Effects of Pioglitazone on Macrovascular Events in Patients with Type 2 Diabetes Mellitus at High Risk of Stroke: The PROFIT-J Study

Abstract

Aim: The present study evaluated the effects of pioglitazone treatment on the incidence of primary cardiovascular events in Japanese subjects with type 2 diabetes mellitus at high risk of stroke. Methods: A prospective, multicenter, randomized, open label, comparative study was conducted among diabetic patients recruited from 50 medical institutions nationwide. A total of 522 patients with hypertension and/or dyslipidemia who had one or more silent cerebral infarcts, advanced carotid atherosclerosis or microalbuminuria at baseline were randomly treated with (n= 254) or without pioglitazone (n = 268) and observed for a medium of 672 days. The hypertension and dyslipidemia were concurrently treated according to the respective treatment guidelines. The primary outcome was the time to the first occurrence of a composite of all-cause death, nonfatal cerebral infarction and nonfatal myocardial infarction. Results: Treatment with pioglitazone resulted in significant reductions in the levels of HbA1c, diastolic blood pressure and LDL-cholesterol and a significant increase in the levels of HDL-cholesterol. The pioglitazone non-users exhibited a significant reduction in the LDL-cholesterol levels alone. Primary events were registered during the study period in nine patients in the pioglitazone group and 10 patients in the non-pioglitazone group. The difference in the cumulative incidence of the primary outcome was not significant between the two groups (1.8% per year). Conclusions: Pioglitazone therapy produces immediate and effective improvements in glycemic control, diastolic blood pressure and lipid profiles. While this study was too underpowered to determine the effects of pioglitazone on the incidence of cardiovascular events, the results indicated that two years of pioglitazone treatment did not produce any statistically significant reductions in the rate of primary cardiovascular events.

Effects of Pioglitazone for Secondary Stroke Prevention in Patients with Impaired Glucose Tolerance and Newly Diagnosed Diabetes: The J-SPIRIT Study

“…Furthermore, pioglitazone significantly attenuated the risk of stroke recurrence in a subgroup analysis from PROactive study populations 22) . We previously reported the effects of pioglitazone on macrovascular events in Japanese patients with type 2 diabetes mellitus at a high risk of stroke (PROFIT-J Study) 23) . However, the effects of pioglitazone for preventing stroke recurrence in patients with IGT or new DM remains unclear.…”

Cardiovascular Safety of Oral Antidiabetic Drugs.

“…The risk of several isolated secondary outcomes was also reduced significantly, as follows: stroke by 47% (p=0.008); recurrent acute coronary syndrome by 37% (p=0.035); and myocardial reinfarction by 28% (p<0.045) 41, 42 . In a meta-analysis of the cardiovascular risk of TZD, unlike rosiglitazone, pioglitazone reduced the risk of all macrovascular events and myocardial infarction in comparison with comparators 43 . The FDA meta-analysis of clinical trials of pioglitazone also demonstrated the beneficial effect of this drug on cardiovascular event reduction 44 .…”

“…Znatno je smanjen i rizik u više pojedinačnih sekundarnih ishoda: od ponovnog moždanog udara za 47 % (p = 0,008), od ponovnoga akutnog koronarnog sindroma za 37 % (p = 0,035) i od ponovnog infarkta miokarda za 28 % (p < 0,045) 41, 42 . U meta-analizi kardiovaskularnog rizika od TZD-a pioglitazon je, različito i suprotno od rosiglitazona, smanjivao rizik od svih makrovaskularnih događaja i infarkta miokarda, u usporedbi s komparatorima 9, 43 . I FDA metaanaliza kliničkih ispitivanja pioglitazona pokazala je takav pozitivan učinak lijeka na smanjenje kardiovaskularnih događaja 44 .…”

Pioglitazone Reduces Vascular Lipid Accumulation in Angiotensin II-Induced Hypertensive Rat

“…Saiki et al reported that pioglitazone suppressed the plasma concentrations of angiotensin II, a marker of adipocyte renin-angiotensin system, in patients with type 2 diabetes 31) . Yoshii et al showed that in patients with type 2 diabetes, pioglitazone significantly improved not only glycemic control but also lipid profiles, including serum levels of LDL-cholesterol and high-density lipoprotein (HDL)-cholesterol, while the cumulative incidence of primary cardiovascular events did not differ according to the treatment with or without pioglitazone during the 2-year study period 32) . In the current study, although pioglitazone treatment significantly reduced vascular lipid accumulation and superoxide production induced by angiotensin II, it did not alter the expression of several fatty Recently, the accumulation of both cholesterol and fatty acid has been suggested to be associated with lipotoxicity in pancreatic -cells 38) .…”