Time to Rethink Metformin as First-Line Therapy? Perspective from ADA 2022

Less than 2 weeks ahead of the American Diabetes Association 82nd Scientific Sessions, new data from the Diabetes Prevention Program Outcomes Study (DPPOS) provided insight into 21 years of follow-up from more than 3,200 adults with prediabetes. As with previous data releases from the program, the new data drew a lot of attention and, for many, it was because the results fly in the face of conventional wisdom: neither lifestyle interventions nor metformin reduced the cardiovascular disease risk among these patients.

With both of these approaches proven to provide benefit for reducing risk of type 2 diabetes, metformin and lifestyle interventions have established themselves as integral parts of treatment algorithms for many people with diabetes. However, in recent years a new emphasis has been placed on not only addressing subpar glycemic control in patients with diabetes, but also addressing the inherent cardiovascular and renal risk in these patients through use of newer agents, such as GLP-1 receptor agonists and SGLT2 inhibitors.

With this in mind, Endocrinology Network asked a trio of experts in diabetes and cardiometabolism what they thought of the recent data from DPPOS and whether or not it is time to shift away from metformin being a first-line therapy for people with type 2 diabetes towards a newer agent or agents. The responses of these experts, Juan Frias, MD, of National Research Institute, W. Timothy Garvey, MD, of University of Alabama at Birmingham, and Hiddo Heerspink, PharmD, PhD, of Groningen University in the Netherlands, can be found below.

Time to Rethink Metformin as First-Line Therapy? Entering an Era of Personalized Medicine

Juan Frias, MD

Juan Frias, MD: That is a great question. My answer would be that metformin is very inexpensive, and oftentimes free, and it is very effective in lowering glucose. In your patients, particularly those with very high glucose, usually you get a greater reduction.

What I would say is that we should not use metformin and delay the use of those agents, such as a GLP-1 or an SGLT2 inhibitor, in patients who are appropriate and need those agents. So, don't use metformin to the exclusion of using the other agents. I think it could certainly be an adjunct in a lot of patients because it does clearly improve glycemic control. Again, it's generic, it's inexpensive, and I would say that it's going to continue to be used. Sulfonylureas continued to be used and I certainly think those should be phased out before metformin gets phased out.

So, we need to just make sure as the guidelines tell us, irrespective of the HbA1c and irrespective of metformin use, that patients with atherosclerotic cardiovascular disease who are at very high risk should be using GLP-1 receptor agonists or SGLT2 inhibitors with proven cardiovascular benefit. In patients with heart failure, they should be using an SGLT2 inhibitor. In patients with chronic kidney disease, an SGLT2 inhibitor and, oftentimes, a combination of SGLT2 inhibitor and GLP-1 receptor agonist, and I think metformin is fine to include there as well. What you don't want to do is be on metformin for 1-2 years and not add those other agents.

W. Timothy Garvey, MD

W. Timothy Garvey, MD: Well, that's a good question. But there's a subanalysis of the DPP data I would point you to looking at patients that lost 10% or more of their body weight. In this subgroup, patients did have a decrease in MACE outcomes: myocardial infarction, nonfatal stroke, and this composite cardiovascular outcome measure. So, this data suggests that it boils down to achieving sufficient weight loss to achieve cardiovascular protection. We don't have these data from these weight loss medications at this point.

There is a study called SELECT that is ongoing with semaglutide 2.4 mg in patients without diabetes, but, again, we won't have those data probably for a couple of years. I also think there is a cardiovascular outcomes trial in process for patients with diabetes for tirzepatide. Again, we're just awaiting those data, but if we can show that these medications, together with lifestyle interventions, achieved sufficient weight loss to put them in the range where we can expect to see cardioprevention, that could be and that should be a game-changer.

I think in terms of how we think about these patients, we need to help increase the access of patients to these evidence-based therapies, which currently for obesity is somewhat limited. Maybe, with these data showing the degree of weight loss and how this weight loss translates into the prevention or treatment of obesity-related complications, I think payers and healthcare systems are going to be more amenable to making these therapies and these interventions available to patients.

Hiddo Heerspink, PharmD, PhD

Hiddo Heerspink, PharmD, PhD: I think it's time to think about prevention of complications of type 2 diabetes or prediabetes. Metformin is a fantastic drug to reduce hyperglycemia, but the outcome data, as you mentioned, is limited. We have fantastic outcome data with SGLT2 inhibitors and fantastic outcome data with GLP-1 receptor agonists.

So, from my perspective, it's really time to rethink our approach for the treatment and the sequencing of tracks. As I've already mentioned, I believe it's about the prevention of outcomes. It's now also prevention of diabetes or new-onset diabetes and we have data from the SGLT2 trials with nondiabetic patients that SGLT2 inhibitors reduced new-onset diabetes by over 33%.

So, it's really important to take that into consideration and rethink our approach. Our approach has been traditionally on the timing of when drugs came to market and we have always added new drugs but now with many new drugs showing cardiovascular benefits, it's time to think about which combination for which patients. So, we are really heading into an area of personalized medicine I've received the near future.

These transcripts have been edited for length and clarity.