1.
Cardiovascular Effects of Pioglitazone or Sulfonylureas According to Pretreatment Risk: Moving Toward Personalized Care.
Vaccaro, O, Lucisano, G, Masulli, M, Bonora, E, Del Prato, S, Rivellese, AA, Giorda, CB, Mocarelli, P, Squatrito, S, Maggioni, AP, et al
The Journal of clinical endocrinology and metabolism. 2019;(8):3296-3302
Abstract
CONTEXT Hypoglycemic drugs with proven cardiovascular (CV) benefits are recommended for patients with type 2 diabetes and CV disease. Whether the beneficial effects extend to those at lower risk remains unclear. AIM: We investigated the long-term CV effects of pioglitazone or sulfonylureas (SUs) across the spectrum of pretreatment CV risk. METHODS Among 2820 participants of the TOSCA.IT trial, four subgroups with different risk of outcome-a composite of all-cause death, nonfatal myocardial infarction, nonfatal stroke, urgent coronary revascularization-were identified by the RECursive Partitioning and AMalgamation (RECPAM) method. Within each group, the effect of SUs or pioglitazone on the outcome was evaluated. RESULTS Sex was the first splitting variable, followed by urinary albumin-to-creatinine ratio (UACR) (>9 mg/g or ≤9 mg/g) and body mass index (BMI) (>28.7 or ≤28.7 kg/m2). Female patients had the lowest risk (reference); male patients with UACR >9 mg/g and BMI >28.7 kg/m2 had the highest risk [hazard ratio (HR), 5.58; 95% CI, 3.32 to 9.69]. Patients in this group present a cluster of conditions suggestive of marked insulin resistance (higher BMI, waist circumference, triglycerides, blood pressure, and UACR and lower high-density lipoprotein cholesterol) than the other groups. Treatment with pioglitazone in this group was associated with a significantly lower occurrence of the outcome than SUs (HR, 0.48; 95% CI, 0.25 to 0.76). No significant difference between study treatments was observed in the other RECPAM classes. CONCLUSIONS It is possible to identify patients with type 2 diabetes early in the stage of their disease and who are largely free from evident CV disease in whom add-on pioglitazone to metformin confers CV protection as compared with SUs.
2.
Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial.
Vaccaro, O, Masulli, M, Nicolucci, A, Bonora, E, Del Prato, S, Maggioni, AP, Rivellese, AA, Squatrito, S, Giorda, CB, Sesti, G, et al
The lancet. Diabetes & endocrinology. 2017;(11):887-897
Abstract
BACKGROUND The best treatment option for patients with type 2 diabetes in whom treatment with metformin alone fails to achieve adequate glycaemic control is debated. We aimed to compare the long-term effects of pioglitazone versus sulfonylureas, given in addition to metformin, on cardiovascular events in patients with type 2 diabetes. METHODS TOSCA.IT was a multicentre, randomised, pragmatic clinical trial, in which patients aged 50-75 years with type 2 diabetes inadequately controlled with metformin monotherapy (2-3 g per day) were recruited from 57 diabetes clinics in Italy. Patients were randomly assigned (1:1), by permuted blocks randomisation (block size 10), stratified by site and previous cardiovascular events, to add-on pioglitazone (15-45 mg) or a sulfonylurea (5-15 mg glibenclamide, 2-6 mg glimepiride, or 30-120 mg gliclazide, in accordance with local practice). The trial was unblinded, but event adjudicators were unaware of treatment assignment. The primary outcome, assessed with a Cox proportional-hazards model, was a composite of first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularisation, assessed in the modified intention-to-treat population (all randomly assigned participants with baseline data available and without any protocol violations in relation to inclusion or exclusion criteria). This study is registered with ClinicalTrials.gov, number NCT00700856. FINDINGS Between Sept 18, 2008, and Jan 15, 2014, 3028 patients were randomly assigned and included in the analyses. 1535 were assigned to pioglitazone and 1493 to sulfonylureas (glibenclamide 24 [2%], glimepiride 723 [48%], gliclazide 745 [50%]). At baseline, 335 (11%) participants had a previous cardiovascular event. The study was stopped early on the basis of a futility analysis after a median follow-up of 57·3 months. The primary outcome occurred in 105 patients (1·5 per 100 person-years) who were given pioglitazone and 108 (1·5 per 100 person-years) who were given sulfonylureas (hazard ratio 0·96, 95% CI 0·74-1·26, p=0·79). Fewer patients had hypoglycaemias in the pioglitazone group than in the sulfonylureas group (148 [10%] vs 508 [34%], p<0·0001). Moderate weight gain (less than 2 kg, on average) occurred in both groups. Rates of heart failure, bladder cancer, and fractures were not significantly different between treatment groups. INTERPRETATION In this long-term, pragmatic trial, incidence of cardiovascular events was similar with sulfonylureas (mostly glimepiride and gliclazide) and pioglitazone as add-on treatments to metformin. Both of these widely available and affordable treatments are suitable options with respect to efficacy and adverse events, although pioglitazone was associated with fewer hypoglycaemia events. FUNDING Italian Medicines Agency, Diabete Ricerca, and Italian Diabetes Society.
3.
Effect of insulin and sulfonylurea therapy, at the same level of blood glucose control, on low density lipoprotein subfractions in type 2 diabetic patients.
Rivellese, AA, Patti, L, Romano, G, Innelli, F, Di Marino, L, Annuzzi, G, Iavicoli, M, Coronel, GA, Riccardi, G
The Journal of clinical endocrinology and metabolism. 2000;(11):4188-92
Abstract
The aim of this study was to evaluate the effect of sc insulin (INS) compared with sulfonylurea (SUL) therapy, at the same level of blood glucose control, on the low density lipoprotein (LDL) subfraction profile in normolipidemic type 2 diabetic patients. Nine normolipidemic type 2 diabetic men (age, 56+/-3 yr; body mass index, 26.5+/-0.9 kg/m2; mean +/- SEM), after a 3-week wash-out period, were assigned to INS or SUL for 2 months in a randomized cross-over design. Doses were adjusted only during the first month and then were kept constant. At the end of the treatments, hemoglobin A1c, plasma lipids, LDL, and very low density lipoprotein (VLDL) subfraction profiles and plasma postheparin lipoprotein lipase and hepatic lipase (HL) activities were evaluated. Despite glucose control was similar at the end of both periods (hemoglobin A1c, 7.4+/-0.3% vs. 7.0+/-0.2%, INS vs. SUL), INS compared with SUL significantly reduced plasma triglyceride (0.9+/-0.1 vs. 1.1+/-0.1 mmol/L; P < 0.05). Although INS did not affect the LDL concentration, it induced a decrease in both the amount (59.0 = 9.8 vs. 76.1+/-16.8 mg/dL; P = NS) and the proportion (31.2+/-3.0% vs. 38.3+/-3.8%; P < 0.03) of small LDL. Moreover, the decrease in small LDL was positively related to the reduction of large VLDL (r = 0.67; P < 0.04) and HL (r = 0.69, P < 0.05) induced by insulin therapy. In conclusion, sc insulin therapy, independently of glucose control and even in the presence of quite low plasma triglyceride levels, is able to reduce small LDL particles in type 2 diabetic patients. This change is related to decreases in both HL activity and large VLDL particles.