Every day, primary care physicians (PCPs) perform delicate balancing acts. They decide which type 2 diabetes medications a patient can tolerate, while simultaneously requiring efficacy.

This reading audience knows well how the body can react to these medications — the gastro side effects of metformin, the muscle aches caused by statins, the urinary tract infections, and genital yeast infections, courtesy of the SGLT2is. And as time passes and comorbidities accumulate, physicians must consider how medications for those diseases will interact with the type 2 diabetes drugs.

Despite the best efforts of tight-rope walking prescribers, patients with diabetes abandon these medications in droves — especially for adverse events and costs. And if physicians try to classify patient characteristics that could at least signal which group is more prone to abandon which medication class — or which medications can lead to that abandonment decision — then that classification attempt is usually based more on experience than science.

Recent studies have tried to imbue more scientific information into the prescription decision-making process. Some, for example, have used demographic information or therapies’ safety profiles to make that call. In the latter study, the complexity of safely prescribing medications expanded as time passed, and the complexity of diabetes — riddled with increasing comorbidities — was clearly spelled out.

“The ongoing metabolic imbalance of DM [diabetes mellitus] increases the risk of serious long-term microvascular and macrovascular complications,” the authors wrote. The study spanned a 3-month window in 2024; 1534 people were involved.

In the 6-year demographic study — 135,410 people were prescribed one of five glucose-lowering medication classes — researchers tried to discern which groups were more likely to abandon a newly prescribed medication within 3 months. The study evaluated the outcomes based on myriad socioeconomic factors, including ethnicity and income, and their medical history, including their BMI, prior prescriptions for statins, and fall history.

Of the 135,410 people, 26,138 (19.30%) of them discontinued their newly prescribed medication within the 3-month timeframe.

These researchers, of the MASTERMIND Consortium, wanted to create a model for medication abandonment based on those factors. It didn’t work. While certain ethnicities (Black, mixed, and others) did abandon thiazolidinedione (TZDs) more than other groups, income didn’t matter for discontinuation of any of the five medications, including GLP-1 receptor agonists (RAs), nor did smoking status.

Women said no to their new prescription more than men across all five drug classes, especially the TZDs.

The researchers’ conclusion: “Instead of likely tolerability, prescribing decisions in T2D should focus on drug‐specific side‐effect risks and differences in the glycaemic and cardiometabolic benefits of available medication classes.” (A side note: Check out the open-access tool these researchers devised to predict a type 2 diabetes therapy’s effectiveness.)

The findings of the demographic study are a good starting point toward making treatment decisions, said Patrick Brent Smith, MD, program director, Mississippi Delta Family Medicine Residency Program, and member, board of director, the American Academy of Family Physicians. If a practitioner keeps that in mind, then the findings are useful, he said. What matters are the informed decisions made after a conversation with the patient.

The Literature

Among those medications that patients abandon significantly, especially for adverse events, belong in the diabetes formulary: GLP-1 RAs, statins, and blood pressure medications.

So researchers seem determined to find data that can help explain why patients consistently jump the prescription ship.

In 2023, researchers, using private health plan claims data for patients with type 2 diabetes, reviewed the data of 82,624 people over a 3-year period who had been prescribed one of five second-line medications: DPP-4is, GLP-1 RAs, SGLT2is, sulfonylureas, or TZD.

Among all, 38% discontinued any kind of medication. Half of those prescribed a GLP-1 RA did so; the discontinuation rates on the other four medications were all between 36.6% and 39.4%.

More people (8.7%) switched out their DPP-4is than any other medication; those on sulfonylureas were the least to do so, at 3.0%. Most people who switched their medication chose a sulfonylurea (32.9% out of 4342 patients). The age group at higher risk for discontinuation was the 18- to 44-year-olds, and women were at risk more than men. This study, like the MASTERMIND Consortium study, didn’t explore reasons for change. Smith said the biggest reason people discontinue medication is cost. (A 2020 review of claims data from nearly 4800 patients prescribed GLP-1 RAs found that by year 2, just 47.4% were still adherent.)

Taking a different road to identify which patients are doing what, a new study in AJMC advocates reviewing pharmacy claims to “identify early warning signs” to see which patients: have delayed refills, stretched their first prescription beyond its limit, had significant out-of-pocket costs, and shown evidence of gastrointestinal adverse effects.

Finding the Prescription Sweet Spot

Experts said the key to matching drugs with patients is to know a drug’s background and patient history, and then talk.

And be ready to change things up, at any time. “You have to be prepared to adjust and move and fit this to the patient’s needs and their desires,” Smith said, adding that the prescription approach today is more holistic than in the past.

As an example, Smith said a patient with constipation issues might welcome a clinically established dose of gastro-upsetting metformin; a person who has limited access to bathrooms during the day might need a smaller dose.

In time, most diabetes patients will end up in a cardiology’s office. Nishant Shah, MD, associate professor of medicine and cardiology, associate program director, Duke Cardiology Fellowship, Duke Heart Center, Duke Clinical Research Institute, Durham, North Carolina, said the following is how he determines a beneficial, safe medication.

First, he determines if the evidence of the therapy under consideration has both a good safety record and will provide positive cardiovascular outcomes.

Then he considers the “the patient-level factors”: How has the patient tolerated past prescribed medications; what are the patient’s comorbidities and current medications so there are no drug interactions.

“The last thing I want is for my patient to have side effects,” he said.

The patient conversation comes next. He discusses his thoughts and rationale, asks for the patient’s opinion, discusses benefits and risks, and then prescribes “if we are both aligned on the plan.” These discussions also include the patient’s ability to access the medications.

Shah also said PCPs should prescribe, if need be, SGLT2is and GLP-1 RAs for their newly diagnosed diabetes patients, who have heart failure and/or atherosclerotic cardiovascular disease. “Providers should certainly consider prescribing these therapies earlier in patients with type 2 diabetes.”

Shah disclosed having external relationships with Amarin, the American Heart Journal, Amgen, and Novartis. Smith reported having no disclosures.