Emerging research is shedding new light on the indications and efficacy of combination therapies in the treatment of type 2 diabetes. A panel of physician-scientists discussed the current evidence for various combination therapies during the symposium Matchmaker, Matchmaker, Make Me a Match—Selecting Glucose-Lowering Combinations for Type 2 Diabetes Mellitus.

The session, which was originally presented Sunday, June 27, can be viewed by registered meeting attendees at ADA2021.org through September 29, 2021. If you haven’t registered for the Virtual 81st Scientific Sessions, register today to access all of the valuable meeting content.

Ralph A. DeFronzo, MD, Professor of Medicine and Chief of the Diabetes Division, University of Texas Health Science Center, and Deputy Director, Texas Diabetes Institute, opened the symposium with a discussion of combination therapies that incorporate incretins, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and pioglitazone—three classes of drugs that have been shown to provide cardiovascular protection.

Ultimately, triple-combination therapy of an SGLT2 inhibitor, a glucagon-like peptide 1 (GLP-1) receptor agonist, and pioglitazone may provide the best results, he said.

“We’ve published extensively on the benefit of combination therapy with SGLT2 inhibitors and GLP-1 receptor agonists, and we’ve also published with SGLT2 inhibitors plus pioglitazone and GLP-1 receptor agonists plus pioglitazone, showing additive effects,” Dr. DeFronzo said.

Studies suggest that the benefits of these therapies outweigh the risks of weight gain, he added.

“The more weight you gain with pioglitazone, the greater the drop in A1C, the greater the improvement in beta cell function, the greater the improvement in insulin resistance, the greater the rise in HDL (high-density lipoproteins), and the greater the decrease in triglycerides,” he said. “One could also add metformin to this group of drugs, but I think this is really where we should be going in terms of glycemic control, preventing microvascular complications, and prevention of cardiovascular and renal complications.”

Chantal Mathieu, MD, PhD, Professor of Endocrinology, University of Leuven, Belgium, discussed the rationale for combining SGLT2 inhibitors and insulin, including the metabolic effects of combining the two agents and whether the cardiorenal protective effects of SGLT2 inhibitors are still seen in those taking insulin.

“It makes sense to combine these two agents on the basis of the pathophysiology of type 2 diabetes and also on the basis of the mechanism of action of these agents,” she said. “Adding an SGLT2 inhibitor to insulin—basal as well as multiple daily injections—gives you an insulin-sparing effect and also it can help in reducing the weight gain that you see with the anabolic effect of the insulin.”

Phase 3 trials have shown that combining insulin and SGLT2 inhibitors is beneficial for A1C, Dr. Mathieu added. And while meta-analyses of studies suggest an association between insulin use and major adverse cardiovascular events in people with type 2 diabetes, she said the beneficial cardiorenal effects of SGLT2 inhibitors still seem to occur in people with type 2 diabetes who need insulin for glucose control.

Tina Vilsbøll, MD, DMSc, Professor of Medicine, University of Copenhagen, Denmark, and Consultant at the Steno Diabetes Center Copenhagen, discussed combination therapies using insulin and GLP-1 receptor agonists.

“Insulin and GLP-1 receptor agonists are a really interesting match in the treatment of type 2 diabetes,” she said. “There are indeed clinical benefits with A1C reduction, with less hypoglycemia and lower body weight with the combination of insulin and GLP-1 receptor agonists.”

When insulin is prescribed, compliance is a key factor and patients should be monitored closely when adding a GLP-1 receptor agonist, Dr. Vilsbøll noted.

“We should decide where we want to go with respect to fasting glucose and how low should we go,” she added. “And [we should] measure C-peptide levels—we do that every time we see a new patient and on a yearly basis—always together with the glucose to get an impression of the current beta cell function.”

In the final presentation, David D’Alessio, MD, Professor of Medicine and Chief of the Division of Endocrinology and Metabolism, Duke University Medical Center, discussed the emerging role of dual and multi-receptor agonists, including tirzepatide, a dual gastric inhibitory polypeptide (GIP)/GLP-1 receptor agonist.

“Human studies support dual agonists as an effective way to lower blood sugar and body weight,” he said. “The potency of tirzepatide in the trials so far supports the strategy of exploring multi-receptor agonists beyond single-receptor agonists.”

While the mechanism of action of multi-receptor agonists is still not clear, Dr. D’Alessio said they represent potential for a broad range of options and appear to be a fertile field for the development of new drugs.

“There’s no question that these drugs have variable potency in receptor activation. And a drug like tirzepatide, even though in cell studies it doesn’t look as potent as the native GLP-1, it may be a very good GLP-1 receptor agonist,” he said. “In the future, we may have computational methods to predict how any single peptide is going to work, but right now I think we’re in the stage of biological iterative refinement—that is, we’re going to have to take these molecules and test them one at a time.”