For years, metformin has been the go-to first-line oral medication for patients newly diagnosed with type 2 diabetes. But with the growing popularity and effectiveness of medications like semaglutide (Ozempic) and tirzepatide (Moujaro), that’s changing — and so are guidelines and recommendations.

Now primary care providers have a decision to make: What’s the best first-line treatment for these patients and what factors contribute to that choice?

First Up: Metformin

For many patients newly diagnosed with type 2 diabetes, lifestyle changes, including improvements to diet and embracing regular exercise, are the first step in the effort to get their blood glucose levels under control.

“Usually the decision to start oral medications is largely dependent on how bad the diabetes is,” said Jay Shah, DO, a primary care physician with Pomona Valley Hospital Medical Center in Pomona, California.

Physicians have long relied on metformin as their first-line medication for treating type 2 diabetes, usually in conjunction with lifestyle changes. The US Food and Drug Administration first approved this antidiabetic agent in 1994 and it quickly took off. By 1995, it was already widely prescribed for type 2 diabetes management.

According to a 2021 study that reviewed data from two large US health insurance databases, metformin was used by 80.6% of Medicare beneficiaries and 83.1% of commercially insured patients in the period between 2013 and 2019. The authors noted that the use of glucagon-like peptide 1 receptor agonist (GLP-1 RA) and sodium-glucose cotransporter 2 (SGLT-2) inhibitors was low but was increasing among patients with cardiovascular disease.

Some physicians say that they still turn to metformin first.

“The usual first-line treatment is still the oldie-but-the-goodie, metformin,” said Neal H. Patel, DO, a family medicine physician with Providence St. Joseph Hospital Orange in Orange, California. “It is probably the most commonly prescribed drug in the world for diabetes and usually is great because it targets the cause of diabetes, which is insulin resistance rather than high blood sugar.”

However, he added, he does take a patient’s kidney function into account, noting that lactic acidosis is a rare but possible complication of metformin use.

Asha Shajahan, MD, also regularly turns to metformin. “Usually I do metformin because it’s the easiest,” said Shajahan, a primary care physician with Corewell Health in Roseville, Michigan. “It’s pretty effective, and you don’t have to be so concerned with your sugars dropping.”

An exception would be a patient with very high blood glucose levels. In that situation, Shajahan would start them on insulin right away and follow them closely until they are stabilized.

The Rise of GLP-1s and SGLT-2s

In 2021, a study published in the journal Therapeutic Advances in Endocrinology and Metabolism asked “Should metformin remain the first-line therapy for treatment of type 2 diabetes?” 

The study’s authors acknowledged that metformin is effective and well-tolerated in the treatment of type 2 diabetes but noted there’s little data about whether metformin confers any cardiovascular benefits.

Meanwhile, GLP-1 RAs and SGLT-2 inhibitors can provide additional protection from diabetes-related complications, such as cardiovascular and renal disease. With data that shows these other anti-hyperglycemic medications provide additional benefits in certain populations, the authors asked if healthcare providers should continue to rely on metformin as the first-line treatment. “You don’t necessarily have to try metformin right away,” said Betul Hatipoglu, MD, an endocrinologist, professor of medicine, and director of the Case Center for Diabetes, Obesity, and Metabolism at Case Western Reserve University School of Medicine in Cleveland. “Some people still use it as it’s cheaper. And that’s okay. I’m not saying that’s wrong.”

But, she added, a physician could go ahead and start the patient out on a GLP-1. If the patient is struggling with obesity and research suggests that losing 5%-10% of their body weight could help them go into remission, “why not give them something from the get-go that could help them?”

Shajahan agreed that she might recommend starting with a GLP-1 to patients newly diagnosed with type 2 diabetes who have struggled with being overweight or obese for many years.

“Those are the people that I tend to be more like, ‘The GLP-1s are better for you,’” she said.

Guidelines have shifted to reflect the new landscape. In 2021, the American Diabetes Association (ADA) updated its guidelines to “elevate the use” of GLP-1 RAs and SGLT-2s to reflect their benefit for patients with cardiovascular and renal comorbidities.

Then in 2022, the ADA and European Association for the Study of Diabetes published a joint report that removed metformin as the only first-line agent and added that GLP-1 RAs or SGLT-2s could be first-line options in patients with cardiovascular and renal disease.

Zoovia Aman, MD, a family medicine physician with Medstar Health in Silver Spring, Maryland, considers the safety, effectiveness, price, and simplicity for her patients with type 2 diabetes when choosing a medication. Although she noted that metformin is safe and well-tolerated by most, she does also consider their kidney function. If their creatine levels are elevated, she might bypass metformin.

“Patients which have high cardiovascular risk or have known cardiovascular disease, I usually prescribe GLP-1s if their insurance does cover it,” she said.

Cost Is Still a Factor

However, physicians say they still have to consider a factor beyond which drug will help their patients most: Cost.

The Therapeutic Advances in Endocrinology and Metabolism study authors noted in their conclusion that cost was a barrier for many people when it came to certain glucose-lowering medications, such as GLP-1 RAs and SGLT-2 inhibitors.

That’s still the case for many patients, as the 2024 study titled “Impact of cost on prescribing diabetes medications for older adults with type 2 diabetes in the outpatient setting” in Research in Social and Administrative Pharmacy cautioned.

Neil Soskel, DO, a family medicine physician with Mount Sinai in Lynbrook, New York, said he will typically prescribe a GLP-1 RA or SGLT-2 inhibitor if a patient has insurance that will cover it, especially if they have a higher body mass index and other comorbidities. But it’s not always easy.

“With most of the insurance companies, it’s still a battle, or the copayments are still so high,” he said.

According to Soskel, it’s been a particular struggle for his Medicare patients. Medicare does allow coverage of Ozempic for patients diagnosed with type 2 diabetes and cardiovascular disease through Medicare Part D coverage, but the coverage depends on whether the medication is covered in the patient’s specific formulary.

Absalon Gutierrez, MD, an endocrinologist at UT Health Houston in Houston, said metformin is still a good place to start if a patient doesn’t have insurance coverage for a medication like Ozempic or Mounjaro. But if they do have coverage, he would recommend a GLP-1 for a patient with known heart disease or kidney disease, or perhaps an SGLT2 inhibitor.

“That’s another good option,” he said. “They won’t lose as much weight with that one, but it’s a good option.”