TOSCA.IT: Similar CV safety for pioglitazone and sulphonylureas in T2D
The incidence of cardiovascular (CV) events at 5 years was similar when adding sulphonylureas or pioglitazone to metformin in patients with type 2 diabetes (T2D) inadequately controlled with metformin alone, according to a head-to-head comparison in the TOSCA.IT* trial.
“[I]f used appropriately, in terms of patient selection and dose ... both of these widely available and affordable treatments are suitable options with respect to efficacy and adverse events … particularly in relation to patients with a low CV risk,” wrote the researchers led by Dr Olga Vaccaro of Frederico II University of Naples in Naples, Italy.
After a median follow-up of 57.3 months, similar rates of the composite primary outcome comprising all-cause death, nonfatal stroke, nonfatal myocardial infarction, or urgent coronary revascularization (7 percent vs 7 percent, hazard ratio [HR], 0.96; p=0.79) or its components occurred in both the pioglitazone and sulphonylurea arms, reported co-investigator Dr Antonio Nicolucci of Center for Outcomes Research and Clinical Epidemiology in Pescara, Italy at the EASD Annual Meeting 2017. [EASD 2017, session S13; Lancet Diabetes Endocrinol 2017;doi:10.1016/ S2213-8587(17)30317-0]
Glycaemic control was slightly, though significantly, better maintained with add-on pioglitazone than sulphonylureas (mean HbA1c over time, 7.24 percent vs 7.30 percent; p=0.01), with fewer patients in the pioglitazone arm experiencing treatment failure and needing insulin rescue therapy (p<0.0001 for both).
Additionally, moderate hypoglycaemic events were more common with add-on sulphonylureas than pioglitazone (32 percent vs 10 percent; p<0.0001). Severe hypoglycaemic events, although fairly uncommon, occurred more frequently in the sulphonylureas-treated patients (p<0.0001).
Although pioglitazone was associated with a better long-term glycaemic control, co-investigator Professor Enzo Bonora of University and Hospital Trust of Verona, Italy, cautioned that the study was done in patients with low CV disease risk, and that “any extrapolation to patients with high CV disease risk for prior events (eg, myocardial infarction or stroke) should be avoided.”
Other findings and clinical implications
The multicentre, prospective, open-label, blinded endpoint study with a pragmatic design involved 3,028 patients aged 50–75 years with T2D who were inadequately controlled on metformin monotherapy. They were randomized 1:1 to add-on pioglitazone 15–45 mg or sulphonylureas (gliclazide 30–120 mg [50 percent], glimepiride 2–6 mg [48 percent], or glibenclamide 5–15 mg [2 percent]).
Although a moderate weight gain of less than 2 kg occurred in both treatment groups during the first 2 years, this subsequently levelled off until study end and there were no significant between-group differences. Other risk factors such as blood pressure, eGFR**, albumin-to-creatinine ratio, and C-reactive protein were also similar in both treatment groups during the course of study.
No significant differences were observed between the two groups with regards to any type of cancer (specifically bladder cancer [p=1.00]), macular oedema (p=0.34), pathological bone fractures (p=0.75), or heart failure (p=0.22).
Body weight increase and heart failure rate were lower than those reported in previous trials, which the investigators attributed to the exclusion of participants with heart failure (NYHA*** class I or higher) or with reduced renal function in the current study. [Lancet 2005;366:1279-1289; N Engl J Med 2016;374:1321-1331]
“These low rates [of known side effects] might be related to the doses of drugs used in both groups of the trial, which were not maximal, another important lesson for clinical practice,” wrote Drs Vivian Fonseca and Dragana Lovre of Tulane University Health Sciences Center in New Orleans, Los Angeles, US, in an accompanying commentary. [Lancet Diabetes Endocrinol 2017;doi:10.1016/S2213-8587(17)30320-0]
“These findings also remind us 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,” they added.
“[F]or patients with early diabetes (baseline HbA1c in the TOSCA.IT trial was 7.7 percent), the choice of a second-line drug might not matter as compared with patients who are poorly controlled (HbA1c of 9 percent or 10 percent),” concluded Fonseca and Lovre, calling for head-to-head comparisons of these drugs with newer antihyperglycaemic drugs in the future.