Miriam E. Tucker
August 03, 2021
The findings, from a retrospective analysis of administrative data from Alberta, Canada, during 2012-2017, also show that the fall-off in metformin adherence was most dramatic during the first 30 days, and in most cases, there was no concomitant substitution of another glucose-lowering drug.
While the majority with newly diagnosed type 2 diabetes were prescribed metformin as first-line therapy, patients started on other agents incurred far higher medication and healthcare costs.
The data were recently published online in Diabetic Medicine by David J. T. Campbell, MD, PhD, of the University of Calgary, Alberta, Canada, and colleagues.
"We realized that even if someone is prescribed metformin that doesn't mean they're staying on metformin even for a year ... the drop-off rate is really quite abrupt," Campbell told Medscape Medical News. Most who discontinued had A1c levels above 7.5%, so it wasn't that they no longer needed glucose-lowering medication, he noted.
People Don't Understand Chronic Use; Meds Don't Make You Feel Better
One reason for the discontinuations, he said, is that patients might not realize they need to keep taking the medication.
"When a physician is seeing a person with newly diagnosed diabetes, I think it's important to remember that they might not know the implications of having a chronic condition. A lot of times we're quick to prescribe metformin and forget about it ... Physicians might write a script for 3 months and three refills and not see the patient again for a year...We may need to keep a closer eye on these folks and have more regular follow-up, and make sure they're getting early diabetes education."
Side effects are an issue, but not for most. "Any clinician who prescribes metformin knows there are side effects, such as upset stomach, diarrhea, and nausea. But certainly, it's not half [who experience these] ... A lot of people just aren't accepting of having to take it lifelong, especially since they probably don't feel any better on it," Campbell said.
James Flory, MD, an endocrinologist at Memorial Sloan Kettering Cancer Center, New York City, told Medscape Medical News only about 25% of patients taking metformin experience gastrointestinal side effects.
Moreover, he noted that the drop-off in adherence is also seen with antihypertensive and lipid-lowering drugs that have fewer side effects than metformin. He pointed to a "striking example" of this, a 2011 randomized trial published in the New England Journal of Medicine, and as reported by Medscape Medical News, showing overall rates of adherence to these medications was only around 50%, even among people who had already had a myocardial infarction.
"People really don't want to be on these medications ... They have an aversion to being medicalized and taking pills. If they're not being pretty consistently prompted and reminded and urged to take them, I think people will find rationalizations, reasons for stopping ... I think people want to handle things through lifestyle and not be on a drug," noted Flory, who has also published on the subject of metformin adherence.
Moreover, Flory explained, "These drugs don't make people feel better. None of them do. At best they don't make you feel worse. You have to really believe in the chronic condition and believe that it's hurting you and that you can't handle it without the drugs to motivate you to keep taking them."
Communication with the patient is key, he said.
"I don't have empirical data to support this, but I feel it's helpful to acknowledge the downsides to patients. I tell them to let me know [if they're having side effects] and we'll work on it. Don't just stop taking the drug and never circle back." At the same time, he added, "I think it's important to emphasize metformin's safety and effectiveness."
For patients experiencing gastrointestinal side effects, options including switching to extended-release metformin or lowering the dose.
Also, while patients are typically advised to take metformin with food, some experience diarrhea when they do that and prefer to take it at bedtime than with dinner. "If that's what works for people, that's what they should do," Flory advised.
"It doesn't take a lot of time to emphasize to patients the safety and this level of flexibility and control they should be able to exercise over how much they take and when. These things should really help."
Metformin Usually Prescribed, but Not Always Taken
Campbell and colleagues analyzed 17,932 individuals with incident type 2 diabetes diagnosed between April 1, 2012 and March 31, 2017. Overall, 89% received metformin monotherapy as their initial diabetes prescription, 7.6% started metformin in combination with another glucose-lowering drug, and 3.3% were prescribed a nonmetformin diabetes medication. (Those prescribed insulin as their first diabetes medication were excluded.)
The most commonly coprescribed drugs with metformin were sulfonylureas (in 47%) and DPP-4 inhibitors (28%). Of those initiated with only nonmetformin medications, sulfonylureas were also the most common (53%) and dipeptidyl peptidase-4 (DPP-4) inhibitors second (21%).
The metformin prescribing rate of 89% reflects current guidelines, Campbell noted.
"In hypertension, clinicians weren't really following the guidelines ... they were prescribing more expensive drugs than the guidelines say ... We showed that in diabetes, contrary to hypertension, clinicians really are generally following the clinical practice guidelines...The vast majority who are started on metformin are started on monotherapy. That was reassuring to us. We're not paying for a bunch of expensive drugs when metformin would do just as well," he said.
However, the proportion who had been dispensed metformin to cover the prescribed number of days dropped by about 10% after 30 days, by a further 10% after 90 days, and yet again after 100 days, resulting in just 54% remaining on the drug by 1 year.
Factors associated with higher adherence included older age, presence of comorbidities, and highest versus lowest neighborhood income quintile.
Those who had been prescribed nonmetformin monotherapy had about twice the total healthcare costs of those initially prescribed metformin monotherapy. Higher healthcare costs were seen among patients who were younger, had lower incomes, higher baseline A1c, had more comorbidities, and were men.
How Will the Newer Type 2 Diabetes Drugs Change Prescribing?
Campbell noted that "a lot has changed since 2017 ... At least in Canada, the sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists were supposed to be reserved as second-line agents in patients with cardiovascular disease, but more and more they're being thought of as first-line agents in high-risk patients."
"I suspect as those guidelines are transmitted to primary care colleagues who are doing the bulk of the prescribing we'll see more and more uptake of these agents."
Indeed, Flory said, "The metformin data at this point are very dated and the body of trials showing health benefits for it is actually very weak compared to the big trials that have been done for the newer agents, to the point where you can imagine a consensus gradually forming where people start to recommend something other than metformin for nearly everybody with type 2 diabetes. The cost implications are just huge, and I think the safety implications as well."
According to Flory, the SGLT2 inhibitors "are fundamentally not as safe as metformin. I think they're very safe drugs — large good studies have established that — but if you're going to give drugs to a large number of people who are pretty healthy at baseline the safety standards have to be pretty high."
Just the elevated risk of euglycemic diabetic ketoacidosis alone is reason for pause, Flory believes. "Even though it's manageable ... metformin just doesn't have a safety problem like that. I'm very comfortable prescribing SGLT2 inhibitors, but If I'm going to give a drug to a million people and have nothing go wrong with any of them, that would be metformin, not an SGLT2 [inhibitor]."
Campbell and colleagues will be conducting a follow-up of prescribing data through 2019, which will of course include the newer agents. They'll also investigate reasons for drug discontinuation and outcomes of those who discontinue versus continue metformin.
Campbell has reported no relevant financial relationships. Flory consults for a legal firm on litigation related to insulin analog pricing issues, not for or pertaining to a specific company.
Health Solutions From Our Sponsors