Metformin is the world’s most-prescribed diabetes drug. For a generation, most Americans with newly diagnosed type 2 diabetes have been prescribed metformin as their first medication.
But now metformin’s reign as the universally acknowledged “first-line” treatment for type 2 diabetes has come to an end. Updated guidance from the American Diabetes Association (ADA), released on December 12, 2022, has substantially minimized the importance of the popular drug. The ADA’s committee of experts removed metformin from key recommendations and now ranks the drug as inferior to other options for blood sugar control, weight loss, and long-term heart and kidney protection.
As a result, the ADA has essentially abandoned the idea of a universal “first-line therapy.” The organization removed multiple significant references to the concept and replaced them with language encouraging clinicians to consider many different medicines for new patients.
“Current treatments are absolutely not one-size-fits-all anymore,” said Robert Gabbay, MD, PhD, chief science and medical officer for the ADA. He told Diabetes Daily that the new recommendations are “about tailoring the therapy based on the patient’s needs.”
A New Progression
The standard treatment progression of previous years — prescribe metformin, monitor the results, and only later prescribe additional medications — has been overturned for an approach that is more complex and potentially more aggressive. Now, doctors are encouraged to consider all diabetes drugs from the very beginning. Previously, the immediate use of drugs more powerful than metformin had been limited to new patients with “special circumstances.”
“It is more about elevating the importance of cardiorenal protective drugs, and not necessarily waiting to start metformin and then move on to the cardiorenal protective medications,” says Dr. Gabbay.
The change was revealed in the newest version of the ADA’s Standards of Care in Diabetes, the guide that establishes diabetes treatment standards for healthcare providers in the United States. This year’s update deleted prominent references to the idea of a “first-line” or “initial” therapy, and has removed metformin from its perch at the top of its signature flowchart.
The U.S. Food and Drug Administration (FDA) appears to be moving in a similar direction. On January 13, the organization announced a label update for Rybelsus, an oral GLP-1 receptor agonist, allowing it to be used as a first-line treatment for type 2 diabetes. Previously, the drug had not been officially indicated for initial therapy.
New Drugs Give Doctors New Treatment Targets
The new ADA recommendation can be seen as a major endorsement for the stars of the newest generation of diabetes drugs: SGLT-2 inhibitors and GLP-1 and GIP/GLP-1 receptor agonists. These options combat hyperglycemia effectively but add other important benefits that metformin cannot claim: enhanced weight loss and more robust protection against cardiovascular and kidney disease.
The latest Standards of Care puts those new treatment targets at the forefront by recommending that patients with additional metabolic health conditions, such as obesity or a high risk of heart disease, should be offered diabetes drugs that address those conditions.
Jeffrey Mechanick, MD, an endocrinologist at New York’s Mount Sinai Hospital, is a supporter of the change. Dr. Mechanick was not involved with the new ADA document but has helped author guidelines for the American Academy of Clinical Endocrinology. He told me that “we needed a paradigm shift.”
Mechanick explained that diabetes experts have moved away from their previous focus on hyperglycemia toward more “comprehensive” approaches. The shift was largely inspired by the results of major clinical trials, beginning with 2008’s ACCORD trial, which unexpectedly showed that aggressively lowering glucose levels with medications such as insulin and sulfonylureas could introduce harm. Next, a series of renal and cardiovascular outcome trials found that the new generation of diabetes drugs protected the kidney, heart, and blood vessels, reducing complications and even saving lives.
“The ordinary physician, when confronted with a patient, shouldn’t just keep adding medicine and adding medicine in order to treat a particular numerical target like A1C or fasting blood sugar,” says Mechanick.
“It’s good that it’s in the guideline. It helps healthcare professionals know that, all things being equal, [newer drugs] would be a better way to manage a patient.”
The new Standards of Care includes a flowchart that offers the best way to visualize who ought to consider more powerful drugs than metformin:
For patients who need to lose weight — reportedly 80 to 90 percent of people with type 2 diabetes — the ADA ranks drugs by efficacy, with semaglutide (a GLP-1 receptor agonist) and tirzepatide (a GIP/GLP-1 receptor agonist) conferring the most weight loss. These two drugs induce levels of weight loss that are unprecedented in obesity medicine.
The ADA now recommends patients with a high risk of atherosclerotic cardiovascular disease, and those who have already developed the condition, take either a SGLT2 inhibitor or a GLP-1 receptor agonist.
The standards also suggest patients with heart failure or chronic kidney disease should take an SGLT2 inhibitor.
A very substantial majority of people with type 2 diabetes fall into one or more of the above categories. While metformin is still a potent therapy — it is scored as “high” efficacy for lowering glucose — it is now only one of several preferred options for treating hyperglycemia.
Mechanick told Diabetes Daily that clinicians “should be thinking of the GLP-1s and SGLT2s much, much earlier. They should think of prescribing these drugs first … if the insurance company will pay for it.”
As of this writing, empagliflozin (Jardiance), an SGLT2 inhibitor, costs nearly $600 per month off the shelf. Semaglutide (Ozempic), a GLP-1 receptor agonist, is over $900. Tirzepatide (Mounjaro), the GIP/GLP-1 receptor agonist that Diabetes Daily called “the best type 2 diabetes drug ever,” costs about $1,000. It will be many years before generics can be developed and approved.
Few members of the diabetes community can afford to pay such prices out of their own pockets, and insurers may be reluctant to cover such pricey medications for new patients without special circumstances.
Mechanick explained that “there was incredible reluctance to elevate GLP-1s and SGLT2s, because they’re really not accessible to everybody.” Endorsing the earlier use of these newer drugs “is consistent with our modern understanding of diabetes and chronic disease prevention, but there are practical issues in mind. It’s just not pragmatic because patients can’t afford it.”
Gabbay insisted that the ADA is “very concerned about access to treatment and the unfortunate health disparities that exist in the diabetes community.” He highlighted the ADA’s Health Equity Now advocacy program as one way that the organization is combating diabetes inequities.
“Metformin still plays an important role for many patients,” says Gabbay, and even if metformin doesn’t offer the comprehensive benefits of the newest drugs, it remains both safe and affordable. Diabetes treatment will not change overnight. Mechanick noted that “just because something’s in a guideline, it doesn’t mandate that it’s done.”
Eventually, insurers may become convinced that SGLT2 inhibitors and GLP-1 and GIP/GLP-1 receptor agonists pay for themselves by reducing the likelihood of complications such as heart and kidney disease. In the meantime, however, it’s easy to envision a near future in which metformin becomes the de facto first-line therapy of the less advantaged. A recent study in The Lancet found that there are already stark racial/ethnic and socioeconomic divides in the use of newer diabetes medications, particularly GLP-1 receptor agonists. It’s unclear if the new ADA recommendations will help bridge those gaps or widen them.