medwireNews: Findings from the TriMaster trial suggest that stratification of people with type 2 diabetes based on clinical features may help to guide the choice of second- or third-line drug for those who require treatment intensification after metformin.
“This is the first trial to directly test and prove a stratified approach in type 2 diabetes,” said study lead Andrew Hattersley (University of Exeter, UK) at the virtual 57th EASD Annual Meeting.
The double-blind, crossover trial involved 525 people with type 2 diabetes with glycated hemoglobin levels of 58–110 mmol/mol (7.5–12.2%) on treatment with metformin alone or in combination with a sulfonylurea. Participants were randomly assigned to receive 16 weeks each of pioglitazone, sitagliptin, and canagliflozin in one of six possible drug order sequences, and outcomes were measured after each treatment period. The 503 participants with available baseline data were aged an average of 62 years and had an average glycated hemoglobin (HbA1c) of 69 mmol/mol (8.5%).
Study lead Andrew Hattersley outlines the findings from TriMaster trial (7:39)
Presenting the results, Beverley Shields (University of Exeter) said that in the overall study population, HbA1c levels were comparable following treatment with each of the three agents, at approximately 59 mmol/mol (7.5%).
However, when participants were stratified by BMI, those with a BMI of less than 30 kg/m2 had lower mean HbA1c levels following treatment with sitagliptin versus pioglitazone, at 58.3 versus 59.7 mmol/mol (7.5 vs 7.6%). The reverse was true for those with a BMI of 30 kg/m2 or greater, who had lower HbA1c levels with pioglitazone, at 59.0 versus 60.5 mmol/mol with sitagliptin (7.5 vs 7.7%). These findings equated to a significant average difference of 2.92 mmol/mol between strata.
“This means if patients are treated with the drug that’s optimal for their strata – so sitagliptin for the BMI less than or equal to 30 group, pioglitazone for the BMI above 30 group – it means they will have, on average, a benefit of around 3 mmol/mol compared with if they were treated with the other drug,” explained Shields.
There were also differences in glycemic control when participants were stratified by kidney function. In the group with estimated glomerular filtration rate (eGFR) of 60–90 mL/min per 1.73 m2, sitagliptin treatment resulted in lower average HbA1c levels than canagliflozin (mean difference 1.74 mmol/mol), whereas canagliflozin resulted in lower HbA1c than sitagliptin in those with higher eGFR (mean difference 1.08 mmol/mol). Similar to the BMI findings, the estimated HbA1c reduction if participants were given the optimal treatment according to their eGFR group was around 3 mmol/mol.
Shields said that there was little or no difference in drug tolerability and rates of hypoglycemia by BMI or eGFR strata. However, bodyweight was higher at the end of the study with pioglitazone versus sitagliptin among patients with a baseline BMI above 30 kg/m2.
The TriMaster investigators also asked participants to choose their preferred drug at the end of the study, finding that preference was “fairly equal,” with 26% choosing pioglitazone, 35% sitagliptin, and 39% canagliflozin. Hattersley noted that participants preferred the drug with the best glycemic outcomes and fewest side effects for them, with “no clear influence of weight” on treatment choice.
Taken together, the TriMaster results indicate that “we can improve on the present approach to diabetes glycemia treatment by a precision medicine approach,” said Hattersley.
He said that when glycemia is the priority, characteristics such as BMI and eGFR can help guide prescribing, but cautioned that “drug choice will need to consider other priorities than glycemia,” including comorbidities and adverse events.
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