs that are working in terms of lowering blood sugar from a complementary standpoint. Again, from a patient’s standpoint, it’s just 1 pill and not multiple pills for that 1 condition.

In this class of combination therapy of the DPP-4 inhibitors and the SGLT-2 inhibitors, there’s a lot that’s there. To take it bullet by bullet, one of the advantages is that they’re all oral therapy. Patients don’t have to worry about injection, they’re all administered once daily and they combine 2 different medications. When we’re looking at a lot of these combination therapies, they come in combination with metformin, but they also come in combination with a DPP-4 inhibitor and an SGLT-2 inhibitor, which we’re discussing. The reason that I point that out is because some patients may already be on a combination therapy of one of the other agents along with metformin.

When the time comes to treatment intensify, metformin is something that is generically available and pretty inexpensive. When you’re combining 2 branded medications, typically a DPP-4 inhibitor and an SGLT-2 inhibitor, into 1 copay and into 1 pill, that usually alleviates some type of cost burden from the patient’s standpoint while maintaining all of the attractive features of each drug alone: specifically, being once daily and having a favorable side-effect profile. It’s simplifying that for the patient and also ensuring that there is some glycemic durability when patients get to goal at an earlier standpoint in their diabetes progression.

When counseling patients on combination therapy, specifically the combination of the DPP-4 and SGLT-2 inhibitors, they’re quite unique in terms of their side effects. It’s going to be pretty easy as a pharmacist to pinpoint where the adverse reaction is coming from. There is some overlap, but they pretty much have very notable side effects associated with them. If we look at the SGLT-2 inhibitors, some of the most common side effects that you see there are infections: urinary tract infections and mycotic infections. If that is reported, it’s pretty easy to tease out of the combination drug which one it was.

The DPP-4 inhibitors are pretty well tolerated, where you don’t have a lot of notable side effects. The hypoglycemia risk is low for both agents from a profile standpoint. It’s not something that patients will complain about or you’ll see a lot of as long as there’s no background therapy of other medications that might be causing low blood sugar, just sulfonylureas. And then, from a weight standpoint, you’re going to see it being weight loss or weight neutral in most of the combinations.