People With Diabetes Choose Agents that Best Control Glucose

Mitchel L. Zoler, PhD

December 09, 2022

Allowing people with type 2 diabetes to try agents from three different classes of antidiabetes drugs showed they usually find a clear preference, often the drug that gives them the best glycemic control and least bothersome adverse effects, according to secondary findings from a randomized study of patients in the UK.

"This is the first study in which the same patient has tried three different types of glucose-lowering drug, enabling them to directly compare them and then choose which one is best for them," said Andrew Hattersley, BMBCh, DM, the study's principal investigator, in a written statement. "We've shown that going with the patients' choice results in better glucose control and fewer side effects than any other approach. When it's not clear which drug is best to use, then patients should try before they choose. Surprisingly, that approach has never been tried before."

These secondary results from the TriMaster study were recently published in Nature Medicine and presented at the European Association for the Study of Diabetes (EASD) 2022 Annual Meeting in September, as reported by Medscape Medical News.

TriMaster enrolled adults 30-80 years old with a clinical diagnosis of type 2 diabetes for at least 12 months whose glycemia was inadequately controlled despite treatment with metformin alone or two classes of oral glucose-lowering therapy that did not include treatment with an agent from any of the three classes tested in the study: dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and thiazolidinediones. The people taking two different drug classes at entry were most often taking metformin and a sulfonylurea.

Do BMI and Renal Function Affect Treatment Response?

TriMaster tested two hypotheses. Firstly, would people with a body mass index (BMI) of more than 30 kg/m2 have greater glucose lowering with the thiazolidinedione pioglitazone (Actos) than with the DPP-4 inhibitor sitagliptin (Januvia), compared to people with a lower BMI?

Secondly, would people with an estimated glomerular filtration rate (eGFR) of 60-90 mL/min/1.73m2 have greater glucose lowering with sitagliptin than with the SGLT2 inhibitor canagliflozin (Invokana), compared to people with higher levels of renal function? The metric for both hypotheses was change in A1c levels from baseline.

The study included 525 adults with type 2 diabetes in a double-blind, three-way crossover trial that assigned each participant a random order of serial 16-week trials of treatment with sitagliptin 100 mg once daily, canagliflozin 100 mg once daily, and pioglitazone 30 mg once daily, with each agent added to the pre-existing background regimen.

Analysis showed that for second- or third-line therapy in people with type 2 diabetes "simple predefined stratification using BMI and renal function can determine the choice of the drug most likely to be effective for glucose lowering," the researchers concluded.

Among those with a BMI of more than 30 kg/m2, patients achieved a lower A1c on pioglitazone compared with sitagliptin, while those with a lower BMI had their best A1c response on sitagliptin. Patients with impaired renal function (eGFR 60-90 mL/min/1.73 m2) had better A1c lowering with sitagliptin, while those with a higher eGFR had better A1c lowering with canagliflozin.

These results appeared in a second article published in Nature Medicine, and the researchers also presented these findings at the EASD 2021 Annual Meeting, as reported by Medscape Medical News at the time.

Patients Identified the Agent They Liked Best

Hattersley and associates used the TriMaster study to also address the secondary question of which of the three tested agents patients preferred, focusing on the 457 patients who provided information on their treatment preference.

The results showed that patient preference varied: 24% liked pioglitazone best, 33% preferred sitagliptin, and 37% said canagliflozin was their favorite, with 6% having no preference. These numbers barely budged when participants learned how well each agent worked for them in terms of reducing their A1c and lowering their BMI.

The findings also showed good correlation between patient preferences and their A1c and adverse-effect responses. The agents that patients identified as their favorite were also the drugs that lowered their A1c the most 53% of the time before they got any feedback on which one gave them their best glycemic control. Once they had this feedback, 70% preferred the most effective agent, with the results likely reflecting that patients feel better when they have improved glucose levels as well as the education patients received that lower A1c levels are better.

Patients also tended to understandably favor the agents that caused the fewest and mildest adverse effects: 68% of the patients who identified a favorite drug picked the one that gave them the best adverse-effect profile.

In an interview at the EASD 2022 Annual Meeting, Hattersley promoted the study's design as a best-practice approach to deciding which drug to next give a person with type 2 diabetes who needs additional glycemic control.

"Whenever you're not sure how to balance adverse effects and positive effects the best person to decide is the one who experiences the effects," he said. "Patients had overwhelming positivity about being able to choose their drug. Do it when you're not certain which drug to prescribe," suggested Hattersley, a professor and diabetologist at the University of Exeter, UK. "We can't know which drug a patient might prefer."

But he also stressed cautioning patients to return for treatment adjustment sooner than 4 months if they can't tolerate a new drug they're trying.

TriMaster received no commercial funding. Hattersley has reported no relevant financial relationships.

Nat Med. Published online December 7, 2022. Abstract

Mitchel L. Zoler is a reporter for Medscape and MDedge based in the Philadelphia area. @mitchelzoler

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