Pioglitazone, Sulfonylureas Safe and Effective in Type 2 Diabetes

Marja-Riitta Taskinen, MD, PhD


September 29, 2017

I am Professor Marja-Riitta Taskinen, and I was invited to be the formal commenter on the TOSCA trial results presented here at the European Association for the Study of Diabetes (EASD) 2017 Congress.

TOSCA[1] was a very well-conducted clinical trial that included about 3000 patients with type 2 diabetes who could not maintain good glycemic control on metformin alone. This was the first head-to-head trial comparing the combination of sulfonylureas or pioglitazone with metformin.

TOSCA was designed in 2007 when these were the only two drugs available to be combined with metformin; this should be recognized when relating the results to current-day practice.

As I said, TOSCA was very well and carefully conducted, particularly when comparing the two drugs on glycemic control. Pioglitazone showed better and more sustainable improvement for glycemic control than sulfonylureas. Importantly, there was modest weight gain with pioglitazone compared with sulfonylureas. This was not significant and contrasted with some previous data, where there was more weight gain and fluid retention when pioglitazone was used with metformin.

There were also very good safety data. There was no [increased incidence] of cancer, heart failure, or bone fractures. Pioglitazone was found to be a safe drug after careful patient follow-up and rigorous evaluation of all side effects.

The primary outcome included all-cause death, myocardial infarction (MI), nonfatal stroke, and coronary revascularization. Three-point major adverse cardiac events (MACE) only includes cardiovascular death, nonfatal MI, and nonfatal stroke, making TOSCA a little more complicated.

The results showed that pioglitazone had no favorable effect on any of these cardiovascular endpoints as compared with sulfonylureas. This must have been a disappointment for the investigators.

What is the relevance of the results?

First of all, pioglitazone in the right patient is safe and can be easily added to metformin. Glucose control was better [compared with sulfonylureas/metformin] and there was less need of insulin therapy. Importantly, there was less hypoglycemia and an almost complete lack of severe hypoglycemia. These are important points because we want antidiabetes drugs to cause no hypoglycemia or weight gain and to have cardiovascular safety. Pioglitazone turned out to be safe.

However, recent trials using glucagon-like peptide-1 (GLP-1) receptor agonists and sodium glucose cotransporter-2 (SGLT2) inhibitors have shown that you can reduce cardiovascular endpoints. This has been the dream for clinicians who treat patients with type 2 diabetes. Although this was not shown for pioglitazone or sulfonylureas, these drugs definitely remain acceptable and available around the world, particularly as we also consider expenses of medications.

Thank you for your attention.


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