Effects on Incidence of Cardiovascular Events of the Addition of Pioglitazone as Compared With a Sulphonylurea in Type 2 Diabetic Patients Inadequately Controlled With Metformin.

Cardiovascular (CV) disease is the most common cause of morbidity and mortality among diabetic patients.The UK Prospective Diabetes Study (UKPDS)clearly showed that tight glycemic control significantly decreases diabetes-related events. Therefore, achievement of HbA1c < 7% is a major goal in the treatment of type 2 diabetes since this parameter still represents the best predictor of micro and macrovascular complications. However, it is often difficult to maintain this goal because of the progressive deterioration of pancreatic beta-cell function and insulin sensitivity. The progressive nature of type 2 diabetes generally requires a stepwise therapeutic approach starting with lifestyle intervention (diet and increased physical activity). After lifestyle changes have failed, drug therapy is initiated and progressively intensified through the combination of different classes of hypoglycemic agents. Since insulin resistance is recognized as a major factor in the pathogenesis of type 2 diabetes and associated CV risk factors, drugs that improve insulin sensitivity are advised as initial pharmacological therapy. Currently, metformin is recommended as the first-line drug for patients with type 2 diabetes. Great uncertainty exists regarding the best therapeutic option in diabetic patients inadequately controlled with metformin, due to the lack of randomized controlled trials that have directly compared the efficacy of different combination regimens in achieving glycemic goals. The paucity of sound clinical evidence in this area is highlighted in a Consensus Statement from the American Diabetes Association and the European Association for the Study of Diabetes, that suggested either a sulphonylurea (SU) or a thiazolidinediones (TZD) as additional medication to metformin, in the absence of data demonstrating the superiority of one combination over the other. Addition of a SU or a TZD to concomitant metformin results in a substantial improvement in glucose control with a mean reduction in HbA1c of 1-1.5%. However, a direct evaluation of these treatment strategies, within a large clinical trial, would be most appropriate, given their different mechanisms of action, side effects and costs. Indeed, the only direct comparison between a SU and a TZD added to metformin has been obtained in a short-term study (24 weeks), which showed a greater reduction in HbA1c with the association metformin-glibenclamide (- 1.5%) compared with the association metformin-rosiglitazone (-1.1%, <0.001). More patients receiving metformin-glibenclamide reached HbA1c <7.0 % than did those receiving metformin-rosiglitazone (60% vs. 47%). In addition, a more favorable lipid profile was present in patients treated with metformin-glibenclamide, although this finding has not been confirmed in other studies. However, the short duration of the study precluded evaluation of CV endpoints.

This lack of information prevents an evidence-based choice between these two treatment options.

In this respect, several studies are underway to investigate the potential of different glucose-lowering therapies on CV outcomes. With regard to SU, retrospective cohort studies have documented a higher risk of adverse outcomes in patients treated with a SU in monotherapy or in combination with metformin as compared to metformin alone. In the UKPDS, diabetic patients treated with a combination of glibenclamide plus metformin showed an increase in CV mortality compared with other groups of treatment. However, these data derive from a post-hoc analysis and, therefore, should be interpreted with caution. In contrast, the ADOPT study has shown a lower proportion of CV events in the glibenclamide group compared with rosiglitazone and metformin. These conflicting reports underline the need to evaluate the rate of CV events induced by the combination metformin-SU in comparison with other treatment strategies. Regarding TZDs, a recent prospective study (PROACTIVE Study) has compared the efficacy of adding pioglitazone (from 15 to 45 mg/die) or placebo to the standard hypoglycemia therapy in the secondary prevention of CV events in type 2 diabetic patients. Pioglitazone treatment did not significantly affect the primary endpoint, which included all-cause mortality, non-fatal MI, stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries and leg amputation, but significantly reduced the number of patients who experienced the secondary endpoint (all-cause mortality, nonfatal MI and stroke). However, patients treated with pioglitazone had 115 more episodes of heart failure than the placebo group. In addition, weight gain was 4 kg greater with pioglitazone than with placebo, and much greater than that expected on the basis of the improved glycemic control. These conflicting reports support the need for large-scale clinical trials that compare the efficacy of the association of metformin plus a SU vs. metformin plus a TZD on CV outcomes. For these reasons, the Italian Diabetes Society has organized a randomized controlled clinical trial on long term cardiovascular effects of these two therapeutic strategies. The aim of this study is to ascertain whether in patients with type 2 diabetes poorly controlled with metformin in monotherapy, the addition of pioglitazone reduces the rate of cardiovascular events as compared with the addition of a SU. Glucose control, major CV risk factors, safety, tolerability and economic costs with the two therapeutic regimens will also be compared.

Design: multicentre, randomized, open-label, comparative, parallel-group trial of 48 months duration (PROBE: Prospective Randomized Open Blinded End-Point).

RECRUITMENT WAS TERMINATED IN JANUARY 20147, WITH 3040 PATIENTS ENROLLED. Screening and follow-up took place at several Clinical Units which will work in collaboration with a network of Diabetes Outpatients Clinics all over Italy. All study procedures will be performed by trained study personnel according to a standardized protocol.