'Vote of Confidence for Sulfonylureas and Pioglitazone' in TOSCA IT

Marlene Busko

September 13, 2017

LISBON, PORTUGAL — There was no cardiovascular safety signal for either of two types of "older," affordable, widely used drugs for second-line therapy in type 2 diabetes, which were compared head-to-head in the Thiazolidinediones or Sulphonylureas Cardiovascular Accidents Intervention Trial (TOSCA IT).]

The study showed that, "if used appropriately, in terms of patient selection and dose, both pioglitazone and a sulfonylurea (glimepiride or gliclazide) as an add-on to metformin are associated with similarly low rates of cardiovascular events and few clinically relevant side effects," Olga Vaccaro, MD, associate professor, Federico II University of Naples, Italy, and colleagues reported.

More specifically, there was no difference in the composite primary outcome of all-cause death, major adverse cardiac events (MACE) or revascularization, Enzo Bonora, MD, PhD, Federico II University of Naples, said here at the European Association for the Study of Diabetes (EASD) 2017 Annual Meeting, where the work was presented. It was also simultaneously published in Lancet Diabetes & Endocrinology.

Thus, "under certain clinical circumstances, pioglitazone and sulfonylureas can still remain an option for the combined treatment of type 2 diabetes," Dr Bonora reported.

Pioglitazone was better for long-term glycemic control, but it is important to note that the patients in this trial had a low risk of cardiovascular disease, he stressed.

Both Similar; Pioglitazone Is Only Insulin Sensitizer Still Available

These are welcome, head-to-head data, session chair Prof Rury R Holman, University of Oxford, United Kingdom, told Medscape Medical News. "Both drugs, I think, did almost exactly the same."

However, the study was underpowered since it had fewer events than anticipated, and the low risk of cardiovascular disease might be due to an effect of metformin rather than the add-on drug, he noted.

Nevertheless, "My bottom line is this is a vote of confidence for sulfonylureas and pioglitazone. You could use these data to perhaps finesse which patients you might give them to."

"The takeaway message is that in the right patients, pioglitazone seems to be tolerable and safe when there is good follow-up and sustainable good glycemic control," assigned commenter Prof Marja-Riitta Taskinen, University of Helsinki, Finland told Medscape Medical News.

"There are no reductions in cardiovascular effect based on the TOSCA trial, but cardiovascular safety is fine."

"The results provide 5-year comparative safety data for two widely used drug classes, with few side effects for both sulfonylureas and pioglitazone when given at the right doses to the right patients," write Vivian A Fonseca, MD, and Dragana Lovre, MD, from Tulane University, in New Orleans, in an accompanying editorial.

These findings are also a reminder that pioglitazone lowers glucose effectively and durably and that it is essentially the only available insulin sensitizer that still has a place in clinical practice.

"The confirmed safety profile, in combination with affordability of pioglitazone and sulfonylureas, might result in continued use of these drugs and stimulate the design of clinical trials to generate more comparative outcome data with newer (more expensive) antihyperglycemic drugs," they conclude.

Cardiovascular Safety of Second-line Diabetes Drugs

Currently metformin is the recommended first-line drug for glycemic control in type 2 diabetes, but the choice for a second-line drug is less clear, Gabriele Riccardi, MD, University of Naples Federico II, said.

Sulfonylureas are the most widely used second-line choice, especially in developing countries, since they are inexpensive and familiar, but their cardiovascular safety "has been questioned."

Pioglitazone could be a suitable alternative, although concerns remain about possible clinically relevant side effects.

Thus, the researchers aimed to compare the long-term effects of pioglitazone vs sulfonylureas added to metformin in patients with type 2 diabetes.

Between September 2008 and January 2014, they randomized 3028 patients aged 50 to 75 years old with type 2 diabetes that was inadequately controlled with metformin monotherapy (2–3 g per day) from 57 diabetes clinics.

The patients received doses of pioglitazone (15–45 mg) or a sulfonylurea (5–15 mg glibenclamide, 2–6 mg glimepiride, or 30–120 mg gliclazide), according to local practice.

Of the patients who received a sulfonylurea, 50% received gliclazide, 48% received glimepiride, and only 2% received glibenclamide.

At baseline, only 335 (11%) participants had had a previous cardiovascular event.

The primary outcome was a composite of first occurrence of all-cause death, nonfatal myocardial infarction, nonfatal stroke, or urgent coronary revascularization.

All-cause death was the measure of mortality included in the outcome because it is difficult to get accurate data for cardiovascular death in Italy, Dr Riccardi said.

Side Effects Low With Pioglitazone and Sulfonylureas: Use Less Than Maximal Doses?

The trial was stopped early, after a median follow-up of 57.4 months, because futility analysis found no between-group difference in the primary outcome between patients in the two groups (hazard ratio [HR], 0.96, = .79).

The rate of hypoglycemia was lower in the pioglitazone group than in the sulfonylureas group (10% vs 34%, < .0001).

Weight gain was moderate (less than 2 kg, on average) in both groups.

The low rates of side effects reported in TOSCA IT "are remarkable," according to the editorialists. Weight gain was mild, hypoglycemia was less frequent than might be expected with a sulfonylurea, and the known side effects of pioglitazone were infrequent, they note.

This may be partly due to the less than maximal doses of drugs, "another important lesson for clinical practice."

Rates of heart failure, bladder cancer, and fractures were not significantly different between treatment groups.

There was slightly and significantly better glycemic control with pioglitazone than with a sulfonylurea.

"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 conclude.

Dr Holmen looks forward to further analysis from these data, including cost analysis, adding that "unpicking this is going to take a lot more thought than just a day."

Vaccaro has received speaker's fees from Novartis and Sanofi; research grants to her institution from Guidotti; and travel support from Sigma Tau. Bonora has received consultancy fees from Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers  Squibb, Bruno Farmaceutici, Janssen, Johnson & Johnson, Eli Lilly,  Merck Sharp & Dohme, Novartis, Novo Nordisk, Roche, Sanofi, Servier, and Takeda; has worked on clinical trials funded by Amgen, Janssen, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, and  Sanofi; and has received research support from AstraZeneca, Genzyme, Menarini Diagnostics, Novo Nordisk, Roche, and Takeda. Riccardi has worked on clinical trials funded by Boehringer Ingelheim, Merck Sharp & Dohme, and Sanofi; has received travel support from Takeda; has received research grants to his institution from Guidotti; and has received speaker's fees from Eli Lilly and Sanofi. Disclosures for the coauthors are listed in the paper. Lovre has received a research grant (to Tulane University) from Lexicon. Fonseco has received research grants (to Tulane University) from Asahi and Bayer; has received honoraria for consulting and lectures from Takeda, Novo Nordisk, Sanofi-Aventis, Eli Lilly, AstraZeneca, and Intarcia; and holds stock options in Microbiome Technologies, BRAVO4 Health, and Insulin Algorithms (companies not involved in the manufacture or distribution of pioglitazone or any of the sulfonylureas).

Lancet Diabetes Endocrinol. Published online September 13, 2017. Abstract, Editorial

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