Diabetes Treatment Debate: Should Metformin Still Be Used First?

In this episode, TRC Healthcare editor, Rachel Cole, PharmD, delves into the debate about whether newer medications for Type 2 diabetes, including SGLT-2 inhibitors or GLP-1 agonists, should be used first-line instead of metformin. She examines the benefitsand drawbacks of these newer medications, including their cardiovascular and kidney benefits, side effects, and costs.

This is an excerpt from our March 2025 Pharmacy Essential Updates continuing education webinar series.

The clinical resources mentioned during the podcast are part of a subscription to Pharmacist’s Letter, Pharmacy Technician’s Letter, and Prescriber Insights: 

• Article: Stay Current on Med Recommendations for Diabetes
• Algorithm: Stepwise Treatment of Type 2 Diabetes
• Chart: Diabetes Medications: Cardiovascular and Kidney Impact
• Resource Hub: Diabetes

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Transcript

This transcript is automatically generated. 

0:00:03 Narrator

Welcome to Clinical Capsules, your go-to podcast and trusted source for quick, evidence-based insights from TRC Healthcare. 

0:00:11 Narrator

For four decades, we've been keeping healthcare professionals at the forefront of drug information and medical knowledge, and now we're bringing these vital clinical updates right to your ears with new episodes every 2nd and 4th Tuesday - delivering practical, actionable takeaways in bite-sized episodes.

0:00:28 Narrator

Today, Assistant Editor and Clinical Pharmacist Rachel Cole discusses the evolving landscape of first-line medications for Type 2 diabetes in an excerpt from our popular Pharmacy Essential Updates webinar series.  Let’s take a closer look…

00:00:47 Rachel Cole

So our article says you'll continue to see SGLT2 inhibitors and GLP-1 agonists gain traction as first line agents for many patients with type 2 diabetes.

00:00:57 Rachel Cole

And as you might imagine, this continues to be a big debate.

00:01:01 Rachel Cole

We're also used to metformin being first line, but you might see injectable GLP-1 agonist like ozempic or SGLT2 inhibitors like Farxiga being used first line for type 2 diabetes in some patients before metformin.

00:01:17 Rachel Cole

So let's look at an example here with our patient, Tanya. She's 59 years old and is a longtime patient at your pharmacy, and she has a new prescription for dapagliflozin or Farxiga, 5 milligrams by mouth once daily for 30 days. No refills. 

00:01:32 Rachel Cole

Now, based on what you see in Tanya's patient profile, you know that she has heart failure and she's taking several medications already for that, including the beta blocker metoprolol succinate and the ACE inhibitor lisinopril. 

00:01:45 Rachel Cole

She's also taking atorvastatin for high cholesterol.

00:01:48 Rachel Cole

But as you're talking with her, she tells you that she was recently diagnosed with diabetes, and her doctor thought this would be the best med for her to start for her diabetes. So what do you think about this? Does it make sense for Tanya to start Farxiga first for managing her Type 2 diabetes, or do you think she should start with metformin instead?   

00:02:09 Rachel Cole

So this is a good example of how this debate will come up in practice. Because Metformin does continue to be the gold standard, first line Med for most patients with type 2 diabetes for several reasons. It's established efficacy and safety. It has a long track record. It's generic and low cost.

00:02:28 Rachel Cole

Metformin also has possible cardiovascular benefits and can be used in patients with impaired kidney function with an EGFR down to 30.

00:02:38 Rachel Cole

But that debate will start to come up more often because our newer classes of diabetes meds, such as SGLT2 inhibitors like dapagliflozin or Farxiga and empagliflozin Jardiance or GLP-1 agonists such as semaglutide or ozempic or liraglutide, Victoza.

00:02:57 Rachel Cole

We've seen more and more evidence of their cardiovascular or kidney benefits. They're getting a lot of buzz for reasons beyond their effects on lowering blood glucose.

00:03:07 Rachel Cole

And there is robust evidence showing that adding a GLP-1 agonist or SGLT2 inhibitor to metformin improves those cardiorenal outcomes.  

00:03:18 Rachel Cole

On top of that, there's more limited data suggesting that those cardiovascular and kidney benefits are even independent of metformin. Now this is based on less robust evidence looking at subgroups and pooled analysis of cardiovascular studies, but that's why diabetes guidelines recommend these newer Med classes first line.

00:03:37 Rachel Cole

For some patients with type 2 diabetes, specifically those patients who have compelling indications like cardiovascular disease or chronic kidney disease, regardless of the patients A1C goal or whether they use metformin.

00:03:54 Rachel Cole

So this is a big change in thinking, the idea that some patients with type 2 diabetes would start out with a Med besides metformin. Considering all of the benefits we discussed with metformin and that it's really been the gold standard, first line Med for Type 2 diabetes for years. But some people are starting to think of the fact that metformin isn't always first.

00:04:17 Rachel Cole

But in reality, these newer meds may not always be practical for patients to use. First line for Type 2 diabetes and metformin isn't going away anytime soon because there are downsides with the newer meds, including side effects and especially considering costs SGLT2 inhibitors and GLP-1 agonists often require prior authorizations or have high co-pays. 

00:04:43 Rachel Cole

So if we look at some of those downsides, for example, SDL 2 inhibitors are linked to volume depletion due to their diuretic effects and possibly hypotension, genital yeast infections, euglycemic DKA, which is a life-threatening complication of diabetes, serious urinary tract infections and more rarely Fournier's gangrene, which can be a life threatening, genital infection.

00:05:08 Rachel Cole

And these meds may need to be held during acute illness or hospital stays.

00:05:13 Rachel Cole

Along with other potential risk like acute kidney injury, plus SGLT2 inhibitors, cost about $600 a month without insurance, whereas metformin can cost less than $5 per month.

00:05:28 Rachel Cole

And GLP-1 agonists have their own downsides. They can cause GI effects like nausea or vomiting. They have warnings, such as a rare pancreatitis or gallbladder disease.

00:05:38 Rachel Cole

And pulmonary aspiration, following deep sedation and these can cost about $1000 a month without insurance. Plus unlike SGLT2 inhibitors which are oral meds, most GLP-1 agonists are injectable, which patients usually don't prefer.

00:05:58 Rachel Cole

So Despite that debate, the bottom line here is we shouldn't abandon metformin. It's still practical, and it's often needed along with other meds for type 2 diabetes anyway, for glucose lowering. So it's definitely not going away anytime.

00:06:13 Rachel Cole

Soon. But it's a good reminder that we may see SGLT2 inhibitors, or GLP-1 agonists use first line before metformin in some patients.

00:06:23 Rachel Cole

And like with many things in pharmacy practice, this will be an individualized decision based on factors such as cost and the patients, other medical conditions. Thinking about those compelling indications that I mentioned before.

00:06:38 Rachel Cole

So when thinking about a patient's comorbidities and whether a Med other than metformin makes sense to start, first line for diabetes, SGLT2 inhibitors may be considered first line in a patient with type 2 diabetes and heart failure or chronic kidney disease or cardiovascular disease, such as a prior heart attack or stroke.

00:06:59 Rachel Cole

Or possibly in patients with multiple cardiovascular risks, because these meds can reduce the risk of heart failure, hospitalization or CV death. And remember our patient, Tanya has heart failure.

00:07:12 Rachel Cole

Some SDLT 2 inhibitors are approved specifically for some of these other indications like heart failure or in chronic kidney disease, and they can also treat diabetes. So it may be a bit of A2 for one approach with SGLT2 inhibitors. If patients have these conditions and type 2 diabetes.

00:07:35 Rachel Cole

Now just a quick sidebar about SGLT2 inhibitors and kidney disease. These meds can be started down to an EGFR of 20 for their kidney and cardiovascular benefits and continued until dialysis starts. But if a patient is using these meds for type 2 diabetes, glucose lowering is limited at a lower EGFR.

00:07:56 Rachel Cole

So they may not get as much glucose lowering effect for diabetes as in a patient with better kidney function.

00:08:05 Rachel Cole

Moving on to those considerations of compelling indications for GLP-1 agonists, there are certain GLP-1 agonists that are proven to have benefit in either cardiovascular disease or in chronic kidney disease.

00:08:17 Rachel Cole

Specifically injectable dulaglutide liraglutide or semaglutide, so you may see these GLP-1 agonists used if a patient has type 2 diabetes along with cardiovascular disease or multiple CV risks, not only for glucose lowering, but to reduce the risk of cardiovascular events.

00:08:36 Rachel Cole

Or you may see one of these GLP-1 agonists used for patients with CKD, especially since Ozempic is now approved in patients with type 2 diabetes and CKD. Because these meds may slow the progression of chronic kidney disease, they also don't require dose adjustments for kidney impairment.

00:08:54 Rachel Cole

But GLP-1 agonists do have less data for CKD than SGLT2 inhibitors and consider a GLP-1 agonist or the GIP/GLP-1 agonist tirzepatide for patients with metabolic liver disease or overweight or obesity.

00:09:13 Rachel Cole

So if we come back to Tanya here, we said she has heart failure and was recently diagnosed with diabetes, and she's starting to dapagliflozin. So based on what we discussed, what do you think about this prescription now?

00:09:27 Rachel Cole

Well, we said that one of those compelling indications for an SGLT2 inhibitor was heart failure. So Tanya has both heart failure and type 2 diabetes. So the SGLT2 inhibitor can benefit both of those conditions and could be a reason why she would start with dapagliflozin instead of metformin.

00:09:47 Rachel Cole

But I'd want to run this through her insurance. If cost is an issue, metformin might be a better choice. A Med can't work if the patient doesn't take it, so it's really going to be an individualized decision, weighing pros and cons overall.

00:10:02 Rachel Cole

Again, Metformin will still be first line for the vast majority of patients, but we'll likely start seeing more of that debate and that shift occurring over time.

00:10:14 Rachel Cole

So all of this is a good reminder for technicians to continue to keep medical conditions current and patient profiles so the pharmacist can evaluate which diabetes meds may have the most benefit.

00:10:24 Rachel Cole

Technicians can also stay alert for errors. For example, some of these meds have look alike sound alike generic names, GLP-1 agonists all end in -tide. Dulaglutide, liraglutide, etcetera, and SGLT2 inhibitors all end in -flozin, dapagliflozin empagliflozin.

00:10:44 Rachel Cole

Also, double check dosing. For example, some GLP-1 agonists are injected once weekly and some others once daily.

00:10:53 Rachel Cole

So diabetes is clearly a huge topic with lots to think about, but our algorithm, stepwise treatment of type 2 diabetes is a great resource to think about all the considerations with managing diabetes.

00:11:08 Rachel Cole

I also wanted to encourage you to visit our diabetes resource hub available on our website. This is a collection of articles, clinical resources and other CEs that are all focused on diabetes. If you're looking for one central location for guidance on helping your patients with diabetes.

00:11:26 Narrator

We hope you enjoyed and gained practical insights from listening to this presentation! 

00:11:31 Narrator

Be sure to follow or subscribe, rate, and review this show in your favorite podcast app. Or find the show on YouTube by searching for ‘TRC Healthcare’ or clicking the link in the show notes. While you’re there, check out our other TRC podcasts like Medication Talk and Rumor vs Truth.

00:11:48 Narrator

Also in the show notes, we’ve linked directly to a few of the excellent resources mentioned today available to subscribers of Pharmacist’s Letter, Pharmacy Technician’s Letter, or Prescriber Insights. On those websites you’ll also find a lot more evidence-based, concise, yet comprehensive resources on this and other medication therapy topics. 

00:12:07 Narrator

And don’t forget to check out our full Pharmacy Essential Updates webinar series for deeper dives into topics that matter to your practice.

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00:12:53 Narrator

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00:12:57 Narrator

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00:13:04 Narrator

Thanks for listening, stay sharp, stay current, and we’ll catch you next time on Clinical Capsules!