medwireNews: The TOCSA.IT investigators have found no differences in cardiovascular disease (CVD) outcomes between patients with type 2 diabetes taking pioglitazone versus sulfonylurea over nearly 5 years.
However, outlining the clinical implications to delegates at the EASD annual meeting in Lisbon, Portugal, investigator Enzo Bonora (University of Verona, Italy) argued that the study overall supports the use of pioglitazone over sulfonylurea after metformin failure, with the findings demonstrating more durable glycemic control at an equivalent safety profile.
Bonora stressed that TOSCA.IT (Thiazolidinediones Or Sulfonylureas Cardiovascular Accidents Intervention Trial) is the only published trial offering a head-to-head comparison of these currently available drugs, with only one other (CAROLINA) on the horizon. And pioglitazone and sulfonylurea are both widely used, and are affordable compared with more recent medications.
“As physicians, we want to make a choice between active drugs, not between an active drug and placebo,” he said.
However, Bonora emphasized that the study participants were relatively low-risk (11% had pre-existing CVD), so the findings are not necessarily applicable to higher-risk patients.
TOSCA design was really initiated in 2007 […] at a time when there was a completely different algorithm for the treatment of patients who had metformin but failed to maintain good glucose control
TOSCA.IT was conducted against a background of uncertainty about the effects of pioglitazone and sulfonylurea on cardiovascular risk when used long-term. The trial was discontinued for futility after a median 57.3 months and 213 adjudicated events, owing to failure to accrue the intended 498 primary endpoint events (all-cause mortality, nonfatal myocardial infarction or stroke, or urgent coronary revascularization).
The study was simultaneously published in The Lancet Diabetes & Endocrinology, with a linked commentary by Vivian Fonseca and Dragana Lovre, both from Tulane University Health Sciences Center in New Orleans, Louisiana, USA.
“The study futility highlights the changing nature of the clinical expression of type 2 diabetes, with the low cardiovascular event rate attributable to effective preventive measures, such as use of statins, antihypertensive agents, and antiplatelet agents,” they write. “The event rate was less than half of that estimated, based on what was seen in PROACTIVE trial just a decade earlier.”
Presenting the cardiovascular outcomes data, Antonio Nicolucci (Center for Outcomes Research and Clinical Epidemiology, Pescara, Italy) said that the hazard ratio for the composite endpoint was 0.96 for patients treated with pioglitazone versus investigators’ choice of sulfonylurea, and there was no difference for any of the individual endpoint components.
There was also no difference between the treatments when the investigators looked at prespecified subgroups based on gender, age, body mass index, diabetes duration, glycated hemoglobin, and presence of kidney disease.
The trial participants had type 2 diabetes of at least 2 years’ duration, which was uncontrolled despite stable treatment with maximum-dose metformin.
All patients had an initial improvement in glycated hemoglobin levels, but the 1535 patients who were randomly assigned to receive pioglitazone had slightly more durable glycemic control, resulting in a reduced risk for treatment failure and insulin initiation, relative to the 1493 patients who received investigators’ choice of sulfonylurea.
“These findings […] remind us that pioglitazone lowers glucose effectively and durably, and that it is essentially the only available insulin sensitiser that still has a place in clinical practice,” say Fonseca and Lovre, in their commentary.
Safety findings were similar for both medications, with no difference in the rate of serious adverse events. Events of special interest (heart failure, bone fracture, macular edema, and cancer) occurred at very low rates, with no significant difference between the groups, although heart failure was slightly more common among patients taking pioglitazone versus sulfonylurea. Conversely, moderate and severe hypoglycemia was more common in the sulfonylurea group.
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