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LISBON -- Pioglitazone (Actos) isn't better than a sulfonylurea as an add-on to metformin for reducing heart events in type 2 diabetes, the pragmatic randomized TOSCA.IT trial showed.

Pioglitazone use came out similar to a sulfonylurea (mostly glimepiride [Amaryl] and gliclazide [not sold in the U.S.]) for the primary composite endpoint of all-cause mortality, nonfatal MI, nonfatal stroke, and urgent coronary revascularization (HR 0.96, 95% CI 0.74-1.26).

Nor were there any significant differences in the components individually or in the key secondary endpoint of ischemic events (sudden death, fatal or non-fatal MI [including silent myocardial infarction], fatal or non-fatal stroke, leg amputation above the ankle, and any revascularization of the coronary, leg, or carotid arteries).

The only significant efficacy difference between groups was for the key secondary endpoint in an on-treatment analysis effect (HR 0.67, P=0.03), "but it must be interpreted with caution," warned Antonio Nicolucci, MD, of the Center for Outcomes Research and Clinical Epidemiology in Pescara, Italy, who presented the main cardiovascular results at a session here at the European Society for the Study of Diabetes meeting.

"Both of these widely available and affordable treatments are suitable options with respect to efficacy and adverse events, although pioglitazone was associated with fewer hypoglycemia events," the researchers concluded in a simultaneously released paper in Lancet Diabetes and Endocrinology.

Another presenter, Enzo Bonora, MD, of the University of Verona in Italy, suggested that many may find the data disappointing or see it as outdated given the potentially hundreds of options for second- and third-line strategies compared with just these two options for add-on dual therapy when the trial started in 2007.

Yet, the researchers pointed out that this is still the only large head-to-head comparison of two available drugs for type 2 diabetes.

"The results of the TOSCA.IT trial ... might help to fill some of this void and provide useful insight into these drugs," noted an accompanying editorial by Vivian Fonseca, MD, and Dragana Lovre, MD, both of Tulane University Health Sciences Center in New Orleans.

In deciding between the agents, cardiovascular impact likely won't be the deciding factor, but in a few other respects pioglitazone was better, Bonora pointed out. Those differences from sulfonylurea add-on therapy included:

• Less hypoglycemia (10% versus 34%, P<0.0001)
• Slightly lower mean hemoglobin A1c over time (7.24% versus 7.30% P=0.01)
• Less need for rescue insulin therapy (11% versus 16%, P<0.0001)

Risk Level

The researchers emphasized over and over in the 1.5-hour session devoted to TOSCA.IT at the conference that the findings apply only to a low-cardiovascular risk population, as patients in the study had an average age of 62, and about 12% had established cardiovascular disease. Generalizing to higher risk patients or to other drug combinations would not be appropriate.

However, guidelines say diabetes itself puts patients at moderate cardiovascular risk, so they could not have been low-risk, countered study discussant Marja-Riitta Taskinen, MD, PhD, of the University of Helsinki in Finland.

"In fact, many of them probably represent patients at high risk and some even very high risk, so there is some dilemma over this because many of these subjects have several of these known cardiovascular risk factors," she told attendees.

Still, the event rate was less than half what had been anticipated based on the PROACTIVE trial just a decade earlier, noted the editorialists.

"Diabetes is no longer universally a cardiovascular risk equivalent, and an appropriate risk evaluation is needed for every patient, although improved methods of risk stratification are needed," they wrote. "One conclusion that could be drawn from TOSCA.IT is that for patients with early diabetes (the baseline HbA1c in the TOSCA.IT trial was 7.7%) the choice of a second-line drug might not matter as compared with patients who are poorly controlled (HbA1c of 9% or 10%)."

Silvio Inzucchi, MD, medical director of the Yale Diabetes Center, commented from the audience that further stratification may be necessary.

"The question is ... whether we should be rethinking these algorithms for diabetes," he said. "I'm believing now after seeing these results as well as the subgroup analyses from CANVAS and LEADERS saying that we need two algorithms. One is for the patient who has no overt or established CVD and one is for the patient who does have a history of established cardiovascular complications, because we should be thinking about these patients completely differently. The evidence-based strategies are necessary for those patients with established disease, and we can use anything in patients who don't have established CVD as long as those drugs are safe."

Bonora agreed that the first thing should be CVD: yes or no; second, presence of chronic kidney disease; then heart failure: yes or no. But also a focus should be on not using drugs causing hypoglycemia, he said.

Safety

The trial, conducted at 57 sites in Italy, included 3,028 patients ages 50 to 75 years with type 2 diabetes inadequately controlled with metformin alone and no heart failure or acute cardiovascular events in the previous 6 months. Choice of pioglitazone or sulfonylurea (almost entirely split between glimepiride or gliclazide) was determined by local practice. The event-driven trial was stopped early for futility after a median follow-up of 57.3 months.

Safety was an important finding of the trial, Taskinen noted. Although there were more permanent drug discontinuations with pioglitazone (28%, which the researchers chalked up to publicized risks of bladder cancer and removal from the market in Germany and France in 2012), the results showed no difference in:

• Malignant neoplasms (including bladder cancer, with eight cases in each group)
• Pathological fractures
• Macular edema
• Overall serious adverse events

"TOSCA was really beautiful in showing that careful evaluation of a patient, exclusion of vulnerable patients, as well as very careful follow-up of the patient during a trial succeeded very well, and in this situation you really can say that pioglitazone is a tolerable drug and can be used," Taskinen concluded.